Standardised packaging for factory made (FM) and roll your own (RYO) tobacco was fully implemented in the UK in May 2017. Around the same time, several changes to the tax system were applied (a ...Minimum Excise Tax (MET) for FM products and tax increases weighted towards RYO products). The tobacco industry claims that standardised packaging will lower prices (a disincentive for quitting) by commoditising the product, yet had itself taken advantage of the previous tax regime to achieve large profits from premium brands while also keeping some products' prices relatively low. Here we evaluate the impact of standardised packaging, the MET and the RYO focussed tax changes on price and industry profitability.
Nielsen electronic point of sale (EPOS) data (May 2015 to April 2018) were used to calculate real (inflation adjusted) monthly price per stick overall, by cigarette type (FM and RYO) and by seven market segments. Trend estimation, using additive mixed models, assessed weighted average price (weighted by volume of sales) and tobacco industry net revenue changes. The beginning and end of the data series were compared in terms of: (a) average monthly price growth, (b) average monthly net revenue growth, and (c) undershifting and overshifting patterns after tax changes. FM and RYO real prices changed little over the 3-year period-overall prices rose by about 1p per stick. There was no evidence of commoditisation with prices of all FM segments (but not RYO) rising faster after the implementation of standardised packaging than immediately beforehand. The prices of the cheapest FM brands rose with the implementation of the MET. RYO price increases did not close the gap to FM pricing levels despite RYO focussed tax increases. Tax changes following the implementation of standardised packaging and the MET were more widely and quickly passed on to smokers in the form of higher prices than the tax change pre-implementation. The main limitations are first that because we do not know the exact mechanism by which Nielsen scales up sample data to provide UK estimates, we could only use data for a set three year period during which the same adjustments are made. Second, the tax and standardised packaging events were sometimes too close in time to separate their consequences statistically. Third, tobacco prices may also be affected by external factors such as changes in smokers' disposable income or availability of electronic nicotine delivery systems.
There was no long-term lowering of tobacco prices after the implementation of standardised packaging as predicted by the industry. The introduction of the MET was successful in increasing the price of the cheapest FM cigarettes and narrowing the price gap between FM brands. The RYO tax increases were, however, insufficient to narrow the price gap between RYO and FM. Overall, undershifting became less extensive indicating that tobacco industry manipulation of the tax system which had previously kept cheap products available had declined. This suggests that standardised packaging and a MET will likely contribute to further declines in UK tobacco use.
Generalized additive models (GAMs) have been popularized by the work of Hastie and Tibshirani (
Generalized Additive Models (1990)) and the availability of user friendly gam software in Splus. ...However, whilst it is flexible and efficient, the gam framework based on backfitting with linear smoothers presents some difficulties when it comes to model selection and inference. On the other hand, the mathematically elegant work of Wahba (
Spline Models for Observational Data (1990)) and co-workers on Generalized Spline Smoothing (GSS) provides a rigorous framework for model selection (SIAM J. Sci. Statist. Comput. 12 (1991) 383) and inference with GAMs constructed from smoothing splines: but unfortunately these models are computationally very expensive with operations counts that are of cubic order in the number of
data. A ‘middle way’ between these approaches is to construct GAMs using penalized regression splines (e.g. Marx and Eilers, Comput. Statist. Data Anal. (1998)). In this paper, we develop this idea further and show how GAMs constructed using penalized regression splines can be used to get most of the practical benefits of GSS models, including well founded model selection and multi-dimensional smooth terms, with the ease of use and low computational cost of backfit GAMs. Inference with the resulting methods also requires slightly fewer approximations than are employed in the GAM modelling software provided in Splus. This paper presents the basic mathematical and numerical approach to GAMs implemented in the
R package
mgcv, and includes two environmental examples using the methods as implemented in the package.
Seafloor methane emissions can affect Earth's climate and ocean chemistry. Vast quantities of methane formed by microbial decomposition of organic matter are locked within gas hydrate and free gas on ...continental slopes, particularly in large areas with high sediment accumulations such as deep-sea fans. The release of methane in slope environments has frequently been associated with dissociation of gas hydrates near the edge of the gas hydrate stability zone on the upper slope, with discharges in greater water depths less understood. Here we show, using data from the Rio Grande Cone (western South Atlantic), that the intrinsic, gravity-induced downslope collapse of thick slope sediment accumulations creates structures that serve as pathways for gas migration, unlocking methane and causing seafloor emissions via giant gas flares in the water column. The observed emissions in the study region (up to 310 Mg year
) are three times greater than estimates for the entire US North Atlantic margin and reveal the importance of collapsing sediment accumulations for ocean carbon cycling. Similar outgassing systems on the Amazon and Niger fans suggest that gravity tectonics on passive margins is a common yet overlooked mechanism driving massive seafloor methane emissions in sediment-laden continental slopes.
The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting ...outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC.
Serum Ang-2 levels were measured in 33 healthy volunteers and 90 patients with CRC. Of these, 34 had metastatic disease and received bevacizumab-containing therapy. To determine the tissue of origin of Ang-2, quantitative real-time PCR was performed on microdissected cryosections of human CRC and in a murine xenograft model of CRC using species-specific amplification.
Ang-2 originated from the stromal compartment of CRC tissues. Serum Ang-2 levels were significantly elevated in patients with metastatic CRC compared with healthy controls. Amongst patients receiving bevacizumab-containing treatment, low pre-therapeutic serum Ang-2 levels were associated with a significant better response rate (82 vs 31%; P<0.01), a prolonged median progression-free survival (14.1 vs 8.5 months; P<0.01) and a reduction of 91% in the hazard of death (P<0.05).
Serum Ang-2 is a candidate biomarker for outcome of patients with metastatic CRC treated with bevacizumab-containing therapy, and it should be further validated to customise combined chemotherapeutic and anti-angiogenic treatment.
Forests store approximately as much carbon as is in the atmosphere, with potential to take in or release carbon rapidly based on growth, climate change and human disturbance. Above-ground biomass ...(AGB) is the largest carbon pool in most forest systems, and the quickest to change following disturbance. Quantifying AGB on a global scale and being able to reliably map how it is changing, is therefore required for tackling climate change by targeting and monitoring policies. AGB can be mapped using remote sensing and machine learning methods, but such maps have high uncertainties, and simply subtracting one from another does not give a reliable indication of changes. To improve the quantification of AGB changes it is necessary to add advanced statistical methodology to existing machine learning and remote sensing methods. This review discusses the areas in which techniques used in statistical research could positively impact AGB quantification. Nine global or continental AGB maps, and a further eight local AGB maps, were investigated in detail to understand the limitations of techniques currently used. It was found that both modelling and validation of maps lacked spatial consideration. Spatial cross validation or other sampling methods, which specifically account for the spatial nature of this data, are important to introduce into AGB map validation. Modelling techniques which capture the spatial nature should also be used. For example, spatial random effects can be included in various forms of hierarchical statistical models. These can be estimated using frequentist or Bayesian inference. Strategies including hierarchical modelling, Bayesian inference, and simulation methods can also be applied to improve uncertainty estimation. Additionally, if these uncertainties are visualised using pixelation or contour maps this could improve interpretation. Improved uncertainty, which is commonly between 30% and 40%, is in addition needed to produce accurate change maps which will benefit policy decisions, policy implementation, and our understanding of the carbon cycle.
Eph receptors comprise the largest family of receptor tyrosine kinases. They are classified into an A family and a B family on the basis of the characteristic properties of the corresponding ephrin ...ligands which are either GPI-anchored peripheral membrane molecules (A class ephrins) or transmembrane molecules (B class ephrins). Eph receptors and ephrin ligands were originally identified as neuronal pathfinding molecules. Yet, gene targeting experiments in mice have identified the EphB/ephrinB system as critical and rate-limiting determinant of arterio-venous differentiation during embryonic vascular development. Identification of vascular EphB/ephrinB functions has in the last few years stimulated two emerging fields of vascular biology research, namely (1) the molecular analysis of the structural and functional mechanisms of arterio-venous differentiation, and (2) the molecular study of the commonalities between vascular and neuronal guidance and patterning mechanisms. This review summarizes the current understanding of vascular Eph receptor and ephrin ligand functions and provides an overview of emerging roles of the Eph/ephrin system in controlling tumor and vascular functions during tumorigenesis and tumor progression.
We develop scalable methods for fitting penalized regression spline based generalized additive models with of the order of 10
4
coefficients to up to 10
8
data. Computational feasibility rests on: ...(i) a new iteration scheme for estimation of model coefficients and smoothing parameters, avoiding poorly scaling matrix operations; (ii) parallelization of the iteration's pivoted block Cholesky and basic matrix operations; (iii) the marginal discretization of model covariates to reduce memory footprint, with efficient scalable methods for computing required crossproducts directly from the discrete representation. Marginal discretization enables much finer discretization than joint discretization would permit. We were motivated by the need to model four decades worth of daily particulate data from the U.K. Black Smoke and Sulphur Dioxide Monitoring Network. Although reduced in size recently, over 2000 stations have at some time been part of the network, resulting in some 10 million measurements. Modeling at a daily scale is desirable for accurate trend estimation and mapping, and to provide daily exposure estimates for epidemiological cohort studies. Because of the dataset size, previous work has focused on modeling time or space averaged pollution levels, but this is unsatisfactory from a health perspective, since it is often acute exposure locally and on the time scale of days that is of most importance in driving adverse health outcomes. If computed by conventional means our black smoke model would require a half terabyte of storage just for the model matrix, whereas we are able to compute with it on a desktop workstation. The best previously available reduced memory footprint method would have required three orders of magnitude more computing time than our new method. Supplementary materials for this article are available online.
Context:
Lactation is associated with decreased areal bone mineral density (aBMD). Replenishment occurs especially after ceased lactation. Changes in volumetric bone mineral density (vBMD), ...microstructure, and dimensional parameters are unknown and may clarify the role of lactation for skeletal health.
Objective and Main Outcomes:
The objective of the study was to test the hypothesis that lactation is associated with changes in aBMD, vBMD, microstructure, and dimensional parameters.
Design:
At baseline (0.5 mo after delivery) and 4, 12, and 18 months thereafter, bone was assessed using dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography.
Participants and Setting:
Eighty-one fair-skinned postpartum women and 21 controls aged 25–40 years were recruited. The completion ratio was 73%. Postpartum women were categorized depending on duration of lactation: 0–3.9, 4–8.9, and 9 months or longer.
Results:
During the first 4 months, aBMD decreased at several sites (geometric mean ± SE; −0.73% ± 0.21% to −3.98% ± 0.76%) in women lactating at least 4 months. During the same time, cortical vBMD at the ultradistal tibia decreased in women lactating 4–8.9 months (−0.26% ± 0.08%) and 9 months or longer (−0.49% ± 0.10%). At 12 months postpartum, cortical thickness (≥9 mo, −2.48% ± 0.41%) and trabecular thickness (4–8.9 mo, −2.14% ± 0.92%; ≥ 9 mo, −2.56% ± 1.21%) also were lower than baseline. No decreases were found in women lactating less than 4 months or in controls in these parameters. At 18 months postpartum, both cortical vBMD (≥9 mo, −0.77% ± 0.17%) and trabecular thickness (4–8.9 mo, −2.25% ± 1.25%; ≥ 9 mo, −3.21% ± 1.41%) were lower in women with long lactation.
Conclusions:
Decreases in cortical vBMD, thickness, and trabecular thickness at the ultradistal tibia were found in women lactating 4 months or longer. Longer follow-up is needed to confirm whether women with extended lactation recover fully or whether the changes could potentially lead to an increased risk of fracture in later life.
Single endothelial cells (EC) seeded in suspension culture rapidly undergo apoptosis. Addition of survival factors, such as VEGF and FGF-2, does not prevent apoptosis of suspended EC. However, when ...cells are allowed to establish cell-cell contacts, they become responsive to the activities of survival factors. These observations have led to the development of a three-dimensional spheroid model of EC differentiation. EC spheroids remodel over time to establish a differentiated surface layer of EC and a center of unorganized EC that subsequently undergo apoptosis. Surface EC become quiescent, establish firm cell-cell contacts, and can be induced to express differentiation antigens (e.g., induction of CD34 expression by VEGF). In contrast, the unorganized center spheroid cells undergo apoptosis if they are not rescued by survival factors. The responsiveness to the survival factor activities of VEGF and FGF-2 was not dependent on cell shape changes since it was retained after cytochalasin D treatment. Taken together, these findings characterize survival factor requirements of unorganized EC and indicate that polarized surface EC differentiate to become independent of exogenous survival factors. Furthermore, they demonstrate that spheroid cell culture systems are useful not just for the study of tumor cells and embryonic stem cells but also for the analysis of differentiated functions of nontransformed cells.
Spatio-temporal modelling of tree defoliation data from the German forest condition survey is statistically challenging, particularly due to irregular grids. In the present study, generalized ...additive mixed models (GAMMs) were used to estimate the spatio-temporal trends in defoliation of the main tree species spruce, pine, beech and oak from 1989 to 2015 and to examine the suitability of different monitoring grid resolutions (standard 16 × 16 km grid and denser grids). Although data has been collected since 1989, this is the first time spatio-temporal modelling for all of Germany has been carried out. GAMMs proved to be a statistically sound and highly flexible choice for spatio-temporal modelling of defoliation data. In addition to the space-time component, stand age showed a significant effect on defoliation. The mean age and the species-specific relation between defoliation and age determined the general level of defoliation. However, further investigations are necessary in order to understand what is behind the age effect. Adjustment for stand age was carried out for identifying hotspots of high defoliation that are not merely the result of the age effect. Fluctuations in defoliation were most likely related to weather conditions. South-western Germany has emerged as the region with the highest defoliation since the drought year 2003. This region was characterized by the strongest water deficits in 2003 compared to the long-term reference period (1961-1990). Furthermore, the spatio-temporal model was used to carry out a simulation study to compare different survey grid resolutions in terms of prediction error. The model-based approach for grid analysis turned out to be appropriate for the given data and sample design. The grid analysis indicated that an 8 × 8 km grid instead of the standard 16 × 16 km grid is necessary for spatio-temporal trend estimation and for detecting hotspots in defoliation in space and time, especially regarding oaks.
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