Long-Term Secondary Care Costs of Endometrial Cancer: A Prospective Cohort Study Nested within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

BackgroundThere is limited evidence on the costs of Endometrial Cancer (EC) by stage of disease. We estimated the long-term secondary care costs of EC according to stage at diagnosis in an English population-based cohort.MethodsWomen participating in UKCTOCS and diagnosed with EC following enrolment (2001–2005) and prior to 31^st Dec 2009 were identified to have EC through multiple sources. Survival was calculated through data linkage to death registry. Costs estimates were derived from hospital records accessed from Hospital Episode Statistics (HES) with additional patient level covariates derived from case notes and patient questionnaires. Missing and censored data was imputed using Multiple Imputation. Regression analysis of cost and survival was undertaken.Results491 of 641 women with EC were included. Five year total costs were strongly dependent on stage, ranging from £9,475 (diagnosis at stage IA/IB) to £26,080 (diagnosis at stage III). Stage, grade and BMI were the strongest predictors of costs. The majority of costs for stage I/II EC were incurred in the first six months after diagnosis while for stage III / IV considerable costs accrued after the first six months.ConclusionsIn addition to survival advantages, there are significant cost savings if patients with EC are detected earlier.     

The Prevalence and Incidence of Atrial Fibrillation in Patients with Acute Pulmonary Embolism

Background

Symptomatic pulmonary embolism (PE) is a major cause of cardiovascular death and morbidity. Estimated prevalence and incidence of atrial fibrillation (AF) in developed countries are between 388–661 per 100,000, and 90–123 per 100,000 person-years respectively. However, the prevalence and incidence of AF in patients presenting with an acute PE and its predictors are not clear.

Methods

Individual patient clinical details were retrieved from a database containing all confirmed acute PE presentations to a tertiary institution from 2001–2012. Prevalence and incidence of AF was tracked from a population registry by systematically searching for AF during any hospital admission (2000–2013) based on International Classification of Disease (ICD-10) code.

Results

Of the 1,142 patients included in this study, 935 (81.9%) had no AF during index PE admission whilst 207 patients had documented baseline AF (prevalence rate 18,126 per 100,000; age-adjusted 4,672 per 100,000). Of the 935 patients without AF, 126 developed AF post-PE (incidence rate 2,778 per 100,000 person-years; age-adjusted 984 per 100,000 person-years). Mean time from PE to subsequent AF was 3.4 ± 2.9 years. Total mortality (mean follow-up 5.0 ± 3.7 years) was 42% (n = 478): 35% (n = 283), 59% (n = 119) and 60% (n = 76) in the no AF, baseline AF and subsequent AF cohorts respectively. Independent predictors for subsequent AF after acute PE include age (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.04–1.08, p<0.001), history of congestive cardiac failure (HR 1.88, 95% CI 1.12–3.16, p = 0.02), diabetes (HR 1.72, 95% CI 1.07–2.77, p = 0.02), obstructive sleep apnea (HR 4.83, 1.48–15.8, p = 0.009) and day-1 serum sodium level during index PE admission (HR 0.94, 95% CI 0.90–0.98, p = 0.002).

Conclusions

Patients presenting with acute PE have a markedly increased age-adjusted prevalence and subsequent incidence of AF. Screening for AF may be of importance post-PE.     

Behavioural Risk Factors in Mid-Life Associated with Successful Ageing,Disability, Dementia and Frailty in Later Life: A Rapid Systematic Review

Background

Smoking, alcohol consumption, poor diet and low levels of physical activity significantly contribute to the burden of illness in developed countries. Whilst the links between specific and multiple risk behaviours and individual chronic conditions are well documented, the impact of these behaviours in mid-life across a range of later life outcomes has yet to be comprehensively assessed. This review aimed to provide an overview of behavioural risk factors in mid-life that are associated with successful ageing and the primary prevention or delay of disability, dementia, frailty and non-communicable chronic conditions.

Methods

A literature search was conducted to identify cohort studies published in English since 2000 up to Dec 2014. Multivariate analyses and a minimum follow-up of five years were required for inclusion. Two reviewers screened titles, abstracts and papers independently. Studies were assessed for quality. Evidence was synthesised by mid-life behavioural risk for a range of late life outcomes.

Findings

This search located 10,338 individual references, of which 164 are included in this review. Follow-up data ranged from five years to 36 years. Outcomes include dementia, frailty, disability and cardiovascular disease. There is consistent evidence of beneficial associations between mid-life physical activity, healthy ageing and disease outcomes. Across all populations studied there is consistent evidence that mid-life smoking has a detrimental effect on health. Evidence specific to alcohol consumption was mixed. Limited, but supportive, evidence was available relating specifically to mid-life diet, leisure and social activities or health inequalities.

Conclusions

There is consistent evidence of associations between mid-life behaviours and a range of late life outcomes. The promotion of physical activity, healthy diet and smoking cessation in all mid-life populations should be encouraged for successful ageing and the prevention of disability and chronic disease.     

Last-Century Increases in Intrinsic Water-Use Efficiency of Grassland Communities Have Occurred over a Wide Range of Vegetation Composition,Nutrient Inputs,and Soil pH

Last-century climate change has led to variable increases of the intrinsic water-use efficiency (W_i; the ratio of net CO₂ assimilation to stomatal conductance for water vapor) of trees and C₃ grassland ecosystems, but the causes of the variability are not well understood. Here, we address putative drivers underlying variable W_i responses in a wide range of grassland communities. W_i was estimated from carbon isotope discrimination in archived herbage samples from 16 contrasting fertilizer treatments in the Park Grass Experiment, Rothamsted, England, for the 1915 to 1929 and 1995 to 2009 periods. Changes in W_i were analyzed in relation to nitrogen input, soil pH, species richness, and functional group composition. Treatments included liming as well as phosphorus and potassium additions with or without ammonium or nitrate fertilizer applications at three levels. W_i increased between 11% and 25% (P < 0.001) in the different treatments between the two periods. None of the fertilizers had a direct effect on the change of W_i (ΔW_i). However, soil pH (P < 0.05), species richness (P < 0.01), and percentage grass content (P < 0.01) were significantly related to ΔW_i. Grass-dominated, species-poor plots on acidic soils showed the largest ΔW_i (+14.7 μmol mol⁻¹). The ΔW_i response of these acidic plots was probably related to drought effects resulting from aluminum toxicity on root growth. Our results from the Park Grass Experiment show that W_i in grassland communities consistently increased over a wide range of nutrient inputs, soil pH, and plant community compositions during the last century.The intrinsic water-use efficiency (W_i) of plants is controlled by photosynthetic carbon assimilation and stomatal conductance via the leaf-level coupling of CO₂ and water fluxes. A general, but variable, increase of W_i under rising atmospheric CO₂ has been observed in long-term studies (Peñuelas et al., 2011; Franks et al., 2013; Saurer et al., 2014), but little is known about other environmental or ecosystem factors, which may interact with the effect of increasing CO₂ on W_i. An improved understanding of putative interactive mechanisms is important because changes in W_i may have significant effects on the global terrestrial carbon and water cycles (Gedney et al., 2006; Betts et al., 2007). This study explores the interactive effects of the increase in atmospheric CO₂ (observed over the last century), nutrient loading, and soil pH together with other related effects on plant species richness and functional group composition on the coupling of plant CO₂ and water fluxes in a seminatural grassland in southeastern England.W_i is a leaf-level efficiency that has also been termed potential water-use efficiency or physiological water-use efficiency, as it excludes the direct influence of vapor pressure deficit (VPD), a parameter determined by environmental conditions, on leaf-level water-use efficiency (Farquhar et al., 1989; Franks et al., 2013). W_i reports the relationship between net CO₂ assimilation rate (A_n) and stomatal conductance for water vapor (g_H2O):(1)According to the first law of Fick, A_n can be given as the product of the stomatal conductance for CO₂ (g_CO2) and the concentration gradient between the atmosphere (c_a) and the leaf internal gas space (c_i): A_n= g_CO2 (c_a – c_i). Using g_CO2 (c_a – c_i) instead of A_n in Equation 1, replacement of g_H2O/g_CO2 by the numerical value of g_H2O/g_CO2 (1.6) and rearrangement yields the following alternative expression of W_i:(2)Equation 2 reveals that past changes of W_i must have been controlled by two parameters: the change of c_a and the concurrent change of 1 – c_i/c_a, the relative gradient for CO₂ diffusion into the leaf (Franks et al., 2013). A change in the relative gradient is determined by the changes in A_n relative to g_H2O, as leaves respond to changing c_a and other environmental factors. In particular, Equation 2 shows that any variation in the climate change response of W_i is determined by the c_i/c_a response, if the comparison is made for vegetation at the same location and in the same period of time.Studies with C₃ vegetation, including trees/forests and C₃ grasslands, have revealed a general increase of W_i in the last century (Bert et al., 1997; Duquesnay et al., 1998; Feng, 1999; Arneth et al., 2002; Saurer et al., 2004; Barbosa et al., 2010; Köhler et al., 2010; Andreu-Hayles et al., 2011). In many cases, c_i/c_a, estimated by ¹³C discrimination (Farquhar et al., 1989), varied relatively little. Indeed, it has been suggested, based on theoretical grounds and empirical evidence from studies over geological/evolutionary to short time scales, that adaptive feedback responses will tend to maintain c_i/c_a approximately constant (Ehleringer and Cerling, 1995; Franks et al., 2013), as plants optimize carbon gain with respect to water loss (Cowan and Farquhar, 1977). Yet, c_i/c_a-dependent variation in the W_i response to climate change has also been noted (Peñuelas et al., 2011; Köhler et al., 2012) over the last century, indicating that additional factors, perhaps including other global change drivers, can modify the W_i response over this time scale, at least transiently. A meta-analysis by Peñuelas et al. (2011) reports c_i/c_a-dependent increases of W_i for different forests between 6% and 36% from the early 1960s to 2000s. A recent study by Saurer et al. (2014) on European forest trees found increases in W_i ranging from 1% to 53% during the last century. The strongest increase of W_i was recorded in regions where summer soil-water availability decreased in the last century. For different grassland communities, the c_i/c_a-dependent increases of W_i varied between 13% and 28% at one site (Köhler et al., 2012) from 1915 to 2009. Evidently, such variation can have important repercussions for the coupling of terrestrial CO₂ and water fluxes. Yet, little is known about the mechanism(s) underlying the variation.At the Park Grass Experiment (PGE) at Rothamsted, England, Köhler et al. (2012) observed a nitrogen supply-dependent enhancement of the W_i response on plots receiving nitrate fertilizer and maintained at a near-neutral soil pH by liming. However, the actual relationship between nitrogen supply and W_i response did not hold when the unlimed control (soil pH approximately 5.2) was included in the comparison. Remarkably, however, there was a significant positive relationship between the grass content of the community and the W_i response of the experimental plots in the investigation. These results suggested that the effect of nutrient supply on the W_i response of the grassland communities was indirect, perhaps working via effects on soil pH and/or vegetation composition (plant species richness or functional group composition).The PGE provides a unique opportunity to study century-scale variation in the c_i/c_a-dependent variation of W_i for a wide range of diverse grassland communities. Much of the extant ecosystem-scale variability of plant species richness and soil pH in temperate grasslands of Europe (Ceulemans et al., 2014) is included in the range of plot-scale plant species richness and soil pH at the PGE (which is reported in this investigation). The different long-term applications of fertilizer and lime over the past century have resulted in substantial changes in soil pH, species richness, and grass content on the experimental plots, but in most cases, within-plot changes over the study period considered here (1915–2009) were comparatively small (Crawley et al., 2005; Silvertown et al., 2006). All experimental plots are located at the same site and are exposed to the same weather conditions. Consequently, trends in climate as a direct driver for differences in W_i between plots can be ruled out.Here, we explore putative mechanisms underlying eventual c_i/c_a-dependent variation of W_i during the last century at the PGE by, first, quantifying the sustained effect of a wide range of contrasting fertilizer treatments (n = 16) on the change of W_i during the last century and, second, analyzing the relationships between the observed W_i response of treatments and the respective nutrient status, soil pH, plant species richness, and plant functional group composition of the grassland communities.     

Evidence for different,host‐dependent functioning of Rx against both wild‐type and recombinant Pepino mosaic virus

The potato Rx gene provides resistance against Pepino mosaic virus (PepMV) in tomato; however, recent work has suggested that the resistance conferred may not be durable. Resistance breaking can probably be attributed to multiple mutations observed to accumulate in the capsid protein (CP) region of resistance‐breaking isolates, but this has not been confirmed through directed manipulation of an infectious PepMV clone. The present work describes the introduction of two specific mutations, A‐T78 and A‐T114, into the coat protein minimal elicitor region of an Rx‐controlled PepMV isolate of the EU genotype. Enzyme‐linked immunosorbent assay (ELISA) and phenotypic evaluation were conducted in three Rx‐expressing and wild‐type solanaceous hosts: Nicotiana benthamiana, Nicotiana tabacum and Solanum lycopersicum. Mutation A‐T78 alone was sufficient to confer Rx‐breaking activity in N. benthamiana and S. lycopersicum, whereas mutation A‐T114 was found to be associated, in most cases, with a secondary A‐D100 mutation to break Rx‐mediated resistance in S. lycopersicum. These results suggest that the need for a second, fitness‐restoring mutation may be dependent on the PepMV mutant under consideration. Both mutations conferred Rx breaking in S. lycopersicum, whereas neither conferred Rx breaking in N. tabacum and only A‐T78 allowed Rx breaking in N. benthamiana, suggesting that Rx may function in a different manner depending on the genetic background in which it is present.     

Global agricultural intensification during climate change: a role for genomics

Agriculture is now facing the ‘perfect storm’ of climate change, increasing costs of fertilizer and rising food demands from a larger and wealthier human population. These factors point to a global food deficit unless the efficiency and resilience of crop production is increased. The intensification of agriculture has focused on improving production under optimized conditions, with significant agronomic inputs. Furthermore, the intensive cultivation of a limited number of crops has drastically narrowed the number of plant species humans rely on. A new agricultural paradigm is required, reducing dependence on high inputs and increasing crop diversity, yield stability and environmental resilience. Genomics offers unprecedented opportunities to increase crop yield, quality and stability of production through advanced breeding strategies, enhancing the resilience of major crops to climate variability, and increasing the productivity and range of minor crops to diversify the food supply. Here we review the state of the art of genomic‐assisted breeding for the most important staples that feed the world, and how to use and adapt such genomic tools to accelerate development of both major and minor crops with desired traits that enhance adaptation to, or mitigate the effects of climate change.