Sex differences in incidence, mortality, and survival in individuals with stroke in Scotland, 1986 to 2005

<p><b>Background and Purpose:</b> The aim of this study was to examine the effect of sex across different age groups and over time for stroke incidence, 30-day case-fatality, and mortality.</p> <p><b>Methods:</b> All first hospitalizations for stroke in Scotland (1986 to 2005) were identified using linked morbidity and mortality data. Age-specific rate ratios (RRs) for comparing women with men for both incidence and mortality were modeled with adjustment for study year and socioeconomic deprivation. Logistic regression was used to model 30-day case-fatality.</p> <p><b>Results:</b> Women had a lower incidence of first hospitalization than men and size of effect varied with age (55 to 64 years, RR=0.65, 95% CI 0.63 to 0.66; 85 years, RR=0.94, 95% CI 0.91 to 0.96). Women aged 55 to 84 years had lower mortality than men and again size of effect varied with age (65 to 74 years, RR=0.79, 95% CI 0.76 to 0.81); 75 to 84 years, RR=0.94, 95% CI 0.92 to 0.95). Conversely, women aged 85 years had 15% higher stroke mortality than men (RR=1.15, 95% CI 1.12 to 1.18). Adjusted risk of death within 30 days was significantly higher in women than men, and this difference increased over the 20-year period in all age groups (adjusted OR in 55 to 64 year olds 1.23, 95% CI 1.14 to 1.33 in 1986 and 1.51, 95% CI 1.39 to 1.63 in 2005).</p> <p><b>Conclusions:</b> We observed lower rates of incidence and mortality in younger women than men. However, higher numbers of older women in the population mean that the absolute burden of stroke is greater in women. Short-term case-fatality is greater in women of all ages and, worryingly, these differences have increased from 1986 to 2005.</p&gt

Explaining trends in alcohol-related harms in Scotland 1991–2011 (II): policy, social norms, the alcohol market, clinical changes and a synthesis

Objective: To provide a basis for evaluating post-2007 alcohol policy in Scotland, this paper tests the extent to which pre-2007 policy, the alcohol market, culture or clinical changes might explain differences in the magnitude and trends in alcohol-related mortality outcomes in Scotland compared to England & Wales (E&W). Study design: Rapid literature reviews, descriptive analysis of routine data and narrative synthesis. Methods: We assessed the impact of pre-2007 Scottish policy and policy in the comparison areas in relation to the literature on effective alcohol policy. Rapid literature reviews were conducted to assess cultural changes and the potential role of substitution effects between alcohol and illicit drugs. The availability of alcohol was assessed by examining the trends in the number of alcohol outlets over time. The impact of clinical changes was assessed in consultation with key informants. The impact of all the identified factors were then summarised and synthesised narratively. Results: The companion paper showed that part of the rise and fall in alcohol-related mortality in Scotland, and part of the differing trend to E&W, were predicted by a model linking income trends and alcohol-related mortality. Lagged effects from historical deindustrialisation and socio-economic changes exposures also remain plausible from the available data. This paper shows that policy differences or changes prior to 2007 are unlikely to have been important in explaining the trends. There is some evidence that aspects of alcohol culture in Scotland may be different (more concentrated and home drinking) but it seems unlikely that this has been an important driver of the trends or the differences with E&W other than through interaction with changing incomes and lagged socio-economic effects. Substitution effects with illicit drugs and clinical changes are unlikely to have substantially changed alcohol-related harms: however, the increase in alcohol availability across the UK is likely to partly explain the rise in alcohol-related mortality during the 1990s. Conclusions: Future policy should ensure that alcohol affordability and availability, as well as socio-economic inequality, are reduced, in order to maintain downward trends in alcohol-related mortality in Scotland

A critical reflection on the use of improvement science approaches in public health

Objective: ‘Improvement science’ is used to describe specific quality improvement methods (including tests of change and statistical process control). The approach is spreading from clinical settings to population-wide interventions and is being extended from supporting the adoption of proven interventions to making generalisable claims about new interventions. The objective of this narrative review is to evaluate the strengths and risks of current improvement science practice, particularly in relation to how they might be used in population health. Methods: A purposive sampling of published studies to identify how improvement science methods are being used and for what purpose. The setting was Scotland and studies that focused on health and wellbeing outcomes. Results: We have identified a range of improvement science approaches which provide practitioners with accessible tools to assess small-scale changes in policy and practice. The strengths of such approaches are that they facilitate consistent implementation of interventions already known to be effective and motivate and empower staff to make local improvements. However, we also identified a number of potential risks. In particular, their use to assess the effectiveness of new interventions often seems to pay insufficient attention to random variation, measurement bias, confounding and ethical issues. Conclusions: The use of current improvement science methods to generate evidence of effectiveness for population-wide interventions is problematic and risks unjustified claims of effectiveness, inefficient resource use and harm to those not offered alternative effective interventions. Newer methodological approaches offer alternatives and should be more widely considered

The role of the Cucumber mosaic virus 2b protein in viral movement and symptom induction

The Cucumber mosaic virus (CMV) 2b protein is a counter-defense factor and symptom determinant. Conserved domains in the 2b protein sequence were mutated in the 2b gene of strain Fny-CMV. The effects of these mutations were assessed by infection of Nicotiana tabacum, N. benthamiana, and Arabidopsis thaliana (ecotype Col-0) with mutant viruses and by expression of mutant 2b transgenes in A. thaliana. We confirmed that two nuclear localization signals were required for symptom induction and found that the N-terminal domain was essential for symptom induction. The C-terminal domain and two serine residues within a putative phosphorylation domain modulated symptom severity. Further infection studies were conducted using Fny-CMVΔ2b, a mutant that cannot express the 2b protein and that induces no symptoms in N. tabacum, N. benthamiana, or A. thaliana ecotype Col-0. Surprisingly, in plants of A. thaliana ecotype C24, Fny-CMVΔ2b induced severe symptoms similar to those induced by the wild-type virus. However, C24 plants infected with the mutant virus recovered from disease while those infected with the wild-type virus did not. Expression of 2b transgenes from either Fny-CMV or from LS-CMV (a mild strain) in Col-0 plants enhanced systemic movement of Fny-CMVΔ2b and permitted symptom induction by Fny-CMVΔ2b. Taken together, the results indicate that the 2b protein itself is an important symptom determinant in certain hosts. However, they also suggest that the protein may somehow synergize symptom induction by other CMV-encoded factors

A cardiovascular disease policy model:part 2-preparing for economic evaluation and to assess health inequalities

Objectives This is the second of two papers introducing a cardiovascular disease (CVD) policy model. The first paper described the structure and statistical underpinning of the state transition model, demonstrating how life expectancy estimates are generated for individuals defined by ASSIGN risk factors. This second paper describes how the model is prepared to undertake economic evaluation. Design To generate quality adjusted life expectancy (QALE), the Scottish Health Survey was used to estimate background morbidity (health utilities) and the impact of CVD events (utility decrements). The SF-6D algorithm generated utilities and decrements were modelled using ordinary least squares (OLS). To generate lifetime hospital costs the Scottish Heart Health Extended Cohort (SHHEC) was linked to the Scottish morbidity and death records (SMR) to cost each Continuous Inpatient Stay (CIS). OLS and restricted cubic splines estimated annual costs before and after each of the first four events. A Kaplan Meier Sample Average (KMSA) estimator was then used to weight expected health related quality of life and costs by the probability of survival. Results The policy model predicts the change in QALE and lifetime hospital costs as a result of an intervention(s) modifying risk factors. Cost effectiveness analysis and a full uncertainty analysis can be undertaken, including probabilistic sensitivity analysis. Notably, the impacts according to socioeconomic deprivation status can be made. Conclusions The policy model can conduct cost effectiveness analysis and decision analysis to inform approaches to primary prevention, including individually targeted and population interventions, and to assess impacts on health inequalities. </p

The SCottish Alcoholic Liver disease Evaluation: a population-level matched cohort study of hospital-based costs, 1991-2011

Studies assessing the costs of alcoholic liver disease are lacking. We aimed to calculate the costs of hospitalisations before and after diagnosis compared to population controls matched by age, sex and socio-economic deprivation. We aimed to use population level data to identify a cohort of individuals hospitalised for the first time with alcoholic liver disease in Scotland between 1991 and 2011.Incident cases were classified by disease severity, sex, age group, socio-economic deprivation and year of index admission. 5 matched controls for every incident case were identified from the Scottish population level primary care database. Hospital costs were calculated for both cases and controls using length of stay from morbidity records and hospital-specific daily rates by specialty. Remaining lifetime costs were estimated using parametric survival models and predicted annual costs. 35,208 incident alcoholic liver disease hospitalisations were identified. Mean annual hospital costs for cases were 2.3 times that of controls pre diagnosis (£804 higher) and 10.2 times (£12,774 higher) post diagnosis. Mean incident admission cost was £6,663. Remaining lifetime cost for a male, 50-59 years old, living in the most deprived area diagnosed with acoholic liver disease was estimated to be £65,999 higher than the matched controls (£12,474 for 7.43 years remaining life compared to £1,224 for 21.8 years). In Scotland, alcoholic liver disease diagnosis is associated with significant increases in admissions to hospital both before and after diagnosis. Our results provide robust population level estimates of costs of alcoholic liver disease for the purposes of health-care delivery, planning and future cost-effectiveness analyses

Salicylic acid treatment and expression of an RNA-dependent RNA polymerase 1 transgene inhibit lethal symptoms and meristem invasion during tobacco mosaic virus infection in Nicotiana benthamiana.

BACKGROUND: Host RNA-dependent RNA polymerases (RDRs) 1 and 6 contribute to antiviral RNA silencing in plants. RDR6 is constitutively expressed and was previously shown to limit invasion of Nicotiana benthamiana meristem tissue by potato virus X and thereby inhibit disease development. RDR1 is inducible by salicylic acid (SA) and several other phytohormones. But although it contributes to basal resistance to tobacco mosaic virus (TMV) it is dispensable for SA-induced resistance in inoculated leaves. The laboratory accession of N. benthamiana is a natural rdr1 mutant and highly susceptible to TMV. However, TMV-induced symptoms are ameliorated in transgenic plants expressing Medicago truncatula RDR1. RESULTS: In MtRDR1-transgenic N. benthamiana plants the spread of TMV expressing the green fluorescent protein (TMV.GFP) into upper, non-inoculated, leaves was not inhibited. However, in these plants exclusion of TMV.GFP from the apical meristem and adjacent stem tissue was greater than in control plants and this exclusion effect was enhanced by SA. TMV normally kills N. benthamiana plants but although MtRDR1-transgenic plants initially displayed virus-induced necrosis they subsequently recovered. Recovery from disease was markedly enhanced by SA treatment in MtRDR1-transgenic plants whereas in control plants SA delayed but did not prevent systemic necrosis and death. Following SA treatment of MtRDR1-transgenic plants, extractable RDR enzyme activity was increased and Western blot analysis of RDR extracts revealed a band cross-reacting with an antibody raised against MtRDR1. Expression of MtRDR1 in the transgenic N. benthamiana plants was driven by a constitutive 35S promoter derived from cauliflower mosaic virus, confirmed to be non-responsive to SA. This suggests that the effects of SA on MtRDR1 are exerted at a post-transcriptional level. CONCLUSIONS: MtRDR1 inhibits severe symptom development by limiting spread of virus into the growing tips of infected plants. Thus, RDR1 may act in a similar fashion to RDR6. MtRDR1 and SA acted additively to further promote recovery from disease symptoms in MtRDR1-transgenic plants. Thus it is possible that SA promotes MtRDR1 activity and/or stability through post-transcriptional effects.We thank Zhixiang Chen for his advice on the RDR assay protocol. Xiaoqiang Wang and Zhentian Lei at the Samuel Roberts Noble Foundation for the AKTA purification protocol and analysis of recombinant MBP:MtRDR1 fusion protein, respectively. David Baulcombe, Peter Palukaitis, Joel Milner and Lydia Hunter are thanked for stimulating discussions and useful advice and Adrienne Pate for expert technical assistance. FSF was funded by grants from the Cambridge Overseas Trust and the Ministry of Education of Taiwan, and WSL was funded by a studentship from the Biotechnology and Biological Sciences Research Council (BBSRC) and work in the Carr lab was funded by BBSRC grants (BB/D008204/1, BB/D014376/1, BB/J011762/1), The Leverhulme Trust (F/09 741/F, RPG-2012-667), and Cambridge University Isaac Newton Trust. RSN and SRC were funded by the Samuel Roberts Noble Foundation, Inc

Cucumber mosaic virus and its 2b RNA silencing suppressor modify plant-aphid interactions in tobacco

The cucumber mosaic virus (CMV) 2b protein not only inhibits anti-viral RNA silencing but also quenches transcriptional responses of plant genes to jasmonic acid, a key signalling molecule in defence against insects. This suggested that it might affect interactions between infected plants and aphids, insects that transmit CMV. We found that infection of tobacco with a 2b gene deletion mutant (CMVD2b) induced strong resistance to aphids (Myzus persicae) while CMV infection fostered aphid survival. Using electrical penetration graph methodology we found that higher proportions of aphids showed sustained phloem ingestion on CMV-infected plants than on CMVD2b-infected or mock-inoculated plants although this did not increase the rate of growth of individual aphids. This indicates that while CMV infection or certain viral gene products might elicit aphid resistance, the 2b protein normally counteracts this during a wild-type CMV infection. Our findings suggest that the 2b protein could indirectly affect aphid-mediated virus transmission

Association of total and differential leukocyte counts with cardiovascular disease and mortality in the UK Biobank

Objective—Elevated white blood cell count is associated with a higher risk of cardiovascular disease (CVD). We aimed to investigate whether specific leukocyte subpopulations, which may more closely indicate a specific inflammatory pathway, are specifically associated with CVD. Approach and Results—Participants (478 259) from UK Biobank with data for white blood cell count were included. Death because of CVD (n=1377) and non-CVD causes (n=8987) occurred during median follow-up time of 7.0 years (interquartile range, 6.3–7.6). In Cox models, deciles of leukocyte counts (lymphocytes, monocytes, neutrophils, eosinophils, and basophils) were examined using the fifth decile as the referent group. Models were stratified by sex and adjusted for a range of classical risk factors. A sensitivity analysis excluded participants with baseline comorbidites and the first 2 years of follow-up. Men (hazard ratio [HR], 1.59; 95% confidence interval, 1.22–2.08) and women (HR, 2.15; 95% confidence interval, 1.38–3.35) in the highest decile of neutrophil count were at higher risk of CVD mortality and nonfatal CVD (men HR, 1.28; 95% confidence interval, 1.16–1.42 and women HR, 1.21; 95% confidence interval, 1.06–1.38). In the sensitivity analysis, the power to investigate CVD mortality was limited, but for both sexes combined, the linear HRs for a 1×109/L cell count increase in white blood cell count and neutrophils, respectively, was 1.05 (1.03–1.07) and 1.07 (1.04–1.11). Conclusions—Among circulating leukocyte subpopulations, neutrophil count in men was most consistently associated with fatal and nonfatal CVD. Further studies of interventions that lower circulating neutrophils, such as canakinumab, are required to investigate causality