Repeated measures of body mass index and C-reactive protein in relation to all-cause mortality and cardiovascular disease: Results from the consortium on health and ageing network of cohorts in Europe and the United States (CHANCES)

Obesity has been linked with elevated levels of C-reactive protein (CRP), and both have been associated with increased risk of mortality and cardiovascular disease (CVD). Previous studies have used a single ‘baseline’ measurement and such analyses cannot account for possible changes in these which may lead to a biased estimation of risk. Using four cohorts from CHANCES which had repeated measures in participants 50 years and older, multivariate time-dependent Cox proportional hazards was used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) to examine the relationship between body mass index (BMI) and CRP with all-cause mortality and CVD. Being overweight (≥25–<30 kg/m2) or moderately obese (≥30–<35) tended to be associated with a lower risk of mortality compared to normal (≥18.5–<25): ESTHER, HR (95 % CI) 0.69 (0.58–0.82) and 0.78 (0.63–0.97); Rotterdam, 0.86 (0.79–0.94) and 0.80 (0.72–0.89). A similar relationship was found, but only for overweight in Glostrup, HR (95 % CI) 0.88 (0.76–1.02); and moderately obese in Tromsø, HR (95 % CI) 0.79 (0.62–1.01). Associations were not evident between repeated measures of BMI and CVD. Conversely, increasing CRP concentrations, measured on more than one occasion, were associated with an increasing risk of mortality and CVD. Being overweight or moderately obese is associated with a lower risk of mortality, while CRP, independent of BMI, is positively associated with mortality and CVD risk. If inflammation links CRP and BMI, they may participate in distinct/independent pathways. Accounting for independent changes in risk factors over time may be crucial for unveiling their effects on mortality and disease morbidity.

Estimating biomass, fishing mortality, and "total allowable discards" for surveyed non-target fish

Demersal fisheries targeting a few high-value species often catch and discard other "non-target" species. It is difficult to quantify the impact of this incidental mortality when population biomass of a non-target species is unknown. We calculate biomass for 14 demersal fish species in ICES Area VIIg (Celtic Sea) by applying species-and length-based catchability corrections to catch records from the Irish Groundfish Survey (IGFS). We then combine these biomass estimates with records of commercial discards (and landings for marketable non-target species) to calculate annual harvesting rates (HR) for each study species. Uncertainty is incorporated into estimates of both biomass andHR. Our survey-based HR estimates for cod and whiting compared well with HR-converted fishing mortality (F) estimates from analytical assessments for these two stocks. Of the non-target species tested, red gurnard (Chelidonichthys cuculus) recorded some annual HRs greater than those for cod or whiting; challenging "Pope's postulate" that F on non-target stocks in an assemblage will not exceed that on target stocks. We relate HR for each species to two corresponding maximum sustainable yield (MSY) reference levels; six non-target species (including three ray species) show annual HRs >= HRMSY. This result suggests that it may not be possible to conserve vulnerable non-target species when F is coupled to that of target species. Based on biomass, HR, and HRMSY, we estimate "total allowable catch" for each non-target species.

A Role for Behavior in the Relationships Between Depression and Hostility and Cardiovascular Disease Incidence, Mortality, and All-Cause Mortality: the Prime Study

BACKGROUND: Behavioral factors are important in disease incidence and mortality and may explain associations between mortality and various psychological traits.

PURPOSE: These analyses investigated the impact of behavioral factors on the associations between depression, hostility and cardiovascular disease(CVD) incidence, CVD mortality, and all-cause mortality.

METHODS: Data from the PRIME Study (N = 6953 men) were analyzed using Cox proportional hazards models, following adjustment for demographic and biological CVD risk factors, and other psychological traits, including social support.

RESULTS: Following initial adjustment, both depression and hostility were significantly associated with both mortality outcomes (smallest SHR = 1.24, p < 0.001). Following adjustment for behavioral factors, all relationships were attenuated both when accounting for and not accounting for other psychological variables. Associations with all-cause mortality remained significant (smallest SHR = 1.14, p = 0.04). Of the behaviors included, the most significant contribution to outcomes was found for smoking, but a role was also found for fruit and vegetable intakes and high alcohol consumption.

CONCLUSIONS: These findings demonstrate well-known associations between depression, hostility, and mortality and suggest the potential importance of behaviors in explaining these relationships.

Physico-geochemical and mineral composition of neem tree soils and relation to organic properties

The Neem tree, the oil of which has a long history of pesticide, fertilizer and medicinal use in India, has been studied extensively for its organic compounds. Here we present a physical, mineralogical and geochemical database resulting from the analyses of two Neem soil profiles (epipedons) in India. Neem tree derivatives are used in the manufacture of a variety of products, from anti-bacterial drugs and insecticides to fertilizers and animal feeds. A preliminary geochemical and mineralogical analysis of Neem soils is made to explore the potential for chemical links between Neem tree derivatives and soils. Physical soil characteristics, including colour, texture and clay mineralogy, suggest the two pedons formed under different hydrological regimes, and hence, are products of different leaching environments, one well-drained site, the other poorly drained. Geochemically, the two Neem soils exhibit similarities, with elevated concentrations of Th and rare earth elements. These elements are of interest because of their association with phosphates, especially monazite and apatite, and the potential link to fertilizer derivatives. Higher concentrations of trace elements in the soils may be linked to nutritional derivatives and to cell growth in the Neem tree.

Models of open populations with space-limited recruitment: extension of theory and application to the barnacle Chthamalus montagui.

1. Barnacles are a good model organism for the study of open populations with space-limited recruitment. These models are applicable to other species with open supply of new individuals and resource limitation. The inclusion of space in models leads to reductions in recruitment with increasing density, and thus predictions of population size and stability are possible. 2. Despite the potential generality of a demographic theory for open space-limited populations, the models currently have a narrow empirical base. In this study, a model for an open population with space-limited recruitment was extended to include size-specific survival and promotions to any size class. The assumptions of this model were tested using data from a pan-European study of the barnacle Chthamalus montagui Southward. Two models were constructed: a 6-month model and a periodic annual model. Predicted equilibria and their stabilities were compared between shores. 3. Tests of model assumptions supported the extension of the theory to include promotions to any size class. Mortality was found to be size-specific and density independent. Studied populations were open, with recruitment proportional to free space. 4. The 6-month model showed a significant interaction between time and location for equilibrium free space. This may have been due to contrasts in the timing of structuring processes (i.e. creating and filling space) between Mediterranean and Atlantic systems. Integration of the 6-month models into a periodic annual model removed the differences in equilibrium-free space between locations. 5. Model predictions show a remarkable similarity between shores at a European scale. Populations were persistent and all solutions were stable. This reflects the apparent absence of density-dependent mortality and a high adult survivorship in C. montagui. As populations are intrinsically stable, observations of fluctuations in density are directly attributable to variations in the environmental forcing of recruitment or mortality

The impact of newly identified loci on coronary heart disease, stroke and total mortality in the MORGAM prospective cohorts

Recently, genome wide association studies (GWAS) have identified a number of single nucleotide polymorphisms (SNPs) as being associated with coronary heart disease (CHD). We estimated the effect of these SNPs on incident CHD, stroke and total mortality in the prospective cohorts of the MORGAM Project. We studied cohorts from Finland, Sweden, France and Northern Ireland (total N=33,282, including 1,436 incident CHD events and 571 incident stroke events). The lead SNPs at seven loci identified thus far and additional SNPs (in total 42) were genotyped using a case-cohort design.We estimated the effect of the SNPs on disease history at baseline, disease events during follow-up and classic risk factors. Multiple testing was taken into account using false discovery rate (FDR) analysis. SNP rs1333049 on chromosome 9p21.3 was associated with both CHD and stroke (HR5=.20, 95% CI 1.08-1.34 for incident CHD events and 1.15, 0.99-1.34 for incident stroke). SNP rs11670734 (19q12) was associated with total mortality and stroke. SNP rs2146807 (10q11.21) showed some association with the fatality of acute coronary event. SNP rs2943634 (2q36.3) was associated with high density lipoprotein (HDL) cholesterol and SNPs rs599839, rs4970834 (1p13.3) and rs17228212 (15q22.23) were associated with non-HDL cholesterol. SNPs rs2943634 (2q36.3) and rs12525353 (6q25.1) were associated with blood pressure. These findings underline the need for replication studies in prospective settings and confirm the candidacy of several SNPs that may play a role in the etiology of cardiovascular disease.

Comparing the decline in coronary heart disease and stroke mortality in neighbouring countries with different healthcare systems

Objective
To examine age and gender specific trends in coronary heart disease (CHD) and stroke mortality in two neighbouring countries, the Republic of Ireland (ROI) and Northern Ireland (NI). Design Epidemiological study of time trends in CHD and stroke mortality.

Setting/patients
The populations of the ROI and NI, 1985–2010.

Interventions
None.

Main outcome measures
Directly age standardised CHD and stroke mortality rates were calculated and analysed using joinpoint regression to identify years where the slope of the linear trend changed significantly. This was performed separately for specific age groups (25–54, 55–64, 65–74 and 75–84 years) and by gender. Annual percentage change (APC) and 95% CIs are presented.

Results
There was a striking similarity between the two countries, with percentage change between 1985 and 1989 and between 2006 and 2010 of 67% and 69% in
CHD mortality, and 64% and 62% in stroke mortality for the ROI and NI, respectively. However, joinpoint analysis identified differences in the pace of change between the two countries. There was an accelerated pace of decline (negative APC) in mortality for both CHD and stroke in both countries from the mid-1990s (APC ROI −8% (95% CI −9.5 to 6.5) and NI −6.6% (−6.9 to −6.3)), but the accelerated decrease started later for CHD mortality in the ROI. In recent years, a levelling off in CHD mortality was observed in the 25–54 year age group in NI and in stroke mortality for men and women in the ROI.

Conclusions
While differences in the pace of change in mortality were observed at different time points, similar, substantial decreases in CHD and stroke mortality were achieved between 1985 and 1989 and between 2006 and 2010 in the ROI and NI despite important differences in health service structures. There is evidence of a levelling in mortality rates in some groups in recent years.

Structural Breaks in Mortality Models and their Consequences

In recent years, the issue of life expectancy has become of upmost importance to pension providers, insurance companies and the government bodies in the developed world. Significant and consistent improvements in mortality rates and, hence, life expectancy have led to unprecedented increases in the cost of providing for older ages. This has resulted in an explosion of stochastic mortality models forecasting trends in mortality data in order to anticipate future life expectancy and, hence, quantify the costs of providing for future aging populations. Many stochastic models of mortality rates identify linear trends in mortality rates by time, age and cohort, and forecast these trends into the future using standard statistical methods. The modeling approaches used failed to capture the effects of any structural change in the trend and, thus, potentially produced incorrect forecasts of future mortality rates. In this paper, we look at a range of leading stochastic models of mortality and test for structural breaks in the trend time series.

Excess mortality in Type 1 diabetes diagnosed in childhood and adolescence: a systematic review of population-based cohorts

Aims: Systematic review of mortality in childhood-/adolescent-diagnosed Type 1 diabetes and examination of factors explaining the mortality variation between studies. 
Methods: Relevant studies were identified from systematic searches of MEDLINE and EMBASE. Observed and expected numbers of deaths were extracted, and standardised mortality ratios (SMRs) and 95 % confidence intervals (CIs) were calculated. Negative binomial regression was used to investigate association between mortality and study/country characteristics.
Results: Thirteen relevant publications with mortality data were identified describing 23 independent studies. SMRs varied markedly ranging from 0 to 854 (chi-squared = 70.68,df = 21, p<0.0001). Significant associations were observed between SMR and mid-year of follow-up [incidence rate ratio (IRR) 0.95, 95 % CI 0.91–0.99 equivalent to a 5 % decrease per year], between SMR and infant mortality rate (IRR 1.07, 95 % CI 1.02–1.12, a 7 % increase for each death per 1,000 live births) and, after omitting an outlier, between SMR and health expenditure as a percentage of gross domestic product (GDP) (IRR 0.79, 95 % CI 0.68–0.93, a 21 % decrease for each one percent increase in GDP). No relationship was detected between SMR and a country’s childhood diabetes incidence rate or GDP.
Conclusions: Excess mortality in childhood-/adolescent diagnosed Type 1 diabetes is apparent across countries worldwide. Excesses were less marked in more recent studies and in countries with lower infant mortality and higher health expenditure.

Smoking and All-cause Mortality in Older Adults: Results From the CHANCES Consortium

INTRODUCTION: Smoking is known to be a major cause of death among middle-aged adults, but evidence on its impact and the benefits of smoking cessation among older adults has remained limited. Therefore, we aimed to estimate the influence of smoking and smoking cessation on all-cause mortality in people aged ≥60 years.

METHODS: Relative mortality and mortality rate advancement periods (RAPs) were estimated by Cox proportional hazards models for the population-based prospective cohort studies from Europe and the U.S. (CHANCES [Consortium on Health and Ageing: Network of Cohorts in Europe and the U.S.]), and subsequently pooled by individual participant meta-analysis. Statistical analyses were performed from June 2013 to March 2014.

RESULTS: A total of 489,056 participants aged ≥60 years at baseline from 22 population-based cohort studies were included. Overall, 99,298 deaths were recorded. Current smokers had 2-fold and former smokers had 1.3-fold increased mortality compared with never smokers. These increases in mortality translated to RAPs of 6.4 (95% CI=4.8, 7.9) and 2.4 (95% CI=1.5, 3.4) years, respectively. A clear positive dose-response relationship was observed between number of currently smoked cigarettes and mortality. For former smokers, excess mortality and RAPs decreased with time since cessation, with RAPs of 3.9 (95% CI=3.0, 4.7), 2.7 (95% CI=1.8, 3.6), and 0.7 (95% CI=0.2, 1.1) for those who had quit <10, 10 to 19, and ≥20 years ago, respectively.

CONCLUSIONS: Smoking remains as a strong risk factor for premature mortality in older individuals and cessation remains beneficial even at advanced ages. Efforts to support smoking abstinence at all ages should be a public health priority.

Predictive Value of Depressive Symptoms for All-Cause Mortality: Findings From the PRIME Belfast Study Examining the Role of Inflammation and Cardiovascular Risk Markers

OBJECTIVES: To improve understanding about the potential underlying biological mechanisms in the link between depression and all-cause mortality and to investigate the role that inflammatory and other cardiovascular risk factors may play in the relationship between depressive symptoms and mortality.

METHODS: Depression and blood-based biological markers were assessed in the Belfast PRIME prospective cohort study (N = 2389 men, aged 50-59 years) in which participants were followed up for 18 years. Depression was measured using the 10-item Welsh Pure Depression Inventory. Inflammation markers (C-reactive protein [CRP], neopterin, interleukin [IL]-1 receptor antagonist [IL-1Ra], and IL-18) and cardiovascular-specific risk factors (N-terminal pro-b-type natriuretic peptide, midregion pro-atrial natriuretic peptide, midregion pro-adrenomedullin, C-terminal pro-endothelin-1 [CT-proET]) were obtained at baseline. We used Cox proportional hazards modeling to examine the association between depression and biological measures in relation to all-cause mortality and explore the mediating effects.

RESULTS: During follow-up, 418 participants died. Higher levels of depressive symptoms were associated with higher levels of CRP, IL-1Ra, and CT-proET. After adjustment for socioeconomic and life-style risk factors, depressive symptoms were significantly associated with all-cause mortality (hazard ratio = 1.10 per scale unit, 95% confidence interval = 1.04-1.16). This association was partly explained by CRP (7.3%) suggesting a minimal mediation effect. IL-1Ra, N-terminal pro-b-type natriuretic peptide, midregion pro-atrial natriuretic peptide, midregion pro-adrenomedullin, and CT-proET contributed marginally to the association between depression and subsequent mortality.

CONCLUSIONS: Inflammatory and cardiovascular risk markers are associated with depression and with increased mortality. However, depression and biological measures show additive effects rather than a pattern of meditation of biological factors in the association between depression and mortality.

Sepsis: the LightCycler SeptiFast Test MGRADE®, SepsiTest™ and IRIDICA BAC BSI assay for rapidly identifying bloodstream bacteria and fungi – a systematic review and economic evaluation

Background: Sepsis can lead to multiple organ failure and death. Timely and appropriate treatment can reduce in-hospital mortality and morbidity. Objectives: To determine the clinical effectiveness and cost-effectiveness of three tests [LightCycler SeptiFast Test MGRADE® (Roche Diagnostics, Risch-Rotkreuz, Switzerland); SepsiTest™ (Molzym Molecular Diagnostics, Bremen, Germany); and the IRIDICA BAC BSI assay (Abbott Diagnostics, Lake Forest, IL, USA)] for the rapid identification of bloodstream bacteria and fungi in patients with suspected sepsis compared with standard practice (blood culture with or without matrix-absorbed laser desorption/ionisation time-offlight mass spectrometry). Data sources: Thirteen electronic databases (including MEDLINE, EMBASE and The Cochrane Library) were searched from January 2006 to May 2015 and supplemented by hand-searching relevant articles. Review methods: A systematic review and meta-analysis of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. A decision tree was used to estimate the costs and quality-adjusted life-years (QALYs) associated with each test; all other parameters were estimated from published sources. The model was populated with evidence from the systematic review or individual studies, if this was considered more appropriate (base case 1). In a secondary analysis, estimates (based on experience and opinion) from seven clinicians regarding the benefits of earlier test results were sought (base case 2). A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Scenario analyses were used to assess uncertainty. Results: For the review of diagnostic test accuracy, 62 studies of varying methodological quality were included. A meta-analysis of 54 studies comparing SeptiFast with blood culture found that SeptiFast had an estimated summary specificity of 0.86 [95% credible interval (CrI) 0.84 to 0.89] and sensitivity of 0.65 (95% CrI 0.60 to 0.71). Four studies comparing SepsiTest with blood culture found that SepsiTest had an estimated summary specificity of 0.86 (95% CrI 0.78 to 0.92) and sensitivity of 0.48 (95% CrI 0.21 to 0.74), and four studies comparing IRIDICA with blood culture found that IRIDICA had an estimated summary specificity of 0.84 (95% CrI 0.71 to 0.92) and sensitivity of 0.81 (95% CrI 0.69 to 0.90). Owing to the deficiencies in study quality for all interventions, diagnostic accuracy data should be treated with caution. No randomised clinical trial evidence was identified that indicated that any of the tests significantly improved key patient outcomes, such as mortality or duration in an intensive care unit or hospital. Base case 1 estimated that none of the three tests provided a benefit to patients compared with standard practice and thus all tests were dominated. In contrast, in base case 2 it was estimated that all cost per QALY-gained values were below £20,000; the IRIDICA BAC BSI assay had the highest estimated incremental net benefit, but results from base case 2 should be treated with caution as these are not evidence based. Limitations: Robust data to accurately assess the clinical effectiveness and cost-effectiveness of the interventions are currently unavailable. Conclusions: The clinical effectiveness and cost-effectiveness of the interventions cannot be reliably determined with the current evidence base. Appropriate studies, which allow information from the tests to be implemented in clinical practice, are required.

The SPHERE Study: Secondary prevention of heart disease in general practice: protocol of a randomised controlled trial of tailored practice and patient care plans with parallel qualitative, economic and policy analyses. [ISRCTN24081411]

Background: The aim of the SPHERE study is to design, implement and evaluate tailored practice and personal care plans to improve the process of care and objective clinical outcomes for patients with established coronary heart disease (CHD) in general practice across two different health systems on the island of Ireland.CHD is a common cause of death and a significant cause of morbidity in Ireland. Secondary prevention has been recommended as a key strategy for reducing levels of CHD mortality and general practice has been highlighted as an ideal setting for secondary prevention initiatives. Current indications suggest that there is considerable room for improvement in the provision of secondary prevention for patients with established heart disease on the island of Ireland. The review literature recommends structured programmes with continued support and follow-up of patients; the provision of training, tailored to practice needs of access to evidence of effectiveness of secondary prevention; structured recall programmes that also take account of individual practice needs; and patient-centred consultations accompanied by attention to disease management guidelines.

Methods: SPHERE is a cluster randomised controlled trial, with practice-level randomisation to intervention and control groups, recruiting 960 patients from 48 practices in three study centres (Belfast, Dublin and Galway). Primary outcomes are blood pressure, total cholesterol, physical and mental health status (SF-12) and hospital re-admissions. The intervention takes place over two years and data is collected at baseline, one-year and two-year follow-up. Data is obtained from medical charts, consultations with practitioners, and patient postal questionnaires. The SPHERE intervention involves the implementation of a structured systematic programme of care for patients with CHD attending general practice. It is a multi-faceted intervention that has been developed to respond to barriers and solutions to optimal secondary prevention identified in preliminary qualitative research with practitioners and patients. General practitioners and practice nurses attend training sessions in facilitating behaviour change and medication prescribing guidelines for secondary prevention of CHD. Patients are invited to attend regular four-monthly consultations over two years, during which targets and goals for secondary prevention are set and reviewed. The analysis will be strengthened by economic, policy and qualitative components.

Ascertainment of cause-specific mortality in COPD - operations of the TORCH clinical endpoint Committee

Background: TORCH (Towards a Revolution in COPD Health) is an international multicentre, randomised, placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease (COPD). The primary outcome is all-cause mortality. Cause-specific mortality and deaths related to COPD are additional outcome measures, but systematic methods for ascertainment of these outcomes have not previously been described. Methods: A Clinical Endpoint Committee (CEC) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic, unbiased and independent manner. The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD-relatedness; the independent review of cases by all members with development of a consensus opinion; and a substantial infrastructure to collect medical information. Results: 911 deaths were reviewed and consensus was reached in all. Cause-specific mortality was: cardiovascular 27%, respiratory 35%, cancer 21%, other 10% and unknown 8%. 40% of deaths were definitely or probably related to COPD. Adjudications were identical in 83% of blindly re-adjudicated cases ( = 0.80). COPD-relatedness was reproduced 84% of the time ( = 0.73). The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52% of cases. Conclusion: A CEC can provide standardised, reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators.

Factors associated with hare mortality during coursing

Hare coursing is a widespread but controversial activity. In an attempt to reduce hare mortality and mitigate the activity's impact on hare welfare, the Irish Coursing Club introduced measures including the compulsory muzzling of dogs in 1993. However, the efficacy of these measures remained the subject of heated debate. Official records, corroborated by independent video evidence, were used to assess the fate of individual Irish hares (Lepus timiclus hibernicus) during coursing events from 1988-2004. Muzzling dogs significantly reduced levels of hare mortality. In courses using unmuzzled dogs from 1988189-1992193 mean hare mortality was 15.8%, compared to 4.1% in courses using muzzled dogs from 1993194-2003104. Further reductions in mortality could not be accounted for by muzzling dogs, supporting the efficacy of other factors such as improved hare husbandry. The duration of the head start given to the hare prior to the release of the dogs significantly affected the outcome of the course. Hares that were killed had head starts of greater duration than those that were chased but survived, suggesting the former may have been slower. The selection of hares by assessment of their running ability may provide means to reduce hare mortality during courses further. Our findings support the efficacy of measures taken to mitigate the impact of coursing on individual hares. However, it is necessary to evaluate the impact of removing hares from the source population and of returning coursed hares to the wild before the wider impact of coursing on wild hare populations can be determined.