Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research

Education and wealth inequalities in healthy ageing in eight harmonised cohorts in the ATHLOS consortium: a population-based study

Background: The rapid growth of the size of the older population is having a substantial effect on health and social care services in many societies across the world. Maintaining health and functioning in older age is a key public health issue but few studies have examined factors associated with inequalities in trajectories of health and functioning across countries. The aim of this study was to investigate trajectories of healthy ageing in older men and women (aged ≥45 years) and the effect of education and wealth on these trajectories. Methods: This population-based study is based on eight longitudinal cohorts from Australia, the USA, Japan, South Korea, Mexico, and Europe harmonised by the EU Ageing Trajectories of Health: Longitudinal Opportunities and Synergies (ATHLOS) consortium. We selected these studies from the repository of 17 ageing studies in the ATHLOS consortium because they reported at least three waves of collected data. We used multilevel modelling to investigate the effect of education and wealth on trajectories of healthy ageing scores, which incorporated 41 items of physical and cognitive functioning with a range between 0 (poor) and 100 (good), after adjustment for age, sex, and cohort study. Findings: We used data from 141 214 participants, with a mean age of 62·9 years (SD 10·1) and an age range of 45–106 years, of whom 76 484 (54·2%) were women. The earliest year of baseline data was 1992 and the most recent last follow-up year was 2015. Education and wealth affected baseline scores of healthy ageing but had little effect on the rate of decrease in healthy ageing score thereafter. Compared with those with primary education or less, participants with tertiary education had higher baseline scores (adjusted difference in score of 10·54 points, 95% CI 10·31–10·77). The adjusted difference in healthy ageing score between lowest and highest quintiles of wealth was 8·98 points (95% CI 8·74–9·22). Among the eight cohorts, the strongest inequality gradient for both education and wealth was found in the Health Retirement Study from the USA. Interpretation: The apparent difference in baseline healthy ageing scores between those with high versus low education levels and wealth suggests that cumulative disadvantage due to low education and wealth might have largely deteriorated health conditions in early life stages, leading to persistent differences throughout older age, but no further increase in ageing disparity after age 70 years. Future research should adopt a lifecourse approach to investigate mechanisms of health inequalities across education and wealth in different societies. Funding: European Union Horizon 2020 Research and Innovation Programme.The ATHLOS project was funded by the European Union Horizon 2020 Research and Innovation Programme (grant number 635316). This study was supported by the 5-year ATHLOS projec

Error determination in the photogrammetric assessment of shoreline changes

The evaluation of error or uncertainty in shoreline change studies is an issue of prime importance for providing an adequate framework for calculated rates of change and to allow the establishment of threshold values above which the rates would be significant. In this note, a practical, easy-to-use method is presented to estimate error involved in the calculation of shoreline changes on aerial photographs, including the three most used types of shoreline indicators: high water line, dune/cliff toe and cliff top. This approach takes into account the specific characteristics of each shoreline proxy, such as relief in the case of the cliff top or tidal oscillations in the case of the high water line. At the same time it includes the error components that are independent from the proxy, basically related to the technical aspects of the process such as photo scanning and georeferencing. A practical example of application of the method is provided for several types of data inputs, based on shoreline changes around the Bay of Cádiz (SW Spain)

Small firms and patenting revisited

In order to observe a patent application at the firm level two conditions need to be met: new products need to be of patentable quality, which depends both on the degree of novelty of innovations and on the total number (portfolio) of innovations; and the benefits of patents need to be higher than the costs of owning them. Analyzing the patent propensity of small and large UK firms using a novel innovation-level survey (the SIPU survey) linked to Community Innovation Survey data we find that when we consider the whole innovation portfolio smaller firms do patent less than larger firms. However, using data on individual innovations, we find that smaller firms are no less likely to patent any specific innovation than larger firms. We argue that size differences in the probability to patent relate primarily to the ‘portfolio effect’, i.e. larger firms generate more innovations than smaller firms and therefore are more likely to create one or more which are patentable. As for the decision to patent a patentable innovation, we find that cost barriers, more than issues of innovation quality or enforceability, deter small firms from patenting specific innovations. Measures to address the costs of patenting for smaller firms – perhaps by considering patents as eligible costs for R&D tax credits – and/or subsidizing SMEs’ participation in IP litigation schemes may both encourage patent use by smaller firms

C7orf30 specifically associates with the large subunit of the mitochondrial ribosome and is involved in translation

In a comparative genomics study for mitochondrial ribosome-associated proteins, we identified C7orf30, the human homolog of the plant protein iojap. Gene order conservation among bacteria and the observation that iojap orthologs cannot be transferred between bacterial species predict this protein to be associated with the mitochondrial ribosome. Here, we show colocalization of C7orf30 with the large subunit of the mitochondrial ribosome using isokinetic sucrose gradient and 2D Blue Native polyacrylamide gel electrophoresis (BN-PAGE) analysis. We co-purified C7orf30 with proteins of the large subunit, and not with proteins of the small subunit, supporting interaction that is specific to the large mitoribosomal complex. Consistent with this physical association, a mitochondrial translation assay reveals negative effects of C7orf30 siRNA knock-down on mitochondrial gene expression. Based on our data we propose that C7orf30 is involved in ribosomal large subunit function. Sequencing the gene in 35 patients with impaired mitochondrial translation did not reveal disease-causing mutations in C7orf30

Combined Influence of Waist and Hip Circumference on Risk of Death in a Large Cohort of European and Australian Adults

Background: Waist circumference and hip circumference are both strongly associated with risk of death; however, their joint association has rarely been investigated.Methods and Results: The MONICA Risk, Genetics, Archiving, and Monograph (MORGAM) Project was conducted in 30 cohorts from 11 countries; 90 487 men and women, aged 30 to 74 years, predominantly white, with no history of cardiovascular disease, were recruited in 1986 to 2010 and followed up for up to 24 years. Hazard ratios were estimated using sex-specific Cox models, stratified by cohort, with age as the time scale. Models included baseline categorical obesity measures, age, total and high-density lipoprotein cholesterol, systolic blood pressure, antihypertensive drugs, smoking, and diabetes mellitus. A total of 9105 all-cause deaths were recorded during a median follow-up of 10 years. Hazard ratios for all-cause death presented J- or U-shaped associations with most obesity measures. With waist and hip circumference included in the same model, for all hip sizes, having a smaller waist was strongly associated with lower risk of death, except for men with the smallest hips. In addition, among those with smaller waists, hip size was strongly negatively associated with risk of death, with approximate to 20% more people identified as being at increased risk compared with waist circumference alone.Conclusions: A more complex relationship between hip circumference, waist circumference, and risk of death is revealed when both measures are considered simultaneously. This is particularly true for individuals with smaller waists, where having larger hips was protective. Considering both waist and hip circumference in the clinical setting could help to best identify those at increased risk of death.</div

Diminished macrophage apoptosis and reactive oxygen species generation after phorbol ester stimulation in Crohn's disease.

BACKGROUND: Crohn's Disease (CD) is a chronic relapsing disorder characterized by granulomatous inflammation of the gastrointestinal tract. Although its pathogenesis is complex, we have recently shown that CD patients have a systemic defect in macrophage function, which results in the defective clearance of bacteria from inflammatory sites. METHODOLOGY/PRINCIPAL FINDINGS: Here we have identified a number of additional macrophage defects in CD following diacylglycerol (DAG) homolog phorbol-12-myristate-13-acetate (PMA) activation. We provide evidence for decreased DNA fragmentation, reduced mitochondrial membrane depolarization, impaired reactive oxygen species production, diminished cytochrome c release and increased IL-6 production compared to healthy subjects after PMA exposure. The observed macrophage defects in CD were stimulus-specific, as normal responses were observed following p53 activation and endoplasmic reticulum stress. CONCLUSION: These findings add to a growing body of evidence highlighting disordered macrophage function in CD and, given their pivotal role in orchestrating inflammatory responses, defective apoptosis could potentially contribute to the pathogenesis of CD

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income&nbsp;countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was &lt;1.1 kg m–2 in the vast majority of&nbsp;countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world