Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials

Background: Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages. Methods: In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups. Findings: 14 483 (8%) of 186 854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4·9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06). Overall, statin or more intensive therapy yielded a 24% (RR 0·76, 95% CI 0·73–0·79) proportional reduction in major coronary events per 1·0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0·009). We observed a 25% (RR 0·75, 95% CI 0·73–0·78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1·0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0·6). Similarly, the proportional reductions in stroke of any type (RR 0·84, 95% CI 0·80–0·89) did not differ significantly across age groups (ptrend=0·7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (ptrend=0·01), and remained non-significant for major vascular events (ptrend=0·3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (ptrend=0·2), but appeared smaller among older than among younger individuals not known to have vascular disease (ptrend=0·05). We found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (ptrend=0·004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0·2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence. Interpretation: Statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials. Funding: Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation

Global Carbon Budget 2022

Accurate assessment of anthropogenic carbon dioxide (CO$_2$) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere in a changing climate is critical to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe and synthesize data sets and methodologies to quantify the five major components of the global carbon budget and their uncertainties. Fossil CO$_2$ emissions (E$_{FOS}$) are based on energy statistics and cement production data, while emissions from land-use change (E$_{LUC}$), mainly deforestation, are based on land use and land-use change data and bookkeeping models. Atmospheric CO$_2$ concentration is measured directly, and its growth rate (G$_{ATM}$) is computed from the annual changes in concentration. The ocean CO$_2$ sink (S$_{OCEAN}$) is estimated with global ocean biogeochemistry models and observation-based data products. The terrestrial CO$_2$ sink (S$_{LAND}$) is estimated with dynamic global vegetation models. The resulting carbon budget imbalance (B$_{IM}$), the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere, is a measure of imperfect data and understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ. For the year 2021, E$_{FOS}$ increased by 5.1 % relative to 2020, with fossil emissions at 10.1 ± 0.5 GtC yr$^{−1}$ (9.9 ± 0.5 GtC yr$^{−1}$ when the cement carbonation sink is included), and E$_{LUC}$ was 1.1 ± 0.7 GtC yr$^{−1}$, for a total anthropogenic CO$_2$ emission (including the cement carbonation sink) of 10.9 ± 0.8 GtC yr$^{−1}$ (40.0 ± 2.9 GtCO$_2$). Also, for 2021, G$_{ATM}$ was 5.2 ± 0.2 GtC yr$^{−1}$ (2.5 ± 0.1 ppm yr$^{−1}$), S$_{OCEAN}$ was 2.9  ± 0.4 GtC yr$^{−1}$, and S$_{LAND}$ was 3.5 ± 0.9 GtC yr$^{−1}$, with a B$_{IM}$ of −0.6 GtC yr$^{−1}$ (i.e. the total estimated sources were too low or sinks were too high). The global atmospheric CO$_2$ concentration averaged over 2021 reached 414.71 ± 0.1 ppm. Preliminary data for 2022 suggest an increase in E$_{FOS}$ relative to 2021 of +1.0 % (0.1 % to 1.9 %) globally and atmospheric CO$_2$ concentration reaching 417.2 ppm, more than 50 % above pre-industrial levels (around 278 ppm). Overall, the mean and trend in the components of the global carbon budget are consistently estimated over the period 1959–2021, but discrepancies of up to 1 GtC yr$^{−1}$ persist for the representation of annual to semi-decadal variability in CO$_2$ fluxes. Comparison of estimates from multiple approaches and observations shows (1) a persistent large uncertainty in the estimate of land-use change emissions, (2) a low agreement between the different methods on the magnitude of the land CO$_2$ flux in the northern extratropics, and (3) a discrepancy between the different methods on the strength of the ocean sink over the last decade. This living data update documents changes in the methods and data sets used in this new global carbon budget and the progress in understanding of the global carbon cycle compared with previous publications of this data set. The data presented in this work are available at https://doi.org/10.18160/GCP-2022 (Friedlingstein et al., 2022b)

Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p&lt;1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p&lt;5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.</p

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been

Global Carbon Budget 2023

Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere in a changing climate is critical to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe and synthesize data sets and methodology to quantify the five major components of the global carbon budget and their uncertainties. Fossil CO2 emissions (EFOS) are based on energy statistics and cement production data, while emissions from land-use change (ELUC), mainly deforestation, are based on land-use and land-use change data and bookkeeping models. Atmospheric CO2 concentration is measured directly, and its growth rate (GATM) is computed from the annual changes in concentration. The ocean CO2 sink (SOCEAN) is estimated with global ocean biogeochemistry models and observation-based f CO2 products. The terrestrial CO2 sink (SLAND) is estimated with dynamic global vegetation models. Additional lines of evidence on land and ocean sinks are provided by atmospheric inversions, atmospheric oxygen measurements, and Earth system models. The resulting carbon budget imbalance (BIM), the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere, is a measure of imperfect data and incomplete understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ. For the year 2022, EFOS increased by 0.9 % relative to 2021, with fossil emissions at 9.9 ± 0.5 Gt C yr−1 (10.2 ± 0.5 Gt C yr−1 when the cement carbonation sink is not included), and ELUC was 1.2 ± 0.7 Gt C yr−1, for a total anthropogenic CO2 emission (including the cement carbonation sink) of 11.1 ± 0.8 Gt C yr−1 (40.7±3.2 Gt CO2 yr−1). Also, for 2022, GATM was 4.6±0.2 Gt C yr−1 (2.18±0.1 ppm yr−1; ppm denotes parts per million), SOCEAN was 2.8 ± 0.4 Gt C yr−1, and SLAND was 3.8 ± 0.8 Gt C yr−1, with a BIM of −0.1 Gt C yr−1 (i.e. total estimated sources marginally too low or sinks marginally too high). The global atmospheric CO2 concentration averaged over 2022 reached 417.1 ± 0.1 ppm. Preliminary data for 2023 suggest an increase in EFOS relative to 2022 of +1.1 % (0.0 % to 2.1 %) globally and atmospheric CO2 concentration reaching 419.3 ppm, 51 % above the pre-industrial level (around 278 ppm in 1750). Overall, the mean of and trend in the components of the global carbon budget are consistently estimated over the period 1959–2022, with a near-zero overall budget imbalance, although discrepancies of up to around 1 Gt C yr−1 persist for the representation of annual to semi-decadal variability in CO2 fluxes. Comparison of estimates from multiple approaches and observations shows the following: (1) a persistent large uncertainty in the estimate of land-use changes emissions, (2) a low agreement between the different methods on the magnitude of the land CO2 flux in the northern extra-tropics, and (3) a discrepancy between the different methods on the strength of the ocean sink over the last decade. This living-data update documents changes in methods and data sets applied to this most recent global carbon budget as well as evolving community understanding of the global carbon cycle. The data presented in this work are available at https://doi.org/10.18160/GCP-2023 (Friedlingstein et al., 2023)

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P <1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P <5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.Peer reviewe

Social Factors Associated With Internalising and Externalising Behaviours in Pacific Island Children, at Age 11 Years

Pacific children experience a disproportionate number of mental health difficulties (Craig, Jackson, Han, & NZCYES Steering Committee, 2007). The World Health Organization (2013) recognizes that 50 percent of all mental health disorders have already begun before the age of 14 and are the main factors underlying disability in adolescence. Internalising and externalising behaviours in children can precede many mental health disorders that have a detrimental effect on other family members and relationships and have the potential to impair a child’s development, educational achievement and their ability to lead normal lives (Cicchetti, 1984). Therefore, it is important to examine the factors that influence the development of these problems in children of Pacific Island descent in the pre-adolescent years. It is anticipated that findings from this research project will assist health practitioners to identify and support ‘at risk’ children. Study aims The aims of this study were to (1) identify the distribution of internalising and externalising behaviours in Pacific Island children at 11- years-of-age, (2) isolate the social factors associated with internalising and externalising behaviours at 11-years of age, and (3) explore the relationships between family, childhood and socio-economic factors to determine whether specific combinations of factors potentially have a greater effect on behaviour. Design and methods The research project uses anonymous secondary data from the Pacific Islands Families Study (PIFS) which is a longitudinal, multi-disciplined study that follows a birth cohort of 1376 Pacific babies and their families born at Middlemore Hospital in 2000. For this thesis, a cross sectional design is used to examine the associations between children’s internalising and externalising behaviour and family circumstances and other variables that have been collected at the 11-year phase (Domholdt, 2005). Data collection utilised a multi-informant approach, including child, parent and teacher participants. Social variables of interest for this thesis are family characteristics (mother’s marital status and family stability, mother’s education), child characteristics (child gender, ethnicity, cultural alignment, achievement at school, peer relationships exposure to bullying and involvement) and socio economic characteristics (mothers and father’s income and household size). Results Findings from the study indicated that the majority of children show no or minimal signs of externalising or internalising behaviours. However, larger than expected numbers of children identified as being involved in bullying, feeling marginalised or having family members or friends that were part of a gang. Analysis showed that there were individual factors that increased the risk of either internalising or externalising behaviours. The study also established that there were specific combinations of factors that had cumulatively greater significance on children’s internalising and externalising behaviours. There was increased likelihood of internalising behaviours for children who were female, had good relationships with their parents, difficulties in forming good relationships with other children, did not consider themselves as being good at sport, and had family members who were part of a gang. The study found that an increased likelihood of externalising behaviours was predominantly associated with socio-economic disadvantage; children with mothers in a less stable relationships, had poor reading ability, were from a low income family, lived in crowded households and had family members who were part of a gang. Discussion Findings from this study should be considered in relation to the possible protective factors; conditions or circumstances that provide positive adaptation despite the presence of risk factors. The ability for children to maintain good quality friendships with peers and caregivers, achieve at school and in sport and develop a satisfactory level of performance in sporting activities build self-confidence are seen as having positive prognostic implications and associated with a reduction in the likelihood of internalising behaviours developing. It is suggested that improving family stability and financial circumstances will help to reduce the prevalence of externalising behaviours. Conclusion This study has successfully identified the distribution of internalising and externalising behaviours (measured as scores) in Pacific Island children at 11 years, old and isolated the social factors associated with internalising and externalising behaviours. It has also established that specific combinations of family, childhood and socio-economic factors have a greater significance. Many of the findings in this study are consistent with the literature and should assist health professionals broadly identify at-risk children. The findings from this study also support government policy initiatives that focus on addressing health and social disparities