ACE and Atherosclerosis: pieces of the puzzle

There is increasing evidence that atherosclerosis is not only involved in cardiovascular diseases (CVD) but also other diseases of the elderly such as Alzheimer’s disease (AD). Since CVD are highly fatal and usually occur earlier than Alzheimer’s disease, the co-morbidity by CVD might hamper studies on the association between atherosclerosis risk factors and AD. Here we used the inverse probability of censoring weighted analyses method to test this hypothesis, in a study on the relationship between the insertion/deletion polymorphism of the angiotensin converting enzyme gene (ACE I/D) and risk of AD. We used data from the Rotterdam Study, a prospective population based study. We .rst performed a Cox proportional hazards model including all available cardiovascular risk factors to calculate the probability of death from CVD and thereby the probability of being free from fatal CVD events. These probabilities were then used to weight the subjects who were uncensored by fatal disease by the inverse of their survival probability. In a weighted analysis we estimated the association between the ACE I/D polymorphism and AD. Among 2431 men that were free from Alzheimer’s disease at baseline, 51 persons were diagnosed for AD and 196 individual had fatal cardiovascular events without occurrence of AD during the follow up. Among 3281 women, these numbers were 89 and 159, respectively. Survival analyses showed that the association between the I allele and AD was mainly present in women (p values for trend was 0.09). In the weighted analyses the hazard ratios did not materially change in any of the gender groups. Our results indicate that the association between the I allele of the ACE gene and Alzheimer’s disease is not due to the co-morbidity effect of CVD

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions. Funding: Bill & Melinda Gates Foundation

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. Methods: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model—a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates—with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality—which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. Findings: The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2–100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1–290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1–211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4–48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3–37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7–9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. Interpretation: Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. Funding: Bill & Melinda Gates Foundation

The outcome of psur assessments of biopharmaceuticals

Background: Recent changes introduced to European legislation amend the requirements for the submission of periodic safety update reports (PSURs). However, information on the outcome of PSUR assessment is lacking. Aim: To describe the outcomes of PSUR assessments.(table present) Methods: A cross sectional analysis was performed of all PSURs and PSUR assessment reports (AR) issued between July 1st 2008 and June 30th 2010 for all biopharmaceuticals centrally approved in the European Union. PSURs and PSUR ARs were obtained from the repository of the Dutch Medicines Evaluation Board, CBG-MEB. Results: PSURs and PSUR ARs were collected for 70 products. Most products in the sample belonged to the ATC group of antineoplastic and immunomodulating agents (n = 26, 37.1%). Of the 70 PSURs included in the sample 26 (37%) covered a period of 6 months, 24 (34%) a period of 1 year and 20 (29%) a period of more than 1 year. The most common outcome of PSUR assessment was monitoring a possible safety issue, which was requested in 55 (79%) of all ARs. Of these, 23 (42%) included new safety concerns not identified before. New safety concerns were identified in 35% of the PSURs that were issued within 5 years of the international birth date (IBD) of the product, and in 40% of the PSURs submitted after 5 years of the IBD (p = 0.795). Cumulative reviews of data relating to a possible safety issue were requested in 31 (44%) of the PSUR assessments and 27 (39%) of the assessments resulted in proposals and/or requests to change the Summary of Product Characteristics (SPC). The proportion of assessments resulting in SPC changes in various subgroups is presented in table I. Conclusions: PSUR assessments are an important tool in the dialogue between regulators and marketing authorization holders. PSUR assessments are involved in the safety management of both new and well established products. New safety concerns occur throughout the lifecycle of biopharmaceuticals and may occur more often for products in different therapeutic and mechanistic classes

The contribution of periodic safety reports (PSURs) to safety related regulatory actions of biopharmaceuticals

Introduction: A periodic safety update report (PSUR), composed by marketing authorization holders and submitted to regulatory authorities on predetermined time points, provides an update of the worldwide safety experience of a pharmaceutical. Information is lacking on how PSURs contribute to safety related regulatory actions. Aim: The objective of the study is to analyze the contribution of PSUR evaluations to the initiation of safety related regulatory actions of biopharmaceuticals. Methods: We performed a retrospective analysis of all safety related type II variations of biological products centrally approved in the European Union (since 1995) for which ≥1 safety-related Direct Health Healthcare Professional Communication (DHPC) was issued until December 2009. An evaluation of the role of PSUR assessments in the initiation of safety associated regulatory actions was performed through an analysis of European Public Assessment Reports and updates of the Summary of Product Characteristics (SPC). We compared “urgent” variations, defined as variations accompanied by the distribution of a DHPC, with “less urgent” variations, i.e. safety related SPC variations for which no DHPC was distributed. For each variation we determined if any reference was made to the contribution of PSUR evaluations. We determined the data source and nature of the safety issues included in the variations. Each variation could include ≥1 safety issue and ≥1 data source could contribute in a single variation. Results: We identified 133 safety related type II variations for 15 biological products. Reference to PSUR evaluations was made in 2/24 (8.4%) of all urgent type II variations and 48/109 (44.0%) of the less urgent variations (x2, p<0.01). Data sources that contributed to the urgent variations were: 14 (58%) spontaneous reports, 9 (28%) clinical trials and 2 (8%) an analysis of pooled data. For the non-urgent variations, these were 53 (49%), 40 (37%) and 18 (17%) respectively. Overall, most of the variations concerned events from the System Organ Classes (SOCs) Infections and Infestations (32%), General Disorders and Administration Site Conditions (26%), Neoplasms (14%), Blood and Lymphatic System Disorders (14%) and Nervous System Disorders (14%). No differences in SOCs were observed between safety-related regulatory actions that did or did not result from PSUR assessments. Conclusions: The contribution of PSUR evaluations was lower in urgent safety related regulatory actions when compared with less urgent safety issues. Despite the modest role of PSURs, spontaneous reports contributed to the majority of the urgent safety related regulatory actions

Smoking-dependent effects of the angiotensin-converting enzyme gene insertion/deletion polymorphism on blood pressure.

Contains fulltext : 57916.pdf (publisher's version ) (Closed access)BACKGROUND: Studies on the role of the angiotensin-converting enzyme (ACE) gene in the development of hypertension have yielded conflicting results. Recent studies suggested that this gene might have smoking-dependent effects on the development of cardiovascular disease. OBJECTIVE: To study the relationship between the ACE insertion/deletion (I/D) polymorphism, blood pressure and risk of hypertension in current, former and non-smokers in a population-based cohort. METHODS: We included 2412 non-smokers, 2794 former smokers and 1508 current smokers, all participants in the Rotterdam Study. In each group, we assessed the relationship between the ACE I/D polymorphism, systolic (SBP) and diastolic (DBP) blood pressures and risk of hypertension. Mean blood pressures and prevalence of hypertension were compared between carriers and non-carriers of the D allele. All analyses were adjusted for age, sex, body mass index, diabetes mellitus, high-density lipoprotein cholesterol, total cholesterol and use of antihypertensive medication. RESULTS: In non-smokers and former smokers, blood pressure and the risk of hypertension did not differ significantly between genotypes. In smokers, we found a significant increase in SBP in DD carriers (139.6 +/- 22.8 mmHg) compared with II carriers (136.0 +/- 22.7 mmHg) (P = 0.04). No effect of ACE genotype was observed for DBP. The risk of hypertension was significantly increased in smokers who carried one [odds ratio (OR) 1.4, 95% confidence interval (CI) 1.0 to 1.9; P = 0.05] or two (OR 1.5, 95% CI 1.1 to 2.2; P = 0.02) copies of the D allele. CONCLUSIONS: The D allele of the ACE polymorphism is associated with a significantly increased SBP and risk of hypertension in smokers. Our study underlines the importance of gene-environment interactions in the study of candidate genes for hypertension

The impact of apolipoprotein E on dementia in persons with Down's syndrome.

Item does not contain fulltextApolipoprotein E (APOE) is consistently associated with dementia in the general population. Findings on the role of this gene in persons with Down's syndrome (DS) are inconclusive. We studied the effects of APOE on mortality and dementia in a longitudinal prospective study of a large population-based sample of persons with DS (n=425), demented and non-demented. There was evidence that APOE epsilon4 is correlated with the rate of decline in the social competence rating scale (SRZ) (p=0.04). In our population, we found overall a modest but not statistical significant effect on the prevalence of dementia (OR=1.57, 95%CI: 0.87-2.82). We did observed a significant long-term effect on the incidence of dementia (HR=4.66, 95%CI: 1.35-16.14), but for those with a follow-up less than 3 years the risk was not significantly increased: HR=0.83 (95%CI 0.35-1.94). When pooling our data in a meta-analysis, the APOE epsilon4 allele shows a 1.59-fold (95%CI: 1.19-2.12) increase in risk of dementia in persons with DS. We conclude that APOE is influencing the risk of dementia in persons with DS

The outcome of psur assessments of biopharmaceuticals

Background: Recent changes introduced to European legislation amend the requirements for the submission of periodic safety update reports (PSURs). However, information on the outcome of PSUR assessment is lacking. Aim: To describe the outcomes of PSUR assessments.(table present) Methods: A cross sectional analysis was performed of all PSURs and PSUR assessment reports (AR) issued between July 1st 2008 and June 30th 2010 for all biopharmaceuticals centrally approved in the European Union. PSURs and PSUR ARs were obtained from the repository of the Dutch Medicines Evaluation Board, CBG-MEB. Results: PSURs and PSUR ARs were collected for 70 products. Most products in the sample belonged to the ATC group of antineoplastic and immunomodulating agents (n = 26, 37.1%). Of the 70 PSURs included in the sample 26 (37%) covered a period of 6 months, 24 (34%) a period of 1 year and 20 (29%) a period of more than 1 year. The most common outcome of PSUR assessment was monitoring a possible safety issue, which was requested in 55 (79%) of all ARs. Of these, 23 (42%) included new safety concerns not identified before. New safety concerns were identified in 35% of the PSURs that were issued within 5 years of the international birth date (IBD) of the product, and in 40% of the PSURs submitted after 5 years of the IBD (p = 0.795). Cumulative reviews of data relating to a possible safety issue were requested in 31 (44%) of the PSUR assessments and 27 (39%) of the assessments resulted in proposals and/or requests to change the Summary of Product Characteristics (SPC). The proportion of assessments resulting in SPC changes in various subgroups is presented in table I. Conclusions: PSUR assessments are an important tool in the dialogue between regulators and marketing authorization holders. PSUR assessments are involved in the safety management of both new and well established products. New safety concerns occur throughout the lifecycle of biopharmaceuticals and may occur more often for products in different therapeutic and mechanistic classes

The contribution of periodic safety reports (PSURs) to safety related regulatory actions of biopharmaceuticals

Introduction: A periodic safety update report (PSUR), composed by marketing authorization holders and submitted to regulatory authorities on predetermined time points, provides an update of the worldwide safety experience of a pharmaceutical. Information is lacking on how PSURs contribute to safety related regulatory actions. Aim: The objective of the study is to analyze the contribution of PSUR evaluations to the initiation of safety related regulatory actions of biopharmaceuticals. Methods: We performed a retrospective analysis of all safety related type II variations of biological products centrally approved in the European Union (since 1995) for which ≥1 safety-related Direct Health Healthcare Professional Communication (DHPC) was issued until December 2009. An evaluation of the role of PSUR assessments in the initiation of safety associated regulatory actions was performed through an analysis of European Public Assessment Reports and updates of the Summary of Product Characteristics (SPC). We compared “urgent” variations, defined as variations accompanied by the distribution of a DHPC, with “less urgent” variations, i.e. safety related SPC variations for which no DHPC was distributed. For each variation we determined if any reference was made to the contribution of PSUR evaluations. We determined the data source and nature of the safety issues included in the variations. Each variation could include ≥1 safety issue and ≥1 data source could contribute in a single variation. Results: We identified 133 safety related type II variations for 15 biological products. Reference to PSUR evaluations was made in 2/24 (8.4%) of all urgent type II variations and 48/109 (44.0%) of the less urgent variations (x2, p<0.01). Data sources that contributed to the urgent variations were: 14 (58%) spontaneous reports, 9 (28%) clinical trials and 2 (8%) an analysis of pooled data. For the non-urgent variations, these were 53 (49%), 40 (37%) and 18 (17%) respectively. Overall, most of the variations concerned events from the System Organ Classes (SOCs) Infections and Infestations (32%), General Disorders and Administration Site Conditions (26%), Neoplasms (14%), Blood and Lymphatic System Disorders (14%) and Nervous System Disorders (14%). No differences in SOCs were observed between safety-related regulatory actions that did or did not result from PSUR assessments. Conclusions: The contribution of PSUR evaluations was lower in urgent safety related regulatory actions when compared with less urgent safety issues. Despite the modest role of PSURs, spontaneous reports contributed to the majority of the urgent safety related regulatory actions