Sperm DNA methylome abnormalities occur both pre- and post-treatment in men with Hodgkin disease and testicular cancer

Combination chemotherapy has contributed to increased survival from Hodgkin disease (HD) and testicular cancer (TC). However, questions concerning the quality of spermatozoa after treatment have arisen. While studies have shown evidence of DNA damage and aneuploidy in spermatozoa years following anticancer treatment, the sperm epigenome has received little attention. Our objectives here were to determine the impact of HD and TC, as well as their treatments, on sperm DNA methylation. Semen samples were collected from community controls (CC) and from men undergoing treatment for HD or TC, both before initiation of chemotherapy and at multiple times post-treatment. Sperm DNA methylation was assessed using genome-wide and locus-specific approaches. Imprinted gene methylation was not affected in the sperm of HD or TC men, before or after treatment. Prior to treatment, using Illumina HumanMethylation450 BeadChip (450 K) arrays, a subset of 500 probes was able to distinguish sperm samples from TC, HD and CC subjects; differences between groups persisted post-treatment. Comparing altered sperm methylation between HD or TC patients versus CC men, twice as many sites were affected in TC versus HD men; for both groups, the most affected CpGs were hypomethylated. For TC patients, the promoter region of GDF2 contained the largest region of differential methylation. To assess alterations in DNA methylation over time/post-chemotherapy, serial samples from individual patients were compared. With restriction landmark genome scanning and 450 K array analyses, some patients who underwent chemotherapy showed increased alterations in DNA methylation, up to 2 to 3 years post-treatment, when compared to the CC cohort. Similarly, a higher-resolution human sperm-specific assay that includes assessment of environmentally sensitive regions, or "dynamic sites," also demonstrated persistently altered sperm DNA methylation in cancer patients post-treatment and suggested preferential susceptibility of "dynamic" CpG sites. Distinct sperm DNA methylation signatures were present pre-treatment in men with HD and TC and may help explain increases in birth defects reported in recent clinical studies. Epigenetic defects in spermatozoa of some cancer survivors were evident even up to 2 years post-treatment. Abnormalities in the sperm epigenome both pre- and post-chemotherapy may contribute to detrimental effects on future reproductive health. The online version contains supplementary material available at 10.1186/s13148-022-01417-1

StrokeCog Markov Model Projected Prevalent and Incident Cases of Stroke and Poststroke Cognitive Impairment to 2035 in Ireland

Background and Purpose: Cognitive impairment no dementia (CIND) and dementia are common stroke outcomes, with significant health and societal implications for aging populations. These outcomes are not included in current epidemiological models. We aimed to develop an epidemiological model to project incidence and prevalence of stroke, poststroke CIND and dementia, and life expectancy, in Ireland to 2035, informing policy and service planning. Methods: We developed a probabilistic Markov model (the StrokeCog model) applied to the Irish population aged 40 to 89 years to 2035. Data sources included official population and hospital-episode statistics, longitudinal cohort studies, and published estimates. Key assumptions were varied in sensitivity analysis. Results were externally validated against independent sources. The model tracks poststroke progression into health states characterized by no cognitive impairment, CIND, dementia, disability, stroke recurrence, and death. Results: We projected 69 051 people with prevalent stroke in Ireland in 2035 (22.0 per 1000 population [95% CI, 20.8-23.1]), with 25 274 (8.0 per 1000 population [95% CI, 7.1-9.0]) of those projected to have poststroke CIND, and 12 442 having poststroke dementia (4.0 per 1000 population [95% CI, 3.2-4.8]). We projected 8725 annual incident strokes in 2035 (2.8 per 1000 population [95% CI, 2.7-2.9]), with 3832 of these having CIND (1.2 per 1000 population [95% CI, 1.1-1.3]), and 1715 with dementia (0.5 per 1000 population [95% CI, 0.5-0.6]). Life expectancy for stroke survivors at age 50 was 23.4 years (95% CI, 22.3-24.5) for women and 20.7 (95% CI, 19.5-21.9) for men. Conclusions: This novel epidemiological model of stroke, poststroke CIND, and dementia draws on the best available evidence. Sensitivity analysis indicated that findings were robust to assumptions, and where there was uncertainty a conservative approach was taken. The StrokeCog model is a useful tool for service planning and cost-effectiveness analysis and is available for adaptation to other national contexts.Peer reviewe

Analysing the Large Decline in Coronary Heart Disease Mortality in the Icelandic Population Aged 25-74 between the Years 1981 and 2006

BACKGROUND: Coronary heart disease (CHD) mortality rates have been decreasing in Iceland since the 1980s. We examined how much of the decrease between 1981 and 2006 could be attributed to medical and surgical treatments and how much to changes in cardiovascular risk factors. METHODOLOGY: The previously validated IMPACT CHD mortality model was applied to the Icelandic population. The data sources were official statistics, national quality registers, published trials and meta-analyses, clinical audits and a series of national population surveys. PRINCIPAL FINDINGS: Between 1981 and 2006, CHD mortality rates in Iceland decreased by 80% in men and women aged 25 to 74 years, which resulted in 295 fewer deaths in 2006 than if the 1981 rates had persisted. Incidence of myocardial infarction (MI) decreased by 66% and resulted in some 500 fewer incident MI cases per year, which is a major determinant of possible deaths from MI. Based on the IMPACT model approximately 73% (lower and upper bound estimates: 54%-93%) of the mortality decrease was attributable to risk factor reductions: cholesterol 32%; smoking 22%; systolic blood pressure 22%, and physical inactivity 5% with adverse trends for diabetes (-5%), and obesity (-4%). Approximately 25% (lower and upper bound estimates: 8%-40%) of the mortality decrease was attributable to treatments in individuals: secondary prevention 8%; heart failure treatments 6%; acute coronary syndrome treatments 5%; revascularisation 3%; hypertension treatments 2%, and statins 0.5%. CONCLUSIONS: Almost three quarters of the large CHD mortality decrease in Iceland between 1981 and 2006 was attributable to reductions in major cardiovascular risk factors in the population. These findings emphasize the value of a comprehensive prevention strategy that promotes tobacco control and a healthier diet to reduce incidence of MI and highlights the potential importance of effective, evidence based medical treatments

Contrasting cardiovascular mortality trends in Eastern Mediterranean populations: contributions from risk factor changes and treatments

Background Middle income countries are facing an epidemic of non-communicable diseases, especially coronary heart disease (CHD). We used a validated CHD mortality model (IMPACT) to explain recent trends in Tunisia, Syria, the occupied Palestinian territory (oPt) and Turkey. Methods Data on populations, mortality, patient numbers, treatments and risk factor trends from national and local surveys in each country were collated over two time points (1995–97; 2006–09); integrated and analysed using the IMPACT model. Results Risk factor trends: Smoking prevalence was high in men, persisting in Syria but decreasing in Tunisia, oPt and Turkey. BMI rose by 1–2 kg/m2 and diabetes prevalence increased by 40%–50%. Mean systolic blood pressure and cholesterol levels increased in Tunisia and Syria. Mortality trends: Age-standardised CHD mortality rates rose by 20% in Tunisia and 62% in Syria. Much of this increase (79% and 72% respectively) was attributed to adverse trends in major risk factors, occurring despite some improvements in treatment uptake. CHD mortality rates fell by 17% in oPt and by 25% in Turkey, with risk factor changes accounting for around 46% and 30% of this reduction respectively. Increased uptake of community treatments (drug treatments for chronic angina, heart failure, hypertension and secondary prevention after a cardiac event) accounted for most of the remainder. Discussion CHD death rates are rising in Tunisia and Syria, whilst oPt and Turkey demonstrate clear falls, reflecting improvements in major risk factors with contributions from medical treatments. However, smoking prevalence remains very high in men; obesity and diabetes levels are rising dramatically

Regards français sur l'Irlande

This article originated in the reading, some time ago, of two French novels set in Ireland. The problem raised was simple : how present a foreign country and maintain communication with one's potential readers ? First comes the need for accuracy while striving to limit details to what is comprehensible to one's compatriots. More important are a profound understanding of a different world and, especially, the choice of a technique helping to bridge the gap between two traditions. Obviously authors who have lived a long time in the foreign land and are steeped in its literature and myths are in a situation other than that of those who have made a brief stay. The quality of the novels studied here clearly varies but, in general, they succeed in conveying, to an Irish reader, some unexpected aspects of his land.La lecture faite il y a quelque temps de deux romans français dont l'action se passe en Irlande est à l'origine de cet article. Elle fit naître une question : comment présenter un pays étranger et, en même temps, maintenir ses rapports avec ses lecteurs potentiels ? Tout d'abord se pose le problème de l'exactitude, en se limitant autant que possible à des détails accessibles à ses compatriotes. Plus importants restent une compréhension profonde d'un monde différent et le choix d'une technique permettant de combler la brèche entre deux traditions. Évidemment les auteurs qui ont vécu longtemps dans le pays étranger, ceux qui ont été imprégnés de sa littérature et de ses mythes, sont dans une situation différente de ceux qui n'y ont fait qu'un bref séjour. Les romans étudiés ici varient en qualité, mais souvent arrivent à présenter à un lecteur irlandais une idée inattendue de certains aspects de son pays.O'Flaherty Kathleen. Regards français sur l'Irlande. In: Études irlandaises, n°13-2, 1988. pp. 31-43

Decline in Coronary Mortality in Sweden between 1986 and 2002: Comparing Contributions from Primary and Secondary Prevention.

The relative importance of risk factor reduction in healthy people (primary prevention) versus that in patients with coronary heart disease (secondary prevention) has been debated. We aimed to quantify the contribution of the two.We used the previously validated IMPACT model to estimate contributions from primary prevention (reducing risk factors in the population, particularly smoking, cholesterol and systolic blood pressure) and from secondary prevention (reducing risk factors in coronary heart disease patients) in the Swedish population.Between 1986 and 2002, about 8,690 fewer deaths were related to changes in the three major risk factors. Population cholesterol fell by 0.64 mmol/L, with approximately 5,210 fewer deaths attributable to diet changes (4,470 in healthy people740 in patients.) plus 810 to statin treatment (200 in healthy people, 610 in patients). Overall smoking prevalence decreased by 10.3%, resulting in 1,195 fewer deaths, attributable to smoking cessation (595 in healthy people, 600 in patients). Mean population systolic blood pressure fell by 2.6 mmHg, resulting in 900 fewer deaths (865 in healthy people, 35 in patients), plus 575 fewer deaths attributable to antihypertensive medication in healthy people. The majority of falls in deaths attributable to risk factors occurred in people without known heart disease: 6,705 fewer deaths compared with 1,985 fewer deaths in patients (secondary prevention), emphasizing the importance of promoting health interventions in the general population.The largest effects on mortality came from primary prevention, giving markedly larger mortality reductions than secondary prevention

Explaining the decline in coronary heart disease mortality in Portugal between 1995 and 2008.

BACKGROUND: We aimed to quantify the contribution of treatments and risk factors to the decline in coronary heart disease (CHD) mortality in Portugal, 1995 to 2008. METHODS AND RESULTS: The IMPACT mortality model was used to integrate data on trends in uptake of treatments and exposure to risk factors to explain the CHD mortality variation. Between 1995 and 2008, CHD mortality rates in Portugal decreased by 29% in men and 21% in women aged 25 to 84 years, corresponding to 3760 fewer deaths in 2008 than expected if 1995 mortality rates had persisted. Approximately 92% of the estimated decrease in number of deaths could be explained by the model; the remaining 8% were attributed to changes in unmeasured factors. Approximately 50% of the decrease explained by the model was attributable to an increased uptake of treatments, mainly antihypertensive medication (12%) and initial treatments after an acute myocardial infarction (10%), and 42% to population risk factor reductions, mainly blood pressure (27% in men and 60% in women), total cholesterol (14% in men and 5% in women), and smoking (11% in men). However, these reductions were partially offset by adverse trends in diabetes mellitus (18% in men and 2% in women) and obesity (6% in men and 5% in women) and smoking (2% in women). CONCLUSIONS: In this low CHD risk population, modern treatments explained approximately half of the overall decline in CHD deaths. The biggest contributions to the CHD mortality decline came from secular decreases in blood pressure and increases in hypertension treatment

Explaining income-related inequalities in cardiovascular risk factors in Tunisian adults during the last decade: comparison of sensitivity analysis of logistic regression and Wagstaff decomposition analysis

BACKGROUND: It is important to quantify inequality, explain the contribution of underlying social determinants and to provide evidence to guide health policy. The aim of the study is to explain the income-related inequalities in cardiovascular risk factors in the last decade among Tunisian adults aged between 35 and 70 years old. METHODS: We performed the analysis by applying two approaches and compared the results provided by the two methods. The methods were global sensitivity analysis (GSA) using logistic regression models and the Wagstaff decomposition analysis. RESULTS: Results provided by the two methods found a higher risk of cardiovascular diseases and diabetes in those with high socio-economic status in 2005. Similar results were observed in 2016. In 2016, the GSA showed that education level occupied the first place on the explanatory list of factors explaining 36.1% of the adult social inequality in high cardiovascular risk, followed by the area of residence (26.2%) and income (15.1%). Based on the Wagstaff decomposition analysis, the area of residence occupied the first place and explained 40.3% followed by income and education level explaining 19.2 and 14.0% respectively. Thus, both methods found similar factors explaining inequalities (income, educational level and regional conditions) but with different rankings of importance. CONCLUSIONS: The present study showed substantial income-related inequalities in cardiovascular risk factors and diabetes in Tunisia and provided explanations for this. Results based on two different methods similarly showed that structural disparities on income, educational level and regional conditions should be addressed in order to reduce inequalities