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BACKGROUND Low birthweight and preterm birth are associated with an increased risk of neonatal death and chronic conditions across the life course. Reducing these adverse birth outcomes is a global public health priority and requires strategies to improve health care during pregnancy. We aimed to assess the effect of a Swiss health policy expansion fully covering illness-related costs during pregnancy on health outcomes in newborn babies. METHODS We implemented a quasi-experimental difference in regression discontinuity design to assess the effect of expansion of Swiss health insurance (on March 1, 2014), to fully cover health-care costs during pregnancy and 8 weeks postpartum, on neonatal outcomes. Before this reform, only costs specific to the standard monitoring of a normal pregnancy were covered. Babies born before March 1, 2014, and their mothers were assigned to the unexposed group, and babies born on or after March 1, 2014, and their mothers were assigned to the exposed group. We included nearly all children born 2011-19 in Switzerland within a period of 9 months around the date March 1, 2014, and control years 2012, 2016, and 2018. Outcomes were birthweight, low birthweight, very low birthweight, gestational age, preterm or extremely preterm birth, and neonatal death. We estimated the intention-to-treat effect of the policy using parametric regression models. FINDINGS 61 910 children were born 9 months before and 63 991 were born 9 months after March 1, 2014. 382 861 children were born in the same time period around the three control dates. In the period before policy implementation, mean birthweight was 3289 g, gestational age was 275 days, and 6·5% of children had low birthweight, 1·0% very low birthweight, 7·1% were preterm, 0·4% were extremely preterm, and 0·3% died within the first 28 days of life. After initiation of the policy (vs before) mean birthweight increased by 23 g (95% CI 5 to 40) and the predicted proportion of low birthweight births decreased by 0·81% (0·14 to 1·48) and of very low birthweight births decreased by 0·41% (0·17 to 0·65). The effect on very low birthweight was not robust in sensitivity analyses. The policy had a negligible effect on gestational age (mean difference 1 day, 95% CI 0 to 1) and no clear effects on the other examined outcomes. The change in predicted proportion for preterm births was -0·39% (95% CI -1·2 to 0·38), for extremely preterm births was -0·09% (-0·27 to 0·08), and for neonatal death was -0·07% (-0·2 to 0·07). INTERPRETATION Free access to prenatal care in Switzerland reduced the risk of some adverse health outcomes in newborn babies. Expanding health-care coverage is a relevant health system intervention to reduce the risk of adverse health outcomes in the newborn baby and, potentially, across the life course. FUNDING Swiss National Science Foundation.

Mortality rates due to coronary heart disease (CHD) and stroke have declined in the last century in high-income countries, including Switzerland. However, these rates have plateaued in several countries. We assessed CHD and stroke mortality trends (1995–2018) in Switzerland. We estimated annual rate changes via JoinPoint regression. Rates decreased steadily in most sex and age groups; however, in those aged 60–74, stroke rates plateaued after 2012 among men and CHD rates plateaued after 2015 among women. Cardiovascular mortality continues to decrease in most of the Swiss population. Prevention efforts should be maintained, especially in individuals aged 60–74.

Adverse socioeconomic circumstances negatively affect the functioning of biological systems, but the underlying mechanisms remain only partially understood. Here, we explore the associations between life-course socioeconomic factors and four markers of epigenetic aging in a population-based setting.We used data from a population-based study conducted in Switzerland (SKIPOGH) to assess the association between childhood, adulthood, and life-course socioeconomic indicators, and blood-derived markers of epigenetic aging (Levine’s, DunedinPoAm38, GrimAge epigenetic age acceleration (EAA) and the mortality risk score (MS)). We used mixed regression to explore the associations between socioeconomic indicators and markers of epigenetic aging independently, and counterfactual mediation to investigate the mechanisms underlying the life-course socioeconomic gradient in epigenetic aging.Individuals reporting a low father’s occupation, adverse financial conditions in childhood, a low income, having financial difficulties, or experiencing unfavorable socioeconomic trajectories were epigenetically older than their more advantaged counterparts. Specifically, this corresponded to an average increase of 1.0-1.5 years for Levine’s epigenetic age when compared to chronological age, 1.1-1.5 additional years for GrimAge, 5%-8% higher DunedinPoAm38 EAA, and 2%-5% higher MS score. By exploring the life-course mechanisms underlying the socioeconomic gradient in epigenetic aging, we found that both childhood and adulthood socioeconomic factors contributed to epigenetic aging, and that detrimental lifestyle factors mediated the relation between socioeconomic circumstances in adulthood and EAA.Our study provides novel empirical evidence for a “sensitive-period” life-course model, whereby adverse socioeconomic circumstances in childhood and adulthood negatively affected epigenetic aging. Counterfactual mediation analyses further showed that the effect of socioeconomic factors in adulthood operated through detrimental lifestyle factors, whereas associations involving early-life socioeconomic factors were less clear.

Multimorbidity disproportionally affects individuals exposed to socioeconomic disadvantage. It is, however, unclear how adverse socioeconomic conditions (SEC) at different periods of the life course predict the occurrence of multimorbidity in later life. In this scoping review, we investigate the association between life course SEC and later-life multimorbidity, and assess to which extent it supports different life course causal models (critical period, sensitive period, accumulation, pathway, or social mobility). We identified four studies (25,209 participants) with the first measure of SEC in childhood (before age 18). In these four studies, childhood SEC was associated with multimorbidity in old age, and the associations were partially or fully attenuated upon adjustment for later-life SEC. These results are consistent with the sensitive period and the pathway models. We identified five studies (91,236 participants) with the first measure of SEC in young adulthood (after age 18), and the associations with multimorbidity in old age as well as the effects of adjustment for later-life SEC differed from one study to the other. Among the nine included studies, none tested the social mobility or the accumulation models. In conclusion, SEC in early life could have an effect on multimorbidity, attenuated at least partly by SEC in adulthood.

Background Lung function is an important predictor of health and a marker of physical functioning at older ages. This study aimed to quantify the years of lung function lost according to disadvantaged socioeconomic conditions across the life-course. Methods This multicohort study used harmonised individual-level data from six European cohorts with information on life-course socioeconomic disadvantage and lung function assessed by forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). 70 496 participants (51% female) aged 18–93 years were included. Socioeconomic disadvantage was measured in early life (low paternal occupational position), early adulthood (low educational level) and adulthood (low occupational position). Risk factors for poor lung function (e.g. smoking, obesity, sedentary behaviour, cardiovascular and respiratory diseases) were included as potential mediators. The years of lung function lost due to socioeconomic disadvantage were computed at each life stage. Results Socioeconomic disadvantage during the life-course was associated with a lower FEV1. By the age of 45 years, individuals experiencing disadvantaged socioeconomic conditions had lost 4–5 years of healthy lung function versus their more advantaged counterparts (low educational level −4.36 (95% CI −7.33–−2.37) for males and −5.14 (−10.32–−2.71) for females; low occupational position −5.62 (−7.98–−4.90) for males and −4.32 (−13.31–−2.27) for females), after accounting for the risk factors for lung function. By the ages of 65 years and 85 years, the years of lung function lost due to socioeconomic disadvantage decreased by 2–4 years, depending on the socioeconomic indicator. Sensitivity analysis using FVC yielded similar results to those using FEV1. Conclusion Life-course socioeconomic disadvantage is associated with lower lung function and predicts a significant number of years of lung function loss in adulthood and at older ages. This work was supported by European regional development fund through the Operational Programme Competitiveness and Internationalisation and national funding from the Foundation for Science and Technology (FCT; Portuguese Ministry of Science, Technology and Higher Education) under the EPIUnit, Instituto de Saúde Pública da Universidade do Porto, Portugal (POCI-01-0145-FEDER-006862; reference: UID/DTP/04750/2019). It is also supported by the European Commission (Horizon 2020 grant number 633666), PhD grant SFRH/BD/103726/2014 (V. Rocha) co-funded by FCT and the POCH/FSE Program, FCT contract info:eu-repo/grantAgreement/FCT/CEEC IND 2017/CEECIND/01516/2017/CP1406/CT0001/PT/CP1406/CT0001 (S. Fraga), and by the University of Lausanne (Pro-Femmes grant, S. Stringhini). M. Kivimaki was supported by the Medical Research Council (K013351, R024227), the US National Institute on Aging (R01AG056477), NordForsk, the Academy of Finland (311492), and Helsinki Institute of Life Science during the conduct of the study. The CoLaus|PsyCoLaus study is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 3200B0_105993, 3200B0_118308, 33CSCO_122661, 33CS30_139468 and 33CS30_14840). The Constances cohort is supported by the Caisse nationale d'assurance maladie and by a grant from the Agence nationale de la recherche (ANR-11-INBS-0002). Funding information for this article has been deposited with the Crossref Funder Registry.

Adverse socioeconomic circumstances negatively affect the functioning of biological systems, but the underlying mechanisms remain only partially understood. Here, we explore the associations between life-course socioeconomic factors and four markers of epigenetic aging in a population-based setting. We included 684 participants (52 % women, mean age 52.6 ± 15.5 years) from a population and family-based Swiss study. We used nine life-course socioeconomic indicators as the main exposure variables, and four blood-derived, second generation markers of epigenetic aging as the outcome variables (Levine's DNAmPhenoAge, DunedinPoAm38, GrimAge epigenetic age acceleration (EAA), and the mortality risk score (MS)). First, we investigated the associations between socioeconomic indicators and markers of epigenetic aging via mixed-effect linear regression models, adjusting for age, sex, participant's recruitment center, familial structure (random-effect covariate), seasonality of blood sampling, and technical covariates. Second, we implemented counterfactual mediation analysis to investigate life-course and intermediate mechanisms underlying the socioeconomic gradient in epigenetic aging. Effect-size estimates were assessed using regression coefficients and counterfactual mediation parameters, along with their respective 95 % confidence intervals. Individuals reporting a low father's occupation, adverse financial conditions in childhood, a low income, having financial difficulties, or experiencing unfavorable socioeconomic trajectories were epigenetically older and had a higher mortality risk score than their more advantaged counterparts. Specifically, this corresponded to an average increase of 1.1-1.5 years for Levine's epigenetic age (β and 95 %CI range, β (minimum and maximum): 1.1-1.5 95 %CI[0.0-0.2; 2.3-3.0]), 1.1-1.5 additional years for GrimAge (β: 1.1-1.5 95 %CI[0.2-0.6; 1.9-3.0]), a 1-3 % higher DunedinPoAm38 age acceleration (β: 0.01-0.03 95 %CI[0.00; 0.03-0.04]), and a 10-50 % higher MS score (β: 0.1-0.4 95 %CI[0.0-0.2; 0.3-0.4]) for the aforementioned socioeconomic indicators. By exploring the life-course mechanisms underlying the socioeconomic gradient in epigenetic aging, we found that both childhood and adulthood socioeconomic factors contributed to epigenetic aging, and that detrimental lifestyle factors mediated the relation between socioeconomic circumstances in adulthood and EAA (31-89 % mediated proportion). This study provides emerging evidence for an association between disadvantaged life-course socioeconomic circumstances and detrimental epigenetic aging patterns, supporting the "sensitive-period" life-course model. Counterfactual mediation analyses further indicated that the effect of socioeconomic factors in adulthood operates through detrimental lifestyle factors, whereas associations involving early-life socioeconomic factors were less clear.

Publisher Copyright: Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved. BACKGROUND: Few studies have examined the interactions between individual socioeconomic position and neighbourhood deprivation and the findings so far are heterogeneous. Using a large sample of diverse cohorts, we investigated the interaction effect of neighbourhood socioeconomic deprivation and individual socioeconomic position, assessed using education, on mortality. METHODS: We did a longitudinal multicohort analysis that included six cohort studies participating in the European LIFEPATH consortium: the CoLaus (Lausanne, Switzerland), E3N (France), EPIC-Turin (Turin, Italy), EPIPorto (Porto, Portugal), Melbourne Collaborative Cohort Study (Melbourne, VIC, Australia), and Whitehall II (London, UK) cohorts. All participants with data on mortality, educational attainment, and neighbourhood deprivation were included in the present study. The data sources were the databases of each cohort study. Poisson regression was used to estimate the mortality rates and associations (relative risk, 95% CIs) with neighbourhood deprivation (Q1 being least deprived to Q5 being the most deprived). Baseline educational attainment was used as an indicator of individual socioeconomic position. Estimates were combined using pooled analysis and the relative excess risk due to the interaction was computed to identify additive interactions. FINDINGS: The cohorts comprised a total population of 168 801 individuals. The recruitment dates were 2003-06 for CoLaus, 1989-91 for E3N, 1992-98 for EPIC-Turin, 1999-2003 for EPIPorto, 1990-94 for MCCS, and 1991-94 for Whitehall II. We use baseline data only and mortality data obtained using record linkage. Age-adjusted mortality rates were higher among participants residing in more deprived neighbourhoods than those in the least deprived neighbourhoods (Q1 least deprived neighbourhoods, 369·7 per 100 000 person-years [95% CI 356·4-383·2] vs Q5-most deprived neighbourhoods 445·7 per 100 000 person-years [430·2-461·7]), but the magnitude of the association varied according to educational attainment (relative excess risk due to interaction=0·18, 95% CI 0·08-0·28). The relative risk for Q5 versus Q1 was 1·31 (1·23-1·40) among individuals with primary education or less, but less pronounced among those with secondary education (1·12; 1·04-1·21) and tertiary education (1·16; 1·07-1·27). Associations remained after adjustment for individual-level factors, such as smoking, physical activity, and alcohol intake, among others. INTERPRETATION: Our study suggests that the detrimental health effect of living in disadvantaged neighbourhoods is more pronounced among individuals with low education attainment, amplifying social inequalities in health. This finding is relevant to policies aimed at reducing health inequalities, suggesting that these issues should be addressed at both the individual level and the community level. FUNDING: The European Commission, European Regional Development Fund, the Portugese Foundation for Science and Technology.

Aims: Sleep disturbances exhibit a strong social patterning, and inadequate sleep has been associated with adverse health outcomes, including cardiovascular disorders (CVD). However, the contribution of sleep to socioeconomic inequalities in CVD is unclear. This study pools data from eight European cohorts to investigate the role of sleep duration in the association between life-course socioeconomic status (SES) and CVD. Methods and results: We used cross-sectional data from eight European cohorts, totalling 111 205 participants. Life-course SES was assessed using father’s and adult occupational position. Self-reported sleep duration was categorized into recommended (6–8.5 h/night), long (>8.5 h/night), and short (

Educational inequalities in mortality have been observed for decades, however the underlying biological mechanisms are not well known. We assessed the mediating role of altered aging of immune cells functioning captured by DNA methylation changes in blood (known as epigenetic clocks) in educational associated all-cause mortality. Data were from eight prospective population-based cohort studies, representing 13,021 participants. We found educational inequalities in mortality were larger for men than for women, estimated by hazard differences and ratios. Epigenetic clocks explained approximately 50% of educational inequalities in mortality for men, while the proportion was small for women. Most of this mediation was explained by differential effects of unhealthy lifestyles and morbidities of the WHO risk factors for premature mortality. These results support DNA methylation-based epigenetic aging as a signature of educational inequalities in life expectancy emphasizing the need for policies to address the unequal social distribution of these WHO risk factors.

The life course epidemiology is an interdisciplinary approach to health resulting from the convergence of centres of interest in social epidemiology, natural sciences (biology, genetics) and social sciences (psychology, sociology, history). It examines the origin of chronic diseases in the past of individuals, considering the duration and timing of exposure to different risk factors, throughout the life of the individual, from gestation to an advanced age. The life course epidemiology is interested as much in bio-psycho-social determinants as in environmental and societal influences on the trajectories of health and various diseases, either somatic or psychic.La perspective dite des parcours de vie en épidémiologie (life course epidemiology) est une approche interdisciplinaire de la santé fruit de la convergence de l’épidémiologie sociale, des sciences naturelles (biologie, génétique) et des sciences sociales (psychologie, sociologie, histoire). Elle invite à considérer l’origine des maladies chroniques dans le passé des individus, en tenant compte de la durée et du timing de l’exposition à différents facteurs de risque, ceci tout au long de la vie de l’individu, de la gestation à un âge avancé. Dans cette perspective des parcours de vie, l’épidémiologie s’intéresse autant aux déterminants bio-psychosociaux qu’aux influences environnementales et sociétales sur les trajectoires de santé et de différentes maladies tant somatiques que psychiques.

As compared with vaginal delivery (VD), caesarean section (CS) birth could be associated with increased risk of obesity in young adult offspring. We aimed to evaluate this association by updating data from a systematic review with meta-analysis of observational studies. From 3774 records identified in PubMed and Embase, we retained six studies and added five studies from the last systematic review, for a total of 11 studies. Crude estimates of the association were retrieved from nine cohort studies (n = 143,869), and maximally adjusted estimates were retrieved from eight cohort studies. Young adults born by CS had higher risk of obesity (body mass index [BMI] ≥ 30 kg/m2 ) than young adults born by VD, corresponding to a crude pooled risk ratio (RR) of 1.30 [95% confidence interval (CI) 1.13 to 1.50] and a maximally adjusted pooled RR of 1.22 [95% CI 1.02 to 1.46]. In a sensitivity analysis pooling, five studies that included maternal prepregnancy BMI, a major potential confounding factor, in the set of controlled covariates, the RR was 1.08 [95% CI 0.92 to 1.27]. We concluded that the association between CS and obesity in young adulthood was mostly explained by confounding from maternal prepregnancy BMI.

Background Previous investigations have reported that adverse socioeconomic circumstances across the life-course lead to the alteration of major biological processes, eventually resulting in a higher disease risk and premature death. In particular, a low life-course socioeconomic position (SEP) has been associated with a modified epigenetic signature of loci involved in inflammation, the physiological response to stress, and other regulatory processes. Methods In this study, we investigated the association between nine indicators of SEP across the life-course and the differential methylation of 451'000 genome-wide CpG markers, using data from 690 adults included in a Swiss population-based study. We further examined the interrelations between the SEP-related CpGs, and the biological pathways in which the identified markers are involved. Results Three SEP indicators in adulthood were associated the differential methylation of 161 genome-wide CpG markers, whereby 156 CpGs were less methylated in people with low versus high SEP. Among the identified CpGs, a substantial proportion of markers were no longer associated with SEP upon accounting for health behaviors and cardiometabolic disorders. In addition, the identified CpGs were found to be involved in immune, inflammatory, and cancer-related processes. Conclusions Our results support the hypothesis that adverse socioeconomic circumstances may lead to the dysregulation of inflammatory processes, eventually resulting in the occurrence of serious chronic conditions such as atherosclerosis, diabetes, or cancer. Key messages Socioeconomic position is a major determinant of health-related outcomes. Epigenetic modifications may constitute a biological mechanism through which socioeconomic circumstances affect health.

As a powerful phenotyping technology, metabolomics provides new opportunities in biomarker discovery through metabolome-wide association studies (MWAS) and identification of metabolites having regulatory effect in various biological processes. While MS-based metabolomics assays are endowed with high-throughput and sensitivity, large-scale MWAS are doomed to long-term data acquisition generating an overtime-analytical signal drift that can hinder the uncovering of true biologically relevant changes.We developed “dbnorm”, a package in R environment, which allows visualization and removal of signal heterogeneity from large metabolomics datasets. “dbnorm” integrates advanced statistical tools to inspect dataset structure, at both macroscopic (sample batch) and microscopic (metabolic features) scales. To compare model performance on data correction, “dbnorm” assigns a score, which allows the straightforward identification of the best fitting model for each dataset. Herein, we show how “dbnorm” efficiently removes signal drift among batches to capture the true biological heterogeneity of data in two large-scale metabolomics studies.

Background: Lung function is an important predictor of health and a marker of physical functioning at older ages. This study aimed to quantify the years of lung function lost according to disadvantaged socioeconomic conditions across life-course. Methods: This multicohort study used harmonised individual-level data from six European cohorts with information on life-course socioeconomic disadvantage and lung function assessed by FEV1 and FVC. 70496 participants (51% women) aged 18-93 years were included. Socioeconomic disadvantage was measured in early life (low paternal occupational position), early adulthood (low educational level), and adulthood (low occupational position). Risk factors for poor lung function (i.e., smoking, obesity, sedentary behaviour, cardiovascular and respiratory diseases) were included as potential mediators. The years of lung function lost due to socioeconomic disadvantage were computed at each life stage. Findings: Socioeconomic disadvantage during life-course was associated with a lower FEV1. By age 45, individuals experiencing disadvantaged socioeconomic conditions had lost 4 to 5 years of healthy lung function vs their more advantaged counterparts (low educational level: -4.36 [95% CI -7.33 to -2.37] for men and -5.14 [-10.32 to -2.71] for women; low occupational position: -5.62 [-7.98 to -4.90] for men and -4.32 [-13.31 to -2.27] for women), after accounting for the risk factors for lung function. By ages 65 and 85, the years lung function lost due to socioeconomic disadvantage decreased by 2 to 4 years, depending on the socioeconomic indicator. Interpretation: Life-course socioeconomic disadvantage is associated with lower lung function and predicts a considerable number of years of lung function loss in adulthood and older ages. Funding: Foundation for Science and Technology; European Commission; University of Lausanne; Medical Research Council; US National Institute on Aging; NordForsk; Helsinki Institute of Life Science; GlaxoSmithKline; Swiss National Science Foundation; Agence Nationale de la recherche. Declaration of Interests: None declared. Ethics Approval Statement: The relevant local or national ethics committees approved each study, and all participants gave written informed consent to participate.

Funded by the European Commission Horizon 2020 programme, the Lifepath research consortium aimed to investigate the effects of socioeconomic inequalities on the biology of healthy aging. The main research questions included the impact of inequalities on health, the role of behavioral and other risk factors, the underlying biological mechanisms, the efficacy of selected policies, and the general implications of our findings for theories and policies. The project adopted a life-course and comparative approach, considering lifetime effects from childhood and adulthood, and pooled data on up to 1.7 million participants of longitudinal cohort studies from Europe, USA, and Australia. These data showed that socioeconomic circumstances predicted mortality and functional decline as strongly as established risk factors currently targeted by global prevention programmes. Analyses also looked at socioeconomically patterned biological markers, allostatic load, and DNA methylation using richly phenotyped cohorts, unraveling their association with aging processes across the life-course. Lifepath studies suggest that socioeconomic circumstances are embedded in our biology from the outset—i.e., disadvantage influences biological systems from molecules to organs. Our findings have important implications for policy, suggesting that (a) intervening on unfavorable socioeconomic conditions is complementary and as important as targeting well-known risk factors, such as tobacco and alcohol consumption, low fruit and vegetable intake, obesity and a sedentary lifestyle, and that (b) effects of preventive interventions in early life integrate interventions in adulthood. The report has an executive summary that refers to the different sections of the main paper. This study was supported by the European Commission (Horizon 2020 grant number 633666) and the Swiss State Secretariat for Education, Research and Innovation SERI.

Disadvantaged socioeconomic conditions in childhood heighten systemic inflammatory levels in adulthood; however, life-course mechanisms underlying this association are largely unknown. In the present observational study, we investigated the roles of adulthood socioeconomic and lifestyle factors in mediating this association. Participants were from two prospective Swiss population-based cohorts (N = 5,152, mean age 60 years). We estimated the total effect of paternal occupational position on adult heightened systemic inflammatory levels (C-reactive protein>3 mg/L), and the indirect effects via adulthood socioeconomic positions (SEPs: education and occupational position), financial hardship, and lifestyle factors (body mass index, smoking status, physical inactivity, and alcohol consumption). We estimated odds ratio (OR) and proportion mediated using counterfactual-based mediation models. Individuals whose father had a low occupational position had an OR of 1.51 [95% confidence interval (CI): 1.25, 1.84] for heightened inflammation compared to their more advantaged counterparts. This was jointly mediated (33 [95% CI: 14, 69]%) by adulthood SEPs, whereby the pathway through education followed by occupational position mediated 30 [95% CI: 11, 64]%, while the pathway via occupational position only mediated 3 [95% CI: 4, 13]%. Individuals with the lowest life-course SEPs had an OR of 2.27 [95% CI: 1.71, 2.98] for heightened inflammation compared to having the highest life-course SEPs. This was jointly mediated (63 [95% CI: 44, 97]%) by financial hardship and lifestyle factors. Our study supports a cumulative effect of life-course SEPs on adult heightened systemic inflammation along the pathway paternal occupational position -> education -> adult occupational position. Financial hardship and lifestyle factors in adulthood mediate half of that effect.

Background Adverse socioeconomic conditions in childhood affect systemic low-grade inflammation in adulthood. Studies in animals and humans suggest that socioeconomic conditions get under the skin from early life thus contributing to shape pro-inflammatory phenotypes. Although the existence of socioeconomic differences in gene regulation of the immune function have been described previously, no study has so far assessed the extent to which these differences actually explain socioeconomic variations in inflammatory markers. Methods First, we ran 2-sample Mendelian Randomization (MR) methods to identify putative genes whose expression drives C-reactive protein (CRP) levels in blood. We used two databases with summary statistics of associations between single nucleotide polymorphisms and gene expression (eQTLGen, N = 31,486 individuals) and CRP (CHARGE, N = 148,164 individuals) in blood. We tested 10,701 genes and retained those with FDR3mg/L) mediated by the selected genes. We estimated odds ratios and mediated proportions through counterfactual-based mediation models. Results We identified 426 genes driving CRP levels (robust to unmeasured confounding thanks to MR). They jointly mediated the effect of low father’s occupation on inflammation in adulthood for a proportion up to about 70% [95% confidence intervals (CI) 11-90%] and with an odds ratio of 1.53 [95% CI 1.05-2.15] compared to individuals with high paternal SEP. Analysis of the effects of life-course SEP trajectories (upward, downward and stable low from paternal to adult SEP) on gene regulation revealed trajectory dependent effects. Conclusions We suggest that adverse childhood SEP affects systemic inflammation in adulthood through a long-lasting effect on gene regulation.

Rationale Socioeconomic disparities have been documented in major non-communicable diseases and in their risk factors, such as obesity, hypertension, diabetes, smoking, physical inactivity, unhealthful diet and heavy drinking. However, a key research question has remained unanswered: is there a separate biological embodiment of socio-economic conditions underlying health disparities, additional and independent of those risk factors? As lifelong socioeconomic circumstances cannot be randomised, one way forward is the examination of different biological layers of evidence, including molecular changes. Method In this methodological paper we report the association of socio-economic disadvantage with (a) long-term health outcomes, before and after taking risk factors into account; (b) biological intermediaries that increase susceptibility to disease, such as childhood obesity; (c) intermediate circulating biomarkers and omic measurements (transcriptomics, DNA methylation, inflammatory proteins, allostatic load); and (d) immunity. In our Lifepath consortium, these analyses have been performed in several cohort studies, countries and contexts, and at different stages of the life course in up to 1.7 million subjects. The main goal is to test the assumption that each layer (death, functional outcomes, DNA, RNA, proteins, infections) is characterized by different types of bias and confounding, and that consistency across layers reinforces causality assessment. Results The findings show consistent associations of social disparities with unfavourable health outcomes spanning inflammatory biomarkers, DNA or RNA-based markers, infection, indicators of physical functioning and mortality. Although each of these associations has a different set of confounders, a dose-response relationship is nevertheless consistently observed, thus showing the power of our multi-layered approach. Conclusions This new evidence supports biological embodiment of social disadvantage, in addition to the impact of known (mainly behavioural) risk factors for disease.

Mouse liver regeneration after partial hepatectomy involves cells in the remaining tissue synchronously entering the cell division cycle. We have used this system and H3K4me3, Pol II and Pol III profiling to characterize adaptations in Pol III transcription. Our results broadly define a class of genes close to H3K4me3 and Pol II peaks, whose Pol III occupancy is high and stable, and another class, distant from Pol II peaks, whose Pol III occupancy strongly increases after partial hepatectomy. Pol III regulation in the liver thus entails both highly expressed housekeeping genes and genes whose expression can adapt to increased demand.

The association of blood pressure (BP) with manganese—an essential trace element required for human health—remains poorly studied. In 734 randomly recruited Swiss participants (mean age, 47.5 years; 51.4% women), we related ambulatory BP to 2 biomarkers, plasma manganese (pMn) and the urinary manganese (uMn) excretion. To allow for diurnal variation, we assessed BP and uMn over 24 hours and during wakefulness and sleep, using split urine samples. Twenty-four-hour, daytime, and nighttime systolic/diastolic BPs averaged 119.8/78.1, 123.8/81.2, and 107.0/68.3 mm Hg; the corresponding median uMn were 199.5, 83.0, and 51.5 μmol and median pMn, 0.52 μg/L. In analyses dichotomized by the median of the biomarkers, greater pMn was associated with higher 24-hour systolic/diastolic BP (+4.1/+2.3 mm Hg; P ≤0.0003), greater daytime uMn with lower daytime BP (−3.5/−1.9 mm Hg; P ≤0.0067), and greater nighttime uMn with higher nighttime BP (+2.9/+1.2 mm Hg; P ≤0.046). In multivariable-adjusted analyses, significance ( P ≤0.030) was retained for the positive association of 24-hour and daytime diastolic BP with pMn and for systolic BP in relation to uMn at night. The association sizes for a 2-fold increment in the biomarkers amounting to 0.77 mm Hg (95% CI, 0.08–1.47 mm Hg), 0.97 (CI, 0.20–1.76) and 1.33 (CI, 0.20–2.50 mm Hg), respectively. In conclusion, there were positive associations between diastolic BP and pMn over 24 hours and during daytime and between systolic BP and uMn at night.

Major biotechnological advances have facilitated a tremendous boost to the collection of (gen-/transcript-/prote-/methyl-/metabol-)omics data in very large sample sizes worldwide. Coordinated efforts have yielded a deluge of studies associating diseases with genetic markers (genome-wide association studies) or with molecular phenotypes. Whereas omics-disease associations have led to biologically meaningful and coherent mechanisms, the identified (non-germline) disease biomarkers may simply be correlates or consequences of the explored diseases. To move beyond this realm, Mendelian randomization provides a principled framework to integrate information on omics- and disease-associated genetic variants to pinpoint molecular traits causally driving disease development. In this review, we show the latest advances in this field, flag up key challenges for the future, and propose potential solutions.

Sleep-disordered breathing is a common condition, related to a higher cardiometabolic and neurocognitive risk. The main risk factors for sleep-disordered breathing include obesity, craniofacial characteristics, male sex and age. However, some studies have suggested that adverse socioeconomic circumstances and lifestyle-related behaviours such as smoking and alcohol use, may also be risk factors for sleep-disordered breathing. Here, we investigate the associations between socioeconomic status and sleep-disordered breathing, as measured by sleep apnea-hypopnea and oxygen desaturation indexes. Furthermore, we assess whether these associations are explained by lifestyle-related factors (smoking, sedentary behaviour, alcohol use and body mass index [BMI]). We used data from the CoLaus|HypnoLaus study, a population-based study including 2162 participants from Lausanne (Switzerland). Socioeconomic status was measured through occupation and education. Sleep-disordered breathing was assessed through polysomnography and measured using the apnea-hypopnea index (AHI: number of apnea/hypopnea events/hr: ≥15/≥30 events), and the ≥3% oxygen desaturation index (ODI: number of oxygen desaturation events/hr: ≥15/≥30 events). Lower occupation and education were associated with higher AHI and ODI (occupation: AHI30, odds ratio (OR) = 1.88, 95% confidence interval (CI) [1.07; 3.31]; ODI30, OR = 2.29, 95% CI [1.19; 4.39]; education: AHI30, OR = 1.21, 95% CI [0.85; 1.72]; ODI30, OR = 1.26, 95% CI [0.83; 1.91]). BMI was associated with socioeconomic status and AHI/ODI, and contributed to the socioeconomic gradient in SDB, with mediation estimates ranging between 43% and 78%. In this Swiss population-based study, we found that low socioeconomic status is a risk factor for sleep-disordered breathing, and that these associations are partly explained by BMI. These findings provide a better understanding of the mechanisms underlying social differences in sleep-disordered breathing and may help implement policies for identifying high-risk profiles for this disorder.

BACKGROUND While the positive relationship between urinary sodium excretion and blood pressure (BP) is well established for middle-aged to elderly individuals using office BP, data are limited for younger individuals and ambulatory BP measurements. METHODS Our analysis included 2,899 individuals aged 18 to 90 years from 2 population-based studies (GAPP, Swiss Kidney Project on Genes in Hypertension [SKIPOGH]). Participants with prevalent cardiovascular disease, diabetes, or on BP-lowering treatment were excluded. In SKIPOGH, 24-hour urinary sodium excretion was used as a measure of sodium intake, while in GAPP it was calculated from fasting morning urinary samples using the Kawasaki formula. Multivariable linear regression models were used to assess the relationships of 24-hour urinary salt excretion with office and ambulatory BP measurements. RESULTS Mean age, ambulatory BP, sodium excretion, and estimated glomerular filtration rate in GAPP and SKIPOGH were 35 and 44 years, 123/78 and 118/77 mm Hg, 4.2 and 3.3 g/d, and 110 and 99 ml/min/1.73 m2, respectively. A weak linear association was observed between 24-hour ambulatory systolic BP and urinary sodium excretion (β (95% confidence interval [CI]) per 1 g increase in sodium excretion (0.33 % (0.09; 0.57); P = 0.008). No significant relationships were observed for 24-hour ambulatory diastolic BP (β (95% CI) (0.13 % (−0.15; 0.40) P = 0.37). When repeating the analyses in different age groups, all BP indices appeared to have stronger relationships in the older age groups (>40 years). CONCLUSIONS In these large cohorts of healthy adults, urinary sodium excretion was only weakly associated with systolic 24-hour ambulatory BP.

Objective To assess the association of low socioeconomic status and risk factors for non-communicable diseases (diabetes, high alcohol intake, high blood pressure, obesity, physical inactivity, smoking) with loss of physical functioning at older ages. Design Multi-cohort population based study. Setting 37 cohort studies from 24 countries in Europe, the United States, Latin America, Africa, and Asia, 1990-2017 Participants 109 107 men and women aged 45-90 years. Main outcome measure Physical functioning assessed using the walking speed test, a valid index of overall functional capacity. Years of functioning lost was computed as a metric to quantify the difference in walking speed between those exposed and unexposed to low socioeconomic status and risk factors. Results According to mixed model estimations, men aged 60 and of low socioeconomic status had the same walking speed as men aged 66.6 of high socioeconomic status (years of functioning lost 6.6 years, 95% confidence interval 5.0 to 9.4). The years of functioning lost for women were 4.6 (3.6 to 6.2). In men and women, respectively, 5.7 (4.4 to 8.1) and 5.4 (4.3 to 7.3) years of functioning were lost by age 60 due to insufficient physical activity, 5.1 (3.9 to 7.0) and 7.5 (6.1 to 9.5) due to obesity, 2.3 (1.6 to 3.4) and 3.0 (2.3 to 4.0) due to hypertension, 5.6 (4.2 to 8.0) and 6.3 (4.9 to 8.4) due to diabetes, and 3.0 (2.2 to 4.3) and 0.7 (0.1 to 1.5) due to tobacco use. In analyses restricted to high income countries, the number of years of functioning lost attributable to low socioeconomic status by age 60 was 8.0 (5.7 to 13.1) for men and 5.4 (4.0 to 8.0) for women, whereas in low and middle income countries it was 2.6 (0.2 to 6.8) for men and 2.7 (1.0 to 5.5) for women. Within high income countries, the number of years of functioning lost attributable to low socioeconomic status by age 60 was greater in the United States than in Europe. Physical functioning continued to decline as a function of unfavourable risk factors between ages 60 and 85. Years of functioning lost were greater than years of life lost due to low socioeconomic status and non-communicable disease risk factors. Conclusions The independent association between socioeconomic status and physical functioning in old age is comparable in strength and consistency with those for established non-communicable disease risk factors. The results of this study suggest that tackling all these risk factors might substantially increase life years spent in good physical functioning. This study was supported by the European Commission (Horizon 2020 grant No 633666) and the Swiss State Secretariat for Education, Research and Innovation SERI. SS was supported by an Ambizione grant (PZ00P3_167732) from the Swiss National Science Foundation. Silvia Fraga is supported by the Portuguese Foundation for Science and Technology (SFRH/BPD/97015/2013). Various sources have supported recruitment, follow-up, and measurements in the 48 cohort studies contributing to this collaborative analysis. MK is supported by the UK Medical Research Council (K013351), NordForsk, the Nordic Programme on Health and Welfare, the Academy of Finland (311492), and the Finnish Work Environment Fund. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of this manuscript.

Introduction Interindividual variations in regional structural properties covary across the brain, thus forming networks that change as a result of aging and accompanying neurological conditions. The alterations of superficial white matter (SWM) in Alzheimer's disease (AD) are of special interest, since they follow the AD-specific pattern characterized by the strongest neurodegeneration of the medial temporal lobe and association cortices. Methods Here, we present an SWM network analysis in comparison with SWM topography based on the myelin content quantified with magnetization transfer ratio (MTR) for 39 areas in each hemisphere in 15 AD patients and 15 controls. The networks are represented by graphs, in which nodes correspond to the areas, and edges denote statistical associations between them. Results In both groups, the networks were characterized by asymmetrically distributed edges (predominantly in the left hemisphere). The AD-related differences were also leftward. The edges lost due to AD tended to connect nodes in the temporal lobe to other lobes or nodes within or between the latter lobes. The newly gained edges were mostly confined to the temporal and paralimbic regions, which manifest demyelination of SWM already in mild AD. Conclusion This pattern suggests that the AD pathological process coordinates SWM demyelination in the temporal and paralimbic regions, but not elsewhere. A comparison of the MTR maps with MTR-based networks shows that although, in general, the changes in network architecture in AD recapitulate the topography of (de)myelination, some aspects of structural covariance (including the interhemispheric asymmetry of networks) have no immediate reflection in the myelination pattern.

Alzheimer's disease (AD) disrupts functional connectivity in distributed cortical networks. We analyzed changes in the S-estimator, a measure of multivariate intraregional synchronization, in electroencephalogram (EEG) source space in 15 mild AD patients versus 15 age-matched controls to evaluate its potential as a marker of AD progression. All participants underwent 2 clinical evaluations and 2 EEG recording sessions on diagnosis and after a year. The main effect of AD was hyposynchronization in the medial temporal and frontal regions and relative hypersynchronization in posterior cingulate, precuneus, cuneus, and parietotemporal cortices. However, the S-estimator did not change over time in either group. This result motivated an analysis of rapidly progressing AD versus slow-progressing patients. Rapidly progressing AD patients showed a significant reduction in synchronization with time, manifest in left frontotemporal cortex. Thus, the evolution of source EEG synchronization over time is correlated with the rate of disease progression and should be considered as a cost-effective AD biomarker. (c) 2013 Elsevier Inc. All rights reserved.

Background: Several social indicators have been used in epidemiological research to describe socioeconomic position (SEP) of people in societies. Among SEP indicators, those more frequently used are education, occupational class and income. Differences in the incidence of several health outcomes have been reported consistently, independently from the indicator employed. Main objectives of the study were to present the socioeconomic classifications of the social indicators which will be employed throughout the LIFEPATH project and to compare social gradients in all-cause mortality observed in the participating adult cohorts using the different SEP indicators. Methods: Information on the available social indicators (education, own and father’s occupational class, income) from eleven adult cohorts participating in LIFEPATH was collected and harmonized. Mortality by SEP for each indicator was estimated by Poisson regression on each cohort and then evaluated using a meta-analytical approach. Results: In the meta-analysis, among men mortality was significantly inversely associated with both occupational class and education, but not with father’s occupational class; among women, the increase in mortality in lower social strata was smaller than among men and, except for a slight increase in the lowest education category, no significant differences were found. Conclusions: Among men, the proposed three-level classifications of occupational class and education were found to predict differences in mortality which is consistent with previous research. Results on women suggest that classifying them through their sole SEP, without considering that of their partners, may imply a misclassification of their social position leading to attenuation of mortality differences. This study is supported by the European Commission (Horizon 2020 grant n° 633666) and the Swiss State Secretariat for Education, Research and Innovation SERI. Silvia Stringhini is supported by an Ambizione Grant (PZ00P3_167732) from the Swiss National Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.