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Stimulated by the European integration process, the need for high-grade transport connections between the major European urban agglomerations is growing. Coinciding with the reurbanisation efforts of the major cities, the high-speed train (HST) is eminently suitable to fill that need, as it essentially connects urban centres, and is relatively environment-friendly. The authors set out to analyse how the HST can make an optimum contribution to the development of welfare in urban regions. The paper is based on an international comparative investigation in fourteen European cities: Amsterdam, Antwerp, Brno, Brussels, Cologne, Geneva, Liège, Lille, Lyons, Marseilles, Nantes, Rotterdam, Strasbourg, and Turin. Some criteria have been derived for the successful integration of the HST system in an urban area: accessibility, economic potential, the quality of the living environment, a balanced spatial distribution of activities, a balanced social distribution of effects, and organising capacity. HST integration should contribute to harmonious long-term urban development, and a balance should therefore be struck between, among other elements, internal accessibility and the quality of the living environment. There is no such thing as a standard solution for optimum HST integration in a city. Each individual city must take account of its own spatial-economic structure and the criteria identified to find out what solution will contribute most to a balanced development of urban welfare. A clear vision of and a well-considered strategy for HST integration remains essential, in order not to lose out on the profitable prospects of economic development opened to the urban region.

In this paper we present a general theory of urban development, which we then compare with the developments in the urban system of the Netherlands, for the years 1970 to 1986. We propose that urban dynamics are started by and are continually influenced by fundamental changes in technology, social values, demography, and politics. Each factor will be more significant in one stage of urban development than in others, and therefore a four stage cycle is produced: stage 1, industrialisation occurs; stage 2, the service sector and transport facilities grow; stage 3, there is a greater appreciation of the environment; stage 4, the society tends to an 'information society'. It appears that the Dutch urban system is in stage 3 of these developments: deconcentration of population peaked in the early 1970s and has since declined (under the influence of economic and demographic changes). Dynamics slowed under poor economic conditions, but by the late 1980s, deconcentration increased with the economic recovery. The Dutch system is progressing towards stage 4, with possible revitalisation of large towns by means of new policy.

Background:DNA methylation at theGFI1-locus has been repeatedly associated with exposure to smoking fromthe foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure tomaternal prenatal smoking with offspring's adult cardio-metabolic health.Methods:We meta-analysed the association between DNA methylation atGFI1-locus with maternal prenatalsmoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe,Australia, and USA (n= 18,212). DNA methylation at theGFI1-locus was measured in whole-blood. Multivari-able regression models werefitted to examine its association with exposure to prenatal and own adult smoking.DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fastingglucose (FG), high-density lipoprotein cholesterol (HDL—C), triglycerides (TG), diastolic, and systolic blood pres-sure (BP).Findings:Lower DNA methylation at three out of eightGFI1-CpGs was associated with exposure to maternal pre-natal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation atcg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when ad-justed for sex, age, and adult smoking with Bonferroni-correctedPb0·012. In contrast, lower DNA methylationatcg09935388,thestrongest adultownsmokinglocus, wasassociated with decreasedBMI, WC,and BP (adjusted1×10−7bPb0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, andcg18146737 was associated with decreased BMI and WC (5 × 10−8bPb0.001). Lower DNA methylation at allthe CpGs was consistently associated with higher TG levels.Interpretation:Epigenetic changes at theGFI1were linked to smoking exposurein-utero/in-adulthood and ro-bustly associated with cardio-metabolic risk factors.Fund:European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595DynaHEALTH.

Abstract Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL—C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 × 10⁻⁷ < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10⁻⁸ < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. Fund: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.