Optimisation of an in vitro human cardiovascular model on-a-chip for toxicological assessment of nicotine delivery products

BackgroundSmoking cigarettes is a cause of serious diseases in smokers, including cardiovascular disease. Through a pathway of endothelial dysfunction, lipid infiltration, macrophage recruitment and vascular remodeling, atherosclerosis is fundamental in the development of most cardiovascular diseases. There is an increasing number of next-generation products (NGP) which provide potentially reduced harm forms of nicotine delivery to adult smokers. This study aimed to optimise an in vitro cardiovascular model to assess such products. Human Coronary Artery Endothelial Cells (HCAECs) were cultured on an OrganoPlate®2-lane chip (Mimetas BV) combined with THP-1 monocytes under flow conditions.MethodsAn aqueous aerosol extract from the 1R6F reference cigarette was compared with two categories of NGP, (a heated tobacco product (HTP) and an electronic nicotine delivery system (ENDS)), to assess relative effects on select atherogenic endpoints (oxidative stress, monocyte adhesion, ICAM-1 expression, and inflammatory markers). Following exposure of THP-1 monocytes with the aqueous extracts, the resulting conditioned medium was then added to the HCAEC vessels.Results1R6F was consistently the most potent test article, eliciting observed responses at 4x lower concentrations than applied for both the HTP and ENDS. The HTP was more potent than the ENDS product across all endpoints, however, all test articles increased monocyte adhesion. ICAM-1 did not appear to be a main driver for monocyte adhesion, however, this could be due to replicate variability. Upon comparison to an extract-only control exposure, THP-1-medium pre-conditioning was an important mediator of the responses observed.ConclusionIn conclusion, the data suggests that the NGP extracts, containing primary aerosol chemical constituents exhibit a marked reduction in biological activity in the early key events associated with atherogenesis when compared to a cigarette, adding to the weight of evidence for the tobacco harm reduction potential of such products

Child mortality: preventing future child deaths and optimizing family support

Worldwide 6.1 million live-born children under the age of five died from natural and external causes in 2014. According to the Convention on the Rights of the Child appropriate measures should be taken by State Parties to ensure the survival and development of the child to a maximum extent and to diminish infant and child mortality. As countries have tried to reduce the global under-five child mortality rate with two-thirds between 1990 and 2015, which is defined as the Millennium Development Goal 4 by the World Health Organization, only 62 of the 195 countries have achieved this degree of reduction. As a consequence world leaders have renewed their goals in which every nation is expected to make every effort to further reduce preventable child deaths. In the Netherlands child mortality has declined in the past centuries due to improvements in social circumstances, sanitation, housing, hygiene and health care, and lower birth rates. Although 1130 Dutch children aged 0 up to and including 19 years (mortality rate 29.4 per 100.000 children) died in 2014, there are still child deaths that are avoidable. Understanding the nature and patterns of child mortality and the factors that have contributed to death is essential to direct preventive strategies. The aim of this thesis is to investigate how to prevent future child deaths and optimize family support in the Netherlands. In order to answer these questions the patterns of child mortality in the Netherlands are described in part A, ‘Epidemiology’. Then, the way Dutch professionals respond the a child’s death, including the support they provide to parents of deceased children, is explored in part B, ‘Responding to child deaths’. As Child Death Review (CDR) has the potential to identify avoidable factors that contributed to death and pays attention to the needs of bereaved parents, CDR might contribute to prevent future child deaths and to improve relatives’ coping with bereavement in the Netherlands. Therefore, the possibility and analyzing child deaths systematically in the Netherlands according to the CDR method is examined in part C, ‘Implementation of Child Death Review.’ The results of this study might support health care professionals and health policy makers in their efforts to prevent future child deaths and optimize family support in the Netherlands

Kindersterfte door ongevallen: ontwikkeling in de afgelopen 40 jaar

Van alle landen in Europa heeft Nederland het op een na laagste sterftecijfer ten gevolge van nietnatuurlijkeoorzaken, waaronder ongevallen, bij kinderen. In dit artikel beschrijven wij de ontwikkeling van de kindersterfte door ongevallen in Nederland in de periode 1969-2011 en geven we mogelijke verklaringen voor deze ontwikkeling. Daartoe zijn de gegevens geanalyseerd over de primaire doodsoorzaken, die sinds 1969 zijn opgenomen in de doodsoorzakenstatistiek van het Centraal Bureau voor de Statistiek (CBS), en beschikbaar zijn via Statline. De sterfte door ongevallen bij kinderen in de leeftijd 0-19 jaar is sinds 1969 sterk afgenomen, met name door de daling in het aantal vervoersongevallen van 20/100.000 in 1973 naar 1,9/100.000 in 2011. Diverse verkeersmaatregelen die vanaf 1973 door de overheid zijn getroffen, lijken te hebben geresulteerd in de enorme afname van het aantal ongevallen in het wegverkeer. Wat betreft de overige ongevallen is de daling van de accidentele verdrinking in de periode 1996-2011 opmerkelijk: van 0,9/100.000 in 1996 naar 0,1/100.000 in 2011. Bij deze afname spelen waarschijnlijk sociaal-culturele factoren en effectieve preventieve maatregelen een rol. Jongens blijken vaker het slachtoffer van ongevallen dan meisjes. De sterfte door ongevallen bij kinderen kan verder afnemen door bestaande preventievemaatregelen te borgen en hiervoor blijvend aandacht te vragen via de professionals in dejeugdgezondheidszorg en beleidsmakers. Verder kan systematische analyse van de aard enomstandigheden van elk sterfgeval aanwijzingen geven voor nieuwe preventiemogelijkhede

Child mortality in the Netherlands in the past decades: an overview of external causes and the role of public health policy

Among European countries, the Netherlands has the second lowest child mortality rate from external causes. We present an overview, discuss possible explanations, and suggest prevention measures. We analyzed mortality data from all deceased children aged 0–19 years for the period 1969–2011. Child mortality declined in the past decades, largely from decreases in road traffic accidents that followed government action on traffic safety. Accidental drowning also showed a downward trend. Although intentional self-harm showed a significant increase, other external causes of mortality, including assault and fatal child abuse, remained constant. Securing existing preventive measures and analyzing the circumstances of each child’s death systematically through Child Death Review may guide further reduction in child mortality