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"Van Pelt, Michel"
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Disentangling potential causal effects of educational duration on well-being, and mental and physical health outcomes
Extensive research has focused on the potential benefits of education on various mental and physical health outcomes. However, whether the associations reflect a causal effect is harder to establish.
To examine associations between educational duration and specific aspects of well-being, anxiety and mood disorders, and cardiovascular health in a sample of European Ancestry UK Biobank participants born in England and Wales, we apply four different causal inference methods (a natural policy experiment leveraging the minimum school-leaving age, a sibling-control design, Mendelian randomization [MR], and within-family MR), and assess if the methods converge on the same conclusion.
A comparison of results across the four methods reveals that associations between educational duration and these outcomes appears predominantly to be the result of confounding or bias rather than a true causal effect of education on well-being and health outcomes. Although we do consistently find no associations between educational duration and happiness, family satisfaction, work satisfaction, meaning in life, anxiety, and bipolar disorder, we do not find consistent significant associations across all methods for the other phenotypes (health satisfaction, depression, financial satisfaction, friendship satisfaction, neuroticism, and cardiovascular outcomes).
We discuss inconsistencies in results across methods considering their respective limitations and biases, and additionally discuss the generalizability of our findings in light of the sample and phenotype limitations. Overall, this study strengthens the idea that triangulation across different methods is necessary to enhance our understanding of the causal consequences of educational duration.
Journal Article
Human Campylobacteriosis in Luxembourg, 2010–2013: A Case-Control Study Combined with Multilocus Sequence Typing for Source Attribution and Risk Factor Analysis
Campylobacteriosis has increased markedly in Luxembourg during recent years. We sought to determine which
Campylobacter
genotypes infect humans, where they may originate from and how they may infect humans. Multilocus sequence typing was performed on 1153
Campylobacter jejuni
and 136
C. coli
human strains to be attributed to three putative animal reservoirs (poultry, ruminants, pigs) and to environmental water using the asymmetric island model. A nationwide case-control study (2010–2013) for domestic campylobacteriosis was also conducted, including 367
C. jejuni
and 48
C. coli
cases and 624 controls. Risk factors were investigated by
Campylobacter
species and for strains attributed to different sources using a combined case-control and source attribution analysis. 282 sequence types (STs) were identified: ST-21, ST-48, ST-572, ST-50 and ST-257 were prevailing. Most cases were attributed to poultry (61.2%) and ruminants (33.3%). Consuming chicken outside the home was the dominant risk factor for both
Campylobacter
species. Newly identified risk factors included contact with garden soil for either species and consuming beef specifically for
C. coli
. Poultry-associated campylobacteriosis was linked to poultry consumption in wintertime and ruminant-associated campylobacteriosis to tap-water provider type. Besides confirming chicken as campylobacteriosis primary source, additional evidence was found for other reservoirs and transmission routes.
Journal Article
Dream missions : space colonies, nuclear spacecraft and other possibilities
\"Dream Missions takes the reader on a journey through the history of extremely large, ambitious, and complex space missions that never came to fruition. Each project described in this book says something about the visions and expectations of their time, and their demise was often linked to important changes in the cultural, political and social state of the world. Various ambitious mission and spacecraft concepts are presented, each covering: overview of its history and design; the philosophy behind the concept; why it was never developed and flown; and intriguingly is there still a chance the mission will actually be carried out, with technology progressing, requirements and constraints changing, and alternataive sources of funding becoming available?\"--Back cover.
Book
Risk factors for hepatitis E virus seropositivity in Dutch blood donors
Background
A marked increase of hepatitis E cases has recently been observed in the Netherlands. Causes of the (re-)emergence of hepatitis E virus (HEV) and exact sources and routes of transmission of HEV infection are currently unknown. We aimed to identify risk factors for HEV seropositivity.
Methods
Using the Wantai EIA, 2100 plasma samples of blood donors from all over the Netherlands aged 18-70 years were tested for anti-HEV IgG antibodies. A questionnaire on socio-demographic characteristics, health, and potential risk factors for HEV exposure was sent to these participants.
Results
The overall IgG-seroprevalence was 31% (648/2100) and increased with age. Several food products were independently associated with IgG-seropositivity in a multivariate analysis adjusting for age and gender among 1562 participants who completed the questionnaire: traditional Dutch dry raw sausages called “cervelaat”, “fijnkost”, “salami” and “salametti” which are generally made from raw pork and beef (aOR 1.5; 95%CI 1.2-1.9), frequent consumption of bovine steak (aOR 1.3; 95%CI 1.0-1.7), and frequent consumption of smoked beef (aOR 1.3 95%CI 1.0-1.7). Although not frequently reported, contact with contaminated water was also a risk factor for seropositivity (aOR 2.5; 95%CI 1.5-4.4). Lower seroprevalence was associated with eating raspberries, going out for dinner, and contact with wild animals and dogs.
Conclusion
Several pork food products, mainly dry raw sausages, and contact with contaminated water were associated with past HEV infection in the Netherlands. Further investigation is needed into the prevalence and infectivity of HEV in these risk factor food products, as well as investigation of the production methods and possible origin of HEV-contamination within these sausages, e.g. very small amounts of pork liver, pig-derived blood products as food additive, or the pork muscle tissue.
Journal Article
Calciprotein particle-activated endothelial cells aggravate smooth muscle cell calcification via paracrine signalling
Background
Vascular calcification is highly prevalent in Chronic Kidney Disease (CKD) and is associated with markedly increased cardiovascular risk. High serum phosphate in CKD increases calcification propensity via generation of circulating calciprotein particles (CPP2), crystalline nanoaggregates composed of calcium, phosphate, and serum proteins. CPP2 induce vascular calcification in vascular smooth muscle cells (VSMCs) in vitro. In vivo, endothelial cells, rather than VSMCs are primarily exposed to CPP2, yet understanding the influence of endothelial cells on vascular calcification is limited.
Methods
We investigated calcification-promoting signalling by endothelial cells on VSMCs. Effects of CPP2 exposure to endothelial cells on CPP2 uptake, endothelial cell activation, and endothelial cell-derived secretome were studied. Effects of the secretome on VSMC calcification were investigated. Using NanoString nCounter analysis the effects of CPP2-activated endothelial cell-conditioned medium on VSMCs gene expression were mapped.
Results
Endothelial cells internalise CPP2 and elevate ICAM-1, E-selectin, and VCAM-1-mRNA expression, indicating endothelial activation. VSMCs cultured in conditioned medium from CPP2-activated endothelial cells demonstrated enhanced calcification, suggesting that CPP2-activated endothelial cells release pro-calcifying soluble factors. Mass spectrometry was utilized to identify 1171 proteins in the CPP2-activated endothelial cells’ secretome. Among these, 76 proteins were differentially expressed compared to control endothelial cells’ secretome, including proteins related to blood vessel development, extracellular matrix remodelling, and oxidative stress-related processes. Finally, endothelial cell-derived paracrine factors present in conditioned medium enhanced mRNA-expression of calcification-related factors in VSMCs.
Conclusions
CPP2-activated endothelial cells promote VSMC calcification via paracrine signalling. In response to these paracrine factors, VSMCs increase the expression of pro-calcification genes.
Journal Article
Pharmacometabolomics Detects Various Unreported Metoprolol Metabolites in Urine of (Potential) Living Kidney Donors and Kidney Transplant Recipients
Metoprolol is primarily metabolized via the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme, which underlies interindividual variation in conversion rates and may benefit from pharmacogenetics-driven therapy personalization. However, the field relies heavily on knowledge of a drug's metabolism, often originating from early-phase clinical trials with single-dose administration in small samples of healthy volunteers. Pharmacogenetics could thus benefit from real-world drug metabolism studies.
We conducted a real-world drug metabolism study for metoprolol in 18 (potential) living kidney donors and 374 kidney transplant recipients from the Transplant Lines Food and Nutrition Biobank and Cohort Study (NCT02811835) using existing liquid chromatography-high resolution mass spectrometry pharmacometabolomic data.
In both groups, we confirmed the presence of seven expected metabolites, including the high-abundance substances metoprolol acid and hydroxymetoprolol. We were unable to detect deisopropylmetoprolol and a metabolite known as \"H 119/68\". However, we did find putative further oxidized forms, namely the expected variant of deisopropylmetoprolol in which the primary amine is removed and the leftover methyl group is oxidized into a carboxylic acid (\"H 104/83\") and an unknown/unreported metoprolol metabolite that we refer to as \"metoprolol benzoic acid\". Moreover, we found nine other previously unknown/unreported metabolites, putatively reflecting N-glucuronidated metoprolol, four glucuronidated versions of hydroxymetoprolol, and a formylated, a glucuronidated, and two hydroxylated versions of metoprolol acid. Interestingly, the same metabolites were detected in potential living kidney donors and kidney transplant recipients, and metabolite profiles did not differ between both groups in principal component analysis.
We found more metoprolol metabolites than previously reported, calling for replication studies and evaluation of pharmacogenetic testing approaches to realize safer, more effective metoprolol therapy.
Journal Article
Tremor, Daily Functioning, and Health-Related Quality of Life in Solid Organ Transplant Recipients
Solid organ transplant recipients (SOTR) frequently report tremor. Data concerning tremor-related impairment and its potential impact on health-related quality of life (HRQoL) are lacking. This cross-sectional study assesses impact of tremor on activities of daily living and HRQoL using validated questionnaires among SOTR enrolled in the TransplantLines Biobank and Cohort Study. We included 689 SOTR (38.5% female, mean [±SD] age 58 [±14] years) at median [interquartile range] 3 [1–9] years after transplantation, of which 287 (41.7%) reported mild or severe tremor. In multinomial logistic regression analyses, whole blood tacrolimus trough concentration was an independent determinant of mild tremor (OR per µg/L increase: 1.11, 95% CI: 1.02 to 1.21, p = 0.019). Furthermore, in linear regression analyses, severe tremor was strongly and independently associated with lower physical and mental HRQoL (β = −16.10, 95% CI: −22.23 to −9.98, p < 0.001 and β = −12.68, 95% CI: −18.23 to −7.14, p < 0.001 resp.). SOTR frequently report tremor-related impairment of activities of daily living. Tacrolimus trough concentrations appeared as a main determinant of tremor among SOTR. The strong and independent association of tremor-related impairment with lower HRQoL warrants further studies into the effects of tacrolimus on tremor. Clinical Trial Registration : ClinicalTrials.gov , Identifier NCT03272841.
Journal Article
Validity of the Skin and UV Neoplasia Transplant Risk Assessment Calculator (SUNTRAC) tool in a Dutch cohort of transplant recipients
Background To identify patients with high risk of skin cancer, risk prediction tools have been developed. Objectives External validation of the Skin and UV Neoplasia Transplant Risk Assessment Calculator (SUNTRAC) in a Dutch cohort of solid organ transplant recipients (SOTR) and exploration of the possibility of incorporating additional risk factors to enhance its predictive performance. Methods We used data from the ongoing, prospective TransplantLines Biobank and Cohort Study of the University Medical Center Groningen (Groningen, The Netherlands). We conducted a survival analysis using Fine and Gray models to determine the subdistribution hazard ratios of the SUNTRAC risk factors and groups, Wolbers C index to assess its discriminative power, and cumulative incidences of skin cancer to assess its calibration. We applied the same methods for the incorporation of additional risk factors to the model. Results A total of 2099 patients were included with a median age at transplantation of 52.1 years (Interquartile range [IQR]: 40.6–60.1) and a median follow‐up time of 6.6 years (IQR: 3.4–12.5). In total 478 (22.8%) patients developed skin cancer. Basal cell carcinoma (53.3%) and cutaneous squamous cell carcinoma (42.9%) were most prevalent. The cumulative incidences of skin cancer per SUNTRAC risk group at 10 years were: low‐risk (1.8%), medium‐risk (12.9%), high‐risk (34.3%) and very high‐risk (68.6%). Significantly different skin cancer risk rates were observed for the medium‐risk (SHR = 9.9, 95% CI: 2.51–39.4), high‐risk (SHR = 21.5, 95% CI: 5.40–85.2) and very high‐risk (SHR = 80.3, 95% CI: 19.26–335.1) groups in reference to the low‐risk group. Wolbers C‐index at 5 years was 0.71. The model was well calibrated for our cohort. The addition of other potential risk factors yielded no or marginal improvement of discriminative value on top of SUNTRAC. Conclusions SUNTRAC is valid for the general Dutch SOTR population, and it can be clinically implemented.
Journal Article