• CA19-9 and Apolipoprotein-A2 isoforms as detection markers for pancreatic cancer - a prospective evaluation.

      Honda, K; Katzke, V A; Hüsing, A; Okaya, S; Shoji, H; Onidani, K; Olsen, A; Tjønneland, A; Overvad, K; Weiderpass, E; et al. (2018-09-27)
      Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. This study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging. This article is protected by copyright. All rights reserved.
    • Calculating incidence rates and prevalence proportions: not as simple as it seems.

      Spronk, Inge; Korevaar, Joke C; Poos, René; Davids, Rodrigo; Hilderink, Henk; Schellevis, François G; Verheij, Robert A; Nielen, Mark M J (2019-05-06)
    • Can Transgenic Maize Affect Soil Microbial Communities?

      Mulder, Christian; Wouterse, Marja; Raubuch, Markus; Roelofs, Willem; Rutgers, Michiel (2006-09-29)
      The aim of the experiment was to determine if temporal variations of belowground activity reflect the influence of the Cry1Ab protein from transgenic maize on soil bacteria and, hence, on a regulatory change of the microbial community (ability to metabolize sources belonging to different chemical guilds) and/or a change in numerical abundance of their cells. Litter placement is known for its strong influence on the soil decomposer communities. The effects of the addition of crop residues on respiration and catabolic activities of the bacterial community were examined in microcosm experiments. Four cultivars of Zea mays L. of two different isolines (each one including the conventional crop and its Bacillus thuringiensis cultivar) and one control of bulk soil were included in the experimental design. The growth models suggest a dichotomy between soils amended with either conventional or transgenic maize residues. The Cry1Ab protein appeared to influence the composition of the microbial community. The highly enhanced soil respiration observed during the first 72 h after the addition of Bt-maize residues can be interpreted as being related to the presence of the transgenic crop residues. This result was confirmed by agar plate counting, as the averages of the colony-forming units of soils in conventional treatments were about one-third of those treated with transgenic straw. Furthermore, the addition of Bt-maize appeared to induce increased microbial consumption of carbohydrates in BIOLOG EcoPlates. Three weeks after the addition of maize residues to the soils, no differences between the consumption rate of specific chemical guilds by bacteria in soils amended with transgenic maize and bacteria in soils amended with conventional maize were detectable. Reaped crop residues, comparable to post-harvest maize straw (a common practice in current agriculture), rapidly influence the soil bacterial cells at a functional level. Overall, these data support the existence of short Bt-induced ecological shifts in the microbial communities of croplands' soils.
    • Can universal access be achieved in a voluntary private health insurance market? Dutch private insurers caught between competing logics.

      Vonk, Robert A A; Schut, Frederik T (2018-05-07)
      For almost a century, the Netherlands was marked by a large market for voluntary private health insurance alongside state-regulated social health insurance. Throughout this period, private health insurers tried to safeguard their position within an expanding welfare state. From an institutional logics perspective, we analyze how private health insurers tried to reconcile the tension between a competitive insurance market pressuring for selective underwriting and actuarially fair premiums (the insurance logic), and an upcoming welfare state pressuring for universal access and socially fair premiums (the welfare state logic). Based on primary sources and the extant historiography, we distinguish six periods in which the balance between both logics changed significantly. We identify various strategies employed by private insurers to reconcile the competing logics. Some of these were temporarily successful, but required measures that were incompatible with the idea of free entrepreneurship and consumer choice. We conclude that universal access can only be achieved in a competitive individual private health insurance market if this market is effectively regulated and mandatory cross-subsidies are effectively enforced. The Dutch case demonstrates that achieving universal access in a competitive private health insurance market is institutionally complex and requires broad political and societal support.
    • Can we predict tuberculosis cure? What tools are available?

      Goletti, Delia; Lindestam Arlehamn, Cecilia S; Scriba, Thomas J; Anthony, Richard; Cirillo, Daniela Maria; Alonzi, Tonino; Denkinger, Claudia M; Cobelens, Frank (2018-11)
      Antibiotic treatment of tuberculosis takes ≥6 months, putting a major burden on patients and health systems in large parts of the world. Treatment beyond 2 months is needed to prevent tuberculosis relapse by clearing remaining, drug-tolerant Mycobacterium tuberculosis bacilli. However, the majority of patients treated for only 2-3 months will cure without relapse and do not need prolonged treatment. Assays that can identify these patients at an early stage of treatment may significantly help reduce the treatment burden, while a test to identify those patients who will fail treatment may help target host-directed therapies.In this review we summarise the state of the art with regard to discovery of biomarkers that predict relapse-free cure for pulmonary tuberculosis. Positron emission tomography/computed tomography scanning to measure pulmonary inflammation enhances our understanding of "cure". Several microbiological and immunological markers seem promising; however, they still need a formal validation. In parallel, new research strategies are needed to generate reliable tests.
    • Capturing multiple-type interactions into practical predictors of type replacement following human papillomavirus vaccination.

      Man, Irene; Auranen, Kari; Wallinga, Jacco; Bogaards, Johannes A (2019-05-27)
      Current HPV vaccines target a subset of the oncogenic human papillomavirus (HPV) types. If HPV types compete during infection, vaccination may trigger replacement by the non-targeted types. Existing approaches to assess the risk of type replacement have focused on detecting competitive interactions between pairs of vaccine and non-vaccine types. However, methods to translate any inferred pairwise interactions into predictors of replacement have been lacking. In this paper, we develop practical predictors of type replacement in a multi-type setting, readily estimable from pre-vaccination longitudinal or cross-sectional prevalence data. The predictors we propose for replacement by individual non-targeted types take the form of weighted cross-hazard ratios of acquisition versus clearance, or aggregate odds ratios of coinfection with the vaccine types. We elucidate how the hazard-based predictors incorporate potentially heterogeneous direct and indirect type interactions by appropriately weighting type-specific hazards and show when they are equivalent to the odds-based predictors. Additionally, pooling type-specific predictors proves to be useful for predicting increase in the overall non-vaccine-type prevalence. Using simulations, we demonstrate good performance of the predictors under different interaction structures. We discuss potential applications and limitations of the proposed methodology in predicting type replacement, as compared to existing approaches. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.
    • Carbapenemase-producerende enterobacteriën in Nederland : Onopgemerkte versprewiding naar verschillende regio's.

      Leenstra, T; Bosch, T; Vlek, A L; Bonten, M J M; van der Lubben, I M; de Greeff, S C (2017-10-24)
      - Carbapenemase producing Enterobacteriaceae (CPE), including Klebsiella pneumoniae and Escherichia coli, are only sporadically seen in the Netherlands and then mainly in patients who have been transferred from foreign hospitals.- CPE are resistant to virtually all beta-lactam antibiotics, including carbapenems, e.g., meropenem and imipenem. Several genes, e.g., OXA-48, KPC and NDM-1, code for carbapenemase enzymes that deactivate carbapenems.- Control of CPE focuses on timely identification of patients who are infected or are carriers and the application of preventive measures to prevent spread.- Genotypic analysis of CPE isolates submitted to the national CPE surveillance revealed close relationships between 8 NDM-1 positive K. pneumoniae isolates of patients from different parts of the Netherlands and isolates obtained through contact tracing during a known hospital outbreak.- Based on retrospective epidemiological investigation, no shared exposure could be found.- These findings indicate unnoticed spread of CPE in the Netherlands.
    • Cardiovascular Risk Factors Associated With Venous Thromboembolism.

      Gregson, John; Kaptoge, Stephen; Bolton, Thomas; Pennells, Lisa; Willeit, Peter; Burgess, Stephen; Bell, Steven; Sweeting, Michael; Rimm, Eric B; Kabrhel, Christopher; et al. (2019-01-16)
      It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. A panel of several established cardiovascular risk factors.
    • Cardiovascular risk model performance in women with and without hypertensive disorders of pregnancy.

      Dam, Veerle; Onland-Moret, N Charlotte; Verschuren, W M Monique; Boer, Jolanda M A; Benschop, Laura; Franx, Arie; Moons, Karel G M; Boersma, Eric; van der Schouw, Yvonne T (2018-09-12)
      Compare the predictive performance of Framingham Risk Score (FRS), Pooled Cohort Equations (PCEs) and Systematic COronary Risk Evaluation (SCORE) model between women with and without a history of hypertensive disorders of pregnancy (hHDP) and determine the effects of recalibration and refitting on predictive performance.
    • Carry-over of dioxins and PCBs from feed and soil to eggs at low contamination levels-- influence of mycotoxin binders on the carry-over from feed to eggs.

      Hoogenboom, L A P; Kan, C A; Zeilmaker, Marco J; Eijkeren, Jan C H van; Traag, Win A (2006-05-01)
      Laying hens were fed with compound feed containing six different levels of dioxins, dioxin-like PCBs and indicator PCBs for a period of 56 days. This was followed by a period of 56 days on clean feed. Dioxin levels in feed varied from background levels to three times the current EU tolerance limit of 0.75 ng TEQ/kg. At all dose levels a rapid increase was observed in the dioxin levels in eggs. There was a clear linear dose-response relationship between the dioxin levels in eggs and feed. The feed containing 0.4 ng TEQ dioxins per kg resulted in egg levels just above the EU limit of 3 pg TEQ/g fat. Dioxin-like and indicator PCB residues followed a pattern very similar to that of dioxins. Exposure to the highest indicator PCB level of 32 microg/kg resulted in egg levels around 300 ng/g fat. Exposure to dioxins through contaminated soil, mixed at 10% into the feed, resulted in a similar carry-over as from feed. Mycotoxin binders, mixed at 0.5% into the feed, had little effect on the carry-over of dioxins from the feed to the egg. It can be concluded that consumption of feed or soil with even moderate levels of dioxins and dioxin-like PCBs rapidly results in increased levels in eggs. The current EU dioxin limit for feed cannot guarantee egg dioxin levels below the EU-limit.
    • Cascading effects of predator activity on tick-borne disease risk.

      Hofmeester, Tim R; Jansen, Patrick A; Wijnen, Hendrikus J; Coipan, Elena C; Fonville, Manoj; Prins, Herbert H T; Sprong, Hein; van Wieren, Sipke E (2017-07-26)
      Predators and competitors of vertebrates can in theory reduce the density of infected nymphs (DIN)-an often-used measure of tick-borne disease risk-by lowering the density of reservoir-competent hosts and/or the tick burden on reservoir-competent hosts. We investigated this possible indirect effect of predators by comparing data from 20 forest plots across the Netherlands that varied in predator abundance. In each plot, we measured the density of questing Ixodes ricinus nymphs (DON), DIN for three pathogens, rodent density, the tick burden on rodents and the activity of mammalian predators. We analysed whether rodent density and tick burden on rodents were correlated with predator activity, and how rodent density and tick burden predicted DON and DIN for the three pathogens. We found that larval burden on two rodent species decreased with activity of two predator species, while DON and DIN for all three pathogens increased with larval burden on rodents, as predicted. Path analyses supported an indirect negative correlation of activity of both predator species with DON and DIN. Our results suggest that predators can indeed lower the number of ticks feeding on reservoir-competent hosts, which implies that changes in predator abundance may have cascading effects on tick-borne disease risk.
    • Case of seasonal reassortant A(H1N2) influenza virus infection, the Netherlands, March 2018.

      Meijer, Adam; Swaan, Corien M; Voerknecht, Martin; Jusic, Edin; van den Brink, Sharon; Wijsman, Lisa A; Voordouw, Bettie Cg; Donker, Gé A; Sleven, Jacqueline; Dorigo-Zetsma, Wendelien W; et al. (2018-04)
      A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general practitioner participating in the routine sentinel surveillance of ILI in the Netherlands. The patient recovered fully. Further epidemiological and virological investigation did not reveal additional cases.
    • Case study: Enschede fireworks disaster: lessons learned.

      van Kamp, I; van der Velden, P; Yzermans, J (2018-11-01)
    • A case-control study into risk factors for acute hepatitis E in the Netherlands, 2015-2017.

      Tulen, Anna Dolores; Vennema, Harry; van Pelt, Wilfrid; Franz, Eelco; Hofhuis, Agnetha (2019-02-08)
      A case-control study was performed (2015-2017) to identify risk factors for acute hepatitis E in the Netherlands. A questionnaire on potential sources of hepatitis E virus (HEV) exposure, health and socio-demographics was completed by 376 patients with acute hepatitis E, and 1534 controls matched for age, gender and region of residence. Traditional Dutch dry raw sausages of pork muscle meat, called "cervelaat", "snijworst", and "boerenmetworst" were reported by 72% of the patients, and 46% of controls (aOR 3.0; 95%CI 2.2-4.1), with a population attributable fraction (PAF) of 48%. Direct contact with pigs and working with a septic tank were strong risk factors (aOR 3.1; 95%CI 1.3-7.3 and aOR 6.9; 95%CI 1.2-40.8, respectively), with a low PAF (2% and 1%, respectively). Host risk factors were pre-existing liver disease (aOR 3.8; 95%CI 2.0-7.1), diabetes (aOR 2.1; 95%CI 1.4-3.2), immunosuppressive medication (aOR 2.5; 95%CI 1.5-4.1), and gastric acid inhibitors (aOR 2.3; 95%CI 1.7-3.1). Dry raw pork sausages were the major source of HEV infection among our study population. The prevalence and cause of HEV contamination in these pork muscle meat products require further investigation. Infrequently reported, yet strong risk factors were contact with pigs, or a septic tank.
    • A category approach for reproductive effects of phthalates.

      Fabjan, Evelin; Hulzebos, Etje; Mennes, W; Piersma, Aldert H (2006-10-01)
      In regulatory toxicology, the experimental assessment of reproductive toxicity is one of the most costly endpoints to perform. Categorizing chemicals is an approach that can be used to reduce animal tests in risk assessments of chemicals, for example, via REACH (Registration, Evaluation, and Authorization of Chemicals). The category approach was tested for reproductive toxicity with a group of 10 ortho-phthalate esters, with different side chain lengths. Three ortho-phthalates were used for testing the category. Phthalates with side-chain lengths C4 to C6 that are commonly known to cause reproductive effects were included, as well as the recently discovered mechanism that indicates antiandrogenic effects. The differences in physicochemical properties, absorption rates, and metabolism between the phthalates investigated could not fully explain the difference in reproductive toxicity. It was concluded that phthalates with the alkyl side-chain length from C4 to C6 produce similar severe reproductive effects in experimental animals. It is expected that phthalates included in the tight boundaries of the proposed category would all show severe reproductive effects, especially the antiandrogenic effects. Further testing might not be needed for phthalates within these boundaries. If necessary, limited testing could focus on the critical endpoints. Detailed mechanistic information is needed on phthalates to apply the categories for regulatory toxicology.
    • The cation competition and electrostatic theory are equally valid in quantifying the toxicity of trivalent rare earth ions (Y and Ce) to Triticum aestivum.

      Gong, Bing; He, Erkai; Qiu, Hao; Li, Jianqiu; Ji, Jie; Peijnenburg, Willie J G M; Liu, Yang; Zhao, Ling; Cao, Xinde (2019-07-01)
      There is a lack of appropriate models to delineate the toxicity of rare earth elements (REEs) while taking into account the factors that affect bioavailability. Here, standardized wheat (Triticum aestivum L.) root elongation tests were conducted to examine the impact of exposure conditions (i.e., varying Ca, Mg, Na, K and pH levels) on Y and Ce toxicity. Cation competition and electrostatic theory were examined for their applicability in explaining the observed variations in toxicity. Only Ca2+ and Mg2+ significantly alleviated the toxicity of Y3+ and Ce3+, while Na+, K+ and H+ showed no significant effects. Based on the cation competition, the derived binding constants for the hypothetical biotic ligands of wheat logKCaBL, logKMgBL, logKYBL, and logKCeBL were 3.87, 3.59, 6.70, and 6.48, respectively. The biotic ligand model (BLM) succeeded in predicting toxicities of Y and Ce, with more than 93% of the variance in toxicity explained. Given the BLM requires large data sets for deriving model parameters, attempts were further made to explore a simpler electrostatic based model to quantify REEs toxicity. The results demonstrated that the predictive capacity of the electrostatic approach, which considers ion activities at the plasma membrane surface, was comparable to that of BLM with at least 87% of the variations in toxicity explained. This suggested that the electrostatic theory can serve as a surrogate to BLM in modeling Y and Ce toxicities. Therefore, we recommend the BLM and electrostatic-based model as effective approaches to incorporate bioavailability in quantifying REEs toxicity in the presence of various levels of other major cations.
    • Cationically modified membranes using covalent layer-by-layer assembly for antiviral applications in drinking water.

      Sinclair TR; Patil A; Raza BG; Reurink D; Hengel SK van den; Rutjes SA; Roda Husman AM de; Roesink HDW; Vos WM de (2019-01-15)
    • CD1b presents self and Borrelia burgdorferi diacylglycerols to human T cells.

      Reinink, Peter; Souter, Michael N T; Cheng, Tan-Yun; van Gorkom, Tamara; Lenz, Stefanie; Kubler-Kielb, Joanna; Strle, Klemen; Kremer, Kristin; Thijsen, Steven F T; Steere, Allen C; et al. (2019-03-10)
      Lyme disease is a common multisystem disease caused by infection with a tick-transmitted spirochete, Borrelia burgdorferi and related Borrelia species. The monoglycosylated diacylglycerol known as B. burgdorferi glycolipid II (BbGL-II) is a major target of antibodies in sera from infected individuals. Here, we show that CD1b presents BbGL-II to human T cells and that the TCR mediates the recognition. However, we did not detect increased frequency of CD1b-BbGL-II binding T cells in the peripheral blood of Lyme disease patients compared to controls. Unexpectedly, mapping the T cell specificity for BbGL-II-like molecules using tetramers and activation assays revealed a concomitant response to CD1b-expressing APCs in absence of BbGL-II. Further, among all major classes of self-lipid tested, BbGL-II responsive TCRs show strong cross-reactivity to diacylglycerol, a self-lipid antigen with structural similarities to BbGL-II. Extending prior work on MHC and CD1b, CD1c, and CD1d proteins, this study provides evidence for cross-reactive CD1b-restricted T cell responses to bacterial and self-antigens, and identifies chemically defined targets for future discovery of self and foreign antigen cross-reactive T cells.
    • CDHR3 gene variation and childhood bronchiolitis.

      Husby, Anders; Pasanen, Anu; Waage, Johannes; Sevelsted, Astrid; Hodemaekers, Hennie; Janssen, Riny; Karjalainen, Minna K; Stokholm, Jakob; Chawes, Bo L; Korppi, Matti; et al. (2017-11)