Background and Purpose-Our study aim was to estimate risk of incident stroke based on levels of hs-cTn (high-sensitivity cardiac troponin), a specific biomarker indicating myocardial injury, in the... Show moreBackground and Purpose-Our study aim was to estimate risk of incident stroke based on levels of hs-cTn (high-sensitivity cardiac troponin), a specific biomarker indicating myocardial injury, in the general population, patients with atrial fibrillation, and patients with previous stroke.Methods-Embase, PubMed, and Web of Science were searched until March 14, 2019 to identify relevant articles. Randomized controlled trials and cohort studies assessing the risk of incident stroke based on hs-cTn were eligible. Pooled adjusted hazard ratios including 95% CI were calculated using a random-effects model due to study heterogeneity per population, coding of hs-cTn (categorical/continuous data), per hs-cTn subunit (T or I), for low risk of bias, and for all-cause and ischemic stroke separately.Results-We included 17 articles with 96 702 participants. In studies conducted in the general population (n=12; 77 780 participants), the pooled adjusted hazard ratio for incident stroke was 1.25 (CI, 1.10-1.40) for high versus low hs-cTn (as defined by included studies) during an average follow-up of 1 to 20 years (median 10). When categorical data were used, this was increased to 1.58 (CI, 1.26-1.90). The results were robust when accounting for stroke classification (all-cause stroke/ischemic stroke), hs-cTn subunit, risk of bias, and coding of hs-cTn. In patients with atrial fibrillation (4 studies; 18 725 participants), the pooled adjusted hazard ratio for incident stroke was 1.95 (CI, 1.29-2.62) for high versus low hs-cTn. Due to lack of data (one study, 197 participants), no meta-analysis could be performed in patients with previous stroke.Conclusions-This meta-analysis suggests that hs-cTn can be regarded as a risk marker for incident stroke, with different effect size in different subgroups. More research about the association between hs-cTn and incident stroke in high-risk populations is needed, especially in patients with history of ischemic stroke. Show less
Hagenbeek, F.A.; Roetman, P.J.; Pool, R.; Kluft, C.; Harms, A.C.; Dongen, J. van; ... ; Boomsma, D.I. 2020
Biomarkers are of interest as potential diagnostic and predictive instruments in personalized medicine. We present the first urinary metabolomics biomarker study of childhood aggression. We aim to... Show moreBiomarkers are of interest as potential diagnostic and predictive instruments in personalized medicine. We present the first urinary metabolomics biomarker study of childhood aggression. We aim to examine the association of urinary metabolites and neurotransmitter ratios involved in key metabolic and neurotransmitter pathways in a large cohort of twins (N = 1,347) and clinic-referred children (N = 183) with an average age of 9.7 years. This study is part of ACTION (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies), in which we developed a standardized protocol for large-scale collection of urine samples in children. Our analytical design consisted of three phases: a discovery phase in twins scoring low or high on aggression (N = 783); a replication phase in twin pairs discordant for aggression (N = 378); and a validation phase in clinical cases and matched twin controls (N = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine (beta = 0.36; SE = 0.09; p = 0.004), and gamma-L-glutamyl-L-alanine (beta = 0.32; SE = 0.09; p = 0.01) remained significant after multiple testing. Although non-significant, the directions of effect were congruent between the discovery and replication analyses for six biomarkers and two neurotransmitter ratios and the concentrations of 6 amines differed between low and high aggressive twins. In the validation analyses, the top biomarkers and neurotransmitter ratios, with congruent directions of effect, showed no significant associations with childhood aggression. We find suggestive evidence for associations of childhood aggression with metabolic dysregulation of neurotransmission, oxidative stress, and energy metabolism. Although replication is required, our findings provide starting points to investigate causal and pleiotropic effects of these dysregulations on childhood aggression. Show less
Introduction: Gaseous microemboli that originate from the cardiopulmonary bypass circuit may contribute to adverse outcome after cardiac surgery. We prospectively evaluated the influence of gaseous... Show moreIntroduction: Gaseous microemboli that originate from the cardiopulmonary bypass circuit may contribute to adverse outcome after cardiac surgery. We prospectively evaluated the influence of gaseous microemboli on the release of various biomarkers after use of a minimally invasive extracorporeal technology system. Methods: In 70 patients undergoing coronary artery bypass grafting with minimized cardiopulmonary bypass, gaseous microemboli were measured intraoperatively with a bubble counter. Intra- and postoperative biomarker levels for inflammatory response (interleukin-6, C5b-9), endothelial damage (von Willebrand factor, soluble vascular cell adhesion molecule-1), oxidative stress (malondialdehyde, 8-isoprostane, neuroketal), and neurological injury (neuron-specific enolase, brain-type fatty acid-binding protein) were analyzed using immune assay techniques. The relationship between gaseous microemboli number or volume and the incremental area under the curve (iAUC(24h)) or peak change for the biomarkers was calculated. Results: All biomarkers except for malondialdehyde increased at least temporarily after coronary artery bypass grafting with a minimally invasive extracorporeal technology system. The median total gaseous microemboli number was 6,174 (interquartile range: 3,507-10,531) and the median total gaseous microemboli volume was 4.31 mu L (interquartile range: 2.71-8.50). There were no significant correlations between total gaseous microemboli number or volume and iAUC(24h) or peak change for any of the biomarkers. After controlling for the variance of possible other predictor variables, multiple linear regression analysis showed no association between gaseous microemboli parameters and release of biomarkers. Conclusion: This study showed no evidence that gaseous microemboli contribute to increased biomarker levels after coronary artery bypass grafting with cardiopulmonary bypass. A reason for the absence of damage by gaseous microemboli may be the relative and considerably small amount of gaseous microemboli entering the patients in this study. Show less
Brunet, M.; Gelder, T. van; Asberg, A.; Haufroid, V.; Hesselink, D.A.; Langman, L.; ... ; Bergan, S. 2019
Checkpoint blockade immunotherapies have revolutionised cancer treatment in the last decade. Nevertheless, these are only beneficial for a small proportion of cancer patients. Important... Show moreCheckpoint blockade immunotherapies have revolutionised cancer treatment in the last decade. Nevertheless, these are only beneficial for a small proportion of cancer patients. Important prognosticators for response to immunotherapy are the mutation burden of tumours as well as the quality and quantity of tumour-infiltrating immune cells. High-throughput multiplex immunophenotyping technologies have a central role in deciphering the complexity of anti-tumour immune responses. Current techniques for the immunophenotyping of solid tumours are held back by the lack of spatial context, limitations in the number of targets that can be visualised simultaneously, and/or cumbersome protocols. We developed a tyramide signal amplification-free method for the simultaneous detection of seven cellular targets by immunofluorescence. This method overcomes limitations posed by most widespread techniques and provides a unique tool for extensive phenotyping by multispectral fluorescence microscopy. Furthermore, it can be easily implemented as a high-throughput technology for validation of discovery sets generated by RNA sequencing or mass cytometry and may serve in the future as a complementary diagnostic tool. Show less
Magro Checa, C.; Steup-Beekman, G.M.; Huizinga, T.W.; Buchem, M.A. van; Ronen, I. 2018
Congenital CMV infection (cCMV) is the most common congenital infection causing permanent long-term impairments (LTI). cCMV immunopathogenesis is largely unknown due to the complex interplay... Show moreCongenital CMV infection (cCMV) is the most common congenital infection causing permanent long-term impairments (LTI). cCMV immunopathogenesis is largely unknown due to the complex interplay between viral, maternal, placental, and child factors. In this study, a large retrospective nationwide cohort of children with cCMV and their mothers was used. HLA-C, HLA-E, and HLA-G were assessed in 96 mother-child pairs in relation to symptoms at birth and LTI at 6 years of age. The mothers were additionally typed for killer cell immunoglobulin-like receptors. The maternal HLA-G 14 bp deletion/deletion polymorphism was associated with a worse outcome, as the immunomodulation effect of higher protein levels may induce less CMV control, with a direct impact on placenta and fetus. The absence of maternal HLA-C belonging to the C2 group was associated with symptoms at birth, as activating signals on decidual NK may override inhibitory signals, contributing to a placental pro-inflammatory environment. Here, the increased HLA-E*0101 and HLA-C mismatches, which were associated with symptoms at birth, may enhance maternal allo-reactivity to fetal Ags, and cause suboptimal viral clearance. Finally, HLA-C non-inherited maternal antigens (NIMAs) were associated with LTI. The tolerance induced in the fetus toward NIMAs may indirectly induce a suboptimal CMV antiviral response throughout childhood. In light of our findings, the potential role of maternal-child HLA in controlling CMV infection and cCMV-related disease, and the clinical value as predictor for long-term outcome certainly deserve further evaluation. Show less
