Background The Netherlands Armed Forces have been successfully using deep-frozen (- 80 degrees C) thrombocyte concentrate (DTC) for the treatment of (massive) bleeding trauma patients in austere... Show moreBackground The Netherlands Armed Forces have been successfully using deep-frozen (- 80 degrees C) thrombocyte concentrate (DTC) for the treatment of (massive) bleeding trauma patients in austere environments since 2001. However, high-quality evidence for the effectiveness and safety of DTCs is currently lacking. Therefore, the MAssive transfusion of Frozen bloOD (MAFOD) trial is designed to compare the haemostatic effect of DTCs versus room temperature-stored platelets (RSP) in the treatment of surgical bleeding. Methods The MAFOD trial is a single-blinded, randomized controlled non-inferiority trial and will be conducted in three level 1 trauma centres in The Netherlands. Patients 12 years or older, alive at hospital presentation, requiring a massive transfusion including platelets and with signed (deferred) consent will be included. The primary outcome is the percentage of patients that have achieved haemostasis within 6 h and show signs of life. Haemostasis is defined as the time in minutes from arrival to the time of the last blood component transfusion (plasma/platelets or red blood cells), followed by a 2-h transfusion-free period. This is the first randomized controlled study investigating DTCs in trauma and vascular surgical bleeding. Discussion The hypothesis is that the percentage of patients that will achieve haemostasis in the DTC group is at least equal to the RSP group (85%). With a power of 80%, a significance level of 5% and a non-inferiority limit of 15%, a total of 71 patients in each arm are required, thus resulting in a total of 158 patients, including a 10% refusal rate. The data collected during the study could help improve the use of platelets during resuscitation management. If proven non-inferior in civilian settings, frozen platelets may be used in the future to optimize logistics and improve platelet availability in rural or remote areas for the treatment of (massive) bleeding trauma patients in civilian settings. Show less
Maas, S.C.E.; Vidaki, A.; Teumer, A.; Costeira, R.; Wilson, R.; Dongen, J. van; ... ; Kayser, M. 2021
Background Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol... Show moreBackground Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol consumption from blood was reported with high accuracy, but these results were based on employing the same dataset for model training and testing, which can lead to accuracy overestimation. Moreover, only subsets of alcohol consumption categories were used, which makes it impossible to extrapolate such models to the general population. By using data from eight population-based European cohorts (N = 4677), we internally and externally validated the previously reported biomarkers and models for epigenetic inference of alcohol consumption from blood and developed new models comprising all data from all categories. Results By employing data from six European cohorts (N = 2883), we empirically tested the reproducibility of the previously suggested biomarkers and prediction models via ten-fold internal cross-validation. In contrast to previous findings, all seven models based on 144-CpGs yielded lower mean AUCs compared to the models with less CpGs. For instance, the 144-CpG heavy versus non-drinkers model gave an AUC of 0.78 +/- 0.06, while the 5 and 23 CpG models achieved 0.83 +/- 0.05, respectively. The transportability of the models was empirically tested via external validation in three independent European cohorts (N = 1794), revealing high AUC variance between datasets within models. For instance, the 144-CpG heavy versus non-drinkers model yielded AUCs ranging from 0.60 to 0.84 between datasets. The newly developed models that considered data from all categories showed low AUCs but gave low AUC variation in the external validation. For instance, the 144-CpG heavy and at-risk versus light and non-drinkers model achieved AUCs of 0.67 +/- 0.02 in the internal cross-validation and 0.61-0.66 in the external validation datasets. Conclusions The outcomes of our internal and external validation demonstrate that the previously reported prediction models suffer from both overfitting and accuracy overestimation. Our results show that the previously proposed biomarkers are not yet sufficient for accurate and robust inference of alcohol consumption from blood. Overall, our findings imply that DNA methylation prediction biomarkers and models need to be improved considerably before epigenetic inference of alcohol consumption from blood can be considered for practical applications. Show less
Harder, A.V.E.; Vijfhuizen, L.S.; Henneman, P.; Dijk, K.W. van; Duijn, C.M. van; Terwindt, G.M.; Maagdenberg, A.M.J.M. van den 2021
Background Migraine is a common brain disorder but reliable diagnostic biomarkers in blood are still lacking. Our aim was to identify, using proton nuclear magnetic resonance (H-1-NMR) spectroscopy... Show moreBackground Migraine is a common brain disorder but reliable diagnostic biomarkers in blood are still lacking. Our aim was to identify, using proton nuclear magnetic resonance (H-1-NMR) spectroscopy, metabolites in serum that are associated with lifetime and active migraine by comparing metabolic profiles of patients and controls. Methods Fasting serum samples from 313 migraine patients and 1512 controls from the Erasmus Rucphen Family (ERF) study were available for H-1-NMR spectroscopy. Data was analysed using elastic net regression analysis. Results A total of 100 signals representing 49 different metabolites were detected in 289 cases (of which 150 active migraine patients) and 1360 controls. We were able to identify profiles consisting of 6 metabolites predictive for lifetime migraine status and 22 metabolites predictive for active migraine status. We estimated with subsequent regression models that after correction for age, sex, BMI and smoking, the association with the metabolite profile in active migraine remained. Several of the metabolites in this profile are involved in lipid, glucose and amino acid metabolism. Conclusion This study indicates that metabolic profiles, based on serum concentrations of several metabolites, including lipids, amino acids and metabolites of glucose metabolism, can distinguish active migraine patients from controls. Show less
Geelhoed, W.J.; Boonekamp, M.; Stadt, H. van de; Badulescu, S.; Lalai, R.A.; Groeneweg, K.E.; ... ; Rotmans, J.I. 2021
The cannulation of blood vessels is one of the most basic and essential interventions in medical practice. A common adverse event of this procedure is miscannulation with infiltration of the second... Show moreThe cannulation of blood vessels is one of the most basic and essential interventions in medical practice. A common adverse event of this procedure is miscannulation with infiltration of the second part of the vessel wall, often resulting in a perivascular hematoma. In hemodialysis patients, surgically created arteriovenous conduits are cannulated 3-4 times per week to provide sufficient blood supply to the hemodialysis machine. However, the high blood flow and pressure in these vascular access sites increase the risk of complications upon miscannulation. A novel needle system that allows for rapid automatic retraction of the needle in response to contact with blood after positioning the cannula in the blood vessel was developed to reduce the risk of miscannulation. The device can easily be incorporated into existing needle designs. The mechanical functionality of the device was validated by testing prototypes in an ex vivo system. Optimization of the needle system was performed to enhance response time and piston shape. A final prototype design was manufactured and validated. The optimal membrane composition and piston shape were determined, which resulted in a needle response time of 40 ms upon contact with fluid at a pressure of 100 mmHg (arterial pressure). Here, we have successfully designed, mechanically validated, and tested a novel automated rapid needle retraction system that allows incorporation into existing needle systems. This device could notably decrease the difficulty of vessel cannulation and the prevalence of hematoma formation. Show less
Heart failure is a major health care problem with high mortality. Although advances have been made in treatment of patients suffering from heart failure with reduced ejection fraction, this is not... Show moreHeart failure is a major health care problem with high mortality. Although advances have been made in treatment of patients suffering from heart failure with reduced ejection fraction, this is not true for patients suffering from heart failure with preserved ejection fraction. The mechanism underlying heart failure with preserved ejection fraction is still unclear. Recent evidence suggests that factors circulating in blood might have an effect on the microvessels, including those in the heart. To diagnose and treat microvascular diseases, we aim to explore the association of circulating plasma factors with microvascular integrity. As current human 2D models with cultured endothelial cells lack sufficient complexity to assess the function of microvascular endothelial-pericyte interactions, research on microvascular loss largely depends on animal models. To mimic the microarchitecture and functions of the human blood vessel in a more efficient way for drug discovery, we developed the microvessel-on-a-chip. This system allowed us to screen microvascular destabilization factors in blood and study the efficacy of potential drugs for microvascular diseases. In conclusion, our platform may serve as a unique tool for microvascular destabilization studies as well as for the development of novel therapeutic strategies to combat microvascular complications. Show less
The incidence of bacterial infections and sepsis, as well as the mortality risk from sepsis, is sex specific. These clinical findings have been attributed to sex differences in immune... Show moreThe incidence of bacterial infections and sepsis, as well as the mortality risk from sepsis, is sex specific. These clinical findings have been attributed to sex differences in immune responsiveness. The aim of the present study was to investigate sex differences in monocyte-derived cytokine production response upon stimulation with the gram-negative stimulus lipopolysaccharide (LPS) using cytokine data from 15 study populations. Individual data on ex vivo cytokine production response upon stimulation with LPS in whole blood were available for 4,020 subjects originating from these 15 study populations, either from the general population or from patient populations with specific diseases. Men had a stronger cytokine production response than women to LPS for tumour necrosis factor-alpha, interleukin (IL)-6, IL-12, IL-1 beta, IL-1RA, and IL-10, but not for interferon-gamma. The granulocyte-macrophage colony-stimulating factor production response was lower in men than in women. These sex differences were independent of chronological age. As men had higher monocyte concentrations, we normalized the cytokine production responses for monocyte concentration. After normalization, the sex differences in cytokine production response to LPS disappeared, except for IL-10, for which the production response was lower in men than in women. A sex-based approach to interpreting immune responsiveness is crucial. Show less
Bergen, A.A.; Arya, S.; Koster, C.; Pilgrim, M.G.; Wiatrek-Moumoulidis, D.; Spek, P.J. van der; ... ; Lengyel, I. 2019
Our current mycosis fungoides (MF) and Sezary Syndrome (SS) staging system includes blood-classification from B0-B2 for patch/plaque/tumour or erythroderma based on manual Sezary counts but results... Show moreOur current mycosis fungoides (MF) and Sezary Syndrome (SS) staging system includes blood-classification from B0-B2 for patch/plaque/tumour or erythroderma based on manual Sezary counts but results from our EORTC survey confirm these are rarely performed in patch/plaque/tumour MF, and there is a trend towards using flow cytometry to measure blood-class. Accurately assigning blood-class effects overall stage and the 'global response' used to measure treatment responses in MF/SS and hence impacts management. The EORTC Cutaneous Lymphoma Task Force Committee have reviewed the literature and held a Workshop (June 2017) to agree a definition of blood-class according to flow cytometry.No large study comparing blood-class as defined by Sezary count with flow cytometry has been performed in MF/SS. The definition of blood-class by flow cytometry varies between publications. Low-level blood involvement occurs in patch/plaque/tumour much less than erythroderma (p < 0.001). The prognostic relevance of blood involvement (B1 or B2) in patch/plaque/tumour is not known. Studies have not shown a statistically worse difference in prognosis in erythrodermic MF patients with low-level blood involvement (IIIB) versus those without (IIIA), but Sezary patients who by definition have a leukaemic blood picture (staged IVA1 or higher) have a worse prognosis.For consistency flow, definition for blood-class must be an objective measurement. We propose absolute counts of either CD4thornCD7-or CD4+CD26- where B0<250/mu L, B1 = 250/mu l -<1000/mu L and B2 >= 1000/mu L plus a T-cell blood clone. Fluctuations between B0 and B1 should not be considered in the treatment response criteria until further prognostic information is known. (C) 2018 The Authors. Published by Elsevier Ltd. Show less
Slieker, R.C.; Heijden, A.A.W.A. van der; Leeuwen, N. van; Mei, H.L.; Nijpels, G.; Beulens, J.W.J.; Hart, L.M. 't 2018
Background: Huntington's disease (HD) is a devastating brain disorder with no effective treatment or cure available. The scarcity of brain tissue makes it hard to study changes in the brain and... Show moreBackground: Huntington's disease (HD) is a devastating brain disorder with no effective treatment or cure available. The scarcity of brain tissue makes it hard to study changes in the brain and impossible to perform longitudinal studies. However, peripheral pathology in HD suggests that it is possible to study the disease using peripheral tissue as a monitoring tool for disease progression and/or efficacy of novel therapies. In this study, we investigated if blood can be used to monitor disease severity and progression in brain. Since previous attempts using only gene expression proved unsuccessful, we compared blood and brain Huntington's disease signatures in a functional context.Methods: Microarray HD gene expression profiles from three brain regions were compared to the transcriptome of HD blood generated by next generation sequencing. The comparison was performed with a combination of weighted gene co-expression network analysis and literature based functional analysis (Concept Profile Analysis). Uniquely, our comparison of blood and brain datasets was not based on (the very limited) gene overlap but on the similarity between the gene annotations in four different semantic categories: "biological process", "cellular component", "molecular function" and "disease or syndrome".Results: We identified signatures in HD blood reflecting a broad pathophysiological spectrum, including alterations in the immune response, sphingolipid biosynthetic processes, lipid transport, cell signaling, protein modification, spliceosome, RNA splicing, vesicle transport, cell signaling and synaptic transmission. Part of this spectrum was reminiscent of the brain pathology. The HD signatures in caudate nucleus and BA4 exhibited the highest similarity with blood, irrespective of the category of semantic annotations used. BA9 exhibited an intermediate similarity, while cerebellum had the least similarity. We present two signatures that were shared between blood and brain: immune response and spinocerebellar ataxias.Conclusions: Our results demonstrate that HD blood exhibits dysregulation that is similar to brain at a functional level, but not necessarily at the level of individual genes. We report two common signatures that can be used to monitor the pathology in brain of HD patients in a non-invasive manner. Our results are an exemplar of how signals in blood data can be used to represent brain disorders. Our methodology can be used to study disease specific signatures in diseases where heterogeneous tissues are involved in the pathology. Show less
Mina, E.; Roon-Mom, W. van; Hettne, K.; Zwet, E. van; Goeman, J.; Neri, C.; ... ; Roos, M. 2016
Chapter 2 describes the results of a RCT on the effect of a restrictive trigger on RBC sparing. In three hospitals, a restrictive transfusion policy was compared with standard care transfusion... Show moreChapter 2 describes the results of a RCT on the effect of a restrictive trigger on RBC sparing. In three hospitals, a restrictive transfusion policy was compared with standard care transfusion policy. A randomised comparison of transfusion triggers in elective orthopaedic surgery using leucocyte-depleted red blood cells was performed. The clinical consequences of this restrictive transfusion policy on post-operative complications and well-being are discussed in Chapter 3. Quality of Life and fatigue scores in relation to postoperative haemoglobin levels were analysed in Chapter 4. In Chapter 5 we investigated the efficacy and feasibility of two types of postoperative drainage and re-infusion systems and compared these to a control group. To evaluate the immuno-modulatory effects of salvaged blood in the post-operative patient, we analysed the effect of autologous salvaged blood re-infusion on the patients__ cytokine gene expression profiles compared to the effect of surgery itself (Chapter 6). Chapter 7 reports the combined strategies of Epo and autologous salvaged blood on RBC use compared to a control group under a restrictive transfusion policy (TOMaat study). In Chapter 8, future trends and ongoing studies are discussed in order to aim for an optimal and Tailor Made Patient Blood Management Program for elective orthopaedic surgery patients. In the final chapter, Chapter 9, an implementation protocol is described to investigate the barriers and facilitators for implementation of the TOMaat study results in daily practice. Show less
