Publications by authors named "Wouter W van Solinge"

121 Publications

Untargeted metabolic profiling in dried blood spots identifies disease fingerprint for pyruvate kinase deficiency.

Haematologica 2020 Sep 10;Online ahead of print. Epub 2020 Sep 10.

Central Diagnostic Laboratory-Research, University Medical Center Utrecht, Utrecht.

The diagnostic evaluation and clinical characterization of rare hereditary anemia (RHA) is to date still challenging. In particular, there is little knowledge on the broad metabolic impact of many of the molecular defects underlying RHA. In this study we explored the potential of untargeted metabolomics to diagnose a relatively common type of RHA: Pyruvate Kinase Deficiency (PKD). In total, 1903 unique metabolite features were identified in dried blood spot samples from 16 PKD patients and 32 healthy controls. A metabolic fingerprint was identified using a machine learning algorithm, and subsequently a binary classification model was designed. The model showed high performance characteristics (AUC 0.990, 95%CI 0.981-0.999) and an accurate class assignment was achieved for all newly added control (13) and patient samples (6), with the exception of one patient (accuracy 94%). Important metabolites in the metabolic fingerprint included glycolytic intermediates, polyamines and several acyl carnitines. In general, the application of untargeted metabolomics in dried blood spots is a novel functional tool that holds promise for diagnostic stratification and studies on disease pathophysiology in RHA.
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http://dx.doi.org/10.3324/haematol.2020.266957DOI Listing
September 2020

Neutrophil fluorescence in clozapine users is attributable to a 14kDa secretable protein.

Pharmacol Res Perspect 2020 10;8(5):e00627

Department of Respiratory Medicine, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

Clozapine is the only antipsychotic agent with demonstrated efficacy in refractory schizophrenia. However, use of clozapine is hampered by its adverse effects, including potentially fatal agranulocytosis. Recently, we showed an association between neutrophil autofluorescence and clozapine use. In this study, we evaluated the subcellular localization of clozapine-associated fluorescence and tried to elucidate its source. Neutrophils of clozapine users were analyzed with fluorescence microscopy to determine the emission spectrum and localization of the fluorescence signal. Next, these neutrophils were stimulated with different degranulation agents to determine the localization of fluorescence. Lastly, isolated neutrophil lysates of clozapine users were separated by SDS-PAGE and evaluated. Clozapine-associated fluorescence ranged from 420 nm to 720 nm, peaking at 500-550 nm. Fluorescence was localized in a large number of small loci, suggesting granular localization of the signal. Neutrophil degranulation induced by Cytochalasin B/fMLF reduced fluorescence, whereas platelet-activating factor (PAF)/fMLF induced degranulation did not, indicating that the fluorescence originates from a secretable substance in azurophilic granules. SDS-PAGE of isolated neutrophil lysates revealed a fluorescent 14kDa band, suggesting that neutrophil fluorescence is likely to be originated from a 14kDa protein/peptide fragment. We conclude that clozapine-associated fluorescence in neutrophils is originating from a 14kDa soluble protein (fragment) present in azurophilic granules of neutrophils. This protein could be an autofluorescent protein already present in the cell and upregulated by clozapine, or a protein altered by clozapine to express fluorescence. Future studies should further explore the identity of this protein and its potential role in the pathophysiology of clozapine-induced agranulocytosis.
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http://dx.doi.org/10.1002/prp2.627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437349PMC
October 2020

Fragile neutrophils in surgical patients: A phenomenon associated with critical illness.

PLoS One 2020 4;15(8):e0236596. Epub 2020 Aug 4.

Department of trauma surgery, University Medical Center Utrecht, Utrecht, the Netherlands.

Leukocyte viability (determined by e.g. propidium iodide [PI] staining) is automatically measured by hematology analyzers to check for delayed bench time. Incidental findings in fresh blood samples revealed the existence of leukocytes with decreased viability in critically ill surgical patients. Not much is known about these cells and their functional and/or clinical implications. Therefore, we investigated the incidence of decreased leukocyte viability, the implications for leukocyte functioning and its relation with clinical outcomes. An automated alarm was set in a routine hematology analyzer (Cell-Dyn Sapphire) for the presence of non-viable leukocytes characterized by increased fluorescence in the PI-channel (FL3:630±30nm). Patients with non-viable leukocytes were prospectively included and blood samples were drawn to investigate leukocyte viability in detail and to investigate leukocyte functioning (phagocytosis and responsiveness to a bacterial stimulus). Then, a retrospective analysis was conducted to investigate the incidence of fragile neutrophils in the circulation and clinical outcomes of surgical patients with fragile neutrophils hospitalized between 2013-2017. A high FL3 signal was either caused by 1) neutrophil autofluorescence which was considered false positive, or by 2) actual non-viable PI-positive neutrophils in the blood sample. These two causes could be distinguished using automatically generated data from the hematology analyzer. The non-viable (PI-positive) neutrophils proved to be viable (PI-negative) in non-lysed blood samples, and were therefore referred to as 'fragile neutrophils'. Overall leukocyte functioning was not impaired in patients with fragile neutrophils. Of the 11 872 retrospectively included surgical patients, 75 (0.63%) were identified to have fragile neutrophils during hospitalization. Of all patients with fragile neutrophils, 75.7% developed an infection, 70.3% were admitted to the ICU and 31.3% died during hospitalization. In conclusion, fragile neutrophils occur in the circulation of critically ill surgical patients. These cells can be automatically detected during routine blood analyses and are an indicator of critical illness.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236596PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402494PMC
October 2020

Low-Density Lipoprotein Cholesterol Target Attainment in Patients With Established Cardiovascular Disease: Analysis of Routine Care Data.

JMIR Med Inform 2020 Apr 2;8(4):e16400. Epub 2020 Apr 2.

Laboratory of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Background: Direct feedback on quality of care is one of the key features of a learning health care system (LHS), enabling health care professionals to improve upon the routine clinical care of their patients during practice.

Objective: This study aimed to evaluate the potential of routine care data extracted from electronic health records (EHRs) in order to obtain reliable information on low-density lipoprotein cholesterol (LDL-c) management in cardiovascular disease (CVD) patients referred to a tertiary care center.

Methods: We extracted all LDL-c measurements from the EHRs of patients with a history of CVD referred to the University Medical Center Utrecht. We assessed LDL-c target attainment at the time of referral and per year. In patients with multiple measurements, we analyzed LDL-c trajectories, truncated at 6 follow-up measurements. Lastly, we performed a logistic regression analysis to investigate factors associated with improvement of LDL-c at the next measurement.

Results: Between February 2003 and December 2017, 250,749 LDL-c measurements were taken from 95,795 patients, of whom 23,932 had a history of CVD. At the time of referral, 51% of patients had not reached their LDL-c target. A large proportion of patients (55%) had no follow-up LDL-c measurements. Most of the patients with repeated measurements showed no change in LDL-c levels over time: the transition probability to remain in the same category was up to 0.84. Sequence clustering analysis showed more women (odds ratio 1.18, 95% CI 1.07-1.10) in the cluster with both most measurements off target and the most LDL-c measurements furthest from the target. Timing of drug prescription was difficult to determine from our data, limiting the interpretation of results regarding medication management.

Conclusions: Routine care data can be used to provide feedback on quality of care, such as LDL-c target attainment. These routine care data show high off-target prevalence and little change in LDL-c over time. Registrations of diagnosis; follow-up trajectory, including primary and secondary care; and medication use need to be improved in order to enhance usability of the EHR system for adequate feedback.
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http://dx.doi.org/10.2196/16400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163416PMC
April 2020

AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes.

Haematologica 2021 01 1;106(1):238-249. Epub 2021 Jan 1.

Laboratory of Clinical Chemistry and Haematology, University Medical Center Utrecht.

Pyruvate kinase (PK) deficiency is a rare hereditary disorder affecting red cell (RBC) glycolysis, causing changes in metabolism including a deficiency in ATP. This affects red cell homeostasis, promoting premature removal of RBCs from the circulation. In this study we characterized and evaluated the effect of AG-348, an allosteric activator of PK that is currently in clinical trials for treatment of PK deficiency, on RBCs and erythroid precursors from PK-deficient patients. In 15 patients ex vivo treatment with AG-348 resulted in increased enzymatic activity in all patient cells after 24 hours (mean increase 1.8-fold, range 1.2-3.4). ATP levels increased (mean increase 1.5-fold, range 1.0-2.2) similar to control cells (mean increase 1.6-fold, range, 1.4-1.8). Generally, PK thermostability was strongly reduced in PK-deficient RBCs. Ex vivo treatment with AG-348 increased residual activity 1.4 to >10-fold than residual activity of vehicle-treated samples. Protein analyses suggests that a sufficient level of PK protein is required for cells to respond to AG-348 treatment ex-vivo, as treatment effects were minimal in patient cells with very low or undetectable levels of PK-R. In half of the patients, ex vivo treatment with AG-348 was associated with an increase in RBC deformability. These data support the hypothesis that drug intervention with AG-348 effectively upregulates PK enzymatic activity and increases stability in PK-deficient RBCs over a broad range of PKLR genotypes. The concomitant increase in ATP levels suggests that glycolytic pathway activity may be restored. AG-348 treatment may represent an attractive way to correct the underlying pathologies of PK deficiency. (AG-348 is currently in clinical trials for the treatment of PK deficiency. ClinicalTrials.gov: NCT02476916, NCT03853798, NCT03548220, NCT03559699).
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http://dx.doi.org/10.3324/haematol.2019.238865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776327PMC
January 2021

Reticulated Platelets as Predictor of Myocardial Injury and 30 Day Mortality After Non-cardiac Surgery.

Eur J Vasc Endovasc Surg 2020 02 4;59(2):309-318. Epub 2019 Dec 4.

Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, the Netherlands. Electronic address:

Objective: A pre-operative marker for identification of patients at risk of peri-operative adverse events and 30 day mortality might be the percentage of young, reticulated platelets (pRP). This study aimed to determine the predictive value of pre-operative pRP on post-operative myocardial injury (PMI) and 30 day mortality, in patients aged ≥ 60 years undergoing moderate to high risk non-cardiac surgery.

Methods: The incidence of PMI (troponin I > 0.06 μg/L) and 30 day mortality was compared for patients with normal and high pRP (≥2.82%) obtained from The Utrecht Patient Orientated Database. The predictive pRP value was assessed using logistic regression. A prediction model for PMI or 30 day mortality with known risk factors was compared with a model including increased pRP using the area under the receiving operator characteristics curve (AUROC).

Results: In total, 26.5% (607/2289) patients showed pre-operative increased pRP. Increased pRP was associated with more PMI and 30 day mortality compared with normal pRP (36.1% vs. 28.3%, p < .001 and 8.6% vs. 3.6%, p < .001). The median pRP was higher in patients suffering PMI and 30 day mortality compared with not (2.21 [IQR: 1.57-3.11] vs. 2.07 [IQR: 1.52-1.78], p = .002, and 2.63 [IQR: 1.76-4.15] vs. 2.09 [IQR: 1.52-3.98], p < .001). pRP was independently related to PMI (OR: 1.28 [95% CI: 1.04-1.59], p = .02) and 30 day mortality (OR: 2.35 [95% CI: 1.56-3.55], p < .001). Adding increased pRP to the predictive model of PMI or 30 day mortality did not increase the AUROC 0.71 vs. 0.72, and 0.80 vs. 0.81.

Conclusion: In patients undergoing major non-cardiac surgery, increased pre-operative pRP is related to 30 day mortality and PMI.
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http://dx.doi.org/10.1016/j.ejvs.2019.06.027DOI Listing
February 2020

Osteoprotegerin is Higher in Sepsis Than in Noninfectious SIRS and Predicts 30-Day Mortality of SIRS Patients in the Intensive Care.

J Appl Lab Med 2019 01 16;3(4):559-568. Epub 2018 Jul 16.

Intensive Care Center, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.

Background: Systemic inflammatory response syndrome (SIRS) is a complex disease involving multiple pathways and organs. Biomarkers reflecting these pathways and organ function could correlate with the severity of the disease. Osteoprotegerin (OPG), mainly known for its role in bone metabolism, is also involved in the immune and vascular system and is therefore an interesting biomarker to study in SIRS patients. In this prospective observational study, we investigated the correlation of plasma OPG concentrations, sepsis, and 30-day mortality of SIRS patients in the intensive care unit (ICU).

Methods: This observational, single-center, cohort study included 313 consecutive patients admitted to the ICU, with an anticipated stay of more than 48 h and SIRS on admission. Data from included patients were collected daily until discharge or death for a maximum of 10 days. Thirty-day mortality was retrospectively assessed. OPG concentrations were measured in the first 48 h after admission. The relation of OPG with no sepsis, sepsis, and septic shock was assessed with the Kruskal-Wallis test and the Mann-Whitney -test. Cox proportional hazards regression was used to study OPG concentrations and 30-day mortality.

Results: OPG concentrations were higher in patients with sepsis and septic shock than in patients without sepsis. Furthermore, patients with OPG concentrations in the highest tertile at admission in the ICU have an increased risk of mortality within 30 days when compared to patients with OPG concentrations in the lowest and middle tertiles, independent of acute physiologic and chronic health evaluation (APACHE) and sequential organ failure assessment (SOFA) scores.

Conclusions: We show that OPG is a biomarker that correlates with sepsis and predicts mortality of SIRS patients in the ICU.
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http://dx.doi.org/10.1373/jalm.2018.026559DOI Listing
January 2019

Association of a Multifaceted Intervention With Ordering of Unnecessary Laboratory Tests Among Caregivers in Internal Medicine Departments.

JAMA Netw Open 2019 07 3;2(7):e197577. Epub 2019 Jul 3.

Section of Acute Medicine, Department of Internal Medicine, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Importance: Inappropriate use of laboratory testing is a challenging problem. Estimated overuse rates of approximately 20% have been reported. Effective, sustainable solutions to stimulate optimal use are needed.

Objective: To determine the association of a multifaceted intervention with laboratory test volume.

Design, Setting, And Participants: A before-after quality improvement study was performed between August 1, 2016, and April 30, 2018, in the internal medicine departments of 4 teaching hospitals in the Netherlands. Data on laboratory order volumes from 19 comparable hospitals were used as controls. The participants were clinicians ordering laboratory tests.

Interventions: The intervention included creating awareness through education and feedback, intensified supervision of residents, and changes in order entry systems. Interventions were performed by local project teams and guided by a central project team during a 6-month period. Sustainability was investigated during an 8-month follow-up period.

Main Outcomes And Measures: The primary outcome was the change in slope for laboratory test volume. Secondary outcomes were change in slope for laboratory expenditure, order volumes and expenditure for other diagnostic procedures, and clinical outcomes. Data were collected on duration of hospital stay, rate of repeated outpatient visits, 30-day readmission rate, and rate of unexpected prolonged duration of hospital stay for patients admitted for pneumonia.

Results: The numbers of internists and residents ordering tests in hospitals 1 to 4 were 16 and 30, 18 and 20, 13 and 17, and 21 and 60, respectively. Statistically significant changes in slope for laboratory test volume per patient contact were found at hospital 1 (change in slope, -1.55; 95% CI, -1.98 to -1.11; P < .001), hospital 3 (change in slope, -0.74; 95% CI, -1.42 to -0.07; P = .03), and hospital 4 (change in slope, -2.18; 95% CI, -3.27 to -1.08; P < .001). At hospital 2, the change in slope was not statistically significant (-0.34; 95% CI, -2.27 to 1.58; P = .73). Laboratory test volume per patient contact decreased by 11.4%, whereas the volume increased by 2.4% in 19 comparable hospitals. Statistically significant changes in slopes for laboratory costs and volumes and costs for other diagnostic procedures were also observed. Clinical outcomes were not associated with negative changes. Important facilitators were education, continuous attention for overuse, feedback, and residents' involvement. Important barriers were difficulties in data retrieval, difficulty in incorporation of principles in daily practice, and high resident turnover.

Conclusions And Relevance: A set of interventions aimed at changing caregivers' mindset was associated with a reduction in the laboratory test volume in all departments, whereas the volume increased in comparable hospitals in the Netherlands. This study provides a framework for nationwide implementation of interventions to reduce unnecessary laboratory testing.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.7577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659142PMC
July 2019

SAFE@HOME - Feasibility study of a telemonitoring platform combining blood pressure and preeclampsia symptoms in pregnancy care.

Eur J Obstet Gynecol Reprod Biol 2019 Sep 15;240:226-231. Epub 2019 Jul 15.

Department of Obstetrics and Gynecology, University Medical Center Utrecht, Utrecht University, the Netherlands.

Objective: To study the feasibility of a telemonitoring platform for hypertensive disease in pregnancy, consisting of a wireless blood pressure monitor and an app in combination with an integrated preeclampsia symptom checklist.

Study Design: Prospective observational study with 14 pregnant women during a 15 weekday study period. For feasibility purposes, compliance was measured by evaluating the number of entered BP and symptom checklists. Comparing all the entered values with the threshold values checked the accuracy of the automatic alerts. Usability and patient satisfaction were measured using questionnaires.

Results: Compliance rates for blood pressure and symptom checklist were 93% and 85% respectively. No false positive or missing alerts were found in the alarm system. The telemonitoring system alarmed 7 times for BP thresholds (3.8% of all received values), Of 167 returned symptom checklists, 93% of symptom alarms could be handled with expectant management because of concurrent normal blood pressure. The majority of participants were satisfied with the system.

Conclusions: This is the first feasibility study of a telemonitoring platform, combining remote monitoring of BP with preeclampsia symptoms in pregnancy care. Action from health care providers during telemonitoring is only needed in case of alarming combinations of results. This system is potentially very useful in care for women at risk for hypertensive disorders during pregnancy.
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http://dx.doi.org/10.1016/j.ejogrb.2019.07.012DOI Listing
September 2019

Density, heterogeneity and deformability of red cells as markers of clinical severity in hereditary spherocytosis.

Haematologica 2020 31;105(2):338-347. Epub 2020 Jan 31.

Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

Hereditary spherocytosis (HS) originates from defective anchoring of the cytoskeletal network to the transmembrane protein complexes of the red blood cell (RBC). Red cells in HS are characterized by membrane instability and reduced deformability and there is marked heterogeneity in disease severity among patients. To unravel this variability in disease severity, we analyzed blood samples from 21 HS patients with defects in ankyrin, band 3, α-spectrin or β-spectrin using red cell indices, eosin-5-maleimide binding, microscopy, the osmotic fragility test, Percoll density gradients, vesiculation and ektacytometry to assess cell membrane stability, cellular density and deformability. Reticulocyte counts, CD71 abundance, band 4.1 a:b ratio, and glycated hemoglobin were used as markers of RBC turnover. We observed that patients with moderate/severe spherocytosis have short-living erythrocytes of low density and abnormally high intercellular heterogeneity. These cells show a prominent decrease in membrane stability and deformability and, as a consequence, are quickly removed from the circulation by the spleen. In contrast, in mild spherocytosis less pronounced reduction in deformability results in prolonged RBC lifespan and, hence, cells are subject to progressive loss of membrane. RBC from patients with mild spherocytosis thus become denser before they are taken up by the spleen. Based on our findings, we conclude that RBC membrane loss, cellular heterogeneity and density are strong markers of clinical severity in spherocytosis.
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http://dx.doi.org/10.3324/haematol.2018.188151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012482PMC
April 2021

Unbound Fraction of Clozapine Significantly Decreases with Elevated Plasma Concentrations of the Inflammatory Acute-Phase Protein Alpha-1-Acid Glycoprotein.

Clin Pharmacokinet 2019 08;58(8):1069-1075

Department of Clinical Pharmacy, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands.

Background: During inflammation, elevated total (unbound plus protein-bound) clozapine plasma concentrations have been observed. Elevated alpha-1-acid glycoprotein concentrations during inflammation are suggested to cause increased plasma clozapine-alpha-1-acid glycoprotein binding, resulting in elevated total clozapine plasma concentrations without significant changes in unbound concentrations. Here, we investigated the association between alpha-1-acid glycoprotein plasma concentrations and clozapine unbound fraction.

Methods: First, 25 and 60 µL of alpha-1-acid glycoprotein solution (20 mg/mL) were added to plasma samples (n = 3) of clozapine users (spiking experiment). Second, the association between alpha-1-acid glycoprotein plasma concentration and clozapine unbound fraction was assessed in patient samples (patient study). Samples were determined by liquid chromatography-tandem mass spectrometry. Data were analyzed with a paired t test (spiking experiment) and an unpaired t test (patient study).

Results: The spiking experiment showed significantly lower mean unbound fractions following 25- and 60-µL alpha-1-acid glycoprotein spikes (relative reductions of 28.3%, p = 0.032 and 43.4%, p = 0.048). In the patient study, total clozapine plasma concentrations were 10% higher in elevated (n = 6) compared with normal alpha-1-acid glycoprotein (n = 20) samples [525 µg/L vs. 479 µg/L, mean difference = 47 µg/L (95% confidence interval -217 to 310), p = 0.72]. Elevated alpha-1-acid glycoprotein samples had a 26% lower mean unbound fraction compared with normal samples [1.22% vs. 1.65%, mean difference = -0.43% (95% confidence interval -0.816 to -0.0443), p = 0.03].

Conclusions: Both the spiking experiment and patient study showed a significant association between elevated alpha-1-acid glycoprotein plasma concentrations and a lower clozapine unbound fraction. Future studies should include clinical data to examine whether this association is clinically relevant, suggesting any clozapine dose adjustments.
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http://dx.doi.org/10.1007/s40262-019-00744-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614135PMC
August 2019

Measuring Free-Living Physical Activity With Three Commercially Available Activity Monitors for Telemonitoring Purposes: Validation Study.

JMIR Form Res 2019 Apr 24;3(2):e11489. Epub 2019 Apr 24.

FocusCura, Driebergen-Rijsenburg, Netherlands.

Background: Remote monitoring of physical activity in patients with chronic conditions could be useful to offer care professionals real-time assessment of their patient's daily activity pattern to adjust appropriate treatment. However, the validity of commercially available activity trackers that can be used for telemonitoring purposes is limited.

Objective: The purpose of this study was to test usability and determine the validity of 3 consumer-level activity trackers as a measure of free-living activity.

Methods: A usability evaluation (study 1) and validation study (study 2) were conducted. In study 1, 10 individuals wore one activity tracker for a period of 30 days and filled in a questionnaire on ease of use and wearability. In study 2, we validated three selected activity trackers (Apple Watch, Misfit Shine, and iHealth Edge) and a fourth pedometer (Yamax Digiwalker) against the reference standard (Actigraph GT3X) in 30 healthy participants for 72 hours. Outcome measures were 95% limits of agreement (LoA) and bias (Bland-Altman analysis). Furthermore, median absolute differences (MAD) were calculated. Correction for bias was estimated and validated using leave-one-out cross validation.

Results: Usability evaluation of study 1 showed that iHealth Edge and Apple Watch were more comfortable to wear as compared with the Misfit Flash. Therefore, the Misfit Flash was replaced by Misfit Shine in study 2. During study 2, the total number of steps of the reference standard was 21,527 (interquartile range, IQR 17,475-24,809). Bias and LoA for number of steps from the Apple Watch and iHealth Edge were 968 (IQR -5478 to 7414) and 2021 (IQR -4994 to 9036) steps. For Misfit Shine and Yamax Digiwalker, bias was -1874 and 2004, both with wide LoA of (13,869 to 10,121) and (-10,932 to 14,940) steps, respectively. The Apple Watch noted the smallest MAD of 7.7% with the Actigraph, whereas the Yamax Digiwalker noted the highest MAD (20.3%). After leave-one-out cross validation, accuracy estimates of MAD of the iHealth Edge and Misfit Shine were within acceptable limits with 10.7% and 11.3%, respectively.

Conclusions: Overall, the Apple Watch and iHealth Edge were positively evaluated after wearing. Validity varied widely between devices, with the Apple Watch being the most accurate and Yamax Digiwalker the least accurate for step count in free-living conditions. The iHealth Edge underestimates number of steps but can be considered reliable for activity monitoring after correction for bias. Misfit Shine overestimated number of steps and cannot be considered suitable for step count because of the low agreement. Future studies should focus on the added value of remotely monitoring activity patterns over time in chronic patients.
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http://dx.doi.org/10.2196/11489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505372PMC
April 2019

A Human(e) Factor in Clinical Decision Support Systems.

J Med Internet Res 2019 03 19;21(3):e11732. Epub 2019 Mar 19.

Laboratory of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

The overwhelming amount, production speed, multidimensionality, and potential value of data currently available-often simplified and referred to as big data -exceed the limits of understanding of the human brain. At the same time, developments in data analytics and computational power provide the opportunity to obtain new insights and transfer data-provided added value to clinical practice in real time. What is the role of the health care professional in collaboration with the data scientist in the changing landscape of modern care? We discuss how health care professionals should provide expert knowledge in each of the stages of clinical decision support design: data level, algorithm level, and decision support level. Including various ethical considerations, we advocate for health care professionals to responsibly initiate and guide interprofessional teams, including patients, and embrace novel analytic technologies to translate big data into patient benefit driven by human(e) values.
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http://dx.doi.org/10.2196/11732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444220PMC
March 2019

Routine Blood Tests Do Not Predict Survival in Patients with Glioblastoma-Multivariable Analysis of 497 Patients.

World Neurosurg 2019 Jun 14;126:e1081-e1091. Epub 2019 Mar 14.

UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. Electronic address:

Background: Multiple reports have attributed a prognostic value to routine blood tests results for patients with glioblastoma. However, these studies have reported conflicting results and have often had small sample sizes. We sought to validate the prognostic value of the described tests in an independent glioblastoma patient population.

Methods: We performed a retrospective single-center multivariable analysis of 497 patients with glioblastoma who had postoperatively undergone radiotherapy and/or chemotherapy to identify the prognostic value for median overall survival of hemoglobin, white blood cell, monocyte, neutrophil, leukocyte, and platelet counts, neutrophil/lymphocyte ratio, C-reactive protein, erythrocyte sedimentation rate, activated partial thromboplastin time, prothrombin time, and lactate dehydrogenase. We also evaluated known prognostic factors for survival such as patient age, intervention type, IDH1 status, Karnofsky clinical performance status, and postoperative treatment modality.

Results: In a multivariable model, after correcting for multiple testing bias, biopsy alone (hazard ratio, 0.35; 95% confidence interval, 0.26-0.49; false discovery rate-adjusted P < 0.001) and monotherapy after surgery (hazard ratio, 0.46; 95% confidence interval, 0.33-0.66; false discovery rate-adjusted P < 0.001) remained significantly associated with worse median overall survival. Patient age and Karnofsky performance status score ≥70 did not significantly influence survival in the multivariable model. No routine blood test included in the multivariable analysis was significantly associated with survival.

Conclusions: In the present study, hemoglobin, white blood cell, monocyte, neutrophil, leukocyte, and platelet counts, neutrophil/lymphocyte ratio, C-reactive protein, erythrocyte sedimentation rate, activated partial thromboplastin time, prothrombin time, and lactate dehydrogenase levels did not independently predict for overall survival in patients with glioblastoma.
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http://dx.doi.org/10.1016/j.wneu.2019.03.053DOI Listing
June 2019

[Data-driven integrated diagnostics: the natural evolution of clinical chemistry?]

Ned Tijdschr Geneeskd 2019 02 28;163. Epub 2019 Feb 28.

UMC Utrecht, Laboratorium Klinische Chemie en Haematologie, Utrecht.

In the near future, making a correct medical diagnosis will be increasingly supported by artificial intelligence. The development of algorithms that integrate all data from an individual into the diagnostic process calls for a multidisciplinary approach that includes not only healthcare professionals and patients, but also data scientists. Because of the position of the clinical chemist in the current health care process, this medical specialist is naturally suited to initiate the development of self-learning diagnostic algorithms and to take the lead in the process to take big data to the next level and create value for health care.
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February 2019

A single preoperative blood test predicts postoperative sepsis and pneumonia after coronary bypass or open aneurysm surgery.

Eur J Clin Invest 2019 Mar 4;49(3):e13055. Epub 2019 Jan 4.

Laboratory of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Major surgery comes with a high risk for postoperative inflammatory complications. Preoperative risk scores predict mortality risk but fail to identify patients at risk for complications following cardiovascular surgery. We therefore assessed the value of preoperative red cell distribution width (RDW) as a predictor for pneumonia and sepsis after cardiovascular surgery and studied the relation of RDW with hematopoietic tissue activity.

Methods: RDW is an easily accessible, yet seldomly used parameter from routine haematology measurements. RDW was extracted from the Utrecht Patient Orientated Database (UPOD) for preoperative measurements in patients undergoing open abdominal aortic anuerysm repair (AAA)(N = 136) or coronary artery bypass grafting (CABG)(N = 2193). The cohorts were stratified in tertiles to assess effects over the different groups. Generalized Linear Models were used to determine associations between RDW and postoperative inflammatory complications. Hematopoietic tissue activity was scored using fluor-18-(18F)-deoxyglucose positron emission tomography and associated with RDW using linear regression models.

Results: In total, 43(31.6%) and 73 patients (3.3%) suffered from inflammatory complications after AAA-repair or CABG, respectively; the majority being pneumonia in both cohorts. Postoperative inflammatory outcome incidence increased from 19.6% in the lowest to 48.9% in the highest RDW tertile with a corresponding risk ratio (RR) of 2.35 ([95%CI:1.08-5.14] P = 0.032) in AAA patients. In the CABG cohort, the incidence of postoperative inflammatory outcomes increased from 1.8% to 5.3% with an adjusted RR of 1.95 ([95%CI:1.02-3.75] P = 0.044) for the highest RDW tertile compared with the lowest RDW tertile. FDG-PET scans showed associations of RDW with tissue activity in the spleen (B = 0.517 [P = 0.001]) and the lumbar bone marrow (B = 0.480 [P = 0.004]).

Conclusion: Elevated RDW associates with increased risk for postoperative inflammatory complications and hematopoietic tissue activity. RDW likely reflects chronic low-grade inflammation and should be considered to identify patients at risk for postoperative inflammatory complications following cardiovascular surgery.
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http://dx.doi.org/10.1111/eci.13055DOI Listing
March 2019

Routinely measured hematological parameters and prediction of recurrent vascular events in patients with clinically manifest vascular disease.

PLoS One 2018 7;13(9):e0202682. Epub 2018 Sep 7.

Department of Cardiology, University Medical Utrecht, University of Utrecht, Utrecht, the Netherlands.

Background And Aims: The predictive value of traditional risk factors for vascular events in patients with manifest vascular disease is limited, underscoring the need for novel biomarkers to improve risk stratification. Since hematological parameters are routinely assessed in clinical practice, they are readily available candidates.

Methods: We used data from 3,922 vascular patients, who participated in the Second Manifestations of ARTerial Disease (SMART) study. We first investigated associations between recurrent vascular events and 22 hematological parameters, obtained from the Utrecht Patient Oriented Database (UPOD), and then assessed whether parameters associated with outcome improved risk prediction.

Results: After adjustment for all SMART risk score (SRS) variables, lymphocyte %, neutrophil count, neutrophil % and red cell distribution width (RDW) were significantly associated with vascular events. When individually added to the SRS, lymphocyte % improved prediction of recurrent vascular events with a continuous net reclassification improvement (cNRI) of 17.4% [95% CI: 2.1, 32.1%] and an increase in c-statistic of 0.011 [0.000, 0.022]. The combination of lymphocyte % and neutrophil count resulted in a cNRI of 22.2% [3.2, 33.4%] and improved c-statistic by 0.011 [95% CI: 0.000, 0.022]. Lymphocyte % and RDW yielded a cNRI of 18.7% [3.3, 31.9%] and improved c-statistic by 0.016 [0.004, 0.028]. However, the addition of hematological parameters only modestly increased risk estimates for patients with an event during follow-up.

Conclusions: Several hematological parameters were independently associated with recurrent vascular events. Lymphocyte % alone and in combination with other parameters enhanced discrimination and reclassification. However, the incremental value for patients with a recurrent event was limited.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202682PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128486PMC
February 2019

A Multicenter Before-After Study on Reducing Unnecessary Diagnostics by Changing the Attitude of Caregivers: Protocol for the RODEO Project.

JMIR Res Protoc 2018 08 21;7(8):e10473. Epub 2018 Aug 21.

Acute Medicine Section, Department of Internal Medicine, VU University Medical Center, Amsterdam, Netherlands.

Background: Appropriate use of diagnostic laboratory tests is challenging, and estimates of 20% for overutilization and 45% for underutilization have been reported. Introducing effective and sustainable solutions to stimulate optimal use of laboratory testing in clinical practice is a challenge. A recent pilot study from our group, focusing on increasing the awareness about appropriate laboratory testing with the aim of changing the mindset of health care workers, has shown promising results. In this project, we aim to extend this multistep intervention to the internal medicine departments of 4 large Dutch hospitals. We aim to reduce unnecessary laboratory testing by 5%.

Objective: Our primary objective is to determine the effect of our intervention on diagnostic laboratory test order volume. Our secondary objectives are to determine the effect of our intervention on laboratory expenditure and order volumes, expenditures for other diagnostic modalities, and clinical patient outcomes. We will also analyze the barriers and facilitators for deimplementation of unnecessary laboratory testing.

Methods: The main interventions of this before-after study will be an intensified supervision of residents by experienced physicians regarding test ordering, creating awareness through education and monthly feedback on ordering patterns, and changes in (computerized) order entry systems.

Results: At the time of publication of this protocol, the project is in the phase of data collection. We expect to present data on reduction early in the fourth quarter of 2018.

Conclusions: In this project, we aim to reduce the unnecessary diagnostic testing in the internal medicine departments of 4 teaching hospitals. Although the main interventions will be similar, each clinic is given the opportunity to focus on the specific facets of the interventions as deemed useful according to the local situation. If effective, the study provides a framework for a nationwide initiative for reducing inappropriate laboratory testing.

Registered Report Identifier: RR1-10.2106/10473.
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http://dx.doi.org/10.2196/10473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123537PMC
August 2018

An increase in myeloid cells after severe injury is associated with normal fracture healing: a retrospective study of 62 patients with a femoral fracture.

Acta Orthop 2018 Oct 6;89(5):585-590. Epub 2018 Aug 6.

a Department of Trauma Surgery , University Medical Center Utrecht , Utrecht.

Background and purpose-Nonunion is common in femoral fractures. Previous studies suggested that the systemic immune response after trauma can interfere with fracture healing. Therefore, we investigated whether there is a relation between peripheral blood cell counts and healing of femur fractures. Patients and methods-62 multi-trauma patients with a femoral fracture presenting at the University Medical Centre Utrecht between 2007 and 2013 were retrospectively included. Peripheral blood cell counts from hematological analyzers were recorded from the 1st through the 14th day of the hospital stay. Generalized estimating equations were used to compare outcome groups. Results-12 of the 62 patients developed nonunion of the femoral fracture. The peripheral blood-count curves of total leukocytes, neutrophils, monocytes, lymphocytes, and platelets were all statistically significantly lower in patients with nonunion, coinciding with significantly higher CRP levels during the first 2 weeks after trauma in these patients. Interpretation-Patients who developed femoral nonunion after major trauma demonstrated lower numbers of myeloid cells in the peripheral blood than patients with normal fracture healing. This absent rise of myeloid cells seems to be related to a more severe post-traumatic immune response.
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http://dx.doi.org/10.1080/17453674.2018.1501974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202765PMC
October 2018

Commonly available hematological biomarkers are associated with the extent of coronary calcifications.

Atherosclerosis 2018 08 12;275:166-173. Epub 2018 Jun 12.

Department of Radiology, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands.

Background And Aims: We aimed to improve the understanding of potential associations between commonly available hematological biomarkers and the coronary artery calcification (CAC) score, which may help unravel the pathophysiology of coronary calcifications and subclinical coronary artery disease.

Methods: A cross-sectional study was performed within the Utrecht Patient Oriented Database (UPOD). Patients with suspected or known coronary artery disease who underwent CT CAC scoring as well as standard hematology analysis that was part of routine clinical care (within 3 months of CT acquisition) were included. Complete hematology datasets were extracted from hematology analyzers. Linear regression adjusted for potential confounders was used to assess if hematological biomarkers were related to the CAC score.

Results: In total, 1504 patients were included, of whom 43% (n = 647) had a CAC score of 0. Mean age (±SD) was 53 ± 13 years, and 34% of patients were women. Red blood cell distribution width (RDW, β = 0.20 [0.05-0.36], p=0.007), the fraction of immature reticulocytes (β = 0.97 [0.10-6.43], p=0.004), coefficient of variation of neutrophil lobularity (β = 0.13 [0.01-0.25], p=0.040) and mean lymphocyte cell size (β = 0.21 [0.08-0.34], p=0.001) were positively associated with the CAC score after adjustment for age, sex, body mass index (BMI), diabetes, glomerular filtration rate (GFR) and high-density lipoprotein (HDL).

Conclusions: This study confirms the known association of RDW with the CAC score, and presents the fraction of immature reticulocytes, coefficient of variation of neutrophil lobularity, and mean lymphocyte cell size as new markers associated with a higher CAC score.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.06.017DOI Listing
August 2018

Squeezing for Life - Properties of Red Blood Cell Deformability.

Front Physiol 2018 1;9:656. Epub 2018 Jun 1.

Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Deformability is an essential feature of blood cells (RBCs) that enables them to travel through even the smallest capillaries of the human body. Deformability is a function of (i) structural elements of cytoskeletal proteins, (ii) processes controlling intracellular ion and water handling and (iii) membrane surface-to-volume ratio. All these factors may be altered in various forms of hereditary hemolytic anemia, such as sickle cell disease, thalassemia, hereditary spherocytosis and hereditary xerocytosis. Although mutations are known as the primary causes of these congenital anemias, little is known about the resulting secondary processes that affect RBC deformability (such as secondary changes in RBC hydration, membrane protein phosphorylation, and RBC vesiculation). These secondary processes could, however, play an important role in the premature removal of the aberrant RBCs by the spleen. Altered RBC deformability could contribute to disease pathophysiology in various disorders of the RBC. Here we review the current knowledge on RBC deformability in different forms of hereditary hemolytic anemia and describe secondary mechanisms involved in RBC deformability.
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http://dx.doi.org/10.3389/fphys.2018.00656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992676PMC
June 2018

A Rise in Neutrophil Cell Size Precedes Organ Dysfunction After Trauma.

Shock 2019 04;51(4):439-446

Department of Trauma Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.

Introduction: Organ dysfunction remains a major cause of morbidity after trauma. The development of organ dysfunction is determined by the inflammatory response, in which neutrophils are important effector cells. A femoral fracture particularly predisposes for the development of organ dysfunction. This study investigated the chronologic relation between neutrophil characteristics and organ dysfunction in trauma patients with a femoral fracture.

Methods: Patients with a femoral fracture presenting at the University Medical Center Utrecht between 2007 and 2013 were included. Data of neutrophil characteristics from standard hematological analyzers were recorded on a daily basis until the 28th day of hospital stay or until discharge. Generalized Estimating Equations were used to compare outcome groups.

Results: In total 157 patients were analyzed, of whom 81 had polytrauma and 76 monotrauma. Overall mortality within 90 days was 6.4% (n = 10). Eleven patients (7.0%) developed organ dysfunction. In patients who developed organ dysfunction a significant increase in neutrophil count (P = 0.024), a significant increase in neutrophil cell size (P = 0.026), a significant increase in neutrophil complexity (P < 0.004), and a significant decrease in neutrophil lobularity (P < 0.001) were seen after trauma. The rise in neutrophil cell size preceded the clinical manifestation of organ dysfunction in every patient.

Conclusion: Patients who develop organ dysfunction postinjury show changes in neutrophil characteristics before organ dysfunction becomes clinically evident. These findings regarding post-traumatic organ dysfunction may contribute to the development of new prognostic tools for immune-mediated complications in trauma patients.

Level Of Evidence: Level II, etiologic study.
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http://dx.doi.org/10.1097/SHK.0000000000001200DOI Listing
April 2019

eHealth as the Next-Generation Perinatal Care: An Overview of the Literature.

J Med Internet Res 2018 06 5;20(6):e202. Epub 2018 Jun 5.

Division of Woman and Baby, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Background: Unrestricted by time and place, electronic health (eHealth) provides solutions for patient empowerment and value-based health care. Women in the reproductive age are particularly frequent users of internet, social media, and smartphone apps. Therefore, the pregnant patient seems to be a prime candidate for eHealth-supported health care with telemedicine for fetal and maternal conditions.

Objective: This study aims to review the current literature on eHealth developments in pregnancy to assess this new generation of perinatal care.

Methods: We conducted a systematic literature search of studies on eHealth technology in perinatal care in PubMed and EMBASE in June 2017. Studies reporting the use of eHealth during prenatal, perinatal, and postnatal care were included. Given the heterogeneity in study methods, used technologies, and outcome measurements, results were analyzed and presented in a narrative overview of the literature.

Results: The literature search provided 71 studies of interest. These studies were categorized in 6 domains: information and eHealth use, lifestyle (gestational weight gain, exercise, and smoking cessation), gestational diabetes, mental health, low- and middle-income countries, and telemonitoring and teleconsulting. Most studies in gestational diabetes and mental health show that eHealth applications are good alternatives to standard practice. Examples are interactive blood glucose management with remote care using smartphones, telephone screening for postnatal depression, and Web-based cognitive behavioral therapy. Apps and exercise programs show a direction toward less gestational weight gain, increase in step count, and increase in smoking abstinence. Multiple studies describe novel systems to enable home fetal monitoring with cardiotocography and uterine activity. However, only few studies assess outcomes in terms of fetal monitoring safety and efficacy in high-risk pregnancy. Patients and clinicians report good overall satisfaction with new strategies that enable the shift from hospital-centered to patient-centered care.

Conclusions: This review showed that eHealth interventions have a very broad, multilevel field of application focused on perinatal care in all its aspects. Most of the reviewed 71 articles were published after 2013, suggesting this novel type of care is an important topic of clinical and scientific relevance. Despite the promising preliminary results as presented, we accentuate the need for evidence for health outcomes, patient satisfaction, and the impact on costs of the possibilities of eHealth interventions in perinatal care. In general, the combination of increased patient empowerment and home pregnancy care could lead to more satisfaction and efficiency. Despite the challenges of privacy, liability, and costs, eHealth is very likely to disperse globally in the next decade, and it has the potential to deliver a revolution in perinatal care.
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http://dx.doi.org/10.2196/jmir.9262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008510PMC
June 2018

Reducing Test Utilization in Hospital Settings: A Narrative Review.

Ann Lab Med 2018 Sep;38(5):402-412

Section Acute Medicine, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.

Background: Studies addressing the appropriateness of laboratory testing have revealed approximately 20% overutilization. We conducted a narrative review to (1) describe current interventions aimed at reducing unnecessary laboratory testing, specifically in hospital settings, and (2) provide estimates of their efficacy in reducing test order volume and improving patient-related clinical outcomes.

Methods: The PubMed, Embase, Scopus, Web of Science, and Canadian Agency for Drugs and Technologies in Health-Health Technology Assessment databases were searched for studies describing the effects of interventions aimed at reducing unnecessary laboratory tests. Data on test order volume and clinical outcomes were extracted by one reviewer, while uncertainties were discussed with two other reviewers. Because of the heterogeneity of interventions and outcomes, no meta-analysis was performed.

Results: Eighty-four studies were included. Interventions were categorized into educational, (computerized) provider order entry [(C)POE], audit and feedback, or other interventions. Nearly all studies reported a reduction in test order volume. Only 15 assessed sustainability up to two years. Patient-related clinical outcomes were reported in 45 studies, two of which found negative effects.

Conclusions: Interventions from all categories have the potential to reduce unnecessary laboratory testing, although long-term sustainability is questionable. Owing to the heterogeneity of the interventions studied, it is difficult to conclude which approach was most successful, and for which tests. Most studies had methodological limitations, such as the absence of a control arm. Therefore, well-designed, controlled trials using clearly described interventions and relevant clinical outcomes are needed.
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http://dx.doi.org/10.3343/alm.2018.38.5.402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973913PMC
September 2018

Hematological Parameters Outperform Plasma Markers in Predicting Long-Term Mortality After Coronary Angiography.

Angiology 2018 Aug 4;69(7):600-608. Epub 2017 Dec 4.

1 Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, the Netherlands.

High-sensitivity troponin I (hsTnI) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) are predictors of coronary artery disease. Recently, routine hematological parameters emerged as mortality predictors. We examined the predictive value of hematological parameters (from the Utrecht Patient Oriented Database) and hsTnI and NT-pro-BNP for mortality in a coronary angiography population (Utrecht Coronary Biobank n = 1913). Using Cox regression, receiver operating characteristics, integrated discrimination improvement (IDI), and continuous net reclassification improvement (cNRI) analysis, we compared the predictive properties of hematological parameters with hsTnI and NT-pro-BNP for mortality. During a median follow-up duration of 1.8 years, 77 deaths occurred. A panel of 7 hematological parameters (leukocyte count, reticulocyte mean corpuscular hemoglobin concentration, red blood cell [RBC] green (FL1) fluorescence, %neutrophils, %large [>120 fL] RBCs, %monocytes, and coefficient of variation of neutrophil complexity) was highly predictive. Added to clinical characteristics, hematological parameters (area under the curve [AUC]: 0.855, P < .001; IDI: 0.04, P = .02; cNRI: 0.41, P < .001) were better predictors than hsTnI (AUC: 0.818) or NT-pro-BNP (AUC: 0.834) alone or combined (AUC: 0.834). Hematological parameters may provide mortality risk information following coronary angiography and may be superior to hsTnI and/or NT-pro-BNP.
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http://dx.doi.org/10.1177/0003319717743679DOI Listing
August 2018

Effect of Monocyte-to-Lymphocyte Ratio on Heart Failure Characteristics and Hospitalizations in a Coronary Angiography Cohort.

Am J Cardiol 2017 Sep 29;120(6):911-916. Epub 2017 Jun 29.

Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands; ICIN-Netherlands Heart Institute, The Netherlands; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cardiovascular Research Institute (CVRI), National University Heart Center (NUHCS), National University Health System, Singapore. Electronic address:

Inflammation is a shared mechanism in coronary artery disease (CAD) and subsequent heart failure (HF), and circulating monocyte and lymphocyte counts predict CAD severity and outcomes. We investigated whether the monocyte-to-lymphocyte ratio (MLR) correlates with biomarkers of HF and extent of CAD, as well as future HF hospitalizations in patients undergoing coronary angiography. Therefore, we studied 1754 patients undergoing coronary angiography for stable CAD, unstable angina, or myocardial infarction. MLR was determined at blood draw before angiography and related cross-sectionally to HF biomarkers (ejection fraction, N-terminal pro-B-type natriuretic peptide [NTproBNP] levels) and CAD severity, as well as longitudinally with risk of HF hospitalizations during follow-up. In the entire cohort, median (interquartile range) MLR was 0.32 (0.24 to 0.43). High MLR was defined as the upper quartile and significantly associated with nonstable CAD (unstable angina; odds ratio [OR] 1.13, 95% confidence interval 1.06 to 1.21] or myocardial infarction [OR 1.10, 1.04 to 1.16]), more severe CAD (OR 1.39, 1.15 to 1.68), poorer ejection fraction (OR 1.63, 1.29 to 2.05), and higher NTproBNP levels (β 0.78, 0.59 to 0.96), all p <0.001. The associations with nonstable CAD and NTproBNP remained highly significant after covariate adjustment. Over a mean follow-up of 1.3 years, 46 HF hospitalizations occurred. A high MLR was significantly and independently predictive of HF hospitalizations during follow-up (hazard ratio 2.1 [1.1 to 4.1], p = 0.039) after adjustment for covariates and addition of MLR to the basic model significantly improved reclassification. In conclusion, MLR is strongly related to HF markers and predicts HF hospitalizations during follow-up in patients with CAD.
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http://dx.doi.org/10.1016/j.amjcard.2017.06.020DOI Listing
September 2017

New mAb therapies in multiple myeloma: interference with blood transfusion compatibility testing.

Curr Opin Hematol 2016 11;23(6):557-562

Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands.

Purpose Of Review: Immunotherapeutic strategies are emerging as novel therapeutic approaches in multiple myeloma, with several mAbs being in advanced stages of clinical development. Of these, CD38 targeting antibodies appear very promising. In trials with anti-CD38 mAb daratumumab, all patients demonstrated panreactivity in red blood cell (RBC) panel testing, complicating the selection of compatible RBCs for transfusion. This review provides an overview of the interferences and solutions to safely transfuse these patients.

Recent Findings: CD38 is weakly expressed on human erythrocytes. Since the first reports on the interference, different solutions have been reported, including the neutralization of anti-CD38 mAbs in plasma by sCD38 or antiidiotype antibodies, CD38 depletion of RBCs using dithiothreitol or cord blood test cells, and transfusion of extensively typed RBCs.

Summary: All methods have (dis)advantages, and it depends on the facilities of the immunohematology laboratory what strategy to choose. As the selection of suitable RBC units can be seriously delayed, hospitals should have protocols to communicate this interference with patients, laboratories, and physicians in a timely manner. As CD38 antibodies may also have a role in the treatment of diseases beyond hematological malignancies, chances are high that health professionals will encounter this issue in the nearby future.
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http://dx.doi.org/10.1097/MOH.0000000000000276DOI Listing
November 2016

The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction.

Eur Heart J 2017 Mar;38(11):828-836

Experimental Cardiology Laboratory (Room G02.523), University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, Utrecht 3508 GA, The Netherlands.

Aims: Myocardial infarction (MI) triggers an intense inflammatory response that is associated with infarct expansion and is detrimental for cardiac function. Interleukin (IL)-1β and IL-18 are key players in this response and are controlled by the NLRP3-inflammasome. In the current study, we therefore hypothesized that selective inhibition of the NLRP3-inflammasome reduces infarct size and preserves cardiac function in a porcine MI model.

Methods And Results: Thirty female landrace pigs were subjected to 75 min transluminal balloon occlusion and treated with the NLRP3-inflammasome inhibitor MCC950 (6 or 3 mg/kg) or placebo for 7 days in a randomized, blinded fashion. After 7 days, 3D-echocardiography was performed to assess cardiac function and Evans blue/TTC double staining was executed to assess the area at risk (AAR) and infarct size (IS). The IS/AAR was lower in the 6 mg/kg group (64.6 ± 8.8%, P = 0.004) and 3 mg/kg group (69.7 ± 7.2%, P = 0.038) compared with the control group (77.5 ± 6.3%). MCC950 treatment markedly preserved left ventricular ejection fraction in treated animals (6 mg/kg 47 ± 8%, P = 0.001; 3 mg/kg 45 ± 7%, P = 0.031; control 37 ± 6%). Myocardial neutrophil influx was attenuated in treated compared with non-treated animals (6 mg/kg 132 ± 72 neutrophils/mm2, P = 0.035; 3 mg/kg 207 ± 210 neutrophils/mm2, P = 0.5; control 266 ± 158 neutrophils/mm2). Myocardial IL-1β levels were dose-dependently reduced in treated animals.

Conclusions: NLRP3-inflammasome inhibition reduces infarct size and preserves cardiac function in a randomized, blinded translational large animal MI model. Hence, NLRP3-inflammasome inhibition may have therapeutic potential in acute MI patients.
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http://dx.doi.org/10.1093/eurheartj/ehw247DOI Listing
March 2017

Proteomics reveals reduced expression of transketolase in pyrimidine 5'-nucleotidase deficient patients.

Proteomics Clin Appl 2016 08;10(8):859-69

Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.

Purpose: To date, it remains a challenge to correctly and timely diagnose red blood cell (RBC) enzymopathies that result in hereditary nonspherocytic hemolytic anemia (HNSHA), the third most common of which is pyrimidine 5'-nucleotidase (P5N) deficiency with just over 100 cases recognized and confirmed worldwide.

Experimental Design: We have investigated the RBC proteome of a patient with P5N deficiency due to a homozygous frameshift mutation in the NT5C3A gene. Protein expression levels were analyzed against healthy controls and against patients with hemolytic anemia of different origin, to account for the patient's elevated reticulocyte versus RBC ratio.

Results: Stringent relative quantification of the patient's protein levels revealed reduced levels of P5N, and unexpectedly, also decreased levels of transketolase, an enzyme involved in the nonoxidative phase of the pentose phosphate pathway, one of the few key pathways active in RBCs. Immunoblotting of whole blood samples from this and other P5N-deficient patients with dissimilar mutations indicated that P5N deficiency was correlated with reduced transketolase levels.

Conclusions And Clinical Relevance: Consequently, insight into patient RBC proteomes illustrates potential benefit of coupling quantitative proteomics strategies with routine HNSHA diagnostic procedures. Proteomics facilitates finding novel biomarkers for HNSHA patients, for example, suffering from P5N deficiency, providing new prospects for future diagnosis and therapy.
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http://dx.doi.org/10.1002/prca.201500130DOI Listing
August 2016

Overestimation of Hypoglycemia in Infants with a High Hematocrit.

J Appl Lab Med 2016 Jul;1(1):77-82

University Medical Center Utrecht, Department of Clinical Chemistry and Haematology, Utrecht, the Netherlands.

Background: In neonates, hypoglycemia is an emergency condition requiring urgent treatment. Therefore, rapid and reliable blood glucose measurements are necessary. However, this step has been proven difficult because of both analytical and preanalytical variables. In our children's hospital, we incidentally observed cases of hypoglycemia that were not in line with the clinical picture of the infants. Remarkably, most of these infants had a high hematocrit.

Methods: Glucose concentrations were determined in blood samples from healthy participants that were collected in Li-heparin capillary and pediatric tubes. The effect of hematocrit on glucose consumption over time was studied by artificially increasing sample hematocrits. To study the effect of sample cooling, glucose concentrations were followed over time in samples stored at room temperature and on ice.

Results: In all samples, glucose concentrations declined with time. This effect was most dramatic [up to 18 mg/dL (1 mmol/L) in the first 30 min] in samples with high hematocrits and collected in capillary tubes. Cooling of samples clearly reduced glucose consumption; however, this was not evident in the first 30 min.

Conclusions: Overestimation of hypoglycemia in infants must be considered if samples are not centrifuged or are not analyzed immediately after sampling. The extent of overestimation is more pronounced in samples with a high hematocrit, collected in capillary tubes. Cooling of samples does not prevent glucose consumption in vitro during the first 30 min. These results emphasize that, for glucose analysis, prompt handling of samples of newborns with a high hematocrit is necessary.
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http://dx.doi.org/10.1373/jalm.2016.020164DOI Listing
July 2016