A Wolf in Sheep's Clothing: Reuse of Routinely Obtained Laboratory Data in Research.

Electronic health records (EHRs) contain valuable data for reuse in science, quality evaluations, and clinical decision support. Because routinely obtained laboratory data are abundantly present, often numeric, generated by certified laboratories, and stored in a structured way, one may assume that they are immediately fit for (re)use in research. However, behind each test result lies an extensive context of choices and considerations, made by both humans and machines, that introduces hidden patterns in the data. If they are unaware, researchers reusing routine laboratory data may eventually draw incorrect conclusions. In this paper, after discussing health care system characteristics on both the macro and micro level, we introduce the reader to hidden aspects of generating structured routine laboratory data in 4 steps (ordering, preanalysis, analysis, and postanalysis) and explain how each of these steps may interfere with the reuse of routine laboratory data. As researchers reusing these data, we underline the importance of domain knowledge of the health care professional, laboratory specialist, data manager, and patient to turn routine laboratory data into meaningful data sets to help obtain relevant insights that create value for clinical care.

Shorter laboratory turnaround time is associated with shorter emergency department length of stay: a retrospective cohort study.

BACKGROUND: A longer emergency department length of stay (EDLOS) is associated with poor outcomes. Shortening EDLOS is difficult, due to its multifactorial nature. A potential way to improve EDLOS is through shorter turnaround times for diagnostic testing. This study aimed to investigate whether a shorter laboratory turnaround time (TAT) and time to testing (TTT) were associated with a shorter EDLOS. METHODS: A retrospective cohort study was performed, including all visits to the emergency department (ED) of an academic teaching hospital from 2017 to 2020 during which a standardized panel of laboratory tests had been ordered. TTT was calculated as the time from arrival in the ED to the ordering of laboratory testing. TAT was calculated as the time from test ordering to the reporting of the results, and was divided into a clinical and a laboratory stage. The outcome was EDLOS in minutes. The effect of TTT and TAT on EDLOS was estimated through a linear regression model. RESULTS: In total, 23,718 ED visits were included in the analysis. Median EDLOS was 199.0 minutes (interquartile range [IQR] 146.0-268.0). Median TTT was 7.0 minutes (IQR 2.0-12.0) and median TAT was 51.1 minutes (IQR 41.1-65.0). Both TTT and TAT were positively associated with EDLOS. The laboratory stage comprised a median of 69% (IQR 59-78%) of total TAT. CONCLUSION: Longer TTT and TAT are independently associated with longer EDLOS. As the laboratory stage predominantly determines TAT, it provides a promising target for interventions to reduce EDLOS and ED crowding.

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

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.

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

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.

Seasonal changes in gene expression represent cell-type composition in whole blood.

Seasonal patterns in behavior and biological parameters are widespread. Here, we examined seasonal changes in whole blood gene expression profiles of 233 healthy subjects. Using weighted gene co-expression network analysis, we identified three co-expression modules showing circannual patterns. Enrichment analysis suggested that this signal stems primarily from red blood cells and blood platelets. Indeed, a large clinical database with 51 142 observations of blood cell counts over 3 years confirmed a corresponding seasonal pattern of counts of red blood cells, reticulocytes and platelets. We found no direct evidence that these changes are linked to genes known to be key players in regulating immune function or circadian rhythm. It is likely, however, that these seasonal changes in cell counts and gene expression profiles in whole blood represent biological and clinical relevant phenomena. Moreover, our findings highlight possible confounding factors relevant to the study of gene expression profiles in subjects collected at geographical locations with disparaging seasonality patterns.

The Nature, Causes, and Clinical Impact of Errors in the Clinical Laboratory Testing Process Leading to Diagnostic Error: A Voluntary Incident Report Analysis.

OBJECTIVES: Diagnostic errors, that is, missed, delayed, or wrong diagnoses, are a common type of medical errors and preventable iatrogenic harm. Errors in the laboratory testing process can lead to diagnostic errors. This retrospective analysis of voluntary incident reports aimed to investigate the nature, causes, and clinical impact of errors, including diagnostic errors, in the clinical laboratory testing process. METHODS: We used a sample of 600 voluntary incident reports concerning diagnostic testing selected from all incident reports filed at the University Medical Center Utrecht in 2017-2018. From these incident reports, we included all reports concerning the clinical laboratory testing process. For these incidents, we determined the following: nature: in which phase of the testing process the error occurred; cause: human, technical, organizational; and clinical impact: the type and severity of the harm to the patient, including diagnostic error. RESULTS: Three hundred twenty-seven reports were included in the analysis. In 77.1%, the error occurred in the preanalytical phase, 13.5% in the analytical phase and 8.0% in the postanalytical phase (1.5% undetermined). Human factors were the most frequent cause (58.7%). Severe clinical impact occurred relatively more often in the analytical and postanalytical phase, 32% and 28%, respectively, compared with the preanalytical phase (40%). In 195 cases (60%), there was a potential diagnostic error as consequence, mainly a potential delay in the diagnostic process (50.5%). CONCLUSIONS: Errors in the laboratory testing process often lead to potential diagnostic errors. Although prone to incomplete information on causes and clinical impact, voluntary incident reports are a valuable source for research on diagnostic error related to errors in the clinical laboratory testing process.

Added diagnostic value of routinely measured hematology variables in diagnosing immune checkpoint inhibitor mediated toxicity in the emergency department.

BACKGROUND: Immune checkpoint inhibitors (ICI) show remarkable results in cancer treatment, but at the cost of immune-related adverse events (irAE). irAE can be difficult to differentiate from infections or tumor progression, thereby challenging treatment, especially in the emergency department (ED) where time and clinical information are limited. As infections are traceable in blood, we were interested in the added diagnostic value of routinely measured hematological blood cell characteristics in addition to standard diagnostic practice in the ED to aid irAE assessment. METHODS: Hematological variables routinely measured with our hematological analyzer (Abbott CELL-DYN Sapphire) were retrieved from Utrecht Patient Oriented Database (UPOD) for all patients treated with ICI who visited the ED between 2013 and 2020. To assess the added diagnostic value, we developed and compared two models; a base logistic regression model trained on the preliminary diagnosis at the ED, sex, and gender, and an extended model trained with lasso that also assessed the hematology variables. RESULTS: A total of 413 ED visits were used in this analysis. The extended model showed an improvement in performance (area under the receiver operator characteristic curve) over the base model, 0.79 (95% CI 0.75-0.84), and 0.67 (95% CI 0.60-0.73), respectively. Two standard blood count variables (eosinophil granulocyte count and red blood cell count) and two advanced variables (coefficient of variance of neutrophil depolarization and red blood cell distribution width) were associated with irAE. CONCLUSION: Hematological variables are a valuable and inexpensive aid for irAE diagnosis in the ED. Further exploration of the predictive hematological variables could yield new insights into the pathophysiology underlying irAE and in distinguishing irAE from other inflammatory conditions.

Rituximab-induced thrombocytopenia: a cohort study.

The combined information of drug exposure and laboratory test results on an individual patient level obtained in daily clinical practice can add important information about the safety of a drug. Thrombocytopenia is a known adverse drug reaction of rituximab, which has already been identified during the preregistration trials, but knowledge on incidence and risk factors in clinical practice is limited. We, therefore, aimed to estimate the incidence and explore the risk factors for the development of rituximab-induced thrombocytopenia (a platelet count, <100 × 10(9) platelets/L) in clinical practice. Ninety patients were eligible for inclusion of which 27 developed thrombocytopenia (cumulative incidence, 30%) within 30 days after administration of rituximab and 18 patients developed grade 3/4 thrombocytopenia (cumulative incidence, 20%). Patients with and without thrombocytopenia were compared to explore risk factors. Patients with a relatively low platelet count (217 vs. 324 × 10(9) /L, P = 0.011) before administration of rituximab had a higher risk for the development of thrombocytopenia, and although not statistically significant, patients treated with rituximab within the oncology setting (OR, 4.7; 95% CI, 1.0-23.3), independent of concomitant use of cytostatics, as compared to the autoimmune diseases and patients with a high platelet distribution width (PDW) (16.1 vs. 15.8, P = 0.051). In conclusion, the incidence of rituximab-induced thrombocytopenia was higher than that identified during the clinical trials. Healthcare professionals should consider thrombocytopenia as a relevant reaction during treatment with rituximab. More frequent monitoring of the platelet count is especially advised in patients treated in the oncology indication and/or with a low platelet count and high PDW.

Redundant laboratory testing on referral from general practice to the outpatient clinic: a post-hoc analysis.

BACKGROUND: Inappropriately repeated laboratory testing is a commonly occurring problem. However, this has not been studied extensively in the outpatient clinic after referral by GPs. AIM: The aim of this study was to investigate how often laboratory tests ordered by the GP were repeated on referral to the outpatient clinic, and how many of the normal test results remained normal on repetition. DESIGN & SETTING: This is a post-hoc analysis of a study on laboratory testing strategies in patients newly referred to the outpatient clinic between April 2015 and April 2017. METHOD: All patients who had a referral letter including laboratory test results ordered by the GP were included. These results were compared with the laboratory test results ordered in the outpatient clinic. RESULTS: Data were available for 295 patients, 191 of which had post-visit testing done. In this group, 56% of tests ordered by the GP were repeated. Tests with abnormal results were repeated more frequently than tests with normal results (65% versus 53%; P<0.001). A longer test interval was associated with slightly smaller odds of tests being repeated (odds ratio [OR] 0.97, 95% confidence interval [CI] = 0.95 to 0.99; P = 0.003). Of the tests with normal test results that were repeated, 90% remained normal. This was independent of testing interval or testing strategy. CONCLUSION: Laboratory tests ordered by the GP are commonly repeated on referral to the outpatient clinic. The number of test results remaining normal on repetition suggests a high level of redundancy in laboratory test repetition.

Discriminative value of platelet size indices for the identification of the mechanism of chemotherapy-induced thrombocytopenia.

CONTEXT: A biomarker for discriminating mechanisms of chemotherapy-induced thrombocytopenia (CIT) (i.e. increased platelet destruction and decreased platelet production) would be valuable in managing treatment. OBJECTIVE: We explored the discriminating value of platelet size indices for this purpose in a population of adult oncology patients. MATERIALS AND METHODS: Mean platelet volume (MPV) and platelet distribution width (PDW) were compared between patients with (i) thrombocytopenia possibly due to increased platelet destruction; (ii) thrombocytopenia possibly due to decreased platelet destruction; and (iii) no thrombocytopenia. RESULTS AND CONCLUSIONS: We obtained negative results, suggesting that these indices are not useful for discriminating different CIT mechanisms.

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

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.

Platelet measurements versus discharge diagnoses for identification of patients with potential drug-induced thrombocytopenia: a cross-sectional study in the Netherlands.

BACKGROUND: In pharmacoepidemiological studies on the risk of drug-induced blood dyscrasias, including drug-induced thrombocytopenia (DIT), hospital discharge diagnoses have been used to identify potential cases. One of the possible limitations of discharge diagnoses is that due to incomplete registration not all potential cases are identified, which may limit statistical power. Clinical laboratory data have been suggested as a data type that is potentially more sensitive for identifying potential cases of adverse drug reactions than discharge diagnoses. OBJECTIVE: To compare the number of patients with potential DIT that could be identified by using platelet measurements with the number of patients with potential DIT that could be identified by using discharge diagnoses for thrombocytopenia within a population of hospitalized patients. METHODS: The study population of this cross-sectional study comprised all patients admitted to the University Medical Center Utrecht in 2004 and 2005, as captured within the Utrecht Patient Oriented Database (UPOD). The ratio of the number of patients with potential DIT based on platelet measurements (>or=1 platelet count below 100x10(9)/L without alternative diagnoses for DIT) to the number of patients with potential DIT based on discharge diagnoses for thrombocytopenia (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] codes 287.3-287.5 without alternative diagnoses for DIT) was determined. RESULTS: Within the study period there were 56,411 hospitalizations. 2817 patients (5.0%) had >or=1 platelet count below 100x10(9)/L. In 96.3% of these patients, alternative diagnoses for DIT were present, resulting in 103 (0.2%) patients with potential DIT based on platelet measurements. There were 74 patients (0.1%) with a discharge diagnosis for thrombocytopenia. In 81.1% of these patients, alternative diagnoses for DIT were present, resulting in 14 (0.02%) patients with potential DIT based on discharge diagnoses. This resulted in a ratio of the number of patients with potential DIT based on platelet measurements to the number of patients with potential DIT based on discharge diagnoses for thrombocytopenia of seven. CONCLUSION: This study showed that the use of platelet measurements is a more sensitive approach to the identification of patients with potential DIT than the use of discharge diagnoses for thrombocytopenia.

Frequency and nature of drug-drug interactions in a Dutch university hospital.

AIM: Drug-drug interactions (DDIs) may lead to often preventable adverse drug events and health damage. Especially within hospitals, this might be an important factor, as patients are severely ill and multiple medications may be prescribed simultaneously. The objective of this study was to measure the frequency and nature of DDI alerts in a Dutch university hospital. METHODS: All patients hospitalized in the University Medical Centre Utrecht in 2006 who were prescribed at least one medication were included. The frequency of DDIs was calculated as: (i) the percentage of patients experiencing at least one DDI, and (ii) the percentage of prescriptions generating a DDI alert. Based on the national professional guideline, DDIs were classified into categories of potential clinical outcome, management advice, clinical relevance (A-F) and available evidence (0-4). RESULTS: Of the 21 277 admissions included, 5909 (27.8%) encountered at least one DDI. Overall, the prescribing physician received a DDI alert in 9.6% of all prescriptions. The most frequently occurring potential clinical consequence of the DDIs was an increased risk of side-effects such as increased bleeding risk (22.0%), hypotension (14.9%), nephrotoxicity (12.6%) and electrolyte disturbances (10.5%). Almost half (48.6%) of the DDIs could be managed by monitoring laboratory values. CONCLUSIONS: Computerized DDI alerts may be a useful tool to prevent adverse drug events within hospitals, but they may also result in 'alert fatigue'. The specificity of alerts could significantly improve by the use of more sophisticated clinical decision support systems taking into account, for example, laboratory values.

Identification of exacerbations in obstructive lung disease through biomarkers.

Inflammation has been identified as an important factor for disease exacerbation in obstructive lung disease. In this study, we used neutrophil and eosinophil counts as biomarkers for exacerbation in obstructive lung disease. We conducted a case-control study within a cohort of patients frequenting an outpatient clinic of Respiratory Medicine using data from the Utrecht Patient Oriented Database (UPOD). Cases were patients with a hospital admission for obstructive lung disease in 2005. For each case, one control patient was sampled from the same study base. We identified 143 cases (118 patients with chronic obstructive pulmonary disease and 25 asthma patients) and 143 controls. Admission was associated with both neutrophilia (adjusted odds ratio (OR) 4.3; 95% confidence interval (CI) 2.2-8.5), and eosinophilia (adjusted OR 2.6; 95% CI 1.1-6.2). The association with eosinophilia was only seen in asthma patients. In conclusion, neutrophil and eosinophil counts seem to be useful biomarkers for identifying exacerbations in pharmacoepidemiological studies on obstructive lung disease.

Compliance with platelet count monitoring recommendations and management of possible heparin-induced thrombocytopenia in hospitalized patients receiving low-molecular-weight heparin.

BACKGROUND: Summaries of product characteristics (SPCs) and clinical guideline recommendations are available for monitoring the platelet count for heparin-induced thrombocytopenia (HIT) in patients receiving low-molecular-weight heparin (LMWH). Testing for the presence of heparin-platelet factor 4 antibodies (HPF4-Ab) and starting alternative anticoagulation is recommended when HIT is suspected. OBJECTIVE: To investigate the frequency of compliance with recommendations for platelet count monitoring and management of possible HIT in hospitalized patients receiving prophylaxis and treatment dosing of LMWH for at least 5 consecutive days. METHODS: A retrospective cohort study within the Utrecht Patient Oriented Database (UPOD) was conducted. For all inpatients, all episodes of exposure to dalteparin or nadroparin for at least 5 consecutive days in 2004-2005 were selected. In 4 different nonexclusive groups of patients (all pts. receiving dalteparin, all pts. receiving nadroparin, surgical pts. with a prophylactic dose of either dalteparin or nadroparin, and pts. exposed to unfractionated heparin [UFH] within 100 days before receiving either dalteparin or nadroparin), compliance with recommendations for platelet count monitoring from SPCs and a clinical guideline was studied. The frequency of compliance with these recommendations was determined. In addition, it was determined whether patient and treatment characteristics were associated with regular platelet count monitoring. Finally, the frequency of testing for HPF4-Ab and the initiation of danaparoid treatment in patients with a drop of at least 50% in platelet count were investigated. RESULTS: A total of 6804 patients, with 7770 episodes of LMWH treatment, were included in the analysis. The frequency of compliance with platelet count monitoring recommendations was 26.3% for all patients receiving dalteparin, 35.6% for all patients receiving nadroparin, 23.0% for surgical patients receiving prophylactic dosing of either dalteparin or nadroparin, and 41.5% for patients exposed to UFH within 100 days before the start of either dalteparin or nadroparin treatment. Regular platelet count monitoring was strongly positively associated with medical patients (relative risk [RR] 2.33), surgical patients (RR 2.03), critically ill patients (RR 2.80), and those with recent exposure to UFH (RR 2.19). The frequency of testing for HPF4-Ab was 5.4% and the initiation of alternative anticoagulation with danaparoid in patients with a 50% drop in platelet count was 0%. CONCLUSIONS: The results suggest that compliance with recommendations for platelet count monitoring and management of possible HIT is low at our institution. Policies and tools to improve compliance with recommended laboratory monitoring should be developed to secure the safe use of LMWH and other medications.

[Data-driven integrated diagnostics: the natural evolution of clinical chemistry?] / Data-gedreven integrale diagnostiek.

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.

Improving home haemodialysis: Stability evaluation of routine clinical chemistry analytes in blood samples of haemodialysis patients.

INTRODUCTION: A growing number of dialysis patients is treated with home haemodialysis. Our current pre-analytical protocols require patients to centrifuge the blood sample and transfer the plasma into a new tube at home. This procedure is prone to errors and precludes accurate bicarbonate measurement, required for determining dialysate bicarbonate concentration and maintaining acid-base status. We therefore evaluated whether cooled overnight storage of gel separated plasma is an acceptable alternative. MATERIALS AND METHODS: Venous blood of 34 haemodialysis patients was collected in 2 lithium heparin blood collection tubes with gel separator (LH PSTTM II, REF 367374; Becton Dickinson, New Jersey, USA). One tube was analysed directly for measurement of bicarbonate, potassium, calcium, phosphate, glucose, urea, lactate, aspartate aminotransferase (AST), and lactate dehydrogenase (LD); whereas the other was centrifuged and stored unopened at 4 °C and analysed 24 h later. To measure analyte stability after 24 h of storage, the mean difference was calculated and compared to the total allowable error (TEa) which was used as acceptance limit. RESULTS: Potassium (Z = - 4.28, P < 0.001), phosphate (Z = - 3.26, P = 0.001), lactate (Z = - 5.11, P < 0.001) and AST (Z = - 2.71, P = 0.007) concentrations were higher, whereas glucose (Z = 4.00, P < 0.001) and LD (Z = 3.13, P = 0.002) showed a reduction. All mean differences were smaller than the TEa and thus not clinically relevant. Bicarbonate (Z = 0.69, P = 0.491), calcium (Z = - 0.23, P = 0.815) and urea (Z = 0.81, P =0.415) concentrations were stable. CONCLUSIONS: Our less complex, user-friendly pre-analytical procedure resulted in at least 24 h stability of analytes relevant for monitoring haemodialysis, including bicarbonate. This allows shipment and analysis the next day.

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

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.

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

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.