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COVID-19 induces haemocytometric changes. Complete blood count changes, including new cell activation parameters, from 982 confirmed COVID-19 adult patients from 11 European hospitals were retrospectively analysed for distinctive patterns based on age, gender, clinical severity, symptom duration and hospital days. The observed haemocytometric patterns formed the basis to develop a multi-haemocytometric-parameter prognostic score to predict, during the first three days after presentation, which patients will recover without ventilation or deteriorate within a two-week timeframe, needing intensive care or with fatal outcome. The prognostic score, with ROC curve AUC at baseline of 0.753 (95% CI 0.723-0.781) increasing to 0.875 (95% CI 0.806-0.926) on day 3, was superior to any individual parameter at distinguishing between clinical severity. Findings were confirmed in a validation cohort. Aim is that the score and haemocytometry results are simultaneously provided by analyser software, enabling wide applicability of the score as haemocytometry is commonly requested in COVID-19 patients.

Many studies have reported hemocytometric changes in COVID-19 infection at admission and during the course of disease, but an overview is lacking. We provide a summary of the literature of hemocytometric changes and evaluate whether these changes may assist clinicians in diagnosing and predicting disease progression of COVID-19. Eighty-three out of 250 articles from December 2019 to 20 May 2020 were included from the databases, PubMed, Web of Science Core Collection, Embase, Cochrane and MedRxiv. Our review of the literature indicates that lymphopenia and an elevated neutrophil/lymphocyte ratio are the most consistent abnormal hemocytometric findings and that these alterations may augment in the course of time, especially in those with severe disease.

BACKGROUND: Monoclonal gammopathies (MGs) are plasma cell disorders defined by the clonal expansion of plasma cells, resulting in the characteristic excretion of a monoclonal immunoglobulin (M-protein). M-protein detection and quantification are integral parts of the diagnosis

Objective: To estimate whether the imbalance of angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor) and fibrinolytic factors (plasminogen activator inhibitor-2 [PAI-2]) might affect placentation in early pregnancy. Methods: We studied the associations of maternal soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 concentrations in the first trimester (before 18 weeks of gestation) and soluble fms-like tyrosine kinase-1 and placental growth factor concentrations in the second trimester (18-25 weeks of gestation) with placental function and adverse pregnancy outcomes. This study was embedded in a population-based prospective cohort study. Data were used from 7,519 women. Biomarker concentrations were divided into deciles and evaluated in multivariable linear and logistic regression models. Results: First-trimester high soluble fms-like tyrosine kinase-1 was associated with a 5.2% lower uterine artery index in the second-trimester and a 1.6% higher birth weight (55 g, confidence interval [CI] 15-95). Neither in the first nor in the second trimester were soluble fms-like tyrosine kinase-1 concentrations significantly associated with preeclampsia. First-trimester low placental growth factor was associated with a 6.1% higher uterine artery index and a 3.4% lower birth weight (-115 g, CI-157 to-74). First-trimester low placental growth factor was associated with fetal growth restriction (odds ratio [OR] 2.62, CI 1.68-4.08) and preeclampsia (OR 2.46, CI 1.49-4.08). First-trimester low PAI-2 was associated with a 1.9% higher uterine artery index and a 2.7% lower birth weight (-94 g, CI-136 to-51). First-trimester low PAI-2 was associated with a higher risk of fetal growth restriction (OR 2.22, CI 1.39-3.55). Conclusion: First-half-of-pregnancy concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 are associated with uteroplacental vascular resistance, placental weight, and birth weight. Moreo

Background: Air pollution exposure during pregnancy might affect placental growth and function, perhaps leading to pregnancy complications. Objective: We prospectively evaluated the associations of maternal air pollution exposure with markers of placental growth and function among 7,801 pregnant women in the Netherlands. Methods: We estimated levels of particulate matter ≤ 10 µm in aerodynamic diameter (PM10) and nitrogen dioxide (NO2) at the home address for different periods during pregnancy using dispersion modeling techniques. Pro- and anti-angiogenic factors [placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), respectively] were measured in first- and second-trimester maternal blood and in fetal cord blood samples at delivery. Pulsatility index of the uterine and umbilical arteries was measured by Doppler ultrasound in second and third trimester, and notching was assessed in third trimester. Placenta weight and birth weight were obtained from medical records. Results: Higher PM10 and NO2 exposure levels were associated with lower second-trimester maternal sFlt-1 and PlGF levels. PM10 and NO2 exposures averaged over total pregnancy were associated with higher sFlt-1 and lower PlGF levels in fetal cord blood, consistent with an anti-angiogenic state. PM10 and NO2 exposures were not consistently associated with second- or third-trimester placental resistance indices. NO2 exposure was associated with third-trimester notching (odds ratio 1.33; 95% CI: 0.99, 1.78 per 10-µg/m3 increase in the prior 2 months). PM10 and NO2 exposures were associated with lower placenta weight (–11.8 g; 95% CI: –20.9, –2.7, and –10.7 g; 95% CI: –19.0, –2.4, respectively, per 10-µg/m3 increase in the prior 2 months), but not with placenta to birth weight ratio. Conclusions: Our results suggest that maternal air pollution exposure may influence markers of placental growth and function. Future studies are needed to confirm these findings and explore the maternal

Public relations (PR) and information to patients are key goals of the Dutch Society of Clinical Chemistry (NVKC). In this paper several initiatives will be discussed that have been undertaken to meet this statement. The Wikipedia project is one of those initiatives in which information concerning clinical chemistry is added or revised to the Dutch version of the online encyclopaedia Wikipedia. Over 100 tests and items of clinical chemistry have been added or revised and are recognized as a separate category within this online encyclopaedia. Statistical analysis showed an increase in the number of visitors to these articles of Wikipedia. Furthermore, by adding and improving the available information, the quality of the information provided online is enhanced. In conclusion: the attribution of health care professionals to this public domain leads to enhanced access of high quality information for the main public to clinical chemistry in general and to specific laboratory blood tests.

Synthetic glucocorticoids are used therapeutically for numerous indications. However, due to their broad physiological effects across many systems, side effects of GC therapy can be extensive and limit the clinical utility of GCs as a drug. One of the main urgent questions at this moment is to develop insights into the cause of the differences in the response between individuals to therapeutically applied GCs. Some patients respond to low doses, with or without side effects, while others do not respond at all. This thesis discusses a number of possible explanations for these differences in GC sensitivity and is focused on genetic, but also on transcriptional and translational aspects of the GR gene. Furthermore, it is also described how glucocorticoid sensitivity disorders can be characterized clinically and biochemically. An important tool in these studies has been a newly developed bioassay, measuring cellular GC sensitivity ex vivo, based on GR action at the transcriptional level by studying GC-regulated mRNA expression (chapter 2). Various polymorphism in the GR gene (N363S, ER22/23EK, and 9beta) are shown to affect GC sensitivity in vivo and in/ex vitro and result in a wide variety of phenotypic signs (chapters 3, 4, and 5). Furthermore, studies described in chapter 4, 5, 6, and 7 have demonstrated that also transcriptional and translational variants of the GR and the use of different promoters could modulate GC sensitivity. These factors modulating inter- individual sensitivity to GCs may have consequences for the use of GCs in a clinical setting. When treating patients with GCs, they need an individually determined optimal dose to obtain a balance between beneficial and adverse effects.

Individual glucocorticoid (GC) sensitivity was determined by measuring the effects of several clinically used GCs on transactivation of the GC-induced leucine zipper (GILZ) gene and on transrepression of the IL-2 gene using quantitative real-time PCR. A clear difference in relative potencies for transactivation and transrepression of the various GCs was observed, suggesting differential effects. To determine whether the in vitro outcomes could predict in vivo effects of GCs, 15 individuals underwent a 0.25-mg dexamethasone (DEX) suppression test (DST) while determining GILZ and IL-2 mRNA levels in their peripheral blood mononuclear cells incubated with hydrocortisone, DEX, budesonide, and prednisolone. No correlations were found between the DST and the two expression assays. However, significant correlations existed between hydrocortisone and DEX (r = 0.52; P = 0.046), hydrocortisone and budesonide (r = 0.48; P = 0.069), and hydrocortisone and prednisolone (r = 0.86; P = 0.007) regarding GILZ mRNA levels, and between hydrocortisone and DEX (r = 0.62; P = 0.014), hydrocortisone and budesonide (r = 0.71; P = 0.003), and hydrocortisone and prednisolone (r = 0.71; P = 0.047) regarding IL-2 mRNA levels. In conclusion, intra- and inter-individual variations in GC sensitivity were observed using two expression assays representing GC-mediated transactivation and transrepression. The two expression assays did not correlate with each other or with the results of the DST. This suggests that regulation of the hypothalamic-pituitary-adrenal axis is more complex. However, within an individual person, these two tests combined might predict what type and dosage of GC will be preferable in individual patients for its inhibitory clinical effects, together with relatively fewer transactivating effects related to adverse effects.

CONTEXT: Interindividual variation in glucocorticoid (GC)-sensitivity can be partly explained by polymorphisms in the GC receptor (GR) gene. The ER22/23EK and N363S polymorphisms have been described to be associated with lower and higher GC sensitivity, respectively. OBJECTIVE AND DESIGN: We examined the basis of this altered GC sensitivity by expressing GR(N363S) and GR(ER22/23EK) in COS-1 cells and investigating their transactivating and transrepressing capacities using a GC response element-luciferase reporter and a p65-activated nuclear factor kappaB-luciferase reporter, respectively. Furthermore, we evaluated the transactivating and transrepressing capacities of the GR in peripheral blood mononuclear lymphocytes of homozygous and heterozygous carriers of these polymorphisms by determining the maximum effect of dexamethasone on transactivation of the GC-induced leucine-zipper and transinhibition of the IL-2 gene by means of real-time RT-PCR. RESULTS: The effects of the polymorphisms in the GR gene previously observed in population studies were also detected at the level of gene expression. The ER22/23EK polymorphism resulted in a significant reduction of transactivating capacity, in both transfection experiments (-14 +/- 5%, P < 0.05) and peripheral blood mononuclear lymphocytes of carriers of this polymorphism (homozygous: -48 +/- 6%, P < 0.01, n = 1; heterozygous: -21 +/- 4%, P = 0.08, n = 3). The N363S polymorphism, associated with increased GC sensitivity, resulted in a significantly increased transactivating capacity, both in vitro (8 +/- 3%; P < 0.02) and ex vivo (homozygous: 204 +/- 19%, P < 0.0001, n = 1; heterozygous: 124 +/- 8%, P = 0.05, n = 3). Neither the ER22/23EK nor the N363S polymorphism seemed to influence the transrepressing capacity of the GR. CONCLUSION: The presence of these and other GC sensitivity-modulating polymorphisms may have consequences for the use of GCs in a clinical setting.

One of the most intriguing polymorphisms in the GR [glucocorticoid (GC) receptor] gene is in codons 22 and 23 [GAGAGG(GluArg) --> GAAAAG (GluLys)]. This polymorphism is associated with a reduced GC sensitivity, a better metabolic and cardiovascular health profile, and an increased survival rate. Recently, Yudt and Cidlowski reported that two different methionine codons in the GR mRNA may be used as initiation codon: AUG-1 and AUG-27, resulting in two isoforms, the GR-A and the GR-B proteins, respectively. They also showed that the GR-B protein had a stronger transactivating effect in transient transfection experiments. In this study, we elucidated the molecular basis for the reduced GC sensitivity by investigating the influence of the ER22/23EK polymorphism on synthesis of GR-A and GR-B by expressing them independently from constructs with and without the polymorphic site. Binding studies with [(3)H]-dexamethasone and transactivation studies showed that, when the ER22/23EK polymorphism is present, approximately 15% more GR-A protein was expressed, whereas total GR levels (GR-A + GR-B) were not af