ABSTRACT
OBJECTIVE: To examine the predictive performance of a previously reported competing-risks model of screening for pre-eclampsia (PE) at 35-37 weeks' gestation by combinations of maternal risk factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1) in a validation dataset derived from the screened population of the STATIN study. METHODS: This was a prospective third-trimester multicenter study of screening for PE in singleton pregnancies by means of a previously reported algorithm that combines maternal risk factors and biomarkers. Women in the high-risk group were invited to participate in a trial of pravastatin vs placebo, but the trial showed no evidence of an effect of pravastatin in the prevention of PE. Patient-specific risks of delivery with PE were calculated using the competing-risks model, and the performance of screening for PE by maternal risk factors alone and by various combinations of risk factors with MAP, UtA-PI, PlGF and sFlt-1 was assessed. The predictive performance of the model was examined by, first, the ability of the model to discriminate between the PE and no-PE groups using the area under the receiver-operating-characteristics curve (AUC) and the detection rate at a fixed false-positive rate of 10%, and, second, calibration by measurements of calibration slope and calibration-in-the-large. RESULTS: The study population of 29 677 pregnancies contained 653 that developed PE. In screening for PE by a combination of maternal risk factors, MAP, PlGF and sFlt-1 (triple test), the detection rate at a 10% false-positive rate was 79% (95% CI, 76-82%) and the results were consistent with the data used for developing the algorithm. Addition of UtA-PI did not improve the prediction provided by the triple test. The AUC for the triple test was 0.923 (95% CI, 0.913-0.932), demonstrating very high discrimination between affected and unaffected pregnancies. Similarly, the calibration slope was 0.875 (95% CI, 0.831-0.919), demonstrating good agreement between the predicted risk and observed incidence of PE. CONCLUSION: The competing-risks model provides an effective and reproducible method for third-trimester prediction of term PE. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
Subject(s)
Pre-Eclampsia/diagnosis , Pregnancy Trimester, Third , Prenatal Diagnosis/methods , Risk Assessment/methods , Adult , Arterial Pressure , Biomarkers/analysis , Calibration , False Positive Reactions , Female , Gestational Age , Humans , Placenta Growth Factor/blood , Pre-Eclampsia/prevention & control , Predictive Value of Tests , Pregnancy , Prospective Studies , Pulsatile Flow , ROC Curve , Randomized Controlled Trials as Topic , Reproducibility of Results , Uterine Artery/diagnostic imaging , Uterine Artery/physiopathology , Vascular Endothelial Growth Factor Receptor-1/bloodABSTRACT
Migration of immunocompetent cells into the central nervous system represents a key event in the immunopathogenesis of multiple sclerosis (MS). Fumaric acid esters have recently been approved for patients with MS. Their mode of action is not fully understood so far. We analyzed the effect of monomethylfumarate (MMF), the immediate metabolite of dimethylfumarate, on migration of lymphocytes and macrophages. Peripheral blood mononuclear cells (PBMCs) were isolated from patients with MS and healthy donors. PBMCs were treated with MMF in vitro and their migratory capacity was studied in a Boyden chamber assay. In addition, expression of matrix metalloproteinases (MMPs), chemokine receptors, adhesion molecules, and molecules of the oxidative stress cascade was assessed. MMF decreased the migratory capacity of T lymphocytes, but not of macrophages. Lymphocytes as well as macrophages responded to MMF by the upregulation of oxidative stress molecules; however, no effect was seen on the expression of MMPs, chemokine receptors, and adhesion molecules. There was no difference in comparison with cells from healthy controls. MMF reduces the migratory activity of lymphocytes most likely by changing their activational state. This points to a potential novel mode of action differentiating this drug from other available immunotherapies.
Subject(s)
Cell Movement/drug effects , Fumarates/pharmacology , Gene Expression Regulation/drug effects , Leukocytes, Mononuclear/drug effects , Maleates/pharmacology , Multiple Sclerosis/blood , Adult , Antigens, CD/metabolism , Cell Movement/physiology , Female , Flow Cytometry , Glutamate-Cysteine Ligase/genetics , Glutamate-Cysteine Ligase/metabolism , Heme Oxygenase-1 , Humans , Leukocytes, Mononuclear/metabolism , Male , NAD(P)H Dehydrogenase (Quinone)/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Signal Transduction/physiology , Statistics, Nonparametric , Time FactorsABSTRACT
BACKGROUND: Damage of the blood-brain barrier and the migration of immunocompetent cells into the CNS represent key events in the immunopathogenesis of multiple sclerosis (MS). Cladribine is an immunosuppressive drug currently investigated in a phase-III clinical trial for relapsing-remitting MS. However, its precise mode of action remains elusive so far. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from five patients with MS and five healthy donors. PBMCs were treated with cladribine in vitro. The migratory capacity was studied in an in vitro Boyden chamber assay; cells and their rate of migration were analyzed by light microscopy and flow cytometry. RESULTS: Cladribine decreased the migratory capacity of CD14(+) monocytes, as well as of CD4(+) and CD8(+) T lymphocytes. T lymphocytes were affected more than monocytes. There was no difference in this effect when comparing mononuclear cells from MS patients with cells from healthy controls. CONCLUSIONS: Cladribine might achieve, at least in part, its clinical and paraclinical efficacy by inhibiting the migration of inflammatory cells into and within the CNS.