Integrated Longitudinal Population Dose-Hemoglobin Response of Daprodustat Following Dose Titration in Patients With Anemia in Chronic Kidney Disease.

Daprodustat, a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor is approved in the United States for the treatment of anemia due to chronic kidney disease (CKD) in adults receiving dialysis for at least 4 months. Pharmacodynamic dose-hemoglobin (Dose-Hgb) models were developed as daprodustat progressed through development. To support global phase III development, a dose-titration algorithm, guided by simulations from the initial Dose-Hgb model based on phase II clinical data, was implemented.

Pharmacokinetics and pharmacodynamics of finerenone in patients with chronic kidney disease and type 2 diabetes: Insights based on FIGARO-DKD and FIDELIO-DKD.

Aims: To perform dose-exposure-response analyses to determine the effects of finerenone doses.

Materials And Methods: Two randomized, double-blind, placebo-controlled phase 3 trials enrolling 13 026 randomized participants with type 2 diabetes (T2D) from global sites, each with an estimated glomerular filtration rate (eGFR) of 25 to 90 mL/min/1.73 m , a urine albumin-creatinine ratio (UACR) of 30 to 5000 mg/g, and serum potassium ≤ 4.

Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) intercalated TKI with chemotherapy for -mutated nonsmall cell lung cancer.

Introduction: Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC).

Materials And Methods: Treatment-naïve patients with an activating mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy.

Finerenone Dose-Exposure-Response for the Primary Kidney Outcome in FIDELIO-DKD Phase III: Population Pharmacokinetic and Time-to-Event Analysis.

Background: Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist that recently demonstrated efficacy in delaying chronic kidney disease progression and reducing cardiovascular events in patients with chronic kidney disease and type 2 diabetes in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either titrated finerenone doses of 10 or 20 mg once daily or placebo, with a median follow-up of 2.6 years.

Methods: Nonlinear mixed-effects population pharmacokinetic models were used to analyze the pharmacokinetics in FIDELIO-DKD, sparsely sampled in all subjects receiving finerenone.

Understanding effect site pharmacology of uprifosbuvir, a hepatitis C virus nucleoside inhibitor: Case study of a multidisciplinary modeling approach in drug development.

Uprifosbuvir is a uridine nucleoside monophosphate prodrug inhibitor of the hepatitis C virus NS5B RNA polymerase. To quantitatively elucidate key metabolic pathways, assess the link between unmeasurable effect site concentrations and viral load reduction, and evaluate the influence of intrinsic and extrinsic factors on pharmacokinetics and pharmacodynamics, a model-informed drug development (MIDD) framework was initiated at an early stage. Originally scoped as a modeling effort focused on minimal physiologically based pharmacokinetic and covariate analyses, this project turned into a collaborative effort focused on gaining a deeper understanding of the data from drug metabolism, biopharmaceutics, pharmacometrics, and clinical pharmacology perspectives.

A new microdialysis probe for continuous lactate measurement during fetal monitoring: Proof of concept in an animal model.

Introduction: Cardiotocography (CTG) is currently the most commonly used method for intrapartum fetal monitoring during labor. However, a high false-positive rate of fetal acidosis indicated by CTG leads to an increase in obstetric interventions. We developed a microdialysis probe that is integrated into a fetal scalp electrode allowing continuous measurement of lactate subcutaneously, thus giving instant information about the oxygenation status of the fetus.

Early and late onset pre-eclampsia and small for gestational age risk in subsequent pregnancies.

Background: Pre-eclampsia shares pathophysiology with intrauterine growth restriction.

Objective: To investigate whether delivery of a small for gestational age (SGA) infant in the 1st pregnancy increases the risk of early and late onset pre-eclampsia in the 2nd pregnancy. Conversely, we investigated whether pre-eclampsia in the 1st pregnancy impacts SGA risk in the 2nd pregnancy.

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development.

Sphingolipidoses are severe, mostly infantile lysosomal storage disorders (LSDs) caused by defective glycosphingolipid degradation. Two of these sphingolipidoses, Tay Sachs and Sandhoff diseases, are caused by β-Hexosaminidase (HEXB) enzyme deficiency, resulting in ganglioside (GM2) accumulation and neuronal loss. The precise sequence of cellular events preceding, and leading to, neuropathology remains unclear, but likely involves inflammation and lysosomal accumulation of GM2 in multiple cell types.

Recurrence risk of preeclampsia in a linked population-based cohort: Effects of first pregnancy maximum diastolic blood pressure and gestational age.

Objective: To estimate preeclampsia occurrence and recurrence risk in the 2nd pregnancy and analyze associated risk factors such as 1st pregnancy maximum diastolic blood pressure (maxDBP) and gestational age at delivery (GA).

Study Design: Linked cohort of 1st and 2nd pregnancies of 272,551 women from the Dutch Perinatal Registry collected between 2000 and 2007. We defined preeclampsia as hypertension (maxDBP ≥90 mmHg or documented hypertension) plus proteinuria (≥300 mg/24 h) and analyzed its 2nd pregnancy occurrence with logistic regression.

Pregnancy outcomes in women with gestational diabetes mellitus diagnosed according to the WHO-2013 and WHO-1999 diagnostic criteria: a multicentre retrospective cohort study.

Background: The World Health Organization (WHO) adopted more stringent diagnostic criteria for GDM in 2013, to improve pregnancy outcomes. However, there is no global consensus on these new diagnostic criteria, because of limited evidence. The objective of the study was to evaluate maternal characteristics and pregnancy outcomes in two cohorts in the Netherlands applying different diagnostic criteria for GDM i.

New diagnostic criteria for gestational diabetes mellitus and their impact on the number of diagnoses and pregnancy outcomes.

Aims/hypothesis: Detection and management of gestational diabetes mellitus (GDM) are crucial to reduce the risk of pregnancy-related complications for both mother and child. In 2013, the WHO adopted new diagnostic criteria for GDM to improve pregnancy outcomes. However, the evidence supporting these criteria is limited.

Randomized Phase III Trial of Erlotinib versus Docetaxel in Patients with Advanced Squamous Cell Non-Small Cell Lung Cancer Failing First-Line Platinum-Based Doublet Chemotherapy Stratified by VeriStrat Good versus VeriStrat Poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung Trial.

Introduction: Docetaxel and erlotinib are registered second-line treatments for wild-type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second-line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS-lung aimed at exploring this predictive effect in patients with squamous cell NSCLC.

Postpartum glucose follow-up and lifestyle management after gestational diabetes mellitus: general practitioner and patient perspectives.

Background: Incidence of type 2 diabetes is high after gestational diabetes mellitus (GDM). We aimed to evaluate the adherence to follow-up six-weeks postpartum visits in secondary care after GDM and glucose monitoring in primary care longer than 12-14 months after delivery and the years thereafter. In addition, we examined the women's lifestyle after delivery.

Changes in cerebral autoregulation in the second half of pregnancy and compared to non-pregnant controls.

Objective: The mechanism by which pregnancy affects the cerebral circulation is unknown, but it has a central role in the development of neurological complications in preeclampsia, which is believed to be related to impaired autoregulation. We evaluated the cerebral autoregulation in the second half of pregnancy, and compared this with a control group of healthy, fertile non-pregnant women.

Methods: In a prospective cohort analysis, cerebral blood flow velocity of the middle cerebral artery (determined by transcranial Doppler), blood pressure (noninvasive arterial volume clamping), and end-tidal carbon dioxide (EtCO2) were simultaneously collected for 7min.

Prediction of progression to severe disease in women with late preterm hypertensive disorders of pregnancy.

Introduction: If hypertensive disorders of pregnancy are diagnosed before term, the benefits of immediate delivery need to be weighed against the neonatal consequences of preterm delivery. If we are able to predict which women are at high risk of progression to severe disease, they could be targeted for delivery and maternal complications might be reduced. In addition, this may prevent unnecessary preterm births in women at low risk.

Neonatal and obstetric outcomes in diet- and insulin-treated women with gestational diabetes mellitus: a retrospective study.

Background: To evaluate the neonatal and obstetric outcomes of pregnancies complicated by gestational diabetes mellitus (GDM). Screening and treatment - diet-only versus additional insulin therapy - were based on the 2010 national Dutch guidelines.

Methods: Retrospective study of the electronic medical files of 820 singleton GDM pregnancies treated between January 2011 and September 2014 in a university and non-university hospital.

Gestational Diabetes Mellitus:current knowledge and unmet needs.

Gestational diabetes mellitus (GDM) is a global health concern, not only because its prevalence is high and on the increase, but also because of the potential implications for the health of mothers and their offspring. Unfortunately, there is considerable controversy in the literature surrounding the diagnosis and treatment of GDM, as well as the possible long-term consequences for the offspring. As a result, worldwide there is a lack of uniformly accepted diagnostic criteria and the advice regarding the treatment of GDM, including diet, insulin therapy, and the use of oral blood glucose-lowering agents, is highly variable.

Immunological Adaptations to Pregnancy in Women with Type 1 Diabetes.

Despite adequate glycemic control, pregnancy outcome of women with type 1 diabetes (T1D) is still unfavorable as compared to healthy women. In a rat-model of T1D under normoglycemic conditions, adverse pregnancy outcome was also observed, which was associated with aberrant immunological adaptations to pregnancy. Because similar processes may occur in women with T1D we studied the systemic immune response in non-pregnant and pregnant women with and without T1D.

Maternal and neonatal outcomes of pregnancy in women with chronic hypertension: a retrospective analysis of a national register.

Introduction: Pregnancies complicated by chronic hypertension are at increased risk of adverse pregnancy outcomes. To assess whether planned early delivery might prevent some of these adverse outcomes, we studied maternal and neonatal outcomes of pregnancy in women with chronic hypertension, including gestational-age-specific outcomes.

Material And Methods: We performed a retrospective, population-based cohort study, using data from the Netherlands Perinatal Register.

Relevance of individual participant data meta-analysis for studies in obstetrics: delivery versus expectant monitoring for hypertensive disorders of pregnancy.

Like many other research subjects in obstetrics, research on immediate delivery versus expectant monitoring for women with hypertensive disorders of pregnancy faces certain challenges when it comes to interpretation and generalisation of the results; relatively rare outcomes are studied, in a clinically heterogeneous population, while the clinical practice in some countries has dictated that studies in term pregnancy were completed before earlier gestational ages could be studied. This has resulted in multiple smaller studies, some studying surrogate outcome measures, with different in- and exclusion criteria, and without enough power for reliable subgroup analyses. All this complicates the generation of definitive answers and implementation of the results into clinical practice.