QTc intervals are not prolonged in former ELBW infants at pre-adolescent age

Background: Whether preterm birth is associated with cardiac conduction or repolarization abnormalities in later life is still poorly explored, with conflicting data on QTc prolongation in former extreme low birth weight (ELBW, &lt;1000 g) infants. Methods: Twelve lead electrocardiograms (ECG) at rest, collected in the PREMATurity as predictor of children’s Cardiovascular-renal Health (PREMATCH) study in former ELBW cases and term controls during pre-adolescence (8–14 years) were analyzed on corrected QT time (QTc, Bazett) and QT dispersion (QTd). ECG findings were compared between groups (Mann−Whitney), and associations with clinical and biochemical findings were explored (Spearman). In ELBW cases, associations between QTc and perinatal characteristics (at birth, neonatal stay) were explored (Mann−Whitney, Spearman). Results: QTc and QTd were similar between 93 ELBW cases and 87 controls [409 (range 360–465) versus 409 (337–460); 40 (0–100) versus 39 (0–110)] ms. Age, height, weight, or body mass index were not associated with the QTc interval, while female sex (median difference 11.4 ms) and lower potassium (r = −0.26) were associated with longer QTc interval. We could not observe any significant association between QTc interval and perinatal characteristics. Conclusions: There were no differences in QTc or QTd between ELBW and term controls in ECGs at rest in pre-adolescents. Impact: This study aimed to assess the differences in QTc and QTd intervals between extreme low birth weight infants (ELBW) and term controls in electrocardiographic measurements at rest during pre-adolescence.This analysis confirmed the absence of significant differences in QTc or QTd findings between ELBW cases and term controls, while female sex and lower potassium were associated with a prolonged QTc interval.These data suggest that QTc screening strategies—including for pharmacovigilance—should not differentiate between former ELBW cases and term controls. Clinical trial registration: ClinicalTrials.gov Identifier NCT02147457.</p

Registration of serial sections: An evaluation method based on distortions of the ground truths

Registration of histological serial sections is a challenging task. Serial sections exhibit distortions and damage from sectioning. Missing information on how the tissue looked before cutting makes a realistic validation of 2D registrations extremely difficult. This work proposes methods for ground-truth-based evaluation of registrations. Firstly, we present a methodology to generate test data for registrations. We distort an innately registered image stack in the manner similar to the cutting distortion of serial sections. Test cases are generated from existing 3D data sets, thus the ground truth is known. Secondly, our test case generation premises evaluation of the registrations with known ground truths. Our methodology for such an evaluation technique distinguishes this work from other approaches. Both under- and over-registration become evident in our evaluations. We also survey existing validation efforts. We present a full-series evaluation across six different registration methods applied to our distorted 3D data sets of animal lungs. Our distorted and ground truth data sets are made publicly available.Comment: Supplemental data available under https://zenodo.org/record/428244

Prospective assessment of inter-rater reliability of a neonatal adverse event severity scale

Introduction: To ensure the quality of clinical trial safety data, universal data standards are required. In 2019 the International Neonatal Consortium (INC) published a neonatal adverse event severity scale (NAESS) to standardize the reporting of adverse event (AE) severity. In this study the reliability of AE severity grading with INC NAESS was prospectively assessed in a real-world setting. Methods: Severity of AEs was assessed by two independent observers at each of four centers across the world. In each center two series of 30 neonatal adverse events were assessed by both observers: in a first phase with a generic (Common Terminology Criteria for Adverse Events, CTCAE) severity scale not specific to neonates, and in a second phase with INC NAESS (after a structured training). Intraclass correlation coefficients (ICC) were calculated to express inter-rater agreement in both phases, and bootstrap sampling was used to compare them. Results: 120 AEs were included in each of both phases. The ICC with the use of INC NAESS in phase 2 was 0.69. This represents a significant but modest improvement in comparison to the initial ICC of 0.66 in phase 1 (confidence interval of ratio of ICC in phase 2 to phase 1 = 1.005–1.146; excludes 1). The ICC was higher for those AEs for which a diagnosis specific AE severity table was available in INC NAESS (ICC 0.80). Discussion: Good inter-rater reliability of the INC NAESS was demonstrated in four neonatal intensive care units (NICUs) across the globe. The ICC is comparable to what is reported for scales with similar purposes in different populations. There is a modest, but significant, improvement in inter-rater agreement in comparison to the naïve phase without INC NAESS. The better performance when reviewers use AE-specific NAESS tables highlights the need to expand the number of AEs that are covered by specific criteria in the current version of INC NAESS.</p

Towards new therapies for bronchopulmonary dysplasia

not applicablestatus: publishe

Neonatal clinical pharmacology: current evolutions and future perspectives

Pharmacotherapy is a very powerful tool to improve outcome in neonates. Clinical pharmacology supports this by predicting drug-related (side)-effects, driven by pharmacokinetics (PK) and pharmacodynamics (PD). The dynamic changes related to maturation and growth in newborns, combined with population-specific disease characteristics result in a unique setting with extensive variability in both PK (drug concentration-time profiles) and PD (drug concentration-effect profiles). Only in part because of these dynamic alterations, neonatal pharmacotherapy is still lagging behind when compared to the available level of knowledge and research tools in other populations. However, relevant progress has been made. We therefore wanted to highlight some ongoing efforts to ‘translate’ this recently emerged knowledge on neonatal pharmacology by facilitating access for prescribers as an obvious need to improve our current clinical practice. The Neodose project and data driven PK software tools hereby serve as illustrations of such clinical ‘translation’ efforts. This will be followed by some perspectives to further improve neonatal drug development and research tools. Adaptations of research tools to the characteristics of neonates are hereby crucial. The relevance of such adaptations will be highlighted, using physiology-based (PB)-PK modeling and the development of an adverse event severity grading research tool tailored to neonates as examples. In conclusion, neonatal pharmacology is still lagging behind and full catch-up on knowledge driven pharmacotherapy has not yet been attained. However, this subdiscipline is for sure on the move to further improve neonatal outcome, driven by multidisciplinary collaboration.status: publishe

Modelling bronchopulmonary dysplasia in animals: arguments for the preterm rabbit model

Bronchopulmonary dysplasia (BPD) remains a frequent and disabling consequence of preterm birth, despite the recent advances in neonatal intensive care. There is a need to further improve outcomes and many novel therapeutic or preventive strategies are therefore investigated in animal models. We discuss in this review the aspects of human BPD pathophysiology and phenotype, which ideally should be mimicked by an animal model for this disease. Prematurity remains the common denominator in the heterogeneous spectrum of human BPD, and preterm animal models thus have a clear translational advantage. Additional factors, like excessive oxygen, mechanical ventilation and infection, which frequently have been studied in animal models, can contribute to preterm lung injury however are not indispensable to develop BPD. The phenotype of human BPD is characterized by alveolar developmental arrest with extracellular matrix remodeling, signs of obstructive airway disease and pulmonary vascular disease. Many animal models mimic this phenotype and have their place in BPD research, but results should be interpreted bearing in mind the specific advantages and disadvantages of the model. Term mice and rats are well suited for basic explorative research on specific disease mechanisms, essential for the generation of new hypotheses, while the larger ventilated preterm baboons and lambs provide a good platform for the ultimate translation of these strategies towards clinical application. The preterm rabbit model seems a promising model as it the smallest model that includes a factor of prematurity and has a unique position between the small and large animal models.status: publishe