A Delphi process to optimize quality and performance of drug evaluation in neonates

Background Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. The objective of this work was to identify the major criteria considered necessary for selecting neonatal intensive care units that are able to perform drug evaluations competently. Methodology and Main Findings This Delphi process was conducted with an international multidisciplinary panel of 25 experts from 13 countries, selected to be part of two committees (a scientific committee and an expert committee), in order to validate criteria required to perform drug evaluation in neonates. Eighty six items were initially selected and classified under 7 headings: “NICUs description - Level of care” (21), “Ability to perform drug trials: NICU organization and processes (15), “Research Experience” (12), “Scientific competencies and area of expertise” (8), “Quality Management” (16), “Training and educational capacity” (8) and “Public involvement” (6). Sixty-one items were retained and headings were rearranged after the first round, 34 were selected after the second round. A third round was required to validate 13 additional items. The final set includes 47 items divided under 5 headings. Conclusion A set of 47 relevant criteria will help to NICUs that want to implement, conduct or participate in drug trials within a neonatal network identify important issues to be aware of. Summary Points 1) Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. 2) The present Delphi study was conducted with an international multidisciplinary panel of 25 experts from 13 countries and aims to identify the major criteria considered necessary for selecting neonatal intensive care units (NICUs) that are able to perform drug evaluations competently. 3) Of the 86 items initially selected and classified under 7 headings - “NICUs description - Level of care” (21), “Ability to perform drug trials: NICU organization and processes (15), “Research Experience” (12), “Scientific competencies and area of expertise” (8), “Quality Management” (16), “Training and educational capacity” (8) and “Public involvement” (6) - 47 items were selected following a three rounds Delphi process. 4) The present consensus will help NICUs to implement, conduct or participate in drug trials within a neonatal network

Plasma concentration guided dosing of drugs used for the treatment of childhood leukaemias: protocol for a systematic review

Introduction: Childhood leukaemia is the most common type of cancer in children and represents among 25% of the diagnoses in children <15 years old. Childhood survival rates have significantly improved within the last 40 years due to a rapid advancement in therapeutic interventions. However, in high-risk groups, survival rates remain poor. Pharmacokinetic (PK) data of cancer medications in children are limited and thus current dosing regimens are based on studies with small sample sizes. In adults, large variability in PK is observed and dose individualisation (plasma concentration guided dosing) has been associated with improved clinical outcomes; whether this is true for children is still unknown. This provides an opportunity to explore this strategy in children to potentially reduce toxicities and ensure optimal dosing. This paper will provide a protocol to systematically review studies that have used dose individualisation of drugs used in the treatment of childhood leukaemias. Methods and analysis: Systematic review methodology will be applied to identify, select and extract data from published plasma guided dosing studies conducted in a paediatric leukaemia cohort. Databases (eg, Ovid Embase, Ovid MEDLINE, Ovid Cochrane) and clinical trial registries (CENTRAL, ClinicalTrials.gov and ISRCTN) will be used to perform the systematic literature search (up until February 2021). Only full empirical studies will be included, with primary clinical outcomes (progression-free survival, toxicities, minimal residual disease status, complete cytogenetic response, partial cytogenetic response and major molecular response) being used to decide whether the study will be included. The quality of included studies will be undertaken, with a subgroup analysis where appropriate. Ethics and dissemination: This systematic review will not require ethics approval as there will not be collection of primary data. Findings of this review will be made available through publications in peer-reviewed journals and conference presentations. Gaps will be identified in current literature to inform future-related research. PROSPERO registration number CRD42021225045

Randomised placebo-controlled multicentre effectiveness trial of adjunct betamethasone therapy in hospitalised children with community-acquired pneumonia: a trial protocol for the KIDS-STEP trial

IntroductionCommunity-acquired pneumonia (CAP) causes around 10 hospitalisations per 1000 child-years, each associated with an average 13 non-routine days experienced and more than 4 parent workdays lost. In adults, steroid treatment shortens time to clinical stabilisation without an increase in complications in patients with CAP. However, despite promising data from observational studies, there is a lack of high-quality evidence for the use of steroids.Methods and analysisThe KIDS-STEP trial is a multicentre, randomised, double-blind, placebo-controlled superiority trial of betamethasone treatment on outcome of hospitalised children with CAP. Children are enrolled in paediatric emergency departments of hospitals across Switzerland and randomised to adjunct oral betamethasone for 2 days or matching placebo in addition to standard of care treatment. The co-primary outcomes are the proportion of children clinically stable 48 hours after randomisation and the proportion of children with CAP-related readmission within 28 days after randomisation. Secondary outcomes include length of hospital stay, time away from routine childcare and healthcare utilisation and total antibiotic prescriptions within 28 days from randomisation.Each of the co-primary outcomes will be analysed separately. We will test clinical stability rates using a proportion test; to test non-inferiority in readmission rates, we will construct 1−α % CI of the estimated difference and test if it contains the pre-defined margin of 7%. Success is conditional on both tests. A simulation-based sample size estimation determined that recruiting 700 patients will ensure a power of 80% for the study.Ethics and disseminationThe trial protocol and materials were approved by ethics committees in Switzerland (lead: Ethikkommission Nordwest und Zentralschweiz) and the regulatory authority Swissmedic. Participants and caregivers provide informed consent prior to study procedures commencing. The trial results will be published in peer-reviewed journals and at national and international conferences. Key messages will also be disseminated via press and social media where appropriate.Trial registration numberNCT03474991 and SNCTP000002864

Detection of mostly viral pathogens and high proportion of antibiotic treatment initiation in hospitalised children with community-acquired pneumonia in Switzerland – baseline findings from the first two years of the KIDS-STEP trial

AIMS OF THE STUDY: Globally, since the introduction of conjugate-vaccines against encapsulated bacteria, respiratory viruses have caused most hospitalisations for community-acquired pneumonia. The aim of this study was to describe pathogens detected and their association with clinical findings in Switzerland. METHODS: Baseline data were analysed for all trial participants enrolled between September 2018 and September 2020 into the KIDS-STEP Trial, a randomised controlled superiority trial on the effect of betamethasone on clinical stabilisation of children admitted with community-acquired pneumonia. Data included clinical presentation, antibiotic use and results of pathogen detection. In addition to routine sampling, nasopharyngeal specimens were analysed for respiratory pathogens using a panel polymerase chain reaction test covering 18 viral and 4 bacterial pathogens. RESULTS: 138 children with a median age of 3 years were enrolled at the eight trial sites. Fever (obligatory for enrolment) had been present for median 5 days before admission. Most common symptoms were reduced activity (129, 93.5%) and reduced oral intake (108, 78.3%). Oxygen saturation <92% was found in 43 (31.2%). Forty-three participants (29.0%) were already on antibiotic treatment prior to admission and 104 participants (75.4%) received antibiotic treatment on admission. Pathogen testing results were available from 132 children: 31 (23.5%) had respiratory syncytial virus detected, 21 (15.9%) human metapneumovirus. The pathogens detected showed expected seasonal and age preponderance and were not associated with chest X-ray findings. CONCLUSIONS: In the context of the predominantly viral pathogens detected, the majority of antibiotic treatment is probably unnecessary. The ongoing trial, as well as other studies, will be able to provide comparative pathogen detection data to compare pre- and post-COVID-19-pandemic settings

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure

Aims: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice. Methods: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l-1 and 0-4 failing organs) using graphical and numerical diagnostics. Results: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) 180%). Conclusion: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure.

Aims: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice. Methods: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77–90 kg, C-reactive protein level 0.1–341 mg l–1 and 0–4 failing organs) using graphical and numerical diagnostics. Results: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) 180%). Conclusion: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia

Peer reviewe

Greenland surface mass-balance observations from the ice-sheet ablation area and local glaciers

Glacier surface mass-balance measurements on Greenland started more than a century ago, but no compilation exists of the observations from the ablation area of the ice sheet and local glaciers. Such data could be used in the evaluation of modelled surface mass balance, or to document changes in glacier melt independently from model output. Here, we present a comprehensive database of Greenland glacier surface mass-balance observations from the ablation area of the ice sheet and local glaciers. The database spans the 123 a from 1892 to 2015, contains a total of similar to 3000 measurements from 46 sites, and is openly accessible through the PROMICE web portal (http://www.promice.dk). For each measurement we provide X, Y and Z coordinates, starting and ending dates as well as quality flags. We give sources for each entry and for all metadata. Two thirds of the data were collected from grey literature and unpublished archive documents. Roughly 60% of the measurements were performed by the Geological Survey of Denmark and Greenland (GEUS, previously GGU). The data cover all regions of Greenland except for the southernmost part of the east coast, but also emphasize the importance of long-term time series of which there are only two exceeding 20 a. We use the data to analyse uncertainties in point measurements of surface mass balance, as well as to estimate surface mass-balance profiles for most regions of Greenland

Early inhaled budesonide for the prevention of bronchopulmonary dysplasia

BACKGROUND Systemic glucocorticoids reduce the incidence of bronchopulmonary dysplasia among extremely preterm infants, but they may compromise brain development. The effects of inhaled glucocorticoids on outcomes in these infants are unclear. METHODS We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to early (within 24 hours after birth) inhaled budesonide or placebo until they no longer required oxygen and positive-pressure support or until they reached a postmenstrual age of 32 weeks 0 days. The primary outcome was death or bronchopulmonary dysplasia, confirmed by means of standardized oxygen-saturation monitoring, at a postmenstrual age of 36 weeks. RESULTS A total of 175 of 437 infants assigned to budesonide for whom adequate data were available (40.0%), as compared with 194 of 419 infants assigned to placebo for whom adequate data were available (46.3%), died or had bronchopulmonary dysplasia (relative risk, stratified according to gestational age, 0.86; 95% confidence interval [CI], 0.75 to 1.00; P = 0.05). The incidence of bronchopulmonary dysplasia was 27.8% in the budesonide group versus 38.0% in the placebo group (relative risk, stratified according to gestational age, 0.74; 95% CI, 0.60 to 0.91; P = 0.004); death occurred in 16.9% and 13.6% of the patients, respectively (relative risk, stratified according to gestational age, 1.24; 95% CI, 0.91 to 1.69; P = 0.17). The proportion of infants who required surgical closure of a patent ductus arteriosus was lower in the budesonide group than in the placebo group (relative risk, stratified according to gestational age, 0.55; 95% CI, 0.36 to 0.83; P = 0.004), as was the proportion of infants who required reintubation (relative risk, stratified according to gestational age, 0.58; 95% CI, 0.35 to 0.96; P = 0.03). Rates of other neonatal illnesses and adverse events were similar in the two groups. CONCLUSIONS Among extremely preterm infants, the incidence of bronchopulmonary dysplasia was lower among those who received early inhaled budesonide than among those who received placebo, but the advantage may have been gained at the expense of increased mortality

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders