A randomised controlled trial comparing two methods of providing volume targeted ventilation in preterm infants :volume guarantee versus volume-controlled ventilation, The VoluVent Trial

M.D. ThesisBackground: Many preterm infants require mechanical ventilation via an endotracheal tube for the treatment of neonatal respiratory distress (RDS). A side effect of mechanical ventilation is lung injury. VTV aims to reduce lung injury by controlling the tidal volumes delivered to the infant by the ventilator. Many VTV modes are widely in use but have not been compared using clinically relevant outcomes. Aim: This was the first trial to compare two modes of VTV in preterm infants with RDS. We aimed to compare volume-controlled ventilation (VCV) with volume guarantee (VG) using clinically relevant outcomes. Hypothesis: We hypothesised that, in preterm infants with RDS, the time taken to be ready for extubation would be shorter in the VG group compared with VCV. The initial sample size calculation indicated that 102 infants were needed to show a 33% reduction in the time taken to be ready for extubation with a significance level of 0.05 and a power of 80%. Methods: This single centre, randomised controlled pilot trial was undertaken in a tertiary neonatal unit from July 2013 – December 2015. Infants were stratified into two groups according to gestational age at birth (<28 weeks’ gestation and 28 – 33+6 weeks’ gestation). The primary outcome was the duration of time from starting the trial mode until being ready for extubation. Readiness for extubation was defined using pre-determined ‘success’ criteria. Secondary outcomes included important clinical outcomes. After four months the consent method was changed from prospective to deferred parental consent. A trial oversight review of data from the first 50 infants identified that the primary outcome data were not likely to be normally distributed. The statistical analysis plan was therefore updated prior to any data analysis. We planned to present data as descriptive summary statistics including survival probabilities, hazard ratios (HRs) and odds ratios (ORs). In addition, using early phase trials statistical methods, a difference of 15% between groups in the numbers of infants reaching the ‘success’ criteria at 48 hours would indicate a potentially significant difference between groups. iv An ancillary study was undertaken using mechanistic data downloaded from ventilators to validate one of the ‘success’ criteria (mean airway pressure). Results: One hundred and thirteen infants were enrolled. One infant was subsequently withdrawn due to a diagnosis consistent with exclusion criteria. The median time to ‘success’ criteria was 23 hours (95% CI 10.78 – 35.22 hours) in the VG group and 36 hours (95% CI 18.03 – 53.97) in the VCV group. The HR was 0.93 (95% CI 0.63 – 1.37). Thirty four infants in the VG group and 33 infants in the VCV group had met the ‘success’ criteria by 48 hours. Subgroup analyses showed that, in infants born at 28 – 33+6 weeks’ gestation, the median time to reach the primary outcome faster in the VG group. The pneumothorax rates and duration of ventilation were lower in the VG group. The use of deferred consent appeared to be more acceptable to parents and led to an improvement in the recruitment rate. The ancillary study showed very good correlation between the mean airway pressure values recorded manually once every hour and the values downloaded with every breath. This validated the use of manual recordings of mean airway pressure as part of the primary outcome. Conclusions: There was a clinical important difference between VG and VCV in the time taken for infants to be ready for extubation. This difference favoured VG but a larger trial is needed to show a definitive result. This trial also highlights current gaps in knowledge regarding short-term clinical outcomes and the use of VTV modes in different subgroups of infants. Deferred consent appears to be acceptable to parents of newborn infants but qualitative research is needed to explore this further. This thesis describes The VoluVent Trial (ISRCTN 04448562), the first clinical trial to compare two types of volume-targeted ventilation (VTV) in preterm infants. One of the known side effects of mechanical ventilation is lung injury. VTV aims to minimise ventilator-associated lung injury and different types of VTV are used widely. However, there is no evidence to confirm whether one type of VTV is better than another for preterm infant

Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

BACKGROUND: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. METHODS: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0·0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0·0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0·001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases). INTERPRETATION: Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes. FUNDING: American Academy of Pediatrics, Boston Children's Hospital Children's Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre

Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study

Background: fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). Methods: in this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. Findings: the cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4–11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). Interpretation: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. Funding: UK Department of Health and Social Care and The Wellcome Trust.</p