Estimating the comparative effectiveness of feeding interventions in the paediatric intensive care unit : a demonstration of longitudinal targeted maximum likelihood estimation

Longitudinal data sources offer new opportunities for the evaluation of sequential interventions. To adjust for time-dependent confounding in these settings, longitudinal targeted maximum likelihood based estimation (TMLE), a doubly robust method that can be coupled with machine learning, has been proposed. This paper provides a tutorial in applying longitudinal TMLE, in contrast to inverse probability of treatment weighting and g-computation based on iterative conditional expectations. We apply these methods to estimate the causal effect of nutritional interventions on clinical outcomes among critically ill children in a United Kingdom study (Control of Hyperglycemia in Paediatric Intensive Care, 2008–2011). We estimate the probability of a child’s being discharged alive from the pediatric intensive care unit by a given day, under a range of static and dynamic feeding regimes. We find that before adjustment, patients who follow the static regime “never feed” are discharged by the end of the fifth day with a probability of 0.88 (95% confidence interval: 0.87, 0.90), while for the patients who follow the regime “feed from day 3,” the probability of discharge is 0.64 (95% confidence interval: 0.62, 0.66). After adjustment for time-dependent confounding, most of this difference disappears, and the statistical methods produce similar results. TMLE offers a flexible estimation approach; hence, we provide practical guidance on implementation to encourage its wider use

The BRACELET Study: surveys of mortality in UK neonatal and paediatric intensive care trials.

BACKGROUND: The subject of death and bereavement in the context of randomised controlled trials in neonatal or paediatric intensive care is under-researched. The objectives of this phase of the Bereavement and RAndomised ControlLEd Trials (BRACELET) Study were to determine trial activity in UK neonatal and paediatric intensive care (2002-06); numbers of deaths before hospital discharge; and variation in mortality across intensive care units and trials and to determine whether bereavement support policies were available within trials. These are essential prerequisites to considering the implications of future policies and practice subsequent to bereavement following a child's enrollment in a trial. METHODS: The units survey involved neonatal units providing level 2 or 3 care, and paediatric units providing level II care or above; the trials survey involved trials where allocation was randomized and interventions were delivered to intensive care patients, or to parents but designed to affect patient outcomes. RESULTS: Information was available from 191/220 (87%) neonatal units (149 level 2 or 3 care); and 28/32 (88%) paediatric units. 90/177 (51%) eligible responding units participated in one or more trial (76 neonatal, 14 paediatric) and 54 neonatal units and 6 paediatric units witnessed at least one death. 50 trials were identified (36 neonatal, 14 paediatric). 3,137 babies were enrolled in neonatal trials, 210 children in paediatric trials. Deaths ranged 0-278 (median [IQR interquartile range] 2 [1, 14.5]) per neonatal trial, 0-4 (median [IQR] 1 [0, 2.5]) per paediatric trial. 534 (16%) participants died post-enrollment: 522 (17%) in neonatal trials, 12 (6%) in paediatric trials. Trial participants ranged 1-236 (median [IQR] 21.5 [8, 39.8]) per neonatal unit, 1-53 (median [IQR] 11.5 [2.3, 33.8]) per paediatric unit. Deaths ranged 0-37 (median [IQR] 3.5 [0.3, 8.8]) per neonatal unit, 0-7 (median [IQR] 0.5 [0, 1.8]) per paediatric unit. Three trials had a formal policy for responding to bereavement. CONCLUSIONS: A substantial number of deaths after trial enrollment were identified, distributed over many trials and units. Few trial teams had responses to bereavement in place. Those with the largest numbers of deaths might be best placed to collaborate in developing and assessing responses to bereavement.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Electrocardiographic variables in children with syndromic craniosynostosis and primary snoring to mild obstructive sleep apnea

Background: In the spectrum of children with symptomatic sleep disordered breathing (SDB), some individuals – such as those with upper airway resistance syndrome (UARS) – do not have abnormalities on polysomnography (PSG). In this study we have assessed whether assessment of respiratory arrhythmia (RA) and heart rate variability (HRV) analysis helps in management of children with syndromic craniosynostosis and none-to-mild obstructive sleep apnea (OSA). Methods: Prospective cohort study in children aged 1–18 years old with syndromic craniosynostosis. Children were selected for HRV analysis from the ECG if their obstructive apnea–hypopnea index (oAHI) was between zero and five per hour (ie, oAHI ≤5/hour). Subjects were divided into groups based on the presence or absence of respiratory arrhythmia (with or without RA respectively) using the electrocardiogram (ECG). The main analysis included studying the relationship between RA and HRV, symptoms, interventions, and sleep architecture. Results: We identified 42 patients with, at worst, mild OSA. We found higher parasympathetic control and higher total power in children with RA during the non-rapid eye movement (non-REM) sleep. Children with RA also have a relatively higher percentage of paradoxical breathing during non-REM sleep (P = 0.042). Intracranial hypertension was distributed equally between groups. Last, RA patients showed increased parasympathetic activity that further increased in non-REM sleep. Conclusion: In syndromic craniosynostosis cases with SDB and PSG showing oAHI ≤5/hour, the presence of RA may indicate subsequent need for treatment interventions, and a trend toward higher occurrence of clinical symptoms. ECG analyses of HRV variables in subjects with RA demonstrate increased parasympathetic activity and total power. Such findings may add to the diagnosis of apparently asymptomatic children

Effective viscosity from cloud-cloud collisions in three-dimensional global SPH simulations

Analytic estimates of the viscous time-scale due to cloud-cloud collisions have been as high as thousands of Gyr. Consequently, cloud collisions are widely ignored as a source of viscosity in galactic disks. However, capturing the hydrodynamics of discs in simple analytic models is a challenge, both because of the wide dynamic range and importance of 2D and 3D effects. To test the validity of analytic models we present estimates for the viscous time-scale that are measured from three dimensional SPH simulations of disc formation and evolution. We have deliberately removed uncertainties associated with star-formation and feedback thereby enabling us to place lower bounds on the time-scale for this process. We also contrast collapse simulations with results from simulations of initially stable discs and examine the impact of numerical parameters and assumptions on our work, to constrain possible systematics in our estimates. We find that cloud-collision viscous time-scales are in the range of 0.6-16 Gyr, considerably shorter than previously estimated. This large discrepency can be understood in terms of how the efficiency of collisions is included in the analytical estimates. We find that the viscous time-scale only depends weakly on the number of clouds formed, and so while the viscous time-scale will increase with increasing resolution, this effect is too weak to alter our conclusions.Comment: 11 pages, accepted to MNRA

Cloud angular momentum and effective viscosity in global SPH simulations with feedback

We examine simulations of isolated galaxies to analyse the effects of localized feedback on the formation and evolution of molecular clouds. Feedback contributes to turbulence and the destruction of clouds, leading to a population of clouds that is younger, less massive, and with more retrograde rotation. We investigate the evolution of clouds as they interact with each other and the diffuse interstellar medium, and determine that the role of cloud interactions differs strongly with the presence of feedback: in models without feedback, scattering events dramatically increase the retrograde fraction, but in models with feedback, mergers between clouds may slightly increase the prograde fraction. We also produce an estimate of the viscous time-scale due to cloud–cloud collisions, which increases with increasing strength of feedback (tν ∼ 20 Gyr versus tν ∼ 10 Gyr), but is still much smaller than previous estimates (tν ∼ 1000 Gyr); although collisions become more frequent with feedback, less energy is lost in each collision than in the models without feedback