Abbreviations: TH -therapeutic hypothermiaFinancial disclosure statement: The authors have no financial relationships relevant to this article to disclose. Funding source: JPB received funding support from Theirworld Potential conflicts of interest: NoneWhat is known about this topic: EEG discontinuity is associated with adverse neurologic outcomes in term infants after hypoxic-ischaemic encephalopathy. What this study adds:In term infants receiving therapeutic hypothermia, EEG discontinuity calculated using a novel algorithm at 24 hours is associated with cerebral tissue injury on MRI and with adverse neurodevelopmental outcomes. Therefore, it may provide a useful tool for early risk stratification when adjunctive therapies are most beneficial. Contributors' Statement:Jonathan M Dunne collected data, carried out the raw EEG data analysis, assisted with the statistical analysis, wrote the first draft of the manuscript and approved the final version of the manuscript.David Wertheim developed the EEG software used to measure discontinuity, assisted with writing the manuscript and approved of the final version of the manuscript.Paul Clarke, obtained ethics approval, collected data, assisted with writing the manuscript and approved the final version of the manuscript.Olga Kapellou reviewed the MR images and approved of the final version of the manuscript.Philippa Chisholm carried out neurodevelopmental testing and approved the final version of the manuscript.James P Boardman reviewed the MR images, assisted with writing the first draft of the manuscript, assisted with statistical analysis and approved the final version of the manuscript.Divyen K Shah conceived the study, collected data, assisted with the EEG reviews, statistical analysis, writing the first draft of the manuscript, approved of the final version of the manuscript and is guarantor. Word Count: 2498Abstract Background and Hypothesis: Prolonged EEG discontinuity has been associated with poor neurodevelopmental outcomes after perinatal asphyxia but its predictive value in the era of therapeutic hypothermia (TH) is unknown. Hypothesis: In infants undergoing TH for hypoxicischaemic encephalopathy (HIE) prolonged EEG discontinuity is associated with cerebral tissue injury on MRI and adverse neurodevelopmental outcome.

A 6‐y retrospective case note review was performed to determine the causes of ketoacidosis. 135 patients and 463 diabetic years were involved. Fifty‐two ketoacidosis episodes occurred: 19 episodes in new patients and 33 episodes in 19 patients with established diabetes. 27% of newly diagnosed patients presented in ketoacidosis. They were similar in terms of age, sex and proportion living in single parent families to those presenting without ketoacidosis. The 33 ketoacidosis episodes occurring in established patients included 12 episodes in 3 children who were transferred to our care because of uncontrolled diabetes. Insulin omission was the cause of ketoacidosis in 9/19 (47%) patients, and was suspected in a further 5/19 (26%). Family and school problems were common and 14/19 patients came from single parent families. Established patients aged ≥11 y were predominantly female (10F, 2M), whereas patients aged ≥10y were predominantly male (6M, 1F). 7 patients with multiple ketoacidosis episodes were all ≥11 y and 6 were female. Families with ≥2 diabetic children appeared vulnerable, 4 cases coming from 3/7 such families.

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Despite increasing knowledge on microRNAs, their role in the pathogenesis of neonatal encephalopathy remains to be elucidated. Herein, we identify let-7b-5p as a significant microRNA in neonates with moderate to severe encephalopathy from dried blood spots using next generation sequencing. Validation studies using Reverse Transcription and quantitative Polymerase Chain Reaction on 45 neonates showed that let-7b-5p expression was increased on day 1 in neonates with moderate to severe encephalopathy with unfavourable outcome when compared to those with mild encephalopathy. Mechanistic studies performed on glucose deprived cell cultures and the cerebral cortex of two animal models of perinatal brain injury, namely hypoxic-ischaemic and intrauterine inflammation models confirm that let-7b-5p is associated with the apoptotic Hippo pathway. Significant reduction in neuronal let-7b-5p expression corresponded with activated Hippo pathway, with increased neuronal/nuclear ratio of Yes Associated Protein (YAP) and increased neuronal cleaved caspase-3 expression in both animal models. Similar results were noted for let-7b-5p and YAP expression in glucose-deprived cell cultures. Reduced nuclear YAP with decreased intracellular let-7b-5p correlated with neuronal apoptosis in conditions of metabolic stress. This finding of the Hippo-YAP association with let-7b needs validation in larger cohorts to further our knowledge on let-7b-5p as a biomarker for neonatal encephalopathy.