Güiza F, Vanhorebeek I, Verstraete S, et al. - Given that early use of parenteral nutrition in the paediatric intensive care unit (PICU) vs omitting parenteral nutrition until PICU day 8 (late parenteral nutrition) has a negative impact on the development of executive functions, externalising behaviour, and visual–motor integration 2 years later, and the molecular basis of this revelation is uncertain, therefore, researchers performed this pre-planned secondary analysis of the multicentre PEPaNIC trial (2012–18), to investigate whether DNA methylation alterations happen during critical illness and whether early parenteral nutrition (or a specific macronutrient component hereof) adds to these alterations, which could explain its negative impacts on neurocognitive development. Random allocation (1:1) of all patients with a last PICU day blood sample (n = 825, aged 0–17 years at PICU admission) to early parenteral nutrition or late parenteral nutrition was done, relative to 352 demographically matched healthy children. Differential methylation of 159 CpG sites was noted, during PICU stay, in patients admitted to the PICU vs in healthy children, with mean effect sizes of 2·6% (SD 2·5) up to 21·6%. The occurrence of these differentially methylated CpG sites was identified in genes implicated in brain development, plasticity, and signalling; neuronal differentiation, migration, and growth; metabolism; transcriptional regulation; physical development and locomotion; and various neurodegenerative and neuropsychiatric diseases. Overall, findings revealed altered DNA methylation as a consequence of early parenteral nutrition during paediatric critical illness, this is indicative of a plausible molecular basis for the negative influence of early parenteral nutrition during PICU on long-term neurocognitive development. The aberrant DNA methylation was mostly explained by early administration of amino acids, rather than of glucose or lipids.