Developing neuroimaging methods for clinical translation and better understanding neonatal brain development

Understanding and measuring pain and brain development in neonates is essential to be able to provide the best care for this vulnerable population. This is particularly important for premature infants, for whom early life is filled with more painful procedures, and earlier exposure to extrauterine stimuli, which can adversely affect development. Infant pain assessments combine behavioural and physiological measures such as facial expression, crying, and heart rate. However, these metrics are not specific to pain experience, nor sensitive enough to provide reliable outcome measures for clinical trials to validate pain treatments in infants. Neuroimaging techniques provide means to study brain health, development and function. EEG and fMRI measurements of noxious-evoked brain activity could be used to develop more objective and specific pain assessment tools. This thesis focusses on using EEG and MRI to measure infant pain and its relation to overall brain development. First, I present tests of the validity of an EEG template measure of noxious response in infants recruited at multiple hospital sites. EEG has been used to quantify noxious-evoked activity and study pain interventions in infants, but a standard generalisable approach needs to be established. I tested whether the EEG template discriminates between noxious and non-noxious stimuli, whether the scale of noxious response is equivalent across different hospital sites, and whether noxious response increases with age in premature infants. I found that noxious-evoked responses are significantly greater than non-noxious responses, but that the scale is not equivalent across study sites, and there was no significant age correlation. This suggests that the EEG template can be reliably used as a surrogate measure of pain, with promise for clinical trials. Additionally, data collection site should be accounted for as a confounding factor as needed. Then, I focus on how MRI can aid our understanding of infant pain and the underlying neurophysiology behind differences in noxious-evoked activity. I present a machine learning model that I developed to predict the magnitude of noxious-evoked responses from resting- state brain activity in infants, using fMRI data. By applying this model to data from the independent Developing Human Connectome Project, I explore how predicted noxious- evoked responses relate to development metrics, including resting-state cortical function and microstructure, as well as prematurity, and assessments of infant cognitive and motor ability at 2-year follow up. I found that prematurity is associated with accelerated development of the nociceptive system, but disrupted neurodevelopment overall. In summary, this thesis demonstrates the potential for neuroimaging techniques to improve our understanding of infant brain development, and improve clinical assessment and treatment of infant pain

Establishing a standardised approach for the measurement of neonatal noxious-evoked brain activity

A pre-registered study to assess the reproducibility of an EEG approach to measuring neonatal noxious-evoked brain activity

Epidemic of carbapenem-resistant Klebsiella pneumoniae in Europe is driven by nosocomial spread

EuSCAPE Working Group: Portugal - Manuela Caniça, Vera ManageiroPublic health interventions to control the current epidemic of carbapenem-resistant Klebsiella pneumoniae rely on a comprehensive understanding of its emergence and spread over a wide range of geographical scales. We analysed the genome sequences and epidemiological data of >1,700 K. pneumoniae samples isolated from patients in 244 hospitals in 32 countries during the European Survey of Carbapenemase-Producing Enterobacteriaceae. We demonstrate that carbapenemase acquisition is the main cause of carbapenem resistance and that it occurred across diverse phylogenetic backgrounds. However, 477 of 682 (69.9%) carbapenemase-positive isolates are concentrated in four clonal lineages, sequence types 11, 15, 101, 258/512 and their derivatives. Combined analysis of the genetic and geographic distances between isolates with different β-lactam resistance determinants suggests that the propensity of K. pneumoniae to spread in hospital environments correlates with the degree of resistance and that carbapenemase-positive isolates have the highest transmissibility. Indeed, we found that over half of the hospitals that contributed carbapenemase-positive isolates probably experienced within-hospital transmission, and interhospital spread is far more frequent within, rather than between, countries. Finally, we propose a value of 21 for the number of single nucleotide polymorphisms that optimizes the discrimination of hospital clusters and detail the international spread of the successful epidemic lineage, ST258/512.This work was funded by The Centre for Genomic Pathogen Surveillance, Wellcome Genome Campus, Wellcome (grant nos. 098051 and 099202) and the NIHR Global Health Research Unit on Genomic Surveillance of Antimicrobial Resistance (NIHR 16/136/111). The EuSCAPE project was funded by ECDC through a specific framework contract (ECDC/2012/055) following an open call for tender (OJ/25/04/2012-PROC/2012/036).info:eu-repo/semantics/publishedVersio

Epidemic of carbapenem-resistant Klebsiella pneumoniae in Europe is driven by nosocomial spread

Public health interventions to control the current epidemic of carbapenem-resistant Klebsiella pneumoniae rely on a comprehensive understanding of its emergence and spread over a wide range of geographical scales. We analysed the genome sequences and epidemiological data of >1,700 K. pneumoniae samples isolated from patients in 244 hospitals in 32 countries during the European Survey of Carbapenemase-Producing Enterobacteriaceae. We demonstrate that carbapenemase acquisition is the main cause of carbapenem resistance and that it occurred across diverse phylogenetic backgrounds. However, 477 of 682 (69.9%) carbapenemase-positive isolates are concentrated in four clonal lineages, sequence types 11,15,101, 258/512 and their derivatives. Combined analysis of the genetic and geographic distances between isolates with different beta-lactam resistance determinants suggests that the propensity of K. pneumoniae to spread in hospital environments correlates with the degree of resistance and that carbapenemase-positive isolates have the highest transmissibility. Indeed, we found that over half of the hospitals that contributed carbapenemase-positive isolates probably experienced within-hospital transmission, and interhospital spread is far more frequent within, rather than between, countries. Finally, we propose a value of 21 for the number of single nucleotide polymorphisms that optimizes the discrimination of hospital clusters and detail the international spread of the successful epidemic lineage, ST258/512