Early biomarkers to predict grade of encephalopathy following hypoxic ischaemic injury

The standard early markers for identifying and grading HIE severity, are not sufficient to ensure all children who would benefit from treatment are identified in a timely fashion. The aim of this thesis was to explore potential early biomarkers of HIE. Methods: To achieve this a cohort of infants with perinatal depression was prospectively recruited. All infants had cord blood samples drawn and biobanked, and were assessed with standardised neurological examination, and early continuous multi-channel EEG. Cord samples from a control cohort of healthy infants were used for comparison. Biomarkers studied included; multiple inflammatory proteins using multiplex assay; the metabolomics profile using LC/MS; and the miRNA profile using microarray. Results: Eighty five infants with perinatal depression were recruited. Analysis of inflammatory proteins consisted of exploratory analysis of 37 analytes conducted in a sub-population, followed by validation of all significantly altered analytes in the remaining population. IL-6 and IL-6 differed significantly in infants with a moderate/severely abnormal vs. a normal-mildly abnormal EEG in both cohorts (Exploratory: p=0.016, p=0.005: Validation: p=0.024, p=0.039; respectively). Metabolomic analysis demonstrated a perturbation in 29 metabolites. A Cross- validated Partial Least Square Discriminant Analysis model was developed, which accurately predicted HIE with an AUC of 0.92 (95% CI: 0.84-0.97). Analysis of the miRNA profile found 70 miRNA significantly altered between moderate/severely encephalopathic infants and controls. miRNA target prediction databases identified potential targets for the altered miRNA in pathways involved in cellular metabolism, cell cycle and apoptosis, cell signaling, and the inflammatory cascade. Conclusion: This thesis has demonstrated that the recruitment of a large cohortof asphyxiated infants, with cord blood carefully biobanked, and detailed early neurophysiological and clinical assessment recorded, is feasible. Additionally the results described, provide potential alternate and novel blood based biomarkers for the identification and assessment of HIE.

Conceptual designs of multi-degree of freedom compliant parallel manipulators composed of wire-beam based compliant mechanisms

This paper proposes conceptual designs of multi-degree(s) of freedom (DOF) compliant parallel manipulators (CPMs) including 3-DOF translational CPMs and 6-DOF CPMs using a building block based pseudo-rigid-body-model (PRBM) approach. The proposed multi-DOF CPMs are composed of wire-beam based compliant mechanisms (WBBCMs) as distributed-compliance compliant building blocks (CBBs). Firstly, a comprehensive literature review for the design approaches of compliant mechanisms is conducted, and a building block based PRBM is then presented, which replaces the traditional kinematic sub-chain with an appropriate multi-DOF CBB. In order to obtain the decoupled 3-DOF translational CPMs (XYZ CPMs), two classes of kinematically decoupled 3-PPPR (P: prismatic joint, R: revolute joint) translational parallel mechanisms (TPMs) and 3-PPPRR TPMs are identified based on the type synthesis of rigid-body parallel mechanisms, and WBBCMs as the associated CBBs are further designed. Via replacing the traditional actuated P joint and the traditional passive PPR/PPRR sub-chain in each leg of the 3-DOF TPM with the counterpart CBBs (i.e. WBBCMs), a number of decoupled XYZ CPMs are obtained by appropriate arrangements. In order to obtain the decoupled 6-DOF CPMs, an orthogonally-arranged decoupled 6-PSS (S: spherical joint) parallel mechanism is first identified, and then two example 6-DOF CPMs are proposed by the building block based PRBM method. It is shown that, among these designs, two types of monolithic XYZ CPM designs with extended life have been presented.