Eleanor Molloy

Neonatal brain injury (NBI) has a heterogenous aetiology with a high economic and social burden. Neonatal encephalopathy describes the babies who require resuscitation at birth and have an abnormal neurological examination. It remains difficult to predict their developmental outcome. Enhanced inflammatory responses are seen in affected infants and correlate with outcomes. Multiorgan dysfunction is common with renal, hepatic, cardiac and haematological abnormalities.We aim to correlate these inflammatory responses with clinical, neurodevelopmental and MRI outcomes to establish biomarkers of brain injury in neonates. This research may allow early recognition of brain injury prior to MRI (Day 5-7) so that new therapies as adjuvants to therapeutic hypothermia can be initiated as soon as possible after birth.

: Persistent systemic inflammation has been implicated in neonatal brain injury and identifying novel inflammatory biomarker combinations will help to determine the aetiology of NE and develop new adjunctive therapies. We have shown that immune cell ROS are produced at abnormally high levels in infants with severe NE and increase over the first week of life despite therapeutic hypothermia (TH) therapy. Babies with NE and age-matched controls will have inflammatory phenotyping in terms of immune cell activation and cytokine production to assess t immune dysregulation. Detailed neuroimaging using MRI/MRS (1.5T & 3.0T) and neurological outcome will be correlated with these results in order to assist with improved prognostic biomarker development. We will examine cellular metabolism and mitochondrial function in samples from infants with NE in comparison to healthy neonates with a view to identifying altered pathways that could be targeted by potential adjunctive therapies.

Traumatic brain injury (TBI) is more common in childhood and adolescence than at any other time of life and is one of the most common causesof neurological morbidity and includes concussion. Post concussion syndrome (PCS) combines clinical, cognitive and behavioral symptoms and occurs in one in sevenschool children sustaining an TBI for three months or longerand is associated with persistent inflammation. At present there are no evidence-based clinical guidelines or accurate early tests to predict PCS in children. We aim to prospectively evaluate novel clinical and biochemical markers neurocognitive function at presentation inthe Emergency department and at 6 weeks in children presenting with TBI.

Down syndrome is associated with increased incidence of infections in childhood and other inflammatory conditions such as rheumatoid arthritis and Alzheimers disease have an earlier onset. Modulation of inflammatory signalling during infection may improve developmental outcomes. We will evaluate detailed clinical multiorgan outcomes and correlate with detailed developmental outcomes including audiology, Bayley’s developmental scales (BSID III) and WIPPSI and explore the effects of organ dysfunction on outcome. We will examine pro and anti-inflammatory cytokine responses and evaluate the innate inflammatory cell phenotype and activation of the inflammasome. This research will improve the understanding of the systemic inflammatory response in children with Down Syndrome and the potential for newer adjunctive therapies. In addition these immune markers may assist in prognosis of multi-organ outcomes in children with DS.

Changes in circadian rhythm are common in many illnesses including neonatal brain injury and neonatal encephalopathy (NE). NE is associated with persistent abnormal systemic inflammatory responses that may be amenable to immunomodulation as an adjunct to therapeutic hypothermia. Alterations in circadian rhythm affect immune function and are associated with changes in melatonin, which has anti-inflammatory properties. Understanding the role of the circadian rhythm in neonatal brain injury and inflammation may lead to simple therapeutic measures such as decreasing the duration duration of light exposure to increase endogenous melatonin production. Therefore, we wish to investigate whether alteration of the circadian rhythm in babies with NE decrease inflammation and improve outcome?

From infancy to old age,males have poorer disease outcomes compared to females.Preterm infants display a marked gender dimorphism as regards outcome and mortality especially at the borders of viability.We will explore the role of infection and gender in preterm infants in a large prospective cohort examining sex steroid hormones, infection, inflammation and neonatal multiorgan outcomes including brain injury. We will also translate the immune results to include possible new immunomodulatory therapies exploring the roles of estradiol, testoterone and glucocorticoids.

Neonatal brain injury has multifactorial etiology and causes significant neurological morbidity such as cerebral palsy. Therapeutic hypothermia is the only treatment available in term infants with neonatal encephalopathy (altered neurological function). Activated leucocytes, infection and persistent inflammation have been implicated in the pathogenesis of brain injury and cerebral palsy. Circadian rhythm plays a key role in innate immune responses and melatonin is an essential regulator. Melatonin has been shown to improve outcomes in combination with hypothermia in animal models of neonatal brain injury. Hypoxia-inducible factor (HIF) 1 alpha is a key transcriptional factor in the hypoxic response and is associated with persistent inflammation.We will examine circadian Rhythm and HIF-1alpha in neonatal NE and Control samples. This research will improve the understanding of the systemic inflammatory response in infants with brain injury and the potential for therapies such asmelatonin in addition to hypothermia.

Despite rapid progress in neonatal intensive care over the past decades, neonatal mortality from sepsis remains unacceptably highand morbidity includes brain injury and developmental delay. Systemic inflammation related to sepsis has been implicated in many common neonatal complications such as brain, lung, or gastrointestinal injuryespecially in preterm infants. Modulation of inflammatory signalling during sepsis may improve survival in preterm infants and prevent related neurodevelopmental complications. This research will improve the understanding of the systemic inflammatory response in preterm infants and the potential for newer adjunctive therapies. In addition these immune markers will assist in prognosis of multi-organ outcomes in preterm infants.

Severe Neurological Impairment (SNI) is a term that has been used to describe a global impairment of the nervous system. This group of children, who have unique challenges, could be considered a sub-group of those with more general medical complexity. However, there is no internationally agreed definition of severe neurological impairment and, therefore, a paucity of literature on its prevalence and medical and social consequences. This information is vital for future resource planning so we can provide the very best care for this vulnerable group of individuals. Objectives 1.To create a consensus definition of SNI 2.To quantify medical complexity in this group 3.To assess wellbeing in the families of children with SNI