Growth, Diabetes, Obesity
- Professor Hoey is President elect of the European Society for Paediatric Endocrinology (ESPE) and hosted the Annual Scientific Conference in Dublin 2014.
- The Irish National Growth Standards were developed by Professor Hilary Hoey based on data from over 7,000 Irish children. These include standards on height, weight and height velocity from birth to 18 years and also standards for skinfold thickness and head circumference These standards are now applied throughout the country in primary, secondary and tertiary care. The Department led the Irish component of the European Longitudinal growth study on children from birth to 3 years to evaluate the effects of feeding, socio-economic environment, disease, genetic and geographical determinants, serum zinc on growth and the construction of European growth standards was performed by the department of paediatrics.
- The Department of Paediatrics in the National Children's Hospital in Tallaght is the Irish centre for the Interational Study of Children Born Small for Gestational Age (NESGAS Study) in collaboration with the Coombe Women's Hospital, national paediatricians and endocrinologists, the Universities of Cambridge Copenhagen and Stockholm. This study is led by Professor Hoey and Dr Edna Roche and has been performed by Dr Susan O'Connell and Ms Elaine O'Mullane RGN, RM. Extensive research on growth, body composition, laboratory growth factors, binding proteins, hormonal assays, lipid analysis and glycaemia. In addition we are the national centre for the European Study on children born small for gestation age this includes clinical assessment, auxology, molecular aspects and of growth factors, binding proteins, hormonal assays, lipid analysis, HbA1c and glucose estimation following growth hormone stimulation tests and intravenous glucose tolerance tests in children born. We have directed the body composition component of this study including assessment and analysis.
- Obesity: Major ongoing national and international research on obesity is being conducted and led by Dr Edna Roche in collaboration with paediatric and adult medical staff at AMNCH, academic departments in TCD including Dr Juliette Hussey, Head of Department of Physiotherapy. Trinity hosted the European Childhood Obesity Conference in September 2009 and Professor Hoey was president of the organising committee.
- Key epidemiological studies of type 1 diabetes have been performed within the department led by Dr Edna Roche including the first national prospective longitudinal study on the incidence of insulin dependent diabetes. Dr Edna Roche has developed a national register for children with diabetes. This study in collaboration with the Eurodiab network and other diabetes registries worldwide, will play a vital role in determining the aetiology of Type 1 diabetes and on its management and outcome.
- A national study on the prevalence of cystic fibrosis related diabetes, insulin secretion and resistance, continuous glucose monitoring, molecular aspects and quality of life in children with cystic fibrosis is led by Professor Hoey and Dr Edna Roche and was conducted in collaboration with Dr Peter Greally and Dr Basil Elnazir in the National Children's Hospital in also in collaboration with the three Dublin childrens' hospitals. The study was conducted by Dr Stephen O'Riordan and Ms Shirly George.
- Major research projects on diabetes are being conducted by the department. International studies on metabolic control and quality of life in children with Type 1 Diabetes including the development of international quality of life instruments for children, adolescents, parents and health professionals caring for young people with diabetes. This research is led by Professor Hilary Hoey who is a member of the steering committee of The Hvidoere International Study Group on Childhood Diabetes and The National Children's Hospital, Tallagh is the Irish centre. A significant number of international research projects have been completed and more are in progress, these include: a longitudinal study of metabolic control, immunological markers, molecular aspects and quality of life on over 2,000 children from 22 countries around the world, including Europe, North America, Australia and Japan. Professor Hoey developed new international quality of life instruments in collaboration with Professor Hannah McGee, RCSI; and Professor Michael Fitzgerald, TCD for the assessment of Quality of life in adolescent with diabetes and Quality of Life and family burden of parents of children with diabetes. These questionnaires have been translated into 17 languages and the ongoing research is being conducted in 22 international centres in Europe, North America, Australia and Japan.
Other major research studies on growth include an extensive national study of children with Prader Willi Syndrome including management, efficacy and safety of growth hormone, body composition, quality of life and family burden by Dr Judith Meehan. The National Children's Hospital in Tallaght is the main tertiary centre for children with Prader Willi Syndrome. Professor Hoey is the Irish medical representative on the International Prader Willi Syndrome Organisation.
Growing Up in Ireland
The Department of Paediatrics is a key participant and contributed to the development of the proposal and protocol in the Growing up in Ireland National Longitudinal Study of Children which is being undertaken jointly by the University of Dublin, Trinity College and the Economic and Social Research Institute of Ireland co-directed by Professor James Williams, ESRI and Professor Sheila Greene, Professor of Childhood Research and Director of the Children's Research Centre at Trinity College with the health component led by Professor Tom O'Dowd.
- National Clinical Guidelines: We have established a National Resource Centre with extensive international research projects on Down Syndrome which have been performed by Dr Joan Murphy. The Department has undertaken the definitive national study of children and young people with Down syndrome and established national medical guidelines for this group. The Department of Paediatrics co-hosted the World Congress on Down Syndrome in Dublin in July 2009, of which Professor Hoey was Chairman of the Scientific Committee and Dr Joan Murphy Honorary Secretary. Both Professor Hoey and Dr Joan Murphy are members of the steering committee of the Down's Syndrome Medical Interest Group of Ireland and UK.
- Down syndrome registry: Prof Roche Ms Fiona McGrane and Prof Molloy have established a National DS Registry
- DISCO project: Down Syndrome Inflammation and Systemic Multiorgan Outcomes
This project will explore multiorgan dysfunction focussing on immunodeficiency and altered immune cell responses in children with DS and will commence in 2017 with funding from National Childrens Hospital Foundation. (2017-20)
- DREAM project: This project will explore multiorgan dysfunction including cardiac, haematological, endocrine and GI issues and their composite association with neurodevelopmental outcome in children with DS. (2017-20)
PROSPER: PaediatRic Otcomes and Serum biomarker Panel in acutE
traumatic bRain injury /concussion to severe traumatic brain injury (2017-20)
Supervisors: by Prof Molloy and Dr. Turlough Bolger.
Collaborators: Dr. Stan Koe, Dr. Ciara Martin, Dr. David Webb, Dr. John McHugh, Dr. Roisin McNamara, Dr. Ike Ofakor, Mr. John Caird & Mr. Darrach Crimmins, Dr Veronica O'Keane, Dr. Carol Blackburn, Dr. Michael Barrett & Dr. Sean Walsh, Dr. Aisling Snow, Prof. Cathal Moran, Prof. Arun Bodke , Prof. Jim Meaney, Prof Louise Gallagher
PhD student: Dr. Emer Ryan
Institutions: CUH, Tallaght, OLCH, NMH, TCD
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 causes of neurological morbidity and includes concussion. Post concussion syndrome (PCS) combines clinical, cognitive and behavioral symptoms and occurs in one in seven school children sustaining an TBI for three months or longer and 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 in the Emergency department and at 6 weeks in children presenting with TBI. We will study the evolution of systemic inflammation associated with traumatic brain injury and correlate with neurocognitive and neuroimaging outcomes. In addition a subgroup of children with TBI and age-matched controls will have 3T MRI performed in SJH by a specialized team with expertise in functional MRI. To complement this project we will retrospectively review the records of children with TBI admitted to the Dublin EDs over a 2 year period to quantify the number of cases with moderate, mild and severe symptoms as well as PCS. Children with severe TBI will be recruited from CUH, which will allow validation of biomarkers and neuroimaging using a spectrum of mild to severe TBI. Finally the group will provide an educational module on the management, assessment and followup of children with TBI. This project will commence in 2017 and is funded by NCHF.
PRISM: PReterm Infection and SysteMic inflammation and neonatal outcomes (2014-7)
PI: E Molloy, Dr. Dave Coghlan, Dr. Denise McDonald, Dr. John Kelleher, Dr. Suzanne Kelleher, Dr. David Rea, Prof J Meaney, Dr. Arun Bodke, Prof. John O'Leary, Prof. Jan Miletin, Dr. Jana Sembrova
PhD student: Dr. Murwan Omer
Institutions: CWIUH, Tallaght hospital, TCD
Background: Despite rapid progress in neonatal intensive care over the past decades, neonatal mortality from sepsis remains unacceptably high and 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 injury especially in preterm infants. Modulation of inflammatory signalling during sepsis may improve survival in preterm infants and prevent related neurodevelopmental complications. Activated leucocytes, infection and persistent inflammation have been implicated in the pathogenesis of brain injury and also cerebral palsy. Antenatal inflammation and neonatal outcome: We will evaluate antenatal inflammation using placental pathology results and blood culture results from mother and baby. Detailed clinical multiorgan outcomes including novel renal biomarkers and echocardiography will be quantified using the Modified Neonatal Multi -Organ Dysfunction (NEOMOD) score. Neuroimaging with cranial ultrasound and/or MRI will be performed and developmental followup including 2-year Bayley's developmental scales (BSID III). Inflammatory response to infection and immunomodulation: We will examine pro and anti-inflammatory cytokine responses using whole blood from preterm infants over the first few weeks of life and correlate with antenatal inflammation. We will evaluate neonatal inflammatory cell phenotype and activation of the inflammasome, which is crucial for inflammatory responses and host defense to pathogens as well as being implicated in several inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis and atherosclerosis. Immunomodulators such as melatonin and specific inflammasome inhibitors will be assessed in vitro as possible methods to ameliorate persistent inflammation.
Conclusion: 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. This project is funded by NCHF and TCD.
NEBULA study: NEonatal brain Injury: Understanding systemic InfLAmmation & immunomodulation (2013-7)
PI: E Molloy
Collaborators: Professor William Watson, Dr Amanda O'Neill, Dr. Veronica Donoghue, Drs. Eoghan Mooney & Paul Downey, Prof Geraldine Boylan, Prof Bryan Lynch, Dr. Eva Jiminez, Dr. Denise McDonald, Dr. Suzanne Kelleher and Dr. John Kelleher
PhD student: Dr. Saima Aslam
Institutions: NMH, UCD, TCD, RCSI, UCC
Background: 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 and Melatonin: 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. We will explore the mechanism underlying the altered activation of neutrophils and monocytes in neonates with brain injury by examining Circadian rhythm and the use of melatonin for neuroprotection. The key regulators of circadian rhythm BMAL-1 and CRY will be measured in infants with NE and neonatal controls. Persistent Inflammation and Circadian Rhythm: Hypoxia-inducible factor (HIF) 1 alpha is a key transcriptional factor in the hypoxic response and is associated with persistent inflammation. We will examine the role of the hypoxia inducible factor (HIF1 alpha) in persistent or sustained inflammation in NE. We will examine HIF 1 alpha expression in innate immune cells as well as modulation by melatonin.
Conclusion: MRI, clinical and neurodevelopmental outcome will be correlated with circadian rhythm as well as multi-organ dysfunction. This research will improve the understanding of the systemic inflammatory response in infants with brain injury and the potential for therapies such as melatonin in addition to hypothermia.
NIMBUS group: Neonatal Inflammation and Multiorgan dysfunction and Brain injUry reSearch group (2016-9)
PI: Eleanor Molloy, Prof Mary King, Dr. Breda Hayes, Dr. Adrienne Foran, Prof John O'Leary, Dr. Claudine Vavasseur, Prof. Afif El-Khuffash, Prof. Martin White, Prof. Rhona Mahony, Dr. Veronica Donoghue, Dr. Eoghan Mooney, Prof. Jan Miletin , Prof. Naomi McCallion, Prof. Jim Meaney, Dr. Deirdre Sweetman, Dr. Paul Downey, Dr. Orla Franklin, Dr. John McHugh, Dr. David Rea, Prof. John Murphy
PhD student: Dr. Mary O'Dea
Postdoctoral researcher: Dr. Lynne Kelly
Insitutions: NMH, Rotunda, CWIUH, TCD, UCD, RCSI
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. Our translational research group includes laboratory scientists and clinicians to evaluate both inflammatory responses and correlate with multiple organ dysfunction. We have incorporated newer modalities for cardiac function (echo speckle tracking, troponin and BNP), brain imaging (EEG, MRI and fMRI), renal biomarkers (eg.NGAL, cystatin c), placental pathology and haematological indices. 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.Developing clinically useful early biomarkers incorporating clinical outcomes are crucial in this group. Although neurological outcomes are evaluated in the short-term in this patient group there is no assessment of longterm cardiac, renal, immune and haematological status and we aim to coordinate followup of these parameters until at 2 years of age. This project is funded by the HRB.
UNICORN study: Underlying mechanisms in Neonatal Immune metaboliC dysregulatiOn and bRain Injury (2016-9)
PI: E Molloy
Collaborators: Prof. Adrienne Foran, Dr. Annie Curtis, Dr. Deirdre Sweetman, Dr. Deirdre Murray, Dr. Ellen Crushell, Prof Ger Boylan, Prof Jim Meaney, Ms Mandy Daly, Prof Richard Porter, Prof Terrie Inder, Dr. Veronica Donoghue
PhD Student: Dr. Mary O'Dea
Institutions: CWIUH, NMh, Rotunda, TCD, RCSI
Background: Neonatal brain injury has a multifactorial aetiology and causes significant neurological morbidity such as cerebral palsy. Therapeutic hypothermia (TH) is the only treatment available for neonatal encephalopathy (NE) but morbidity and mortality rates remain high. There is an urgent need for adjunctive therapies to improve neurodevelopmental outcomes. Persistent inflammation: Persistent systemic inflammation has been implicated in neonatal brain injury and identifying new inflammatory biomarkers will help to determine the aetiology of NE and new adjunctive therapies. There is a narrow therapeutic window to activate neuroprotective therapies during ischaemic reperfusion in NE. Ischaemia reperfusion injury occurs when a hypoxic tissue is reperfused rapidly in NE resulting in oxidative damage, cellular apoptosis and atypical immune responses generated through the production of mitochondrial oxygen species (ROS). We demonstrated that immune cell ROS are produced at abnormally high levels in infants with severe NE and increase over the first week of life despite hypothermia therapy. Babies with NE, children aged 4-6years who had NE and age-matched controls will have inflammatory phenotyping to assess persistent immune dysregulation. Detailed 1.5T MRI, MRS and 3.0T MRI and neurological outcome will be correlated with these results. Mechanisms of persistent inflammation & immunomodulation: Exploring immune activation and persistent dysfunction is crucial in the development of new treatments for NE and brain injury and there are several potential targets including: Hypoxia-inducible factor(HIF-1)-alpha and succinate metabolism. HIF1a is a key transcription factor in the hypoxia response and as well as mitochondrial dysfunction and succinate accumulation is associated with persistent inflammation and may be a potential therapeutic target.
Conclusions: Understanding the function and metabolism of systemic inflammatory cells is important in the pathogenesis of neonatal brain injury to find relevant biomarkers of severity.
CHAMPION Study: Childhood Followup of Multiple organ dysfunction after Neonatal encephalopathy : (2014-7)
PI: E Molloy and D McDonald
Collaborators: D Sweetman, B.ElNazir, D.Coughlan, S.Quinn, C.Mc Donnell, D.Webb, J.Murphy, C.McMahon, O.Franklin,O.Smith,B.Nolan,E.Crushell,V.Donoghue, M.Riordran
Funding: NCH foundation
PhD student: Z.Zareen
Postdoc: V McEneaney
Perinatal global hypoxia ischaemia is associated with neonatal encephalopathy and results in multi-organ dysfunction. Early multi organ dysfunction in neonates with encephalopathy may persist in later childhood, therefore multi-organ and neurodevelopmental follow up studies are required to ensure complete resolution and avoid complications in later childhood. Predictions about long term outcomes following NE are improving both qualitatively and quantitatively. Better insight into multi organ dysfunction post NE can be gained by using novel biomarkers and new diagnostic tools. Further research with multidisciplinary involvement can provide better predictive data and contribute to improved prognosis. In addition, to gain insight into the long-term effects neurodevelopmental effects of NE, follow-up is required throughout the school age as specific cognitive functions continue to develop throughout childhood