Crumlin, Ireland
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Kenny D.P.,Our Ladys Childrens Hospital | Kenny D.P.,Cornell College | Hijazi Z.M.,Our Ladys Childrens Hospital | Hijazi Z.M.,Cornell College
Circulation Research | Year: 2017

Percutaneous therapies for congenital heart disease have evolved rapidly in the past 3 decades. This has occurred despite limited investment from industry and support from regulatory bodies resulting in a lack of specific device development. Indeed, many devices remain off-label with a best-fit approach often required, spurning an innovative culture within the subspecialty, which had arguably laid the foundation for many of the current and evolving structural heart interventions. Challenges remain, not least encouraging device design focused on smaller infants and the inevitable consequences of somatic growth. Data collection tools are emerging but remain behind adult cardiology and cardiac surgery and leading to partial blindness as to the longer-term consequences of our interventions. Tail coating on the back of developments in other fields of adult intervention will soon fail to meet the expanding needs for more precise interventions and biological materials. Increasing collaboration with surgical colleagues will require development of dedicated equipment for hybrid interventions aimed at minimizing the longer-term consequences of scar to the heart. Therefore, great challenges remain to ensure that children and adults with congenital heart disease continue to benefit from an exponential growth in minimally invasive interventions and technology. This can only be achieved through a concerted collaborative approach from physicians, industry, academia, and regulatory bodies supporting great innovators to continue the philosophy of thinking beyond the limits that has been the foundation of our specialty for the past 50 years. © 2017 American Heart Association, Inc.


Jenkins P.V.,St James's Hospital | Rawley O.,St James's Hospital | Smith O.P.,Our Ladys Childrens Hospital | O'Donnell J.S.,St James's Hospital
British Journal of Haematology | Year: 2012

Modern thrombophilia testing fails to identify any underlying prothrombotic tendency in a significant number of patients presenting with objectively confirmed venous thromboemboembolism (VTE). This observation has led to a search for other novel inherited or acquired human thrombophilias. Although a number of putative mechanisms have been described, the evidence behind many of these candidates remains weak. In contrast, an increasing body of work supports the hypothesis that increased plasma factor VIII (FVIII) levels may be important in this context. An association between elevated plasma FVIII levels and VTE was first described in the Leiden Thrombophilia Study (LETS). Subsequently, these conclusions have been supported by an increasing number of independent case-control studies. Cumulatively, these studies have clearly demonstrated that high FVIII levels constitute a prevalent, dose-dependent risk factor for VTE. Furthermore, more recent studies have shown that the risk of recurrent venous thrombosis is also significantly increased in patients with high FVIII levels. In this review, we present the evidence supporting the hypothesis that elevated FVIII levels constitute a clinically important thrombophilia. In addition, we examine the biological mechanisms that may underlie persistently elevated FVIII levels, and the pathways through which high FVIII may serve to increase thrombotic risk. © 2012 Blackwell Publishing Ltd.


McNicholas F.,Our Ladys Childrens Hospital
European Child and Adolescent Psychiatry | Year: 2012

Two factors predict treatment outcome, how effective the treatment is and whether the patient takes or follows the treatment plan. As clinicians or scientists, we strive to develop newer and more effective treatments, both pharmacological and non-pharmacological to improve treatment outcome in our patient population. Adherence is the single most modifiable factor associated with treatment outcome, yet how often is the issue of adherence addressed in clinical consultations? The best treatment is rendered useless if not adhered to. Initial adherence rates are low and get worse with time, but methodological difficulties in studies make it difficult to determine both the clinical implication of suboptimal adherence and successful strategies. Further research should apply more rigour to the area of definition and measurement, be sufficiently powered and long term, and measure possible confounders, to allow for an understanding on the link and impact between adherence and clinical outcome. This article reviews some of the main issues with regard to adherence and cost implications of suboptimal adherence and suggests future directions. © 2012 Springer-Verlag.


O'Regan G.M.,Our Ladys Childrens Hospital | Irvine A.D.,Our Ladys Childrens Hospital | Irvine A.D.,Trinity College Dublin
Clinical and Experimental Allergy | Year: 2010

Atopic dermatitis (AD) is an inflammatory disease characterized by pruritic skin lesions, immunodysregulation, disrupted epidermal barrier function and IgE-mediated sensitization to food and environmental allergens. Identification of the aetiology of AD has become increasingly a priority, as it is clear that the disease burden exceeds AD alone, with many children suffering severe, multi-system and occasionally life-threatening allergic disease. Previous approaches to understanding AD have centred on mechanisms in the adaptive immune system, often with an emphasis on the Th1-Th2 paradigm. Recently, the conceptual focus has increasingly shifted to include a primary defect in the epithelial barrier as a threshold event in moderate-to-severe AD. Familial aggregation of the disease is well established through many family studies of AD, asthma and allergic rhinitis, suggesting a significant heritable component. The identification of loss-of-function mutations in the filaggrin (FLG) gene, whose product is a key structural protein in the outermost layer of the epidermis in up to 50% of patients with AD, provides a significant insight into explaining disease initiation and points to a complex secondary interplay of environmental and immunological sequelae once barrier disruption is established. The elucidation of the environmental, genetic and immunobiological modifiers of this structural molecule may also direct our understanding of the pathomechanisms and endotypes central to the atopic diathesis. The recent identification of a murine model for FLG-AD, with the detection of a homozygous frame-shift mutation in the Flg gene in flaky-tail (ft/ft) mice, stands to rapidly accelerate our understanding of mechanisms and therapeutic intervention points in AD. Refining the molecular understanding of AD and its subtypes will allow for specific diagnostic, treatment and ultimately, preventative algorithms, and has opened an exciting new world of investigative challenges and collaborations. © 2010 Blackwell Publishing Ltd.


Friedmacher F.,Our Ladys Childrens Hospital | Puri P.,Our Ladys Childrens Hospital
Pediatric Surgery International | Year: 2012

Purpose: Management of newborns with long-gap esophageal atresia (LGEA) remains a challenge for pediatric surgeons. Since spontaneous growth of the esophageal segments occurs without mechanical stretching, initial gastrostomy followed by delayed primary anastomosis (DPA) comprises treatment in most LGEA patients. This meta-analysis aimed to investigate the complications and long-term outcome in patients with LGEA managed by DPA. Methods: A systematic literature search was conducted for relevant articles published between 1981 and 2011, and a meta-analysis of complications and long-term outcome was performed. Results: Forty-four articles presented data on 451 newborns with LGEA managed by DPA. Most common variants were pure LGEA (194/451) and LGEA with tracheoesophageal fistula (257/451). Initial gap lengths ranged from 1.9 to 7.0 cm. At the time of DPA, performed at a mean of 11.9 weeks (range 0.5-54.0), the gap had decreased to 0.5-3.0 cm. Mean follow-up was 5.5 years (range 0.5-27.0). Frequent complications were anastomotic leaks/strictures, gastroesophageal reflux (GER), esophagitis and dysphagia. Relative risk for strictures was significantly higher in patients who previously had a leak (p<0.0001) or GER (p<0.0001). Patients with GER also had a significantly higher risk for esophagitis (p = 0.0283) and dysphagia (p = 0.0174). The majority of patients could eat without swallowing difficulties at follow-up. Conclusion: DPA provides good long-term functional results. However, the high incidence of GER and associated strictures requires early intervention to prevent feeding problems. © Springer-Verlag 2012.


McAleer M.A.,Our Ladys Childrens Hospital | McAleer M.A.,Trinity College Dublin | Irvine A.D.,Our Ladys Childrens Hospital | Irvine A.D.,Trinity College Dublin
Journal of Allergy and Clinical Immunology | Year: 2013

Filaggrin is a major structural protein in the stratum corneum of the epidermis. Mutations in the filaggrin gene are the most significant known genetic risk factor for the development of atopic dermatitis. Mutations in the human filaggrin gene (FLG) also confer risk for the associated allergic diseases of food allergy, asthma, and allergic rhinitis. These discoveries have highlighted the importance of skin barrier function in the pathogenesis of atopic diseases and have motivated a surge in research characterizing the filaggrin-deficient skin barrier and its consequences. In this review we discuss the mechanisms through which mutations in this protein contribute to the pathogenesis of atopic dermatitis and associated atopic conditions. We focus on recent human and murine discoveries characterizing the filaggrin-deficient epidermis with respect to biophysical, immunologic, and microbiome abnormalities. © 2013 American Academy of Allergy, Asthma & Immunology.


Kavanagh R.G.,Our Ladys Childrens Hospital
The Journal of bone and joint surgery. American volume | Year: 2013

Pediatric orthopaedic surgery owes its development to many pioneering individuals, and the studies that these individuals have undertaken form the basis for the clinical decisions made on the modern pediatric orthopaedic service. The aim of our study was to use citation analysis to identify the top 100 papers in pediatric orthopaedic surgery. Using the Thomson Reuters Web of Knowledge, we searched for citations of all papers relevant to pediatric orthopaedics. The number of citations, authorship, year of publication, journal of publication, and country and institution of origin were recorded for each paper. The most cited paper was found to be the classic paper from 1963 by Salter and Harris that introduced the now-eponymous classification system for physeal injuries in the skeletally immature patient. The second most cited was Salter's paper describing the widely used osteotomy for the treatment of developmental dysplasia of the hip, and the third most cited was Catterall's description of the natural history of Legg-Calvé-Perthes disease. Most papers originated in the U.S., and most were published in this journal. A number of authors including Salter, Ponseti, Graf, and Loder had more than one paper in the top-100 list. This paper's identification of the classic papers of pediatric orthopaedic surgery gives us a unique insight into the development of pediatric orthopaedic surgery in the twentieth and early twenty-first centuries and identifies those individuals who have contributed the most to the body of knowledge used to guide evidence-based clinical decision-making in pediatric orthopaedics today.


The use of procedural sedation outside the operating theatre has increased in hospital settings and has gained popularity among non-anesthesiologists. Sedative agents used for procedural pain, although effective, also pose significant risks to the patient if used incorrectly. There is currently no universally accepted program of education for practitioners using or introducing procedural sedation into their practice. There is emerging literature identifying structured procedural sedation programs (PSPs) as a method of ensuring a standardized level of competency among staff and reducing risks to the patient. We hypothesize that programs of education for healthcare professionals using procedural sedation outside the operating theatre are beneficial in improving patient care, safety, practitioner competence and reducing adverse event rates. Electronic databases will be systematically searched for studies (randomized and non-randomized) examining the effectiveness of structured PSPs from 1966 to present. Database searches will be supplemented by contact with experts, reference and citation checking, and a grey literature search. No language restriction will be imposed. Screening of titles and abstracts, and data extraction will be performed by two independent reviewers. All disagreements will be resolved by discussion with an independent third party. Data analysis will be completed adhering to procedures outlined in the Cochrane Handbook of Systematic Reviews of Interventions. If the data allows, a meta-analysis will be performed. This review will cohere evidence on the effectiveness of structured PSPs on sedation events and patient outcomes within the hospital and other acute care settings. In addition, it will examine key components identified within a PSP associated with patient safety and improved patient outcomes. PROSPERO registration number: CRD42013003851.


Campbell M.,Trinity College Dublin | Doyle S.L.,Trinity College Dublin | Doyle S.L.,Our Ladys Childrens Hospital
Journal of Molecular Medicine | Year: 2013

Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. While activation of the immune system has been implicated in disease progression, the pathways involved remain relatively unclear. Typically, inflammatory responses are caused as a result of pathogenic infection. However, in chronic conditions, like AMD, a form of 'sterile' inflammation can exist in localised areas of the body in response to modified host-derived elements and particulate matter accumulation, due to the activation of a complex termed the 'inflammasome'. Inflammasomes control the activity of two major pro-inflammatory cytokines, namely, interleukin (IL)-1β and IL-18, by allowing for their cleavage from inactive pro-forms into mature cytokines. The major pathological hallmark common to both 'dry' and 'wet' AMD is the presence of extracellular deposits, known as drusen, below the retinal pigment epithelium in the macula of the eye. Past studies have shown that host-derived particulate matter such as amyloid deposits and atherosclerotic plaques can be 'sensed' by the NLRP3-inflammasome causing cleavage of pro-IL-1β and pro-IL-18. We have recently reported that the NLRP3-inflammasome can also 'sense' drusen isolated from human AMD donor eyes and that IL-18 protects against the development of choroidal neovascularisation in a model that mimics 'wet' AMD. In fact, since then, a number of studies have reported roles for the NLRP3-inflammasome in AMD. This review will focus on describing, comparing and contrasting these reports and analyzing the potential for manipulating the NLRP3-inflammasome as a therapy for AMD. © 2013 Springer-Verlag Berlin Heidelberg.


O'Grady M.J.,Our Ladys Childrens Hospital | Cody D.,Our Ladys Childrens Hospital
Archives of Disease in Childhood | Year: 2011

Subclinical hypothyroidism (SH) is defined as an elevated thyroid stimulating hormone (TSH) in association with a normal total or free thyroxine (T4) or triiodothyronine (T3). It is frequently encountered in both neonatology and general paediatric practice; however, its clinical significance is widely debated. Currently there is no broad consensus on the investigation and treatment of these patients; specifically who to treat and what cutoff level of TSH should be used. This paper reviews the available evidence regarding investigation, treatments and outcomes reported for childhood SH.

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