St Vincent University Hospital

Ireland

St Vincent University Hospital

Ireland
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Setta-Kaffetzi N.,King's College London | Simpson M.A.,King's College London | Navarini A.A.,King's College London | Patel V.M.,King's College London | And 19 more authors.
American Journal of Human Genetics | Year: 2014

Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis. © 2014 The American Society of Human Genetics.


Obinwa O.,Portiuncula Hospital | Obinwa O.,Materials Misericordiae University Hospital | Peirce C.,Portiuncula Hospital | Peirce C.,St Vincent University Hospital | And 3 more authors.
International Journal of Colorectal Disease | Year: 2015

Purpose: To analyse the diagnostic value of simple clinical measurements in ensuring an early and accurate detection of advanced appendicitis (perforation, mass and peri-appendicular abscess) and possible complications. Methods: A retrospective, single-centre study of all paediatric (age 0–14 years) appendicectomies was conducted over a 14-year period. Preoperative symptoms, signs and laboratory results, intra-operative findings and postoperative complications were analyzed. Receiver operating characteristic (ROC) curves were used to estimate sensitivity and specificity of significant (p ≤ 0.05) predictor variables based on multivariate logistic regression models. Results: One thousand and thirty-seven patients were included. Perforations were seen in 88 (8.5 %) cases, and abscesses were seen in 35 (3.4 %) cases. Of all the clinical variables evaluated, preoperative temperature ≥37.5 °C was most discriminatory for advanced appendicitis. Significant other discriminatory clinical variables were WBC count ≥15,100/μL, preoperative anorexia and rebound tenderness. Postoperative complications occurred in 74 (7.1 %) patients and were associated with pre-operative temperature ≥37.5 °C and advanced appendicitis. Conclusion: Independent clinical predictors of advanced appendicitis exist but lack individual accuracy. In this study, preoperative pyrexia is shown to be highly associated with both advanced appendicitis and development of postoperative complications. This independent factor may point to early need for antibiotic treatment, urgent imaging and subsequent intervention in patients with appendicitis. © 2015, Springer-Verlag Berlin Heidelberg.


Nichol A.,University of Melbourne | Nichol A.,University College Dublin | Nichol A.,Monash University | Ahmed B.,St Vincent University Hospital
Anaesthesia and Intensive Care Medicine | Year: 2014

Shock may result from a number of distinct disease processes and it is commonly associated with trauma, infection and cardiovascular dysfunction. Shock results in significant morbidity and mortality and is a leading causes of death in hospital patients. In order to improve patient outcomes it is important to recognize shock early, then assess and treat the shocked patient in a systematic way. The clinical classification of shock into cardiogenic, obstructive, hypovolaemic or distributive shock can help the clinician to understand the underlying cause of the shock. However, it is important to note that considerable overlap between these different types of shock can exist in practice. After identification of patients in shock, immediate resuscitation with goal-directed therapy to prevent further deterioration and improve outcome is vital. ABCDE approach can be useful systematic way for initial assessment and resuscitation. Basic monitoring should be instituted as soon as possible and in severe or unresponsive shock this should be escalated to invasive monitoring. Immediate generic laboratory, microbiological and radiological tests should be carried out as soon as possible and should include a blood lactate level. Further targeted tests should then be tailored to the history and clinical findings. These targeted investigations should help to pin point the specific cause of the shock and drive definitive management. © 2014 Elsevier Ltd. All rights reserved.


Aloraifi F.,University College Dublin | Aloraifi F.,Trinity College Dublin | Alshehhi M.,National Center for Medical Genetics | McDevitt T.,National Center for Medical Genetics | And 11 more authors.
European Journal of Surgical Oncology | Year: 2015

Aims: Women with inherited pathogenic mutations in the BRCA1 or BRCA2 genes have up to an 85% risk of developing breast cancer in their lifetime. However, only about 20% of familial breast cancer is attributed to mutations in BRCA1 and BRCA2, while a further 5-10% are attributed to mutations in other rare susceptibility genes such as TP53, STK11, PTEN, ATM and CHEK2. Despite extensive efforts to explain the missing heritability of this disease, the majority of familial clustering in breast cancer remains largely unexplained. We aim to analyze the pathology of familial cases of which no pathogenic mutation is yet identified. Methods: We compared the pathological phenotype of BRCA1/BRCA2 negative familial breast cancer (BRCAx) to BRCA1-positive, BRCA2-positive and sporadic cases without a family history. Age-adjusted analysis is summarized in odd's ratios and confidence intervals for tumor type, grade, lymph node, ER and HER2 status. Results: We found non-familial cases to be more likely to be ER positive (P=0.041) as compared with BRCAx tumors. More cases of lobular carcinoma were found with BRCAx as compared to BRCA1 tumors (P=0.05). After multivariate logistic regression analysis, BRCAx tumors are more likely ER positive (P=0.001) and HER2 positive (P=0.047) in comparison to BRCA1. Conversely, BRCAx cases are less likely to be ER positive (P=0.02) but more likely to be HER2 positive (P=0.021) as compared with BRCA2 tumors. Conclusion: Our findings suggest that BRCA1, BRCA2 and BRCAx tumors differ in phenotype from non-familial and familial BRCA1-positive and BRCA2-positive tumors. Further studies will need to be performed in this important population in order to develop strategies for early detection and prevention. © 2015 Elsevier Ltd.


Shah A.R.,St Vincent University Hospital
BMJ case reports | Year: 2014

We report a case of a 35-year-old man who presented with 4-week history of haemoptysis, with a history of intravenous drug use. There was no other significant medical or surgical history and no recollection of any foreign body aspiration. Chest X-ray and CT scan showed 40 mm long needle in left main bronchus, partly lying outside the bronchus into the mediastinum. Flexible and rigid bronchoscopes proved to be unsuccessful in retrieving the needle. We proceeded with left posterolateral thoracotomy and the left main bronchus was explored to take out this 21-gauge (green) injection needle. The distal half of the needle with the sharp end was lying in the mediastinum piercing through the bronchial wall. Surgery was uneventful with good postoperative recovery and the patient was discharged 4 days later.


Aloraifi F.,Trinity College Dublin | McDevitt T.,Our Ladys Hospital | Martiniano R.,Trinity College Dublin | McGreevy J.,Trinity College Dublin | And 9 more authors.
FEBS Journal | Year: 2015

The identification of the breast cancer susceptibility genes BRCA1 and BRCA2 enhanced clinicians' ability to select high-risk individuals for aggressive surveillance and prevention, and led to the development of targeted therapies. However, BRCA1/2 mutations account for only 25% of familial breast cancer cases. To systematically identify rare, probably pathogenic variants in familial cases of breast cancer without BRCA1/2 mutations, we developed a list of 312 genes, and performed targeted DNA enrichment coupled to multiplex next-generation sequencing on 104 'BRCAx' patients and 101 geographically matched controls in Ireland. As expected, this strategy allowed us to identify mutations in several well-known high-susceptibility and moderate-susceptibility genes, including ATM (~ 5%), RAD50 (~ 3%), CHEK2 (~ 2%), TP53 (~ 1%), PALB2 (~ 1%), and MRE11A (~ 1%). However, we also identified novel pathogenic variants in 30 other genes, which, when taken together, potentially explain the etiology of the missing heritability in up to 35% of BRCAx patients. These included novel potential pathogenic mutations in MAP3K1, CASP8, RAD51B, ZNF217, CDKN2B-AS1, and ERBB2, including a splice site mutation, which we predict would generate a constitutively active HER2 protein. Taken together, this work extends our understanding of the genetics of familial breast cancer, and supports the need to implement hereditary multigene panel testing to more appropriately orientate clinical management. © 2015 FEBS.


Shah A.R.,St Vincent University Hospital | Smyth L.,St Vincent University Hospital | Tolan M.,St Vincent University Hospital | Bartosik W.,St Vincent University Hospital
BMJ Case Reports | Year: 2014

We report a case of a 35-year-old man who presented with 4-week history of haemoptysis, with a history of intravenous drug use. There was no other significant medical or surgical history and no recollection of any foreign body aspiration. Chest X-ray and CT scan showed 40 mm long needle in left main bronchus, partly lying outside the bronchus into the mediastinum. Flexible and rigid bronchoscopes proved to be unsuccessful in retrieving the needle. We proceeded with left posterolateral thoracotomy and the left main bronchus was explored to take out this 21-gauge (green) injection needle. The distal half of the needle with the sharp end was lying in the mediastinum piercing through the bronchial wall. Surgery was uneventful with good postoperative recovery and the patient was discharged 4 days later. Copyright 2014 BMJ Publishing Group. All rights reserved.


Kelly D.,University of Ulster | Donnelly S.,St Vincent University Hospital | Caulfield B.,Insight Centre for Data Analytics
Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS | Year: 2015

Over 3.2 million people in the UK alone have the lung disease Chronic Obstructive Pulmonary Disease. Identifying when COPD patients are at risk of an exacerbation is a major problem and there is a need for smart solutions that provide us with a means of tracking patient health status. Smart-phone sensor technology provides us with an opportunity to automatically monitor patients. With sensors providing the ability to measure aspects of a patient's daily life, such a motion, methods to interpret these signals and infer health related information are needed. In this work we aim to investigate the feasibility of utilizing motion sensors, built within smartphones, to measure patient movement and to infer the health related information about the patient. We perform experiments, based on 7 COPD patients using data collected over a 12 week period for each patient, and identify a measure to distinguish between periods when a patient feels well Vs periods when a patient feels unwell. © 2015 IEEE.


PubMed | St Vincent University Hospital, Trinity College Dublin and Our Ladys Hospital
Type: Journal Article | Journal: The FEBS journal | Year: 2015

The identification of the breast cancer susceptibility genes BRCA1 and BRCA2 enhanced clinicians ability to select high-risk individuals for aggressive surveillance and prevention, and led to the development of targeted therapies. However, BRCA1/2 mutations account for only 25% of familial breast cancer cases. To systematically identify rare, probably pathogenic variants in familial cases of breast cancer without BRCA1/2 mutations, we developed a list of 312 genes, and performed targeted DNA enrichment coupled to multiplex next-generation sequencing on 104 BRCAx patients and 101 geographically matched controls in Ireland. As expected, this strategy allowed us to identify mutations in several well-known high-susceptibility and moderate-susceptibility genes, including ATM (~ 5%), RAD50 (~ 3%), CHEK2 (~ 2%), TP53 (~ 1%), PALB2 (~ 1%), and MRE11A (~ 1%). However, we also identified novel pathogenic variants in 30 other genes, which, when taken together, potentially explain the etiology of the missing heritability in up to 35% of BRCAx patients. These included novel potential pathogenic mutations in MAP3K1, CASP8, RAD51B, ZNF217, CDKN2B-AS1, and ERBB2, including a splice site mutation, which we predict would generate a constitutively active HER2 protein. Taken together, this work extends our understanding of the genetics of familial breast cancer, and supports the need to implement hereditary multigene panel testing to more appropriately orientate clinical management.


PubMed | St Vincent University Hospital, University of Limerick and University of Chicago
Type: Journal Article | Journal: Canadian Urological Association journal = Journal de l'Association des urologues du Canada | Year: 2015

We compare the survival outcomes of patients with clear cell renal cell carcinoma (RCC) treated with adrenal sparing radical nephrectomy (ASRN) and non-adrenal sparing radical nephrectomy (NASRN).We conducted an observational study based on a composite patient population from two university teaching hospitals who underwent RN for RCC between January 2000 and December 2012. Only patients with pathologically confirmed RCC were included. We excluded patients undergoing cytoreductive nephrectomy, with loco-regional lymph node involvement. In total, 579 patients (ASRN = 380 and NASRN = 199) met our study criteria. Patients were categorized by risk groups (all stage, early stage and locally advanced RCC). Overall survival (OS) and cancer-specific survival (CSS) were analyzed for risk groups. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression.The median follow-up was 41 months (range: 12-157). There were significant benefits in OS (ASRN 79.5% vs. NASRN 63.3%; p = 0.001) and CSS (84.3% vs. 74.9%; p = 0.001), with any differences favouring ASRN in all stage. On multivariate analysis, there was a trend towards worse OS (hazard ratio [HR] 1.759, 95% confidence interval [CI] 0.943-2.309, p = 0.089) and CSS (HR 1.797, 95% CI 0.967-3.337, p = 0.064) in patients with NASRN (although not statistically significant). Of these patients, only 11 (1.9%) had adrenal involvement.The inherent limitations in our study include the impracticality of conducting a prospective randomized trial in this scenario. Our observational study with a 13-year follow-up suggests ASRN leads to better survival than NASRN. ASRN should be considered the gold standard in treating patients with RCC, unless it is contraindicated.

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