St. Vincent's University Hospitalhttp://hdl.handle.net/10147/1284302024-03-26T15:23:05Z2024-03-26T15:23:05ZFK506-Binding Protein like (FKBPL) Has an Important Role in Heart Failure with Preserved Ejection Fraction Pathogenesis with Potential Diagnostic Utility.Chhor, MichaelChen, HaoNikolić, Valentina NPavlović, MilanVučić, Rada MWatson, Chris JLedwidge, MarkMcDonald, KennethRobson, TracyMcClements, LanaJerotic, DjurdjaRayner, BenjaminMcGrath, KristineTesic, Miloradhttp://hdl.handle.net/10147/6351992023-04-05T02:08:49Z2023-02-18T00:00:00ZFK506-Binding Protein like (FKBPL) Has an Important Role in Heart Failure with Preserved Ejection Fraction Pathogenesis with Potential Diagnostic Utility.
Chhor, Michael; Chen, Hao; Nikolić, Valentina N; Pavlović, Milan; Vučić, Rada M; Watson, Chris J; Ledwidge, Mark; McDonald, Kenneth; Robson, Tracy; McClements, Lana; Jerotic, Djurdja; Rayner, Benjamin; McGrath, Kristine; Tesic, Milorad
Heart failure (HF) is the leading cause of hospitalisations worldwide, with only 35% of patients surviving the first 5 years after diagnosis. The pathogenesis of HF with preserved ejection fraction (HFpEF) is still unclear, impeding the implementation of effective treatments. FK506-binding protein like (FKBPL) and its therapeutic peptide mimetic, AD-01, are critical mediators of angiogenesis and inflammation. Thus, in this study, we investigated-for the first time-FKBPL's role in the pathogenesis and as a biomarker of HFpEF. In vitro models of cardiac hypertrophy following exposure to a hypertensive stimulus, angiotensin-II (Ang-II, 100 nM), and/or AD-01 (100 nM), for 24 and 48 h were employed as well as human plasma samples from people with different forms of HFpEF and controls. Whilst the FKBPL peptide mimetic, AD-01, induced cardiomyocyte hypertrophy in a similar manner to Ang-II (p < 0.0001), when AD-01 and Ang-II were combined together, this process was abrogated (p < 0.01-0.0001). This mechanism appears to involve a negative feedback loop related to FKBPL (p < 0.05). In human plasma samples, FKBPL concentration was increased in HFpEF compared to controls (p < 0.01); however, similar to NT-proBNP and Gal-3, it was unable to stratify between different forms of HFpEF: acute HFpEF, chronic HFpEF and hypertrophic cardiomyopathy (HCM). FKBPL may be explored for its biomarker and therapeutic target potential in HFpEF.
2023-02-18T00:00:00ZFK506-Binding Protein like (FKBPL) Has an Important Role in Heart Failure with Preserved Ejection Fraction Pathogenesis with Potential Diagnostic Utility.Chhor, MichaelChen, HaoNikolić, Valentina NPavlović, MilanVučić, Rada MWatson, Chris JLedwidge, MarkMcDonald, KennethRobson, TracyMcClements, LanaMcGrath, KristineRayner, BenjaminJerotic, DjurdjaTesic, Miloradhttp://hdl.handle.net/10147/6351412023-03-16T03:01:22Z2023-02-18T00:00:00ZFK506-Binding Protein like (FKBPL) Has an Important Role in Heart Failure with Preserved Ejection Fraction Pathogenesis with Potential Diagnostic Utility.
Chhor, Michael; Chen, Hao; Nikolić, Valentina N; Pavlović, Milan; Vučić, Rada M; Watson, Chris J; Ledwidge, Mark; McDonald, Kenneth; Robson, Tracy; McClements, Lana; McGrath, Kristine; Rayner, Benjamin; Jerotic, Djurdja; Tesic, Milorad
Heart failure (HF) is the leading cause of hospitalisations worldwide, with only 35% of patients surviving the first 5 years after diagnosis. The pathogenesis of HF with preserved ejection fraction (HFpEF) is still unclear, impeding the implementation of effective treatments. FK506-binding protein like (FKBPL) and its therapeutic peptide mimetic, AD-01, are critical mediators of angiogenesis and inflammation. Thus, in this study, we investigated-for the first time-FKBPL's role in the pathogenesis and as a biomarker of HFpEF. In vitro models of cardiac hypertrophy following exposure to a hypertensive stimulus, angiotensin-II (Ang-II, 100 nM), and/or AD-01 (100 nM), for 24 and 48 h were employed as well as human plasma samples from people with different forms of HFpEF and controls. Whilst the FKBPL peptide mimetic, AD-01, induced cardiomyocyte hypertrophy in a similar manner to Ang-II (p < 0.0001), when AD-01 and Ang-II were combined together, this process was abrogated (p < 0.01-0.0001). This mechanism appears to involve a negative feedback loop related to FKBPL (p < 0.05). In human plasma samples, FKBPL concentration was increased in HFpEF compared to controls (p < 0.01); however, similar to NT-proBNP and Gal-3, it was unable to stratify between different forms of HFpEF: acute HFpEF, chronic HFpEF and hypertrophic cardiomyopathy (HCM). FKBPL may be explored for its biomarker and therapeutic target potential in HFpEF.
2023-02-18T00:00:00ZTraumatic open brachial plexus injuries: The importance of interdisciplinary collaboration.Jeantet, Quentin W AKhoo, S GuanDowdall, JosephKilleen, RonanCronin, KevinDolan, Roisin Thttp://hdl.handle.net/10147/6350482023-02-23T01:57:37Z2022-06-01T00:00:00ZTraumatic open brachial plexus injuries: The importance of interdisciplinary collaboration.
Jeantet, Quentin W A; Khoo, S Guan; Dowdall, Joseph; Killeen, Ronan; Cronin, Kevin; Dolan, Roisin T
Open traumatic brachial plexus injuries are rare, yet can be life threatening and require rapid clinic assessment. Early interdisciplinary collaboration is critical to achieve superior patient outcomes. This case of a 24-year-old female of a traumatic neck injury with contralateral brachial plexus injury demonstrates the limitations of early clinical assessment due to the potential for haemodynamic instability and highlights the priority of patient stabilisation. Early and active interdisciplinary collaboration in this case demonstrates its importance in accurate diagnosis and timely intervention to achieve better patient outcomes. As published in recent guidelines, this report shows the importance of early interdisciplinary involvement following stabilisation and resuscitation of the patient.
2022-06-01T00:00:00ZRecommendations from the European Commission Initiative on Breast Cancer for multigene testing to guide the use of adjuvant chemotherapy in patients with early breast cancer, hormone receptor positive, HER-2 negative.Giorgi Rossi, PaoloLebeau, AnnetteCanelo-Aybar, CarlosSaz-Parkinson, ZuleikaQuinn, CecilyLangendam, MirandaMcGarrigle, HelenWarman, SueRigau, DavidAlonso-Coello, PabloBroeders, MireilleGraewingholt, AxelPosso, MargaritaDuffy, StephenSchünemann, Holger Jhttp://hdl.handle.net/10147/6334302022-07-16T01:48:10Z2021-02-18T00:00:00ZRecommendations from the European Commission Initiative on Breast Cancer for multigene testing to guide the use of adjuvant chemotherapy in patients with early breast cancer, hormone receptor positive, HER-2 negative.
Giorgi Rossi, Paolo; Lebeau, Annette; Canelo-Aybar, Carlos; Saz-Parkinson, Zuleika; Quinn, Cecily; Langendam, Miranda; McGarrigle, Helen; Warman, Sue; Rigau, David; Alonso-Coello, Pablo; Broeders, Mireille; Graewingholt, Axel; Posso, Margarita; Duffy, Stephen; Schünemann, Holger J
Background: Predicting the risk of recurrence and response to chemotherapy in women with early breast cancer is crucial to optimise adjuvant treatment. Despite the common practice of using multigene tests to predict recurrence, existing recommendations are inconsistent. Our aim was to formulate healthcare recommendations for the question "Should multigene tests be used in women who have early invasive breast cancer, hormone receptor-positive, HER2-negative, to guide the use of adjuvant chemotherapy?"
Methods: The European Commission Initiative on Breast Cancer (ECIBC) Guidelines Development Group (GDG), a multidisciplinary guideline panel including experts and three patients, developed recommendations informed by systematic reviews of the evidence. Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision frameworks were used. Four multigene tests were evaluated: the 21-gene recurrence score (21-RS), the 70-gene signature (70-GS), the PAM50 risk of recurrence score (PAM50-RORS), and the 12-gene molecular score (12-MS).
Results: Five studies (2 marker-based design RCTs, two treatment interaction design RCTs and 1 pooled individual data analysis from observational studies) were included; no eligible studies on PAM50-RORS or 12-MS were identified and the GDG did not formulate recommendations for these tests.
Conclusions: The ECIBC GDG suggests the use of the 21-RS for lymph node-negative women (conditional recommendation, very low certainty of evidence), recognising that benefits are probably larger in women at high risk of recurrence based on clinical characteristics. The ECIBC GDG suggests the use of the 70-GS for women at high clinical risk (conditional recommendation, low certainty of evidence), and recommends not using 70-GS in women at low clinical risk (strong recommendation, low certainty of evidence).
2021-02-18T00:00:00ZThe Role of Organoids as a Novel Platform for Modeling of Inflammatory Bowel Disease.O'Connell, LaurenWinter, Des CAherne, Carol Mhttp://hdl.handle.net/10147/6333512022-07-06T01:52:56Z2021-02-17T00:00:00ZThe Role of Organoids as a Novel Platform for Modeling of Inflammatory Bowel Disease.
O'Connell, Lauren; Winter, Des C; Aherne, Carol M
Inflammatory bowel disease (IBD) is a chronic relapsing-remitting immune-mediated disorder affecting the gut. It is common in Westernized regions and is increasing in incidence in developing countries. At a molecular level, intrinsic deficiencies in epithelial integrity, mucosal barrier function, and mechanisms of immune response and resolution contribute to the development of IBD. Traditionally two platforms have been utilized for disease modeling of IBD; in-vitro monolayer cell culture and in-vivo animal models. Both models have limitations, including cost, lack of representative cell types, lack of complexity of cellular interactions in a living organism, and xenogeneity. Organoids, three-dimensional cellular structures which recapitulate the basic architecture and functional processes of the organ of origin, hold potential as a third platform with which to investigate the pathogenesis and molecular defects which give rise to IBD. Organoids retain the genetic and transcriptomic profile of the tissue of origin over time and unlike monolayer cell culture can be induced to differentiate into most adult intestinal cell types. They may be used to model intestinal host-microbe interactions occurring at the mucosal barrier, are amenable to genetic manipulation and can be co-cultured with other cell lines of interest. Bioengineering approaches may be applied to render a more faithful representation of the intestinal epithelial niche. In this review, we outline the concept of intestinal organoids, discuss the advantages and disadvantages of the platform comparative to alternative models, and describe the translational applications of organoids in IBD.
2021-02-17T00:00:00ZAssociation of artificial turf and concussion in competitive contact sports: a systematic review and meta-analysis.O' Leary, FrankAcampora, NicHand, FionaO' Donovan, Jameshttp://hdl.handle.net/10147/6319042022-05-14T01:52:22Z2020-05-26T00:00:00ZAssociation of artificial turf and concussion in competitive contact sports: a systematic review and meta-analysis.
O' Leary, Frank; Acampora, Nic; Hand, Fiona; O' Donovan, James
Objective: To determine the incidence of head injuries and concussion in contact sports, comparing natural grass with artificial turf surfaces.
Design: Systematic review and meta-analysis via the RevMan V.5.3 software.
Eligibility criteria for selecting studies: All studies describing competitive contact sports played on both natural grass and artificial turf. The primary outcome measured was occurrence of head injury and concussion.
Data sources: The databases include PubMed, Embase, Cochrane, Medline and Sport Discus. The last search took place on 23 May 2019. The Newcastle-Ottawa Quality Assessment Scale evaluated the methodological quality of the selected studies with a funnel plot designed to determine publication bias. Study screening and data extraction were performed by two independent reviewers.
Results: Initial screening generated 42 publications, with 12 meeting criteria for inclusion. Eight studies described concussion only. The rate ratio (RR) of head injury and concussion was less on artificial turf compared with natural grass (RR=0.89, 95% CI 0.77 to 1.04) as was the rate ratio of concussion only (RR=0.72, 95% CI 0.58 to 0.89).
Conclusion: Analysis of published data demonstrates a decreased incidence of head injury and concussion when contact sports are played on artificial turf. This difference was most marked for sports such as rugby and American football. However, artificial turf has no association with the incidence of head injury or concussion while playing soccer.
Keywords: concussion; contact sports; environment; head; injuries.
2020-05-26T00:00:00ZP084 The impact of the SARS-CoV-2 pandemic on people living with cystic fibrosis in Ireland: real-world data from the Irish cystic fibrosis registryRees, H.Babu, S.Fletcher, G.Kirwan, L.http://hdl.handle.net/10147/6319012022-05-14T01:52:02Z2021-06-11T00:00:00ZP084 The impact of the SARS-CoV-2 pandemic on people living with cystic fibrosis in Ireland: real-world data from the Irish cystic fibrosis registry
Rees, H.; Babu, S.; Fletcher, G.; Kirwan, L.
The impact of the SARS-CoV-2 pandemic on people living with
cystic fibrosis (PWCF) in Ireland was investigated by comparing the
utilisation of regular hospital facilities in 2020, with data collected in 2019.
2021-06-11T00:00:00ZReal‑world challenge for clinicians treating advanced gastroesophageal adenocarcinoma (Review).Baxter, Mark APetty, Russell DSwinson, DanielHall, Peter SO'Hanlon, Shanehttp://hdl.handle.net/10147/6317742022-04-23T01:45:28Z2021-03-24T00:00:00ZReal‑world challenge for clinicians treating advanced gastroesophageal adenocarcinoma (Review).
Baxter, Mark A; Petty, Russell D; Swinson, Daniel; Hall, Peter S; O'Hanlon, Shane
Gastroesophageal adenocarcinoma (GOA) is a disease of older people. Incidence is rising in the developed world and the majority of patients present with advanced disease. Based on clinical trial data, systemic chemotherapy in the advanced setting is associated with improvements in quality of life and survival. However, there is a recognised mismatch between trial populations and the patients encountered in clinical practice in terms of age, comorbidity and fitness. Appropriate patient selection is essential to safely deliver effective treatment. In this narrative review, we discuss the challenges faced by clinicians when assessing real‑world patients with advanced GOA for systemic therapy. We also highlight the importance of frailty screening and the current available evidence we can use to guide our management.
2021-03-24T00:00:00ZDynamic Change and Clinical Relevance of Postinfectious SARS-CoV-2 Antibody Responses.Mallon, PatrickTinago, WillardLeon, Alejandro GarciaMcCann, KathleenKenny, GraceMcGettrick, PadraigGreen, SandraInzitari, RosannaCottere, Aoife GFeeney, Eoin RSavinelli, StefanoDoran, Peterhttp://hdl.handle.net/10147/6317232022-04-06T01:44:45Z2021-03-26T00:00:00ZDynamic Change and Clinical Relevance of Postinfectious SARS-CoV-2 Antibody Responses.
Mallon, Patrick; Tinago, Willard; Leon, Alejandro Garcia; McCann, Kathleen; Kenny, Grace; McGettrick, Padraig; Green, Sandra; Inzitari, Rosanna; Cottere, Aoife G; Feeney, Eoin R; Savinelli, Stefano; Doran, Peter
Background: Although reports suggest that most individuals with coronavirus disease 2019 (COVID-19) develop detectable antibodies postinfection, the kinetics, durability, and relative differences between immunoglobulin M (IgM) and immunoglobulin G (IgG) responses beyond the first few weeks after symptom onset remain poorly understood.
Methods: Within a large, well-phenotyped, diverse, prospective cohort of subjects with and without severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR)-confirmed infection and historical controls derived from cohorts with high prevalence of viral coinfections and samples taken during prior flu seasons, we measured SARS-CoV-2 serological responses (both IgG and IgM) using commercially available assays. We calculated sensitivity, specificity, and relationship with disease severity and mapped the kinetics of antibody responses over time using generalized additive models.
Results: We analyzed 1001 samples from 752 subjects, 327 with confirmed SARS-CoV-2 (29.7% with severe disease) spanning a period of 90 days from symptom onset. Sensitivity was lower (44.1%-47.1%) early (<10 days) after symptom onset but increased to >80% after 10 days. IgM positivity increased earlier than IgG-targeted assays, but positivity peaked between days 32 and 38 post-onset of symptoms and declined thereafter, a dynamic that was confirmed when antibody levels were analyzed, with a more rapid decline observed with IgM. Early (<10 days) IgM but not IgG levels were significantly higher in those who subsequently developed severe disease (signal/cutoff 4.20 [0.75-17.93] vs 1.07 [0.21-5.46]; P = .048).
Conclusions: This study suggests that postinfectious antibody responses in those with confirmed COVID-19 begin to decline relatively early postinfection and suggests a potential role for higher IgM levels early in infection in the prediction of subsequent disease severity.
2021-03-26T00:00:00ZColonisation of the colonic mucus gel layer with butyrogenic and hydrogenotropic bacteria in health and ulcerative colitis.Earley, HelenLennon, GrainneCoffey, J CalvinWinter, Desmond CO'Connell, P Ronanhttp://hdl.handle.net/10147/6316902022-04-02T01:47:45Z2021-03-31T00:00:00ZColonisation of the colonic mucus gel layer with butyrogenic and hydrogenotropic bacteria in health and ulcerative colitis.
Earley, Helen; Lennon, Grainne; Coffey, J Calvin; Winter, Desmond C; O'Connell, P Ronan
Butyrate is the primary energy source for colonocytes and is essential for mucosal integrity and repair. Butyrate deficiency as a result of colonic dysbiosis is a putative factor in ulcerative colitis (UC). Commensal microbes are butyrogenic, while others may inhibit butyrate, through hydrogenotropic activity. The aim of this study was to quantify butyrogenic and hydrogenotropic species and determine their relationship with inflammation within the colonic mucus gel layer (MGL). Mucosal brushings were obtained from 20 healthy controls (HC), 20 patients with active colitis (AC) and 14 with quiescent colitis (QUC). Abundance of each species was determined by RT-PCR. Inflammatory scores were available for each patient. Statistical analyses were performed using Mann-Whitney-U and Kruskall-Wallis tests. Butyrogenic R. hominis was more abundant in health than UC (p < 0.005), prior to normalisation against total bacteria. Hydrogenotropic B. wadsworthia was reduced in AC compared to HC and QUC (p < 0.005). An inverse correlation existed between inflammation and R. hominis (ρ - 0.460, p < 0.005) and B. wadsworthia (ρ - 0.646, p < 0.005). Other hydrogenotropic species did not widely colonise the MGL. These data support a role for butyrogenic bacteria in UC. Butyrate deficiency in UC may be related to reduced microbial production, rather than inhibition by microbial by-products.
2021-03-31T00:00:00Z