HRB Clinical Research Facility at UCC - Journal Articles
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Item The effect of short-term vitamin D supplementation on calcium status in vitamin D insufficient renal transplant recipients at risk of hypercalcemia(W.B. Saunders, 2019) Lynch Cronin, Irene; Byrne, Fiona; Doyle, Ross; Fraser, William D.; Chipchase, Allison; Eustace, Joseph A.Objective: Vitamin D insufficiency is highly prevalent among renal transplant recipients and in observational studies is associated with adverse outcomes. Hypercalcemia, usually due to persistent hyperparathyroidism, also commonly occurs in this population and often coexists with vitamin D insufficiency. However, concern that vitamin D supplementation might exacerbate the pre-existing hypercalcemia often leads clinicians to avoid vitamin D supplementation in such patients. This feasibility study aimed to quantify the effect on serum calcium of short-term low-dose cholecalciferol supplementation in a group of renal transplant recipients with a recent history of serum calcium levels >10 mg/dL. Design: A 2-week, single arm, open-label trial. Setting: Renal transplant follow-up clinic in an Irish University Hospital. Subjects: Eighteen vitamin D–insufficient adult patients with a functioning renal allograft (estimated glomerular filtration rate > 30 mL/minute/1.73 m 2 ) and a recent history of serum calcium >10 mg/dL. Intervention: Two weeks of treatment with 1,000 IU cholecalciferol/day. Main Outcome Measure: Change in ionized calcium and urine calcium:creatinine ratio at follow-up compared with baseline. Results: Mean (standard deviation [SD]) baseline 25 (OH) vitamin D (25 (OH) D) concentration was 15.9 (5.97) ng/mL and mean (SD) baseline serum calcium was 10.50 (0.6) mg/dL. Following the 2-week intervention, median (interquartile range [IQR]) change in serum calcium from baseline was −0.08 (−3.6 to 0.08) mg/dL, P =.3. Mean (SD) ionized calcium decreased from 5.24 (0.32) mg/dL at baseline to 5.16 (0.28) mg/dL, P =.05. Median (IQR) change in the urinary calcium:creatinine ratio was 0.001 (−0.026 to 0.299) mg/mg, P =.88. Median (IQR) change in 25 (OH) D was 3.6 (2.9-6.2) ng/mL, P <.05. Conclusions: In vitamin D–insufficient renal transplant recipients at risk of hypercalcemia, low-dose short-term oral cholecalciferol supplementation improves 25 (OH) D concentrations without exacerbating hypercalcemia or increasing the urinary calcium:creatinine ratio. © 2018 National Kidney Foundation, Inc.Item Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses(BMJ Publishing Group Ltd, 2020-05-14) Molina-Montes, Esther; Coscia, Claudia; Gómez-Rubio, Paulina; Fernández, Alba; Boenink, Rianne; Rava, Marta; Márquez, Mirari; Molero, Xavier; Löhr, Matthias; Sharp, Linda; Michalski, Christoph W.; Farré, Antoni; Perea, José; O’Rorke, Michael; Greenhalf, William; Iglesias, Mar; Tardón, Adonina; Gress, Thomas M.; Barberá, Victor M.; Crnogorac-Jurcevic, Tatjana; Muñoz-Bellvís, Luis; Dominguez-Muñoz, J. Enrique; Renz, Harald; Balcells, Joaquim; Costello, Eithne; Ilzarbe, Lucas; Kleeff, Jörg; Kong, Bo; Mora, Josefina; O’Driscoll, Damian; Poves, Ignasi; Scarpa, Aldo; Yu, Jingru; Hidalgo, Manuel; Lawlor, Rita T.; Ye, Weimin; Carrato, Alfredo; Real, Francisco X.; Malats, Núria; Instituto de Salud Carlos III; Red Temática de Investigación Cooperativa en Cáncer, Spain; Sixth Framework Programme; Seventh Framework Programme; Associazione Italiana per la Ricerca sul Cancro; Cancer Focus Northern Ireland; VetenskapsrådetObjectives: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI). Design: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis. Results: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55). Conclusion: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.Item Extended-culture and culture-independent molecular analysis of the airway microbiota in cystic fibrosis following CFTR modulation with ivacaftor(Elsevier B.V., 2021-09-21) Einarsson, Gisli G.; Ronan, Nicola J.; Mooney, Denver; McGettigan, Clodagh; Mullane, David; NiChroinin, Muireann; Shanahan, Fergus; Murphy, Desmond M.; McCarthy, Mairead; McCarthy, Yvonne; Eustace, Joseph A.; Gilpin, Deirdre F.; Elborn, J. Stuart; Plant, Barry J.; Tunney, Michael M.; Seventh Framework ProgrammeBackground: Treatment with Ivacaftor provides a significant clinical benefit in people with cystic fibrosis (PWCF) with the class III G551D-CFTR mutation. This study determined the effect of CFTR modulation with ivacaftor on the lung microbiota in PWCF. Methods: Using both extended-culture and culture-independent molecular methods, we analysed the lower airway microbiota of 14 PWCF, prior to commencing ivacaftor treatment and at the last available visit within the following year. We determined total bacterial and Pseudomonas aeruginosa densities by both culture and qPCR, assessed ecological parameters and community structure and compared these with biomarkers of inflammation and clinical outcomes. Results: Significant improvement in FEV1, BMI, sweat chloride and levels of circulating inflammatory biomarkers were observed POST-ivacaftor treatment. Extended-culture demonstrated a higher density of strict anaerobic bacteria (p = 0.024), richness (p = 1.59*10−4) and diversity (p = 0.003) POST-treatment. No significant difference in fold change was observed by qPCR for either total bacterial 16S rRNA copy number or P. aeruginosa density for oprL copy number with treatment. Culture-independent (MiSeq) analysis revealed a significant increase in richness (p = 0.03) and a trend towards increased diversity (p = 0.07). Moreover, improvement in lung function, richness and diversity displayed an inverse correlation with the main markers of inflammation (p < 0.05). Conclusions: Following treatment with ivacaftor, significant improvements in clinical parameters were seen. Despite modest changes in overall microbial community composition, there was a shift towards a bacterial ecology associated with less severe CF lung disease. Furthermore, a significant correlation was observed between richness and diversity and levels of circulating inflammatory markers.Item Microbiome-immune interactions and relationship to asthma severity(Elsevier Inc., 2021-12-22) Trujillo, Juan; Lunjani, Nonhlanhla; Ryan, Dermot; O’Mahony, LiamMicrobial-derived factors are integral components of the molecular circuitry that regulates immune and metabolic functions required for host fitness and survival. Recent advances in culture-based methods and sequencing technologies have revealed previously unappreciated complex communities of bacteria, fungi, and viruses that inhabit the respiratory tract and whose composition and activity are correlated with acute and chronic inflammatory responses. In this article, we will summarize our knowledge to date on the role of the microbiota in severe asthma, acknowledging that data specific to severe asthma are currently limited.Item Advancing the evidence base for public policies impacting on dietary behaviour, physical activity and sedentary behaviour in Europe: the Policy Evaluation Network promoting a multidisciplinary approach(Elsevier, 2020-01) Lakerveld, Jeroen; Woods, Catherine; Hebestreit, Antje; Brenner, Hermann; Flechtner-Mors, Marion; Harrington, Janas M.; Kamphuis, Carlijn B. M.; Laxy, Michael; Luszczynska, Aleksandra; Mazzocchi, Mario; Murrin, Celine; Poelman, Maartje P.; Steenhuis, Ingrid; Roos, Gun; Steinacker, Jürgen M.; Stock, Christian C.; van Lenthe, Frank; Zeeb, Hajo; Zukowska, Joanna; Ahrens, Wolfgang; Joint Programming Initiative A healthy diet for a healthy life; Bundesministerium für Bildung und Forschung; Health Research Board; Ministero dell’Istruzione, dell’Università e della Ricerca; ZonMw; University of Auckland; Norges Forskningsråd; Narodowe Centrum Badań i Rozwoju; Institut National de la Recherche AgronomiqueNon-communicable diseases (NCDs) are the leading cause of global mortality. As the social and economic costs of NCDs have escalated, action is needed to tackle important causes of many NCD's: low physical activity levels and unhealthy dietary behaviours. As these behaviours are driven by upstream factors, successful policy interventions are required that encourage healthy dietary behaviours, improve physical activity levels and reduce sedentary behaviours of entire populations. However, to date, no systematic research on the implementation and evaluation of policy interventions related to these health behaviours has been conducted across Europe. Consequently, no information on the merit, gaps, worth or utility of cross-European policy interventions is available, and no guidance or recommendations on how to enhance this knowledge across European countries exists. As part of the Joint Programming Initiative "A Healthy Diet for a Healthy Life" (JPI HDHL), 28 research institutes from seven European countries and New Zealand have combined their expertise to form the Policy Evaluation Network (PEN). PEN's aim is to advance tools to identify, evaluate, implement and benchmark policies designed to directly or indirectly target dietary behaviours, physical activity, and sedentary behaviour in Europe, as well as to understand how these policies increase or decrease health inequalities. Using well-defined evaluation principles and methods, PEN will examine the content, implementation and impact of policies addressing dietary behaviour, physical activity levels and sedentary behaviour across Europe. It will realise the first steps in a bespoke health policy monitoring and surveillance system for Europe, and refine our knowledge of appropriate research designs and methods for the quantification of policy impact. It will contribute to our understanding of how to achieve successful transnational policy implementation and monitoring of these policies in different cultural, demographic or socioeconomic settings. PEN will consider equity and diversity aspects to ensure that policy actions are inclusive and culturally sensitive. Finally, based on three policy cases, PEN will illustrate how best to evaluate the implementation and impact of such policies in order to yield healthy diets and activity patterns that result in healthier lives for all European citizens.