HRB Clinical Research Facility at UCC - Journal Articles

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    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 Programme
    Background: 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.
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    Microbiome-immune interactions and relationship to asthma severity
    (Elsevier Inc., 2021-12-22) Trujillo, Juan; Lunjani, Nonhlanhla; Ryan, Dermot; O’Mahony, Liam
    Microbial-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.
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    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 Agronomique
    Non-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.
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    Open-label follow-on study evaluating the efficacy, safety, and quality of life with extended daily oral immunotherapy in children with peanut allergy
    (John Wiley & Sons, Inc., 2021-07-28) Fernandez-Rivas, Montserrat; Vereda, Andrea; Vickery, Brian P.; Sharma, Vibha; Nilsson, Caroline; Muraro, Antonella; Hourihane, Jonathan O'B.; DunnGalvin, Audrey; du Toit, George; Blumchen, Katharina; Beyer, Kirsten; Smith, Alex; Ryan, Robert; Adelman, Daniel C.; Jones, Stacie M.; Aimmune Therapeutics
    Background: The benefit of daily administration of Peanut (Arachis hypogaea) Allergen Powder-dnfp (PTAH)-formerly AR101-has been established in clinical trials, but limited data past the first year of treatment are available. This longitudinal analysis aimed to explore the impact of continued PTAH therapeutic maintenance dosing (300 mg/day) on efficacy, safety/tolerability, and food allergy-related quality of life.Methods: We present a subset analysis of PALISADE-ARC004 participants (aged 4-17 years) who received 300 mg PTAH daily for a total of similar to 1.5 (Group A, n = 110) or similar to 2 years (Group B, n = 32). Safety assessments included monitoring the incidence of adverse events (AEs), accidental exposures to food allergens, and adrenaline use. Efficacy was assessed by double-blind, placebo-controlled food challenge (DBPCFC); skin prick testing; peanut-specific antibody assays; and Food Allergy Quality of Life Questionnaire (FAQLQ) and Food Allergy Independent Measure (FAIM) scores.Results: Continued maintenance with PTAH increased participants' ability to tolerate peanut protein: 48.1% of completers in Group A (n = 50/104) and 80.8% in Group B (n = 21/26) tolerated 2000 mg peanut protein at exit DBPCFC without dose-limiting symptoms. Immune biomarkers showed a pattern consistent with treatment-induced desensitization. Among PTAH-continuing participants, the overall and treatment-related exposure-adjusted AE rate decreased throughout the intervention period in both groups. Clinically meaningful improvements in FAQLQ and FAIM scores over time suggest a potential link between increased desensitization as determined by the DBPCFC and improved quality of life.Conclusions: These results demonstrate that daily PTAH treatment for peanut allergy beyond 1 year leads to an improved safety/tolerability profile and continued clinical and immunological response.
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    Treatment estimands in clinical trials of patients hospitalised for COVID-19: Ensuring trials ask the right questions
    (BioMed Central Ltd, 2020) Kahan, Brennan C.; Morris, Tim P.; White, Ian R.; Tweed, Conor D.; Cro, Suzie; Dahly, Darren; Pham, Tra My; Esmail, Hanif; Babiker, Abdel; Carpenter, James R.; Medical Research Council
    When designing a clinical trial, explicitly defining the treatment estimands of interest (that which is to be estimated) can help to clarify trial objectives and ensure the questions being addressed by the trial are clinically meaningful. There are several challenges when defining estimands. Here, we discuss a number of these in the context of trials of treatments for patients hospitalised with COVID-19 and make suggestions for how estimands should be defined for key outcomes. We suggest that treatment effects should usually be measured as differences in proportions (or risk or odds ratios) for outcomes such as death and requirement for ventilation, and differences in means for outcomes such as the number of days ventilated. We further recommend that truncation due to death should be handled differently depending on whether a patient- or resource-focused perspective is taken; for the former, a composite approach should be used, while for the latter, a while-alive approach is preferred. Finally, we suggest that discontinuation of randomised treatment should be handled from a treatment policy perspective, where non-adherence is ignored in the analysis (i.e. intention to treat).