ORCID Profile
0000-0001-5494-5438
Current Organisations
Queen's University Belfast
,
University of Nottingham
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Publisher: Microbiology Society
Date: 2021
DOI: 10.1099/MIC.0.000987
Abstract: Staphylococcus aureus is the most prevalent organism isolated from the airways of people with cystic fibrosis (CF), predominantly early in life. Yet its role in the pathology of lung disease is poorly understood. In mice, and many experiments using cell lines, the bacterium invades cells or interstitium, and forms abscesses. This is at odds with the limited available clinical data: interstitial bacteria are rare in CF biopsies and abscesses are highly unusual. Bacteria instead appear to localize in mucus plugs in the lumens of bronchioles. We show that, in an established ex vivo model of CF infection comprising porcine bronchiolar tissue and synthetic mucus, S. aureus demonstrates clinically significant characteristics including colonization of the airway lumen, with preferential localization as multicellular aggregates in mucus, initiation of a small colony variant phenotype and increased antibiotic tolerance of tissue-associated aggregates. Tissue invasion and abscesses were not observed. Our results may inform ongoing debates relating to clinical responses to S. aureus in people with CF.
Publisher: Public Library of Science (PLoS)
Date: 04-09-2014
Publisher: Elsevier BV
Date: 11-2017
Publisher: American Thoracic Society
Date: 2019
Publisher: BMJ
Date: 09-2022
DOI: 10.1136/BMJOPEN-2021-056528
Abstract: Pulmonary exacerbations are associated with increased morbidity and mortality in people with cystic fibrosis (CF). There is no consensus about which outcomes should be evaluated in studies of pulmonary exacerbations or how these outcomes should be measured. Outcomes of importance to people with lived experience of the disease are frequently omitted or inconsistently reported in studies, which limits the value of such studies for informing practice and policy. To better standardise outcome reporting and measurement, we aim to develop a core outcome set for studies of pulmonary exacerbations in people with CF (COS-PEX) and consensus recommendations for measurement of core outcomes. Preliminary work for development of COS-PEX has been reported, including (1) systematic reviews of outcomes and methods for measurement reported in existing studies of pulmonary exacerbations (2) workshops with people affected by CF within Australia and (3) a Bayesian knowledge expert elicitation workshop with health professionals to ascertain outcomes of importance. Here we describe a protocol for the additional stages required for COS-PEX development and consensus methods for measurement of core outcomes. These include (1) an international two-round online Delphi survey and (2) consensus workshops to review and endorse the proposed COS-PEX and to agree with methods for measurement. National mutual ethics scheme approval has been provided by the Child and Adolescent Health Service Human Research Ethics Committee (RGS 4926). Results will be disseminated via consumer and research networks and peer-reviewed publications. This study is registered with the Core Outcome Measures in Effectiveness Trials database.
Publisher: BMJ
Date: 29-04-2021
DOI: 10.1136/THORAXJNL-2020-216085
Abstract: Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV 1 ) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV 1 decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of ‘normal’ (FEV 1 ≥90% predicted) and ‘mild lung disease’ (FEV 1 70%–89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques. The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article. Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups. Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised. To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled ‘Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis’, was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted.
Publisher: BMJ
Date: 10-2021
DOI: 10.1136/BMJRESP-2021-000877
Abstract: A standardised framework for selecting outcomes for evaluation in trials has been proposed by the Core Outcome Measures in Effectiveness Trials working group. However, this method does not specify how to ensure that the outcomes that are selected are causally related to the disease and the health intervention being studied. Causal network diagrams may help researchers identify outcomes that are both clinically meaningful and likely to be causally dependent on the intervention, and endpoints that are, in turn, causally dependent on those outcomes. We aimed to (1) develop a generalisable method for selecting outcomes and endpoints in trials and (2) apply this method to select outcomes for evaluation in a trial investigating treatment strategies for pulmonary exacerbations of cystic fibrosis (CF). We conducted a series of online surveys and workshops among people affected by CF. We used a modified Delphi approach to develop a consensus list of important outcomes. A workshop involving domain experts elicited how these outcomes were causally related to the underlying pathophysiological processes. Meaningful outcomes were prioritised based on the extent to which each outcome captured separate rather than common aspects of the underlying pathophysiological process. The 10 prioritised outcomes were: breathing difficulty ain, sputum production/clearance, fatigue, appetite, pain (not related to breathing), motivation/demoralisation, fevers/night sweats, treatment burden, inability to meet personal goals and avoidance of gastrointestinal symptoms. This proposed method for selecting meaningful outcomes for evaluation in clinical trials may improve the value of research as a basis for clinical decisions.
Publisher: Oxford University Press (OUP)
Date: 10-05-2016
DOI: 10.1093/JAC/DKW135
Abstract: Antibiotics are among the most important interventions in healthcare. Resistance of bacteria to antibiotics threatens the effectiveness of treatment. Systematic reviews of antibiotic treatments often do not address resistance to antibiotics even when data are available in the original studies. This omission creates a skewed view, which emphasizes short-term efficacy and ignores the long-term consequences to the patient and other people. We offer a framework for addressing antibiotic resistance in systematic reviews. We suggest that the data on background resistance in the original trials should be reported and taken into account when interpreting results. Data on emergence of resistance (whether in the body reservoirs or in the bacteria causing infection) are important outcomes. Emergence of resistance should be taken into account when interpreting the evidence on antibiotic treatment in randomized controlled trials or systematic reviews.
Publisher: European Respiratory Society (ERS)
Date: 28-05-2015
DOI: 10.1183/09031936.00225214
Abstract: Pseudomonas aeruginosa produces quorum sensing signal molecules that are potential biomarkers for infection. A prospective study of 60 cystic fibrosis patients with chronic P. aeruginosa, who required intravenous antibiotics for pulmonary exacerbations, was undertaken. Clinical measurements and biological s les were obtained at the start and end of the treatment period. Additional data were available for 29 of these patients when they were clinically stable. Cross-sectionally, quorum sensing signal molecules were detectable in the sputum, plasma and urine of 86%, 75% and 83% patients, respectively. They were positively correlated between the three biofluids. Positive correlations were observed for most quorum sensing signal molecules in sputum, plasma and urine, with quantitative measures of pulmonary P. aeruginosa load at the start of a pulmonary exacerbation. Plasma concentrations of 2-nonyl-4-hydroxy-quinoline (NHQ) were significantly higher at the start of a pulmonary exacerbation compared to clinical stability (p .01). Following the administration of systemic antibiotics, plasma 2-heptyl-4-hydroxyquinoline (p=0.02) and NHQ concentrations (p .01) decreased significantly. In conclusion, quorum sensing signal molecules are detectable in cystic fibrosis patients with pulmonary P. aeruginosa infection and are positively correlated with quantitative measures of P. aeruginosa . NHQ correlates with clinical status and has potential as a novel biomarker for P. aeruginosa infection.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-08-2020
DOI: 10.1097/CCM.0000000000004584
Abstract: There are over 4,000 trials conducted in people with coronavirus disease 2019. However, the variability of outcomes and the omission of patient-centered outcomes may diminish the impact of these trials on decision-making. The aim of this study was to generate a consensus-based, prioritized list of outcomes for coronavirus disease 2019 trials. In an online survey conducted in English, Chinese, Italian, Portuguese, and Spanish languages, adults with coronavirus disease 2019, their family members, health professionals, and the general public rated the importance of outcomes using a 9-point Likert scale (7–9, critical importance) and completed a Best-Worst Scale to estimate relative importance. Participant comments were analyzed thematically. International. Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public, and health professionals (including clinicians, policy makers, regulators, funders, and researchers). None. None. In total, 9,289 participants from 111 countries (776 people with coronavirus disease 2019 or family members, 4,882 health professionals, and 3,631 members of the public) completed the survey. The four outcomes of highest priority for all three groups were: mortality, respiratory failure, pneumonia, and organ failure. Lung function, lung scarring, sepsis, shortness of breath, and oxygen level in the blood were common to the top 10 outcomes across all three groups (mean 7.5, median ≥ 8, and 70% of respondents rated the outcome as critically important). Patients/family members rated fatigue, anxiety, chest pain, muscle pain, gastrointestinal problems, and cardiovascular disease higher than health professionals. Four themes underpinned prioritization: fear of life-threatening, debilitating, and permanent consequences addressing knowledge gaps enabling preparedness and planning and tolerable or infrequent outcomes. Life-threatening respiratory and other organ outcomes were consistently highly prioritized by all stakeholder groups. Patients/family members gave higher priority to many patient-reported outcomes compared with health professionals.
Publisher: Wiley
Date: 16-07-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-08-2020
DOI: 10.1097/CCM.0000000000004585
Abstract: The outcomes reported in trials in coronavirus disease 2019 are extremely heterogeneous and of uncertain patient relevance, limiting their applicability for clinical decision-making. The aim of this workshop was to establish a core outcomes set for trials in people with suspected or confirmed coronavirus disease 2019. Four international online multistakeholder consensus workshops were convened to discuss proposed core outcomes for trials in people with suspected or confirmed coronavirus disease 2019, informed by a survey involving 9,289 respondents from 111 countries. The transcripts were analyzed thematically. The workshop recommendations were used to finalize the core outcomes set. International. Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public and health professionals (including clinicians, policy makers, regulators, funders, researchers). None. None. Six themes were identified. “Responding to the critical and acute health crisis” reflected the immediate focus on saving lives and preventing life-threatening complications that underpinned the high prioritization of mortality, respiratory failure, and multiple organ failure. “Capturing different settings of care” highlighted the need to minimize the burden on hospitals and to acknowledge outcomes in community settings. “Encompassing the full trajectory and severity of disease” was addressing longer term impacts and the full spectrum of illness (e.g. shortness of breath and recovery). “Distinguishing overlap, correlation and collinearity” meant recognizing that symptoms such as shortness of breath had distinct value and minimizing overlap (e.g. lung function and pneumonia were on the continuum toward respiratory failure). “Recognizing adverse events” refers to the potential harms of new and evolving interventions. “Being cognizant of family and psychosocial wellbeing” reflected the pervasive impacts of coronavirus disease 2019. Mortality, respiratory failure, multiple organ failure, shortness of breath, and recovery are critically important outcomes to be consistently reported in coronavirus disease 2019 trials.
Publisher: Wiley
Date: 05-06-2013
Publisher: John Wiley & Sons, Ltd
Date: 07-10-2009
Publisher: Elsevier BV
Date: 03-2017
Publisher: Microbiology Society
Date: 10-2021
DOI: 10.1099/JMM.0.001420
Abstract: Introduction. Pseudomonas aeruginosa produces quorum sensing signalling molecules including 2-alkyl-4-quinolones (AQs), which regulate virulence factor production in the cystic fibrosis (CF) airways. Hypothesis/Gap statement. Culture can lead to condition-dependent artefacts which may limit the potential insights and applications of AQs as minimally-invasive biomarkers of bacterial load. Aim. We aimed to use culture-independent methods to explore the correlations between AQ levels and live P. aeruginosa load in adults with CF. Methodology. Seventy-five sputum s les at clinical stability and 48 paired sputum s les obtained at the beginning and end of IV antibiotics for a pulmonary exacerbation in adults with CF were processed using a viable cell separation technique followed by quantitative P. aeruginosa polymerase chain reaction (qPCR). Live P. aeruginosa qPCR load was compared with the concentrations of three AQs (HHQ, NHQ and HQNO) detected in sputum, plasma and urine. Results. At clinical stability and the beginning of IV antibiotics for pulmonary exacerbation, HHQ, NHQ and HQNO measured in sputum, plasma and urine were consistently positively correlated with live P. aeruginosa qPCR load in sputum, compared to culture. Following systemic antibiotics live P. aeruginosa qPCR load decreased significantly ( P .001) and was correlated with a reduction in plasma NHQ (plasma: r=0.463, P =0.003). Conclusion. In adults with CF, AQ concentrations correlated more strongly with live P. aeruginosa bacterial load measured by qPCR compared to traditional culture. Prospective studies are required to assess the potential of systemic AQs as biomarkers of P. aeruginosa bacterial burden.
Publisher: Elsevier BV
Date: 05-2012
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2021
Publisher: Wiley
Date: 27-12-2016
DOI: 10.1002/PPUL.23370
Abstract: Pulmonary infection and malnutrition in cystic fibrosis are associated with decreased survival. Glutamine has a possible anti-microbial effect, with a specific impact against Pseudomonas aeruginosa. We aimed to test the hypothesis that oral glutamine supplementation (21 g/day) for 8 weeks in adults with cystic fibrosis would decrease pulmonary inflammation and improve clinical status. The study design was a randomized double-blind placebo-controlled study design with an iso-nitrogenous placebo. The primary analysis was intention to treat, and the primary outcome was change in induced sputum neutrophils. Thirty-nine in iduals were recruited and thirty-six completed the study. Glutamine supplementation had no impact on any of the outcome measures in the intention-to-treat analysis. In the per protocol analysis, glutamine supplementation was associated with an increase in induced sputum neutrophils (P = 0.046), total cells (P = 0.03), and in Pseudomonas isolation agar colony forming units (P = 0.04) compared to placebo. There was no effect of glutamine supplementation on markers of pulmonary inflammation in the intention-to-treat analysis.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.JCF.2021.11.010
Abstract: Treatment for pulmonary exacerbations of cystic fibrosis (CF) can produce a range of positive and negative outcomes. Understanding which of these outcomes are achievable and desirable to people affected by disease is critical to agreeing to goals of therapy and determining endpoints for trials. The relative importance of outcomes resulting from treatment of these episodes are not reported. We aimed to (i) quantify the relative importance of outcomes resulting from treatment for pulmonary exacerbations and (ii) develop patient and proxy carer-reported weighted outcome measures for use in adults and children, respectively. A discrete choice experiment (DCE) survey was conducted. Participants were asked to make a series of hypothetical decisions about treatment for pulmonary exacerbations to assess how they make trade-offs between different attributes of health. Data were analysed using a conditional logistic regression model. The correlation coefficients from these data were rescaled to enable generation of a composite health outcome score between 0 and 100 (worst to best health state). 362 in iduals participated (167 people with CF and 195 carers) of these, 206 completed the survey (56.9%). Most participants were female and resided in Australia. Difficult ainful breathing had the greatest impact on the preferred health state amongst people with CF and carers alike. Avoidance of gastrointestinal problems also heavily influenced decision-making. These data should be considered when making treatment decisions and determining endpoints for trials. Further research is recommended to quantify the preferences of children and to determine whether these align with those of their carer(s).
Publisher: Informa UK Limited
Date: 04-01-2022
DOI: 10.1080/09638237.2021.2022637
Abstract: The coronavirus (COVID-19) pandemic has seen a global surge in anxiety, depression, post-traumatic stress disorder (PTSD), and stress. This study aimed to describe the perspectives of patients with COVID-19, their family, health professionals, and the general public on the impact of COVID-19 on mental health. A secondary thematic analysis was conducted using data from the COVID-19 COS project. We extracted data on the perceived causes and impact of COVID-19 on mental health from an international survey and seven online consensus workshops. We identified four themes (with subthemes in parenthesis): anxiety amidst uncertainty (always on high alert, ebb and flow of recovery) anguish of a threatened future (intense frustration of a changed normality, facing loss of livelihood, trauma of ventilation, a troubling prognosis, confronting death) bearing responsibility for transmission (fear of spreading COVID-19 in public overwhelming guilt of infecting a loved one) and suffering in isolation (severe solitude of quarantine, sick and alone, separation exacerbating grief). We found that the unpredictability of COVID-19, the fear of long-term health consequences, burden of guilt, and suffering in isolation profoundly impacted mental health. Clinical and public health interventions are needed to manage the psychological consequences arising from this pandemic.
Publisher: Elsevier BV
Date: 11-2020
Publisher: European Respiratory Society (ERS)
Date: 07-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-01-2021
DOI: 10.1097/CCM.0000000000004817
Abstract: Respiratory failure, multiple organ failure, shortness of breath, recovery, and mortality have been identified as critically important core outcomes by more than 9300 patients, health professionals, and the public from 111 countries in the global coronavirus disease 2019 core outcome set initiative. The aim of this project was to establish the core outcome measures for these domains for trials in coronavirus disease 2019. Three online consensus workshops were convened to establish outcome measures for the four core domains of respiratory failure, multiple organ failure, shortness of breath, and recovery. International. About 130 participants (patients, public, and health professionals) from 17 countries attended the three workshops. None. Respiratory failure, assessed by the need for respiratory support based on the World Health Organization Clinical Progression Scale, was considered pragmatic, objective, and with broad applicability to various clinical scenarios. The Sequential Organ Failure Assessment was recommended for multiple organ failure, because it was routinely used in trials and clinical care, well validated, and feasible. The Modified Medical Research Council measure for shortness of breath, with minor adaptations (recall period of 24 hr to capture daily fluctuations and inclusion of activities to ensure relevance and to capture the extreme severity of shortness of breath in people with coronavirus disease 2019), was regarded as fit for purpose for this indication. The recovery measure was developed de novo and defined as the absence of symptoms, resumption of usual daily activities, and return to the previous state of health prior to the illness, using a 5-point Likert scale, and was endorsed. The coronavirus disease 2019 core outcome set recommended core outcome measures have content validity and are considered the most feasible and acceptable among existing measures. Implementation of the core outcome measures in trials in coronavirus disease 2019 will ensure consistency and relevance of the evidence to inform decision-making and care of patients with coronavirus disease 2019.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.JCF.2021.08.030
Abstract: Pseudomonas aeruginosa produces specific signalling molecules, 2-alkyl-4-quinolones (AQs) that are detectable in the sputum of adults with cystic fibrosis (CF) and who have pulmonary infection with this opportunistic pathogen. This study aimed to determine whether AQs could be detected in saliva of patients with CF and known infection with Pseudomonas aeruginosa. Saliva and sputum s les were obtained from 89 adults with CF and analyzed using liquid chromatography-tandem mass spectrometry. AQs were detected in 39/89 (43.8%) saliva s les and 70/77(90.9%) sputum s les. Salivary AQs had a sensitivity of 50% (95%CI 37.8 62.2), specificity of 100% (95%CI 47.8 100), when compared to a molecular microbiological measure of P. aeruginosa in sputum as measured using polymerase chain reaction. Specific AQs produced by P. aeruginosa can be detected in the saliva and warrant investigation as potential non-invasive biomarkers of pulmonary P. aeruginosa.
Publisher: Elsevier BV
Date: 09-2023
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Alan Smyth.