36270 research outputs found
Sort by
Addressing methodological issues associated with using the Kidney Disease Quality of Life (KDQoL) questionnaire in a trial measuring the clinical and cost-effectiveness of nocturnal haemodialysis
No full textBackgroundThis thesis addresses methodological issues that arise during clinical trials measuring quality of life using the Kidney Disease Quality of Life (KDQoL) questionnaire. This thesis focuses on the use of statistical methods to account for dropouts when analysing the KDQoL and the use of statistical methods to allow for the KDQoL to be used in a cost-utility analysis.MethodsA systematic review assesses the current practice of trials using the KDQoL in their handling of dropouts and the implementation and reporting of the KDQoL as a quality of life measure. A patient level simulation demonstrates how the methods currently used to estimate the KDQoL scores respond to the presence of random and non-random dropouts. Novel methods including a standard joint model and joint model with competing risks of dropouts is then applied to two respective datasets. A novel prediction model for the estimation of EQ-5D-5L utility values from KDQoL responses is developed.ResultsThe systematic review highlights the underreporting of dropouts and an inconsistency in the reporting of the KDQoL. The simulation highlights the inadequacy of the current statistical methods used when non-random dropouts are present. A standard joint model presents issues when applied to KDQoL data due to the unique problem of dropouts due to transplants and death. A competing risk joint model is provided as an alternative. A comparison of statistical methods to predict EQ-5D-5L utility values supports the use of mixture modelling over standard linear models.ConclusionThis thesis demonstrates the inadequacy of current methods for handling dropouts in KDQoL data and proposes a competing risks joint model as a solution. While effective these methods require sufficient sample sizes and event numbers due to computational complexity. This thesis also provides researchers with the ability to estimate EQ-5D-5L utility values from KDQoL responses using a robust methodological framework.</p
The Role of the KCa3.1 Channel in Aortic Stenosis
No full textIntroduction: Aortic stenosis (AS) is the most common heart valve lesion requiring surgery. It is characterised by progressive fibrosis and calcification of the aortic valve (AV) leaflets. Despite its prevalence, no medical therapies have been proven to ameliorate disease progression. Myofibroblasts are key effector cells driving AV fibrosis owing to their exaggerated extracellular matrix production and contractile activity. KCa3.1 channels are expressed by myofibroblasts and promote pro-fibrotic activity in rodent hearts and several human organs by regulating myofibroblast secretion, proliferation, and contraction. However, the role of KCa3.1 in AS has not been explored.Methods: AVs were collected from patients with severe tricuspid AS undergoing surgical AV replacement. AV myofibroblasts were isolated from the AV tissue and cultured. KCa3.1 mRNA and protein expression were assessed in AS valve tissue, isolated myofibroblast cells and human ventricular fibroblasts using qRT-PCR and immunofluorescence. Patch clamp electrophysiology was used to confirm the presence of functional KCa3.1 channels in the plasma membrane. The effects of transforming growth factor β1 (TGFβ1, 10 ng/ml), and the selective KCa3.1 blocker senicapoc (100 nM) were evaluated on fibrotic mRNA expression, stress fibre formation, contractility, proliferation and wound healing. An ex vivo AS valve culture model was also developed and optimised for future anti-fibrotic drug testing.Results: KCa3.1 mRNA and protein expression were detected in all AS valves tested and in all isolated myofibroblasts (n=7 valves and n=8 myofibroblast cultures). Cultured AV myofibroblasts expressed functional KCa3.1 currents (n=5 myofibroblast cultures, n=13 cells measured), with currents elicited by the KCa3.1 opener 1-EBIO, and inhibited by senicapoc. Stimulation of myofibroblasts with TGFβ1 significantly increased KCa3.1 and α-smooth muscle actin (αSMA) mRNA expression. The TGFβ1-dependent upregulation of αSMA mRNA expression was significantly decreased by senicapoc. TGFβ1-dependent αSMA stress fibre formation and TGFβ1-dependent myofibroblast contraction in collagen gels were also significantly reduced by senicapoc.Conclusions: This is the first study to demonstrate KCa3.1 expression and function in human AS valve tissue and myofibroblasts. The findings identify KCa3.1 as a novel modulator of TGFβ1-dependent AV myofibroblast activation and contractility. Targeting KCa3.1 may represent a novel anti-fibrotic strategy in AS. Moreover, as senicapoc was well tolerated for 12 months in a phase 3 clinical trial for sickle cell disease, there is the potential for the rapid translation of these findings to the clinic.</p
Exploring chronic obstructive pulmonary disease (COPD) phenotypes: evaluating associations between molecular profile, airway microbiome and impact of anti-eosinophil treatment
No full textBackground: Chronic obstructive pulmonary disease (COPD) is characterised by persistent symptoms and airflow obstruction. In COPD there is heterogeneity in the airway inflammation and microbiome. Neutrophilic inflammation is the commonest pattern of airway inflammation in COPD but in some patients, there is eosinophilic inflammation. Biological drugs targeting cytokines associated with type 2-mediated immunity have had limited benefit in COPD in contrast to the substantial benefit in severe asthma suggesting that different mechanisms drive eosinophilic COPD and asthma.Methods: In sputum samples the airway microbiome in COPD was compared with healthy controls. The stability and strain change of an important pathogen was explored in stable state and exacerbations of COPD. Post hoc the effect on the airway microbiome in a randomised placebo-controlled trial of anti-interleukin-5 receptor monoclonal therapy (Benralizumab) was examined. Gene expression RNAseq of bronchial epithelial brushes was examined in COPD compared to asthma subjects with and without eosinophilic inflammation.Results: The microbiome in COPD was distinct from healthy controls and was independent of smoking history. At the phyla level there was a predominance of Proteobacteria in COPD in association with neutrophilic inflammation and Firmicutes in health. The airway pathogen, Moraxella catarrhalis, demonstrated substantial strain diversity with no specific strain associated with exacerbations. Benralizumab reduced total bacterial load and Streptococcus pneumoniae. Bronchial epithelial gene expression showed 12 genes were associated with eosinophilic inflammation in COPD in contrast to 1197 genes in asthma with only CST1 common to both.Conclusion: Microbial dysbiosis mediated by increased Proteobacteria is a feature of COPD, which was not promoted by anti-eosinophil therapy. Strain change of the respiratory pathogen Moraxella catarrhalis was not associated with exacerbations. Bronchial epithelial gene expression profiling suggests the molecular mechanisms of eosinophilic COPD and asthma are distinct.</p
Investigating the Role of Pharmacists in the Management of Chronic Kidney Disease
No full textChronic kidney disease (CKD) is a progressive condition characterised by a gradual loss in function and/or structure of the kidneys over time. With an estimated global prevalence of 9%, CKD is associated with reduced quality of life, high morbidity and mortality, in which those with CKD are five to ten times more likely to die prematurely than progressing to end-stage kidney disease. Pharmacists are well-positioned with their clinical knowledge in pharmacotherapy to manage people with CKD, where they deliver various interventions, such as managing cardiovascular risk factors, dose adjustment, and patient education.The main aim of this thesis was to identify clinical opportunities and supporting evidence for pharmacist interventions in CKD. An epidemiological analysis of a cross-sectional study conducted in a diverse CKD population in England sought to establish medication prescribing patterns and polypharmacy prevalence. The prevalence of polypharmacy and inappropriate prescribing was high in people with CKD, where factors such as age, CKD type (worsening CKD and/or being a KTR), and number of comorbidities increased the odds of having polypharmacy.A systematic review and meta-analysis of randomised controlled trials was conducted and found pharmacist interventions in people with CKD have a mixed effect on clinical, economic, and humanistic outcomes. Improvements were reported in outcomes such as systolic blood pressure and haemoglobin levels, but not in other outcomes such as diastolic blood pressure and creatinine.Finally, the plethora of outcomes from the review resulted in the development of a core outcome set (COS) in nephrology for pharmacist research studies via an e-Delphi consensus study. This is the first COS in nephrology that is intervention-specific and reflects outcomes that were of importance to various stakeholder groups and will help reduce research waste.</p
The Ecological Role of Bacteriophages in Chronic Obstructive Pulmonary Disease
No full textChronic obstructive pulmonary disease (COPD) is a progressive and inflammatory disease caused by long-term inhalation exposure to respiratory irritants. Sputum samples from COPD patients have a higher-than-average bacterial load present consisting of Proteobacteria, Actinobacteria and Firmicutes. Patients often experience exacerbations and require antibiotics and/or steroids to stabilize their condition, but this is undetermined if these bacterial shifts are commensal or pathogenic. Many of the bacteria found in COPD lungs are multi-drug-resistant and antimicrobial-resistant, leading to persistent infections and degradation of patients' lungs.Bacteriophages are predatory viruses that only infect bacteria and help meditate microbiomes. In the past few decades, bacteriophage presence and their potential impact within niche environments has been reported through metagenomic analysis. This scientific expansion has been used to understand diseases and biome shifts in various patient types but has not been observed in COPD. With the ability to uncover the presence of a phage virome in COPD lungs via metagenomics, a foundational framework could be built for later use in diagnosing patients. The added discovery and characterization of lytic phages against clinical bacterial isolates could then also expand the therapeutic applications available, and aid in patient condition and stability.This study expands the current collection of bacterial strains found within COPD lungs. This library was utilized in the isolation of five novel phages against known COPD strains, including Stenotrophomonas maltophilia and Enterobacter cloacae. Metagenomic analysis of sputum provided by various lung types resulted in the discovery of thousands of vOTUs, eight of which were determined as complete genomes and putative phages. The diversity, presence and abundance of these vOTUs is both comparable and contrastable between lung types, along with a core set of shared vOTUs in all lung types. All together this has built a framework for future phage microbiome lung analysis.</p
Contextualising ELSI in African Genomics
No full textGenomics is increasingly influencing healthcare globally, yet in many African contexts it remains unfamiliar outside specialist circles, with ethical, legal, and social implications (ELSI) often overlooked. This socio-legal analysis examines how law, ethics, and social context shape the implementation of genomics in Africa beyond biomedical considerations alone. It argues that Africa’s readiness for genomics depends not only on regulatory reform, but on embedding ELSI awareness and capacity across stakeholder groups. Strengthening ELSI can support African-led governance, data sovereignty, trust, and equitable benefit-sharing, while avoiding the uncritical adoption of Global North regulatory models.Poster accepted for presentation at the Festival of Genomics & Biodata 2026, London, UK, 28–29 January 2026.</p
The Biosocial Life of Nostalgia, Memory, and Emotion
No full textIncorporation of the body's biological processes has a long history of being tentatively applied in geography at the risk of being deemed ‘deterministic’. This paper, however, develops an original conceptual approach, ‘biosocial geography’, to consider the body's social and biological worlds in tandem. And in doing so, it demonstrates how a consideration of biological/neurological processes that enrich the study of memory and emotion. Specifically, this paper incorporates biological knowledge of neurological networks to enhance geography's understanding of nostalgia, a bittersweet emotional response to the past, to demonstrate how the processes of nostalgia can enrich an individual's connection with their immediate environment. Drawing upon in-depth interviews, mobile video ethnography, four biosensing measures (heart rate, electrodermal activity, skin temperature, and blood volume pulse), and GPS tracking from residents in three areas of Birmingham (UK), it is shown that nostalgia is a moment where the entanglement of the body and its surroundings establishes an emotional and memorial flow between bodies and space. This paper demonstrates a union of conceptual and methodological developments in the biological sciences to develop a novel way to investigate memory that incorporates knowledge from the cognitive/biological sciences and social sciences to enrich understandings of body, memory, emotion, and place.</p
Catalytic deoxygenation of methyl esters over unreduced NiCo/TiO2 catalyst for transport fuel application
No full textThe current study explored the novel production pathway of catalytic deoxygenation of methyl esters to upgrade into hydrocarbons suited for transport fuel application. Ni- and Co-based mono and bimetallic catalysts supported by TiO2 were developed to deoxygenate methyl esters under H2 and N2 atmospheres. Experimental results showed the influence of different reaction parameters on the conversion and hydrocarbon selectivity from methyl esters deoxygenation under non-pressurised conditions. The optimal experimental methyl esters conversion of 93.55 %, yielded 15.15 % alkanes and 25.16 % alkenes, which were obtained under H2 atmosphere at 370 °C with a 5 wt% catalyst loading. Statistical analysis indicated that H2 atmosphere and bimetallic NiCo/TiO2 catalyst were more suited for methyl esters deoxygenation, with temperature and time deemed as highly predictive parameters. The fuel properties of deoxygenated product were evaluated and was found to meet the EN 590 standards for viscosity and flash point. Although the H2 atmosphere deoxygenation showed a higher conversion of methyl esters, the N2 atmosphere under similar reaction conditions also yielded 78.36 % conversion with 9.55 % alkane and 18.11 % alkene selectivity, which is a potential environmentally friendly approach, thereby eliminating the use of H2 for the production process.</p
Association of symptoms at heart failure diagnosis with hospitalisation and mortality at 6 and 12 months: a retrospective cohort study using UK primary care health records
No full textBackground
We investigated symptoms reported before and after heart failure (HF) diagnosis and their associations with 3-month hospitalisation and mortality.
Objectives
To examine associations between symptoms recorded in primary care and short-term hospitalisation and mortality in HF patients.
Design
Landmark analysis using Royston-Parmar survival models at baseline (diagnosis), 6 and 12 months post-diagnosis.
Setting
Primary care database (Clinical Practice Research Datalink) linked to hospital and mortality data (1998–2020).
Participants
Adults (>40 years) with a first HF diagnosis.
Exposures
Shortness of breath, ankle swelling, oedema, fatigue, chest pain, depression and anxiety in the 3 months before diagnosis and at 6 and 12 months.
Outcomes
3-month all-cause hospitalisation and mortality; secondary outcomes included HF and non-cardiovascular hospitalisation.
Results
Among 86 882 HF patients (62 742 and 54 555 surviving to 6 and 12 months, respectively), the magnitude of symptom risk varied by timepoint. Specifically, the symptoms with the strongest associations with adverse outcomes were: depression for all-cause hospitalisation at diagnosis (HR: 1.26; 95% CI 1.15 to 1.39) and 6 months (1.46; 1.25 to 1.70); ankle swelling for mortality (1.49; 1.14 to 1.94) at 6 months and SOB for HF hospitalisation (1.18; 1.12 to 1.26) at diagnosis and 12 months (1.99; 1.68 to 2.35).
Conclusions
Symptoms persisted and were more prominent at 6 and 12 months post-diagnosis than at diagnosis.</p
Communicative liminality and its practices: A case of political journalists, social media and anonymous sourcing
No full textPolitical journalists have long used anonymous sourcing within their journalistic outputs. This form of non-attributed sourcing has developed within a context of increasing intensification between journalists and their political sources (or “mediated reflexivity”) and is often regarded as regulated and routinised by the practices and products of traditional journalism. Still, potentially opening the aperture on elite communicative activity are the more varied and less regulated forms of journalism that characterise the non-institutionalised space of social media. This paper explores this suggestion and charts UK political journalists’ anonymous sourcing practices that emerge within the liminal space of journalists’ social media accounts, a process we term “communicative liminality”. Its analysis reveals that journalists’ sourcing practices reflect the logics of this liminal space alongside a general journalistic interest in political conflict occurring across the period (i.e., 2016–2020). Both allow, in turn, anonymity to be used by the most powerful, but increasingly also by the less powerful as an “inter-elite strategic” tool in the political process. The paper suggests that such observations grant greater insight into the visibility of the interrelationship between journalists and politicians characterising this political age, including its moments of political disruption and conflict.</p