3,743 research outputs found

    The PREVENT Study: Preventing hospital admissions attributable to gout

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    BackgroundGout is the most common form of inflammatory arthritis, affecting 1 in 40 people in the UK. Despite highly effective treatments, hospital admissions for gout flares have doubled in England over the last 20 years. Many of these admissions may have been prevented if optimal gout management had been delivered to patients.Objectives1. Describe the epidemiology of gout management in primary and secondary care in the UK.2. Develop an intervention package for implementation during hospitalisations for gout flares, with the aim of improving care and reducing hospitalisations.3. Implement and evaluate this intervention in people hospitalised for gout.MethodsI used population-level health datasets (CPRD, OpenSAFELY, NHS Digital Hospital Episode Statistics) to evaluate outcomes for people with incident gout diagnoses over a 20-year period. I used multivariable regression and survival modelling to analyse factors associated with outcomes, including: i) initiation of urate-lowering therapies (ULT); ii) attainment of serum urate targets; and iii) hospitalisations for gout flares.With extensive stakeholder input, I developed an evidence-based intervention package to optimise hospital gout care. This incorporated the findings of a systematic literature review and process mapping of the admitted patient journey in a cohort of hospitalised gout patients. My intervention consisted of a care pathway, based upon British (BSR), European (EULAR) and American (ACR) gout management guidelines, which encouraged ULT initiation prior to discharge, followed by a nurse-led, post-discharge review to facilitate handover to primary care. I implemented this intervention in patients hospitalised for gout flares at King’s College Hospital over a 12-month period, and evaluated outcomes including ULT initiation, urate target attainment and re-admission rates.ResultsIn the UK, between 2004 and 2020, I showed that only 29% of patients with gout were initiated on ULT within 12 months of diagnosis, while only 36% attained urate targets. No significant improvements in these outcomes were observed after publication of updated BSR and EULAR gout management guidelines. Comorbidities, including chronic kidney disease, heart failure and obesity, associated with increased odds of ULT initiation but decreased odds of attaining urate targets. For patients who were diagnosed with gout during the COVID-19 pandemic, I showed that ULT initiation improved modestly, relative to before the pandemic, while urate target attainment trends were similar. Underlying these trends was a 31% decrease in incident gout diagnoses in England during the first year of the pandemic.Using linked primary and secondary care data, I showed that the risk of hospitalisations for gout flares is greatest within the first 6 months after diagnosis. ULT initiation is associated with more hospitalisations for flares within the first 6 months of diagnosis, but a reduced risk of hospitalisations beyond 12 months; particularly when urate targets are attained.After process mapping the admitted patient journey and systematically appraising the evidence base, I developed and implemented a multi-faceted intervention at King’s College Hospital, with the aim of improving hospital gout care. Following implementation of this intervention, the proportion of hospitalised gout patients who initiated ULT increased from 49% to 92%; more patients achieved serum urate targets; and there were 38% fewer repeat hospitalisations for gout flares.ConclusionsAt a population level, ULT initiation and urate target attainment remain sub-optimal for people with gout in the UK, despite updated management guidelines. Initiation of ULT is associated with long-term reductions in hospitalisations for flares; however, only a minority of patients hospitalised for gout flares are initiated on ULT. After designing and implementing a strategy to optimise hospital gout care, over 90% of patients were initiated on ULT, urate target attainment improved, and repeat hospitalisations decreased. My findings suggest that improved primary-secondary care integration is essential if we are to reverse the epidemic of gout hospitalisations

    Regional variation in diagnosis, prognosis and treatment of Guillain-Barré syndrome

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    Genomic investigation of antimicrobial resistant enterococci

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    Enterococcus faecium and Enterococcus faecalis are important causes of healthcare-associated infections in immunocompromised patients. Enterococci thrive in modern healthcare settings, being able to resist killing by a range of antimicrobial agents, persist in the environment, and adapt to changing circumstances. In Scotland, rates of vancomycin resistant E. faecium (VREfm) have risen almost 150% in recent years leaving few treatment options and challenging healthcare delivery. Resistance to the last line agent linezolid has also been detected in E. faecalis. Whole genome sequencing (WGS) allows investigation of the population structure and transmission of microorganisms, and identification of antimicrobial resistance mechanisms. The aim of this thesis was to use WGS to understand the molecular epidemiology of antimicrobial resistant enterococci from human healthcare settings in Scotland. Analysis of some of the earliest identified Scottish linezolid-resistant E. faecalis showed the resistance mechanism, optrA, was present in unrelated lineages and in different genetic elements, suggesting multiple introductions from a larger reservoir. To inform transmission investigations, within-patient diversity of VREfm was explored showing ~30% of patients carried multiple lineages and identifying a within-patient diversity threshold for transmission studies. WGS was then applied to a large nosocomial outbreak of VREfm, highlighting a complex network of related variants across multiple wards. Having examined within-hospital transmission, the role of regional relationships was investigated which showed that VREfm in Scotland is driven by multiple clones transmitted within individual Health Boards with occasional spread between regions. The most common lineage in the national collection (ST203) was estimated to have been present in Scotland since around 2005, highlighting its persistence in the face of increasing infection prevention and control measures. This thesis provides a starting point for genomic surveillance of enterococci in Scotland, and a basis for interventional studies aiming to reduce the burden of enterococcal infections."This work was supported by the Chief Scientist Office (Scotland) [grant number SIRN/10]; the Wellcome Trust [grant numbers 105621/Z/14/Z, 206194]; and the BBSRC [grant number BB/S019669/1]."—Fundin

    An examination of the verbal behaviour of intergroup discrimination

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    This thesis examined relationships between psychological flexibility, psychological inflexibility, prejudicial attitudes, and dehumanization across three cross-sectional studies with an additional proposed experimental study. Psychological flexibility refers to mindful attention to the present moment, willing acceptance of private experiences, and engaging in behaviours congruent with one’s freely chosen values. Inflexibility, on the other hand, indicates a tendency to suppress unwanted thoughts and emotions, entanglement with one’s thoughts, and rigid behavioural patterns. Study 1 found limited correlations between inflexibility and sexism, racism, homonegativity, and dehumanization. Study 2 demonstrated more consistent positive associations between inflexibility and prejudice. And Study 3 controlled for right-wing authoritarianism and social dominance orientation, finding inflexibility predicted hostile sexism and racism beyond these factors. While showing some relationships, particularly with sexism and racism, psychological inflexibility did not consistently correlate with varied prejudices across studies. The proposed randomized controlled trial aims to evaluate an Acceptance and Commitment Therapy intervention to reduce sexism through enhanced psychological flexibility. Overall, findings provide mixed support for the utility of flexibility-based skills in addressing complex societal prejudices. Research should continue examining flexibility integrated with socio-cultural approaches to promote equity

    Placental origins of health & disease:Therapeutic opportunities

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    Regional variation in diagnosis, prognosis and treatment of Guillain-Barré syndrome

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    Placental origins of health & disease:Therapeutic opportunities

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    Investigating the role of complement in the pathogenesis of pre-eclampsia in previously healthy pregnant women, and in high-risk groups.

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    Pre-eclampsia (PE) is a leading cause of obstetric morbidity and mortality. Certain groups of women, including those with chronic kidney disease (CKD) and those of sub-Saharan African (SSA) ethnicity, are at particularly high risk. There remains no definitive treatment other than expedited delivery of baby and placenta. Previous studies suggest a role for complement dysregulation in the pathogenesis of PE, but results are often conflicting, and it remains unclear whether changes in circulating complement concentrations reflect a general heightened inflammatory state in PE or are directly associated with placental complement-mediated injury. This thesis tested the hypothesis that PE is associated with excessive complement activation within placental tissue, with concurrent complement activation within the maternal and fetal circulation, and that groups with a high prevalence of PE, and of PE with severe features (women with CKD and women of SSA ethnicity) would exhibit a greater degree of systemic complement activation. Three arms of research were conducted, and I report: • In a cohort of previously healthy women, PE was associated with significant placental complement deposition, associated with concurrent changes in maternal and fetal circulating complement markers (reduced maternal properdin and C4, and elevated maternal and fetal Ba). Placental C4d deposition was strongly correlated with maternal properdin and C4, suggesting that those patients with the most excessive changes in circulating markers of complement activation also have the greatest extent of placental complement-mediated damage. • There was no evidence of excessive complement activation in the maternal circulation in superimposed PE in a cohort of women with CKD. However, raised Ba levels were associated with adverse pregnancy outcomes in women with CKD. • There was no evidence of excessive complement activation in PE in a Ghanaian cohort of women of SSA ethnicity when compared to healthy pregnant controls. However, pregnant women of SSA ethnicity did have significantly elevated levels of C5b-9, serum free light chains, and immunoglobulin G, when compared to the UK-recruited cohorts; suggestive of a baseline elevated inflammatory state. The results suggest that inhibition of complement activation is a potential therapeutic target for certain groups of women with PE. However, PE is a heterogenous syndrome and additional pathophysiological mechanisms may contribute to the development of disease in women with CKD and women of SSA ethnicity

    Idiopathic inflammatory myopathies and cancer : familial risk, genetics and consequences

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    Idiopathic inflammatory myopathies (IIMs) are a group of rare rheumatic inflammatory diseases (RIDs), characterised by a diverse range of clinical, serological and histopathological characteristics, with muscle weakness as a shared hallmark. While advancements in disease management have improved the survival rates of patients with IIM, the mortality rate among patients with IIM is still higher than the general population, mainly due to association with comorbidities such as cancer. The pathogenesis of IIM, the pathological link between IIM and cancer and the impact of cancer on the survival of patients with IIM remain a subject of uncertainty. The rarity and heterogeneity inherent in IIM pose significant challenges in filing these knowledge gaps. This thesis encompasses five studies, which aimed at addressing research questions concerning the genetic contribution to IIM and its link with other autoimmune diseases and cancer, as well as the disease burden in the context of cancer in a large representative population of patients with IIM. Study I was a population-based case-control family study including 7,615 first-degree relatives of 1,620 patients with IIM diagnosis between 1997 and 2016 and 37,309 first-degree relatives of 7,797 matched comparators without IIM. Patients with IIM were four times more likely to have at least one first-degree relative affected by IIM compared to matched comparators without IIM. The heritability of IIM, a proportion of the phenotypic variance that can be explained by additive genetic variance, was 22% in the Swedish population. Study II, with the same study population as in Study I, analysed the familial associations between IIM and a variety of autoimmune diseases under a causal framework. We found shared familial factors between IIM and other RIDs, inflammatory bowel diseases, autoimmune thyroid diseases and celiac disease. Study III, with a similar study population and analytical approach as in Study II, comprehensively investigated the familial co-aggregation of IIM and cancer. We did not observe a familial association between IIM and cancer overall but modification effect by sex was noted: there was a modest familial association (adjusted odds ratio=1.39) with cancer in male first-degree relatives of patients with IIM. We also found that offspring of patients with IIM were more likely to have a cancer diagnosis at age younger than 50 years compared to those of matched comparators without IIM. In the exploratory analysis by specific cancer types, findings suggest that IIM shared familial factors with myeloid malignancies and liver cancer. Study IV explored genetic correlation between IIM and B-cell lymphomas via a cross-trait secondary analysis using summary statistics from genome-wide associations studies of IIM and four common B-cell lymphoma subtypes including diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma. We detected a limited number of genomic loci, predominantly within the human leukocyte antigen region, demonstrating significant genetic correlations between IIM and common Bcell lymphoma subtypes. Study V, a cohort study, followed 1,826 patients to (first and second) cancer and death (overall and cause-specific death) events since IIM diagnosis for more than 20 years. Compared to patients with no cancer diagnosis after IIM, patients with a first cancer diagnosis after IIM faced a greater five-year mortality (22% versus 49%). This excessive risk was due to an increased risk of death from cancer. In patients with a first cancer diagnosis after IIM, the one-year risk of having a second primary cancer was 11% and having a second cancer diagnosis slightly increased the risk of death. We also reported several prognostic factors associated with increased risks of cancer and death (overall, from cancer and from other causes). This thesis offers useful insight into the role of genetics in IIM pathogenesis and its connections with other autoimmune diseases and cancer, as well as the impact of cancer on the survival of patients with IIM. The observed familial aggregation of IIM and familial associations between IIM and other autoimmune diseases suggest genetic involvement in the development of IIM. Family history of IIM, other RIDs, inflammatory bowel diseases, autoimmune thyroid diseases and celiac disease may serve as indicators pointing towards an IIM diagnosis. Missing heritability is suggested by the discrepancy between our family-based heritability and the SNP-based heritability, implying yet-to-be discovered genetic variants associated with IIM. The acquired knowledge of shared familial factors between IIM and other autoimmune diseases may inform future genetic studies aiming to uncover novel IIMassociated genetic variants. There is a limited shared familial/genetic susceptibility between IIM and cancer. The human leukocyte antigen region plays an important role in the limited shared genetic susceptibility between IIM and common B-cell lymphoma subtypes. IIM concomitant with cancer leads to a substantial increase in mortality, mainly due to cancer. Future research should focus on reducing cancer-related disease burden in patients with IIM

    Multiplexed High-Resolution Imaging Approach to Decipher the Cellular Heterogeneity of the Kidney and its Alteration in Kidney Disease and Nephrolithiasis

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    Indiana University-Purdue University Indianapolis (IUPUI)Kidney disease and nephrolithiasis both present a major burden on the health care system in the US and worldwide. The cellular and molecular events governing the pathogenesis of these diseases are not fully understood. We propose that defining the cellular heterogeneity and niches in human and mouse kidney tissue specimens from controls and various models of renal disease could provide unique insights into the molecular pathogenesis. For that purpose, a multiplexed fluorescence imaging approach using co-detection by Indexing (CODEX) was used, using a panel of 33 and 38 markers for mouse and human kidney tissues, respectively. A customized computational analytical pipeline was developed and applied to the imaging data using unsupervised and/or semi-supervised machine learning and statistical approaches. The goal was to identify various cell populations present within the tissues, as well as identify unique cellular niches that may be altered with disease and/or injury. In mice, we examined disease models of acute kidney injury (AKI) and in human tissues we analyzed specimens from patients with AKI, IgA nephropathy, chronic kidney disease, systemic lupus erythematosus, and nephrolithiasis. In both mice and humans, the disease and reference samples show similar broad cell populations for the main segments of the nephron, endothelium, as well as similar groups of immune cells, such as resident macrophages and neutrophils. When comparing between health and disease, however, a change in the distribution of few sub-populations occurred. For example, in human kidney tissues, the abundance and distribution of a subpopulation of proximal tubules positive for THY1 (a marker of differentiation and repair), was markedly reduced with disease. Changes observed in mouse tissues included shifts in the immune cell population types and niches with disease. We propose that our analytical workflow and the observed changes in situ will play an important role in deciphering the pathogenesis of kidney disease
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