Magnetic Resonance Imaging of synovitis without the use of intravenous gadolinium.

Synovitis is an important feature in arthritis and is commonly visualised using contrast enhanced magnetic resonance imaging (MRI). Currently, the reference standard for assessing synovitis is gadolinium enhanced MRI which requires an intravenous injection and carries significant potential risks such as nephrogenic systemic fibrosis. Removing the necessity for using gadolinium will reduce these risks and result in greater patient acceptance of MRI investigation of synovitis. The aims of this thesis were to investigate the use of MRI imaging sequences and include them in a novel non-contrast MRI protocol, The COSMOS protocol (contrast-obviated MRI scanning of synovitis) to identify synovitis in the knees of patients with osteoarthritis. Potential sequences, both qualitative and quantitative, that could be included in the COSMOS protocol were identified initially through (i) a comprehensive review of the literature and (ii) review of historic images within a large research centre. The sequences were then trialled, optimised and then assessed on a large cohort of patients with knee osteoarthritis in order to determine the protocol’s suitability to identify synovitis without contrast. The results of the new COSMOS protocol show that it is feasible and practical to delineate synovitis in the knee using MRI without the use of intravenous gadolinium contrast. The characteristics of the tissues within the knee can be measured using magnetisation transfer ratio and T1 values to provide empirical differentiation of structures. The identification of a distinct range in T1 values for synovitis provided data that was exploited to produce a further inversion recovery sequence that was optimised to supress synovitis in patients with knee osteoarthritis (OA). While further work is required to validate the COSMOS protocol, this thesis has demonstrated that it is possible to image synovitis without intravenous gadolinium contrast agents in a cohort of patients with a clinical diagnosis of OA knee

The Clinicians’ Skills, Capability, and Organisational Research Readiness (SCORR) Tool

A research-active healthcare workforce contributes to improved quality of care. Clinicians may be unaware that they are applying early research skills during their everyday practice. Greater understanding of their level of research attainment may improve their awareness and confidence in their research skills. This article describes the development of the Clinicians Skills, Capability, and Organisational Research Readiness (SCORR) Tool, a simple innovation that assesses and captures research skills and attainment at 1) clinician, and 2) organisational level. The SCORR Tool was initially developed to assess levels of research attainment and to promote discussion during annual appraisals for podiatrists working across secondary and community care in a northern region of England. The levels (1 to 5) of attainment recognise UK Health and Care Professions Council (HCPC) registration requirements for chiropodists/podiatrists (Standards 12 to 14). Following testing and feedback, research levels were adapted (Levels 0 to 5) to accommodate all healthcare professionals (with the exception of doctors and dentists). The SCORR Tool may be used individually by clinicians, or in collaboration with their manager, to better understand the level of research attainment and to prompt discussion to increase research activity. It may also be used across a workforce (e.g. during an appraisal) to understand the organisational research readiness. The SCORR Tool requires additional testing and evaluation to validate it as a tool for use across a variety of organisational environments

A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease

Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1. Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1. To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba(-/-) mice and the control littermate (gba(+/+)) by infecting differentiated primary cortical neurons in culture with an EF1 alpha-SV40T lentivirus. Immortalized gba(-/-) neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba(+/+) neurons. This null allele gba(-/-) mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies

The Prehabilitation Radiotherapy Exercise, smoking Habit cessation and Balanced diet Study (PREHABS) protocol to explore the feasibility of embedding behavioural modifications into the clinical pathway for patients undergoing radical radiotherapy for lung cancer

Patients with curable non-surgical lung cancer are often current smokers, have co-existing medical comorbidities and are treated with curative radiotherapy. To maximise the benefits of modern radiotherapy, there is an urgent need to optimise the patient’s health to improve survival and quality of life.Methods and analysis The Yorkshire Cancer Research-funded Prehabilitation Radiotherapy Exercise, smoking Habit cessation and Balanced diet Study (PREHABS) (L426) is a single-centre prospective feasibility study to assess embedding behavioural changes into the radical radiotherapy pathway of patients with lung cancer. Feasibility will be assessed by measuring acceptability, demand and implementation. The duration of the study is 24 months. PREHABS has two workstreams: the intervention study and the theory of change (ToC) study.Intervention study: PREHABS will commence at the R-IDEAL phase 2 trial (exploratory) based on existing evidence and includes support for smoking cessation, increasing activity and dietary well-being. Patients undergoing radical radiotherapy for lung cancer will be recruited from the oncology department at Leeds Teaching Hospitals NHS Trust (LTHT). ToC study: to maximise the acceptability and adherence to the PREHABS, we will use a ToC approach to qualitatively explore the key barriers and enablers of implementing a tailored programme of ‘prehabilitation’. The PREHABS ToC study participants will be recruited from patients with lung cancer undergoing radical radiotherapy and staff from the LTHT oncology department.Analysis The primary endpoint analysis will report the number of participants and adherence to the study interventions. Secondary endpoints include continued engagement with study interventions post-treatment. The analysis will focus on descriptive statistics. Thematic analysis of the qualitative data from the ToC study will identify consensus on intervention optimisation and delivery

"If we use the strength of diversity among researchers we can only improve the quality and impact of our research": Issues of equality, diversity, inclusion, and transparency in the process of applying for research funding

This paper sets out the recommendations that have emerged from a six-month-long exploration and discussion of the processes that take place before research is submitted for funding: the ‘pre-award’ environment. Our work concentrated on how this environment is experienced by researchers at all career stages and from a variety of backgrounds, demographics, and disciplines, as well as by research managers and research support professionals. In the later stages of our exploration, representatives from research funders were also involved in the discussions. The primary component of this project was an analysis of pre-award activities and processes at UK universities, using information collated from workshops with researchers and research management and support staff. The findings of this analysis were presented as a workflow diagram, which was then used to surface issues relating to equality, diversity, inclusion, and transparency in context. The workflow diagram and the issues highlighted by it were used to structure discussions at a symposium for a range of research stakeholders, held in Bristol, UK, in January 2023. The recommendations set out in this paper are drawn from discussions that took place at that event. This paper is not an exhaustive landscape analysis, nor a review of existing research and practice in the area of pre-award processes or of recent thinking on the topics of equality, diversity, and inclusion (EDI). Instead, it aims to summarise and encapsulate the suggestions put forward by the stakeholders during the symposium. These recommendations, from experienced professionals working in the field, are based on their encounters with the issues raised in the project. They do not solely relate to those working on pre-award processes, but may also apply to funders, policymakers, university leaders, and professional associations, since many of the challenges flagged in our research are systemic and cultural, and reach far beyond the research office

Patients' willingness and ability to participate actively in the reduction of clinical errors: a systematic literature review

This systematic review identifies the factors that both support and deter patients from being willing and able to participate actively in reducing clinical errors. Specifically, we add to our understanding of the safety culture in healthcare by engaging with the call for more focus on the relational and subjective factors which enable patients' participation (Iedema, Jorm, & Lum, 2009; Ovretveit, 2009). A systematic search of six databases, ten journals and seven healthcare organisations' web sites resulted in the identification of 2714 studies of which 68 were included in the review. These studies investigated initiatives involving patients in safety or studies of patients' perspectives of being actively involved in the safety of their care. The factors explored varied considerably depending on the scope, setting and context of the study. Using thematic analysis we synthesized the data to build an explanation of why, when and how patients are likely to engage actively in helping to reduce clinical errors. The findings show that the main factors for engaging patients in their own safety can be summarised in four categories: illness; individual cognitive characteristics; the clinician-patient relationship; and organisational factors. We conclude that illness and patients' perceptions of their role and status as subordinate to that of clinicians are the most important barriers to their involvement in error reduction. In sum, patients' fear of being labelled "difficult" and a consequent desire for clinicians' approbation may cause them to assume a passive role as a means of actively protecting their personal safety

TOR kinase complexes and cell migration

Cell migration is a fundamental process in a wide array of biological and pathological responses. It is regulated by complex signal transduction pathways in response to external cues that couple to growth factor and chemokine receptors. In recent years, the target of rapamycin (TOR) kinase, as part of either TOR complex 1 (TORC1) or TOR complex 2 (TORC2), has been shown to be an important signaling component linking external signals to the cytoskeletal machinery in a variety of cell types and organisms. Thus, these complexes have emerged as key regulators of cell migration and chemotaxis

RANTES/CCL5 and Risk for Coronary Events: Results from the MONICA/KORA Augsburg Case-Cohort, Athero-Express and CARDIoGRAM Studies

BACKGROUND: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. METHODS AND FINDINGS: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75-1.42] and 1.11 [0.81-1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years). CONCLUSIONS: High RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies

RANTES/CCL5 and risk for coronary events: Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies

Background: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. Methods and Findings: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±