“Being Human”: A Grounded Theory of Complexity and Serendipity in Cancer Clinical Trials.

Abstract Background Cancer presents a complex and intractable disease resulting in millions of deaths worldwide each year. As a metastatic disease bearing metamorphic characteristics, cancer’s emergent properties continue to challenge science, medicine, and society. Cancer research is a specialist field crucial to the advancement of patient treatment and care, yet it faces growing challenges due to the complex nature of an evolving disease, stratified treatments, and intensive trial protocols, compounded by increasing global disease burdens. Human ingenuity and resiliency are central to overcoming the greatest challenges facing contemporary populations, achieved through research innovation and knowledge exchange across ranging disciplines. Improving population health and patient-centred outcomes stands at the fore of global challenges facing society in the twenty first century, requiring novel and dynamic responses to increasing chronic disease burdens and exposure risks to emergent viral pathogens. Aims The aim of this thesis was to understand the nature of cancer clinical trial operational delivery, evaluating challenges and burdens of professionals and patients participating in cancer research studies. The nature of multi-agency working and transdisciplinarity across health sciences is as complex as the biological and societal challenges that their research seeks to address. Establishing sustainable, cohesive, and collaborative relationships across the medical continuum is pivotal to solving persistent challenges of complex diseases and societal burdens. The study sought to develop a contextualised grounded theory elucidating situated challenges and complexity experienced at NHS sites in the UK. The purpose of the grounded theory would be to support the development of enhanced, person-centred models of clinical research operational delivery, which could respond to emergent and dynamically adaptive healthcare and epidemiological population needs. Methods Evaluating Follow-up and Complexity in cancer Clinical Trials (EFACCT), the study presented in this thesis, was conducted at ranging NHS secondary care sites in England and Scotland. Drawing on constructivist grounded theory (Charmaz, 2006), the multi-faceted realities of cancer clinical trial delivery are unveiled, using a mixed methods–grounded theory (MM-GT) design. The comprehensive, contextual evaluation combines evidence from quantitative and qualitative paradigms, using inductive and deductive methods. The study drew together multifaceted perspectives and values of 165 participants from six studies; Delphi, questionnaire, and interview studies, separated into patient and professional cohorts. Results The research provides original insights into the nature of cancer research delivery, its challenges and complexities, highlighting the importance of coherency in healthcare systems. The Constructivist Grounded Theory presented in this thesis, provides an organising framework and practical model for managing and embracing transformative learning and practice in response to dynamically evolving challenges that exist within complex healthcare delivery systems and networks. The original data generated provides new knowledge on the human aspects of clinical research and the contexts for its practice. The situated experiences led to the development of a grounded theory of human perceptions of complexity and serendipity in clinical research and the conception of a Prismatic Coherence Model (PCM) for the evaluation and designing of patient care and follow-up and the effective operational management of complex relationships, practices and processes existing within adaptive clinical research and healthcare delivery systems. PCM is an inclusive and responsive strategic design approach, sensitive to variable contexts and system complexities, and promotes transdisciplinarity in order to advance opportunities, knowledge and resources to advance population health through clinical research

A Protocol for an Evaluation Study of Patient Follow-Up and Cancer Clinical Trial Complexity: the EFACCT study.

Abstract Background Clinical research delivery is crucial in advancing treatment and care options for cancer. There is a burgeoning problem internationally in delivering cancer trials due to complex protocols, stratified treatments and increasing patient populations in follow-up with extended needs. The EFACCT study will evaluate the phenomena of cancer clinical trial delivery at NHS secondary care sites identifying burdens and implications for participants and organisations. Method This mixed-methods study adopting grounded theory will analyse operational processes and protocols at sites delivering Phase I-IV cancer trials for commercial and non-commercial studies. Research professionals and cancer patients who have participated in clinical trials will contribute to the development of an objective methodology defining and quantifying trial complexity, intensity and workload to enhance models of trial delivery. This in-depth study involving a two-arm e-Delphi, questionnaires, semi-structured interviews as well as trial documentation, database and systematic reviews will optimise clinical trial performance data in combination with qualitative evidence to form optimal models for cancer clinical trial delivery. Data from 12 geographically dispersed sites will be synthesised and continually compared until saturation is achieved. A total UK sample of 185 participants and documentation sample of 100 studies incorporates theoretical, purposive, quota and snowball sampling techniques leveraging the benefits of health informatics and rich participant contextual data. Results Data analysis will include descriptive statistics, thematic content analysis, theoretical, open, axial and selective coding and constant comparison methods. Statistical summaries will use measures of central tendency and levels of dispersion. Conclusion The study outcomes will involve the implementation of a trial rating and complexity assessment tool (TRACAT) and an evaluative theoretical model for cancer research operational management. These elements will create new knowledge supporting future research models, strategic planning, trial implementation and evaluation alongside the provision of a mechanism to optimise recruitment and enhance patient outcomes

Evaluating follow- up and complexity in cancer clinical trials (EFACCT): an eDelphi study of research professionals’ perspectives.

Objectives: To evaluate patient follow-up and complexity in cancer clinical trial delivery, using consensus methods to: (1) identify research professionals’ priorities, (2) understand localised challenges, (3) define study complexity and workloads supporting the development of a trial rating and complexity assessment tool (TRACAT). Design: A classic eDelphi completed in three rounds, conducted as the launch study to a multiphase national project (evaluating follow-up and complexity in cancer clinical trials). Setting: Multicentre online survey involving professionals at National Health Service secondary care hospital sites in Scotland and England varied in scale, geographical location and patient populations. Participants: Principal investigators at 13 hospitals across nine clinical research networks recruited 33 participants using pre-defined eligibility criteria to form a multidisciplinary panel. Main outcome measures: Statements achieving a consensus level of 70% on a 7-point Likert-type scale and ranked trial rating indicators (TRIs) developed by research professionals. Results: The panel developed 75 consensus statements illustrating factors contributing to complexity, follow-up intensity and operational performance in trial delivery, and specified 14 ranked TRIs. Seven open questions in the first qualitative round generated 531 individual statements. Iterative survey rounds returned rates of 82%, 82% and 93%. Conclusions: Clinical trials operate within a dynamic, complex healthcare and innovation system where rapid scientific advances present opportunities and challenges for delivery organisations and professionals. Panellists highlighted cultural and organisational factors limiting the profession’s potential to support growing trial complexity and patient follow-up. Enhanced communication, interoperability, funding and capacity have emerged as key priorities. Future operational models should test dialectic Singerian-based approaches respecting open dialogue and shared values. Research capacity building should prioritise innovative, collaborative approaches embedding validated review and evaluation models to understand changing operational needs and challenges. TRACAT provides a mechanism for continual knowledge assimilation to improve decision-making

Doing something 'worthwhile': intersubjectivity and morality in gap year narratives

Gap years are often put forward as an opportunity to engage in individualized, reflexive, identity work. In contrast to this position, I draw upon a qualitative analysis of young people's travel blogs to highlight the tendency for gap year narratives to stick to standard scripts. Four key narratives frame gap years, which centre on making the most of time to do something worthwhile. I explore issues of intersubjectivity in the representation of gap year experiences, in terms of tacit consensus, moral boundary-drawing and reflexivity prompted by dialogue. Considering intersubjectivity in such accounts can add to our understanding of critical reflection in self-development strategies without resorting to the voluntarism of a reflexive model of identity. It also provides a critique of the individualized responsibility placed on young people to make the right choices

The RNA annealing mechanism of the HIV-1 Tat peptide: conversion of the RNA into an annealing-competent conformation

The annealing of nucleic acids to (partly) complementary RNA or DNA strands is involved in important cellular processes. A variety of proteins have been shown to accelerate RNA/RNA annealing but their mode of action is still mainly uncertain. In order to study the mechanism of protein-facilitated acceleration of annealing we selected a short peptide, HIV-1 Tat(44–61), which accelerates the reaction efficiently. The activity of the peptide is strongly regulated by mono- and divalent cations which hints at the importance of electrostatic interactions between RNA and peptide. Mutagenesis of the peptide illustrated the dominant role of positively charged amino acids in RNA annealing—both the overall charge of the molecule and a precise distribution of basic amino acids within the peptide are important. Additionally, we found that Tat(44–61) drives the RNA annealing reaction via entropic rather than enthalpic terms. One-dimensional-NMR data suggest that the peptide changes the population distribution of possible RNA structures to favor an annealing-prone RNA conformation, thereby increasing the fraction of colliding RNA molecules that successfully anneal

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Sexual Health Research in Coastal and Rural Environments.

Sexual Health Research in Coastal and Rural Environments (SHORE) Aim The research aims to develop new understanding of situated patterns of sexual health behaviours and outcomes within a remote and disadvantaged coastal population on England’s East Coast. Study Overview: The SHORE study is a collaborative case study between University College London (UCL), the Lincoln International Institute for Rural Health (LIIRH) and the School of Health and Social Care, University of Lincoln (UoL). The study aims to build new collaborative research partnerships between academics, policymakers, healthcare providers and coastal community stakeholders, to explore sexual health and disease determinants in one of England’s most deprived areas. The research will, with permission, incorporate NATSAL methodology, focusing on the study of sexually transmitted infections, their pathogenesis and epidemiology. The study seeks to develop new understanding of situated patterns of sexual behaviours and measures of sexual disfunction within an ageing, remote and disadvantaged coastal community. The SHORE study commenced in November 2022 and is led by Professor Ros Kane. It forms part of the Lincoln International Institute for Rural Health’s coastal and rural research portfolio. As the study is based in one of the UK’s most deprived coastal communities, this research provides a unique opportunity to observe and evaluate the prevalence and incidence of sexual health conditions and behaviours and associated contextual challenges impacting public health and the provision of sexual health services. Milestone 1 will involve meetings with key community stakeholders to facilitate community engagement, participation, retention, and relevance. Milestone 2 will involve researchers from the UCL and UoL, who will conduct a scoping review investigating data and service provision pertaining to sexual health across the geography of the study. Milestone 3 will comprise a series of Town Hall meetings (conjunction with the SANDS study) to co-produce, with the Mablethorpe community, research tools, adapted from the existing NATSAL questionnaire to be applied to ascertain the prevalence of public health behaviours and determinants of health influencing the community’s risk and quality of life relating to chronic and infectious diseases and health. The SHORE research element will focus on rural healthcare challenges in relation to sexually transmitted infections and behaviours

Quantum Perspectives in a New Era of Research

Conference presentation exploring quantum perspectives and the application of quantum theory principles as an approach to advancing operational practice in healthcare and taking clinical research delivery to new heights

A Protocol for an Evaluation Study of Patient Follow-Up and Cancer Clinical Trial Complexity: the EFACCT study.

Abstract Background Clinical research delivery is crucial in advancing treatment and care options for cancer. There is a burgeoning problem internationally in delivering cancer trials due to complex protocols, stratified treatments and increasing patient populations in follow-up with extended needs. The EFACCT study will evaluate the phenomena of cancer clinical trial delivery at NHS secondary care sites identifying burdens and implications for participants and organisations. Method This mixed-methods study adopting grounded theory will analyse operational processes and protocols at sites delivering Phase I-IV cancer trials for commercial and non-commercial studies. Research professionals and cancer patients who have participated in clinical trials will contribute to the development of an objective methodology defining and quantifying trial complexity, intensity and workload to enhance models of trial delivery. This in-depth study involving a two-arm e-Delphi, questionnaires, semi-structured interviews as well as trial documentation, database and systematic reviews will optimise clinical trial performance data in combination with qualitative evidence to form optimal models for cancer clinical trial delivery. Data from 12 geographically dispersed sites will be synthesised and continually compared until saturation is achieved. A total UK sample of 185 participants and documentation sample of 100 studies incorporates theoretical, purposive, quota and snowball sampling techniques leveraging the benefits of health informatics and rich participant contextual data. Results Data analysis will include descriptive statistics, thematic content analysis, theoretical, open, axial and selective coding and constant comparison methods. Statistical summaries will use measures of central tendency and levels of dispersion. Conclusion The study outcomes will involve the implementation of a trial rating and complexity assessment tool (TRACAT) and an evaluative theoretical model for cancer research operational management. These elements will create new knowledge supporting future research models, strategic planning, trial implementation and evaluation alongside the provision of a mechanism to optimise recruitment and enhance patient outcomes

Evaluating Follow-up and Complexity In Cancer Clinical Trials (EFACCT): A Mixed Methods Grounded Theory Study

Objectives/purpose: The Evaluating Follow-up and Complexity in cancer Clinical Trials (EFACCT) study aimed to understand the nature of cancer clinical trial operational delivery, evaluating challenges and burdens of professionals and patients participating in cancer research studies. The study sought to develop a contextualised grounded theory elucidating situated challenges and complexity experienced at NHS sites in the UK. Methods: The research used a mixed methods–grounded theory (MM-GT) design. The comprehensive, contextual evaluation combined evidence from quantitative and qualitative paradigms, using inductive and deductive methods. The study drew together multifaceted perspectives and values of 165 participants from six studies; Delphi, questionnaire, and interview studies, separated into patient and professional cohorts. Results: The data generated new knowledge on the perceptions and experiences of key NHS stakeholders, leading to the conception of a Prismatic Coherence Model (PCM), a model evaluating and interrogating features of patient care, management and follow-up in complex network and transactional pathways existing within healthcare and clinical research delivery environments. PCM is an inclusive and responsive strategic approach, sensitive to context which embraces system complexity and transdisciplinarity, in order to advance opportunities for maximising population health. Conclusion and clinical implications: The findings have the potential to support future research models, strategic planning, trial implementation and evaluation alongside the provision of system-based designs capable of supporting transdisciplinary approaches to advancing clinical cancer research and improving patient-centred outcomes