National Health Service Research Ethics Research Articles

P071 Exploring experiences and preferences of people with rheumatoid arthritis for digital interventions to promote physical activity (PA)

Abstract Background/Aims Physical activity (PA) is effective for managing symptoms of rheumatoid arthritis (RA) but people with RA are less active than their healthy counterparts. A digital intervention (DI) to promote PA, is a potential solution. There is a paucity of literature available exploring the requirements of people with RA for a digital intervention. It is important to explore experiences and preferences before developing such an intervention. Aims: 1. Identify digital technology currently used by people with RA to support PA. 2. Understand the preferences and acceptability of people with RA for potential DI delivery. Methods A survey was developed to address these aims. A patient research partner (CS) and ‘think aloud’ pilots contributed to development. The survey was circulated once to members of the National Rheumatoid Arthritis Society in November 2022. This study was approved by the National Health Service Research Ethics Committee (reference 22/NE/0158). Results 1178 people consented to take part (86% female, 64% aged 55-74). The majority used digital technology every day (97%). 84% anticipated using a potential DI to support PA, most preferably every day (48%) or 2-3 times a week (14%). 16% never anticipated using DI to support PA. 34% reported currently using technology to support PA; mostly an app without healthcare professional (HCP) interaction (42%) or internet videos (40%). A further 27% had tried technology to support PA but discontinued, and 39% had never tried. An app was the most preferable delivery platform (56%), followed by a website (43%) or internet videos (28%). 51% would prefer to be offered or signposted to digital technology to support PA by an exercise professional with specific rheumatology training or a healthcare professional (22%). Potential DI delivery methods were rated on a Likert scale of 1-5 for general acceptability, a score of five indicating highest acceptability: automated response mean[SD] 3.6[0.9], ad-hoc HCP interaction 3.5[0.8] pre-arranged HCP interaction 3.4[1] and no interaction 3.1[1]. Conclusion People with RA are using digital technology regularly and many anticipated using a DI to support PA. Despite this, only a third are currently using digital technology to support PA. An app or website platform was the preferred delivery method suggesting that an internet delivered intervention is acceptable. Acceptability ratings of DI delivery methods were similar. Further sub-group analysis and exploration of free text responses is planned to inform tailoring of DI delivery. Disclosure C. Gerlis: None. A. Berry: None. S. Halls: None. M. Loizou: None. C. Swales: None. F. Cramp: None.

Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial

BackgroundLiver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD).Methods/designThe BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD.The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child–Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival.DiscussionThe BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care.Ethics and disseminationThe trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website (www.boppp-trial.org) and partners in the British Liver Trust (BLT) organisation.Trial registrationEUDRACT reference number: 2018–002509-78.ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.

Randomised controlled trial of population screening for atrial fibrillation in people aged 70 years and over to reduce stroke: protocol for the SAFER trial

IntroductionThere is a lack of evidence that the benefits of screening for atrial fibrillation (AF) outweigh the harms. Following the completion of the Screening for Atrial Fibrillation with ECG to...

Effectiveness and cost-effectiveness of a web-based cardiac rehabilitation programme for people with chronic stable angina: protocol for the ACTIVATE (Angina Controlled Trial Investigating the Value of the ‘Activate your heart’ Therapeutic E-intervention) randomised controlled trial

IntroductionChronic stable angina is common and disabling. Cardiac rehabilitation is routinely offered to people following myocardial infarction or revascularisation procedures and has the potential to help people with chronic stable...

Perceptions on artificial intelligence-based decision-making for coexisting multiple long-term health conditions: protocol for a qualitative study with patients and healthcare professionals

IntroductionCoexisting multiple health conditions is common among older people, a population that is increasing globally. The potential for polypharmacy, adverse events, drug interactions and development of additional health conditions complicates...

Study protocol for a case series: implementation and evaluation of an integrated mental and physical healthcare programme to screen for mental health symptoms in people with epilepsy

IntroductionThe prevalence of mental health symptoms in people with epilepsy (PWE) is elevated compared with that of the general population. These symptoms can negatively impact epilepsy management and patient outcomes...

Associations between post-traumatic stress disorders and psychotic symptom severity in adult survivors of developmental trauma: a multisite cross-sectional study in the UK and South Korea

Childhood maltreatment is a risk factor for the development of post-traumatic stress disorders and psychosis. However, the association between post-traumatic stress disorder (PTSD), including complex PTSD, and psychotic symptoms is unknown. We investigated whether the presence of PTSD and complex PTSD was associated with psychotic symptom severity within survivors of developmental trauma. As part of the Investigating Mechanisms underlying Psychosis Associated with Childhood Trauma (IMPACT) study, from Aug 20, 2020, to Jan 24, 2021, and from Sept 9, 2022, to Feb 21, 2023, using study advertisement on online platforms we recruited adult (≥18 years) participants who had experienced developmental trauma without a psychiatric diagnosis in the UK and South Korea. We measured whether participants met diagnostic thresholds for PTSD and complex PTSD using the self-reported International Trauma Questionnaire, and psychotic symptoms using the self-reported Community Assessment of Psychic Experiences. We used linear regression, adjusting for sociodemographic variables such as age, sex, ethnicity, educational attainment, and socioeconomic status, to examine whether there was an association between PTSD and complex PTSD and psychotic symptoms. The study is registered in the UK (University College London Research Ethics Committee [14317/001] and the National Health Service Research Ethics Committee [22/YH/0096]) and South Korea (Institutional Review Board of Seoul National University Bundang Hospital [B-2011-648-306]), and is ongoing. Of the 2675 participants who took part in the study, 1273 had experienced developmental trauma and were included in the study in the UK (n=475) and South Korea (n=798), comprising 422 (33%) men and 851 (67%) women with a mean age of 26·9 years (SD 6, range 18-40), mostly of White British (n=328) or South Korean (n=798) ethnicity. We found no significant association between PTSD and psychotic symptom severity (total severity β=-2·40 [SE 3·28], p=0·47), compared with participants who did not meet PTSD or complex PTSD caseness. We found a significant relationship between complex PTSD and psychotic symptom severity (total severity β=22·62 [SE 1·65], p<0·0001), including for positive (β=12·07 [SE 0·99], p<0·0001) and negative symptoms (β=10·5 [SE 0·95], p<0·0001), compared with participants who did not meet PTSD or complex PTSD caseness. Health systems must assess individuals with previous developmental trauma for complex PTSD and treat those affected. These individuals should also be assessed for psychotic symptoms, and if necessary, preventative measures should be taken to reduce risk of conversion. Further work should assess whether treating complex PTSD modifies the risk of conversion to psychosis. UKRI Future Leaders Fellowship, British Medical Association Margaret Temple Award for Schizophrenia Research, and the National Research Foundation of Korea-Korea Government.

Non-randomised feasibility study testing a primary care intervention to promote engagement in an online health community for adults with troublesome asthma: protocol

IntroductionIn the UK, approximately 4.3 million adults have asthma, with one-third experiencing poor asthma control, affecting their quality of life, and increasing their healthcare use. Interventions promoting emotional/behavioural self-management can...

Protocol for the CoNoR Study: A prospective multi-step study of the potential added benefit of two novel assessment tools in colorectal liver metastases technical resectability decision-making

IntroductionLiver resection is the only curative treatment for colorectal liver metastases (CLM). Resectability decision-making is therefore a key determinant of outcomes. Wide variation has been demonstrated in resectability decision-making, despite...

Designing a library of lived experience for mental health (LoLEM): protocol for integrating a realist synthesis and experience based codesign approach

IntroductionPeople with lived expertise in managing mental health challenges can be an important source of knowledge and support for other people facing similar challenges, and for carers to learn how...

Pharmacist and Homeless Outreach Engagement and Non-medical Independent prescribing Rx (PHOENIx): a study protocol for a pilot randomised controlled trial

IntroductionThe number of people experiencing homelessness (PEH) is increasing worldwide. Systematic reviews show high levels of multimorbidity and mortality. Integrated health and social care outreach interventions may improve outcomes. No...

METRIC-EF: magnetic resonance enterography to predict disabling disease in newly diagnosed Crohn’s disease—protocol for a multicentre, non-randomised, single-arm, prospective study

IntroductionCrohn’s disease (CD) is characterised by discontinuous, relapsing enteric inflammation. Instituting advanced therapies at an early stage to suppress inflammation aims to prevent future complications such as stricturing or penetrating...

Which patients received a ReSPECT form, what was documented and what were the patient outcomes? A protocol for a retrospective observational study investigating the impact of the COVID-19 pandemic on the implementation of the ReSPECT process

IntroductionRecommended Summary Plan for Emergency Care and Treatment (ReSPECT) is a UK advance care planning (ACP) initiative aiming to standardise the process of creating personalised recommendations for a person’s clinical...

PARIS: protocol for a prospective single arm, theory-based, group-based feasibility intervention study to increase Physical Activity and reduce sedentary behaviouR after barIatric Surgery

IntroductionIncreased physical activity and reduced sedentary behaviour can encourage favourable outcomes after bariatric surgery. However, there is a lack of evidence as to how to support patients with behaviour change....

Adult Mortality in Children Exposed to State Care: Systematic Review and Meta-Analysis of Prospective Cohort Studies

Background: Removal from family of origin to placement in state care is a highly challenging and increasingly prevalent childhood experience. The purpose of this report was to synthesise published and unpublished prospective evidence on adult mortality in people with a history of state care in early life. Methods: For this systematic review and meta-analysis, we searched PubMed and Embase from their inception to May 31st 2021, extracting standard estimates of association and variance from qualifying studies. We augmented these findings with analyses of unpublished individual-participant data from the 1958 and 1970 Birth Cohort Studies (total N = 21,936). Study-specific estimates were aggregated using random-effect meta-analysis. The Cochrane Risk of Bias Tool was used to assess study quality. This review is PROSPERO-registered (CRD42021254665). Findings: We identified 209 potentially eligible published articles, of which 11 prospective cohort studies from the UK, Sweden, Finland, the USA, and Canada met the inclusion criteria (2 unpublished). In 2,273,998 individuals (10 studies), relative to those without a care history in childhood, those who were exposed had 2.5 times the risk of total mortality in adulthood (summary rate ratio; 95% confidence interval: 2.58; 1.96 to 3.39), study-specific estimates varying between 1.53 and 5.77 (I2=92%). Despite some attenuation, this association held following adjustment for other measures of early life adversity; extended into middle- and older-age; was stronger in higher quality studies; and was of equal magnitude according to sex and geographical region. There was a suggestion of sensitive periods of exposure to care, whereby individuals who entered public care for the first time in adolescence (3.54; 2.00 to 6.29) experienced greater rates of total mortality than those doing so earlier in the life course (1.69; 1.35 to 2.12). In five studies capturing 1,524,761 individuals (5 studies), children in care had more than three times the risk of competed suicide in adulthood (3.37; 2.64 to 4.30) with study-specific estimates ranging between 2.42 and 5.85 (I2=68%). The magnitude of this relationship was weaker after adjustment for multiple covariates; in men versus women; and in lower quality studies. Interpretation: The excess rates of total and suicide mortality in children exposed to state care suggest child protection systems and social policy following care graduation are insufficient to mitigate the effects of the adverse experiences of care itself and the social disadvantage that preceded it. Funding: GDB is supported by the UK Medical Research Council (MR/P023444/1) and the US National Institute on Aging (1R56AG052519-01; 1R01AG052519-01A1); MK by the Wellcome Trust (221854/Z/20/Z), the MRC (R024227, S011676), NIA (R01AG056477), the Academy of Finland (329202), and Helsinki Institute of Life Science (H970); and PF by the UK Economic and Social Research Council & Biotechnology and Biological Sciences Research Council (Soc-B Centre for Doctoral Training). Declaration of Interest: None to declare. Ethical Approval: Data collection for the 1958 cohort study was approved by the National Health Service Research Ethics committee, and for the 1970 cohort study by the London Central Research Ethics Committee. No ethics was needed for this study.

Association of Postoperative Clinical Outcomes With Sarcopenia, Frailty, and Nutritional Status in Older Patients With Colorectal Cancer: Protocol for a Prospective Cohort Study.

BackgroundOlder patients account for a significant proportion of patients undergoing colorectal cancer surgery and are vulnerable to a number of preoperative risk factors that are not often present in younger patients. Further, three preoperative risk factors that are more prevalent in older adults include frailty, sarcopenia, and malnutrition. Although each of these has been studied in isolation, there is little information on the interplay between them in older surgical patients. A particular area of increasing interest is the use of urine metabolomics for the objective evaluation of dietary profiles and malnutrition.ObjectiveHerein, we describe the design, cohort, and standard operating procedures of a planned prospective study of older surgical patients undergoing colorectal cancer resection across multiple institutions in the United Kingdom. The objectives are to determine the association between clinical outcomes and frailty, nutritional status, and sarcopenia.MethodsThe procedures will include serial frailty evaluations (Clinical Frailty Scale and Groningen Frailty Indicator), functional assessments (hand grip strength and 4-meter walk test), muscle mass evaluations via computerized tomography morphometric analysis, and the evaluation of nutritional status via the analysis of urinary dietary biomarkers. The primary feasibility outcome is the estimation of the incidence rate of postoperative complications, and the primary clinical outcome is the association between the presence of postoperative complications and frailty, sarcopenia, and nutritional status. The secondary outcome measures are the length of hospital stay, 30-day hospital readmission rate, and mortality rate at days 30 and 90.ResultsOur study was approved by the National Health Service Research Ethics Committee (reference number: 19/WA/0190) via the Integrated Research Application System (project ID: 231694) prior to subject recruitment. Cardiff University is acting as the study sponsor. Our study is financially supported through an external, peer-reviewed grant from the British Geriatrics Society and internal funding resources from Cardiff University. The results will be disseminated through peer-review publications, social media, and conference proceedings.ConclusionsAs frailty, sarcopenia, and malnutrition are all areas of common derangement in the older surgical population, prospectively studying these risk factors in concert will allow for the analysis of their interplay as well as the development of predictive models for those at risk of commonly tracked surgical complications and outcomes.International Registered Report Identifier (IRRID)PRR1-10.2196/16846

Protocol for a multi-centre observational and mixed methods pilot study to identify factors predictive of poor functional recovery after major gastrointestinal surgery and strategies to enhance uptake of perioperative optimization: Optimizing the care and treatment pathways for older patients facing major gastrointestinal surgery (OCTAGON).

National datasets report large variations in outcomes from older people (≥65years) between different UK surgical units. This implies that not all patients receive the same level of care or access to resources, such as rehabilitation or allied health professional input. This might impact functional decline. Our aim is to evaluate the baseline status of older patients facing major gastrointestinal surgery and the impact of variation in perioperative assessment and provision of perioperative support on functional outcomes. Patients' experiences and views of assessment and optimization will be explored via integrated qualitative semi-structured interviews. This multi-centre, pilot cohort study will include patients ≥65years presenting via both elective and emergency pathways at three to five South Yorkshire NHS hospitals (Clinical Trials registration NCT04545125). The primary outcome is functional recovery measured using the World Health Organization Disability Assessment Schedule 2.0 at 6weeks post-operation. Secondary outcomes include feasibility, quality of life, length of stay and complication rate. An opportunistic sample size of 120has been estimated and will inform the design of a future, adequately powered study. For the qualitative study, 20-30 semi-structured patient interviews will be undertaken with patients from the cohort study to explore experiences of assessment and optimization. Interviews will be digitally recorded, transcribed verbatim and analysed according to the framework approach. This study has been approved by the National Health Service Research Ethics Committee and is registered centrally with Health Research Authority. It has been adopted by the National Institute for Health Research Portfolio scheme. Dissemination will be via international and national surgical and geriatric conferences.

The Role of Procalcitonin in Severe COVID-19

Background: The variability of Covid-19 severity between patients has driven efforts to identify prognosticating laboratory markers that could potentially guide clinical decision making. Procalcitonin (PCT) is classically used as a diagnostic marker in bacterial infections, but its role in predicting Covid-19 disease severity is emerging. We aim to identify the association between PCT and Covid-19 disease severity in a critical care setting and whether bacterial co-infection is implicated.Methods: We retrospectively reviewed Covid-19 patients who had PCT levels measured and were treated in a critical care setting at our institution between February to September 2020. Patient demographics, laboratory markers including peak procalcitonin values and corresponding haematological and biochemistry parameters and bacterial culture results were analysed. The primary outcomes were defined as requirement of invasive mechanical ventilation and inpatient mortality and the secondary outcome was defined as duration of invasive mechanical ventilation.Findings: In total 60 patients were included for analysis; 41 (68%) required invasive mechanical ventilation and 27 (45%) died as inpatient. Univariate analysis identified higher peak PCT levels significantly associated with both the requirement for invasive mechanical ventilation and inpatient mortality. Calculated odds ratios of peak PCT levels to the use of invasive mechanical ventilation and inpatient mortality were 3.2 (95% CI 1.2-8.2, p=0.02) and 2.6 (95% CI 1.1-6.2, p=0.03) respectively. There was a significant positive correlation between increased peak PCT levels with duration on invasive mechanical ventilation. No significant difference was found between mean peak PCT levels of patients with positive and negative bacterial cultures. Interpretation: Patients with elevated PCT levels are more likely to develop respiratory failure requiring prolonged invasive mechanical ventilation and are at an increased risk of in-hospital death. This association may be independent of bacterial co-infection. Further study is required to elucidate the mechanisms through which PCT is increased in severe Covid-19.Funding Statement: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.Declaration of Interests: All authors understand the policy of declaration of interests. RH, AKJM, JK, PS, PC, IALW, DG, and CGM all declare that that they have no competing interests.Ethics Approval Statement: As a retrospective analysis using clinically collected, non-identifiable data, this work does not fall under the remit of National Health Service Research Ethics Committees. This study was approved by our institution’s Research, Quality improvement and Audit Department with reference FH205.

Worldwide Variation in Case Mix, Quality of Care and Mortality of Patients Receiving Emergency Neurosurgery for Traumatic Brain Injury in the Global Neurotrauma Outcomes Study (GNOS) – A Prospective, Observational Cohort Study Involving 1,635 Patients in 159 Hospitals in 57 Countries

Background: Traumatic brain injury (TBI) is increasingly recognised as being responsible for a substantial proportion of the global burden of disease. Neurosurgical intervention for TBI is an extremely important aspect of its care but epidemiological data on this patient population are lacking. We aimed to characterise differences in case mix, quality of care and in-hospital mortality of TBI across human development settings. Methods: This was a prospective, observational cohort study of consecutive TBI patients undergoing emergency neurosurgery conducted in a convenience sample of 159 hospitals in 57 countries. The primary outcome measure was survival to discharge or 14-days post-operatively (whichever came first). Countries were stratified according to their Human Development Index (HDI) into very high (VH-HDI), high (H-HDI), medium (M-HDI) and low (L-HDI). Mixed effects logistic regression was used to examine the effect of HDI on mortality while accounting for and quantifying between-hospital and country variation. The study was registered on ClinicalTrials.gov, NCT04212754. Findings: Of the 1,635 patients enrolled between 1 November 2018 and 31 January 2020, 328 (20%) were from VH-HDI, 539 (33%) from H-HDI, 614 (38%) from M-HDI and 154 (9%) from L-HDI countries. There was significant variation in age, mechanism of injury, severity of TBI and procedure performed as well as preoperative and postoperative care across countries and HDI tiers. Overall mortality was 18%. After adjustment for case mix, the odds of in-hospital mortality were greater in the M-HDI (OR 2.84 95% CI 1.55-5.2) and H-HDI (OR 2.26 95% CI 1.23-4.15) tiers relative to the VH-HDI tier. There was significant between-hospital variation in mortality (MOR 2.00 95% CI 1.17-2.49). Interpretation: Patients receiving emergency neurosurgery for TBI differed considerably in their admission characteristics, management received and outcomes across human development settings. Level of human development was associated with mortality. Funding: National Institute for Health Research Global Health Research Group. Declaration of Interest: All authors declare no competing interests. Ethical Approval: UK National Health Service Research Ethics Service considered this study exempt from formal research registration (South East Scotland Research Ethics Service)

Multimodal Testing Reveals Subclinical Neurovascular Dysfunction in Prediabetes, Challenging the Diagnostic Threshold of Diabetes

Background: There is growing evidence that small nerve fibre and retinal neurovascular damage occur in prediabetes before the onset of type 2 diabetes. Methods: Participants with normoglycaemia, prediabetes or type 2 diabetes underwent corneal confocal microscopy (CCM), electrochemical skin conductance (ESC), optical coherence tomography angiography (OCT-A), and handheld electroretinography (ERG) measurements. Findings: Seventy-five participants with normoglycaemia (n=20), prediabetes (n=29) and type 2 diabetes (n=26) were studied. Compared with normoglycaemia, mean peak ERG amplitudes of retinal responses at low (16 Td·s: 4·05 µV, 95% confidence interval (CI) 0·96-7·13) and high (32 Td·s: 5·20 µV, 95% CI 1·54-8·86) retinal illuminance were lower in prediabetes, as were OCT-A parafoveal vessel densities in superficial (0.051 pixels/mm2, 95% CI 0·005-0·095) and deep (0·048 pixels/mm2, 95% CI 0·003-0·093) retinal layers. There were no differences in CCM or ESC measurements between these two groups. Correlations between HbA1c and peak ERG amplitude at 32 Td·s (r=-0.256, p=0·028), implicit time at 32 Td·s (r=0·422, p=0·0002) and 16 Td·s (r=0·327, p=0·005), OCT parafoveal vessel density in the superficial (r=-0·238, p=0·049) and deep (r=-0·3, p=0·017) retinal layers, corneal nerve fibre length (CNFL) (r=-0·293, p=0·017), and hand ESC (r=-0·244, p=0·035) were observed. HOMA-IR was a predictor of CNFD (β=-0·94, 95% CI -1·66 to -0·21, p=0·012) and CNBD (β=-5·02, 95% CI -10·01 to -0·05, p=0·048). Interpretation: The diagnosis of diabetes is based on historical data showing emergent retinopathy on fundus examination; newer tests reveal abnormal retinal neurovascular structure (OCT-A) and function (ERG) occurring before retinopathy. Funding: This research received no funding support. Declaration of Interests: None of the authors have any relevant financial disclosures to declare. LKC Technologies Inc. and Impeto Medical Inc. provided free use of the RETeval and SUDOSCAN devices, respectively, for this study. CB is part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Ethics Approval Statement: This study adhered to the Declaration of Helsinki (2008) and was approved by an independent National Health Service Research Ethics Committee in November 2018 (REC ID: 18/LO/2126). Written informed consent was obtained from all participants.