Mike Bradburn

Background: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Formal psychological therapies are not routinely part of United Kingdom standard motor neuron disease care due to a lack of evidence-based guidance resulting from a paucity of clinical trials. We aimed to evaluate the clinical and cost-effectiveness of Acceptance and Commitment Therapy plus usual care compared to usual care alone for improving psychological health in people living with motor neuron disease. Methods: We conducted qualitative interviews with 15 people living with motor neuron disease, 10 caregivers and 12 healthcare professionals. Findings were used to develop an Acceptance and Commitment Therapy intervention specifically for people living with motor neuron disease. Next, we examined its acceptability and feasibility in an uncontrolled feasibility study with 29 people living with motor neuron disease. Findings from qualitative interviews with 14 people living with motor neuron disease and 11 therapists were used to revise the intervention. Finally, we conducted a multicentre, parallel, two-arm randomised controlled trial in 16 United Kingdom motor neuron disease care centres/clinics. Eligible participants were aged ≥ 18 years with motor neuron disease. Participants were randomly assigned (1 : 1) to receive up to eight sessions of Acceptance and Commitment Therapy plus usual care or usual care alone and followed up at 6 and 9 months post randomisation by blinded outcome assessors. The primary outcome was total score on the McGill Quality of Life Questionnaire-Revised at 6 months. Secondary outcomes included health status using the EuroQol-5 Dimensions, five-level version. Primary analyses were by intention to treat. Results: Acceptance and Commitment Therapy was acceptable to people living with motor neuron disease, and it was feasible to recruit participants, hence trial progression criteria were met. From September 2019 to August 2022, 191 participants were recruited: 97 were allocated to Acceptance and Commitment Therapy plus usual care and 94 to usual care alone. Mean age was 61.9 years (standard deviation 11.4), 58% were male and 95% were White/White British. Acceptance and Commitment Therapy plus usual care was superior to usual care alone on the McGill Quality of Life Questionnaire-Revised at 6 months [adjusted mean difference 0.66 (95% confidence interval 0.22 to 1.10); Cohen’s d = 0.46 (95% confidence interval 0.16 to 0.77); p = 0.003] and 9 months [adjusted mean difference 0.76 (95% confidence interval 0.30 to 1.22); Cohen’s d = 0.53 (95% confidence interval 0.21 to 0.85); p = 0.001]. Mean differences in total costs and quality-adjusted life-years at 9 months between Acceptance and Commitment Therapy plus usual care versus usual care alone were not statistically significant [costs: £1019 (95% confidence interval −£34 to £2074); quality-adjusted life-years: 0.019 (95% confidence interval −0.07 to 0.05)]. The incremental cost-effectiveness ratio was £88,507/quality-adjusted life-year: this decreased to £13,817/quality-adjusted life-year in those with medium disease-related deterioration in subgroup analyses. Conclusion: Acceptance and Commitment Therapy plus usual care is clinically effective at maintaining or improving psychological health, as measured by the McGill Quality of Life Questionnaire-Revised, in people living with motor neuron disease compared to usual care alone. It was not cost-effective overall when calculated using a standard health status measure (EuroQol-5 Dimensions, five-level version). However, it was cost-effective in a subgroup of people experiencing a medium rate of disease-related deterioration. Limitations: Participants from ethnic minorities were under-represented, despite recruiting from sites with diverse communities. Between-group differences in outcomes may have been partly attributable to expectancy or non-specific therapeutic effects due to the lack of an active control. Cost-effectiveness analyses may have been underpowered to detect significant between-group differences. Future work: Studies should examine the effectiveness of Acceptance and Commitment Therapy in diverse populations, compared to an active control, using a more appropriate measure to assess cost-effectiveness, and in those with different rates of disease-related deterioration. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/81/01.

Introduction Amyotrophic lateral sclerosis (ALS) is a devastating illness that leads to muscle weakness and death usually within around 3 years of diagnosis. People with ALS (pwALS) often lose weight due to raised energy requirements and symptoms of the disease presenting significant challenges to taking adequate oral diet, with those who lose more weight being at a greater chance of earlier death. There is also some evidence to suggest that a higher calorie diet may benefit the disease course in pwALS, but further research is needed. Methods and analysis Two armed, parallel group, superiority, open labelled, randomised controlled trial, with internal pilot, to assess the effectiveness of an early high calorie diet on functional outcomes in ALS, comprising two treatment arms: (1) standard care, (2) standard care with additional active management using the OptiCALS complex intervention to achieve a high calorie diet (initially randomised 1:1, then 1:2 following a protocol amendment). Using a food first approach, pwALS will be encouraged and supported to follow a diet that meets an individualised calorie target from food before prescribing oral nutritional supplements. 259 pwALS will be recruited from up to 20 ALS centres across the United Kingdom and Ireland and followed up for a period of 12 months. Primary outcome is functional change measured over 12 months, using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Secondary end points include measures of functional health, quality of life, calorie intake and weight, as well as time to gastrostomy and survival. A health economic analysis and process evaluation will also be undertaken. Participant recruitment is expected to complete in September 2025, and participant follow-up is expected to complete in September 2026. The results of this study are expected in March 2027. Ethics and dissemination The trial was approved by Greater Manchester—North West Research Ethics Committee, reference 20/NW/0334 on 8 September 2020. We will publish the study findings in peer-reviewed academic journals and present at local, national and international conferences where possible. Trial registration number ISRCTN30588041.

Background: There is no consensus on optimal management of pilonidal disease. Surgical practice is varied, and existing literature is mainly single-centre cohort studies of varied disease severity, interventions and outcome assessments. Objectives: A prospective cohort study to determine: disease severity and intervention relationship most valued outcomes and treatment preference by patients recommendations for policy and future research. Design: Observational cohort study with nested mixed-methods case study. Discrete choice experiment. Clinician survey. Three-stage Delphi survey for patients and clinicians. Inter-rater reliability of classification system. Setting: Thirty-one National Health Service trusts. Participants: Patients aged > 16 years referred for elective surgical treatment of pilonidal disease. Interventions: Surgery. Main outcome measures: Pain postoperative days 1 and 7, time to healing and return to normal activities, complications, recurrence. Outcomes compared between major and minor procedures using regression modelling, propensity score-based approaches and augmented inverse probability weighting to account for measured potential confounding features. Results: Clinician survey: There was significant heterogeneity in surgeon practice preference. Limited training opportunities may impede efforts to improve practice. Cohort study: Over half of patients (60%; N = 667) had a major procedure. For these procedures, pain was greater on day 1 and day 7 (mean difference day 1 pain 1.58 points, 95% confidence interval 1.14 to 2.01 points, n = 536; mean difference day 7 pain 1.53 points, 95% confidence interval 1.12 to 1.95 points, n = 512). There were higher complication rates (adjusted risk difference 17.5%, 95% confidence interval 9.1 to 25.9%, n = 579), lower recurrence (adjusted risk difference −10.1%, 95% confidence interval −18.1 to −2.1%, n = 575), and longer time to healing (>34 days estimated difference) and time to return to normal activities (difference 25.9 days, 95% confidence interval 18.4 to 33.4 days). Mixed-methods analysis: Patient decision-making was influenced by prior experience of disease and anticipated recovery time. The burden involved in wound care and the gap between expected and actual time for recovery were the principal reasons given for decision regret. Discrete choice experiment: The strongest predictors of patient treatment choice were risk of infection/persistence (attribute importance 70%), and shorter recovery time (attribute importance 30%). Patients were willing to trade off these attributes. Those aged over 30 years had a higher risk tolerance (22.35–34.67%) for treatment failure if they could experience rapid recovery. There was no strong evidence that younger patients were willing to accept higher risk of treatment failure in exchange for a faster recovery. Patients were uniform in rejecting excision-and-leave-open because of the protracted nursing care it entailed. Wysocki classification analysis: There was acceptable inter-rater agreement (κ = 0.52, 95% confidence interval 0.42 to 0.61). Consensus exercise: Five research and practice priorities were identified. The top research priority was that a comparative trial should broadly group interventions. The top practice priority was that any interventions should be less disruptive than the disease itself. Limitations: Incomplete recruitment and follow-up data were an issue, particularly given the multiple interventions. Assumptions were made regarding risk adjustment. Conclusions and future work: Results suggest the burden of pilonidal surgery is greater than reported previously. This can be mitigated with better selection of intervention according to disease type and patient desired goals. Results indicate a framework for future higher-quality trials that stratify disease and utilise broad groupings of common interventions with development of a patient-centred core outcome set. Trial registration: This trial is registered as ISRCTN95551898. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/17/02) and is published in full in Health Technology Assessment; Vol. 28, No. 33. See the NIHR Funding and Awards website for further award information.

Background: Guidelines for sepsis recommend treating those at highest risk within 1 hour. The emergency care system can only achieve this if sepsis is recognised and prioritised. Ambulance services can use prehospital early warning scores alongside paramedic diagnostic impression to prioritise patients for treatment or early assessment in the emergency department. Objectives: To determine the accuracy, impact and cost-effectiveness of using early warning scores alongside paramedic diagnostic impression to identify sepsis requiring urgent treatment. Design: Retrospective diagnostic cohort study and decision-analytic modelling of operational consequences and cost-effectiveness. Setting: Two ambulance services and four acute hospitals in England. Participants: Adults transported to hospital by emergency ambulance, excluding episodes with injury, mental health problems, cardiac arrest, direct transfer to specialist services, or no vital signs recorded. Interventions: Twenty-one early warning scores used alongside paramedic diagnostic impression, categorised as sepsis, infection, non-specific presentation, or other specific presentation. Main outcome measures: Proportion of cases prioritised at the four hospitals; diagnostic accuracy for the sepsis-3 definition of sepsis and receiving urgent treatment (primary reference standard); daily number of cases with and without sepsis prioritised at a large and a small hospital; the minimum treatment effect associated with prioritisation at which each strategy would be cost-effective, compared to no prioritisation, assuming willingness to pay £20,000 per quality-adjusted life-year gained. Results: Data from 95,022 episodes involving 71,204 patients across four hospitals showed that most early warning scores operating at their pre-specified thresholds would prioritise more than 10% of cases when applied to non-specific attendances or all attendances. Data from 12,870 episodes at one hospital identified 348 (2.7%) with the primary reference standard. The National Early Warning Score, version 2 (NEWS2), had the highest area under the receiver operating characteristic curve when applied only to patients with a paramedic diagnostic impression of sepsis or infection (0.756, 95% confidence interval 0.729 to 0.783) or sepsis alone (0.655, 95% confidence interval 0.63 to 0.68). None of the strategies provided high sensitivity (> 0.8) with acceptable positive predictive value (> 0.15). NEWS2 provided combinations of sensitivity and specificity that were similar or superior to all other early warning scores. Applying NEWS2 to paramedic diagnostic impression of sepsis or infection with thresholds of > 4, > 6 and > 8 respectively provided sensitivities and positive predictive values (95% confidence interval) of 0.522 (0.469 to 0.574) and 0.216 (0.189 to 0.245), 0.447 (0.395 to 0.499) and 0.274 (0.239 to 0.313), and 0.314 (0.268 to 0.365) and 0.333 (confidence interval 0.284 to 0.386). The mortality relative risk reduction from prioritisation at which each strategy would be cost-effective exceeded 0.975 for all strategies analysed. Limitations: We estimated accuracy using a sample of older patients at one hospital. Reliable evidence was not available to estimate the effectiveness of prioritisation in the decision-analytic modelling. Conclusions: No strategy is ideal but using NEWS2, in patients with a paramedic diagnostic impression of infection or sepsis could identify one-third to half of sepsis cases without prioritising unmanageable numbers. No other score provided clearly superior accuracy to NEWS2. Research is needed to develop better definition, diagnosis and treatments for sepsis. Study registration: This study is registered as Research Registry (reference: researchregistry5268). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/136/10) and is published in full in Health Technology Assessment; Vol. 28, No. 16. See the NIHR Funding and Awards website for further award information.

Some text in this abstract has been reproduced from Lindsay J, Din S, Hawkey C, Hind D, Irving P, Lobo A, et al. OFR-9 An RCT of autologous stem-cell transplantation in treatment refractory Crohn’s disease (low-intensity therapy evaluation): ASTIClite. Gut 2021;70(Suppl. 4):A4. Background: Treatment-refractory Crohn’s disease is characterised by chronic symptoms, poor quality of life and high costs to the NHS, and through days of work lost by patients. A previous trial of autologous haematopoietic stem cell transplant (HSCT) failed its end point of medication-free clinical remission for 3 months with no evidence of disease activity, and reported high toxicity. Subsequent studies suggest that HSCT achieves complete mucosal healing in 50% of patients, and that toxicity likely relates to the cyclophosphamide dose. Objectives: The primary objective was to assess the efficacy of HSCTlite (HSCT with low-dose cyclophosphamide) compared with standard care for inducing regression of intestinal ulceration in patients with refractory Crohn’s disease at week 48. Secondary objectives included the assessment of disease activity, quality of life and regimen safety. Mechanistic objectives included immune reconstitution after HSCTlite. Design: Two-arm, parallel-group randomised controlled trial with a 2 : 1 (intervention : control) allocation ratio. Setting: Nine NHS trusts (eight trusts were recruitment sites; one trust was a treatment-only site). Participants: Adults with treatment-refractory Crohn’s disease, for whom surgery was inappropriate or who had declined surgery. Interventions: The intervention treatment was HSCTlite using cyclophosphamide, and the control was any current available treatment for Crohn’s disease, apart from stem cell transplantation. Main outcomes: The primary outcome was treatment success at week 48 [mucosal healing (Simple Endoscopic Score for Crohn’s Disease ulcer subscore of 0) without surgery or death], assessed by central readers blinded to allocation and timing of assessment. Key secondary outcomes were clinical remission, Simple Endoscopic Score for Crohn’s Disease scores at week 48, change in Crohn’s Disease Activity Index scores and safety. Results: The trial was halted owing to Suspected unexpected serious adverse events that took place after randomising 23 patients (HSCTlite arm, n = 13; usual-care arm, n = 10). Ten out of the 13 patients randomised to the HSCTlite arm received the intervention and nine (one death) reached the 48-week follow-up. In the usual-care arm 9 out of the 10 patients randomised reached the 48-week follow-up (one ineligible). The primary outcome was available for 7 out of 10 HSCTlite patients (including the patient who died) and six out of nine usual-care patients. Absence of endoscopic ulceration without surgery or death was reported in three out of seven (43%) HSCTlite patients, compared with zero out of six (0%) usual-care patients. Centrally read Simple Endoscopic Score for Crohn’s Disease scores [mean (standard deviation)] were 10.8 (6.3) and 10.0 (6.1) at baseline, compared with 2.8 (2.9) and 18.7 (9.1) at week 48, in the HSCT and usual-care arms, respectively. Clinical remission (Crohn’s Disease Activity Index scores of < 150) occurred in 57% and 17% of patients in the HSCTlite and usual-care arms, respectively, at week 48. Serious adverse events were more frequent in the HSCTlite arm [38 in 13 (100%) patients] than in the usual-care arm [16 in 4 (40%) patients]. Nine suspected unexpected serious adverse reactions were reported in six HSCTlite patients, including three cases of delayed renal failure due to proven thrombotic microangiopathy. Two HSCTlite patients died. Conclusions: Within the limitations of reduced patient recruitment and numbers of patients assessed, HSCTlite meaningfully reduced endoscopic disease activity, with three patients experiencing resolution of ulceration. Suspected unexpected serious adverse reactions, particularly relating to thrombotic microangiopathy, make this regimen unsuitable for future clinical use. Limitations: The early trial closure prevented complete recruitment, and the impact of the coronavirus pandemic prevented completion of some study investigations. Small participant numbers meant analysis could only be descriptive. Future work: Owing to undetermined aetiology of thrombotic microangiopathy, further trials of HSCTlite in this population are not considered appropriate. Priorities should be to determine optimal treatment strategies for patients with refractory Crohn’s disease, including those with a stoma or multiple previous resections. Trial registration: This trial is registered as ISRCTN17160440 and EudraCT 2017-002545-30. Funding: This award was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership. This is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 3. See the NIHR Funding and Awards website for further award information.

Objectives We evaluated the accuracy of using routine health service data to identify hospital-acquired thrombosis (HAT) and major bleeding events (MBE) compared with a reference standard of case note review. Design A multicentre observational cohort study. Setting Four acute hospitals in the UK. Participants A consecutive unselective cohort of general medical and surgical patients requiring hospitalisation for a period of >24 hours during the calendar year 2021. We excluded paediatric, obstetric and critical care patients due to differential risk profiles. Interventions We compared preidentified sources of routinely collected information (using hospital coding data and local contractually mandated thrombosis datasets) to data extracted from case notes using a predesigned workflow methodology. Primary and secondary outcome measures We defined HAT as objectively confirmed venous thromboembolism occurring during hospital stay or within 90 days of discharge and MBE as per international consensus. Results We were able to source all necessary routinely collected outcome data for 87% of 2008 case episodes reviewed. The sensitivity of hospital coding data (International Classification of Diseases 10th Revision, ICD-10) for the diagnosis of HAT and MBE was 62% (95% CI, 54 to 69) and 38% (95% CI, 27 to 50), respectively. Sensitivity improved to 81% (95% CI, 75 to 87) when using local thrombosis data sets. Conclusions Using routinely collected data appeared to miss a substantial proportion of outcome events, when compared with case note review. Our study suggests that currently available routine data collection methods in the UK are inadequate to support efficient study designs in venous thromboembolism research. Trial registration number NIHR127454.

Background: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared. Objectives: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain. Design: A randomised crossover trial with health economic analysis. Setting: Twenty-one secondary care centres in the UK. Participants: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0–10). Interventions: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded. Outcomes: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory – Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0–10), Patient Global Impression of Change score at week 16 and patients’ preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost–utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective. Results: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of –0.1 points (98.3% confidence interval –0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of –0.1 points (98.3% confidence interval –0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval –0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6–16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval –0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin –0.002 (95% confidence interval –0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline –0.006 (95% confidence interval –0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin −£113 (95% confidence interval −£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval −£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval −£13 to £398)]. Limitations: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable. Future work: Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief. Conclusions: The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients’ preference in terms of side effects. Trial registration: The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 39. See the NIHR Journals Library website for further project information.

Background: In breast cancer management, age-related practice variation is widespread, with older women having lower rates of surgery and chemotherapy than younger women, based on the premise of reduced treatment tolerance and benefit. This may contribute to inferior outcomes. There are currently no age- and fitness-stratified guidelines on which to base treatment recommendations. Aim: We aimed to optimise treatment choice and outcomes for older women (aged ≥ 70 years) with operable breast cancer. Objectives: Our objectives were to (1) determine the age, comorbidity, frailty, disease stage and biology thresholds for endocrine therapy alone versus surgery plus adjuvant endocrine therapy, or adjuvant chemotherapy versus no chemotherapy, for older women with breast cancer; (2) optimise survival outcomes for older women by improving the quality of treatment decision-making; (3) develop and evaluate a decision support intervention to enhance shared decision-making; and (4) determine the degree and causes of treatment variation between UK breast units. Design: A prospective cohort study was used to determine age and fitness thresholds for treatment allocation. Mixed-methods research was used to determine the information needs of older women to develop a decision support intervention. A cluster-randomised trial was used to evaluate the impact of this decision support intervention on treatment choices and outcomes. Health economic analysis was used to evaluate the cost–benefit ratio of different treatment strategies according to age and fitness criteria. A mixed-methods study was used to determine the degree and causes of variation in treatment allocation. Main outcome measures: The main outcome measures were enhanced age- and fitness-specific decision support leading to improved quality-of-life outcomes in older women (aged ≥ 70 years) with early breast cancer. Results: (1) Cohort study: the study recruited 3416 UK women aged ≥ 70 years (median age 77 years). Follow-up was 52 months. (a) The surgery plus adjuvant endocrine therapy versus endocrine therapy alone comparison: 2854 out of 3416 (88%) women had oestrogen-receptor-positive breast cancer, 2354 of whom received surgery plus adjuvant endocrine therapy and 500 received endocrine therapy alone. Patients treated with endocrine therapy alone were older and frailer than patients treated with surgery plus adjuvant endocrine therapy. Unmatched overall survival and breast-cancer-specific survival were higher in the surgery plus adjuvant endocrine therapy group (overall survival: hazard ratio 0.27, 95% confidence interval 0.23 to 0.33; p < 0.001; breast-cancer-specific survival: hazard ratio 0.41, 95% confidence interval 0.29 to 0.58; p < 0.001) than in the endocrine therapy alone group. In matched analysis, surgery plus adjuvant endocrine therapy was still associated with better overall survival (hazard ratio 0.72, 95% confidence interval 0.53 to 0.98; p = 0.04) than endocrine therapy alone, but not with better breast-cancer-specific survival (hazard ratio 0.74, 95% confidence interval 0.40 to 1.37; p = 0.34) or progression-free-survival (hazard ratio 1.11, 95% confidence interval 0.55 to 2.26; p = 0.78). (b) The adjuvant chemotherapy versus no chemotherapy comparison: 2811 out of 3416 (82%) women received surgery plus adjuvant endocrine therapy, of whom 1520 (54%) had high-recurrence-risk breast cancer [grade 3, node positive, oestrogen receptor negative or human epidermal growth factor receptor-2 positive, or a high Oncotype DX^® (Genomic Health, Inc., Redwood City, CA, USA) score of > 25]. In this high-risk population, there were no differences according to adjuvant chemotherapy use in overall survival or breast-cancer-specific survival after propensity matching. Adjuvant chemotherapy was associated with a lower risk of metastatic recurrence than no chemotherapy in the unmatched (adjusted hazard ratio 0.36, 95% confidence interval 0.19 to 0.68; p = 0.002) and propensity-matched patients (adjusted hazard ratio 0.43, 95% confidence interval 0.20 to 0.92; p = 0.03). Adjuvant chemotherapy improved the overall survival and breast-cancer-specific survival of patients with oestrogen-receptor-negative disease. (2) Mixed-methods research to develop a decision support intervention: an iterative process was used to develop two decision support interventions (each comprising a brief decision aid, a booklet and an online tool) specifically for older women facing treatment choices (endocrine therapy alone or surgery plus adjuvant endocrine therapy, and adjuvant chemotherapy or no chemotherapy) using several evidence sources (expert opinion, literature and patient interviews). The online tool was based on models developed using registry data from 23,842 patients and validated on an external data set of 14,526 patients. Mortality rates at 2 and 5 years differed by < 1% between predicted and observed values. (3) Cluster-randomised clinical trial of decision support tools: 46 UK breast units were randomised (intervention, n = 21; usual care, n = 25), recruiting 1339 women (intervention, n = 670; usual care, n = 669). There was no significant difference in global quality of life at 6 months post baseline (difference –0.20, 95% confidence interval –2.7 to 2.3; p = 0.90). In women offered a choice of endocrine therapy alone or surgery plus adjuvant endocrine therapy, knowledge about treatments was greater in the intervention arm than the usual care arm (94% vs. 74%; p = 0.003). Treatment choice was altered, with higher rates of endocrine therapy alone than of surgery in the intervention arm. Similarly, chemotherapy rates were lower in the intervention arm (endocrine therapy alone rate: intervention sites 21% vs. usual-care sites 15%, difference 5.5%, 95% confidence interval 1.1% to 10.0%; p = 0.02; adjuvant chemotherapy rate: intervention sites 10% vs. usual-care site 15%, difference 4.5%, 95% confidence interval 0.0% to 8.0%; p = 0.013). Survival was similar in both arms. (4) Health economic analysis: a probabilistic economic model was developed using registry and cohort study data. For most health and fitness strata, surgery plus adjuvant endocrine therapy had lower costs and returned more quality-adjusted life-years than endocrine therapy alone. However, for some women aged > 90 years, surgery plus adjuvant endocrine therapy was no longer cost-effective and generated fewer quality-adjusted life-years than endocrine therapy alone. The incremental benefit of surgery plus adjuvant endocrine therapy reduced with age and comorbidities. (5) Variation in practice: analysis of rates of surgery plus adjuvant endocrine therapy or endocrine therapy alone between the 56 breast units in the cohort study demonstrated significant variation in rates of endocrine therapy alone that persisted after adjustment for age, fitness and stage. Clinician preference was an important determinant of treatment choice. Conclusions: This study demonstrates that, for older women with oestrogen-receptor-positive breast cancer, there is a cohort of women with a life expectancy of < 4 years for whom surgery plus adjuvant endocrine therapy may offer little benefit and simply have a negative impact on quality of life. The Age Gap decision tool may help make this shared decision. Similarly, although adjuvant chemotherapy offers little benefit and has a negative impact on quality of life for the majority of older women with oestrogen-receptor-positive breast cancer, for women with oestrogen-receptor-negative breast cancer, adjuvant chemotherapy is beneficial. The negative impacts of adjuvant chemotherapy on quality of life, although significant, are transient. This implies that, for the majority of fitter women aged ≥ 70 years, standard care should be offered. Limitations: As with any observational study, despite detailed propensity score matching, residual bias cannot be excluded. Follow-up was at median 52 months for the cohort analysis. Longer-term follow-up will be required to validate these findings owing to the slow time course of oestrogen-receptor-positive breast cancer. Future work: The online algorithm is now available (URL: https://agegap.shef.ac.uk/; accessed May 2022). There are plans to validate the tool and incorprate quality-of-life and 10-year survival outcomes. Trial registration: This trial is registered as ISRCTN46099296. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 10, No. 6. See the NIHR Journals Library website for further project information.

Background: Infective endocarditis is a heart infection with a first-year mortality rate of ≈ 30%. It has long been thought that infective endocarditis is causally associated with bloodstream seeding with oral bacteria in ≈ 40–45% of cases. This theorem led guideline committees to recommend that individuals at increased risk of infective endocarditis should receive antibiotic prophylaxis before undergoing invasive dental procedures. However, to the best of our knowledge, there has never been a clinical trial to prove the efficacy of antibiotic prophylaxis and there is no good-quality evidence to link invasive dental procedures with infective endocarditis. Many contend that oral bacteria-related infective endocarditis is more likely to result from daily activities (e.g. tooth brushing, flossing and chewing), particularly in those with poor oral hygiene. Objective: The aim of this study was to determine if there is a temporal association between invasive dental procedures and subsequent infective endocarditis, particularly in those at high risk of infective endocarditis. Design: This was a self-controlled, case-crossover design study comparing the number of invasive dental procedures in the 3 months immediately before an infective endocarditis-related hospital admission with that in the preceding 12-month control period. Setting: The study took place in the English NHS. Participants: All individuals admitted to hospital with infective endocarditis between 1 April 2010 and 31 March 2016 were eligible to participate. Interventions: This was an observational study; therefore, there was no intervention. Main outcome measure: The outcome measure was the number of invasive and non-invasive dental procedures in the months before infective endocarditis-related hospital admission. Data sources: NHS Digital provided infective endocarditis-related hospital admissions data and dental procedure data were obtained from the NHS Business Services Authority. Results: The incidence rate of invasive dental procedures decreased in the 3 months before infective endocarditis-related hospital admission (incidence rate ratio 1.34, 95% confidence interval 1.13 to 1.58). Further analysis showed that this was due to loss of dental procedure data in the 2–3 weeks before any infective endocarditis-related hospital admission. Limitations: We found that urgent hospital admissions were a common cause of incomplete courses of dental treatment and, because there is no requirement to record dental procedure data for incomplete courses, this resulted in a significant loss of dental procedure data in the 2–3 weeks before infective endocarditis-related hospital admissions. The data set was also reduced because of the NHS Business Services Authority’s 10-year data destruction policy, reducing the power of the study. The main consequence was a loss of dental procedure data in the critical 3-month case period of the case-crossover analysis (immediately before infective endocarditis-related hospital admission), which did not occur in earlier control periods. Part of the decline in the rate of invasive dental procedures may also be the result of the onset of illness prior to infective endocarditis-related hospital admission, and part may be due to other undefined causes. Conclusions: The loss of dental procedure data in the critical case period immediately before infective endocarditis-related hospital admission makes interpretation of the data difficult and raises uncertainty over any conclusions that can be drawn from this study. Future work: We suggest repeating this study elsewhere using data that are unafflicted by loss of dental procedure data in the critical case period. Trial registration: This trial is registered as ISRCTN11684416. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 28. See the NIHR Journals Library website for further project information.