Introduction Falls are a major public health concern, particularly among older adults. Without life-threatening symptoms, ambulance calls may be triaged as low priority and people may remain on the floor and experience a “long lie”, risking dehydration, pressure injury, muscle damage and psychological distress. However, there is currently limited evidence on the scale, clinical impact and subsequent care trajectory for people who have experienced a long lie. This study aims to address this gap by exploring the characteristics, outcomes, and potential interventions for people who experience a long lie after a fall. Methods This is a comprehensive, 27-month, mixed-methods study structured across seven interlinked work packages (WPs). Quantitative work (WP1 & WP2) will analyse linked ambulance, emergency department, and hospital data from one ambulance service region to characterise individuals who experience long lies, quantify their care trajectories, estimate resource use, and explore and refine the definition of a ‘harmful long lie’ threshold. WP3 involves a detailed review of 200 patient hospital notes to understand the mechanisms by which long lies impact health outcomes and care trajectories. Qualitative work (WP4, WP5, & WP6) includes analysis of surveys and semi-structured interviews with ambulance staff, care home managers, key stakeholders, and, crucially, individuals with lived experience of a long lie and their carers. WP7 will synthesize all findings in workshops with national stakeholders to co-produce clear, evidence-based guidance and policy recommendations for managing long lies. Discussion By integrating quantitative data on scale and cost of long lies with qualitative data on lived experience and professional practice, this study will provide in-depth understanding of the clinical, social, and economic impact of long lies. The findings will inform the development of interventions to mitigate the harmful effects of prolonged time on the floor leading to improved care pathways and better outcomes for individuals who experience a long lie after a fall.

Background:Overactive bladder is a common problem affecting the United Kingdom adult female population. Symptoms include urinary urgency, with or without urgency incontinence, increased daytime urinary frequency and nocturia. Initial conservative treatments for overactive bladder are unsuccessful in 25-40% of women (refractory overactive bladder). Before considering invasive treatments, such as botulinum toxin injection-A or sacral neuromodulation, guidelines recommend urodynamics to confirm diagnosis of detrusor overactivity. However, the clinical and cost effectiveness of urodynamics has never been robustly assessed. Objectives:To compare the clinical and cost effectiveness of urodynamics plus comprehensive clinical assessment versus comprehensive clinical assessment only in the management of refractory overactive bladder in women. Design:Parallel-group, multicentre, superiority, open-label, randomised controlled trial. Allocation by remote web-based randomisation (1 : 1 ratio). The cost-effectiveness analysis took the National Health Service perspective with a model-based lifetime time horizon, as informed by a within-trial analysis. Setting:Sixty-three United Kingdom secondary and tertiary hospitals. Participants:Women aged ≥ 18 years with refractory overactive bladder or urgency-predominant mixed urinary incontinence who had failed conservative management and pharmacological treatment and were being considered for invasive treatment. Women were excluded if any of the following criteria were met: predominant stress urinary incontinence; previous urodynamics in last 12 months; current pelvic malignancy or clinically significant pelvic mass; bladder pain syndrome; neurogenic bladder; urogenital fistulae; previous treatment with botulinum toxin injection-A or sacral neuromodulation for urinary incontinence; previous pelvic radiotherapy; prolapse beyond introitus; pregnant or planning pregnancy; recurrent urinary tract infection where a significant pathology has not been excluded; and inability to give an informed consent. Interventions:Urodynamics plus comprehensive clinical assessment (urodynamics arm) versus comprehensive clinical assessment only. Main outcome measures:Participant-reported success at the last follow-up time point as measured by the Patient Global Impression of Improvement. Primary economic outcome was incremental cost per quality-adjusted life-year gained as modelled over the lifetime of participants. Results:A total of 1099 participants were included: 550 randomised to the urodynamics arm and 549 to the comprehensive clinical assessment only arm. At the final follow-up time point, participant-reported success rates of 'very much improved' and 'much improved' were not superior in the urodynamics arm (117 participants; 23.6%) compared to the comprehensive clinical assessment only arm (114 participants; 22.7%) [adjusted odds ratio 1.12 (95% confidence interval 0.73 to 1.74); p = 0.601]. Serious adverse events were low and similar between groups. Based on the estimated incremental costs and quality-adjusted life-years of urodynamics (£463 and 0.011, respectively), the incremental cost-effectiveness ratio was £42,643 per quality-adjusted life-year gained. The cost-effectiveness acceptability curve shows that urodynamics has a 34% probability of being cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained. This probability reduced further when the results were extrapolated over the patient's lifetime. Limitations include: only short-term outcomes were available, and as most participants underwent botulinum toxin injection-A treatment, pre-planned secondary analyses for some outcomes such as sacral neuromodulation were not possible. Conclusion:Participant-reported success in the urodynamics arm was not superior to the comprehensive clinical assessment only arm at 15-months follow-up. Urodynamics is not cost-effective at a threshold of £20,000 per quality-adjusted life-year gained. Longer-term follow-up is required to explore need for further interventions and treatments and their effect on the clinical and cost-effectiveness analyses. Trial registration:This trial is registered as ISRCTN63268739. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/150/05) and is published in full in Health Technology Assessment Vol. 29, No. 27. See the NIHR Funding and Awards website for further award information.

OBJECTIVES:To estimate the cost-effectiveness of using invasive urodynamic studies (UDS) in the management of women with refractory overactive bladder (OAB) symptoms using the results of the FUTURE trial. PATIENTS AND METHODS:The FUTURE study is the largest randomised controlled trial evaluating the clinical effectiveness of UDS with comprehensive clinical assessment (CCA) in this patient population compared to CCA only. We developed an economic model that replicates the 24-month results of FUTURE, then models the lifetime costs and quality-adjusted life-years (QALYs) using long-term studies of treatment outcomes. RESULTS:Over the patient cohort's lifetime the UDS plus CCA group is £1380 more costly and is associated with 0.002 fewer QALYs than the CCA only group, with only a 23.4% chance of being cost-effective at £20 000 per QALY gained. The sensitivity analysis shows that the results are robust to all changes except for the use of parameters based on the complete case analysis of the FUTURE trial. For the subgroup of patients with an initial diagnosis of mixed urinary incontinence, the UDS group gains more QALYs than the CCA group, albeit at a higher cost. The incremental cost-effectiveness ratio for UDS is £26 462, with a probability of being cost-effective of 45.3% at £20 000 per QALY gained and 53.8% at £30 000 per QALY gained. CONCLUSION:The use of UDS in women with a diagnosis of OAB and whose condition is refractory to initial medical and conservative treatments is unlikely to be cost-effective when examined from a UK perspective and with a lifetime horizon. Despite having access to the FUTURE study data, the parameterisation of the model is limited by the current evidence base. An ongoing long-term follow-up study will help reduce these uncertainties.

Purpose We aim to assess the performance of methods for adjusting estimates of treatment effectiveness for patient nonadherence in the context of health technology assessment using simulation methods.Methods We simulated trial datasets with nonadherence, prognostic characteristics, and a time-to-event outcome. The simulated scenarios were based on a trial investigating immunosuppressive treatments for improving graft survival in patients who had had a kidney transplant. The primary estimand was the difference in restricted mean survival times in all patients had there been no nonadherence. We compared generalized methods (g-methods; marginal structural model with inverse probability of censoring weighting [IPCW], structural nested failure time model [SNFTM] with g-estimation) and simple methods (intention-to-treat [ITT] analysis, per-protocol [PP] analysis) in 90 scenarios each with 1,900 simulations. The methods' performance was primarily assessed according to bias.Results In implementation nonadherence scenarios, the average percentage bias was 20% (ranging from 7% to 37%) for IPCW, 20% (8%-38%) for SNFTM, 20% (8%-38%) for PP, and 40% (20%-75%) for ITT. In persistence nonadherence scenarios, the average percentage bias was 26% (9%-36%) for IPCW, 26% (14%-39%) for SNFTM, 26% (14%-36%) for PP, and 47% (16%-72%) for ITT. In initiation nonadherence scenarios, the percentage bias ranged from -29% to 110% for IPCW, -34% to 108% for SNFTM, -32% to 102% for PP, and between -18% and 200% for ITT.Conclusion In this study, g-methods and PP produced more accurate estimates of the treatment effect adjusted for nonadherence than the ITT analysis did. However, considerable bias remained in some scenarios.

OBJECTIVES:This study's primary objective was to test the feasibility of using the online personal utility function (OPUF) approach and develop a preliminary utility tariff for the EQ-5D-5L based on a South African community sample. METHODS:The need for an ethnically and socioeconomically diverse sample was seen as essential. This led to the need for interviewer assistance during completion of the survey instrument and translation of the instrument into multiple languages. English, Zulu, Tswana, and Afrikaans were chosen to allow the vast majority of a community sample people to participate. A sample size of sixty respondents was based on a previous OPUF pilot valuation study for the EQ-5D-5L, and a pilot study of twenty respondents was undertaken using the English language version of OPUF. RESULTS:There were sixty-one respondents in the main study with most respondent characteristics being well matched with national figures, except for language. Personal utility functions could be calculated for sixty respondents, with the mean tariff showing monotonically declining utility decrements within each dimension. An examination of individual functions showed two contrasting sets of preferences that were driven by the respondents' rating of death. A separate subgroup analysis also showed preference heterogeneity based on the home language of the respondents. CONCLUSIONS:Our study showed that the application of the OPUF approach is possible in a socioeconomically diverse population in South Africa. The examination of individual personal utility functions shows marked heterogeneity of preferences that needs to be explored further so that the source of this can be established.

BACKGROUND:Overactive bladder is a common problem affecting women worldwide, with a negative effect on their social and professional lives. Before considering invasive treatments, guidelines recommend urodynamics to identify detrusor overactivity. However, the clinical-effectiveness and cost-effectiveness of urodynamics has never been robustly assessed in this cohort of women. We aimed to compare the clinical-effectiveness and cost-effectiveness of urodynamics plus comprehensive clinical assessment (CCA) versus CCA only in the management of women with refractory overactive bladder symptoms. METHODS:We did a multicentre, superiority, parallel, open-label, randomised controlled trial in 63 UK hospitals. Women aged 18 years or older with refractory overactive bladder or urgency predominant mixed urinary incontinence, with failed conservative management and being considered for invasive treatment, were randomly assigned (1:1) to urodynamics plus CCA versus CCA only. Assignment used an internet-based application with stratified random permuted blocks and site and baseline diagnosis as stratum. Primary outcome was participant-reported success at the last follow-up timepoint, measured by the Patient Global Impression of Improvement at 15 months after randomisation. Primary economic outcome was incremental cost per quality-adjusted life-year (QALY) gained modelled over the participants lifetime. Analysis was based on the intention-to-treat principle. This study is registered with ISRCTN registry (ISRCTN63268739). FINDINGS:Between Nov 6, 2017, and March 1, 2021, 1099 participants were randomly assigned to urodynamics plus CCA (n=550) or CCA only (n=549). At the final follow-up timepoint, participant-reported success rates of "very much improved" and "much improved" were not superior in the urodynamics plus CCA group (117 [23·6%] of 496) versus the CCA-only group (114 [22·7%] of 503; adjusted odds ratio 1·12 [95% CI 0·73-1·74]; p=0·60). Serious adverse events were low and similar between groups. Incremental cost-effectiveness ratio was £42 643 per QALY gained. The cost-effectiveness acceptability curve showed urodynamics had a 34% probability of being cost-effective at a willingness-to-pay threshold of £20 000 per QALY gained, which reduced further when extrapolated over the patient's lifetime. INTERPRETATION:In women with refractory overactive bladder or urgency predominant mixed urinary incontinence, the participant-reported success in the urodynamics plus CCA group was not superior to the CCA-only group, and urodynamics was not cost-effective at the £20 000 per QALY gained threshold. FUNDING:UK National Institute for Health and Care Research Health Technology Assessment Programme.

Background Self-management education and support programmes help people with type 2 diabetes to manage their diabetes better. However, most people do not attend these programmes. Objective Increase type 2 diabetes self-management programme attendance. Design Workstream 1: develop intervention (mixed methods). Workstream 2: refine intervention and trial design (feasibility study). Workstream 3: evaluate effectiveness (18-month wait-list cluster randomised controlled trial with ethnography component; baseline: months −3 to 0; step one: months 1–9; step two: months 10–18; minimum clinically significant difference in glycated haemoglobin: 1.1 mmol/mol; target sample size: 66 practices). Workstream 4: health economics analysis; 12-month observational follow-up of trial population; qualitative substudy. Setting Primary care practices and providers of self-management programmes (East Midlands, Thames Valley and South Midlands, Yorkshire and Humber). Participants Workstream 1: 103 stakeholders. Workstream 2: 6 practices. Workstreams 3–4: 64 practices (92,977 people with type 2 diabetes). Qualitative substudy: 30 participants. Intervention Embedding Package (marketing strategy for self-management programmes; user-friendly referral pathway; new/amended professional roles; resources toolkit) delivered through an online portal for practices and providers (‘toolkit’; 88 live accounts; average of 19 page views/week); people working with practices and providers to embed self-management programmes into routine practice (‘embedders’). Additionally, a patient digital support programme (MyDESMOND) was developed. The comparator was usual care. Main outcome measures Patient-level glycated haemoglobin (primary outcome, continuous, mmol/mol) and referrals to, and attendance at, self-management programmes (main secondary outcomes; binary yes/no variables) compared between control (wait-list: baseline and step one; immediate: baseline) and intervention (wait-list: step two; immediate: steps one and two) conditions. Data sources Existing interviews, published literature, workshops, patient-level practice data, patient self-completed questionnaire, patient-level provider data, ethnographic data and one-to-one interviews. Results Workstreams 1 and 2: intervention and trial successfully developed then refined. Workstream 3: glycated haemoglobin was not significantly different (p = 0.503) between intervention and control conditions (adjusted mean difference −0.10 mmol/mol, 95% confidence interval −0.38 to 0.18; −0.01%, 95% confidence interval −0.03% to 0.02%). Both patient-level referral to, and attendance at, structured self-management education programmes were lower or similar during the intervention than control conditions. There was no significant difference in most other secondary outcomes. Prespecified analyses indicated that glycated haemoglobin was statistically significantly lower (p = 0.004) among ethnic minority individuals during intervention than control conditions (−0.64 mmol/mol, 95% confidence interval −1.08 to −0.20; −0.06%, 95% confidence interval −0.10 to −0.02). This difference was not clinically significant and self-management programme attendance did not improve. Ethnography analyses found that the intervention’s attractiveness and usefulness were not self-evident to practices and providers, much of the activity was led by the embedders, and embedders covering multiple localities were not best placed to adapt the intervention to local contexts. Workstream 4: the intervention cost £0.52 per patient. There was no evidence of a difference in costs (−£33, 95% confidence interval −£2195 to +£2171) or quality-adjusted life-years (+0.002, 95% confidence interval −0.100 to +0.098) in the base-case analysis. The trial plus 12-month observational follow-up data showed that glycated haemoglobin was statistically significantly lower (−0.56 mmol/mol, 95% confidence interval −0.71 to −0.42; −0.05, 95% confidence interval −0.06% to −0.04%; p < 0.001) and self-management programme attendance higher (adjusted odds ratio 1.13, 95% confidence interval 1.02 to 1.25; p = 0.017) in intervention than control conditions, although it should be noted that the difference was not clinically significant. The qualitative substudy indicated that virtual programmes have a place in future self-management programme delivery, with highly positive feedback, particularly around financial and logistical benefits. Limitations The COVID-19 pandemic affected this research. A delayed start to the feasibility study prevented all learnings being taken into the wait-list trial, particularly around implementing the intervention at provider, not practice level. Practice engagement with the intervention was limited and variable. National Health Service commissioning restructures in England meant that, for many localities, changes to the provision of diabetes self-management programme commissioning included funding and capacity to co-ordinate and promote uptake in a similar way to the Embedding Package. With the wait-list design, a proxy primary outcome for self-management programme attendance was used, which may have affected the sensitivity of results. Finally, baseline structured self-management education programme attendance was higher than expected, and data sources were between 39% and 66% complete. Conclusions There were difficulties implementing the intervention, which probably contributed to the trial showing that, overall, the Embedding Package was unlikely to have affected glycated haemoglobin, self-management programme referrals and attendance or most other secondary outcomes. Future work Focus should be on which organisation(s)/role(s) can best drive change around embedding type 2 diabetes self-management programmes into routine care, and the role of blended face-to-face and virtual programmes. Trial registration This trial is registered as Current Controlled Trials ISRCTN23474120. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1212-20004) and is published in full in Programme Grants for Applied Research; Vol. 13, No. 2. See the NIHR Funding and Awards website for further award information. Plain language summary The problem: Self-management education and support programmes help people with type 2 diabetes to manage their diabetes. National Health Service guidelines recommend these programmes, but many people are not offered them and most do not attend. What we did: We tried to increase attendance at type 2 diabetes self-management programmes. We created an evidence-based ‘package’ of practical solutions, which included a website with useful resources and a person to encourage organisations to use these resources. We also created a patient digital self-management programme (MyDESMOND) as another way to receive support. We used the package in a small study and improved it based on what we learnt. We then carried out a large study to see whether the package worked and provided value-for-money. What we found: The package did not increase attendance at self-management programmes or improve patient glucose levels. There were many reasons for this; for example, many organisations did not use the package. However, there were small improvements in glucose levels among people from ethnic minority backgrounds, who are generally less likely to access self-management programmes. Also, glucose levels and programme attendance improved slightly when we looked at a longer period than the main study. The package was very low cost (52 pence per person). What does this mean? This package is a starting point for helping more people with type 2 diabetes access support to manage their diabetes, but more work is needed. Scientific summary Background Type 2 diabetes mellitus (T2DM) remains a major health challenge in the United Kingdom. Structured self-management education (SSME) programmes help people with T2DM to manage their diabetes. These programmes are typically designed to engage people in developing and maintaining healthy habits (e.g. food, physical activity, medication taking, glucose monitoring) through peer and professional support and education. Evidence shows that SSME programmes are effective and cost-effective. T2DM SSME programmes are therefore recommended in national and international guidelines. Uptake of SSME programmes is poor, however, with the latest National Diabetes Audit figures showing that, within 12 months of diagnosis, 75% of people with T2DM were offered SSME but only 11% attended. Aim We aimed to develop and test an intervention (‘Embedding Package’) to increase T2DM SSME uptake by addressing barriers and supporting enablers to uptake at patient, healthcare professional and organisational levels. Objectives There were four workstreams. Public involvement underpinned the programme. Workstream 1: develop and tailor Embedding Package, including further development of a digital SSME programme (MyDESMOND); build capacity and develop resources; establish public involvement reference groups. Workstream 2: pilot Embedding Package to assess feasibility and suitability of components; Assess feasibility of collecting data with sufficient accuracy and completeness; refine Embedding Package. Workstream 3: conduct a wait-list cluster randomised controlled trial (RCT) with ethnographic study to compare and understand impact of Embedding Package with usual care on glycated haemoglobin (HbA1c) and SSME attendance [minimum clinically significant difference in HbA1c: 1.1 mmol/mol (0.1 %); target sample size: 66 practices]. Workstream 4: assess cost-effectiveness and sustainability of Embedding Package; conduct qualitative substudy to understand the impact of virtual SSME programmes. Methods Workstream 1: developing Embedding Package Mixed-methods development work for the Embedding Package, including: (1) secondary analysis of existing qualitative data, systematic literature review and the merging of the resulting coded data with further analysis; (2) stakeholder consultation through workshops and interviews; and (3) analysis of all collected data. This resulted in a list of evidence-based components needed by an intervention to increase SSME uptake. The multifaceted Embedding Package was then designed by a specialist education team based on this list. Workstream 2: feasibility study A single-arm, mixed-methods feasibility study in six practices across two Clinical Commissioning Groups (CCGs; East Midlands) piloted two patient recruitment approaches, data collection methods and intervention delivery in three participant groups: patients, practice staff, staff in SSME providers. Quantitative data were collected from primary care electronic medical records (extracted data, 2877 patients) and self-completed patient questionnaires (self-reported data, 423 participants). Health economics data were collected from SSME provider databases and questionnaires and interviews with practice managers and CCG staff. An integrated ethnographic study included observations, interviews and document analysis. Workstream 3: randomised controlled trial Using a wait-list cluster randomised design, with practice-level randomisation, we compared the Embedding Package with usual care (i.e. practices referred patients to SSME following their current standards). All practices provided usual care for 3 months (baseline, months −3–0). Practices were then randomised (1 : 1) to receive the Embedding Package for steps one and two of the RCT (months 1–18; immediate group; 33 practices; 16,340 patients) or for step two only (months 10–18; wait-list group; 31 practices; 18,393 patients). The primary outcome was patient-level HbA1c compared between intervention and control conditions as a proxy for SSME attendance, which was not suitable as a primary outcome due to the wait-list design. The main secondary outcomes were patient-level referral to and attendance at SSME (binary yes/no). Analysis used mixed models to account for patient- and practice-level clustering. Secondary analyses compared the completeness of SSME referral and attendance data from three sources (self-report, practice, SSME provider). The ethnography study used e-mail communications between the embedders (a key role introduced as part of the Embedding Package) and practices/providers, an intervention ‘tracker’ (database completed by the embedders to track embedding activities), embedder-generated documents, interviews with the embedders and one SSME provider, and observations of meetings between embedders and practices. Interpretive thematic analysis informed by normalisation process theory (NPT) was conducted. Workstream 4: assess cost-effectiveness and sustainability and enable implementation For the health economics, the primary (base-case) analysis estimated the costs of embedding activities as implemented across all practices within the RCT, and the discounted quality-adjusted life-years (QALYs) and costs in the intervention and control conditions. To assess sustainability, a 12-month observational follow-up took place immediately after the RCT during which the study team no longer actively reinforced the Embedding Package, but practices and providers could continue using it (minus the embedder). The RCT models for HbA1c, SSME referral and SSME attendance were repeated using the RCT data plus the observational data. The qualitative substudy (two primary care practices) comprised one-to-one telephone or video calls with practice staff (who were also virtual SSME educators) and people with T2DM who attended virtual SSME (‘attendees’). Topic schedules were mapped on the NPT and theoretical domains framework. Thematic analysis informed the data analysis. Intervention The Embedding Package comprised the key components of an intervention to embed SSME (see Results) delivered through a ‘toolkit’ and ‘embedder’. The toolkit was an online portal of resources, including tools, how-to guides and sample resources for anyone actively involved in implementing SSME (e.g. commissioners, providers, primary care staff). There were 88 live toolkit accounts, which could be accessed by multiple individuals. There were 19 page views on average per week for the toolkit (including by study staff as data could not be separated). The embedder also formed part of the intervention and was a new/amended role to work with practices and programme providers to embed support programmes into routine practice locally. The most and least common embedder activities were ‘promoting to patients’ (41% of activities) and ‘increasing referrals’ (3% of activities), respectively. Additionally, a patient digital support programme (MyDESMOND) was developed due to the absence of an online option at the time. The comparator was usual care. Results Workstream 1: developing the Embedding Package We developed the intervention as planned. Key components of an intervention to embed SSME into primary care were identified as: A clear marketing strategy for SSME. A user-friendly and effective referral pathway. New/amended professional roles. A toolkit of resources. Workstream 2: feasibility study The feasibility study showed that the RCT would be feasible, albeit with design improvements. Key findings included that the RCT primary outcome data (HbA1c) were over 90% complete in primary care, and 91% of patient-participants completing questionnaires consented to their responses being linked with their extracted primary care data. There was limited engagement from most participating practices and focusing the intervention implementation on practice staff was not feasible given capacity constraints in practices. It was therefore planned that, in the RCT, the focus of intervention implementation would be SSME providers. However, this proved difficult because RCT data were collected at the practice level, therefore embedders had to maintain a practice-level focus. Workstream 3: randomised controlled trial Baseline SSME attendance was higher than expected, at 64% and 38% in the wait-list and immediate groups, respectively. While providers were included in the RCT, much of the embedding activities remained focused at the practice level. The practices interacted minimally with both the embedder and the toolkit. Of the 66 RCT practices, 17 did not engage and 4 only used display boards in waiting areas. The remaining 45 practices had at least an initial meeting with an embedder. The primary outcome (HbA1c) was not significantly different (p = 0.503) between intervention and control conditions [adjusted mean difference, −0.10 mmol/mol, 95% confidence interval (CI) −0.38 to 0.18; −0.01%, 95% CI −0.03% to 0.02%]. There was also no significant difference in most of the secondary outcomes. Prespecified analyses indicated that HbA1c was statistically significantly lower (p = 0.004) among ethnic minority individuals during intervention than control conditions (adjusted mean difference −0.64 mmol/mol, 95% CI −1.08 to −0.20 or −0.06%, 95% CI −0.10% to −0.02%). This difference was not clinically significant and SSME attendance was not significantly different between intervention and control conditions. There was no difference in HbA1c among white individuals between the intervention and control periods. The three data sources for SSME referral and attendance data (practice, self-report and provider data) ranged from 39% to 66% complete. The ethnography component found that the attractiveness and usefulness of the Embedding Package were not self-evident to participating practices and providers, and most activity was led by the embedder, with much less active engagement from practice/provider staff. The analysis showed the importance of adapting the Embedding Package to local contexts, and that an embedder covering multiple localities was not necessarily best placed to undertake this. Workstream 4: assess cost-effectiveness and sustainability and enable implementation The pooled cost per patient of the Embedding Package was £0.52. There was no evidence of a difference in costs (−£33, 95% CI −£2195 to +£2171) or QALYs (+0.002, 95% CI −0.100 to +0.098) in the base-case analysis. The sustainability analyses (18-month trial data plus 12-month observational follow-up data) showed that HbA1c was statistically significantly lower (−0.56 mmol/mol, 95% CI −0.71 to −0.42, or −0.05%, 95% CI −0.06% to −0.04%; p < 0.001) and support programme attendance higher (adjusted odds ratio 1.13, 95% CI 1.02 to 1.25; p = 0.017) during intervention than control conditions. There was no statistically significant difference in SSME referrals. The qualitative substudy strongly indicated that virtual SSME programmes have a place in future education delivery. Feedback on virtual programmes was highly positive, particularly for the financial and logistical benefits. Negative perceptions included information technology challenges, a lack of interaction and informal conversations with fellow attendees, and difficulties in reading body language and visual cues during virtual delivery. Conclusions This programme was designed to address a gap in understanding how to improve uptake to T2DM SSME. We found that, although there was initial enthusiasm for the Embedding Package in some practices, there were difficulties in implementing it, and so many practices did not receive the intervention as it was intended. These were in part due to the embedder role sitting centrally with the study team, rather than in the locations where the package was being implemented or with the local provider organisation. Furthermore, since the proposal for this programme, the structure of NHS commissioning was reformed within England, which meant that, for many localities, changes to the provision of diabetes self-management programme in commissioning plans included funding and capacity to co-ordinate and promote uptake in a similar way to the Embedding Package. This limited uptake of the Embedding Package likely contributed to it having no overall effect on the primary or main secondary outcomes. It is also important to consider the impact of the COVID-19 pandemic, as this started during the latter step of the RCT and meant that all activities by the embedder were stopped prematurely. There were, nevertheless, some promising results. First, HbA1c (primary outcome) improved among ethnic minority groups during the periods when the Embedding Package was being implemented. However, recorded SSME attendance did not improve among this group, and so this may not have been due to the Embedding Package. Second, during the longer-term analyses, HbA1c was lower and SSME attendance higher during the intervention than control periods. This finding suggests that the positive impact of the Embedding Package may have taken longer than expected to realise highlighting that system-wide change such as this may require longer to be realised. However, other external factors could have also brought about this improvement. Implications for health care National roll-out of the Embedding Package in its current format is not suitable given the findings of this programme. However, given the low per-patient cost of the intervention and that the results were indicative of positive changes in the long term, we will instead create a PDF version of the toolkit so that the information contained within it can still be accessed by practices and SSME providers. The potential improvement in HbA1c among ethnic minority groups is of note. T2DM is known to disproportionately impact ethnic minority groups. It is therefore imperative that any initiatives to increase uptake to T2DM SSME do not further widen inequalities around access to support, which is the case with most initiatives in the UK and other industrialised countries. Conversely, implementation of the Embedding Package was associated with improvements in HbA1c in people in an ethnic minority population. This suggests that the Embedding Package, or parts of it, may have a role in future efforts to increase SSME uptake among ethnic minority groups. MyDESMOND became more important during the COVID-19 pandemic and is now among the top four diabetes applications (apps) on the ORCHA app library. Further evaluation is needed. The qualitative substudy findings suggest that patient choice could be important, particularly around having the option to attend SSME face-to-face and/or virtually. Key recommendations for research Consider how best to increase uptake to SSME within the new context of increased focus on digital/virtual modalities due in part to the COVID-19 pandemic, while maintaining the benefits to some underserved populations without alienating others and widening disparities (e.g. those without internet access). Consider how to tailor initiatives to embed SSME into routine care for underserved populations. Consider how best to embed SSME into routine care, particularly whether a local embedder working within a provider organisation is best placed to drive change. Evaluate blended approaches that combine face-to-face and virtual SSME delivery. Further evaluate MyDESMOND. Patient and public involvement The purpose of patient and public involvement was to involve people affected by the research and potential outcomes of the research at all levels of the project. The public involvement plan comprised five main areas of work: (1) public contributors involvement in study groups; (2) oversight and wider involvement through practice Patient Participant Groups (PPGs) and other local groups; (3) support via a local stakeholder group; (4) MyDESMOND development and consultation; and (5) dissemination of findings. Contributors provided governance and oversight of the project, offered advice on recruitment, publicity, local culture and dissemination, and acted as a critical friend giving feedback on project delivery in the local context. Public involvement was challenging because we needed to grow new networks in the localities involved in the RCT. The PPGs at participating primary care practices offered a potential solution to this that could be a useful approach in other research studies. Trial registration This trial is registered as Current Controlled Trials ISRCTN23474120. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1212-20004) and is published in full in Programme Grants for Applied Research; Vol. 13, No. 2. See the NIHR Funding and Awards website for further award information.

Abstract Background Opioids kill more people than any other class of drug. Naloxone is an opioid antagonist which can be distributed in kits for peer administration. We assessed the feasibility of implementing a Take-home Naloxone (THN) intervention in emergency settings, as part of designing a definitive randomised controlled trial (RCT). Methods We undertook a clustered RCT on sites pairing UK Emergency Departments (ED) and ambulance services. At intervention sites, we recruited emergency healthcare practitioners to supply THN to patients presenting with opioid overdose or related condition, with recruitment across 2019–2021. We assessed feasibility of intervention implementation against four predetermined progression criteria covering site sign up and staff training; identification of eligible patients; issue of THN kits and Serious Adverse Events. Results At two intervention sites, randomly selected from 4, 299/687 (43.5%) clinical staff were trained (ED1 = 107, AS1 = 121, ED2 = 25, AS2 = 46). Sixty THN kits were supplied to eligible patients (21.7%) (n: ED1 = 36, AS1 = 4, ED2 = 16, AS2 = 4). Across sites, kits were not issued to eligible patients on a further 164 occasions, with reasons reported including: staff forgot (n = 136), staff too busy (n = 15), and suspected intentional overdose (n = 3), no kit available (n = 2), already given by drugs nurse (n = 4), other (n = 4). Staff recorded 626 other patients as ineligible but considered for inclusion, with reasons listed as: patient admitted to hospital (n = 194), patient absconded (n = 161) already recruited (n = 64), uncooperative or abusive (n = 55), staff not trained (n = 43), reduced consciousness level (n = 41), lack of capacity (n = 35), patient in custody (n = 21), other (n = 12). No adverse events were reported. Conclusion Staff and patient recruitment were low and varied widely by site. This feasibility study did not meet progression criteria; a fully powered RCT is not planned. Trial Registration ISRCTN13232859 (Registered 16/02/2018).

Abstract Introduction Post stroke elbow spasticity (PSES) affects over a third of individuals following stroke and negatively impacts on functional recovery, comfort and quality of life. Drug therapies have limited efficacy and unwanted side effects, botulinum toxin, although effective, is costly, and conventional electrical stimulation therapies are limited long term by habituation. We aim to investigate the efficacy of Sheffield Adaptive Patterned Electrical Stimulation (SHAPES), that delivers temporally and spatially varying pattern of electrical stimulation, against transcutaneous electrical stimulation (TENS) and standard care at reducing PSES. Methods and design Overall, 297 people with PSES will be randomised (1:1:1) to one of 3 arms: Standard care (no electrical stimulation), TENS (conventional patterned electrical stimulation) or SHAPES (adaptive patterned electrical stimulation). Both SHAPES and TENS are delivered using a specially designed electrical stimulation sleeve used for 60 min each day for 6-weeks. Outcome measures are completed at baseline, end of treatment (EOT 6 weeks) and then 6-weeks, 12-weeks and 24-weeks after the end of treatment. Efficacy will be determined based on the proportion of participants experiencing meaningful improvement (18%) in the 7-day Numerical Rating Scale (NRS-S) for PSES, compared between both intervention arms and standard care, and between the two intervention groups. Measures of arm motor function (Action Research Arm Test, MRC scale), and quality of life (SQoL-6D, EQ-5D) will also be measured along with a parallel health economic evaluation. Discussion The results of the SHAPES trial will inform management of elbow spasticity after stroke. The SHAPES intervention is a low cost, self-administered intervention for the management of spasticity that can be used repeatedly, and if found to be more effective than TENS or control has the potential to be widely implemented in the UK NHS healthcare setting. Furthermore, despite the wide use of TENS in the management of spasticity, this study will provide critically required evidence regarding its efficacy. The trial has been registered with the ISRCTN registry (ISRCTN26060261).

Background Opioids kill more people than any other class of drug. Naloxone is an opioid antagonist which can be distributed in kits for peer administration. We aimed to determine feasibility of undertaking a definitive randomised controlled trial (RCT) of Take-home Naloxone (THN) in emergency settings. Methods Using individual-level-routine health records (2015-21) we tested feasibility of developing a discriminant function to identify people at high-risk of fatal opioid poisoning for outcome comparisons. We undertook a clustered RCT on paired UK Emergency Department (ED) and ambulance service sites. At intervention sites, we recruited practitioners to administer THN to patients presenting with opioid overdose or related condition during ta 1year recruitment period, 2019 – 21. We assessed feasibility of intervention and trial methods against predetermined progression criteria. Results Within routine health records on the population of Wales (~3,200,000), we identified 1,105 adult deaths from opioid poisoning, of whom 307 (27.8%) had no ED or drugs service contacts in the year before death. At a predicted probability threshold of 0.0003, a discriminant function based on demographics and recent healthcare contacts identified 809 opioid related deaths within 1 year (sensitivity 74.7%) in 989,151 people, missing 274 cases. Lowering the threshold to 0.0002 increased sensitivity to 86.1% but included a further 608,191 non-cases; raising it to 0.0004 reduced sensitivity to 65.4% and inclusion of non-cases to 646,750. At two intervention sites, randomly selected from 4: 299/687 (43.5%) clinical staff were trained; 60/277 eligible patients (21.7%) were supplied with a THN kit and no adverse events were reported. Conclusion With a low incidence of opioid-related death and significant proportion with no contact with ED or drug services in the year before death, the numbers needed to reach a reasonable sensitivity was very high. This study did not meet progression criteria, a fully powered trial is not planned. Trial Registration ISRCTN13232859 (Registered 16/02/2018)

Background A substantial number of Emergency Department (ED) attendances by care home residents are potentially avoidable. Health Call Digital Care Homes is an app-based technology that aims to streamline residents' care by recording their observations such as vital parameters electronically. Observations are triaged by remote clinical staff. This study assessed the effectiveness of the Health Call technology to reduce unplanned secondary care usage and associated costs.Methods A retrospective analysis of health outcomes and economic impact based on an intervention. The study involved 118 care homes across the North East of UK from 2018 to 2021. Routinely collected NHS secondary care data from County Durham and Darlington NHS Foundation Trust was linked with data from the Health Call app. Three outcomes were modelled monthly using Generalised Linear Mixed Models: counts of emergency attendances, emergency admissions and length of stay of emergency admissions. A similar approach was taken for costs. The impact of Health Call was tested on each outcome using the models.Findings Data from 8,702 residents were used in the analysis. Results show Health Call reduces the number of emergency attendances by 11% [6-15%], emergency admissions by 25% [20-39%] and length of stay by 11% [3-18%] (with an additional month-by-month decrease of 28% [24-34%]). The cost analysis found a cost reduction of 57 pound per resident in 2018, increasing to 113 pound in 2021.Interpretation The introduction of a digital technology, such as Health Call, could significantly reduce contacts with and costs resulting from unplanned secondary care usage by care home residents.

Background:Opioids kill more people than any other drug. Naloxone is an opioid antagonist which can be distributed in take-home 'kits' for peer administration (take-home naloxone). Aim:To determine the feasibility of carrying out a definitive randomised controlled trial of take-home naloxone in emergency settings. Design:We used Welsh routine data (2015-21) to test the feasibility of developing a discriminant function to identify people at high risk of fatal opioid overdose. We carried out a cluster randomised controlled trial and qualitative study to examine experiences of service users and providers. We assessed feasibility of intervention and trial methods against predetermined progression criteria related to: site sign-up, staff trained, identification of eligible patients, proportion given kits, identification of people who died of opioid poisoning, data linkage and retrieval of outcomes. Setting:This study was carried out in the emergency environment; sites comprised an emergency department and associated ambulance service catchment area. Participants:At intervention sites, we invited emergency department clinicians and paramedics to participate. We recruited adult patients who arrived at the emergency department or were attended to by ambulance paramedics for a problem related to opioid use with capacity to consent to receiving the take-home naloxone and related training. Interventions:Usual care comprised basic life support plus naloxone by paramedics or emergency department staff. The take-home naloxone intervention was offered in addition to usual care, with guidance for recipients on basic life support, the importance of calling the emergency services, duration of effect, safety and legality of naloxone administration. Discriminant function:With low numbers of opioid-related deaths (1105/3,227,396) and a high proportion having no contact with health services in the year before death, the predictive link between death and opioid-related healthcare events was weak. Logistic regression models indicated we would need to monitor one-third of the population to capture 75% of the decedents from opioid overdose in 1-year follow-up. Randomised controlled trial:Four sites participated in the trial and 299 of 687 (44%) eligible clinical staff were trained. Sixty take-home naloxone kits were supplied to patients during 1-year recruitment. Eligible patients were not offered take-home naloxone kits 164 times: 'forgot' (n = 136); 'too busy' (n = 15); suspected intentional overdose (n = 3). Qualitative interviews:Service users had high levels of knowledge about take-home naloxone. They were supportive of the intervention but noted concerns about opioid withdrawal and resistance to attending hospital for an overdose. Service providers were positive about the intervention but reported barriers including difficulty with consenting and training high-risk opioid users. Health economics:We were able to calculate costs to train staff at three sites (£40 per AS and £17 in Site 1 ED). No adverse events were reported. Progression criteria were not met - fewer than 50% of eligible staff were trained, fewer than 50% of eligible patients received the intervention and outcomes were not retrieved within reasonable timescales. Future work:The take-home naloxone intervention needs to be developed and evaluated in emergency care settings, with appropriate methods. Limitations:The Take-home naloxone Intervention Multicentre Emergency setting study was interrupted by coronavirus disease. Conclusions:This study did not meet progression criteria for intervention or trial methods feasibility, so outcomes were not followed up and a fully powered trial is not planned. Trial registration:This trial is registered as ISRCTN13232859. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/91/04) and is published in full in Health Technology Assessment; Vol. 28, No. 74. See the NIHR Funding and Awards website for further award information.

Background: The presence of dental caries impacts on children's daily lives, particularly among those living in deprived areas. There are successful interventions across the United Kingdom for young children based on toothbrushing with fluoride toothpaste. However, evidence is lacking for oral health improvement programmes in secondary-school pupils to reduce dental caries and its sequelae. Objectives: To determine the clinical and cost effectiveness of a behaviour change intervention promoting toothbrushing for preventing dental caries in secondary-school pupils. Design: A multicentre, school-based, assessor-blinded, two-arm cluster randomised controlled trial with an internal pilot and embedded health economic and process evaluations. Setting: Secondary schools in Scotland, England and Wales with above-average proportion of pupils eligible for free school meals. Randomisation occurred within schools (year-group level), using block randomisation stratified by school. Participants: Pupils aged 11-13 years at recruitment, who have their own mobile telephone. Interventions: Two-component intervention based on behaviour change theory: (1) 50-minute lesson delivered by teachers, and (2) twice-daily text messages to pupils' mobile phones about toothbrushing, compared with routine education. Main outcome measures: Primary outcome: presence of at least one treated or untreated carious lesion using DICDAS4-6MFT (Decayed, Missing and Filled Teeth) in any permanent tooth, measured at pupil level at 2.5 years. Secondary outcomes included: number of DICDAS4-6MFT; presence and number of DICDAS1-6MFT; plaque; bleeding; twice-daily toothbrushing; health-related quality of life (Child Health Utility 9D); and oral health-related quality of life (Caries Impacts and Experiences Questionnaire for Children). Results: Four thousand six hundred and eighty pupils (intervention, n = 2262; control, n = 2418) from 42 schools were randomised. The primary analysis on 2383 pupils (50.9%; intervention 1153, 51.0%; control 1230, 50.9%) with valid data at baseline and 2.5 years found 44.6% in the intervention group and 43.0% in control had obvious decay experience in at least one permanent tooth. There was no evidence of a difference (odds ratio 1.04, 95% confidence interval 0.85 to 1.26, p = 0.72) and no statistically significant differences in secondary outcomes except for twice-daily toothbrushing at 6 months (odds ratio 1.30, 95% confidence interval 1.03 to 1.63, p = 0.03) and gingival bleeding score (borderline) at 2.5 years (geometric mean difference 0.92, 95% confidence interval 0.85 to 1.00, p = 0.05). The intervention had higher incremental mean costs (1.02 pound, 95% confidence interval -1.29 to 3.23) and lower incremental mean quality-adjusted life-years (-0.003, 95% confidence interval -0.009 to 0.002). The probability of the intervention being cost-effective was 7% at 2.5 years. However, in two subgroups, pilot trial schools and schools with higher proportions of pupils eligible for free school meals, there was an 84% and 60% chance of cost effectiveness, respectively, although their incremental costs and quality-adjusted life-years remained small and not statistically significant. The process evaluation revealed that the intervention was generally acceptable, although the implementation of text messages proved challenging. The COVID-19 pandemic hampered data collection. High rates of missing economic data mean findings should be interpreted with caution. Conclusions: Engagement with the intervention and evidence of 6-month change in toothbrushing behaviour was positive but did not translate into a reduction of caries. Future work should include work with secondary-school pupils to develop an understanding of the determinants of oral health behaviours, including toothbrushing and sugar consumption, particularly according to free school meal eligibility.

OBJECTIVES:This multicentre, assessor-blinded, two-arm cluster randomized trial evaluated the clinical and cost-effectiveness of a behaviour change intervention promoting toothbrushing for preventing dental caries in UK secondary schools. METHODS:Pupils aged 11-13 years with their own mobile telephone attending secondary schools with above average free school meals eligibility were randomized (at year-group level) to receive a lesson and twice-daily text messages or to usual care. Year-groups (n = 84) from 42 schools including 4680 pupils (intervention, n = 2262; control, n = 2418) were randomized. RESULTS:In 2383 participants with valid data at baseline and 2.5 years, the primary outcome of presence of at least one treated or untreated carious lesion (D4-6 MFT [Decayed, Missing and Filled Teeth] in permanent teeth using International Caries Detection and Assessment System) was 44.6% in the intervention group and 43.0% in control (odds ratio [OR] 1.04, 95% CI 0.85-1.26, p = .72). There were no statistically significant differences in secondary outcomes of presence of at least one treated or untreated carious lesion (D1-6 MFT), number of D4-6 MFT and D1-6 MFT, plaque and bleeding scores or health-related- (Child Health Utility 9D) or oral health-related- quality of life (CARIES-QC). However, twice-daily toothbrushing, reported by 77.6% of pupils at baseline, increased at 6 months (intervention, 86.9%; control, 83.0%; OR 1.30, 95% CI 1.03-1.63, p = .03), but returned to no difference at 2.5 years (intervention, 81.0%; control, 79.9%; OR 1.05, 95% CI 0.84-1.30, p = .69). Estimated incremental costs and quality-adjusted life-years (QALYs) of the intervention, relative to control, were £1.02 (95% CI -1.29 to 3.23) and -0.003 (95% CI -0.009 to 0.002), respectively, with a 7% chance of being cost-effective (£20 000/QALY gained threshold). CONCLUSION:There was no evidence of statistically significant difference for caries prevalence at 2.5-years. The intervention's positive 6-month toothbrushing behaviour change did not translate into caries reduction. (ISRCTN 12139369). COVID-19 pandemic adversly affected follow-up.

Abstract Background Self-management education programmes are cost-effective in helping people with type 2 diabetes manage their diabetes, but referral and attendance rates are low. This study reports on the effectiveness of the Embedding Package, a programme designed to increase type 2 diabetes self-management programme attendance in primary care. Methods Using a cluster randomised design, 66 practices were randomised to: (1) a wait-list group that provided usual care for nine months before receiving the Embedding Package for nine months, or (2) an immediate group that received the Embedding Package for 18 months. ‘Embedders’ supported practices and self-management programme providers to embed programme referral into routine practice, and an online ‘toolkit’ contained embedding support resources. Patient-level HbA1c (primary outcome), programme referral and attendance data, and clinical data from 92,977 patients with type 2 diabetes were collected at baseline (months − 3–0), step one (months 1–9), step 2 (months 10–18), and 12 months post-intervention. An integrated ethnographic study including observations, interviews, and document analysis was conducted using interpretive thematic analysis and Normalisation Process Theory. Results No significant difference was found in HbA1c between intervention and control conditions (adjusted mean difference [95% confidence interval]: -0.10 [-0.38, 0.18] mmol/mol; -0.01 [-0.03, 0.02] %). Statistically but not clinically significantly lower levels of HbA1c were found in people of ethnic minority groups compared with non-ethnic minority groups during the intervention condition (-0.64 [-1.08, -0.20] mmol/mol; -0.06% [-0.10, -0.02], p = 0.004), but not greater self-management programme attendance. Twelve months post-intervention data showed statistically but not clinically significantly lower HbA1c (-0.56 [95% confidence interval: -0.71, -0.42] mmol/mol; -0.05 [-0.06, -0.04] %; p < 0.001), and higher self-management programme attendance (adjusted odds ratio: 1.13; 95% confidence interval: 1.02, 1.25; p = 0.017) during intervention conditions. Themes identified through the ethnographic study included challenges for Embedders in making and sustaining contact with practices and providers, and around practices’ interactions with the toolkit. Conclusions Barriers to implementing the Embedding Package may have compromised its effectiveness. Statistically but not clinically significantly improved HbA1c among ethnic minority groups and in longer-term follow-up suggest that future research exploring methods of embedding diabetes self-management programmes into routine care is warranted. Trial registration ISRCTN23474120, registered 05/04/2018.

OBJECTIVE:Worldwide, adults and children are at risk of adrenal insufficiency largely due to infectious diseases and adrenal suppression from use of anti-inflammatory glucocorticoids. Home waking salivary cortisone is an accurate screening test for adrenal insufficiency, it has potential to reduce costs, and patients prefer it to the adrenocorticotropin (ACTH) (synacthen) stimulation test. We carried out a service evaluation of home waking salivary cortisone in clinical care to identify implementation barriers. DESIGN, PATIENTS AND MEASUREMENTS:Service evaluation in a centre where 212 patients referred for adrenal insufficiency had a waking salivary cortisone. Problems encountered during testing were recorded and patient feedback, via focus groups, collected. RESULTS:From all patients providing a waking salivary cortisone 55% had a normal test, 23% adrenal suppression, and 22% an equivocal result requiring a clinical centre ACTH stimulation test. The median (interquartile range [IQR]) for the time of the saliva sample was 07:40 (07:00-08:40). The median (IQR) days between collection and (i) delivery to local laboratory was 1 (0.25-2) day; (ii) reporting by local laboratory was 13 (11-18) days. Patients considered the test is "easy to do" and preferred it to the inpatient ACTH stimulation test. The principal challenge to clinical implementation was results reporting to clinicians due to delays at the local laboratory. CONCLUSIONS:This service evaluation provides real-world evidence that home waking salivary cortisone is an effective, practical screening test for adrenal insufficiency. It identified key barriers to testing implementation that need to be addressed when introducing the test to a health service.

Abstract Disclosure: N.R. Lawrence: None. B.G. Keevil: None. C. Elder: None. J. Fearnside: None. S. Caunt: None. S. Dixon: None. J.D. Newell-Price: Consulting Fee; Self; Diurnal, Recordati, Crinetics, HRA Pharma. R.J. Ross: Employee; Self; Diurnal. M. Debono: None. Background: The ACTH (Cosyntropin) stimulation test (AST) is the reference standard for diagnosis of adrenal insufficiency. We have demonstrated recently that home waking salivary cortisone accurately predicts the ACTH stimulation test outcome and confirms or excludes adrenal insufficiency in 70% of high-risk patients (in press: Home Waking Salivary Cortisone to Screen for Adrenal Insufficiency NEJM Evidence). 11-hydroxyandrostenedione (11-OHA4) is a weak adrenal androgen whose synthesis is dependent on CYP11B1. Since ACTH drives steroidogenesis, and adrenal androgens are low in patients with adrenal insufficiency, we hypothesised that waking 11-OHA4 could also predict adrenal status. Methods: A prospective, diagnostic accuracy study of waking salivary cortisone was performed in 173 patients at high risk of AI. All patients collected a salivary sample on waking, and then attended the endocrine clinic for an AST with the 30-minute cortisol used to diagnose AI. Salivary cortisone and 11-OHA4 was measured in the waking salivary sample. Biomarker discrimination was assessed by calculation of area under the curve (AUC) of the receiver operator characteristics (ROC) plot. Equivocal results were defined to maintain a sensitivity of 95% and specificity of 95%, and percentage of AST saved by calculating the number of AST needed if used only in equivocal cases. Results: The median (IQR) for 11-OHA4 for patients with AI and no AI was 55 (45 to 110) pmol/l vs 508 (255 to 765) pmol/l; p<0.0001. Salivary 11-OHA4 on waking was highly predictive of adrenal insufficiency (R2=0.63, ROC AUC 0.94), similar to waking salivary cortisone alone (R2=0.65, AUC 0.94). Waking 11-OHA4 performed better than either serum cortisol (R2=0.65, AUC 0.88) or salivary cortisone (R2=0.74, AUC 0.93) collected at the baseline of the AST. Combining both waking salivary 11-OHA4 with waking salivary cortisone further improved discrimination (R2=0.70, AUC 0.96), and using this combination would mean that 78% of ACTH-stimulation tests could be avoided. Conclusion: Waking salivary 11-OHA4 can accurately predict AI with similar discriminatory value as waking salivary cortisone. Combining waking 11-OHA4 with waking salivary cortisone improves discrimination for adrenal insufficiency, is a simple non-invasive test that can be used widely in clinical practice in the ambulatory setting, and obviates the need for AST in 78% of cases with greater patient convenience and lower costs. Presentation: Sunday, June 18, 2023

BackgroundWorldwide, adults and children are at risk of adrenal insufficiency as a result of adrenal suppression from use of anti-inflammatory glucocorticoids and opiates, as well as infectious diseases. The adrenocorticotropin (ACTH) stimulation test is the reference standard for diagnosis of adrenal insufficiency but requires clinic attendance and venesection. Salivary cortisone reflects free serum cortisol, and samples can be collected at home and posted to a laboratory. We tested whether home waking salivary cortisone level could be used to screen for adrenal insufficiency.MethodsA prospective, diagnostic accuracy study was performed in patients at high risk of adrenal insufficiency. Patients collected a home salivary sample on waking and then attended the clinical facility for an ACTH stimulation test. Salivary cortisone was measured by liquid chromatography–tandem mass spectrometry. Receiver-operating characteristic curves were computed, and positive and negative predictive values were calculated.ResultsTwo hundred twenty patients were recruited. As measured by an ACTH stimulation test, the prevalence of adrenal insufficiency was 44%. The area under the receiver-operating characteristic curve for waking salivary cortisone as a predictor of adrenal insufficiency was 0.95 (95% confidence interval [CI], 0.92 to 0.97). Cutoffs to ensure a minimum of 95% sensitivity and specificity gave a negative predictive value of 96% (95% CI, 90 to 99) and a positive predictive value of 95% (95% CI, 87 to 99) to exclude and confirm adrenal insufficiency, respectively. Waking salivary cortisone data provided information similar to that of an ACTH stimulation test in 70% of participants. Eighty-three percent of patients preferred home salivary collection to clinic attendance.ConclusionsHome waking salivary cortisone sampling has accuracy for the diagnosis of adrenal insufficiency similar to that of a standard ACTH stimulation test. Patients found the at-home test to be more convenient than the hospital-based test. (Funded by the National Institute for Health Research.)