P-tau217 and other blood biomarkers of dementia: variation with time of day.

Plasma biomarkers of dementia, including phosphorylated tau (p-tau217), offer promise as tools for diagnosis, stratification for clinical trials, monitoring disease progression, and assessing the success of interventions in those living with Alzheimer's disease. However, currently, it is unknown whether these dementia biomarker levels vary with the time of day, which could have implications for their clinical value. In two protocols, we studied 38 participants (70.8 ± 7.6 years; mean ± SD) in a 27-h laboratory protocol with either two samples taken 12 h apart or 3-hourly blood sampling for 24 h in the presence of a sleep-wake cycle. The study population comprised people living with mild Alzheimer's disease (PLWA, n = 8), partners/caregivers of PLWA (n = 6) and cognitively intact older adults (n = 24). Single-molecule array technology was used to measure phosphorylated tau (p-tau217) (ALZpath), amyloid-beta 40 (Aß40), amyloid-beta 42 (Aß42), glial fibrillary acidic protein, and neurofilament light (NfL) (Neuro 4-Plex E). Analysis with a linear mixed model (SAS, PROC MIXED) revealed a significant effect of time of day for p-tau217, Aß40, Aß42, and NfL, and a significant effect of participant group for p-tau217. For p-tau217, the lowest levels were observed in the morning upon waking and the highest values in the afternoon/early evening. The magnitude of the diurnal variation for p-tau217 was similar to the reported increase in p-tau217 over one year in amyloid-ß-positive mild cognitively impaired people. Currently, the factors driving this diurnal variation are unknown and could be related to sleep, circadian mechanisms, activity, posture, or meals. Overall, this work implies that the time of day of sample collection may be relevant in the implementation and interpretation of plasma biomarkers in dementia research and care.

Safety and procedural success of daycase-based endovascular procedures in lower extremity arteries of patients with peripheral artery disease: a systematic review and meta-analysis.

Background: Timely and economic provision of revascularisation procedures is a major healthcare need. We aimed to examine the safety and efficacy of daycase-based lower extremity endovascular revascularisation procedures in patients with peripheral artery disease. Methods: In this systematic review and meta-analysis, we searched MEDLINE and Embase for studies from Jan 01, 2000 through Apr 01, 2024 reporting complications of lower limb endovascular revascularisation procedures with same-day discharge. Eligibility-criteria, complications, and patient characteristics were extracted, methodological quality assessed (adapted Newcastle-Ottawa Scale), and meta-analyses of complications and technical success performed to provide pooled estimates. This study is registered with PROSPERO, CRD42022316466. Findings: Thirty observational studies (17 retrospective, 13 prospective) and 1 RCT reported 2427 minor and 653 major complications after 99,600 daycase procedures (93,344 patients). Eighteen studies reported daycase eligibility-criteria including 'responsible adult companion' (78%), 'proximity to hospital', and 'telephone availability' and excluding unstable and severe co-morbidities, offset coagulation, and severe chronic kidney disease. Pooled incidences of minor (4.7% [95% CI 3.8-5.6%], I 2 = 96%) and major (0.64% [95% CI 0.48-0.79%], I 2  = 46%) complications were low and technical success high (93% [95% CI 91-96%], I 2 = 97%). Most complications were related to the puncture site. Pooled conversion-to-hospitalisation rates and re-admission after discharge were 1.6% (95% CI 1.1-2.2%, I 2 = 82%) and 0.11% (95% CI 0.095-0.23%, I 2 = 97%), respectively. Meta-regression identified that minor complications decreased since 2000. Male sex and coronary artery disease were associated with more frequent, and higher age and closure device use with less minor complications. Diabetes mellitus and chronic kidney disease were associated with less major complications. Six studies reported complication rates both in daycases and inpatients and there was no significant difference (-0.8% [95% CI -1.9 to 0.3%]). Interpretation: After careful evaluation of eligibility, lower limb angioplasty can be performed safely with high technical success in a daycase setting. Most complications arise from the puncture site and not the procedure itself highlighting the importance of optimal access site management. The heterogeneity between studies warrants standardised monitoring of complications and outcomes. Funding: European Partnership on Metrology, co-financed from European Union's Horizon Europe Research and Innovation Programme and UK Research and Innovation, and Medical Research Council.

Can we improve the management of inoperable malignant bowel obstruction? Results of a feasibility study of elemental diet as an alternative to parenteral nutrition in patients with advanced gynaecological cancer.

PURPOSE: Nutrition support in inoperable bowel obstruction (IBO) remains challenging. Parenteral nutrition (PN) is recommended if the prognosis is > 2 months. An elemental diet (ED) is licensed for strictures in Crohn's disease but has not been used in malignant bowel obstruction. The aim of this study was to evaluate the use of ED in patients with IBO and provide a proof of concept of ED as an acceptable feeding option. METHODS: This was a mixed-methods single-arm feasibility study. The primary endpoint was to provide a 'proof of concept' of ED as an acceptable feeding option for patients with IBO. Secondary endpoints included taste acceptability, incidences of vomiting and pain, the proportion of women who tolerated ED, the number of cartons drunk, quality of life (QOL) and the number of women treated with chemotherapy. Patients (> 18 years) with CT-confirmed IBO who could tolerate 500 ml of liquid in 24 h remained on the trial for 2 weeks. RESULTS: A total of 29 patients were recruited; of those, 19 contributed to the analysis for the primary endpoint; 13 (68.4%) participants tolerated the ED; 26 patients contributed to MSAS and EORTC QLQ questionnaires at baseline to allow for the assessment of symptoms. At the start of the study, 18 (69%) of patients experienced vomiting, reducing to 4 (25%) by the end of day 15 of the study; 24 (92%) of patients reported pain at consent, reducing to 12 (75%) by the end of day 15. QOL scores improved from 36.2 (95% CI 27.7-44.7) at baseline to 53.1 (95% CI 40.3-66) at the end of day 15; 16 (84%) participants commenced chemotherapy within the first week of starting ED. The number of cartons across all participants showed a median of 1.3 cartons per day (range 0.8 to 2.5). CONCLUSION: ED is well tolerated by patients with IBO caused by gynaecological malignancies and may have a positive effect on symptom burden and QOL.

Artificial Intelligence to Facilitate Clinical Trial Recruitment in Age-Related Macular Degeneration.

Objective: Recent developments in artificial intelligence (AI) have positioned it to transform several stages of the clinical trial process. In this study, we explore the role of AI in clinical trial recruitment of individuals with geographic atrophy (GA), an advanced stage of age-related macular degeneration, amidst numerous ongoing clinical trials for this condition. Design: Cross-sectional study. Subjects: Retrospective dataset from the INSIGHT Health Data Research Hub at Moorfields Eye Hospital in London, United Kingdom, including 306 651 patients (602 826 eyes) with suspected retinal disease who underwent OCT imaging between January 1, 2008 and April 10, 2023. Methods: A deep learning model was trained on OCT scans to identify patients potentially eligible for GA trials, using AI-generated segmentations of retinal tissue. This method's efficacy was compared against a traditional keyword-based electronic health record (EHR) search. A clinical validation with fundus autofluorescence (FAF) images was performed to calculate the positive predictive value of this approach, by comparing AI predictions with expert assessments. Main Outcome Measures: The primary outcomes included the positive predictive value of AI in identifying trial-eligible patients, and the secondary outcome was the intraclass correlation between GA areas segmented on FAF by experts and AI-segmented OCT scans. Results: The AI system shortlisted a larger number of eligible patients with greater precision (1139, positive predictive value: 63%; 95% confidence interval [CI]: 54%-71%) compared with the EHR search (693, positive predictive value: 40%; 95% CI: 39%-42%). A combined AI-EHR approach identified 604 eligible patients with a positive predictive value of 86% (95% CI: 79%-92%). Intraclass correlation of GA area segmented on FAF versus AI-segmented area on OCT was 0.77 (95% CI: 0.68-0.84) for cases meeting trial criteria. The AI also adjusts to the distinct imaging criteria from several clinical trials, generating tailored shortlists ranging from 438 to 1817 patients. Conclusions: This study demonstrates the potential for AI in facilitating automated prescreening for clinical trials in GA, enabling site feasibility assessments, data-driven protocol design, and cost reduction. Once treatments are available, similar AI systems could also be used to identify individuals who may benefit from treatment. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Exploring Analysis Approaches for Using the Dopamine Transporter Striatal Binding Ratio in Early- to Mid-Stage Parkinson's Disease Modification Trials.

BACKGROUND: The dopamine transporter striatal binding ratio (DAT SBR) has been used as an outcome measure in Parkinson's disease (PD) trials of potential disease-modifying therapies; however, both patient characteristics and analysis approach potentially complicate its interpretation. OBJECTIVE: The aim was to explore how well DAT SBR reflects PD motor severity across different striatal subregions and the relationship to disease duration, and side of onset. METHODS: DAT SBR for the anterior and posterior putamen and caudate in both hemispheres was obtained using validated automated quantitative software on baseline scans of 132 patients recruited for the Exenatide PD2 and PD3 trials. Associations between mean and lateralized SBR subregions (posterior and anterior putamen and caudate) and summed and lateralized motor characteristics were explored using regression analysis. Analyses were repeated considering disease duration and limiting analysis to the less-affected hemisphere. RESULTS: Lateralized bradykinesia was most consistently associated with the loss of DAT uptake in the contralateral anterior putamen. There was much higher variance in the posterior putamen, and in all regions in those with longer duration disease, although bradykinesia remained robustly associated with anterior putaminal DAT uptake even in longer-duration patients. Restricting analyses to the less-affected side did not usefully reduce the variance compared to the overall cohort. CONCLUSION: These data suggest that DAT SBR could be a useful biomarker in disease-modifying trials, but a focus on anterior striatal subregions and incorporating disease duration into analyses may improve its utility.

MIRRORS ICG: Perfusion Assessment Using Indocyanine Green (ICG) Peritoneal Angiography during Robotic Interval Cytoreductive Surgery for Advanced Ovarian Cancer.

Indocyanine green (ICG) is a fluorescent dye used for sentinel lymph node assessment and the assessment of perfusion in skin flaps and bowel anastomoses. ICG binds serum proteins and behaves as a macromolecule in the circulation. Tumour tissue has increased vascular permeability and reduced drainage, causing macromolecules to accumulate within it. MIRRORS ICG is designed to determine whether indocyanine green (ICG) helped identify metastatic deposits in women undergoing robotic interval cytoreductive surgery for advanced-stage (3c+) ovarian cancer. Peritoneal surfaces of the abdominal and pelvic cavity were inspected under white light and near-infrared light (da Vinci Si and Xi Firefly Fluorescence imaging, Intuitive Surgical Inc.) following intravenous injection of 20 mg ICG in sterile water. Visibly abnormal areas were excised and sent to histopathology, noting IGC positivity. In total, 102 biopsies were assessed using ICG. Intravenous ICG assessment following neoadjuvant chemotherapy had a sensitivity of 91.1% (95% CI [82.6-96.4%]), a specificity of 13.0% (95% CI [2.8-33.6%]), a positive predictive value of 78.3% (95% CI [68.4-86.2%]), and a negative predictive value of 30.0% (95% CI [6.7-65.2%]) False-positive samples were seen in 9/20 patients. Psammoma bodies were noted in the histopathology reports of seven of nine of these patients with false-positive results, indicating that a tumour had been present (chemotherapy-treated disease). This study demonstrates the appearance of metastatic peritoneal deposits during robotic cytoreductive surgery following the intravenous administration of ICG in women who have undergone neoadjuvant chemotherapy for stage 3c+ advanced ovarian cancer. A perfusion assessment using indocyanine green (ICG) peritoneal angiography during robotic interval cytoreductive surgery for advanced ovarian cancer did not clinically improve metastatic disease identification in patients with high-volume disease. The use of ICG in patients with excellent response to chemotherapy where few tumour deposits remained shows some promise. The potential of molecular imaging to enhance precision surgery and improve disease identification using the robotic platform is a novel avenue for future research.

Patients' and Clinicians' Perceptions of the Clinical Utility of Predictive Risk Models for Chemotherapy-Related Symptom Management: Qualitative Exploration Using Focus Groups and Interviews.

BACKGROUND: Interest in the application of predictive risk models (PRMs) in health care to identify people most likely to experience disease and treatment-related complications is increasing. In cancer care, these techniques are focused primarily on the prediction of survival or life-threatening toxicities (eg, febrile neutropenia). Fewer studies focus on the use of PRMs for symptoms or supportive care needs. The application of PRMs to chemotherapy-related symptoms (CRS) would enable earlier identification and initiation of prompt, personalized, and tailored interventions. While some PRMs exist for CRS, few were translated into clinical practice, and human factors associated with their use were not reported. OBJECTIVE: We aim to explore patients' and clinicians' perspectives of the utility and real-world application of PRMs to improve the management of CRS. METHODS: Focus groups (N=10) and interviews (N=5) were conducted with patients (N=28) and clinicians (N=26) across 5 European countries. Interactions were audio-recorded, transcribed verbatim, and analyzed thematically. RESULTS: Both clinicians and patients recognized the value of having individualized risk predictions for CRS and appreciated how this type of information would facilitate the provision of tailored preventative treatments or supportive care interactions. However, cautious and skeptical attitudes toward the use of PRMs in clinical care were noted by both groups, particularly in relationship to the uncertainty regarding how the information would be generated. Visualization and presentation of PRM information in a usable and useful format for both patients and clinicians was identified as a challenge to their successful implementation in clinical care. CONCLUSIONS: Findings from this study provide information on clinicians' and patients' perspectives on the clinical use of PRMs for the management of CRS. These international perspectives are important because they provide insight into the risks and benefits of using PRMs to evaluate CRS. In addition, they highlight the need to find ways to more effectively present and use this information in clinical practice. Further research that explores the best ways to incorporate this type of information while maintaining the human side of care is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT02356081; https://clinicaltrials.gov/study/NCT02356081.

Clinical features of audible upper airway secretions ("death rattle") in patients with cancer in the last days of life.

PURPOSE: Audible upper airway secretions ("death rattle") is a common problem in cancer patients at the end-of-life. However, there is little information about its clinical features. METHODS: This is a secondary analysis of a cluster randomised trial of clinically-assisted hydration in cancer patients in the last days of life. Patients were assessed 4 hourly for end-of-life problems (including audible secretions), which were recorded as present or absent, excepting restlessness/agitation, which was scored using the modified Richmond Agitation and Sedation Scale. Patients were followed up until death. RESULTS: 200 patients were recruited, and 186 patients died during the study period. Overall, 54.5% patients developed audible secretions at some point during the study, but only 34.5% patients had audible secretions at the time of death. The prevalence of audible secretions increased the closer to death, with a marked increase in the last 12-16 h of life (i.e. the prevalence of audible secretions was highest at the time of death). Of those with audible secretions at the time of death, 24 had had a previous episode that had resolved. Development of audible secretions was not associated with use of clinically-assisted hydration, but there was an association between audible secretions and restlessness/agitation, and audible secretions and pain. However, most patients with audible secretions were not restless/agitated, or in pain, when assessed. CONCLUSION: Audible secretions ("death rattle") are common in cancer patients at the end-of-life, but their natural history is extremely variable, with some patients experiencing multiple episodes during the terminal phase (although not necessarily experiencing an episode at the time of death).

MIRRORS: a prospective cohort study assessing the feasibility of robotic interval debulking surgery for advanced-stage ovarian cancer.

OBJECTIVE: To establish the feasibility and safety of robotic interval debulking surgery following the MIRRORS protocol (robot-assisted laparoscopic assessment prior to robotic or open surgery) in women with advanced-stage ovarian cancer. MIRRORS is the first of three planned trials: MIRRORS, MIRRORS-RCT (pilot), and MIRRORS-RCT. METHODS: The participants were patients with stage IIIc-IVb epithelial ovarian cancer undergoing neo-adjuvant chemotherapy, suitable for interval debulking surgery with a pelvic mass ≤8 cm. The intervention was robot-assisted laparoscopic assessment prior to robotic or open interval debulking surgery (MIRRORS protocol). The primary outcome was feasibility of recruitment, and the secondary outcomes were quality of life (EORTC QLQC30/OV28, HADS questionnaires), pain, surgical complications, complete cytoreduction rate (%), conversion to open surgery (%), and overall and progression-free survival at 1 year. RESULTS: Overall, 95.8% (23/24) of patients who were eligible were recruited. Median age was 68 years (range 53-83). All patients had high grade serous histology and were BRCA negative. In total, 56.5% were stage IV, 43.5% were stage III, 87.0% had a partial response, while 13.0% had stable disease by RECIST 1.1. Median peritoneal cancer index was 24 (range 6-38). Following MIRRORS protocol, 87.0% (20/23) underwent robotic interval debulking surgery, and 13.0% (3/23) had open surgery. All patients achieved R<1 (robotic R0=47.4%, open R0=0%). No patients had conversion to open. Median estimated blood loss was 50 mL for robotic (range 20-500 mL), 2026 mL for open (range 2000-2800 mL) (p=0.001). Median intensive care length of stay was 0 days for robotic (range 0-8) and 3 days (range 3-13) for MIRRORS Open (p=0.012). The median length of stay was 1.5 days for robotic (range 1-17), 6 days for open (range 5-41) (p=0.012). The time to chemotherapy was as follows 18.5 days for robotic (range 13-28), 25 days for open (range 22-28) (p=0.139). CONCLUSIONS: Robotic interval debulking surgery appears safe and feasible for experienced robotic surgeons in patients with a pelvic mass ≤8 cm. A randomized controlled trial (MIRRORS-RCT) will determine whether MIRRORS protocol has non-inferior survival (overall and progression-free) compared with open interval debulking surgery.

The SEE-IT Trial: emergency medical services Streaming Enabled Evaluation In Trauma: a feasibility randomised controlled trial.

BACKGROUND: Use of bystander video livestreaming from scene to Emergency Medical Services (EMS) is becoming increasingly common to aid decision making about the resources required. Possible benefits include earlier, more appropriate dispatch and clinical and financial gains, but evidence is sparse. METHODS: A feasibility randomised controlled trial with an embedded process evaluation and exploratory economic evaluation where working shifts during six trial weeks were randomised 1:1 to use video livestreaming during eligible trauma incidents (using GoodSAM Instant-On-Scene) or standard care only. Pre-defined progression criteria were: (1) ≥ 70% callers (bystanders) with smartphones agreeing and able to activate live stream; (2) ≥ 50% requests to activate resulting in footage being viewed; (3) Helicopter Emergency Medical Services (HEMS) stand-down rate reducing by ≥ 10% as a result of live footage; (4) no evidence of psychological harm in callers or staff/dispatchers. Observational sub-studies included (i) an inner-city EMS who routinely use video livestreaming to explore acceptability in a diverse population; and (ii) staff wellbeing in an EMS not using video livestreaming for comparison to the trial site. RESULTS: Sixty-two shifts were randomised, including 240 incidents (132 control; 108 intervention). Livestreaming was successful in 53 incidents in the intervention arm. Patient recruitment (to determine appropriateness of dispatch), and caller recruitment (to measure potential harm) were low (58/269, 22% of patients; 4/244, 2% of callers). Two progression criteria were met: (1) 86% of callers with smartphones agreed and were able to activate livestreaming; (2) 85% of requests to activate livestreaming resulted in footage being obtained; and two were indeterminate due to insufficient data: (3) 2/6 (33%) HEMS stand down due to livestreaming; (4) no evidence of psychological harm from survey, observations or interviews, but insufficient survey data from callers or comparison EMS site to be confident. Language barriers and older age were reported in interviews as potential challenges to video livestreaming by dispatchers in the inner-city EMS. CONCLUSIONS: Progression to a definitive RCT is supported by these findings. Bystander video livestreaming from scene is feasible to implement, acceptable to both 999 callers and dispatchers, and may aid dispatch decision-making. Further assessment of unintended consequences, benefits and harm is required. TRIAL REGISTRATION: ISRCTN 11449333 (22 March 2022). https://www.isrctn.com/ISRCTN11449333.

Prognostic and predictive value of ultrasound-based estimated ankle brachial pressure index at early follow-up after endovascular revascularization of chronic limb-threatening ischaemia: a prospective, single-centre, service evaluation.

Background: Ankle brachial pressure index can be estimated (eABPI) using cuffless ankle Doppler ultrasound. We evaluated the prognostic value of eABPI measured during pre- and post-procedural ultrasound exams to predict the clinical outcome after endovascular revascularisations. Methods: In this prospective, single-centre, service evaluation, consecutive patients with symptomatic peripheral artery disease undergoing lower limb endovascular revascularisations between July, 26 2018 and January, 13 2022 at Surrey and Sussex Healthcare NHS Trust (Redhill, UK) were analysed. eABPI was determined using the higher acceleration index measured with angle-corrected duplex ultrasound in ankle arteries before and ≤1 month post-procedure. Clinical outcomes (mortality, major amputations, amputation-free survival [AFS], clinically driven target lesion revascularization [cdTLR], major adverse limb events [MALE; cdTLR and major amputation], wound healing) were assessed over 1 year. Findings: Of 246 patients treated, for 219 patients (median 75 [IQR 66-83] years) pre- and post-procedural eABPI (0.50 [0.33-0.59] and 0.90 [0.69-1.0], p < 0.0001) were available, respectively. In n = 199 patients with chronic limb-threatening ischaemia (CLTI) Kaplan-Meier survival analyses showed that higher post-procedural, but not pre-procedural, eABPI was associated with favourable AFS, MALE, cdTLR, and wound healing. This was confirmed in Cox regression analysis and remained significant with adjustment for pre-procedural eABPI, age, sex, co-morbidities, treated levels, wound score, and foot infection. Whereas all clinical outcomes, except for survival, were significantly better at ≥0.7 vs <0.7, wound healing (unadjusted: HR 1.7 (95% CI 1.2-2.6), adjusted: HR 2.1 (95% CI 1.3-3.1), cdTLR, and MALE (unadjusted: HR 0.41 (95% CI 0.18-0.93), adjusted: HR 0.28 (95% CI 0.11-0.74) were significantly improved at ≥0.9 vs <0.9. Interpretation: Post-procedural eABPI can provide valid, clinically important prognostic and predictive information. Our data indicate that revascularisations should target values of at least 0.9 to achieve optimal outcomes. Future studies need to confirm generalisability and cost-effectiveness in a wider context. Funding: European Partnership on Metrology, co-financed from European Union's Horizon Europe Research and Innovation Programme and UK Research and Innovation.

Cost-Utility Analysis of Total Ankle Replacement Compared with Ankle Arthrodesis for Patients Aged 50-85 Years with End-Stage Ankle Osteoarthritis: The TARVA Study.

BACKGROUND: Patients with end-stage ankle osteoarthritis suffer from reduced mobility and quality of life and the main surgical treatments are total ankle replacement (TAR) and ankle fusion (AF). OBJECTIVES: Our aim was to calculate the mean incremental cost per quality-adjusted life-year (QALY) of TAR compared with AF in patients with end-stage ankle osteoarthritis, over 52 weeks and over the patients' lifetime. METHOD: We conducted a cost-utility analysis of 282 participants from 17 UK centres recruited to a randomised controlled trial (TARVA). QALYs were calculated using index values from EQ-5D-5L. Resource use information was collected from case report forms and self-completed questionnaires. Primary analysis was within-trial analysis from the National Health Service (NHS) and Personal Social Services (PSS) perspective, while secondary analyses were within-trial analysis from wider perspective and long-term economic modelling. Adjustments were made for baseline resource use and index values. RESULTS: Total cost at 52 weeks was higher in the TAR group compared with the AF group, from the NHS and PSS perspective (mean adjusted difference £2539, 95% confidence interval [CI] £1142, £3897). The difference became very small from the wider perspective (£155, 95% CI -  £1947, £2331). There was no significant difference between TAR and AF in terms of QALYs (mean adjusted difference 0.02, 95% CI -  0.015, 0.05) at 52 weeks post-operation. The incremental cost-effectiveness ratio (ICER) was £131,999 per QALY gained 52 weeks post-operation. Long-term economic modelling resulted in an ICER of £4200 per QALY gained, and there is a 69% probability of TAR being cost effective at a cost-effectiveness threshold of £20,000 per QALY gained. CONCLUSION: TAR does not appear to be cost effective over AF 52 weeks post-operation. A decision model suggests that TAR can be cost effective over the patients' lifetime but there is a need for longer-term prospectively collected data. Clinical trial registration ISRCTN60672307 and ClinicalTrials.gov NCT02128555.

PRIORITY Trial: Results from a feasibility randomised controlled trial of a psychoeducational intervention for parents to prevent disordered eating in children and young people with type 1 diabetes.

AIMS: Children and young people (CYP) with type 1 diabetes (T1D) are at increased risk of disordered eating. This study aimed to determine the feasibility and acceptability of a novel, theoretically informed, two-session psychoeducational intervention for parents to prevent disordered eating in CYP with T1D. METHODS: Parents of CYP aged 11-14 years with T1D were randomly allocated to the intervention or wait-list control group. Self-reported measures including the Diabetes Eating Problem Survey-Revised (DEPS-R), Problem Areas in Diabetes Parent Revised (PAID-PR), Child Eating Behaviour Questionnaire subscales (CEBQ), Warwick Edinburgh Mental Wellbeing Scale (WEMWBS), clinical outcomes (e.g. HbA1c, BMI, medication and healthcare utilisation) and process variables, were collected at baseline, 1-and 3-month assessments. Acceptability data were collected from intervention participants via questionnaire. RESULTS: Eighty-nine parents were recruited, which exceeded recruitment targets, with high intervention engagement and acceptability (<80% across domains). A signal of efficacy was observed across outcome measures with moderate improvements in the CEBQ subscale satiety responsiveness (d = 0.55, 95% CI 0.01, 1.08) and child's BMI (d = -0.56, 95% CI -1.09, 0.00) at 3 months compared with controls. Trends in the anticipated direction were also observed with reductions in disordered eating (DEPS-R) and diabetes distress (PAID-PR) and improvements in wellbeing (WEMWBS). CONCLUSIONS: This is the first study to have co-designed and evaluated a novel parenting intervention to prevent disordered eating in CYP with T1D. The intervention proved feasible and acceptable with encouraging effects. Preparatory work is required prior to definitive trial to ensure the most relevant primary outcome measure and ensure strategies for optimum outcome completion.

Understanding the Impact of COVID-19 on Angioplasty Service and Outcome of Patients Treated for Chronic Limb-Threatening Ischaemia: A Single-Centre Retrospective Cohort Study.

We evaluated the impact of COVID-19 restriction on the angioplasty service and outcome of chronic limb-threatening ischaemia (CLTI) patients undergoing lower-limb angioplasty in a UK secondary care setting. Consecutive patients were analysed retrospectively. Pre-COVID-19 (08/2018-02/2020), 106 CLTI patients (91% Fontaine 4; 60% diabetes mellitus) and during COVID-19 (03/2020-07/2021) 94 patients were treated (86% Fontaine 4; 66% diabetes mellitus). While the average monthly number of patients treated did not change, the proportion of day cases significantly increased (53% to 80%), and hospitalised patients decreased. Patients treated in ≤14/5 days after referral significantly increased to 64/63%. Kaplan-Meier survival analysis (30-day/1-year) showed that neither wound healing nor mortality were significantly changed during COVID-19. In day cases, 1-year but not 30-day major amputations significantly increased, and clinically driven target-lesion revascularisation decreased during COVID-19. One-year mortality was significantly worse in hospitalised compared to day cases (14% vs. 43%) at similar wound healing rates (83% vs. 84%). The most frequent known cause of death was infectious disease (64%), while cardiovascular (21%) was less frequent. Despite COVID-19 restrictions, a safe and effective angioplasty service was maintained while shortening waiting times. Very high mortality rates in hospitalised patients may indicate that CLTI patients need to be referred and treated more aggressively earlier.

Addressing a critical need: A randomised controlled feasibility trial of acceptance and commitment therapy for bariatric surgery patients at 15-18 months post-surgery.

Bariatric surgery is an effective treatment for obesity. However, around one in five people experience significant weight regain. Acceptance and Commitment Therapy (ACT) teaches acceptance of and defusion from thoughts and feelings which influence behaviour, and commitment to act in line with personal values. To test the feasibility and acceptability of ACT following bariatric surgery a randomised controlled trial of 10 sessions of group ACT or Usual Care Support Group control (SGC) was delivered 15-18 months post bariatric surgery (ISRCTN registry ID: ISRCTN52074801). Participants were compared at baseline, 3, 6 and 12 months using validated questionnaires to assess weight, wellbeing, and healthcare use. A nested, semi-structured interview study was conducted to understand acceptability of the trial and group processes. 80 participants were consented and randomised. Attendance was low for both groups. Only 9 (29%) ACT participants completed > = half of the sessions, this was the case for 13 (35%) SGC participants. Forty-six (57.5%) did not attend the first session. At 12 months, outcome data were available from 19 of the 38 receiving SGC, and from 13 of the 42 receiving ACT. Full datasets were collected for those who remained in the trial. Nine participants from each arm were interviewed. The main barriers to group attendance were travel difficulties and scheduling. Poor initial attendance led to reduced motivation to return. Participants reported a motivation to help others as a reason to join the trial; lack of attendance by peers removed this opportunity and led to further drop out. Participants who attended the ACT groups reported a range of benefits including behaviour change. We conclude that the trial processes were feasible, but that the ACT intervention was not acceptable as delivered. Our data suggest changes to recruitment and intervention delivery that would address this.

The SEE-IT Trial: emergency medical services Streaming Enabled Evaluation In Trauma: study protocol for an interventional feasibility randomised controlled trial.

INTRODUCTION: Accurate and timely dispatch of emergency medical services (EMS) is vital due to limited resources and patients' risk of mortality and morbidity increasing with time. Currently, most UK emergency operations centres (EOCs) rely on audio calls and accurate descriptions of the incident and patients' injuries from lay 999 callers. If dispatchers in the EOCs could see the scene via live video streaming from the caller's smartphone, this may enhance their decision making and enable quicker and more accurate dispatch of EMS. The main aim of this feasibility randomised controlled trial (RCT) is to assess the feasibility of conducting a definitive RCT to assess the clinical and cost effectiveness of using live streaming to improve targeting of EMS. METHODS AND ANALYSIS: The SEE-IT Trial is a feasibility RCT with a nested process evaluation. The study also has two observational substudies: (1) in an EOC that routinely uses live streaming to assess the acceptability and feasibility of live streaming in a diverse inner-city population and (2) in an EOC that does not currently use live streaming to act as a comparator site regarding the psychological well-being of EOC staff using versus not using live streaming. ETHICS AND DISSEMINATION: The study was approved by the Health Research Authority on 23 March 2022 (ref: 21/LO/0912), which included NHS Confidentiality Advisory Group approval received on 22 March 2022 (ref: 22/CAG/0003). This manuscript refers to V.0.8 of the protocol (7 November 2022). The trial is registered with the ISRCTN (ISRCTN11449333). The first participant was recruited on 18 June 2022.The main output of this feasibility trial will be the knowledge gained to help inform the development of a large multicentre RCT to evaluate the clinical and cost effectiveness of the use of live streaming to aid EMS dispatch for trauma incidents. TRIAL REGISTRATION NUMBER: ISRCTN11449333.

Total ankle replacement versus ankle arthrodesis for patients aged 50-85 years with end-stage ankle osteoarthritis: the TARVA RCT.

Background: We aimed to compare the clinical effectiveness, cost-effectiveness and complication rates of total ankle replacement with those of arthrodesis (i.e. ankle fusion) in the treatment of end-stage ankle osteoarthritis. Methods: This was a pragmatic, multicentre, parallel-group, non-blinded randomised controlled trial. Patients with end-stage ankle osteoarthritis who were aged 50-85 years and were suitable for both procedures were recruited from 17 UK hospitals and randomised using minimisation. The primary outcome was the change in the Manchester-Oxford Foot Questionnaire walking/standing domain scores between the preoperative baseline and 52 weeks post surgery. Results: Between March 2015 and January 2019, 303 participants were randomised using a minimisation algorithm: 152 to total ankle replacement and 151 to ankle fusion. At 52 weeks, the mean (standard deviation) Manchester-Oxford Foot Questionnaire walking/standing domain score was 31.4 (30.4) in the total ankle replacement arm (n = 136) and 36.8 (30.6) in the ankle fusion arm (n = 140); the adjusted difference in the change was -5.6 (95% confidence interval -12.5 to 1.4; p = 0.12) in the intention-to-treat analysis. By week 52, one patient in the total ankle replacement arm required revision. Rates of wound-healing issues (13.4% vs. 5.7%) and nerve injuries (4.2% vs. < 1%) were higher and the rate of thromboembolic events was lower (2.9% vs. 4.9%) in the total ankle replacement arm than in the ankle fusion arm. The bone non-union rate (based on plain radiographs) in the ankle fusion arm was 12.1%, but only 7.1% of patients had symptoms. A post hoc analysis of fixed-bearing total ankle replacement showed a statistically significant improvement over ankle fusion in Manchester-Oxford Foot Questionnaire walking/standing domain score (-11.1, 95% confidence interval -19.3 to -2.9; p = 0.008). We estimate a 69% likelihood that total ankle replacement is cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over the patient's lifetime. Limitations: This initial report contains only 52-week data, which must therefore be interpreted with caution. In addition, the pragmatic nature of the study means that there was heterogeneity between surgical implants and techniques. The trial was run across 17 NHS centres to ensure that decision-making streams reflected the standard of care in the NHS as closely as possible. Conclusions: Both total ankle replacement and ankle fusion improved patients' quality of life at 1 year, and both appear to be safe. When total ankle replacement was compared with ankle fusion overall, we were unable to show a statistically significant difference between the two arms in terms of our primary outcome measure. The total ankle replacement versus ankle arthrodesis (TARVA) trial is inconclusive in terms of superiority of total ankle replacement, as the 95% confidence interval for the adjusted treatment effect includes both a difference of zero and the minimal important difference of 12, but it can rule out the superiority of ankle fusion. A post hoc analysis comparing fixed-bearing total ankle replacement with ankle fusion showed a statistically significant improvement of total ankle replacement over ankle fusion in Manchester-Oxford Foot Questionnaire walking/standing domain score. Total ankle replacement appears to be cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over a patient's lifetime based on long-term economic modelling. Future work: We recommend long-term follow-up of this important cohort, in particular radiological and clinical progress. We also recommend studies to explore the sensitivity of clinical scores to detect clinically important differences between arms when both have already achieved a significant improvement from baseline. Trial registration: This trial is registered as ISRCTN60672307 and ClinicalTrials.gov NCT02128555. 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. 27, No. 5. See the NIHR Journals Library website for further project information.

Each year, over 29,000 patients with ankle osteoarthritis seek a specialist opinion, of whom 4000 undergo NHS surgical treatment. The main surgical treatments for severe ankle osteoarthritis are total ankle replacement or arthrodesis (i.e. ankle fusion). Both are known to be good treatments to relieve pain, and each has its advantages. Total ankle replacement is a more popular patient choice than ankle fusion. When deciding whether to undergo ankle replacement or fusion, patients consult various sources, but the majority of them rely on the advice of their surgeon to make a final decision. To the best of our knowledge, there has never been a high-quality randomised clinical trial comparing these two treatments and there are no published guidelines on the most suitable management. In this study, 303 patients were randomised to a type of ankle surgery: 138 in the total ankle replacement arm and 144 in the ankle fusion arm received surgery. We found that both total ankle replacement and ankle fusion improved patients' walking ability, but we did not find a statistically significant difference between the treatment arms based on our primary outcome measure at 1 year. When we considered the type of total ankle replacement implant, we found that the implant most commonly used in the NHS (a fixed-bearing two-component implant) had better outcomes at 1 year than ankle fusion. Both total ankle replacement and ankle fusion appear to be safe. However, there were more wound-healing issues and nerve injuries in the total ankle replacement arm than in the ankle fusion arm. Twelve per cent of patients experienced bone non-union in the ankle fusion arm, but only 7.1% experienced symptoms. We estimate that there is a 69% chance that total ankle replacement would be cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over a patient's lifetime. This study provides the NHS with important information that could help to obtain the best possible outcome for patients with severe ankle arthritis.

COVAC1 phase 2a expanded safety and immunogenicity study of a self-amplifying RNA vaccine against SARS-CoV-2.

Background: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is well tolerated and immunogenic in SARS-CoV-2 seronegative and seropositive individuals aged 18-75. Methods: A phase 2a expanded safety and immunogenicity study of a saRNA SARS-CoV-2 vaccine candidate LNP-nCoVsaRNA, was conducted at participating centres in the UK between 10th August 2020 and 30th July 2021. Participants received 1 µg then 10 µg of LNP-nCoVsaRNA, ∼14 weeks apart. Solicited adverse events (AEs) were collected for one week post-each vaccine, and unsolicited AEs throughout. Binding and neutralisating anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, and SARS-CoV-2 pseudoneutralisation assay. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). Findings: 216 healthy individuals (median age 51 years) received 1.0 µg followed by 10.0 µg of the vaccine. 28/216 participants were either known to have previous SARS-CoV2 infection and/or were positive for anti-Spike (S) IgG at baseline. Reactogenicity was as expected based on the reactions following licensed COVID-19 vaccines, and there were no serious AEs related to vaccination. 80% of baseline SARS-CoV-2 naïve individuals (147/183) seroconverted two weeks post second immunization, irrespective of age (18-75); 56% (102/183) had detectable neutralising antibodies. Almost all (28/31) SARS-CoV-2 positive individuals had increased S IgG binding antibodies following their first 1.0 µg dose with a ≥0.5log10 increase in 71% (22/31). Interpretation: Encapsulated saRNA was well tolerated and immunogenic in adults aged 18-75 years. Seroconversion rates in antigen naïve were higher than those reported in our dose-ranging study. Further work is required to determine if this difference is related to a longer dosing interval (14 vs. 4 weeks) or dosing with 1.0 µg followed by 10.0 µg. Boosting of S IgG antibodies was observed with a single 1.0 µg injection in those with pre-existing immune responses. Funding: Grants and gifts from the Medical Research Council UKRI (MC_PC_19076), the National Institute for Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, and Restore the Earth.

Flow-mediated dilation reference values for evaluation of endothelial function and cardiovascular health.

AIMS: Endothelial function is essential for cardiovascular health, and flow-mediated dilation (FMD) is an established technique to measure it. This paper aims to assess FMD values in apparently healthy individuals and provides reference values to facilitate wider clinical use. METHODS AND RESULTS: In 1,579 apparently healthy individuals (aged 18-76), fasted FMD values (data from 44 studies, 6 institutions, 22 operators) were normally distributed and inversely univariately correlated with age, body mass index, glucose, cholesterol, blood pressure, and brachial artery (BA) diameter. Significant multivariate predictors of FMD were age (-0.4%/decade), BMI (0.04%/kg/m2), smoking (-0.7%), and BA diameter (-0.44%/mm) that together explained 19% of the variability independent of operator, institution or ultrasound machine. Individuals in the high FMD tertile (>6.8%) were younger, had smaller BA diameter, lower blood pressure and cholesterol. In individuals with low- and intermediate fatal cardiovascular risk (SCORE), 26% and 53% of individuals, respectively, had FMD values in the low tertile (<5.4%). After adding data from 385 patients with stable coronary artery disease (CAD), ROC analysis (c = 0.841, P < 0.001) showed that FMD of >6.5% excluded CAD (95% sensitivity; 60% specificity) and FMD <3.1% excluded 95% healthy individuals (95% specificity, 31% sensitivity). A meta-analysis and meta-regression of 82 clinical trials (11 countries, n = 3,509) using similar FMD methodology showed that despite considerable heterogeneity (I2 = 0.97) FMD in healthy individuals was on average 6.4% (95%CI: 6.2%, 6.7%) with no significant differences between countries but a significant age-dependent decline (-0.3%/decade, R2 = 0.13). CONCLUSIONS: We provide an age-adapted frame of FMD reference intervals in apparently healthy individuals for use as a biomarker of cardiovascular health. As the degree of vascular endothelial function integrates environmental and genetic factors with classical CV risk factors, FMD may more comprehensively classify individuals with and without standard modifiable cardiovascular risk factors and serve as a target for cardiovascular prevention.

Age-Dependent Decline in Common Femoral Artery Flow-Mediated Dilation and Wall Shear Stress in Healthy Subjects.

Femoral artery (FA) endothelial function is a promising biomarker of lower extremity vascular health for peripheral artery disease (PAD) prevention and treatment; however, the impact of age on FA endothelial function has not been reported in healthy adults. Therefore, we evaluated the reproducibility and acceptability of flow-mediated dilation (FMD) in the FA and brachial artery (BA) (n = 20) and performed cross-sectional FA- and BA-FMD measurements in healthy non-smokers aged 22−76 years (n = 50). FMD protocols demonstrated similar good reproducibility. Leg occlusion was deemed more uncomfortable than arm occlusion; thigh occlusion was less tolerated than forearm and calf occlusion. FA-FMD with calf occlusion was lower than BA-FMD (6.0 ± 1.1% vs 6.4 ± 1.3%, p = 0.030). Multivariate linear regression analysis indicated that age (−0.4%/decade) was a significant independent predictor of FA-FMD (R2 = 0.35, p = 0.002). The age-dependent decline in FMD did not significantly differ between FA and BA (pinteraction agexlocation = 0.388). In older participants, 40% of baseline FA wall shear stress (WSS) values were <5 dyne/cm2, which is regarded as pro-atherogenic. In conclusion, endothelial function declines similarly with age in the FA and the BA in healthy adults. The age-dependent FA enlargement results in a critical decrease in WSS that may explain part of the age-dependent predisposition for PAD.