Abstract Objective Treatment of acute COVID-19 with anti-viral and immunomodulator medications demonstrates a reduced risk of long-term outcomes. To date, remdesivir, an intravenous (IV) antiviral that prevents RNA transcription, has not been evaluated in people with Long COVID (LC). This study assessed the feasibility of a five-day IV remdesivir intervention for individuals with LC. Methods Seventy-three participants aged ≥18 years with a confirmed LC diagnosis were recruited across two sites in the United Kingdom to receive a five-day course of IV remdesivir. Primary feasibility outcomes included recruitment, treatment completion, acceptability, and safety. Exploratory patient-reported (e.g. Fatigue Assessment Scale [FAS]) and clinical outcomes (e.g. 6-minute walk test [6MWT]) were also collected. Results Of 106 individuals screened, 73 were enrolled and 71 (97%) completed the 5-day IV remdesivir regimen. Follow-up assessments were completed by 70 participants (96%), with high completion rates observed across clinical assessments, patient-reported outcomes and symptom tracking. No severe adverse reactions were reported. Improvements were also observed in several exploratory patient-reported and clinical outcomes. Conclusion We demonstrated the feasibility and acceptability of administering IV remdesivir in people with LC. Analysis of secondary outcomes suggests therapeutic promise, but rigorous evaluation in large-scale randomised controlled trials is essential to determine the true efficacy and clinical utility of intravenous remdesivir in this population. Lay Summary Long COVID (LC) can cause ongoing symptoms like fatigue and reduced physical ability after a COVID-19 infection. Some medicines used during acute COVID-19 infections, such as antivirals, may lower the risk of long-term problems, but it isn’t clear whether they can help people who already have Long COVID. This study looked at whether it is practical and safe to give remdesivir (an antiviral drug given through a drip in the arm) to people with Long COVID over five days. A total of 73 adults with Long COVID took part across two sites in the UK. Almost all participants (97%) were able to complete the full treatment. About one-third experienced side effects, but none were serious. Researchers also saw signs of improvement in symptoms like fatigue and in physical performance tests, although these were not the main focus of the study. Overall, the study shows that giving remdesivir to people with Long COVID is feasible and generally well tolerated. While early results suggest it might help, larger and more rigorous studies are needed to find out if it truly works.

The ERASE-LC feasibility trial will evaluate the feasibility of using remdesivir for the treatment of long coronavirus disease (COVID) with a wide range of outcome measures. This paper focuses on the nested parametric PET/computed tomography study and outlines the novel protocol utilized. The PET/computed tomography scans will be performed at one of the sites in 20 participants with an overall recruitment target of 72 participants across both centers. The PET/computed tomography scans will be performed at day 11 for the baseline scan and day 55 for the follow-up scan, with an estimated effective radiation dose of approximately 22 mSv under typical study conditions and a maximum anticipated exposure of 31.2 mSv. Dynamic scans will be acquired using the FlowMotion acquisition on a Siemens Biograph Vision 600 scanner with an acquisition time of 75-90 min depending on the height of the participant. Patient and public involvement and engagement was undertaken throughout the study design. The early experiences of performing this protocol demonstrated that participants were able to tolerate the scan duration and positioning. In conclusion, this protocol demonstrates a novel use of parametric PET/computed tomography fluorine-18 fluorodeoxyglucose whole body scans for the assessment of long COVID and response to remdesivir.

OBJECTIVES:We determined whether large artery stiffness (LAS) and systemic microvascular function were associated with cognitive function in older adults, and whether systemic microvascular function mediated the association between LAS and cognitive function. METHODS:Older adults with diverse cardiovascular risk ( n  = 435, 162F) participated in this study. Estimated pulse wave velocity (ePWV) as an estimate of LAS was calculated from age and blood pressure. Skin microvascular function was assessed by acetylcholine (ACh) and sodium nitroprusside (SNP) responses using iontophoresis, and expressed as the area under the curve of each vasodilator (ACh_auc and SNP_auc, respectively). Validated cognitive tasks [Addenbrooke's Cognitive Examination Revised (ACE-R), Trail Making Test Part-A (TMT-A) and Part-B (TMT-B)] were administered to assess participants' cognitive function. RESULTS:One standard deviation (SD) increase in ePWV was positively associated with TMT-A [ β  = 0.339 (0.226, 0.467), P  < 0.001] and TMT-B [ β  = 0.342 (0.232, 0.451), P  < 0.001] after accounting for conventional cardiovascular risk factors. One SD increase in ACh_auc was also associated inversely with TMT-B after similar adjustments [ β  = -0.113 (-0.201, -0.024), P  = 0.013]. A mediation analysis revealed that the association between ePWV and TMT-B was partially mediated by ACh_auc explaining about 3% of the total effect in the crude model, but this did not persist in the adjusted model. CONCLUSION:Increased LAS and skin microvascular dysfunction were associated with poorer cognitive function in older adults, but LAS and skin microvascular function may independently influence cognitive function in our cohort.

Background Delirium is a common neurocognitive disorder in older adults and is associated with poor outcomes. Cognitive, mood and functional deficits can persist for months following an episode, impacting long-term well-being. While previous research has focused on delirium prevention and guidelines exist for short-term management, there remains a critical gap in understanding and supporting longer-term recovery. Objectives Objectives were to: (1) develop an intervention to improve recovery after delirium; (2) conduct a feasibility study of the intervention in people who have had delirium; and (3) conduct a definitive randomised controlled trial and cost-effectiveness analysis of the intervention in people who have had delirium compared with usual care, with parallel process evaluation and an embedded implementation study. Design The study consisted of four work packages. In work package 1, we designed a complex, theory-based rehabilitation intervention informed by a realist review, qualitative research and expert panel input. Work package 2, using a single-arm study, assessed the feasibility of the intervention and of undertaking a definitive randomised controlled trial and cost-effectiveness analysis with an embedded process evaluation, while the aim of work package 3 was to test its effectiveness in a definitive randomised controlled trial, and the aim of work package 4 was to focus on implementation in real-world settings. Setting Acute admissions wards and community follow-up after discharge at six National Health Service hospital sites. Participants Patients aged ≥ 65 years experiencing delirium during acute hospital admission. Intervention Home-based rehabilitation programme designed to support recovery after hospital discharge, addressing cognitive, physical, physiological and psychosocial needs. Delivered by a trained team of occupational therapists, physiotherapists and rehabilitation support workers, the intervention included a comprehensive home assessment, collaborative goal setting, up to 10 personalised therapy sessions over 12 weeks, the use of a recovery record to guide progress, education and psychosocial support. Main outcome measures The main objective of work package 1 was the development of a theory-based and person-centred rehabilitation intervention for individuals recovering from delirium. It included structured components targeting physical, cognitive and emotional recovery, along with an intervention manual and training materials for healthcare professionals. In work package 2, we assessed feasibility, including eligibility, recruitment, data collection, attrition, acceptability of the rehabilitation intervention and the cost-effectiveness framework for a subsequent definitive trial. Patient and carer participants and professional delivering the intervention were interviewed in a process evaluation. Results The intervention was developed using insights from a realist review, stakeholder interviews and expert panel discussions, identifying key recovery domains: physical, cognitive and emotional. Key facilitators included carer involvement, tailoring to individual needs, fostering interpersonal connections and promoting positive self-expression. The feasibility study identified 435 patients with delirium across 6 hospitals, of whom 36 (8%) met eligibility criteria, with 19 (53%) of these consenting to participate. Among those enrolled, 13 (68%) started the intervention, and 10 (53%) completed the final follow-up. Participants had a mean (standard deviation) baseline disability assessment for dementia score of 43.7 (27.1), reflecting the functional status of the recruited population. The mean cost of delivering the intervention was £1249 per participant. The process evaluation highlighted the intervention’s flexibility, acceptability and strong continuity of care, although challenges in recruitment and retention were noted. Limitations In work package 2, the study was limited by a lack of ethnic diversity, reliance on clinical teams for delirium diagnosis and potential selection bias due to staff capacity constraints, which may have impacted recruitment and generalisability. Recruitment was insufficient to progress to the definitive randomised controlled trial, preventing further evaluation and the final implementation study. Following a funding review, the programme was discontinued after work package 2. Patient and public involvement and engagement A patient and public involvement and engagement group of people who had experienced delirium and carers was involved throughout the programme. They assisted with participant materials, design of the intervention, interpretation of the results and recruitment strategies. Conclusions A multidisciplinary rehabilitation intervention for delirium recovery was successfully developed and implemented, with high engagement from participants who remained in the study. However, challenges in recruitment and retention to an evaluation study must be addressed. Future work Future research should focus on understanding hospital processes, the natural history of delirium recovery, community pathways and available services. Refining inclusion criteria will be essential to ensure the feasibility of conducting a randomised controlled trial or other evaluation of the intervention. Study registration This study is registered as ISRCTN15676570, registered 13 December 2022. https://doi.org/10.1186/ISRCTN15676570 Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: NIHR202338) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 7. See the NIHR Funding and Awards website for further award information. Plain language summary Delirium is a serious condition that often affects older people, especially those with dementia. It causes confusion, difficulty focusing and problems with memory and thinking. People with delirium in hospital often need more help on returning home due to problems with mobility and thinking. While most research has focused on preventing delirium, not enough attention has been given to helping people recover from it once back at home. The RecoverED programme was designed to help older adults recover from delirium by supporting their physical, mental and emotional well-being. The programme included exercises to help with physical recovery, activities to improve memory and thinking, and support to help people feel emotionally better. The first part of the study focused on creating the best possible recovery plan by talking to experts, patients and carers. In the second part, the programme was tested with older adults who had delirium in hospital, once they were back at home. We found 435 patients with delirium across 6 hospitals. Thirty-six (8%) were suitable for the trial and 19 took part. Ten people (53%) completed the final follow-up. The results showed that people found the programme to be helpful and felt better after taking part. However, if we had been able to recruit more people, we may have found more changes that needed to be made. The study also faced difficulty in finding enough participants, community rehabilitation staff to deliver it and making sure the programme reached people from all backgrounds. We planned to go on to a full randomised controlled trial of the programme and a study of how to make it work in the National Health Service. However, we were unable to do this because of the difficulties in finding participants in the second part of the study. The study showed that we need to improve how we recruit people, make it clearer who the programme is best suited to and find better ways to support those with complex health needs. Future studies will need to address the challenges we found in recruitment. They should focus on involving people from different backgrounds and finding ways to make the programme available to more people who need it. Scientific summary Background Delirium is a common and serious neurocognitive disorder affecting older adults, particularly those with pre-existing dementia. It is characterised by acute disturbances in attention, awareness and cognition, and it is associated with prolonged hospital stays, functional decline and increased mortality. Beyond the immediate episode, delirium has lasting consequences, with many individuals experiencing persistent cognitive and functional impairments and an increased likelihood of institutionalisation. The condition also places significant emotional and practical burdens on carers while contributing to healthcare costs. Despite its widespread impact, research on delirium has largely focused on prevention and short-term management, leaving a critical gap in understanding and supporting long-term recovery. Emerging evidence suggests that rehabilitation could aid recovery following delirium, yet older adults with cognitive impairment are often incorrectly perceived as having limited rehabilitation potential. Current guidelines highlight the need for effective, non-pharmacological interventions to support long-term recovery after an episode of delirium, particularly for individuals with delirium superimposed on dementia. However, there remains a lack of structured rehabilitation strategies tailored to this population. Addressing this gap requires a deeper understanding of the factors influencing recovery and the development of targeted interventions that promote cognitive and functional improvements, enhance patient and caregiver well-being and reduce healthcare burdens. Aims, objectives and summary of approach The aim of the RecoverED research programme was to develop an intervention to improve recovery following delirium and to evaluate its effectiveness, cost-effectiveness and feasibility for implementation in clinical practice. The intervention targeted the cognitive, functional and emotional aspects of recovery, providing a comprehensive approach to supporting individuals who have experienced delirium. Work package 1: intervention design Work package (WP) 1 aimed to develop a comprehensive programme theory to understand what improves recovery after delirium, for whom and in what context. This programme theory provided the foundation for co-designing a complex rehabilitation intervention for older adults (aged ≥ 65 years) recovering from delirium following acute hospital admission. Work package 2: feasibility and acceptability Work package 2 was a single-arm feasibility single-arm study aimed at assessing the feasibility and acceptability of a home-based rehabilitation intervention designed for older adults who have experienced delirium during acute hospitalisation. The primary objective was to evaluate trial feasibility, whether the intervention was acceptable to both participants and their carers. Secondary objectives included examining the intervention’s acceptability among diverse populations, testing the feasibility of collecting outcome data for a definitive randomised controlled trial (RCT), testing the framework for a future cost-effectiveness analysis (CEA) alongside a definitive trial and engaging in iterative refinements of the intervention. Stop-go criteria determined whether to go on to a full trial. The programme was coproduced with our patient and public involvement and engagement (PPIE) group. Work package 3 was planned to be a definitive RCT of the intervention in 12 sites across the UK. WP4 was planned to be an implementation study of the intervention in two sites, with clinical teams identifying participants rather than research teams. However, following a funding review, the programme was discontinued after WP2 due to significant challenges in identifying and recruiting participants. Despite efforts to refine recruitment strategies, the feasibility study faced persistent difficulties, which limited the number of participants who could take part. These challenges raised concerns about the viability of progressing to a full-scale RCT. As a result, plans for a definitive RCT, CEA and implementation study were halted. Methods and results Work package 1: methods Work package 1 of the RecoverED programme followed Medical Research Council guidelines for complex interventions, using a realist approach to develop a programme theory on improving delirium recovery. This involved five key stages: (1) a rapid realist review to synthesise mechanisms for improving recovery from delirium; (2) qualitative realist interviews with 8 older people who had experienced delirium, 14 carers and 24 healthcare professionals (HCPs) to understand rehabilitation needs; (3) an expert panel workshop to refine the theory and review findings; (4) a series of programme theory development meetings with the core team to revise and produce a logic model and (5) an evaluation of the intervention’s implementation, assessing fidelity and acceptability. A multidisciplinary approach was used in the intervention design, integrating expertise from physiotherapy, occupational therapy, psychology, geriatric medicine and other specialists, informed by the International Classification of Functioning, Disability and Health framework. Continued engagement with our PPIE group ensured that the intervention remained practical, patient-centred and culturally relevant. Work package 1: results The realist review identified three recovery domains: physical recovery through exercise, cognitive recovery with reality orientation and stimulation and emotional recovery through conversations with skilled professionals. Four key facilitators were identified: carer involvement, tailoring the intervention to individual needs, fostering interpersonal connections and promoting positive self-expression. Stakeholder interviews further emphasised the importance of rehabilitation, emotional support, delirium education and addressing health conditions. Expert panel discussions refined the programme theory, emphasising a person-centred approach, integration of rehabilitation into daily life, carer engagement and continuity of relationships with professional carers. This theory guided the development of the RecoverED intervention, ensuring that it addressed the complex needs of delirium recovery. Work package 2: methods Work package 2 employed a multicentre, single-arm feasibility study design with an embedded process evaluation. Participants were recruited from six NHS hospitals in the UK, focusing on individuals aged ≥ 65 years who had been diagnosed with delirium and were expected to return home. The RecoverED intervention, aimed at supporting recovery, began within 2 weeks of discharge and consisted of a structured rehabilitation programme, including assessments by physiotherapists (PTs) and occupational therapists (OTs) and up to 10 sessions delivered by a rehabilitation support worker (RSW) over 12 weeks. Feasibility outcomes were assessed through recruitment and retention rates, with mixed methods used to evaluate implementation fidelity and acceptability. The resources required to deliver the RecoverED intervention and their associated costs, health-related quality of life and well-being outcomes measured using instruments suitable for generating quality-adjusted life-years (QALYs) and well-being-adjusted life-years (WALYs), and participants’ use of health, social care and wider societal resources and their associated costs were also assessed to inform a potential future CEA. Work package 2: results Out of 435 patients identified with delirium across 6 hospitals, 36 (8.2%) met the eligibility criteria, and 19 (53%) of patient–carer pairs consented to participate. Of these, 13 participants (68%) started the intervention, and 10 (53%) completed the final follow-up. The mean participant age was 83.8 years, with 60% being men and 26% having dementia as a comorbidity. Participants had a mean [standard deviation (SD)] baseline disability assessment for dementia scores of 43.7 (SD: 27.1), reflecting the functional status of the recruited population. Intervention adherence was 53%, with 10 participants completed at least 6 or more intervention sessions. At baseline, 79% of participants showed delirium markers, but none did at follow-up. The mean cost per participant for delivering the RecoverED intervention was £1249, although challenges arose in gathering data for non-contact activities. Mean (SD) QALY gains for patients and carers, based on self-reported EuroQol-5 Dimensions, five-level version responses over the 6-month follow-up period, were 0.273 (0.168) and 0.403 (0.092), respectively. Mean (SD) WALY gains were 0.368 (0.075) for patients (based on ICEpop CAPability measure for older people) and 0.427 (0.056) for carers (ICEpop CAPability measure for adults), indicating positive effects on health-related quality of life and well-being in both groups. Analysis of total participant resource use and costs was limited due to missing data. Challenges in recruitment and retention were identified, with health-related withdrawals and inconsistent delirium screening contributing to lower recruitment than anticipated. The process evaluation showed that the intervention was well received and delivered with good fidelity. It was flexible and tailored to individual needs, with strong continuity of care provided by the same HCP team. While some mobility tasks were underdelivered due to health issues or poor weather, the intervention was largely seen as acceptable and beneficial. Discussion The RecoverED programme has several notable strengths, including its comprehensive, theory-driven design developed through an iterative co-design process. This process integrated expertise from geriatricians, PTs, OTs and clinical psychologists, ensuring the intervention’s clinical relevance and theoretical foundation. The involvement of a PPIE group ensured that the intervention was practical and patient-centred. Moreover, the development of a structured manual and training programme for RSWs was a significant achievement, enhancing their preparedness and ability to implement the intervention effectively. The intervention was well received by participants, with positive feedback regarding its perceived value and benefits. High consent rates among eligible participants and strong engagement from those who remained in the study further underscore the potential of the intervention. Despite these strengths, the study encountered several limitations. Recruitment was a significant challenge, with only a small percentage of screened patients meeting the eligibility criteria. This was partly due to staff capacity constraints, inconsistent routine delirium screening practices and the predominance of clinical teams diagnosing delirium rather than research staff. Since clinical teams were responsible for diagnosing delirium as part of routine care, there was variability in how and when delirium was identified, leading to potential inconsistencies in patient eligibility for the study. By contrast, if research staff had been directly involved in the screening and diagnosis process using standardised criteria, it may have improved consistency and ensured a more reliable identification of eligible participants. Additionally, missing data on intervention costs and participant resource use limited the ability to conduct a full economic evaluation. Future studies should implement more robust data collection strategies to ensure a more comprehensive assessment of cost-effectiveness. The process evaluation was limited due to the small number of participants and the withdrawal of more impaired participants from the trial. A more extensive evaluation may have revealed more weaknesses in the intervention and a need for further refinement. Another limitation was the homogeneity of the study sample, as all participants were White, which limits the understanding of how the intervention may be received by different ethnic and cultural groups. Furthermore, the reliance on clinical teams for diagnosis rather than standardised research staff-based approaches revealed weaknesses in the screening process, leading to missed recruitment opportunities. Finally, the absence of participants from minority ethnic, racial or linguistic groups and the challenges in retaining participants due to health deterioration or relocation suggest the need for improved inclusion strategies and a more inclusive approach to recruitment in future studies. Conclusion The RecoverED programme successfully developed a theory-driven, multidisciplinary intervention aimed at supporting recovery following delirium. Despite recruitment challenges and limitations in participant diversity, the qualitative data from the feasibility study demonstrated some evidence that the intervention could be delivered in clinical practice, was well received and participants reported perceived benefits. The process evaluation provided some insights into how the intervention was implemented and how it could be refined for future studies, but more participants were needed for a comprehensive evaluation. The findings from this study underline the importance of addressing key challenges in recruiting and retaining a diverse sample, including individuals from minority ethnic groups and those transitioning to care homes. Further research is needed to explore how the intervention can be adapted and optimised to support these groups. Given the pressing need for effective delirium recovery interventions, future studies should consider novel trial designs and alternative funding models to enable the continued development and evaluation of this important area of health care. Study registration This study is registered as ISRCTN15676570, registered 13 December 2022. https://doi.org/10.1186/ISRCTN15676570 Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: NIHR202338) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 7. See the NIHR Funding and Awards website for further award information.

Type 2 diabetes (T2D) imposes significant personal challenges and societal costs. Continuous glucose monitoring (CGM) is recognised as a state-of-the-art tool, but remains underutilised. Adoption of CGM in primary care should be informed by a broader understanding of the technology’s capabilities and limitations. An expert panel was convened to review current literature and clinical experience to provide practical approaches to CGM for primary care practitioners and discuss the technology’s value in the routine management of T2D. The goals were to review and reach consensus on the current state of CGM in non-specialist practice settings and on strategies for successfully initiating and maintaining people on CGM. Initiation and maintenance of CGM therapy can be successfully conducted in primary care settings. CGM therapy should include proper patient selection, proper setting of expectations, and evidence-based adjustments to therapy. Most patients are likely to see quick, meaningful, and lasting improvements in their diabetes, along with a better understanding of their condition and greater motivation for successful management. Retrospective report interpretation is feasible and intuitive. Barriers to adoption and sustained use include cost, technological limitations, behavioural or psychological factors, and therapeutic inertia. Addressing these barriers is critical to enable better access to CGM. Continuous glucose monitoring can be leveraged by primary care teams to inform treatment decisions and also by patients to inform diabetes self-management. CGM should be considered for all people with T2D. The recommendations provided here should simplify adoption and maintenance use of CGM in primary care and maximise the glycaemic and psychosocial benefits of the technology.

Cardiovascular, kidney and metabolic (CKM) conditions are interrelated, significantly contributing to morbidity, mortality and healthcare burden. Despite therapeutic advances, traditional disease-specific approaches often fail to address their complex interplay. Key therapeutic agents-including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dual GLP-1/glucose-dependent insulinotropic polypeptide RAs, sodium glucose co-transporter inhibitors and the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone-offer multi-organ benefits. Emerging therapies, such as triple receptor agonists and second-generation MRAs, target new pathways further expanding treatment options for CKM conditions. A holistic CKM management approach must address and recognise that conditions such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, obstructive sleep apnoea and obesity are part of the CKM spectrum. Frailty assessment is also important alongside CKM conditions, warranting comprehensive geriatric assessment and deprescribing when appropriate. Multidisciplinary care-including lifestyle interventions, pathway redesign, pharmacological advances and novel technologies-is essential for improving outcomes. As the CKM landscape evolves, future strategies should prioritise early intervention, personalised treatment and addressing unmet needs in high-risk populations. This review advocates for an integrated CKM framework, exploring treatment strategies, emerging therapies and technological innovations. It also examines the role of artificial intelligence and digital health tools in risk stratification, early diagnosis and long-term condition management, alongside ethical and regulatory considerations.

AIMS:There is current apprehension among some clinicians and conflicting evidence regarding ocular complications in relation to Glucagon-like peptide-1 receptor agonists (GLP-1RAs). We aimed to generate multi-disciplinary, expert-led consensus recommendations relating to ocular complications to facilitate optimum prescribing of GLP-1RAs. MATERIALS AND METHODS:A modified Delphi was conducted following the ACcurate COnsensus Reporting Document (ACCORD) for Delphi research. A structured literature review informed an anonymous online Delphi questionnaire, followed by a virtual consensus meeting. Eligible participants included ophthalmologists, diabetologists, and obesity specialists practising in Europe. RESULTS:Responses from 58 participants across 17 countries were analysed. Respondents agreed that diabetic retinopathy (DR) worsening events are primarily linked to rapid blood glucose-lowering, rather than a direct drug effect. The benefits of GLP-1RAs were deemed to outweigh potential ocular risks and should not limit access to these medicines. Prescribers should ensure that people with diabetes are screened for diabetic retinopathy before commencing GLP-1RAs, particularly in high-risk populations (>10 years duration and/or poor glucose control, (haemoglobin A1c [HbA1c] >10% or 86 mmol/mol)). When prescribing GLP-1RA to those with sight loss in one eye and/or prior history of non-arteritic anterior ischaemic optic neuropathy (NAION), the risk of ocular complications should be discussed. The Delphi study highlighted current uncertainty in the evidence, with some topics on the relationship between GLP-1RAs and ocular complications reaching limited consensus. CONCLUSIONS:Further research is needed into the direct effects of GLP-1RAs on the retina and ocular complications. New evidence should be disseminated rapidly to optimise outcomes and safety.

OBJECTIVE:Long COVID can include impaired cognition ('brain fog'; a term encompassing multiple symptoms) and mental health conditions. We performed a systematic review and meta-analysis to estimate their prevalence and to explore relevant factors associated with the incidence of impaired cognition and mental health conditions. METHODS:Searches were conducted in Medline and PsycINFO to cover the start of the pandemic until August 2023. Included studies reported prevalence of mental health conditions and brain fog in adults with long COVID after clinically-diagnosed or PCR-confirmed SARS-CoV-2 infection. FINDINGS:17 studies were included, reporting 41,249 long COVID patients. Across all timepoints (3-24 months), the combined prevalence of mental health conditions and brain fog was 20·4% (95% CI 11·1%-34·4%), being lower among those previously hospitalised than in community-managed patients(19·5 vs 29·7% respectively; p = 0·047). The odds of mental health conditions and brain fog increased over time and when validated instruments were used. Odds of brain fog significantly decreased with increasing vaccination rates (p = ·000). CONCLUSIONS:Given the increasing prevalence of mental health conditions and brain fog over time, preventive interventions and treatments are needed. Research is needed to explore underlying mechanisms that could inform further research in development of effective treatments. The reduced risk of brain fog associated with vaccination emphasizes the need for ongoing vaccination programs.

Objective: Amyloid-beta (Aβ) peptides are considered to play a prominent role in Alzheimer's disease, but emerging experimental and clinical observations link Aβ40 with adverse extracerebral vascular manifestations and cardiovascular disease events. However, it is unclear if Aβ40 adversely influences both large artery stiffness and cutaneous microvascular function in humans. We sought to determine whether Aβ40 was associated with large artery stiffness and cutaneous microvascular function in older adults with diverse cardiovascular risk. Design and method: This cross-sectional study analysed data from 610 older adults (65.7±8.7 yrs, 242F). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (CFPWV) using a SphygmoCor device, and cutaneous microvascular function was assessed by measuring acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) responses following iontophoresis. Plasma Aβ40 concentration was measured using a human Aβ40 assay kit (Simoa Human A β40). Results: One standard deviation increase in Aβ40 was significantly associated with 0.74 (0.52, 0.96) m/s greater CFPWV in an age- and sex-adjusted model (Model-1, p<0.001), which remained significant after further adjustments for conventional cardiovascular disease risk factors [Model-2, 0.46 (0.26, 0.66) m/s, p<0.001]. Additionally, one standard deviation increase in Aβ40 was significantly associated with lower cutaneous acetylcholine [-27.3 (-38.9, -15.7) au] and sodium nitroprusside [-27.0 (-38.1, -15.9) au] responses in Model-1 (both p<0.001). Further adjustments for conventional cardiovascular disease risk factors did not modify the inverse association [Model-2, acetylcholine response, -20.7 (-32.5, -8.8) au: sodium nitroprusside response, -21.1 (-32.3, -9.9) au: both p<0.001]. Subgroup analyses found an indication of interaction effect whereby female sex influenced more on the association between Aβ40 and CFPWV, and type 2 diabetes influenced more on the association between Aβ40 and cutaneous acetylcholine responses (both p<0.05). Conclusions: Aβ40 was associated with increased large artery stiffness and decreased cutaneous microvascular function in older adults with diverse cardiovascular risk. These findings suggest a potential mechanistic link between Aβ40 deposition in the systemic circulation and previously observed adverse cardiovascular disease outcomes.

Objectives: The COVID-19 pandemic has highlighted the critical need for comprehensive preparedness strategies for future pandemics, particularly those caused by unknown pathogens, or Disease X. Study Design: Our systematic review examined current literature on COVID-19 risk factors, identifying significant gaps and inconsistencies in data reporting. Methods: A systematic literature search was conducted including all English language published retrospective and prospective observational studies which documented clinical outcomes of COVID-19 in adult patients, on Ovid MEDLINE(R) and Epub databases (December 2019 to March 2023). Results: The search yielded 440 articles of which 29 were included in the systematic review. We identified major risk factors for severe outcomes. However, inconsistencies in reporting comorbidities, age, disease control levels, medication use, vaccination status, and variant type, limited our analysis. In many publications, this information was not included. Additionally, variations in public attitudes, knowledge, and behaviours regarding COVID-19 vaccines further complicated resource distribution. We propose the CLARITY model to address these gaps by standardizing risk factor reporting, encompassing detailed comorbidity profiles, disease control metrics, age analyses, medication and vaccination data, and variant-specific information. Conclusions: Implementing the CLARITY model could improve preparedness and response strategies for Disease X, enabling healthcare professionals and systems to allocate resources more effectively and mitigate the impact of future pandemics. This review underscores the necessity for a coordinated global effort to enhance pandemic preparedness through improved data reporting and risk stratification. ### Competing Interest Statement Boivin has received payment or honoraria from Teva, Pfizer, Novo Nordisk, mdBriefcase, J & J, Abbvie, Astra Zeneca, Boehringer Ingelheim, Moderna, Canopy, Valneva, and Abbott Diabetes and participated on advisory board for Novo-Nordisk, Emergent BioSolutions, Pfizer, Novavax, and GSK. Bourbeau has received grants or contracts from Canadian Institute of Heath Research (CIHR), Reseau en sante respiratoire du FRQS, McGill University, McGill University Health Centre Foundation, AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Grifols, Novartis, Sanofi, and Trudell Canada Ltd and has had payment or honoraria from AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Pfizer Canada Ltd, Trudell Canada Ltd, and COVIS Pharma Canada Ltd. Connelly has received grants or contracts from Pfizer, AstraZeneca, Boehringer Ingelheim, Servier, Novo Nordisk, Merck, Novartis, and Amgen, payment or honoraria from Pfizer, AstraZeneca, and Boehringer Ingelheim, payment for expert testimony from Servier, Novo Nordisk, and Merck, support for attending meetings from Novartis and Amgen, and patents planned, issued or pending from Boehringer Ingelheim. Jain has received consulting fees from Abbott, Acerus, AstraZeneca, Amgen, Bausch Healthcare, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, HLS Therapeutics, Insulet, Janssen, Medtronic, Novo Nordisk, Partners in Progressive Medical Education, PocketPills, Sanofi Aventis, and Takeda and payment or honoraria from Abbott, Acerus, AstraZeneca, Amgen, Bausch Healthcare, Bayer, Boehringer Ingelheim, Care to Know, CCRN, Connected in Motion, CPD Network, Dexcom, Diabetes Canada, Eli Lilly, HLS Therapeutics, Janssen, Master Clinician Alliance, MDBriefcase, Merck, Medtronic, Moderna, Novo Nordisk, Partners in Progressive Medical Education, Pfizer, Sanofi Aventis, Timed Right, and WebMD. Lin has received payment or honoraria from Moderna, Pfizer, and AstraZeneca. Mazer holds a leadership or fiduciary role with the COVID-19 Immunity Task Force, Public Health Agency of Canada. Horvat and Sedeno are employees of Respiplus and Bourbeau is an administrator of Respiplus. Respiplus is a non-profit society who received a grant from Moderna Biopharma Canada Corporation for this publication. Boivin, Connelly, Jain, Li, Lin, Mazer, Noueihed, Saposnik, and Strain have received honoraria from Respiplus. Noueihed, Li, Horvat, Saposnik, and Sedeno have no additional conflict to disclose. Strain has received consulting fees from Pfizer, payment or honoraria from Moderna, Pfizer, and AstraZeneca, payment for testimony from NICE, and holds a leadership or fiduciary role with the British Medical Association. ### Funding Statement This study received financial support from Moderna Biopharma Canada Corporation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

AbstractBackgroundCoronary microvascular disease is often defined by symptoms in the absence of epicardial coronary artery stenosis. There is, however, a growing interest in exploring the vascular physiology of patients with chest pain syndromes who have been confirmed to have unobstructed coronary arteries. As it is known that people with microvascular coronary disease have an additive poor prognosis, we aimed to determine whether this was part of a systemic microvascular dysregulation. As such, we explored the correlations between cardiovascular magnetic resonance (CMR) myocardial perfusion with cutaneous maximal hyperaemic response (MHR) and post-occlusive reactive hyperaemia (PORH), as assessed by laser Doppler fluximetry, in patients with known coronary anatomy determined via computed tomography coronary angiography (CTCA).MethodsMHR was measured in response to local heating to 42°C and PORH was measured in response to a 4-minute ischaemic stimulus in 102 participants with and without diabetes and/or coronary artery disease, defined as coronary artery calcification of >0 Agatston units. Subepicardial and subendocardial perfusion at rest and in response to adenosine stress was measured via CMR.ResultsOut of 102 participants, 47 (45.1%) had diabetes, and 59 (57.8%) had coronary artery disease, with 32 (31.4%) having both. MHR and PORH were attenuated in participants with diabetes. Resting, but not stressed, CMR perfusion in all subepicardial and subendocardial territories was proportionately impaired in those with attenuated MHR. This association was independent of conventional risk factors including age, sex, blood pressure, glycaemia, coronary artery disease and body habitus (standardised beta 0.315, p=0.012). Conversely, PORH did not correlate with CMR perfusion at rest or after stress.ConclusionsMaximal hyperaemic response is associated with resting CMR perfusion independent of conventional risk factors. This suggests that cardiac microvascular dysfunction may represent a manifestation of wider microcirculatory derangements. Further research is required to determine whether interventions that improve systemic vascular disturbances may improve cardiac microcirculation.Translational PerspectiveIt is recognised that coronary microvascular dysfunction is associated with residual symptoms in people with angina, after the correction of occlusive coronary arterial disease. As such it is a promising target for symptom control, however development of proof-of-concept trials is limited by the ability to monitor the coronary microcirculation in those trials.This manuscript identifies an appropriate surrogate endpoint that can be easily and non-invasively monitored and validates it against MRI imaging of the coronary microcirculation.

SARS-CoV-2 is highly transmissible and affects the respiratory system. People with COVID-19 are at higher risk of physical and mental health conditions, which could impact bone health. The aim of this review was to explore the effects of COVID-19 on BMD, BTMs, and joints. An electronic search of the PubMed, Web of Science, Scopus, and Ovid Medline databases considered studies published between 1 January 2020 and 1 November 2023. The search was limited to English, original studies in adult humans. The title and abstract of the identified papers were screened, followed by a full-text review using inclusion and exclusion criteria. The data extracted included the study and participant characteristics, BTMs, BMD, and joint abnormalities. The Newcastle–Ottawa scale quality assessment tool was used to assess the risk of bias. Five studies involving 305 out of 495 infected individuals observed a reduced BMD after COVID-19, with the most significant reduction occurring a year later. Both bone resorption and bone formation markers decreased, while regulatory markers showed higher levels in infected patients. COVID-19 may harm bone health by increasing bone regulatory markers and reducing bone formation and absorption, leading to a lower BMD. Elderly, frail, and osteopenic or osteoporotic individuals are at higher risk and should be regularly monitored for bone loss if they have long COVID.

BACKGROUND:As a consequence of their occupation, doctors and other healthcare workers were at higher risk of contracting coronavirus disease 2019 (COVID-19), and more likely to experience severe disease compared to the general population. However, systematic information on post-acute COVID complications in doctors is very limited.AIMS:This study aimed to determine the symptoms, perceived determinants, health and occupational impact, and consequent needs relating to post-acute COVID complications in UK doctors.METHODS:An online cross-sectional survey was distributed to UK doctors self-identifying as having Long COVID or other post-acute COVID complications.RESULTS:Of 795 responses, 603 fulfilled the inclusion criteria of being a UK-based medical doctor experiencing one or more post-acute COVID complications. Twenty-eight per cent reported a lack of adequate Respiratory Protective Equipment at the time of contracting COVID-19. Eighteen per cent of eligible respondents reported that they had been unable to return to work since acquiring COVID.CONCLUSIONS:Post-acute COVID (Long COVID) in UK doctors is a substantial burden for respondents to our questionnaire. The results indicated that insufficient respiratory protection could have contributed to occupational disease, with COVID-19 being contracted in the workplace, and resultant post-COVID complications. Although it may be too late to address the perceived determinants of inadequate protection for those already suffering with Long COVID, more investment is needed in rehabilitation and support of those afflicted.

The UK Research Excellence Framework (REF) is an assessment of the quality of research carried out in UK Higher Education Institutions (HEIs), performed in 7-year cycles. The outcome impacts the rankings and funding of UK HEIs, which afford the exercise high priority. Much of what REF measures is known to be biased against academics with protected characteristics: for example, women and ethnic minority researchers are less likely to win grants or be published in prestigious journals. Despite changes to REF since 2014, the risk remains that the process might amplify well-recognised existing disparities. The BMA Women in Academic Medicine and Medical Academic Staff Committee carried out a survey of UK clinical academics’ experiences of REF2021. The data indicated the persistence of activities previously characterised as ‘extremely harmful’ in Research England-commissioned work, affecting up to 10% of clinical academics. While acknowledging the limitations of the data, women appeared to be disproportionately affected.

The importance of integrated care for complex, multiple long term conditions was acknowledged before the COVID pandemic but remained a challenge. The pandemic and consequent development of Long COVID required rapid adaptation of health services to address the population's needs, requiring service redesigns including integrated care. This Delphi consensus study was conducted in the UK and found similar integrated care priorities for Long COVID and complex, multiple long term conditions, provided by 480 patients and health care providers, with an 80% consensus rate. The resultant recommendations were based on more than 1400 responses from survey participants and were supported by patients, health care professionals, and by patient charities. Participants identified the need to allocate resources to: support integrated care, provide access to care and treatments that work, provide diagnostic procedures that support the personalization of treatment in an integrated care environment, and enable structural consultation between primary and specialist care settings including physical and mental health care. Based on the findings we propose a model for delivering integrated care by a multidisciplinary team to people with complex multisystem conditions. These recommendations can inform improvements to integrated care for complex, multiple long term conditions and Long COVID at international level.

The delivery of COVID-19 vaccines was successful in reducing hospitalizations and mortality. However, emergence of the Omicron variant resulted in increased virus transmissibility. Consequently, booster vaccination programs were initiated to decrease the risk of severe disease and death among vulnerable members of the population. This study aimed to estimate the effects of the booster program and alternative vaccination strategies on morbidity and mortality due to COVID-19 in the UK. A Susceptible-Exposed-Infectious-Recovered (SEIR) model was used to assess the impact of several vaccination strategies on severe outcomes associated with COVID-19, including hospitalizations, mortality, National Health Service (NHS) capacity quantified by hospital general ward and intensive care unit (ICU) bed days, and patient productivity. The model accounted for age-, risk- and immunity-based stratification of the UK population. Outcomes were evaluated over a 48-week time horizon from September 2022 to August 2023 considering the actual UK autumn 2022/spring 2023 booster campaigns and six counterfactual strategies. The model estimated that the autumn 2022/spring 2023 booster campaign resulted in a reduction of 18,921 hospitalizations and 1463 deaths, compared with a no booster scenario. Utilization of hospital bed days due to COVID-19 decreased after the autumn 2022/spring 2023 booster campaign. Expanding the booster eligibility criteria and improving uptake improved all outcomes, including averting twice as many ICU admissions, preventing more than 20