Importance:Hospital-based ophthalmology faces increasing demand for long-term monitoring of neovascular age-related macular degeneration (nAMD). Safe redistribution of routine monitoring to community clinicians is relevant to integrated community (primary)-secondary care models. Objective:To examine whether community optometrist-led monitoring of nAMD is noninferior to hospital-based monitoring for detecting disease activity requiring treatment. Design, Setting, and Participants:This multicenter, noninferiority randomized clinical trial was conducted from October 8, 2019, to January 31, 2024, at secondary centers (17 hospitals) and primary centers (60 community optometry practices) with 12-month follow-up. Statisticians were masked to patient grouping. Adults 55 years or older with quiescent AMD in at least 1 eye (and quiescent or nonneovascular disease in the other) were recruited at participating hospitals. Data analysis was performed from October 2024 to March 2025. Interventions:Participants were randomized 1:1 to monitoring sessions once every 2 months in hospitals (control) or community practices (intervention). Trained and accredited optometrists performed optical coherence tomography imaging, clinical examination, patient management, and online reporting at each visit. Main Outcomes and Measures:The primary outcome (participant level) was a binary indicator of whether a false-negative clinical management decision occurred at any visit within 12 months (missed quiescent nAMD reactivation or new fellow-eye nAMD, adjudicated by a central reading-center reference standard). The noninferiority margin was a 10-percentage point absolute risk difference. Secondary outcomes were false-positive clinical management decisions, attendance adherence, visual acuity change, harms, loss to follow-up, suspicious classifications, and confirmation visit outcomes. Results:Of 704 randomized participants, 635 (90.2%) completed at least 1 follow-up visit, including 287 at community practices (mean [SD] age, 80.6 [8.1] years; 236 [67.4%] female) and 348 at hospitals (mean [SD] age, 80.1 [8.5] years; 203 [57.3%] female). False-negative clinical management decisions occurred in 11 of 287 community participants (3.8%) vs 27 of 348 hospital participants (7.8%) (risk difference, -3.9 percentage points; 95% CI, -7.4 to -0.3 percentage points; P = .04; adjusted odds ratio, 0.51; 95% CI, 0.24-1.07; P = .08), meeting noninferiority. False-positive clinical management decisions occurred in 24 of 287 community participants (8.4%) vs 12 of 348 hospital participants (3.5%) (risk difference, 4.9 percentage points; 95% CI, 0.9-9.0 percentage points). Findings were consistent across per-protocol, cluster-adjusted, and relative risk sensitivity analyses. No adverse event-related withdrawals occurred. Conclusions and Relevance:In this randomized clinical trial, community optometrist-led monitoring of quiescent nAMD was noninferior to hospital monitoring for detecting disease activity requiring treatment. These results provide evidence for its use in integrated clinical care models. Trial Registration:ClinicalTrials.gov Identifier: NCT03893474.

QuestionIs community optometrist-led monitoring of quiescent neovascular age-related macular degeneration noninferior to hospital monitoring for identifying disease activity requiring treatment?FindingsIn this randomized clinical trial of 635 adults, false-negative clinical management decisions occurred in 3.8% in the community group and 7.8% in the hospital group for a difference of -3.9 percentage points, meeting the criterion for noninferiority.MeaningThis study's results support the use of community optometrist-led monitoring of quiescent neovascular age-related macular degeneration for detecting disease activity requiring treatment in integrated clinical care models. This randomized clinical trial examines whether community-based monitoring of neovascular age-related macular degeneration is noninferior to hospital monitoring for identifying disease activity requiring treatment. ImportanceHospital-based ophthalmology faces increasing demand for long-term monitoring of neovascular age-related macular degeneration (nAMD). Safe redistribution of routine monitoring to community clinicians is relevant to integrated community (primary)-secondary care models.ObjectiveTo examine whether community optometrist-led monitoring of nAMD is noninferior to hospital-based monitoring for detecting disease activity requiring treatment.Design, Setting, and ParticipantsThis multicenter, noninferiority randomized clinical trial was conducted from October 8, 2019, to January 31, 2024, at secondary centers (17 hospitals) and primary centers (60 community optometry practices) with 12-month follow-up. Statisticians were masked to patient grouping. Adults 55 years or older with quiescent AMD in at least 1 eye (and quiescent or nonneovascular disease in the other) were recruited at participating hospitals. Data analysis was performed from October 2024 to March 2025.InterventionsParticipants were randomized 1:1 to monitoring sessions once every 2 months in hospitals (control) or community practices (intervention). Trained and accredited optometrists performed optical coherence tomography imaging, clinical examination, patient management, and online reporting at each visit.Main Outcomes and MeasuresThe primary outcome (participant level) was a binary indicator of whether a false-negative clinical management decision occurred at any visit within 12 months (missed quiescent nAMD reactivation or new fellow-eye nAMD, adjudicated by a central reading-center reference standard). The noninferiority margin was a 10-percentage point absolute risk difference. Secondary outcomes were false-positive clinical management decisions, attendance adherence, visual acuity change, harms, loss to follow-up, suspicious classifications, and confirmation visit outcomes.ResultsOf 704 randomized participants, 635 (90.2%) completed at least 1 follow-up visit, including 287 at community practices (mean [SD] age, 80.6 [8.1] years; 236 [67.4%] female) and 348 at hospitals (mean [SD] age, 80.1 [8.5] years; 203 [57.3%] female). False-negative clinical management decisions occurred in 11 of 287 community participants (3.8%) vs 27 of 348 hospital participants (7.8%) (risk difference, -3.9 percentage points; 95% CI, -7.4 to -0.3 percentage points; P = .04; adjusted odds ratio, 0.51; 95% CI, 0.24-1.07; P = .08), meeting noninferiority. False-positive clinical management decisions occurred in 24 of 287 community participants (8.4%) vs 12 of 348 hospital participants (3.5%) (risk difference, 4.9 percentage points; 95% CI, 0.9-9.0 percentage points). Findings were consistent across per-protocol, cluster-adjusted, and relative risk sensitivity analyses. No adverse event-related withdrawals occurred.Conclusions and RelevanceIn this randomized clinical trial, community optometrist-led monitoring of quiescent nAMD was noninferior to hospital monitoring for detecting disease activity requiring treatment. These results provide evidence for its use in integrated clinical care models.Trial RegistrationClinicalTrials.gov Identifier: NCT03893474

Background Telemedicine can support integrated care between community and hospital services for disease management, potentially enhanced by medical artificial intelligence (AI). Common retinal disease exemplifies this opportunity. Optometry-to-hospital referral pathways generate unnecessary visits, exacerbating hospital pressures. Evidence for the effectiveness of teleophthalmology and AI in optimising these pathways is scarce. Methods This cluster randomised controlled trial was done at optometry practices that referred to four hospital sites in the UK and that were randomly assigned (1:1) to standard care or teleophthalmology using random permuted blocks of varying sizes stratified by hospital site. Statisticians were masked to group assignment for the primary analysis. Individuals aged 18 years or older with suspected macular disease and good quality optical coherence tomography (OCT) scans were included; same-day emergency cases were excluded. In the teleophthalmology group, OCT scans were remotely reviewed by hospital clinicians; the standard care group followed standard referral pathways. The primary outcome was false-positive referral rate (unnecessary overall or urgent [ie, <2 weeks] referrals) against an independent reference standard, analysed in the enrolled and referred populations (superiority margin 30%) using a modified intention-to-treat analysis. A parallel prospective, observational, diagnostic accuracy (validation) study evaluated automated referral recommendations by the Moorfields-DeepMind-AI model, assessing sensitivity and specificity. This trial is registered with ISRCTN.com (ISRCTN18106677) and is closed. Findings Between Jan 26, 2021, and Dec 14, 2022, 71 optometry sites were assessed for eligibility and 26 recruited and randomly assigned to standard care (13 sites) or teleophthalmology (13 sites). Between July 5, 2021, and March 31, 2023, 304 participants were recruited, of whom 294 were included in the analysis (136 in the standard care group and 158 in the teleophthalmology group; 127 [43%] of 294 participants were male, and 167 [57%] were female). Among all enrolled participants, false-positive referrals occurred in ten (7%) of 136 participants in the standard care group versus two (1%) of 158 in the teleophthalmology group (absolute difference 6% [95% CI –5 to 17]; odds ratio [OR] 6·16 [95% CI 1·28 to 58·80]; p=0·018); urgent false-positive referrals occurred in 24 (18%) of 136 versus one (1%) of 158 (17% [11 to 24]; OR 33·37 [5·28 to 1392·05]; p=0·0004). In referred participants only, false-positive referrals occurred in ten (8%) of 125 versus two (2%) of 124 (6% [–5 to 18]; OR 5·27 [1·09 to 50·52]; p=0·035); urgent false-positive referrals occurred in 24 (63%) of 38 versus one (4%) of 27 (59% [41 to 78]; OR 42·00 [5·69–1901·06]; p=0·0001). The superiority margin of a 30% reduction in false-positive referrals was met only for urgent referred cases. Moorfields-DeepMind-AI could process images from 204 (52%) of 396 participants with sensitivity and specificity of 96% (95% CI 92–99) and 20% (8–37), respectively, for all referrals, and 74% (54–89) and 90% (85–94), respectively, for urgent referrals. No serious adverse events occurred. Interpretation Teleophthalmology significantly reduced unnecessary urgent hospital referrals, the main source of capacity pressure in retinal care, demonstrating superiority among referred participants and supporting timely, safe care. Its impact on overall unnecessary referrals was inconclusive due to the low number of non-referred participants. When evaluable (in ∼50% participants), Moorfields-DeepMind-AI recommended more unnecessary referrals overall than clinically indicated. Simulating human experts, AI performed worse than hospital specialists in the teleophthalmology pathway, and similarly to community optometrists in standard care, probably reflecting differences between clinician judgement and fixed AI rules. Funding National Institute for Health and Care Research.

Background:Community-based optometrists, a major provider of primary eye care in the United Kingdom, are the main source of referrals to hospital eye services. The widespread introduction of optical coherence tomography devices in community practices provides community-based optometrists with an opportunity to identify a broader range of treatable diseases. Standard referral pathways do not effectively filter unnecessary referrals, with misclassification of urgency, and erroneous diagnoses. Objectives:To assess the effectiveness of a teleophthalmology referral pathway between community-based optometrists and hospital eye services for retinal diseases. To measure the accuracy of an artificial intelligence decision support system for diagnosis and referral management of retinal disease. Design:A multicentre, superiority cluster randomised controlled trial to assess the effectiveness of a teleophthalmology referral pathway. A prospective, observational diagnostic accuracy study to measure the performance of artificial intelligence decision support system. A comprehensive economic evaluation was conducted. Settings:United Kingdom-based community optometry practices with an optical coherence tomography device and hospital eye services. Participants:Adults requiring referral for retinal disease at the opinion of the community-based optometrists. Interventions:Community optometry practices were randomised 1 : 1 to standard care or teleophthalmology. Referrals sent via the teleophthalmology platform were remotely reviewed by human experts based at the corresponding hospital eye services. A referral decision was provided within 48 hours. Suitable optical coherence tomography scans were solely processed by artificial intelligence decision support system (the 'Octane' model). Main outcome measures:Cluster randomised controlled trial's primary outcome was the proportion of false-positive referrals (not required or not urgent) per arm in overall participants and in referred-only participants against an independent reference standard. Secondary outcomes included the proportion of wrong diagnosis, wrong referral urgency, false-negative referrals, safely triaged referrals for rare diseases, time from referral to consultation and treatment and cost-effectiveness of teleophthalmology. Primary outcome for the artificial intelligence study was the sensitivity and specificity of artificial intelligence referral decisions against the reference standard. Results:Teleophthalmology significantly reduces the proportion of false-positive urgent referrals by 59% compared to standard care in referred participants. Due to the observed low event rate for false positive referrals, teleophthalmology's role for reducing false positives overall was inconclusive. No significant difference between arms for safety of referral decisions (false negatives) was found. After accounting for external factors, the time to consultation demonstrated both clinically and statistically significant benefits for the teleophthalmology arm. The time to treatment showed a clinically significant benefit. Of 396 recruited participants, the Octane artificial intelligence model processed images contributed by 204 participants (51.5%). For referral decisions, the model showed comparable sensitivity and specificity against its own preset referral rules (rule-based reference standard) (post hoc analysis), but it showed inferior sensitivity and specificity when compared to human expert assessors making these referral decisions (clinical reference standard) (primary AI analysis). The artificial intelligence model presented challenges relating to its generalisability in a real-world evaluation context. Limitations:Technical limitations in optometry practices, lack of ethnicity data. Conclusions:Asynchronous teleophthalmology reduces the number of unnecessary urgent referrals, the main drivers of increasing hospital capacity pressures, provides more appropriate referral-to-treatment times and is more cost-effective compared to standard care. The Octane artificial intelligence model could not process images from 48.5% of study participants. Compared to hospital-based experts for referral decisions, Octane was less accurate at making routine and urgent referral decisions and of similar accuracy to community optometrists. Future work:Applied health research, human-artificial intelligence interaction and artificial intelligence clinical trial design. Trial registration:This trial is registered as ISRCTN18106677. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127773) and is published in full in Health Technology Assessment; Vol. 29, No. 69. See the NIHR Funding and Awards website for further award information.

BACKGROUND AND AIMS:Contrast-induced nephropathy (CIN), also known as contrast-associated acute kidney injury (CA-AKI) underlies a significant proportion of the morbidity and mortality following coronary angiographic procedures in high-risk patients and remains a significant unmet need. In pre-clinical studies inorganic nitrate, which is chemically reduced in vivo to nitric oxide, is renoprotective but this observation is yet to be translated clinically. In this study, the efficacy of inorganic nitrate in the prevention of CIN in high-risk patients presenting with acute coronary syndromes (ACS) is reported.METHODS:NITRATE-CIN is a double-blind, randomized, single-centre, placebo-controlled trial assessing efficacy of inorganic nitrate in CIN prevention in at-risk patients presenting with ACS. Patients were randomized 1:1 to once daily potassium nitrate (12 mmol) or placebo (potassium chloride) capsules for 5 days. The primary endpoint was CIN (KDIGO criteria). Secondary outcomes included kidney function [estimated glomerular filtration rate (eGFR)] at 3 months, rates of procedural myocardial infarction, and major adverse cardiac events (MACE) at 12 months. This study is registered with ClinicalTrials.gov: NCT03627130.RESULTS:Over 3 years, 640 patients were randomized with a median follow-up of 1.0 years, 319 received inorganic nitrate with 321 received placebo. The mean age of trial participants was 71.0 years, with 73.3% male and 75.2% Caucasian; 45.9% had diabetes, 56.0% had chronic kidney disease (eGFR <60 mL/min) and the mean Mehran score of the population was 10. Inorganic nitrate treatment significantly reduced CIN rates (9.1%) vs. placebo (30.5%, P < .001). This difference persisted after adjustment for baseline creatinine and diabetes status (odds ratio 0.21, 95% confidence interval 0.13-0.34). Secondary outcomes were improved with inorganic nitrate, with lower rates of procedural myocardial infarction (2.7% vs. 12.5%, P = .003), improved 3-month renal function (between-group change in eGFR 5.17, 95% CI 2.94-7.39) and reduced 1-year MACE (9.1% vs. 18.1%, P = .001) vs. placebo.CONCLUSIONS:In patients at risk of renal injury undergoing coronary angiography for ACS, a short (5 day) course of once-daily inorganic nitrate reduced CIN, improved kidney outcomes at 3 months, and MACE events at 1 year compared to placebo.

Introduction: Patients with refractory symptomatic left ventricular (LV) mid-cavity obstructive (LVMCO) hypertrophic cardiomyopathy (HCM) have extremely limited therapeutic options. Hypothesis: We hypothesized that site-specific-pacing would induce regionalized contractile dyssynchrony to reduce LVMCO gradients and improve symptoms. Methods: Symptomatic-drug-refractory LVMCO patients were recruited for a randomized blinded trial of personalized prescription of pacing (PPoP). Multiple LV and apical RV pacing sites were assessed during invasive hemodynamic study. Patient-specific optimal pacing site and atrioventricular (AV) delays were selected on basis of LVMCO gradient reduction and pacing parameters. Patients were randomized to 6 months active or back-up pacing in cross-over design. Primary outcome examined invasive gradient change with PPoP. Secondary outcomes assessed quality of life and exercise. Results: A total of 17 patients were recruited; 16 met primary endpoints. Baseline NYHA was 3±0.6 despite medical therapy. Hemodynamic effects were assessed during pacing at RV apex and a mean of 8 LV sites (range 4-16). Optimal PPoP was achieved via LV pacing in 14 (88%) patients and RV apex in 2. Mean baseline gradient 80±29 mmHg fell to 31±21 mmHg with PPoP (p<0.0001). Cardiac vein perforation occurred in one case, and 15 patients entered into cross-over; 2 withdrawals occurred during cross-over (myocardial infarction, persistent atrial fibrillation). Of the 13 completing cross-over, 9 (69%) chose active pacing as their preferred setting. PPoP was associated with better 6-minute walking test performance (329±100 vs 286±106 meters, p=0.018); other outcome measures also indicated benefit with PPoP. Conclusions: In a randomized placebo-controlled trial, PPoP reduces obstruction and improves exercise performance in severely symptomatic LVMCO patients. A personalized approach to pacing site selection is a key component of this novel therapy.

The total effect of ethnicity on COVID-19 outcomes is underestimated when conditioning for comorbidities: Response to Learoyd et alJournal of Clinical EpidemiologyPreview Full-Text PDF

BACKGROUND:Throughout the Covid-19 pandemic, researchers have made use of electronic health records to research this disease in a rapidly evolving environment of questions and discoveries. These studies are prone to collider bias as they restrict the population of Covid-19 patients to only those with severe disease. Inverse probability weighting is typically used to correct for this bias but requires information from the unrestricted population. Using electronic health records from a South London NHS trust, this work demonstrates a method to correct for collider bias using externally sourced data while examining the relationship between minority ethnicities and poor Covid-19 outcomes. METHODS:The probability of inclusion within the observed hospitalised cohort was modelled based on estimates from published national data. The model described the relationship between patient ethnicity, hospitalisation, and death due to Covid-19 - a relationship suggested to be susceptible to collider bias. The obtained probabilities (as applied to the observed patient cohort) were used as inverse probability weights in survival analysis examining ethnicity (and covariates) as a risk factor for death due to Covid-19. RESULTS:Within the observed cohort, unweighted analysis of survival suggested a reduced risk of death in those of Black ethnicity - differing from the published literature. Applying inverse probability weights to this analysis amended this aberrant result to one more compatible with the literature. This effect was consistent when the analysis was applied to patients within only the first wave of Covid-19 and across two waves of Covid-19 and was robust against adjustments to the modelled relationship between hospitalisation, patient ethnicity, and death due to Covid-19 made as part of a sensitivity analysis. CONCLUSIONS:In conclusion, this analysis demonstrates the feasibility of using external publications to correct for collider bias (or other forms of selection bias) induced by the restriction of a population to a hospitalised cohort using an example from the recent Covid-19 pandemic.

BACKGROUND:We aimed to identify and characterise the longitudinal patterns of multimorbidity associated with stroke. METHODS:We used an unsupervised patient-oriented clustering approach to analyse primary care electronic health records (EHR) of 30 common long-term conditions (LTC) in patients with stroke aged over 18, registered in 41 general practices in south London between 2005 and 2021. RESULTS:Of 849,968 registered patients, 9,847 (1.16%) had a record of stroke and 46.5% were female. The median age at record of stroke was 65.0 year (IQR: 51.5-77.0) and the median number of LTCs in addition to stroke was 3 (IQR: 2-5). We identified eight clusters of multimorbidity with contrasted socio-demographic characteristics (age, gender, and ethnicity) and risk factors. Beside a core of 3 clusters associated with conventional stroke risk-factors, minor clusters exhibited less common combinations of LTCs including mental health conditions, asthma, osteoarthritis and sickle cell anaemia. Importantly, complex profiles combining mental health conditions, infectious diseases and substance dependency emerged. CONCLUSION:This novel longitudinal and patient-oriented perspective on multimorbidity addresses existing gaps in mapping the patterns of stroke-associated multimorbidity not only in terms of LTCs, but also socio-demographic characteristics, and suggests potential for more efficient and patient-oriented healthcare models.

This study examined associations between adverse childhood experiences (ACEs) and mental health and health-risk behaviours, including differences by sexual minority (SM) identity. We included 8,686 adolescents (males = 50.7%, SM = 10.3%) from the UK-wide Millennium Cohort Study with data on eight ACEs (e.g., domestic violence, parental psychological distress, bullying) recorded between ages 3-14 and a wide-range of health indicators and health-risk behaviours at age 17. Associations between 1) Sexual identity and ACEs were analysed using multinomial logistic regression and 2) Cumulative ACE scores and all outcomes were analysed using linear/logistic regression (with appropriate interactions assessing differences in ACE-outcome associations by sexual identity and adjusted for sex, ethnicity, and parental income). Results showed SM individuals had a higher prevalence of bullying (33.9% vs. 20.3%) and experiencing ≥3ACEs [Bisexual: RRR 1.87 (95% CI 1.35, 2.57), Gay/Lesbian RRR 2.08 (1.24, 3.48)]. The number of individuals experiencing adverse mental health outcomes increased in relation to greater ACE exposure with evidence for effect-moderation by sexual identity in certain outcomes. For example, among individuals with 0 ACEs, 8% of heterosexual adolescents reported psychological distress vs. 22% in bisexual and 17% in gay/lesbian peers, increasing to 16% in heterosexual vs. 41% in bisexual and 45% in gay/lesbian adolescents with ≥3 ACEs. Similar patterns were observed for other health indicators (e.g., self-harm, suicidality, sleep quality) and health-risk behaviours (e.g., risky sex). Our findings indicate that ACEs are associated (with a gradient) with worse mental health and well-being, and higher risk of some health-risk behaviours. However, the detrimental effect of ACEs on health is worse in SM adolescents compared to heterosexual peers.

Background Patients with non-severe ANCA-associated vasculitis (AAV) are often prescribed immunosuppressive medications that are associated with severe side effects and a reduced quality of life. There is an unmet need for safer effective treatments for these patients. Hydroxychloroquine is being explored due to its effect in similar autoimmune conditions such as systemic lupus erythematosus. Methods Double-blind, placebo-controlled multicentre trial recruiting 76 patients across 20 sites. Participants will be randomised 1:1 to hydroxychloroquine or placebo in addition to standard of care immunosuppressive therapies over the course of 52 weeks. A phase II selection design will be used to determine hdroxychloroquine’s efficacy, using prednisolone dosage and Birmingham Vasculitis Activity Score as a measure of disease activity. Secondary outcomes will explore other elements of AAV progression, including disease flares and time to remission. Discussion This trial aims to explore Hydroxychloroquine as a treatment for patients with AAV. If effective, the need for immunosuppressive treatments such as prednisolone could be reduced. Hydroxychloroquine is safer, cheaper and has fewer adverse effects than conventional immunosuppressive treatments. This could improve patient outcomes while saving money for the NHS. Trial registration ISRCTN: ISRCTN79334891. Registered 07 June 2021. EudraCT: 2018-001268-40. Registered 13 September 2019. Clinicaltrials.gov: NCT04316494. Registered 20 March 2020.

OBJECTIVES:Studies from the first waves of the coronavirus disease 2019 (COVID-19) pandemic suggest that individuals from minority ethnicities are at an increased risk of worse outcomes. Concerns exist that this relationship is potentially driven by bias from analyzing hospitalized patients only. We investigate this relationship and the possible presence of bias. STUDY DESIGN AND SETTING:Using data from South London hospitals across two COVID-19 waves (February 2020 - May 2021), the relationship between ethnicity and COVID-19 outcomes was examined using regression models. Three iterations of each model were completed: 1) an unadjusted analysis, 2) adjusting for covariates (medical history and deprivation), and 3) adjusting for covariates and bias induced by conditioning on hospitalization. RESULTS:Among 3,133 patients, those who were Asian had a two-fold increased risk of death during the hospital stay that was consistent across the two COVID-19 waves and was not affected by correcting for conditioning on hospitalization. However, wave-specific effects demonstrate significant differences between ethnic groups until bias from using a hospitalized cohort was corrected for. CONCLUSION:Worsened COVID-19 outcomes in minority ethnicities may be minimized by correcting for bias induced by conditioning on hospitalization. Consideration of this bias should be a key component of study design.

Background Kidney transplantation is the gold-standard treatment for patients with kidney failure. However, one-third of patients awaiting a kidney transplant are highly sensitized to human leukocyte antigens (HLA), resulting in an increased waiting time for a suitable kidney, more acute and chronic rejection, and a shorter graft survival compared to non-highly sensitised patients. Current standard immunosuppression protocols do not adequately suppress memory responses, and so alternative strategies are needed. Autologous polyclonally expanded regulatory T cells (Tregs) have been demonstrated to be safe in transplant settings and could be a potential alternative to modulate memory immune alloresponses. Methods The aim of this trial is to determine whether adoptive transfer of autologous Tregs into HLA sensitised patients can suppress memory T and B cell responses against specific HLA antigens. This is a two-part, multi-centre, prospective clinical trial, comprising an observational phase (Part 1) aiming to identify patients with unregulated cellular memory responses to HLA (Pure HLA Proteins) followed by an interventional phase (Part 2). The first 9 patients identified as being eligible in Part 1 will undergo baseline immune monitoring for 2 months to inform statistical analysis of the primary endpoint. Part 2 is an adaptive, open labelled trial based on Simon’s two-stage design, with 21 patients receiving Good Manufacturing Practice (GMP)-grade polyclonally expanded Tregs to a dose of 5–10 × 106 cells/kg body weight. The primary EP is suppression of in vitro memory responses for 2 months post-infusion. 12 patients will receive treatment in stage 1 of Part 2, and 9 patients will receive treatment in stage 2 of Part 2 if ≥ 50% patients pass the primary EP in stage 1. Discussion This is a prospective study aiming to identify patients with unregulated cellular memory responses to Pure HLA Proteins and determine baseline variation in these patterns of response. Part 2 will be an adaptive phase IIa clinical trial with 21 patients receiving a single infusion of GMP-grade polyclonally expanded Tregs in two stages. It remains to be demonstrated that modulating memory alloresponses clinically using Treg therapy is achievable. Trial registration EudraCT Number: 2021–001,664-23. REC Number: 21/SC/0253. Trial registration number ISRCTN14582152.

INTRODUCTION:Obesity drives type 2 diabetes (T2DM) development. Laparoscopic adjustable gastric banding (LAGB) has lower weight reduction than other bariatric procedures. Liraglutide, a GLP-1 receptor agonist, improves weight and glycaemic control in patients with T2DM. This study aimed to determine the efficacy and safety of liraglutide 1.8 mg in participants undergoing LAGB. METHODS:GLIDE, a pilot randomised, double-blind, placebo-controlled trial, evaluated LAGB with either liraglutide 1.8 mg or placebo in participants with T2DM and obesity. Participants were randomised (1:1) to 6-months therapy post-LAGB, with further 6 months off-treatment follow-up. The primary outcome was change in HbA1c from randomisation to the end of treatment, secondary outcomes included body weight change. A sample size of 58 (29 per group) had 80% power to detect a 0.6% difference in HbA1c between groups. RESULTS:Twenty-seven participants were randomised to liraglutide (n = 13) or placebo (n = 14). Multivariate analysis showed no difference between placebo and liraglutide arms in HbA1c at 6 months (HbA1c:0.2 mmol/mol, -11.3, 11.6, p = 0.98) however, at 12 months HbA1c was significantly higher in the liraglutide arm (HbA1c:10.9 mmol/mol, 1.1, 20.6, p = 0.032). There was no difference between arms in weight at 6 months (BW:2.0 kg, -4.2, 8.1, p = 0.50), however, at 12 months weight was significantly higher in the liraglutide arm (BW:8.2 kg, 1.6, 14.9, p = 0.02). There were no significant differences in adverse events between groups. CONCLUSIONS:Our pilot data suggest no additional improvement in glycaemic control or BW with LAGB and liraglutide therapy. However, this trial was significantly underpowered to detect a significant change in the primary or secondary outcomes. Further trials are needed to investigate whether GLP-1 agonists, and particularly with more effective weekly agents (i.e. semaglutide or tirzepatide), are of benefit following metabolic surgery. CLINICAL TRIAL REGISTRATION:EudraCT number 2015-005402-11.

Life course epidemiology of chronic diseases has been dominated so far by the environmental approach. Whether it focuses on early life exposures and events or later lifestyle behaviors, this approach assumes that previous life experiences interact at each stage of life and shape subsequent health trajectories. Inspired by the analysis of social trajectories, focusing on transitions between multiple states, in multiple dimensions of the social experience, we propose in this paper a novel empirical approach to multiple time-to-event health data, denoted as multiple state analysis. Alike the so-called state sequence analysis, the aim of multiple state analysis is to create typologies of the main life course trajectories. This approach is illustrated by the analysis of records from a south London general practice electronic health record from which multiple long term conditions associated with myocardial infarction were considered. Among expected results such as the recurrent role of hypertension, multiple state analysis shows that different patterns of long term conditions including physical and mental health conditions, are associated with the onset timing of myocardial infarction but also with socio-demographics such as sex and ethnicity.

Introduction Recent years have witnessed an upsurge of demand in eye care services in the UK. With a large proportion of patients referred to Hospital Eye Services (HES) for diagnostics and disease management, the referral process results in unnecessary referrals from erroneous diagnoses and delays in access to appropriate treatment. A potential solution is a teleophthalmology digital referral pathway linking community optometry and HES. Methods and analysis The HERMES study (Teleophthalmology-enabled and artificial intelligence-ready referral pathway for community optometry referrals of retinal disease: a cluster randomised superiority trial with a linked diagnostic accuracy study) is a cluster randomised clinical trial for evaluating the effectiveness of a teleophthalmology referral pathway between community optometry and HES for retinal diseases. Nested within HERMES is a diagnostic accuracy study, which assesses the accuracy of an artificial intelligence (AI) decision support system (DSS) for automated diagnosis and referral recommendation. A postimplementation, observational substudy, a within-trial economic evaluation and discrete choice experiment will assess the feasibility of implementation of both digital technologies within a real-life setting. Patients with a suspicion of retinal disease, undergoing eye examination and optical coherence tomography (OCT) scans, will be recruited across 24 optometry practices in the UK. Optometry practices will be randomised to standard care or teleophthalmology. The primary outcome is the proportion of false-positive referrals (unnecessary HES visits) in the current referral pathway compared with the teleophthalmology referral pathway. OCT scans will be interpreted by the AI DSS, which provides a diagnosis and referral decision and the primary outcome for the AI diagnostic study is diagnostic accuracy of the referral decision made by the Moorfields-DeepMind AI system. Secondary outcomes relate to inappropriate referral rate, cost-effectiveness analyses and human–computer interaction (HCI) analyses.

Introduction Recent years have witnessed an upsurge of demand in eye care services in the UK. With a large proportion of patients referred to Hospital Eye Services (HES) for diagnostics and disease management, the referral process results in unnecessary referrals from erroneous diagnoses and delays in access to appropriate treatment. A potential solution is a teleophthalmology digital referral pathway linking community optometry and HES. Methods and analysis The HERMES study (Teleophthalmology-enabled and artificial intelligence-ready referral pathway for community optometry referrals of retinal disease: a cluster randomised superiority trial with a linked diagnostic accuracy study) is a cluster randomised clinical trial for evaluating the effectiveness of a teleophthalmology referral pathway between community optometry and HES for retinal diseases. Nested within HERMES is a diagnostic accuracy study, which assesses the accuracy of an artificial intelligence (AI) decision support system (DSS) for automated diagnosis and referral recommendation. A postimplementation, observational substudy, a within-trial economic evaluation and discrete choice experiment will assess the feasibility of implementation of both digital technologies within a real-life setting. Patients with a suspicion of retinal disease, undergoing eye examination and optical coherence tomography (OCT) scans, will be recruited across 24 optometry practices in the UK. Optometry practices will be randomised to standard care or teleophthalmology. The primary outcome is the proportion of false-positive referrals (unnecessary HES visits) in the current referral pathway compared with the teleophthalmology referral pathway. OCT scans will be interpreted by the AI DSS, which provides a diagnosis and referral decision and the primary outcome for the AI diagnostic study is diagnostic accuracy of the referral decision made by the Moorfields-DeepMind AI system. Secondary outcomes relate to inappropriate referral rate, cost-effectiveness analyses and human-computer interaction (HCI) analyses. Ethics and dissemination Ethical approval was obtained from the London-Bromley Research Ethics Committee (REC 20/LO/1299). Findings will be reported through academic journals in ophthalmology, health services research and HCI.

Background and Objectives Endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) are effective treatments for dysplastic Barrett’s esophagus (BE). This study evaluates efficacy, durability and safety in a single high-volume UK tertiary centre with 15-years’ experience. Methods Prospective data were collected from Nottingham University Hospitals 2004–2019 for endotherapy of dysplastic BE or intramucosal adenocarcinoma. Procedural outcome measures include complete resection, complications and surgery rates. Efficacy outcomes include complete remission of dysplasia (CR-D) and intestinal metaplasia (CR-IM), recurrence, treatment failure rates, durability of RFA, median follow up and tumor-associated mortality. Results A total of 319 lesions were resected; 671 RFAs were performed on 239 patients. Median age was 67 (±9.5) years, male:female ratio was 5:1 and median BE length was C3 [interquartile range (IQR): 6] M6 (IQR: 5). The most common lesion was Paris IIa (64%) with a median size of 10 mm (3–70). Final histology was adenocarcinoma in 50%. Complete resection rates were 96%. The multiband mucosectomy technique (91%) was most commonly used. The median number of RFA sessions was 3 (IQR: 2). The rates of CR-D and CR-IM were 90.4%% and 89.8% achieved after a median of 20.1 (IQR: 14) months. The most common complications: EMR was bleeding 2.2% and RFA was stricture (5.4%) requiring a median of 2 (range 1-7) dilatations. Median follow up post CR-IM/CR-D was 38 months (14–60). Metachronous lesions developed in 4.7% after CR-D and tumor-related mortality was 0.8%. Dysplasia and intestinal metaplasia-free survival at 5 years was 95 and 90%, respectively. Conclusion BE endotherapy is minimally invasive, effective, safe and deliverable in a day-case setting.

Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models. Merino sheep underwent middle cerebral artery occlusion (MCAO) followed by GTN or control patch administration (0.2 mg/h). Monitoring of numerous physiologically relevant measures over 24 h showed that GTN administration was associated with decreased intracranial pressure, infarct volume, cerebral oedema and midline shift compared to vehicle treatment (p < 0.05). No significant changes in blood pressure or cerebral perfusion pressure were observed. Using optical imaging spectroscopy and laser speckle imaging, the effect of varying doses of GTN (0.69–50 µg/h) on cerebral blood flow and tissue oxygenation was examined in mice. No consistent effect was found. Additional mice undergoing MCAO followed by GTN administration (doses varying from 0–60 µg/h) also showed no improvement in infarct volume or neurological score within 24 h post-stroke. GTN administration significantly improved numerous stroke-related physiological outcomes in sheep but was ineffective in mice. This suggests that, whilst GTN administration could potentially benefit patients, further research into mechanisms of action are required.