The HAVEN study-hydroxychloroquine in ANCA vasculitis evaluation-a multicentre, randomised, double-blind, placebo-controlled trial: study protocol and statistical analysis plan.

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.

Cardiometabolic outcomes up to 12 months after COVID-19 infection. A matched cohort study in the UK.

BACKGROUND: Acute Coronavirus Disease 2019 (COVID-19) has been associated with new-onset cardiovascular disease (CVD) and diabetes mellitus (DM), but it is not known whether COVID-19 has long-term impacts on cardiometabolic outcomes. This study aimed to determine whether the incidence of new DM and CVDs are increased over 12 months after COVID-19 compared with matched controls. METHODS AND FINDINGS: We conducted a cohort study from 2020 to 2021 analysing electronic records for 1,356 United Kingdom family practices with a population of 13.4 million. Participants were 428,650 COVID-19 patients without DM or CVD who were individually matched with 428,650 control patients on age, sex, and family practice and followed up to January 2022. Outcomes were incidence of DM and CVD. A difference-in-difference analysis estimated the net effect of COVID-19 allowing for baseline differences, age, ethnicity, smoking, body mass index (BMI), systolic blood pressure, Charlson score, index month, and matched set. Follow-up time was divided into 4 weeks from index date ("acute COVID-19"), 5 to 12 weeks from index date ("post-acute COVID-19"), and 13 to 52 weeks from index date ("long COVID-19"). Net incidence of DM increased in the first 4 weeks after COVID-19 (adjusted rate ratio, RR 1.81, 95% confidence interval (CI) 1.51 to 2.19) and remained elevated from 5 to 12 weeks (RR 1.27, 1.11 to 1.46) but not from 13 to 52 weeks overall (1.07, 0.99 to 1.16). Acute COVID-19 was associated with net increased CVD incidence (5.82, 4.82 to 7.03) including pulmonary embolism (RR 11.51, 7.07 to 18.73), atrial arrythmias (6.44, 4.17 to 9.96), and venous thromboses (5.43, 3.27 to 9.01). CVD incidence declined from 5 to 12 weeks (RR 1.49, 1.28 to 1.73) and showed a net decrease from 13 to 52 weeks (0.80, 0.73 to 0.88). The analyses were based on health records data and participants' exposure and outcome status might have been misclassified. CONCLUSIONS: In this study, we found that CVD was increased early after COVID-19 mainly from pulmonary embolism, atrial arrhythmias, and venous thromboses. DM incidence remained elevated for at least 12 weeks following COVID-19 before declining. People without preexisting CVD or DM who suffer from COVID-19 do not appear to have a long-term increase in incidence of these conditions.

Teleophthalmology-enabled and artificial intelligence-ready referral pathway for community optometry referrals of retinal disease (HERMES): a Cluster Randomised Superiority Trial with a linked Diagnostic Accuracy Study-HERMES study report 1-study protocol.

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. TRIAL REGISTRATION NUMBER: ISRCTN18106677 (protocol V.1.1).

Stroke Care in the United Kingdom During the COVID-19 Pandemic.

BACKGROUND AND PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has potentially caused indirect harm to patients with other conditions via reduced access to health care services. We aimed to describe the impact of the initial wave of the pandemic on admissions, care quality, and outcomes in patients with acute stroke in the United Kingdom. METHODS: Registry-based cohort study of patients with acute stroke admitted to hospital in England, Wales, and Northern Ireland between October 1, 2019, and April 30, 2020, and equivalent periods in the 3 prior years. RESULTS: One hundred fourteen hospitals provided data for a study cohort of 184 017 patients. During the lockdown period (March 23 to April 30), there was a 12% reduction (6923 versus 7902) in the number of admissions compared with the same period in the 3 previous years. Admissions fell more for ischemic than hemorrhagic stroke, for older patients, and for patients with less severe strokes. Quality of care was preserved for all measures and in some domains improved during lockdown (direct access to stroke unit care, 1-hour brain imaging, and swallow screening). Although there was no change in the proportion of patients discharged with good outcome (modified Rankin Scale score, ≤2; 48% versus 48%), 7-day inpatient case fatality increased from 6.9% to 9.4% (P<0.001) and was 22.0% in patients with confirmed or suspected COVID-19 (adjusted rate ratio, 1.41 [1.11-1.80]). CONCLUSIONS: Assuming that the true incidence of acute stroke did not change markedly during the pandemic, hospital avoidance may have created a cohort of untreated stroke patients at risk of poorer outcomes or recurrent events. Unanticipated improvements in stroke care quality should be used as an opportunity for quality improvement and to learn about how to develop resilient health care systems.

FENETRE study: quality-assured follow-up of quiescent neovascular age-related macular degeneration by non-medical practitioners: study protocol and statistical analysis plan for a randomised controlled trial.

OBJECTIVE: Management of age-related macular degeneration (AMD) places a high demand on already constrained hospital-based eye services. This study aims to assess the safety and quality of follow-up within the community led by suitably trained non-medical practitioners for the management of quiescent neovascular AMD (QnAMD). METHODS/DESIGN: This is a prospective, multisite, randomised clinical trial. 742 participants with QnAMD will be recruited and randomised to either continue hospital-based secondary care or to receive follow-up within a community setting. Participants in both groups will be monitored for disease reactivation over the course of 12 months and referred for treatment as necessary. Outcomes measures will assess the non-inferiority of primary care follow-up accounting for accuracy of the identification of disease reactivation, patient loss to follow-up and accrued costs and the budget impact to the National Health Service. ETHICS AND DISSEMINATION: Research ethics approval was obtained from the London Bloomsbury Ethics Committee. The results of this study will be disseminated through academic peer-reviewed publications, conferences and collaborations with eye charities to insure the findings reach the appropriate patient populations. TRIAL REGISTRATION NUMBER: NCT03893474.

Antihypertensive medications and COVID-19 diagnosis and mortality: Population-based case-control analysis in the United Kingdom.

AIMS: Antihypertensive drugs have been implicated in coronavirus disease 2019 (COVID-19) susceptibility and severity, but estimated associations may be susceptible to bias. We aimed to evaluate antihypertensive medications and COVID-19 diagnosis and mortality, accounting for healthcare-seeking behaviour. METHODS: A population-based case-control study was conducted including 16 866 COVID-19 cases and 70 137 matched controls from the UK Clinical Practice Research Datalink. We evaluated all-cause mortality among COVID-19 cases. Exposures were angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (B), calcium-channel blockers (C), thiazide diuretics (D) and other antihypertensive drugs (O). Analyses were adjusted for covariates and consultation frequency. RESULTS: ACEIs were associated with lower odds of COVID-19 diagnosis (adjusted odds ratio [AOR] 0.82, 95% confidence interval [CI] 0.77-0.88) as were ARBs (AOR 0.87, 95% CI 0.80-0.95) with little attenuation from adjustment for consultation frequency. C and D were also associated with lower odds of COVID-19 diagnosis. Increased odds of COVID-19 for B (AOR 1.19, 95% CI 1.12-1.26) were attenuated after adjustment for consultation frequency (AOR 1.01, 95% CI 0.95-1.08). Patients treated with ACEIs or ARBs had similar odds of mortality (AOR 1.00, 95% CI 0.83-1.20) to patients treated with classes B, C, D or O or patients receiving no antihypertensive therapy (AOR 0.99, 95% CI 0.83-1.18). CONCLUSIONS: There was no evidence that antihypertensive therapy is associated with increased risk of COVID-19 diagnosis or mortality; most classes of antihypertensive therapy showed negative associations with COVID-19 diagnosis.

The ROX index has greater predictive validity than NEWS2 for deterioration in Covid-19.

BACKGROUND: Patients admitted to hospital with Covid-19 are at risk of deterioration. The National Early Warning Score (NEWS2) is widely recommended, however it's validity in Covid-19 is not established and indices more specific for respiratory failure may be more appropriate. We aim to describe the physiological antecedents to deterioration, test the predictive validity of NEWS2 and compare this to the ROX index ([SpO2/FiO2]/respiratory rate). METHOD: A single centre retrospective cohort study of adult patients who were admitted to a medical ward, between 1/3/20 and 30/5/20, with positive results for SARS-CoV-2 RNA. Physiological observations and the NEWS2 were extracted and analysed. The primary outcome was a composite of cardiac arrest, unplanned critical care admission or death within 24 hours. A generalized linear model was used to assess the association of physiological values, NEWS2 and ROX with the outcome. FINDINGS: The primary outcome occurred in 186 patients (26%). In the preceding 24 hours, deterioration was most marked in respiratory parameters, specifically in escalating oxygen requirement; tachypnoea was a late sign, whilst cardiovascular observations remained stable. The area under the receiver operating curve was 0.815 (95% CI 0.804-0.826) for NEWS2 and 0.848 (95% CI 0.837-0.858) for ROX. Applying the optimal level of ROX, the majority of patients triggered four hours earlier than with NEWS2 of 5. INTERPRETATION: NEWS2 may under-perform in Covid-19 due to intrinsic limitations of the design and the unique pathophysiology of the disease. A simple index utilising respiratory parameters can outperform NEWS2 in predicting the occurrence of adverse events.

Evaluation and improvement of the National Early Warning Score (NEWS2) for COVID-19: a multi-hospital study.

BACKGROUND: The National Early Warning Score (NEWS2) is currently recommended in the UK for the risk stratification of COVID-19 patients, but little is known about its ability to detect severe cases. We aimed to evaluate NEWS2 for the prediction of severe COVID-19 outcome and identify and validate a set of blood and physiological parameters routinely collected at hospital admission to improve upon the use of NEWS2 alone for medium-term risk stratification. METHODS: Training cohorts comprised 1276 patients admitted to King's College Hospital National Health Service (NHS) Foundation Trust with COVID-19 disease from 1 March to 30 April 2020. External validation cohorts included 6237 patients from five UK NHS Trusts (Guy's and St Thomas' Hospitals, University Hospitals Southampton, University Hospitals Bristol and Weston NHS Foundation Trust, University College London Hospitals, University Hospitals Birmingham), one hospital in Norway (Oslo University Hospital), and two hospitals in Wuhan, China (Wuhan Sixth Hospital and Taikang Tongji Hospital). The outcome was severe COVID-19 disease (transfer to intensive care unit (ICU) or death) at 14 days after hospital admission. Age, physiological measures, blood biomarkers, sex, ethnicity, and comorbidities (hypertension, diabetes, cardiovascular, respiratory and kidney diseases) measured at hospital admission were considered in the models. RESULTS: A baseline model of 'NEWS2 + age' had poor-to-moderate discrimination for severe COVID-19 infection at 14 days (area under receiver operating characteristic curve (AUC) in training cohort = 0.700, 95% confidence interval (CI) 0.680, 0.722; Brier score = 0.192, 95% CI 0.186, 0.197). A supplemented model adding eight routinely collected blood and physiological parameters (supplemental oxygen flow rate, urea, age, oxygen saturation, C-reactive protein, estimated glomerular filtration rate, neutrophil count, neutrophil/lymphocyte ratio) improved discrimination (AUC = 0.735; 95% CI 0.715, 0.757), and these improvements were replicated across seven UK and non-UK sites. However, there was evidence of miscalibration with the model tending to underestimate risks in most sites. CONCLUSIONS: NEWS2 score had poor-to-moderate discrimination for medium-term COVID-19 outcome which raises questions about its use as a screening tool at hospital admission. Risk stratification was improved by including readily available blood and physiological parameters measured at hospital admission, but there was evidence of miscalibration in external sites. This highlights the need for a better understanding of the use of early warning scores for COVID.