The Effectiveness, cost-effectiveness and acceptability of Community versus Hospital Eye Service follow-up for patients with neovascular age-related macular degeneration with quiescent disease (ECHoES): a virtual randomised balanced incomplete block trial

Background Patients with neovascular age-related macular degeneration (nAMD) usually attend regular reviews, even when the disease is quiescent. Reviews are burdensome to health services, patients and carers. Objectives To compare the proportion of correct lesion classifications made by community-based optometrists and ophthalmologists from vignettes of patients; to estimate the cost-effectiveness of community follow-up by optometrists compared with follow-up by ophthalmologists in the Hospital Eye Service (HES); to ascertain views of patients, their representatives, optometrists, ophthalmologists and clinical commissioners on the proposed shared care model. Design Community-based optometrists and ophthalmologists in the HES classified lesions from vignettes comprising clinical information, colour fundus photographs and optical coherence tomography images. Participants’ classifications were validated against experts’ classifications (reference standard). Setting Internet-based application. Participants Ophthalmologists had to have≥3 years post-registration experience in ophthalmology, have passed part 1 of the Royal College of Ophthalmologists, Diploma in Ophthalmology or equivalent examination, and have experience in the age-related macular degeneration service. Optometrists had to be fully qualified, be registered with the General Optical Council for≥3 years and not be participating in nAMD shared care. Interventions The trial sought to emulate a conventional trial in comparing optometrists’ and ophthalmologists’ decision-making, but vignettes, not patients, were assessed; therefore, there were no interventions. Participants received training prior to assessing vignettes Main Outcome Measures Primary outcome–correct classification of the activity status of a lesion based on a vignette, compared with a reference standard. Secondary outcomes–frequencies of potentially sight-threatening errors, participants’ judgements about specific lesion components, participant-rated confidence in their decisions and cost-effectiveness of follow-up by community-based optometrists compared with HES ophthalmologists. Results In total, 155 participants registered for the trial; 96 (48 in each professional group) completed training and main assessments and formed the analysis population. Optometrists and ophthalmologists achieved 1702 out of 2016 (84.4%) and 1722 out of 2016 (85.4%) correct classifications, respectively [odds ratio (OR) 0.91, 95% confidence interval (CI) 0.66 to 1.25; p=0.543]. Optometrists’ decisionmaking was non-inferior to ophthalmologists’ with respect to the pre-specified limit of 10% absolute difference (0.298 on the odds scale). Frequencies of sight-threatening errors were similar for optometrists and ophthalmologists [57/994 (5.7%) vs. 62/994 (6.2%), OR 0.93, 95% CI 0.55 to 1.57;p=0.789]. Ophthalmologists assessed lesion components as present less often than optometrists and were more confident about their lesion classifications than optometrists. The mean care-pathway cost for assessment was very similar by group, namely £397.33 for ophthalmologists and £410.78 for optometrists. The optometrist-led monitoring reviews were slightly more costly and less effective than ophthalmologist-led reviews, although the differences were extremely small. There was consensus that optometrist-led monitoring has the potential to reduce clinical workload and be more patient-centred. However, potential barriers are ophthalmologists’ perceptions of optometrists’ competence, the need for clinical training, the ability of the professions to work collaboratively and the financial feasibility of shared care for Clinical Commissioning Groups Conclusions The ability of optometrists to make nAMD retreatment decisions from vignettes is non-inferior to that of ophthalmologists. Various barriers to implementing shared cared for nAMD were identified. Future Work Recommendations The Effectiveness, cost-effectiveness and acceptability of Community versus Hospital Eye Service follow-up for patients with neovascular age-related macular degeneration with quiescent disease (ECHoES) study web application was robust and could be used for future training or research. The benefit of reducing HES workload was not considered in the economic evaluation. A framework of programme budgeting and marginal analysis could explicitly explore the resource implications of shifting resources within a given health service area, as the benefit of reducing HES workload was not considered in the economic evaluation. Future qualitative research could investigate professional differences of opinion that were identified in multidisciplinary focus groups.</p

Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdOx1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFluCOV): a multicentre, randomised, controlled, phase 4 trial

Background: Concomitant administration of COVID-19 and influenza vaccines could reduce burden on health-care systems. We aimed to assess the safety of concomitant administration of ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine.Methods: In this multicentre, randomised, controlled, phase 4 trial, adults in receipt of a single dose of ChAdOx1 or BNT162b2 were enrolled at 12 UK sites and randomly assigned (1:1) to receive concomitant administration of either an age-appropriate influenza vaccine or placebo alongside their second dose of COVID-19 vaccine. 3 weeks later the group who received placebo received the influenza vaccine, and vice versa. Participants were followed up for 6 weeks. The influenza vaccines were three seasonal, inactivated vaccines (trivalent, MF59C adjuvanted or a cellular or recombinant quadrivalent vaccine). Participants and investigators were masked to the allocation. The primary endpoint was one or more participant-reported solicited systemic reactions in the 7 days after first trial vaccination(s), with a difference of less than 25% considered non-inferior. Analyses were done on an intention-to-treat basis. Local and unsolicited systemic reactions and humoral responses were also assessed. The trial is registered with ISRCTN, ISRCTN14391248.Findings: Between April 1 and June 26, 2021, 679 participants were recruited to one of six cohorts, as follows: 129 ChAdOx1 plus cellular quadrivalent influenza vaccine, 139 BNT162b2 plus cellular quadrivalent influenza vaccine, 146 ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine, 79 BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine, 128 ChAdOx1 plus recombinant quadrivalent influenza vaccine, and 58 BNT162b2 plus recombinant quadrivalent influenza vaccine. 340 participants were assigned to concomitant administration of influenza and a second dose of COVID-19 vaccine at day 0 followed by placebo at day 21, and 339 participants were randomly assigned to concomitant administration of placebo and a second dose of COVID-19 vaccine at day 0 followed by influenza vaccine at day 21. Non-inferiority was indicated in four cohorts, as follows: ChAdOx1 plus cellular quadrivalent influenza vaccine (risk difference for influenza vaccine minus placebo –1·29%, 95% CI –14·7 to 12·1), BNT162b2 plus cellular quadrivalent influenza vaccine (6·17%, –6·27 to 18·6), BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine (–12·9%, –34·2 to 8·37), and ChAdOx1 plus recombinant quadrivalent influenza vaccine (2·53%, –13·3 to 18·3). In the other two cohorts, the upper limit of the 95% CI exceeded the 0·25 non-inferiority margin (ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine 10·3%, –5·44 to 26·0; BNT162b2 plus recombinant quadrivalent influenza vaccine 6·75%, –11·8 to 25·3). Most systemic reactions to vaccination were mild or moderate. Rates of local and unsolicited systemic reactions were similar between the randomly assigned groups. One serious adverse event, hospitalisation with severe headache, was considered related to the trial intervention. Immune responses were not adversely affected.Interpretation: Concomitant vaccination with ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine raises no safety concerns and preserves antibody responses to both vaccines. Concomitant vaccination with both COVID-19 and influenza vaccines over the next immunisation season should reduce the burden on health-care services for vaccine delivery, allowing for timely vaccine administration and protection from COVID-19 and influenza for those in need

Preface and Acknowledgements

On March 23, 2011 – on the 111th anniversary of Arthur Evans’ first working day at Knossos – the international conference “Minoan Archaeology. Challenges and Perspectives for the 21st Century” was launched at the Institute of Classical Archaeology, University of Heidelberg. For five days, early career researchers shared their ideas and concepts with some leading scholars of the field and engaged in discussions revolving around the current character, potential and scopes of Minoan Archaeology...

Introduction: “Minoan Archaeology”

Conference participants, photographed in front of the Heuscheuer at Heidelberg The turn of the new century coincided with the completion of 100 years of systematic archaeological research on Crete. The occasion of this anniversary has already triggered several retrospective and prospective views on the aims, methods, deficits and potentials of this discipline. On 23rd March 2011 – exactly 111 years after Sir Arthur Evans’ spade made the first cut into the earth above the now well-known Palace..

Not worth the risk? Attitudes of adults with learning difficulties, and their informal and formal carers to the hazards of everyday life

Twenty adults with learning difficulties (adults) living at home with informal carers, mostly parents, and attending Adult Training Centres (ATCs) were interviewed about their everyday lives and information was also obtained from informal and formal carers. The problem of dealing with the hazards of everyday life emerged as an important theme. The thinking of adults and informal carers could be understood in terms of the moral dimension of hazards, through the distinction between risks, to be calculated, and dangers, to be avoided. Adults and informal carers within families largely agreed in their categorization of hazards but differences were found. In families where the head of the household had had a professional or skilled manual occupation, adults and informal carers were most likely to agree that hazards for the adult were dangers to be avoided. In families which had a history of unemployment or unskilled occupations adults and informal carers were most likely to treat certain hazards as risks to be taken. The latter families were also less likely to have 2 informal carers. Adults from more risk-tolerant families appeared to be achieving more of their potential in everyday living skills. Formal carers at ATCs were more accepting of risks for adults with learning difficulties than informal carers and there was misunderstanding and conflict between formal and informal carers as a result

Working under short timescales to deliver a national trial:a case study of the ComFluCOV trial from a statistician’s perspective

BackgroundIn early 2021, the Department of Health and Social Care in the UK called for research on the safety and immunogenicity of concomitant administration of COVID-19 and influenza vaccines. Co-administration of these vaccines would facilitate uptake and reduce the number of healthcare visits required. The ComFluCOV trial was designed to deliver the necessary evidence in time to inform the autumn (September–November) 2021 vaccination policy. This paper presents the statistical methodology applied to help successfully deliver the trial results in 6 months.MethodsComFluCOV was a parallel-group multicentre randomised controlled trial managed by the Bristol Trials Centre. Two study statisticians, supported by a senior statistician, worked together on all statistical tasks. Tools were developed to aid the pre-screening process. Automated data monitoring reports of clinic data and electronic diaries were produced daily and reviewed by the trial team and feedback provided to sites. Analyses were performed independently in parallel, and derivations and results of all outcomes were compared.ResultsSet-up was achieved in less than a month, and 679 participants were recruited over 8 weeks. A total of 537 [at least] daily reports outlining recruitment, protocol adherence, and data quality, and 695 daily reports of participant electronic diaries identifying any missed diary entries and adverse events were produced over a period of 16 weeks. A preliminary primary outcome analysis of validated data was reported to the Department of Health and Social Care in May 2021. The database was locked 6 weeks after the final participant follow-up and final analyses completed 3 weeks later. A pre-print publication was submitted within 14 days of the results being made available. The results were reported 6 months after first discussions about the trial.ConclusionThe statistical methodologies implemented in ComFluCOV helped to deliver the study in the timescale set. Working in a new clinical area to tight timescales was challenging. Having two statisticians working together on the study provided a quality assurance process that enabled analyses to be completed efficiently and ensured data were interpreted correctly. Processes developed could be applied to other studies to maximise quality, reduce the risk of errors, and overall provide enhanced validation methods

Minoan Archaeology

More than 100 years ago Sir Arthur Evans' spade made the first cut into the earth above the now well-known Palace at Knossos. His research at the Kephala hill as well as contemporary fieldwork at further sites on Crete saw the birth of a new discipline: Minoan Archaeology. Since these beginnings in the first decades of the 20th century, the investigation of Bronze Age Crete has experienced fundamental progress. The impressive wealth of new data relating to the sites and material culture of this Bronze Age society and its impact beyond the island's shores, the refinement of its chronology, the constant development of hermeneutical approaches to social, religious or political issues, and new methods and instruments employed for the exploration and conservation of the archaeological remains have shaped the dynamic trajectory of this discipline for more than a century. In March 2011 - exactly 111 years after the beginning of Evans' work at Knossos - a conference on Minoan Archaeology took place at Heidelberg with the aim to outline current trends and prospects of this scientific field, by setting up an open dialogue between renowned scholars and the young generation of researchers. The present volume brings together most of the papers presented during the conference. They are subsumed under six chapters highlighting current key issues in the study of Bronze Age Crete with a pronounced focus on the broad subject of society

Minoan Archaeology

More than 100 years ago Sir Arthur Evans' spade made the first cut into the earth above the now well-known Palace at Knossos. His research at the Kephala hill as well as contemporary fieldwork at further sites on Crete saw the birth of a new discipline: Minoan Archaeology. Since these beginnings in the first decades of the 20th century, the investigation of Bronze Age Crete has experienced fundamental progress. The impressive wealth of new data relating to the sites and material culture of this Bronze Age society and its impact beyond the island's shores, the refinement of its chronology, the constant development of hermeneutical approaches to social, religious or political issues, and new methods and instruments employed for the exploration and conservation of the archaeological remains have shaped the dynamic trajectory of this discipline for more than a century. In March 2011 - exactly 111 years after the beginning of Evans' work at Knossos - a conference on Minoan Archaeology took place at Heidelberg with the aim to outline current trends and prospects of this scientific field, by setting up an open dialogue between renowned scholars and the young generation of researchers. The present volume brings together most of the papers presented during the conference. They are subsumed under six chapters highlighting current key issues in the study of Bronze Age Crete with a pronounced focus on the broad subject of society