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Abstract 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 Recent advances in stroke care have led to improvements in survival and rates of stroke recurrence. However, there is a lack of data on trends of major vascular events, and risk factors associated with non-fatal and fatal outcomes. We aim to identify demographical and clinical factors leading to incidence of subsequent major vascular events after the first-ever stroke.Methods 6051 patients’ records with first-ever stroke between 1995 and 2018 in South London, UK were analysed. Semicompeting risks models were constructed to estimate factors affecting time to incidence of recurrent stroke, myocardial infarction (MI), mortality and transitions from poststroke recurrence/MI to mortality (indirect mortality). Cumulative incidence functions were plotted for each major vascular event, stratified by stroke subtypes. All models were adjusted for age, sex, socioeconomic status, comorbidities, stroke severity and stroke subtype.Results Five years of cumulative incidences were 9.2% (95% CI (8.4% to 10.0%)) for recurrent stroke, 4.4% (95% CI 3.9% to 5.0%) for MI, and 45% (95% CI 44% to 47%) for mortality. Prior atrial fibrillation was associated with 47% increased risk of mortality (HR=1.47 (95% CI 1.23 to 1.75)) and a previous diagnosis of MI was the strongest risk factor for poststroke MI (HR=9.17 (95% CI 6.28 to 13.39)). Stroke unit was associated with a 40% lower hazard of mortality without having a recurrent stroke/MI (HR=0.60 (95% CI 0.50 to 0.72)) and a 39% lower hazard of indirect mortality (HR=0.57 (95% CI 0.37 to 0.87)).Conclusion Major vascular events are prevalent after stroke, particularly among those with concurrent vascular conditions. The rate of stroke recurrence plateaued in the last decade, yet MI incidence increased. Targeted strategies to control risk factors are required to reduce the incidence of a second vascular event and prevent progression to mortality in these high-risk groups.

Abstract Background The problem of suicide has become increasingly common in individuals with major depressive disorder (MDD). Transcranial direct current stimulation (tDCS) is an effective treatment for MDD with 2 milliamperes (mA) for at least 30 min per day for 2 weeks. This study aims to investigate the efficacy of daily duration-doubled tDCS as an adjunctive intervention for rapidly reducing suicidal ideation and improving depression in MDD patients. Methods In this double-blind, randomized, sham-controlled study, 76 MDD patients with suicidal ideation are randomly assigned to either active (n=38) or sham (n=38) tDCS group. The anode and cathode are placed over the scalp areas corresponding to left and right dorsolateral prefrontal cortex (DLPFC), respectively, and each stimulation lasts for 60 min. The primary outcome is defined as change of Beck Scale for Suicide Ideation (BSI) after 5 and 10 sessions. The change of other clinical assessments, blood biomarkers related to suicidal ideation and depressive sumptoms are defined as secondary outcomes. Blood biomarkers related to suicidal ideation are collected at baseline and after 10 sessions. Discussion This study suggests the adjunctive duration-doubled tDCS might be a novel method to rapidly reduce suicidal ideation and improve depressive symptom. The variation of biomarkers could be potential predictive models of suicide risk. Trial registration The trial protocol is registered with ClinicalTrials.gov under protocol registration number NCT05555927. Registered on September 25, 2022.

Background & Aims: Von Willebrand factor antigen (vWFAg), a protein measured to test the level of vWF released from the vascular endothelium has gained much attention as a marker for portal hypertension (PHT) severity. The objectives of this study were to investigate the use of vWFAg as a biomarker along with liver and spleen stiffness measurements by transient elastography as potential predictors of clinically significant varices (CSV), variceal bleeding (VB) and decompensation in children with PHT. Methods: This observational prospective cohort study included 117 children (median age 10 [IQR 6-14] years) who underwent oesophagogastroduodenoscopy between January’2012 to November’2021 and a validation group of 33 children who underwent the same procedure between December’2021 to March’2023. Measurements of vWFAg and glycoprotein Ib binding activity of VWF (GPIbR) were available in 97 patients in the study group and in all patients in the validation group.Results: vWFAg and GPIbR were significantly higher in children with CSV (223 IU/dl and 166 IU/dl; p = 0.015 and p = 0.04, respectively) and VB (218 IU/dl and 174 IU/dl; p = 0.077 and p = 0.03, respectively) than in those without CSV or VB, respectively. Ninety-six patients had liver and spleen stiffness measurements. Spleen stiffness was significantly higher in patients with CSV compared to those without CSV (p = 0.003). In a chronic liver disease subgroup, a predictive scoring tool based on vWFAg, GPIbR, platelet count, and spleen/liver stiffness measurements could predict CSV with an AUROC of 0.76 (p = 0.04). Conclusions: This study suggests the predictive value of vWF for CSV and VB increases when combined with spleen stiffness, with AUROCs of 0.88 and 0.82, respectively. Hence, a combination of biomarkers could assist clinicians in diagnosing CSV, preventing unnecessary invasive procedures. Impacts and implications: Surveillance endoscopies in children with portal hypertension (PHT) have their own risks and non-invasive markers, such as von Willebrand factor antigen, glycoprotein Ib binding activity of VWF (GPIbR), and transient elastography could be used to predict clinically significant varices, variceal bleeding and disease compensation in children with PHT. Such non-invasive markers for PHT and varices are lacking in the paediatric population. The results show that von Willebrand factor and GPIbR along with transient elastography can be used to formulate a scoring system which can be used as a clinical tool by paediatric hepatologists to monitor the progression of PHT and risk of bleeding, and hence to stratify the performance of invasive endoscopic procedures under general anaesthesia. However, there is a need to validate the scoring system in children with portal vein thrombosis and for hepatic decompensation in a multi-centre registry in the future.

Abstract 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.

Background The hospice movement has provided an excellent model of specialist palliative care for those with advanced illness approaching the end of life. However, there are marked inequities in provision of this care, and major geographical variations in the resourcing of palliative care, often resulting in a poor match between the needs of a patient/family and resources provided to meet those needs. Objective To develop/test a casemix classification to accurately capture the complex needs of patients with advanced disease, better quantify those needs and more fairly allocate resources to meet them. A ‘casemix classification’ groups patients into classes according to differing care needs to help inform the resources needed to meet those care needs. Design Workstream 1 comprised the validating and refining of patient-centred measures of health status and well-being. In workstream 2, stakeholder interviews with patients, families, policy-makers, service providers and commissioners were carried out to understand complexity/casemix and models of specialist palliative care. In workstream 2 the casemix classification was developed through a multicentre cohort study. Workstream 4 comprised a longitudinal mixed-methods study to test the casemix classification, with a nested qualitative study to explore experiences of transitions between care settings. Setting Voluntary sector and NHS specialist palliative care services across England. Participants Patients ≥ 18 years receiving specialist palliative care, their families and the professionals delivering this care. Results For the Integrated Palliative care Outcome Scale validation: data from 376 patient participants and 161 clinicians showed this measure has a strong ability to distinguish between clinically relevant groups, good internal consistency (α = 0.77), and acceptable-to-good test–retest reliability (60% of items kw > 0.60). The Phase of Illness measure showed function and symptoms/concerns varied significantly by Phase of Illness, but Phase of Illness reflected additional construct(s) and so is important for casemix (workstream 1 conducted 2013–15). To gain stakeholder perspectives, 65 participants were interviewed. Based on emergent themes, we developed a theoretical framework to conceptualise complexity in specialist palliative care. This framework emphasises that considering physical, psychological and social needs is not enough to characterise complexity. Number, severity and range of needs all need to be considered in the development of a meaningful casemix classification. To understand models of care, semistructured interviews were conducted with 14 participants, 54 further participants took part in a two-round Delphi survey and interviews were conducted with 21 service leads. Twenty criteria were adopted to define/distinguish models of specialist palliative care (workstream 2 conducted 2014–16). For the development of the casemix classification, a total of 2469 patients were recruited, providing data on 2968 episodes of specialist palliative care. The mean age was 71.6 years, 51% of patients were male, 74% were white and 25% were non-cancer patients. Episodes of care lasted a median of 8 days (range 1–402 days) in hospital advisory care, 12 days (range 1–140 days) in inpatient units, 30 days (range 1–313 days) in the community. The median costs per day (lower–upper quartiles) were: £56 (£31–£100) in hospital advisory, £365 (£176–£698) for inpatient, and £21 (£6–£49) in community care. Seven hospital advisory, six inpatient and six community casemix classes for specialist palliative care were developed, based on levels of pain, other physical symptoms, psychological symptoms, functional status, palliative Phase of Illness, living alone and family distress (workstream 3 conducted 2016–18). For the testing of the casemix classification, a total of 309 patients (mean age 66.9 years, 55% female, 85% white) provided data on 751 episodes of specialist palliative care. The casemix classification was able to accurately predict the actual cost-per-day of care, especially for hospital advisory and community care. The actual costs of inpatient hospice care were consistently higher than predicted class costs, although cost weights remained consistent. Interviews to understand transitions between care settings were conducted with 26 participants (mean age 68 years, range 36–91 years). Four themes emerged: uncertainty about the new care setting, biographical disruption, the importance of continuity of care and the need for emotional/practical support during transition (workstream 4 conducted 2018–19). Limitations Recruitment was challenging but adding new sites helped to overcome this. Models of palliative care proved more diverse and harder to categorise than expected. This casemix classification needs broader testing among those with non-cancer conditions, especially those with multiple conditions. Conclusions The Integrated Palliative care Outcome Scale is a valid, reliable outcome measure for use in advanced illness. We have developed (1) an evidence-based framework to conceptualise complexity of palliative care needs, (2) defined criteria to characterise/differentiate models of specialist palliative care and (3) a casemix classification for specialist palliative care. Each person needing specialist palliative care is different, with varying degrees of complex needs. We now have the casemix classification to understand and capture this, systematically and at scale, for practice, policy and research. This has the potential to help address inequities and provide more equitable specialist palliative care to all who need it. Future research is needed, including further validation of measures, more detailed research into models of care, and further testing of the casemix classification. Study registration This trial is registered as ISRCTN90752212. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and is published in full in Programme Grants for Applied Research; Vol. 11, No. 7. See the NIHR Funding and Awards website for further award information. It was also supported by the NIHR Applied Research Collaboration South London (NIHR ARC South London, previously Collaboration for Leadership in Applied Health Research and Care) at King’s College Hospital NHS Foundation Trust. Plain language summary Hospices have provided an excellent model of palliative care for those with advanced illness in the last months of life. However, some people do not get the care they need and provision varies considerably between different regions of England. We therefore aimed to develop a classification system to accurately reflect the care needs of those with advanced illness, so that resources can be better matched to needs. We interviewed different patients, families, service providers and funders to understand the complex care needs that people have and how a system could be developed. Then we undertook a large study with those with advanced illness to develop a system. Finally, we tested the system with a new group of people experiencing advanced illness. Sixty-five participants were interviewed. Based on these interviews, we developed a way to better understand complex needs, with the individual person at the heart of this understanding. A total of 2469 people contributed to our large study. We established the resources used to provide palliative care: on average, the cost per patient was an additional £56 per day for those receiving specialist palliative care in hospital, £365 per day for those receiving inpatient hospice care and £21 per day for those receiving specialist palliative care at home. We developed a system based on factors such as pain and other symptoms, level of family distress, and whether or not the patient was living alone. These factors indicate what palliative care is needed and how much it might cost. We tested this system with 309 further people with advanced illness, and it was able to predict costs well. Scientific summary Background The hospice movement has provided an excellent model of specialist palliative care for those with advanced disease in the last year of life. However, little is known about costs of care and there are marked inequities in provision across England. Older patients or those with non-cancer conditions access specialist palliative care less often and receive proportionately fewer resources when they do. There are also major geographical variations in resourcing palliative and end-of-life care, often resulting in a poor match between the needs of a patient/family, the resources provided to meet those needs and the improvement in well-being achieved. Aims The aims of this programme were to develop and test a person-centred, nationally applicable casemix classification for adult specialist palliative care provision in England, to accurately capture the complex needs of patients with advanced disease in last year of life, to better quantify those needs and to support more equitable allocation of resources to meet them. Objectives The C-CHANGE programme had five objectives: to validate or refine new and existing person-centred outcome measures designed to assess the main health status and symptoms/concerns of patients receiving specialist palliative care to utilise the perspectives of key stakeholders on the complexity in palliative care to inform subsequent casemix development to understand the criteria which distinguish different models of palliative care to help inform how a casemix classification can be utilised across different models of specialist palliative care to develop a person-centred palliative care casemix classification, based on individual patient needs and costs of care, for adults with both cancer and non-cancer conditions in the last year of life to test this person-centred palliative care casemix classification in terms of ability to predict resource use in the last year of life and to better understand transitions between services in order to improve care. Methods Workstream 1: measures In Workstream 1, several studies were undertaken from 2013 to 2015 to improve our knowledge of the psychometrics, relationships and clinical utility of the measures proposed for workstreams 3 and 4: A cognitive interview study to refine the prototype Integrated Palliative care Outcome Scale (IPOS), a brief measure of symptoms/concerns in advanced illness. Purposively sampled patients were recruited from four inpatient and community settings. Interviews were analysed using thematic analysis, and the prototype measure refined accordingly. A validation study for the IPOS to validate both the patient self-report and staff proxy-report versions. In a longitudinal cohort study, we tested construct validity (factor analysis, known-group comparisons and correlational analysis), reliability (internal consistency, agreement and test–retest reliability), and responsiveness. A secondary analysis of routinely collected clinical data to describe palliative Phase of Illness, and determine associations between Phase of Illness and the other measures proposed for this programme. A survey to examine patients’ Views on Care (VoC), a brief measure of patient perspectives on the quality of their care. Adults receiving specialist palliative care in eight hospital, hospice inpatient and community settings across England were recruited. We reported associations between VoC and changes in health status. Secondary analysis of pre-existing qualitative interviews to understand patient experiences of uncertainty and how these influence understanding of care. Interviews were sampled using maximum variation sampling and analysed using a thematic approach. Workstream 2: stakeholder perspectives To explore the perspectives of key stakeholders on complexity in palliative care, we undertook a qualitative study using semistructured interviews with key stakeholders in specialist palliative care between 2014 and 2015. Participants were professionals from participating sites or were policy/national leads. Data were analysed using framework analysis. To understand the criteria which characterise/distinguish different models of palliative care, we undertook a mixed-methods study during 2015–16, which comprised the following: Semistructured interviews about preliminary criteria with clinical leads from 14 participating sites. Findings were used to expand/refine these criteria. A two-round Delphi survey [conducted following CREDES (Conducting and REporting DElphi Studies in palliative care) guidance], which identified additional criteria, sought consensus on criteria definitions and ranked criteria by importance. Structured interviews with service providers to assess the acceptability and feasibility of the final criteria, with participants recruited from participating sites from workstreams 3 and 4. Workstream 3: development of the casemix classification To determine the costs of specialist palliative care and develop a casemix classification for UK specialist palliative care, we undertook a multicentre prospective cohort study between 2017 and 2018, collecting potential casemix variables and actual costs over episodes of specialist palliative care. Guidance for Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) was followed. Patients were recruited from four hospital advisory, five inpatient hospice and seven community-based services. Consecutive adult patients (aged ≥ 18 years) were included. Casemix variables included were age, sex, ethnicity, living circumstances, need for interpreter, primary diagnosis, palliative Phase of Illness, functional status, dependency and symptoms/problem severity. Our primary outcome was the cost of specialist palliative care per day. The sample size estimation was 2674 episodes of care. For the analyses we examined the distribution of costs by setting and developed a cost-predictive model using classification and regression tree analysis. Workstream 4: testing of the casemix classification To test the palliative care casemix classification developed in workstream 3, we undertook a multicentre prospective cohort study between 2018 and 2019, following patients during episodes of specialist palliative care, with a qualitative nested component (i.e. interviews with a subsample of participants to better understand the experience of transitions between care settings). Patients were recruited from: three hospital advisory, eight inpatient hospice and five community-based services. Inclusion criteria were adult patients (≥ 18 years) able to consent. Exclusion criteria were < 18 years, unable to consent. Collected data included demographic and clinical variables, episode start and end dates, casemix variables and costs of providing care. The casemix classes developed in workstream 3 were applied to predict costs for episodes of care and this was compared/contrasted with the actual costs captured for each episode. A subsample of participants experiencing at least two transitions between care settings were interviewed, using purposive sampling criteria of age, sex, diagnosis and types of transitions. We undertook thematic analysis, with attention to patient/family perspectives on the experience of transitions between care settings and how these were supported/resourced. Results Workstream 1: measures Twenty-five cognitive interviews were conducted. Overall, comprehension and acceptability of the prototype IPOS was good. Identified difficulties were comprehension problems with some specific terms and judgement difficulties. Based on these findings, the prototype IPOS was refined. In the IPOS validation study, we recruited 376 patients and 161 clinicians. We confirmed a three-factor structure (physical symptoms, emotional symptoms and communication/practical issues). The measure showed strong ability to distinguish between clinically relevant groups; total IPOS scores and IPOS subscale scores were higher – reflecting more problems – in those with ‘unstable’ or ‘deteriorating’ versus ‘stable’ Phase of Illness (F = 15.1; p < 0.001). The IPOS showed good internal consistency (α = 0.77) and acceptable-to-good test–retest reliability (60% of items kw > 0.60). In the study of Phase of Illness, function and symptoms/other concerns varied significantly by Phase of Illness. Mean function (scored using the Australia-modified Karnofsky Performance Status from 0–100, where 100 is best function) was highest in the stable phase [65.9, 95% confidence interval (CI) 63.4 to 68.3] and lowest in dying phase (16.6, 95% CI 15.3 to 17.8). Mean pain (scored 0–4 where 4 is worst pain) was highest in the unstable phase (1.43, 95% CI 1.36 to 1.51). Palliative Phase of Illness reflects additional construct beyond function and symptoms. In the survey to examine VoC, 212 participants were recruited, with a mean age of 65.84 years [standard deviation (SD) 13.5 years]. Most indicated that palliative care was giving positive benefit. Participants reporting that ‘things had got better’ were more likely to have improved overall health status (χ2 = 6.057; p = 0.48). There was significant positive association between those reporting that ‘things had got better’ and improved physical symptoms (χ2 = 11.254; p = 0.004). In the secondary analysis of pre-existing qualitative interviews to understand patient experiences of uncertainty, 30 transcripts were analysed. Participants had a median age of 75 years (range 43–95 years). A typology of patient responses to uncertainty was developed, depending on the level of engagement of each individual patient with their illness and treatment, their preferences for information and their temporal focus. Workstream 2: stakeholder perspectives In study of stakeholder perspectives on complexity, 65 participants (comprising patients, family, health-care professionals and policy makers) were recruited. Based on the emergent themes, we developed a theoretical framework – adapted from Bronfenbrenner’s Ecological Systems Theory – to conceptualise complexity in specialist palliative care. This framework emphasises that considering physical, psychological, social and spiritual domains is not enough to characterise complexity. The number, severity and range of needs – as well as ‘hidden’ or overlooked aspects of complexity – all need to be considered in the development of a meaningful casemix classification for specialist palliative care. Semistructured interviews were conducted with 14 service leads discussing 12 settings of care (five hospice inpatient units, two hospital advisory teams and five community teams). Of the 28 initial criteria to describe models of care, 11 were removed, 17 were refined and a further 17 were created. Thirty-four criteria were taken into the Delphi survey. Fifty-four participants took part in the Delphi survey. In round 1, six criteria did not reach the pre-defined consensus standard and four new criteria were created; this resulted in a refined list of criteria. In round 2, the revised criteria were ranked and rated, and 16 criteria reached the pre-defined consensus standard. In the third component of this study, interviews were then conducted with 21 service leads from 19 different services (six hospice inpatients, four hospital advisory and nine community settings). Criteria were acceptable and feasible, but four contextual criteria were added, resulting in 20 final criteria to define a model of specialist palliative care. Workstream 3: development of the casemix classification In the multicentre prospective cohort study to develop the casemix classification, 2469 patients were recruited, providing data on 2968 complete episodes of specialist palliative care. Patients had a mean age 71.6 years (SD 13.9 years) and were 51% male, 74% white and 25% non-cancer patients. Episodes of care lasted a median of 8 days (range 1–402 days) in hospital advisory care, 12 days (range 1–140 days) in inpatient units and 30 days (range 1–313 days) in community-based care. The median costs per day (lower-upper quartiles) were £56 (£31–100) in hospital advisory care, £365 (£176–698) for inpatient care and £21 (£6–49) in community care. Seven hospital advisory, six inpatient, and six community casemix classes for specialist palliative care were developed, based on seven casemix variables (pain, other physical symptoms, psychological symptoms, functional status, palliative Phase of Illness, living alone and family distress). These casemix criteria, measured at the start of the episode of care, provided the optimal classes to predict costs per day for the episode of care. The per cent variance explained (and root-mean-squared error) were 20% (0.30), 51% (0.51) and 27% (0.36) for hospital advisory, inpatient hospice and community episodes, respectively. Workstream 4: testing of the casemix classification In the multicentre prospective cohort study to test the casemix classification, 309 patients (mean age 66.9 years, SD 13.1 years; 55% female, 85% white) were recruited, providing data on 751 episodes of specialist palliative care. As expected, the median duration of an episode of care was shortest for hospital advisory episodes (10 days) and longest for community episodes (26 days). The casemix classification was able to accurately predict the actual cost per day of care, especially for hospital advisory and community care. The actual costs of inpatient hospice care were consistently higher than the predicted class costs, although the cost weights remained consistent. For the qualitative nested interviews, to understand transitions between care settings, 20 interviews with 26 participants were conducted (mean age 68 years, range 36–91 years). Fourteen interviews were individual and six were joint interviews. Four themes emerged: uncertainty about the new care setting – a lack of information about the new setting of care added to feelings of uncertainty and stress biographical disruption – a loss of independence and difficulty maintaining a sense of normality challenged participants’ self-identity as they moved place of care importance of continuity of care – continuity of care had an impact on feelings of safety in the new care setting and also influenced decisions about the transition need for emotional/practical support – most participants expressed a greater need for emotional and practical support when transitioning to a new care setting. Conclusions The Integrated Palliative care Outcome Scale is a valid and reliable outcome measure, both in its patient self-report and staff proxy-report versions. It can assess/monitor symptoms and concerns in advanced illness, reflect the impact of healthcare interventions and demonstrate quality of care. This represents a major step forward internationally for palliative care outcome measurement. Palliative Phase of Illness has value as a clinical measure of overall palliative need, capturing additional information beyond function and symptoms. In addition, VoC (reflecting patient perspectives on quality of care) is brief and easy to use with patients receiving palliative care across different settings. To the best of our knowledge, it is unique in its brevity and ease of use for ill patients receiving palliative care, which allows the measure to provide patient-level feedback in real time. To the best of our knowledge, workstream 2 provided for the first time in palliative care an evidence-based framework to conceptualise the complexity of palliative care needs of those with advanced illness. Overall, participants reported that they thought it acceptable to measure complexity at the individual patient level using the proposed criteria. To our knowledge, until now there has not been a clear set of criteria to define models of UK specialist palliative care, making it challenging to compare different models of care provided by services. This component of the programme identified the criteria needed to characterise and differentiate models of specialist palliative care, a major paradigm shift to enable accurate reporting and comparison in practice and research. Our detailed evidence on specialist palliative care costs and the casemix classification for specialist palliative care deliver a major advance for the sector. Each person needing specialist palliative care is different, with varying degrees of complex needs. We now have the means to understand this, systematically and at scale, for practice, policy (including resourcing of palliative care) and research. The casemix classes show cost weight variations up to 4.5-fold in inpatient hospices and almost 3-fold in community care. The needs of each person are varied – not fixed – and require different resources to deliver care effectively. Understanding this has the potential to help address inequities and provide more equitable specialist palliative care to all who need it. The casemix classification will inform NHS England currency development. Study registration This trial is registered as ISRCTN90752212. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and is published in full in Programme Grants for Applied Research; Vol. 11, No. 7. See the NIHR Funding and Awards website for further award information. It was also supported by the NIHR Applied Research Collaboration South London (NIHR ARC South London, previously Collaboration for Leadership in Applied Health Research and Care) at King’s College Hospital NHS Foundation Trust.

ObjectiveMonoclonal antibody (Mab) treatments have significantly improved the quality and quantity of life, but they are some of the most expensive treatments, resulting in a degree of hesitancy to introduce new Mab agents. A system for estimating the effect of Mab drugs, in general, would optimally inform health strategy and fully realize how a single scientific discovery can deliver health benefits. We evaluated such a method with several well-established Mab regimens.MethodsWe selected five different Mab regimens in oncology and rheumatology in England. We carried out two systematic literature reviews and meta-analyses to assess health outcomes (Health Assessment Questionnaire-Disability Index for rheumatoid arthritis; overall mortality for melanoma) from real-world data and compared them to the outcomes from randomized control trials (RCTs). We applied economic modeling to estimate the net monetary benefits for health outcomes for the estimated patient population size for each Mab regimen.ResultsMeta-analyses of 27 eligible real-world data (RWD) sets and 26 randomized controlled trial (RCT) sets found close agreement between the observed and expected health outcomes. A Markov model showed the net positive monetary benefit in three Mab regimens and the negative benefit in two regimens. However, because of limited access to NHS data, the economic model made several assumptions about the number of treated patients and the cost of treatment to the NHS, the accuracy of which may affect the estimation of the net monetary benefit.ConclusionRCT results reliably inform the real-world experience of Mab treatments. Calculation of the net monetary benefit by the algorithm described provides a valuable overall measure of the health impact, subject to the accuracy of data inputs. This study provides a compelling case for building a comprehensive, systematized, and accessible database and related analytics, on all Mab treatments within health services.

Objective The objective of this systematic review was to examine how the record linkage process is reported in multimorbidity research.Methods A systematic search was conducted in Medline, Web of Science and Embase using predefined search terms, and inclusion and exclusion criteria. Published studies from 2010 to 2020 using linked routinely collected data for multimorbidity research were included. Information was extracted on how the linkage process was reported, which conditions were studied together, which data sources were used, as well as challenges encountered during the linkage process or with the linked dataset.Results Twenty studies were included. Fourteen studies received the linked dataset from a trusted third party. Eight studies reported variables used for the data linkage, while only two studies reported conducting prelinkage checks. The quality of the linkage was only reported by three studies, where two reported linkage rate and one raw linkage figures. Only one study checked for bias by comparing patient characteristics of linked and non-linked records.Conclusions The linkage process was poorly reported in multimorbidity research, even though this might introduce bias and potentially lead to inaccurate inferences drawn from the results. There is therefore a need for increased awareness of linkage bias and transparency of the linkage processes, which could be achieved through better adherence to reporting guidelines.PROSPERO registration number CRD42021243188.

Abstract Background Patients presenting with acute hypercapnic respiratory failure due to exacerbations of chronic obstructive pulmonary disease (AECOPD) are typically managed with non-invasive ventilation (NIV). The impact of low-flow extracorporeal carbon dioxide removal (ECCO2R) on outcome in these patients has not been explored in randomised trials. Methods Open-label randomised trial comparing NIV (NIV arm) with ECCO2R (ECCO2R arm) in patients with AECOPD at high risk of NIV failure (pH

Objectives The objective for this systematic review was to examine how the record linkage process was reported and to understand challenges related to accessing, linking, and analysing linked routinely collected data used for multimorbidity research. Approach A systematic search for relevant studies was conducted in three online databases (Medline, Web of Science and Embase) in May 2021 using predefined search terms, and inclusion and exclusion criteria. Studies using linked routinely collected data for multimorbidity research were included. Information was extracted on how the linkage process was reported, which conditions were studied together, which data sources were used, as well as challenges encountered during the linkage process or with the linked dataset. The findings from this study will feed into further guidance to understand and minimise bias due to linkage error in medical research. Results Twenty studies were included, of which seventeen looked at the relationship between two specified long-term conditions. Fourteen studies received the linked dataset from an external data linkage provider. Hospital Episode Statistics was the most common source of data (n=5). Eight studies reported variables used for the data linkage, while only two studies reported pre-linkage checks. The quality of the linkage was assessed by three studies, of which two reported linkage rate and one reported raw linkage figures. Only one study checked for bias by comparing patient characteristics of linked and non-linked records. Conclusions The linkage process was poorly reported in multimorbidity research, even though this might introduce bias and potentially lead to inaccurate inferences drawn from the results. There is therefore a need for increased awareness of linkage bias and transparency of the linkage processes, which could be achieved through better adherence to reporting guidelines.

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. Emma Rezel-Potts and colleagues investigate whether the incidence of new diabetes mellitus and cardiovascular diseases are increased over 12 months after Covid-19 compared with matched controls. Author summary Why was this study done? ➢ Acute Coronavirus Disease 2019 (COVID-19) may be associated with cardiovascular complications and disorders of blood glucose. ➢ It is not known whether patients recovering from COVID-19 remain at increased risk of cardiovascular disease (CVD) or diabetes mellitus (DM). ➢ This study aimed to find out whether new diagnoses of DM and CVDs are increased over 12 months after COVID-19 compared with matched control patients who did not have COVID-19. What did the researchers do and find? ➢ We analysed electronic records for 428,650 COVID-19 patients who were matched with 428,650 control patients and followed up to January 2022. We evaluated new diagnoses of DM and CVD up to 12 months after COVID-19 infection. We compared COVID-19 patients with controls and adjusted for baseline differences in risk. ➢ DM diagnoses were increased by 81% in acute COVID-19 and remained elevated by 27% from 4 to 12 weeks after the infection. ➢ Acute COVID-19 was associated with a 6-fold increase in cardiovascular diagnoses overall, including an 11-fold increase in pulmonary embolism, a 6-fold increase in atrial arrythmias, and a 5-fold increase in venous thromboses. CVD diagnoses declined from 4 to 12 weeks after COVID-19 and returned to baseline levels or below from 12 weeks to 1 year after the infection. What do these findings mean? ➢ Acute COVID-19 is associated with increased risk of cardiovascular disorders, but risk generally returns to background levels soon after the infection. ➢ The risk of new DM remains increased for at least 12 weeks following COVID-19 before declining. ➢ Patients recovering from COVID-19 should be advised to consider measures to reduce diabetes risk including healthy diet and taking exercise. ➢ 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.

Abstract 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.

Summary: Background: Given the projected trends in population ageing and population growth, the number of people with dementia is expected to increase. In addition, strong evidence has emerged supporting the importance of potentially modifiable risk factors for dementia. Characterising the distribution and magnitude of anticipated growth is crucial for public health planning and resource prioritisation. This study aimed to improve on previous forecasts of dementia prevalence by producing country-level estimates and incorporating information on selected risk factors. Methods: We forecasted the prevalence of dementia attributable to the three dementia risk factors included in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 (high body-mass index, high fasting plasma glucose, and smoking) from 2019 to 2050, using relative risks and forecasted risk factor prevalence to predict GBD risk-attributable prevalence in 2050 globally and by world region and country. Using linear regression models with education included as an additional predictor, we then forecasted the prevalence of dementia not attributable to GBD risks. To assess the relative contribution of future trends in GBD risk factors, education, population growth, and population ageing, we did a decomposition analysis. Findings: We estimated that the number of people with dementia would increase from 57·4 (95% uncertainty interval 50·4–65·1) million cases globally in 2019 to 152·8 (130·8–175·9) million cases in 2050. Despite large increases in the projected number of people living with dementia, age-standardised both-sex prevalence remained stable between 2019 and 2050 (global percentage change of 0·1% [–7·5 to 10·8]). We estimated that there were more women with dementia than men with dementia globally in 2019 (female-to-male ratio of 1·69 [1·64–1·73]), and we expect this pattern to continue to 2050 (female-to-male ratio of 1·67 [1·52–1·85]). There was geographical heterogeneity in the projected increases across countries and regions, with the smallest percentage changes in the number of projected dementia cases in high-income Asia Pacific (53% [41–67]) and western Europe (74% [58–90]), and the largest in north Africa and the Middle East (367% [329–403]) and eastern sub-Saharan Africa (357% [323–395]). Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia. Interpretation: Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group. Country-level estimates can be used to inform national planning efforts and decisions. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia. Funding: Bill & Melinda Gates Foundation and Gates Ventures.

Abstract Background Chronic obstructive pulmonary disease (COPD) is a common cause of chronic respiratory failure and its course is punctuated by a series of acute exacerbations which commonly lead to hospital admission. Exacerbations are managed through the application of non-invasive ventilation and, when this fails, tracheal intubation and mechanical ventilation. The need for mechanical ventilation significantly increases the risk of death. An alternative therapy, extracorporeal carbon dioxide removal (ECCO2R), has been shown to be efficacious in removing carbon dioxide from the blood; however, its impact on respiratory physiology and patient outcomes has not been explored. Methods/design A randomised controlled open label trial of patients (12 in each arm) with acute exacerbations of COPD at risk of failing conventional therapy (NIV) randomised to either remaining on NIV or having ECCO2R added to NIV with a primary endpoint of time to cessation of NIV. The change in respiratory physiology following the application of ECCO2R and/or NIV will be measured using electrical impedance tomography, oesophageal pressure and parasternal electromyography. Additional outcomes, including patient tolerance, outcomes, need for readmission, changes in blood gases and biochemistry and procedural complications, will be measured. Physiological changes will be compared within one patient over time and between the two groups. Healthcare costs in the UK system will also be compared between the two groups. Discussion COPD is a common disease and exacerbations are a leading cause of hospital admission in the UK and worldwide, with a sizeable mortality. The management of patients with COPD consumes significant hospital and financial resources. This study seeks to understand the feasibility of a novel approach to the management of patients with acute exacerbations of COPD as well as to understand the underlying physiological changes to explain why the approach does or does not assist this patient cohort. Detailed respiratory physiology has not been previously undertaken using this technique and there are no other randomised controlled trials currently in the literature. Trial registration ClinicalTrials.gov, NCT02086084.

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.

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.

Despite early reports of an impact of complement C3 polymorphism on liver transplant patient and graft survival, subsequent evidence has been conflicting. Our aim was to clarify the contributions of donor and recipient C3 genotype, separately and together, on patient and graft outcomes and acute rejection incidence in liver transplant recipients. Eight donor/recipient groups were analyzed according to their genotype and presence or absence of C3 F allele (FFFS, FFSS, FSFF, FSFS, FSSS, SSFF, SSFS, and SSSS) and correlated with clinical outcomes of patient survival, graft survival, and rejection. The further impact of brain death vs. circulatory death during liver donation was also considered. Over a median 5.3 y follow-up of 506 patients with clinical information and matching donor and recipient tissue, five-year patient and graft survival (95% confidence interval) were 90(81-91)% and 77(73-85)%, respectively, and 72(69-94)% were rejection-free. Early disadvantages to patient survival were associated with donor C3 F variant, especially in brain-death donors. Recipient C3 genotype was an independent determinant of graft survival by Cox proportional hazards analysis (hazard ratio 0.26, P=0.04), and the C3 F donor variant was again associated with worse liver graft survival, particularly in brain-death donors. C3 genotype did not independently determine rejection incidence, but a greater proportion of recipient C3 F carriers were rejection-free in the circulatory death, but not the brain-death cohort. Cox proportional hazards analysis revealed significant effects of acute rejection on patient survival (hazard ratio 0.24, P=0.018), of retransplantation on rejection risk (hazard ratio 6.3, P=0.009), and of donor type (circulatory-death vs. brain-death) on rejection incidence (hazard ratio 4.9, P=0.005). We conclude that both donor and recipient complement C3 genotype may influence patient and graft outcomes after liver transplantation but that the type of liver donor is additionally influential, possibly via the inflammatory environment of the transplant.

Background and purposeMachine learning (ML) has attracted much attention with the hope that it could make use of large, routinely collected datasets and deliver accurate personalised prognosis. The aim of this systematic review is to identify and critically appraise the reporting and developing of ML models for predicting outcomes after stroke.MethodsWe searched PubMed and Web of Science from 1990 to March 2019, using previously published search filters for stroke, ML, and prediction models. We focused on structured clinical data, excluding image and text analysis. This review was registered with PROSPERO (CRD42019127154).ResultsEighteen studies were eligible for inclusion. Most studies reported less than half of the terms in the reporting quality checklist. The most frequently predicted stroke outcomes were mortality (7 studies) and functional outcome (5 studies). The most commonly used ML methods were random forests (9 studies), support vector machines (8 studies), decision trees (6 studies), and neural networks (6 studies). The median sample size was 475 (range 70-3184), with a median of 22 predictors (range 4-152) considered. All studies evaluated discrimination with thirteen using area under the ROC curve whilst calibration was assessed in three. Two studies performed external validation. None described the final model sufficiently well to reproduce it.ConclusionsThe use of ML for predicting stroke outcomes is increasing. However, few met basic reporting standards for clinical prediction tools and none made their models available in a way which could be used or evaluated. Major improvements in ML study conduct and reporting are needed before it can meaningfully be considered for practice.

Abstract Background Stroke rehabilitation aims to optimise function and reduce complications post-stroke. Rehabilitation to optimise physical function post-stroke has beneficial effects for survivors of mild to moderate stroke. However, little is known about the effectiveness of interventions to rehabilitate physical function or manage immobility-related complications for survivors of severe stroke. The systematic review aims to evaluate the effectiveness of rehabilitation interventions on physical function and immobility-related complications in severe stroke and identify topics for future research in this area. Methods A systematic review of relevant electronic databases (MEDLINE, Embase, CINAHL, AMED, PEDro, DORIS and CENTRAL) between January 1987 and July 2017 will be undertaken to identify eligible published randomised controlled trials (RCTs) in any language. Ongoing RCTs will be identified by searching health-care trial registers (Stroke Trials Registry, ClinicalTrials.gov). Hand searches of identified study reference lists will also be performed. The PRISMA statement will be used to guide the systematic review. Two reviewers will screen search results, select studies using pre-defined selection criteria, extract data from and assess risk of bias for selected studies. Studies comparing the effect of one type of rehabilitation intervention to another or usual care on physical function and immobility-related complications for patients with severe stroke will be included. Studies may include participants with all levels of stroke severity but must provide sub-group analysis based on stroke severity. Studies will focus on any phase of the stroke rehabilitation pathway and will be grouped and analysed according to their timeframe post-stroke into acute and early sub-acute (up to 3 months post-stroke), early sub-acute to late sub-acute (from 3 to 6 months post-stroke) and chronic (greater than 6 months post-stroke). If sufficient studies demonstrate homogeneity, a meta-analysis will pool results of individual outcomes. The GRADE approach will be used to assess the evidence strength. Discussion The results of this systematic review will summarise the strength of evidence for rehabilitation interventions used in the rehabilitation of physical function and immobility-related complications in severe stroke and identify gaps in evidence. Systematic review registration The systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO)—registration number CRD77737.

Abstract Background Despite the problem of inadequate recruitment to randomised trials, there is little evidence to guide researchers on decisions about how people are effectively recruited to take part in trials. The PRioRiTy study aimed to identify and prioritise important unanswered trial recruitment questions for research. The PRioRiTy study - Priority Setting Partnership (PSP) included members of the public approached to take part in a randomised trial or who have represented participants on randomised trial steering committees, health professionals and research staff with experience of recruiting to randomised trials, people who have designed, conducted, analysed or reported on randomised trials and people with experience of randomised trials methodology. Methods This partnership was aided by the James Lind Alliance and involved eight stages: (i) identifying a unique, relevant prioritisation area within trial methodology; (ii) establishing a steering group (iii) identifying and engaging with partners and stakeholders; (iv) formulating an initial list of uncertainties; (v) collating the uncertainties into research questions; (vi) confirming that the questions for research are a current recruitment challenge; (vii) shortlisting questions and (viii) final prioritisation through a face-to-face workshop. Results A total of 790 survey respondents yielded 1693 open-text answers to 6 questions, from which 1880 potential questions for research were identified. After merging duplicates, the number of questions was reduced to 496. Questions were combined further, and those that were submitted by fewer than 15 people and/or fewer than 6 of the 7 stakeholder groups were excluded from the next round of prioritisation resulting in 31 unique questions for research. All 31 questions were confirmed as being unanswered after checking relevant, up-to-date research evidence. The 10 highest priority questions were ranked at a face-to-face workshop. The number 1 ranked question was “How can randomised trials become part of routine care and best utilise current clinical care pathways?” The top 10 research questions can be viewed at www.priorityresearch.ie. Conclusion The prioritised questions call for a collective focus on normalising trials as part of clinical care, enhancing communication, addressing barriers, enablers and motivators around participation and exploring greater public involvement in the research process.

Abstract Background There is emerging evidence of the central role of neutrophils in both atherosclerotic plaque formation and rupture. Patients with lower neutrophil counts following acute coronary syndromes tend to have a greater coronary flow reserve, which is a strong predictor of long-term cardiovascular health. But so far, no data are available regarding the impact of neutrophil inhibition on cardiovascular clinical or surrogate endpoints. Therefore, the aim of this study is to investigate the effects of AZD5069, a cysteine-X-cysteine chemokine receptor 2 (CXCR2) inhibitor, on coronary flow reserve and coronary structure and function in patients with coronary artery disease. Methods/Design Ninety subjects with coronary artery disease undergoing percutaneous coronary intervention will be included in this investigator-driven, randomised, placebo-controlled, double-blind, phase IIa, single-centre study. Participants will be randomised to receive either AZD5069 (40 mg) administered orally twice daily or placebo for 24 weeks. Change in coronary flow reserve as determined by 13N-ammonia positron emission tomography-computed tomography will be the primary outcome. Change in the inflammatory component of coronary plaque structure and the backward expansion wave, an invasive coronary physiological measure of diastolic function, will be assessed as secondary outcomes. Discussion Cardiovascular surrogate parameters, such as coronary flow reserve, may provide insights into the potential mechanisms of the cardiovascular effects of CXCR2 inhibitors. Currently, ongoing trials do not specifically focus on neutrophil function as a target of intervention, and we therefore believe that our study will contribute to a better understanding of the role of neutrophil-mediated inflammation in coronary artery disease. Trial registration EudraCT, 2016-000775-24 . Registered on 22 July 2016. International Standard Randomised Controlled Trial Number, ISRCTN48328178 . Registered on 25 February 2016.

Abstract Background Delayed graft function (DGF) is traditionally defined as the requirement for dialysis during the first week after transplantation. DGF is a common complication of renal transplantation, and it negatively affects short- and long-term graft outcomes. Ischaemia reperfusion injury (IRI) is a prime contributor to the development of DGF. It is well established that complement system activation plays a pivotal role in the pathogenesis of IRI. Mirococept is a highly effective complement inhibitor that can be administered ex vivo to the donor kidney just before transplantation. Preclinical and clinical evidence suggests that Mirococept inhibits inflammatory responses that follow IRI. The EMPIRIKAL trial (REC 12/LO/1334) aims to evaluate the efficacy of Mirococept in reducing the incidence of DGF in cadaveric renal transplantation. Methods/design EMPIRIKAL is a multicentre double-blind randomised case-control trial designed to test the superiority of Mirococept in the prevention of DGF in cadaveric renal allografts, as compared to standard cold perfusion fluid (Soltran®). Patients will be randomised to Mirococept or placebo (Pbo) and will be enrolled in cohorts of N = 80 with a maximum number of 7 cohorts. The first cohort will be randomised to 10 mg of Mirococept or Pbo. After the completion of each cohort, an interim analysis will be carried out in order to evaluate the dose allocation for the next cohort (possible doses: 5–25 mg). Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. The enrolment will take approximately 24 months, and patients will be followed for 12 months. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Secondary endpoints include duration of DGF, functional DGF, renal function at 12 months, acute rejection episodes at 6 and 12 months, primary non-function and time of hospital stay on first admission and in the first year following transplant. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events. Discussion The EMPIRIKAL trial is the first study to evaluate the efficacy of an ex vivo administered complement inhibitor (Mirococept) in preventing DGF in cadaveric human renal transplantation. Mirococept has a unique ‘cytotopic’ property that permits its retention in the organ microvasculature. Trial registration ISRCTN registry, ISRCTN49958194 . Registered on 3 August 2012.

ObjectivesTo assess the impact of specialist contraceptive support after abortion on effective contraceptive use at six months and subsequent abortions within two years.MethodsMulticentre randomised controlled trial among women undergoing induced abortion in three London boroughs. Allocation was through electronically concealed stratified randomisation by centre, blinding clinicians and participants to arm allocation until interventions. Control group received standard care, comprising advice to follow up with their general practitioner or contraceptive clinic as needed. Intervention group additionally received specialist contraceptive support via telephone or face-to-face consultation at 2-4 weeks and 3 months post-abortion. Primary outcome was rate of effective contraceptive use at six months post-abortion. Secondary outcomes were subsequent abortions within two years.Results569 women were recruited between October 2011 and February 2013, randomised to intervention (282) and control (287) groups; 290 (142 intervention, 148 control) were available for primary outcome analysis. Intention-to-treat analysis showed no significant difference between the two groups in effective contraceptive use after abortion (62%, vs 54%, p = 0·172), long-acting contraceptive use (42% versus 32%, p = 0·084), and subsequent abortion (similar rates, at 1 year: 10%, p = 0·895, between 1-2 years: 6%, p = 0·944). Per-protocol analysis showed those who received the complete intervention package were significantly more likely to use effective contraception (67% versus 54%, p = 0·048), in particular long-acting contraception (49% versus 32%, p = 0·010) and showed a non-significant reduction in subsequent abortions within 2 years (at 1 year: 5% versus 10%, p = 0·098; and between 1-2 years: 3% versus 6%, p = 0·164, respectively).ConclusionsStructured specialist support post-abortion did not result in significant use of effective contraception at six months or reduction in subsequent abortions within two years. Participants engaging with the intervention showed positive effect on effective contraception at six months post-abortion. The potential benefit of such intervention may become evident through further studies with increased patient participation.

BackgroundStroke care and outcomes have improved significantly over the past decades. It is unclear if patients who had a stroke in hospital (in-hospital stroke, IHS) experienced similar improvements to those who were admitted with stroke (community-onset stroke, COS).MethodsData from the South London Stroke Register were analysed to estimate trends in processes of care and outcomes across three cohorts (1995-2001, 2002-2008, 2009-2015). Kaplan-Meier survival curves were calculated for each cohort. Associations between patient location at stroke onset, processes of care, and outcomes were investigated using multiple logistic regression and Cox proportional hazards models.ResultsOf 5,119 patients admitted to hospital and registered between 1995 and 2015, 552(10.8%) had IHS. Brain imaging rates increased from 92.4%(COS) and 78.3%(IHS) in 1995-2001 to 100% for COS and IHS in 2009-2015. Rates of stroke unit admission rose but remained lower for IHS (1995-2001: 32.2%(COS) vs. 12.4%(IHS), 2002-2008: 77.1%(COS) vs. 50.0%(IHS), 2009-2015: 86.3%(COS) vs. 65.4%(IHS)). After adjusting for patient characteristics and case-mix, IHS was independently associated with lower rates of stroke unit admission in each cohort (1995-2001: OR 0.49, 95%CI 0.29-0.82, 2002-2008: 0.29, 0.18-0.45, 2009-2015: 0.22, 0.11-0.43). In 2009-2015, thrombolysis rates were lower for ischaemic IHS (17.8%(COS) vs. 13.8%(IHS)). Despite a decline, in-hospital mortality remained significantly higher after IHS in 2009-2015 (13.7%(COS) vs. 26.7%(IHS)). Five-year mortality rates declined for COS from 58.9%(1995-2001) to 35.2%(2009-2015) and for IHS from 80.8%(1995-2001) to 51.1%(2009-2015). In multivariable analysis, IHS was associated with higher mortality over five years post-stroke in each cohort (1995-2001: HR 1.27, 95%CI 1.03-1.57, 2002-2008: 1.24, 0.99-1.55, 2009-2016: 1.39, 0.95-2.04).ConclusionsDespite significant improvements for IHS patients similar to those for COS patients, rates of stroke unit admission and thrombolysis remain lower, and short- and long-term outcomes poorer after IHS. Factors preventing IHS patients from entering evidence-based stroke-specific hospital pathways in a timely fashion need further investigation.

This study assesses five year outcomes of patients with cognitive deficits within the first three months after stroke. Population-based data from the South London Stroke Register between 1995 and 2018 were studied. Cognitive function was assessed using the Abbreviated-Mental-Test or Mini-Mental-State-Examination. Multivariable Poisson regression models with robust standard errors were constructed, to evaluate relative risks (RRs) and associations between post-stroke deterioration in cognitive function during the first three months on dependency, mortality, depression and institutionalisation. A total of 6504 patients with first-ever strokes were registered with a mean age of 73 (SD: 13.2). During the first three months post-stoke, approximately one-third of these stroke survivors either cognitively improved (37%), deteriorated (30%) or remained unchanged (33%). Post-stroke cognitive impairment was associated with increases, in five years, of the risks of mortality, dependency, depression and being institutionalised by RRs 30% (95% confidence interval: 1.1–1.5), 90% (1.3–2.6), 60% (1.1–2.4) and 50% (1.1–2.3), respectively. Deterioration in cognitive function by 10% or more between seven days and three months was associated with an approximate two-fold increased risk in mortality, dependency, and being institutionalised after one year, compared to stable cognitive function; RRs 80% (1.1–3.0), 70% (1.2–2.4) and two-fold (1.3–3.2), respectively. Monitoring further change to maintain cognitive abilities should be a focus to improve outcomes.

We aim to identify and critically appraise clinical prediction models of mortality and function following ischaemic stroke.Electronic databases, reference lists, citations were searched from inception to September 2015. Studies were selected for inclusion, according to pre-specified criteria and critically appraised by independent, blinded reviewers. The discrimination of the prediction models was measured by the area under the curve receiver operating characteristic curve or c-statistic in random effects meta-analysis. Heterogeneity was measured using I2. Appropriate appraisal tools and reporting guidelines were used in this review.31395 references were screened, of which 109 articles were included in the review. These articles described 66 different predictive risk models. Appraisal identified poor methodological quality and a high risk of bias for most models. However, all models precede the development of reporting guidelines for prediction modelling studies. Generalisability of models could be improved, less than half of the included models have been externally validated(n = 27/66). 152 predictors of mortality and 192 predictors and functional outcome were identified. No studies assessing ability to improve patient outcome (model impact studies) were identified.Further external validation and model impact studies to confirm the utility of existing models in supporting decision-making is required. Existing models have much potential. Those wishing to predict stroke outcome are advised to build on previous work, to update and adapt validated models to their specific contexts opposed to designing new ones.

Background: We previously reported that repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses, comparable with conventional high-dose subcutaneous and sublingual immunotherapy. Objective: To evaluate the efficacy and mechanism of grass pollen intradermal immunotherapy for treatment of allergic rhinitis. Design: A Phase II, double-blind, randomised controlled parallel-group trial. Setting: Single-centre UK study. Participants: Adults aged 18–65 years, with grass pollen-induced allergic rhinoconjunctivitis. Interventions: Seven 2-weekly intradermal injections were given into the forearm, containing either Phleum pratense soluble grass pollen extract (7 ng of the major allergen Phl p 5) or histamine control. Main outcome measures: The primary outcome was a combined symptom and medication score (CSMS) during the 2013 grass pollen season. Secondary clinical outcomes were overall symptom scores; individual symptoms scores for nose, mouth, eyes and lungs; overall medication scores; CSMSs during the peak season; visual analogue scale (VAS) scores for nose and eye symptoms; Mini Rhinitis Quality of Life Questionnaire scores; health-related quality-of-life scores (European Quality of Life-5 Dimensions, 5-levels); a global evaluation of symptoms, number of symptom-free and medication-free days; number of days when prednisolone was used; and adverse events. Mechanistic studies included measurement of late-phase skin response sizes, allergen-specific antibody titres, analysis of skin biopsies and basophil activation tests. Results: There was no significant difference in CSMSs between treatment arms [difference in median area under curve (AUC) 14, 95% confidence interval (CI) –172.5 to 215.1; p = 0.80]. Paradoxically, among the secondary outcomes, nasal symptoms measured with daily scores were higher in the active arm (difference in median AUC 35, 95% CI 4.0 to 67.5; p = 0.03), with a trend for higher nasal symptoms measured by VASs (difference in median AUC 53, 95% CI –11.6 to 125.2; p = 0.05). No differences were seen in other clinical outcomes in the main intention-to-treat analysis. In mechanistic studies, active treatment increased P. pratense-, Phl p 1- and Phl p 5-specific immunoglobulin E (all p = 0.001) compared with the control. T cells cultured from skin biopsies of active intradermal immunotherapy subjects showed higher T helper type 2 cell (Th2) marker CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) expression (p