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Sample size calculations for cluster-randomised trials require inclusion of an inflation factor taking into account the intra-cluster correlation coefficient. Often, estimates of the intra-cluster correlation coefficient are taken from pilot trials, which are known to have uncertainty about their estimation. Given that the value of the intra-cluster correlation coefficient has a considerable influence on the calculated sample size for a main trial, the uncertainty in the estimate can have a large impact on the ultimate sample size and consequently, the power of a main trial. As such, it is important to account for the uncertainty in the estimate of the intra-cluster correlation coefficient. While a commonly adopted approach is to utilise the upper confidence limit in the sample size calculation, this is a largely inefficient method which can result in overpowered main trials. In this paper, we present a method of estimating the sample size for a main cluster-randomised trial with a continuous outcome, using numerical methods to account for the uncertainty in the intra-cluster correlation coefficient estimate. Despite limitations with this initial study, the findings and recommendations in this paper can help to improve sample size estimations for cluster randomised controlled trials by accounting for uncertainty in the estimate of the intra-cluster correlation coefficient. We recommend this approach be applied to all trials where there is uncertainty in the intra-cluster correlation coefficient estimate, in conjunction with additional sources of information to guide the estimation of the intra-cluster correlation coefficient.

This study aimed to determine whether nosocomial coronavirus disease 2019 (COVID-19) has a worse outcome compared with community-acquired COVID-19. This was a prospective cohort study of all hospitalized patients with confirmed COVID-19 in three acute hospitals on 9th April 2020. Patients were followed-up for at least 30 days. Nosocomial infection was defined as a positive swab after 7 days of admission. In total, one hundred and seventy-three patients were identified, and 19 (11.0%) had nosocomial infection. Thirty-two (18.5%) patients died within 30 days (all cause) of a positive swab test; there were no significant differences in 30-day all-cause mortality rates between the three groups (i.e. patients admitted with suspected COVID-19, patients with incidental COVID-19 and patients with nosocomial COVID-19): 21.1% vs 17.6% vs 21.6% (P=0.755). Nosocomial COVID-19 is not associated with increased mortality compared with community-acquired COVID-19.

Summary Background Genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Methods We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1–2·3 × 106 cells per kg and adults received UCART19 doses of 6 × 106 cells, 6–8 × 107 cells, or 1·8–2·4 × 108 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952. Findings Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and received UCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3–4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%. Interpretation These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable. Funding Servier.

Introduction: A sample size justification is required for all studies and should give the minimum number of subjects to be recruited for the study to achieve its primary objective. This aim of this review is to describe sample sizes from agreement studies with continuous or categorical endpoints published within the PubMed database, and determine whether sample size justification was provided.Methods: Data were gathered from the PubMed database with a time interval of 28th September 2018 to 28th September 2020. The search returned 5257 studies of which 82 studies were eligible for final assessment after duplicates and ineligible studies were excluded.Results: We observed a wide range of sample sizes. Of the 82 studies assessed, only 27 (32.9%) gave justification for their sample size. Forty-six studies (56.1%) used a continuous outcome measure, 28 (34.1%) used categorical and eight (9.8%) used both. Median sample sizes were 50 for continuous endpoints and 119 for categorical endpoints. Bland-Altman limits of agreement were the most common method of statistical analysis for continuous variables and Kappa coefficients for categorical variables.Conclusions: All studies need a sample size justification. Not all studies need a sample size calculation. Despite the importance of a sample size justification we found that two-thirds of agreement studies did not provide one. We recommend that all agreement studies provide rationale for their sample size even if they do not include a formal sample size calculation.

The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia remains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product derived from healthy donors and available for immediate clinical use, offers a potential therapeutic option for such patients. The CALM trial is a first-in-human study evaluating the safety and antileukaemic activity of UCART19 in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia.This phase 1, open-label study was conducted at eight centres across France, the UK, the USA, and Japan. Adult patients aged 16-70 years with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukaemia who had morphological relapse or a minimal residual disease level of at least 1 × 10Between Aug 1, 2016, and June 30, 2020, 25 patients were enrolled in the study and treated with UCART19. Median duration of follow-up was 12·8 months (IQR 2·8-24·8). Median age was 37 years (IQR 28-45). 14 (56%) patients were male and 11 (44%) female. 17 (68%) patients were White, two (8%) Black, two (8%) Asian, and four (16%) from other racial or ethnic groups. Three patients developed dose-limiting toxicities (one at each dose level); one had grade 4 cytokine release syndrome and two had grade 4 prolonged cytopenias. Grade 3 or higher cytokine release syndrome was reported in six (24%) patients and grade 3 or higher neurological toxicity in one (4%) patient. Grade 3 or higher infections occurred in seven (28%) patients, and grade 4 prolonged cytopenia in four (16%) patients. Two (8%) patients developed grade 1 acute cutaneous graft-versus-host disease. 14 patients died, nine from progressive disease and five from infections or other complications, of which four were considered to be related to UCART19 or lymphodepletion, or both. After a median of follow-up of 12·8 months (IQR 2·8-24·8), overall response rate was 48% (95% CI 28-69; 12 of 25 patients), duration of response and median relapse-free survival were 7·4 months (95% CI 1·8 to not calculable), progression-free survival was 2·1 months (95% CI 1·2-2·8), and overall survival was 13·4 months (95% CI 4·8-23·0).UCART19 had a manageable safety profile, and showed evidence of antileukaemic activity in heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This study shows that allogeneic off-the-shelf CAR T cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia.Servier.

ObjectiveFrequent attendance at the ED is a worldwide problem. We hypothesised that frequent attendance could be understood as a feature of a complex system comprising patients, healthcare and society. Complex systems have characteristic statistical properties, with stable patterns at the level of the system emerging from unstable patterns at the level of individuals who make up the system.MethodsAnalysis of a linked dataset of routinely collected health records from all 13 hospital trusts providing ED care in the Yorkshire and Humber region of the UK (population 5.5 million). We analysed the distribution of attendances per person in each of 3 years and measured the transition of individual patients between frequent, infrequent and non-attendance. We fitted data to power law distributions typically seen in complex systems using maximum likelihood estimation.ResultsThe data included 3.6 million attendances at EDs in 13 hospital trusts. 29/39 (74.3%) analyses showed a statistical fit to a power law; 2 (5.1%) fitted an alternative distribution. All trusts’ data fitted a power law in at least 1 year. Differences over time and between hospital trusts were small and partly explained by demographics. In contrast, individual patients’ frequent attendance was unstable between years.ConclusionsED attendance patterns are stable at the level of the system, but unstable at the level of individual frequent attenders. Attendances follow a power law distribution typical of complex systems. Interventions to address ED frequent attendance need to consider the whole system and not just the individual frequent attenders.

Aims, Objectives and BackgroundAttendances at emergency departments in England continue to increase above the capacity of the urgent and emergency care system. There is significant variability in the rates of attendance at emergency departments across different localities. The aim of this study is to model the association of deprivation and non-urgent attendances with locality-based emergency department attendance rates. The secondary aim is to create an interactive data visualisation tool to engage stakeholders, clinicians, and the public with the research.Method and DesignWe undertook a retrospective, observational study using routinely collected emergency department attendance data from Yorkshire and the Humber (population 5.4 million) between January 2013 and March 2017. We calculated average annual age and sex standardised attendance rates at emergency departments for small localities known as lower layer super output areas.The association between emergency department attendance rates, deprivation and non-urgent attendances was examined using multivariable linear and logistic regression models, which were adjusted for travel time to the nearest emergency department.The data was visualised to create an interactive choropleth map using R.Abstract 1502 Figure 1Screenshot of interactive data visualisation tool showing age and sex standardised annual emergency department attendance rates in Yorkshire and the HumberResults and ConclusionThe analytical sample included 6,389,383 attendances across 2,880 localities, with a median age and sex standardised annual emergency department attendance rate of 308 per 1000 population (interquartile range 130).The fully adjusted linear regression model was significant (Adjusted R2 = 0.648, F (7, 2872)=757, pA large proportion of the variability in emergency department attendance rates in different geographical areas can be explained by deprivation levels and proportion of non-urgent attendances. This provides an opportunity for targeted interventions to reduce emergency department attendances.

Background: Evidence suggests that triple therapy for patients with chronic obstructive pulmonary disease (COPD) is being used in a broader range of patients than recommended by guidelines, which may have health and cost implications. Objective: To explore the relationship between national health technology assessment (HTA) agency appraisals and market penetration of two fixed-dose combination (FDC) triple therapies. Study design: HTAs from Q3 2017 to Q1 2020 from 10 countries were evaluated. Intervention: Glycopyrronium bromide/formoterol fumarate/beclomethasone (Trimbow®) and umeclidinium/vilanterol/fluticasone furoate (Trelegy™ Ellipta®). Main outcome measure: HTA restrictions and prescribing rates (days of therapy). Results: Seven countries (70%) imposed restrictions on use including prescription only for patients stable on free-combination triple therapy or not controlled on dual therapy, requirement of a specialist prescription or therapeutic plan, prescription only for patients with severe COPD, and use as second-line therapy or later. In general, countries that have imposed restrictions on the use of FDC triple therapies have seen a lower than average uptake. Conclusion: Payer guidance on prescribing FDC triple therapy may potentially support more appropriate prescribing in line with clinical guidelines. It is important for payers to consider which restrictions would ensure the most efficient use of scarce resources.

ObjectiveHigh use of the ED is a worldwide problem. We hypothesised that high use of the ED could be understood as a feature of a complex system comprising patients, healthcare and society. Complex systems have characteristic statistical properties, with stable patterns at the level of the system emerging from unstable patterns at the level of individuals who make up the system.MethodsAnalysis of a linked dataset of routinely collected health records from all 13 hospital trusts providing ED care in the Yorkshire and Humber region of the UK (population 5.5 million). We analysed the distribution of attendances per person in each of three years and measured the transition of individual patients between high, low and non-attendance. We fitted data to power law distributions typically seen in complex systems using maximum likelihood estimation.ResultsThe data included 3.6 million attendances at EDs in 13 hospital trusts. 29/39 (74.3%) analyses showed a statistical fit to a power law; 2 (5.1%) fitted an alternative distribution.. All trusts’ data fitted a power law in at least one year. Differences over time and between hospital trusts were small and partly explained by demographics. In contrast, individual patients’ high use was unstable between years.ConclusionsED attendance patterns are stable at the level of the system, but unstable at the level of individual high users. Attendances follow a power law distribution typical of complex systems. Interventions to address ED high use need to consider the whole system and not just the individual high users.

Background and aims Hypertension is associated with an increased risk of severe outcomes with COVID-19 disease. Angiotensin Converting Enzyme (ACE) inhibitors are widely used as a first line medication for the treatment of hypertension in the UK, although their use was suggested in early reports to increase the risk associated with SARS-CoV-2 infection. Methods A prospective cohort study of hospitalised patients with laboratory confirmed COVID-19 was conducted across three hospital sites with patients identified on the 9th April 2020. Demographic and other baseline data were extracted from electronic case records, and patients grouped depending on ACE inhibitor usage or not. The 60-day all-cause mortality and need for intubation compared. Results Of the 173 patients identified, 88 (50.8%) had hypertension. Of these 27 (30.7%) used ACE inhibitors. We did not find significant differences in 60-day all-cause mortality, the requirement for invasive ventilation or length of stay between our patient cohorts after adjusting for covariates. Conclusion This study contributes to the growing evidence supporting the continued use of ACE inhibitors in COVID-19 disease, although adequately powered randomised controlled trials will be needed to confirm effects.

Rationale and aims Lung health of people with cystic fibrosis (PwCF) can be preserved by daily use of inhaled therapy. Adherence to inhaled therapy, therefore, provides an important process measure to understand the success of care and can be used as a quality indicator. Defining adherence is problematic, however, since the number of prescribed treatments varies considerably between PwCF. The problem is less pronounced among those with Pseudomonas aeruginosa (PA), for whom at least three daily doses of nebulized therapy should be prescribed and who thus constitute a more homogeneous group. The UK CF Registry provides routine data on PA status, but data are only available 12 months after collection. In this study, we aim to prospectively identify contemporary PA status from historic registry data. Method UK CF Registry data from 2011 to 2015 for PwCF aged ≥16 was used to determine a pragmatic prediction rule for identifying contemporary PA status using historic registry data. Accuracy of three different prediction rules was assessed using the positive predictive value (PPV). The number and proportion of adults predicted to have PA infection were determined overall and per center for the selected prediction rule. Known characteristics linked to PA status were explored to ensure the robustness of the prediction rule. Results Having CF Registry defined chronic PA status in the two previous years is the selected definition to predict a patient will have PA infection within the current year (population‐level PPV = 96%‐97%, centre level PPV = 85%‐100%). This approach provides a subset of data between 1852 and 1872 patients overall and a range of 8 to 279 patients per center. Conclusion Historic registry data can be used to contemporaneously identify a subgroup of patients with chronic PA. Since this patient group has a narrower treatment schedule, this can facilitate a better benchmarking of adherence across centers.

Art holds powerful potential to break the social and cultural stigma around menstruating bodies by making the invisible visible and pushing the boundaries of what we know about the menstrual cycle. This chapter presents a selection of artwork and artists’ statements from Widening the Cycle, a historic exhibit curated by Jen Lewis and first shown at the 2015 Society for Menstrual Cycle Research conference in Boston, USA.

Background Guidelines recommend that treatment with a long-acting β2 agonist (LABA), a long-acting muscarinic antagonist (LAMA), and inhaled corticosteroids (ICS), i.e. triple therapy, is reserved for a select group of symptomatic patients with chronic obstructive pulmonary disease (COPD) who continue to exacerbate despite treatment with dual therapy (LABA/LAMA). A number of single-inhaler triple therapies are now available and important clinical questions remain over their role in the patient pathway. We compared the efficacy and safety of single-inhaler triple therapy to assess the magnitude of benefit and to identify patients with the best risk-benefit profile for treatment. We also evaluated and compared study designs and population characteristics to assess the strength of the evidence base. Methods We conducted a systematic search, from inception to December 2018, of randomised controlled trials (RCTs) of single-inhaler triple therapy in patients with COPD. The primary outcome was the annual rate of moderate and severe exacerbations. Results We identified 523 records, of which 15 reports/abstracts from six RCTs were included. Triple therapy resulted in the reduction of the annual rate of moderate or severe exacerbations in the range of 15–52% compared with LAMA/LABA, 15–35% compared to LABA/ICS and 20% compared to LAMA. The patient-based number needed to treat for the moderate or severe exacerbation outcome ranged between approximately 25–50 (preventing one patient from having an event) and the event-based number needed to treat of around 3–11 (preventing one event). The absolute benefit appeared to be greater in patients with higher eosinophil counts or historical frequency of exacerbations and ex-smokers. In the largest study, there was a significantly higher incidence of pneumonia in the triple therapy arm. There were important differences in study designs and populations impacting the interpretation of the results and indicating there would be significant heterogeneity in cross-trial comparisons. Conclusion The decision to prescribe triple therapy should consider patient phenotype, magnitude of benefit and increased risk of adverse events. Future research on specific patient phenotype thresholds that can support treatment and funding decisions is now required from well-designed, robust, clinical trials. Trial registration PROSPERO #CRD42018102125.

Our interest is in the neural circuitry which supports the discovery and encoding of novel actions. We discuss the significant existing literature which identifies the basal ganglia, a complex of subcortical nuclei, as important in both the selection of actions and in reinforcement learning. We discuss the complementarity of these problems of action selection and action learning. Two basic mechanisms of biasing action selection are identified: (a) adjusting the relative strengths of competing inputs and (b) adjusting the relative sensitivity of the receiver of reinforced inputs. We discuss the particular importance of the phasic dopamine signal in the basal ganglia and its proposed role in conveying a reward prediction error. Temporal constraints of this signal limit the information it can convey to immediately surprising sensory events, thus—we argue—making it inappropriate to convey information regarding the economic value of actions (as proposed by the reward prediction error hypothesis). Rather, we suggest this signal is ideal to support the identification of novel actions and their encoding via the biasing of future action selection.