Effectiveness of financial incentives to improve adherence to maintenance treatment with antipsychotics: cluster randomised controlled trial

Objective: To test whether offering financial incentives to patients with psychotic disorders is effective in improving adherence to maintenance treatment with antipsychotics. Design: Cluster randomised controlled trial. Setting: Community mental health teams in secondary psychiatric care in the United Kingdom. Participants: Patients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder, who were prescribed long acting antipsychotic (depot) injections but had received 75% or less of the prescribed injections. We randomly allocated 73 teams with a total of 141 patients. Primary outcome data were available for 35 intervention teams with 75 patients (96% of randomised) and for 31 control teams with 56 patients (89% of randomised). Interventions: Participants in the intervention group were offered £15 (€17; $22) for each depot injection over a 12 month period. Participants in the control condition received treatment as usual. Main outcome measure: The primary outcome was the percentage of prescribed depot injections given during the 12 month intervention period. Results 73 teams with 141 consenting patients were randomised, and outcomes were assessed for 131 patients (93%).⇓ Average baseline adherence was 69% in the intervention group and 67% in the control group. During the 12 month trial period adherence was 85% in the intervention group and 71% in the control group. The adjusted effect estimate was 11.5% (95% confidence interval 3.9% to 19.0%, P=0.003). A secondary outcome was an adherence of ≥95%, which was achieved in 28% of the intervention group and 5% of the control group (adjusted odds ratio 8.21, 95% confidence interval 2.00 to 33.67, P=0.003). Although differences in clinician rated clinical improvement between the groups failed to reach statistical significance, patients in the intervention group had more favourable subjective quality of life ratings (β=0.71, 95% confidence interval 0.26 to 1.15, P=0.002). The number of admissions to hospital and adverse events were low in both groups and did not show substantial differences. Conclusion: Offering modest financial incentives to patients with psychotic disorders is an effective method for improving adherence to maintenance treatment with antipsychotics

Literature review of visual representation of the results of benefit–risk assessments of medicinal products

Background The PROTECT Benefit–Risk group is dedicated to research in methods for continuous benefit–risk monitoring of medicines, including the presentation of the results, with a particular emphasis on graphical methods. Methods A comprehensive review was performed to identify visuals used for medical risk and benefit–risk communication. The identified visual displays were grouped into visual types, and each visual type was appraised based on five criteria: intended audience, intended message, knowledge required to understand the visual, unintentional messages that may be derived from the visual and missing information that may be needed to understand the visual. Results Sixty-six examples of visual formats were identified from the literature and classified into 14 visual types. We found that there is not one single visual format that is consistently superior to others for the communication of benefit–risk information. In addition, we found that most of the drawbacks found in the visual formats could be considered general to visual communication, although some appear more relevant to specific formats and should be considered when creating visuals for different audiences depending on the exact message to be communicated. Conclusion We have arrived at recommendations for the use of visual displays for benefit–risk communication. The recommendation refers to the creation of visuals. We outline four criteria to determine audience–visual compatibility and consider these to be a key task in creating any visual. Next we propose specific visual formats of interest, to be explored further for their ability to address nine different types of benefit–risk analysis information

Recommendations for benefit–risk assessment methodologies and visual representations

Purpose The purpose of this study is to draw on the practical experience from the PROTECT BR case studies and make recommendations regarding the application of a number of methodologies and visual representations for benefit–risk assessment. Methods Eight case studies based on the benefit–risk balance of real medicines were used to test various methodologies that had been identified from the literature as having potential applications in benefit–risk assessment. Recommendations were drawn up based on the results of the case studies. Results A general pathway through the case studies was evident, with various classes of methodologies having roles to play at different stages. Descriptive and quantitative frameworks were widely used throughout to structure problems, with other methods such as metrics, estimation techniques and elicitation techniques providing ways to incorporate technical or numerical data from various sources. Similarly, tree diagrams and effects tables were universally adopted, with other visualisations available to suit specific methodologies or tasks as required. Every assessment was found to follow five broad stages: (i) Planning, (ii) Evidence gathering and data preparation, (iii) Analysis, (iv) Exploration and (v) Conclusion and dissemination. Conclusions Adopting formal, structured approaches to benefit–risk assessment was feasible in real-world problems and facilitated clear, transparent decision-making. Prior to this work, no extensive practical application and appraisal of methodologies had been conducted using real-world case examples, leaving users with limited knowledge of their usefulness in the real world. The practical guidance provided here takes us one step closer to a harmonised approach to benefit–risk assessment from multiple perspectives

Meeting report : 1st international functional metagenomics workshop May 7–8, 2012, St. Jacobs, Ontario, Canada

This report summarizes the events of the 1st International Functional Metagenomics Workshop. The workshop was held on May 7 and 8 in St. Jacobs, Ontario, Canada and was focused on building a core international functional metagenomics community, exploring strategic research areas, and identifying opportunities for future collaboration and funding. The workshop was initiated by researchers at the University of Waterloo with support from the Ontario Genomics Institute (OGI), Natural Sciences and Engineering Research Council of Canada (NSERC) and the University of Waterloo

Managing Injuries of the Neck Trial (MINT) : design of a randomised controlled trial of treatments for whiplash associated disorders

Background: A substantial proportion of patients with whiplash injuries develop chronic symptoms. However, the best treatment of acute injuries to prevent long-term problems is uncertain. A stepped care treatment pathway has been proposed, in which patients are given advice and education at their initial visit to the emergency department (ED), followed by review at three weeks and physiotherapy for those with persisting symptoms. MINT is a two-stage randomised controlled trial to evaluate two components of such a pathway: 1. use of The Whiplash Book versus usual advice when patients first attend the emergency department; 2. referral to physiotherapy versus reinforcement of advice for patients with continuing symptoms at three weeks. Methods: Evaluation of the Whiplash Book versus usual advice uses a cluster randomised design in emergency departments of eight NHS Trusts. Eligible patients are identified by clinicians in participating emergency departments and are sent a study questionnaire within a week of their ED attendance. Three thousand participants will be included. Patients with persisting symptoms three weeks after their ED attendance are eligible to join an individually randomised study of physiotherapy versus reinforcement of the advice given in ED. Six hundred participants will be randomised. Follow-up is at 4, 8 and 12 months after their ED attendance. Primary outcome is the Neck Disability Index (NDI), and secondary outcomes include quality of life and time to return to work and normal activities. An economic evaluation is being carried out. Conclusion: This paper describes the protocol and operational aspects of a complex intervention trial based in NHS emergency and physiotherapy departments, evaluating two components of a stepped-care approach to the treatment of whiplash injuries. The trial uses two randomisations, with the first stage being cluster randomised and the second individually randomised

Spitzer Photometry of WISE-Selected Brown Dwarf and Hyper-Luminous Infrared Galaxy Candidates

We present Spitzer 3.6 and 4.5 $\mu$m photometry and positions for a sample of 1510 brown dwarf candidates identified by the WISE all-sky survey. Of these, 166 have been spectroscopically classified as objects with spectral types M(1), L(7), T(146), and Y(12); Sixteen other objects are non-(sub)stellar in nature. The remainder are most likely distant L and T dwarfs lacking spectroscopic verification, other Y dwarf candidates still awaiting follow-up, and assorted other objects whose Spitzer photometry reveals them to be background sources. We present a catalog of Spitzer photometry for all astrophysical sources identified in these fields and use this catalog to identify 7 fainter (4.5 $\mu$m $\sim$ 17.0 mag) brown dwarf candidates, which are possibly wide-field companions to the original WISE sources. To test this hypothesis, we use a sample of 919 Spitzer observations around WISE-selected high-redshift hyper-luminous infrared galaxy (HyLIRG) candidates. For this control sample we find another 6 brown dwarf candidates, suggesting that the 7 companion candidates are not physically associated. In fact, only one of these 7 Spitzer brown dwarf candidates has a photometric distance estimate consistent with being a companion to the WISE brown dwarf candidate. Other than this there is no evidence for any widely separated ($>$ 20 AU) ultra-cool binaries. As an adjunct to this paper, we make available a source catalog of $\sim$ 7.33 $\times 10^5$ objects detected in all of these Spitzer follow-up fields for use by the astronomical community. The complete catalog includes the Spitzer 3.6 and 4.5 $\mu$m photometry, along with positionally matched $B$ and $R$ photometry from USNO-B; $J$, $H$, and $K_s$ photometry from 2MASS; and $W1$, $W2$, $W3$, and $W4$ photometry from the WISE all-sky catalog

Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial

BACKGROUND: Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD. METHODS: We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926). FINDINGS: Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated: 50 (50%) to receive cyclophosphamide and 51 (50%) to receive rituximab. 48 (96%) participants in the cyclophosphamide group and 49 (96%) in the rituximab group received at least one dose of treatment and were included in analyses; 43 (86%) participants in the cyclophosphamide group and 42 (82%) participants in the rituximab group completed 24 weeks of treatment and follow-up. At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL [SD 329]) and the rituximab group (97 mL [234]); in the adjusted mixed-effects model, the difference in the primary endpoint at 24 weeks was -40 mL (95% CI -153 to 74; p=0·49) between the rituximab group and the cyclophosphamide group. KBILD quality-of-life scores were improved at 24 weeks by a mean 9·4 points (SD 20·8) in the cyclophosphamide group and 8·8 points (17·0) in the rituximab group. No significant differences in secondary endpoints were identified between the treatment groups, with the exception of change in GDA score at week 48, which favoured cyclophosphamide (difference 0·90 [95% CI 0·11 to 1·68]). Improvements in lung function and respiratory-related quality-of-life measures were observed in both treatment groups. Lower corticosteroid exposure over 48 weeks of follow-up was recorded in the rituximab group. Two (4%) of 48 participants who received cyclophosphamide and three (6%) of 49 who received rituximab died during the study, all due to complications of CTD or ILD. Overall survival, progression-free survival, and time to treatment failure did not significantly differ between the two groups. All participants reported at least one adverse event during the study. Numerically fewer adverse events were reported by participants receiving rituximab (445 events) than those receiving cyclophosphamide (646 events). Gastrointestinal and respiratory disorders were the most commonly reported adverse events in both groups. There were 62 serious adverse events of which 33 occurred in the cyclophosphamide group and 29 in the rituximab group. INTERPRETATION: Rituximab was not superior to cyclophosphamide to treat patients with CTD-ILD, although participants in both treatment groups had increased FVC at 24 weeks, in addition to clinically important improvements in patient-reported quality of life. Rituximab was associated with fewer adverse events. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiring intravenous therapy. FUNDING: Efficacy and Mechanism Evaluation Programme (Medical Research Council and National Institute for Health Research, UK)

Twin peaks: the Omicron SARS-CoV-2 BA.1 and BA.2 epidemics in England

BACKGROUND Rapid transmission of the SARS-CoV-2 Omicron variant has led to record-breaking incidence rates around the world. Sub-lineages have been detected in many countries with BA.1 replacing Delta and BA.2 replacing BA.1. METHODS The REal-time Assessment of Community Transmission-1 (REACT-1) study has tracked SARS-CoV-2 infection in England using RT-PCR results from self-administered throat and nose swabs from randomly-selected participants aged 5+ years. Rounds of data collection were approximately monthly from May 2020 to March 2022. RESULTS In March 2022, weighted prevalence was 6.37% (N=109,181), more than twice that in February 2022 following an initial Omicron peak in January 2022. Of the lineages determined by viral genome sequencing, 3,382 (99.97%) were Omicron, including 346 (10.2%) BA.1, 3035 (89.7%) BA.2 and one (0.03%) BA.3 sub-lineage; the remainder (1, 0.03%) was Delta AY.4. The BA.2 Omicron sub-lineage had a growth rate advantage (compared to BA.1 and sub-lineages) of 0.11 (95% credible interval [CrI], 0.10, 0.11). Prevalence was increasing overall (reproduction number R=1.07, 95% CrI, 1.06, 1.09), with the greatest increase in those aged 55+ years (R=1.12, 95% CrI, 1.09, 1.14) among whom estimated prevalence on March 31, 2022 was 8.31%, nearly 20-fold the median prevalence since May 1, 2020. CONCLUSIONS We observed unprecedented levels of SARS-CoV-2 infection in England in March 2022 and an almost complete replacement of Omicron BA.1 by BA.2. The high and increasing prevalence in older adults may increase hospitalizations and deaths despite high levels of vaccination. (Funded by the Department of Health and Social Care in England.

Practical help for specifying the target difference in sample size calculations for RCTs: the DELTA2 five-stage study, including a workshop

BACKGROUND: The randomised controlled trial is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to its design is a calculation of the number of participants needed (the sample size) for the trial. The sample size is typically calculated by specifying the magnitude of the difference in the primary outcome between the intervention effects for the population of interest. This difference is called the 'target difference' and should be appropriate for the principal estimand of interest and determined by the primary aim of the study. The target difference between treatments should be considered realistic and/or important by one or more key stakeholder groups. OBJECTIVE: The objective of the report is to provide practical help on the choice of target difference used in the sample size calculation for a randomised controlled trial for researchers and funder representatives. METHODS: The Difference ELicitation in TriAls2 (DELTA2) recommendations and advice were developed through a five-stage process, which included two literature reviews of existing funder guidance and recent methodological literature; a Delphi process to engage with a wider group of stakeholders; a 2-day workshop; and finalising the core document. RESULTS: Advice is provided for definitive trials (Phase III/IV studies). Methods for choosing the target difference are reviewed. To aid those new to the topic, and to encourage better practice, 10 recommendations are made regarding choosing the target difference and undertaking a sample size calculation. Recommended reporting items for trial proposal, protocols and results papers under the conventional approach are also provided. Case studies reflecting different trial designs and covering different conditions are provided. Alternative trial designs and methods for choosing the sample size are also briefly considered. CONCLUSIONS: Choosing an appropriate sample size is crucial if a study is to inform clinical practice. The number of patients recruited into the trial needs to be sufficient to answer the objectives; however, the number should not be higher than necessary to avoid unnecessary burden on patients and wasting precious resources. The choice of the target difference is a key part of this process under the conventional approach to sample size calculations. This document provides advice and recommendations to improve practice and reporting regarding this aspect of trial design. Future work could extend the work to address other less common approaches to the sample size calculations, particularly in terms of appropriate reporting items. FUNDING: Funded by the Medical Research Council (MRC) UK and the National Institute for Health Research as part of the MRC-National Institute for Health Research Methodology Research programme

Exponential growth, high prevalence of SARS-CoV-2, and vaccine effectiveness associated with the Delta variant.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.The study was funded by the Department of Health and Social Care in England. Sequencing was provided through funding from the COVID-19 Genomics UK (COG-UK) Consortium. P.E. is Director of the Medical Research Council (MRC) Centre for Environment and Health (MR/L01341X/1, MR/S019669/1). P.E. acknowledges support from Health Data Research UK (HDR UK); the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre; NIHR Health Protection Research Units (HPRUs) in Chemical and Radiation Threats and Hazards, and Environmental Exposures and Health; the British Heart Foundation Centre for Research Excellence at Imperial College London (RE/18/4/34215); and the UK Dementia Research Institute at Imperial (MC_PC_17114). S.R., C.A.D. acknowledge support: MRC Centre for Global Infectious Disease Analysis, NIHR HPRU in Modelling and Health Economics, Wellcome Trust (200861/Z/16/Z, 200187/Z/15/Z), and Centres for Disease Control and Prevention (US, U01CK0005-01-02). G.C. is supported by an NIHR Professorship. H.War. acknowledges support from an NIHR Senior Investigator Award and the Wellcome Trust (205456/Z/16/Z). We thank The Huo Family Foundation for their support of our work on COVID-19. Quadram authors gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC); their research was funded by the BBSRC Institute Strategic Programme Microbes in the Food Chain BB/R012504/1 and its constituent project BBS/E/F/000PR10352. We thank members of the COVID-19 Genomics Consortium UK (COG-UK) for their contributions to generating the genomic data used in this study. COG-UK is supported by funding from the MRC, part of UK Research & Innovation (UKRI), NIHR and Genome Research Limited, operating as the Wellcome Sanger Institute