Post-trial follow-up methodology in large randomised controlled trials: a systematic review.

BACKGROUND: Randomised controlled clinical trials typically have a relatively brief in-trial follow-up period which can underestimate safety signals and fail to detect long-term hazards, which may take years to appear. Extended follow-up after the scheduled closure of the trial allows detection of both persistent or enhanced beneficial effects following cessation of study treatment (i.e. a legacy effect) and the emergence of possible adverse effects (e.g. development of cancer). METHODS: A systematic review was conducted following PRISMA guidelines to qualitatively compare post-trial follow-up methods used in large randomised controlled trials. Five bibliographic databases, including Medline and the Cochrane Library, and one trial registry were searched. All large randomised controlled trials (more than 1000 adult participants) published from March 2006 to April 2017 were evaluated. Two reviewers screened and extracted data attaining > 95% concordance of papers checked. Assessment of bias in the trials was evaluated using the Cochrane Risk of Bias tool. RESULTS: Fifty-seven thousand three hundred and fifty-two papers were identified and 65 trials which had post-trial follow-up (PTFU) were included in the analysis. The majority of trials used more than one type of follow-up. There was no evidence of an association between the retention rates of participants in the PTFU period and the type of follow-up used. Costs of PTFU varied widely with data linkage being the most economical. It was not possible to assess associations between risk of bias during the in-trial period and proportions lost to follow-up during the PTFU period. DISCUSSION: Data captured during the post-trial follow-up period can add scientific value to a trial. However, there are logistical and financial barriers to overcome. Where available, data linkage via electronic registries and records is a cost-effective method which can provide data on a range of endpoints. SYSTEMATIC REVIEW REGISTRATION: Not applicable for PROSPERO registration

Intensive support teams for adults with intellectual disabilities displaying challenging behaviour : the IST-ID mixed-methods study

Background: National policy recommends intensive support teams for all areas of England for adults with intellectual disabilities who display challenging behaviour. However, to the best of our knowledge, there has not been a systematic evaluation of intensive support teams to date. Objectives: Our objectives were to identify and describe the geographical distribution and characteristics of intensive support teams in England; to create a typology of intensive support teams; to investigate clinical and cost outcomes of intensive support team models and factors associated with those outcomes; and to explore professionals’, service users’ and carers’ experiences and describe the wider system context in which they operate. Design: This was a two-phase mixed-methods study. In phase 1, a national survey examined the intensive support team models in operation in England. In phase 2, an observational study of adults with intellectual disabilities investigated the clinical effectiveness and cost-effectiveness of the two intensive support team models. Semistructured interviews with intensive support team managers and professionals, carers, and adults with intellectual disabilities explored their experiences of intensive support team care. In parallel, we examined service-level outcomes related to the function of intensive support teams. Setting: Phase 1 included 80 intensive support teams serving 242 community intellectual disability services in England. Phase 2 included 21 intensive support teams, half of which were in the enhanced intensive support teams model and half of which were in the independent model. Participants: In phase 1, a total of 73 intensive support team managers provided data. In phase 2, a total of 226 participants with intellectual disabilities from 21 intensive support teams (enhanced: teams, n = 11; participants, n = 115; independent: teams, n = 10; participants, n = 111) were enrolled in the study. A total of 42 stakeholders were interviewed. Main outcome measure: The main outcome measure was the Aberrant Behaviour Checklist-Community, version 2, total score. Additional data sources were the carer and self-reported questionnaires, qualitative interviews and focus groups. Results: Two intensive support team models were identified in England – enhanced and independent. Challenging behaviour at 9 months was reduced in both intensive support team models (β 3.08, 95% confidence interval –7.32 to 13.48; p = 0.561), but the observed Aberrant Behaviour Checklist-Community, version 2, score reduction appeared larger in the independent model than in the enhanced model (21% vs. 13%, respectively). No statistically significant differences were found in the secondary outcomes [Psychiatric Assessment Schedule for Adults with Developmental Disabilities Clinical Interview organic condition (odds ratio 1.09, 95% confidence interval 0.39 to 3.02), affective or neurotic disorder (odds ratio 0.91, 95% confidence interval 0.32 to 2.59), or psychotic disorder score (odds ratio 1.08, 95% confidence interval 0.21 to 5.50); risk score (β 1.12, 95% confidence interval –0.44 to 2.68); or quality of life questionnaire score (β –2.63, 95% confidence interval –5.65 to 0.40)]. Similarly, no differences were observed between models in relation to cost-effectiveness (health and social care costs mean difference £3409.95, 95% confidence interval –£9957.92 to £4039.89; societal costs mean difference –£4712.30, 95% confidence interval –£11,124.85 to £2106.36). The experiences of stakeholders did not differ between the intensive support team models, with carers and adults with intellectual disabilities valuing service accessibility, person-centred care and engagement. All stakeholders reported a range of barriers to intensive support team care. Service-level data and the operational policies from intensive support teams showed variation in organisational function and the roles of intensive support teams. The most commonly delivered intervention was positive behaviour support. Conclusions: The study describes the operation of intensive support teams in England and identified two distinct models. We did not find advantages or disadvantages associated with clinical outcomes between models, nor did we find cost differences. On this basis, we recommend that local services decide which model best suits their circumstances. Limitations: This was not a randomised controlled trial. It is possible that confounding factors have not been controlled for as there was no matching between intensive support teams. Last, there was no comparison with usual care. Future work: There is need to develop model fidelity and investigate clinical effectiveness and cost-effectiveness in a randomised controlled evaluation of intensive support teams against treatment as usual. Study registration: This study is registered as ClinicalTrials.gov NCT03586375, Integrated Research Application System (IRAS) 239820 and National Institute for Health and Care Research (NIHR) Central Portfolio Management System (CPMS) 38554. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 33. See the NIHR Journals Library website for further project information

Understanding Intracellular Biology to Improve mRNA Delivery by Lipid Nanoparticles

Poor understanding of intracellular delivery and targeting hinders development of nucleic acid‐based therapeutics transported by nanoparticles. Utilizing a siRNA‐targeting and small molecule profiling approach with advanced imaging and machine learning biological insights is generated into the mechanism of lipid nanoparticle (MC3‐LNP) delivery of mRNA. This workflow is termed Advanced Cellular and Endocytic profiling for Intracellular Delivery (ACE‐ID). A cell‐based imaging assay and perturbation of 178 targets relevant to intracellular trafficking is used to identify corresponding effects on functional mRNA delivery. Targets improving delivery are analyzed by extracting data‐rich phenotypic fingerprints from images using advanced image analysis algorithms. Machine learning is used to determine key features correlating with enhanced delivery, identifying fluid‐phase endocytosis as a productive cellular entry route. With this new knowledge, MC3‐LNP is re‐engineered to target macropinocytosis, and this significantly improves mRNA delivery in vitro and in vivo. The ACE‐ID approach can be broadly applicable for optimizing nanomedicine‐based intracellular delivery systems and has the potential to accelerate the development of delivery systems for nucleic acid‐based therapeutics

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and diseaserelated end points. Here we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy

The CORE Service Improvement Programme for mental health Crisis Resolution Teams: results from a cluster-randomised trial

Background: Crisis Resolution Teams (CRTs) offer brief, intensive home treatment for people experiencing mental health crisis. CRT implementation is highly variable; positive trial outcomes have not been reproduced in scaled up CRT care. Aims: To evaluate a one-year programme to improve CRTs’ model fidelity in a non-blind, cluster randomised trial. Methods: Fifteen CRTs in England received an intervention, informed by the US Implementing Evidence Based Practice project, involving support from a CRT Facilitator, online implementation resources and regular team fidelity reviews. Ten control CRTs received no additional support. The primary outcome was service user satisfaction, measured by the Client Satisfaction Questionnaire (CSQ-8), completed by fifteen service users per team at CRT discharge (N=375). Secondary outcomes: CRT model fidelity, continuity of care, staff wellbeing, inpatient admissions and bed use and CRT readmissions were also evaluated. Results: All CRTs were retained in the trial. Median follow-up CSQ-8 score was 28 in each group: the adjusted average in the intervention group was higher than in the control group by 0.97 (CI -1.02, 2.97) but this was not significant (p=0.34). There were fewer inpatient admissions, lower inpatient bed use and better staff psychological health in intervention teams. Model fidelity rose in most intervention teams and was significantly higher than in control teams at follow up. There were no significant effects for other outcomes. Conclusions: The CRT Service Improvement Programme did not achieve its primary aim of improving service user satisfaction. It showed some promise in improving CRT model fidelity and reducing acute inpatient admissions

Impact on mental health care and on mental health service users of the COVID-19 pandemic: a mixed methods survey of UK mental health care staff

PURPOSE: The COVID-19 pandemic has potential to disrupt and burden the mental health care system, and to magnify inequalities experienced by mental health service users. METHODS: We investigated staff reports regarding the impact of the COVID-19 pandemic in its early weeks on mental health care and mental health service users in the UK using a mixed methods online survey. Recruitment channels included professional associations and networks, charities, and social media. Quantitative findings were reported with descriptive statistics, and content analysis conducted for qualitative data. RESULTS: 2,180 staff from a range of sectors, professions, and specialties participated. Immediate infection control concerns were highly salient for inpatient staff, new ways of working for community staff. Multiple rapid adaptations and innovations in response to the crisis were described, especially remote working. This was cautiously welcomed but found successful in only some clinical situations. Staff had specific concerns about many groups of service users, including people whose conditions are exacerbated by pandemic anxieties and social disruptions; people experiencing loneliness, domestic abuse and family conflict; those unable to understand and follow social distancing requirements; and those who cannot engage with remote care. CONCLUSION: This overview of staff concerns and experiences in the early COVID-19 pandemic suggests directions for further research and service development: we suggest that how to combine infection control and a therapeutic environment in hospital, and how to achieve effective and targeted tele-health implementation in the community, should be priorities. The limitations of our convenience sample must be noted

Peer-supported self-management for people discharged from a mental health crisis team:a randomised controlled trial

BACKGROUND: High resource expenditure on acute care is a challenge for mental health services aiming to focus on supporting recovery, and relapse after an acute crisis episode is common. Some evidence supports self-management interventions to prevent such relapses, but their effect on readmissions to acute care following a crisis is untested. We tested whether a self-management intervention facilitated by peer support workers could reduce rates of readmission to acute care for people discharged from crisis resolution teams, which provide intensive home treatment following a crisis. METHODS: We did a randomised controlled superiority trial recruiting participants from six crisis resolution teams in England. Eligible participants had been on crisis resolution team caseloads for at least a week, and had capacity to give informed consent. Participants were randomly assigned to intervention and control groups by an unmasked data manager. Those collecting and analysing data were masked to allocation, but participants were not. Participants in the intervention group were offered up to ten sessions with a peer support worker who supported them in completing a personal recovery workbook, including formulation of personal recovery goals and crisis plans. The control group received the personal recovery workbook by post. The primary outcome was readmission to acute care within 1 year. This trial is registered with ISRCTN, number 01027104. FINDINGS: 221 participants were assigned to the intervention group versus 220 to the control group; primary outcome data were obtained for 218 versus 216. 64 (29%) of 218 participants in the intervention versus 83 (38%) of 216 in the control group were readmitted to acute care within 1 year (odds ratio 0·66, 95% CI 0·43–0·99; p=0·0438). 71 serious adverse events were identified in the trial (29 in the treatment group; 42 in the control group). INTERPRETATION: Our findings suggest that peer-delivered self-management reduces readmission to acute care, although admission rates were lower than anticipated and confidence intervals were relatively wide. The complexity of the study intervention limits interpretability, but assessment is warranted of whether implementing this intervention in routine settings reduces acute care readmission

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Effects of ocean sprawl on ecological connectivity: impacts and solutions

The growing number of artificial structures in estuarine, coastal and marine environments is causing “ocean sprawl”. Artificial structures do not only modify marine and coastal ecosystems at the sites of their placement, but may also produce larger-scale impacts through their alteration of ecological connectivity - the movement of organisms, materials and energy between habitat units within seascapes. Despite the growing awareness of the capacity of ocean sprawl to influence ecological connectivity, we lack a comprehensive understanding of how artificial structures modify ecological connectivity in near- and off-shore environments, and when and where their effects on connectivity are greatest. We review the mechanisms by which ocean sprawl may modify ecological connectivity, including trophic connectivity associated with the flow of nutrients and resources. We also review demonstrated, inferred and likely ecological impacts of such changes to connectivity, at scales from genes to ecosystems, and potential strategies of management for mitigating these effects. Ocean sprawl may alter connectivity by: (1) creating barriers to the movement of some organisms and resources - by adding physical barriers or by modifying and fragmenting habitats; (2) introducing new structural material that acts as a conduit for the movement of other organisms or resources across the landscape; and (3) altering trophic connectivity. Changes to connectivity may, in turn, influence the genetic structure and size of populations, the distribution of species, and community structure and ecological functioning. Two main approaches to the assessment of ecological connectivity have been taken: (1) measurement of structural connectivity - the configuration of the landscape and habitat patches and their dynamics; and (2) measurement of functional connectivity - the response of organisms or particles to the landscape. Our review reveals the paucity of studies directly addressing the effects of artificial structures on ecological connectivity in the marine environment, particularly at large spatial and temporal scales. With the ongoing development of estuarine and marine environments, there is a pressing need for additional studies that quantify the effects of ocean sprawl on ecological connectivity. Understanding the mechanisms by which structures modify connectivity is essential if marine spatial planning and eco-engineering are to be effectively utilised to minimise impacts