When participants get involved: reconsidering patient and public involvement in clinical trials at the MRC Clinical Trials Unit at UCL.

BACKGROUND: Patient and public involvement (PPI) in clinical trials aims to ensure that research is carried out collaboratively with patients and/or members of the public. However, current guidance on involving clinical trial participants in PPI activities is not consistent. METHODS: We reviewed the concept of participant involvement, based on our experience. Two workshops were held at the MRCCTU at UCL with the aim of defining participant involvement, considering its rationale; benefits and challenges; and identifying appropriate models for participant involvement in clinical trials. We considered how participant involvement might complement the involvement of other public contributors. Both workshops were attended by two patient representatives and seven staff members with experience of PPI in trials. Two of the staff members had also been involved in studies that had actively involved participants. They shared details of that work to inform discussions. RESULTS: We defined trial participants as individuals taking part in the study in question, including those who had already completed their trial treatment and/or follow-up. Because of their direct experience, involving participants may offer advantages over other public contributors; for example, in studies of new interventions or procedures, and where it is hard to identify or reach patient or community groups that include or speak for the study population. Participant involvement is possible at all stages of a trial; however, because there are no participants to involve during the design stage of a trial, prior to enrolment, participant involvement should complement and not replace involvement of PPI stakeholders. A range of models, including those with managerial, oversight or responsive roles are appropriate for involving participants; however, involvement in data safety and monitoring committees may not be appropriate where there is a potential risk of unblinding. Involvement of participants can improve the trial experience for other participants; optimising study procedures, improving communications; however, there are some specific, notably, managing participant confidentiality and practicalities relating to payments. CONCLUSIONS: Participant involvement in clinical trials is feasible and complements other forms of PPI in clinical trials. Involving active participants offers significant advantages, particularly in circumstances where trials are assessing new, or otherwise unavailable, therapies or processes. We recommend that current guidance on PPI should be updated to routinely consider including participants as valid stakeholders in PPI and potentially useful approach to PPI

Site staff perspectives on communicating trial results to participants : Cost and feasibility results from the Show RESPECT cluster randomised, factorial, mixed-methods trial

We are grateful to the patients and site staff who participated in this study. We dedicate this article to the memory of Amanda Hunn, who was part of the steering group for this study until she passed away in 2022. We thank other members of the steering group for their input into the study, especially Conor Tweed and Liz James. We acknowledge the hard work and diligence of Cara Purvis, the trial manager, and the data managers for Show RESPECT. We also thank the ICON8 trial team for their support, particularly Babasola Popoola, Francesca Schiavone, Jonathan Badrock, Andrew Clamp and Rick Kaplan.Peer reviewe

Site staff perspectives on communicating trial results to participants: Cost and feasibility results from the Show RESPECT cluster randomised, factorial, mixed-methods trial

BACKGROUND/AIMS: Sharing trial results with participants is an ethical imperative but often does not happen. Show RESPECT (ISRCTN96189403) tested ways of sharing results with participants in an ovarian cancer trial (ISRCTN10356387). Sharing results via a printed summary improved patient satisfaction. Little is known about staff experience and the costs of communicating results with participants. We report the costs of communication approaches used in Show RESPECT and the views of site staff on these approaches. METHODS: We allocated 43 hospitals (sites) to share results with trial participants through one of eight intervention combinations (2 × 2 × 2 factorial; enhanced versus basic webpage, printed summary versus no printed summary, email list invitation versus no invitation). Questionnaires elicited data from staff involved in sharing results. Open- and closed-ended questions covered resources used to share results and site staff perspectives on the approaches used. Semi-structured interviews were conducted. Interview and free-text data were analysed thematically. The mean additional site costs per participant from each intervention were estimated jointly as main effects by linear regression. RESULTS: We received questionnaires from 68 staff from 41 sites and interviewed 11 site staff. Sites allocated to the printed summary had mean total site costs of sharing results £13.71/patient higher (95% confidence interval (CI): -3.19, 30.60; p = 0.108) than sites allocated no printed summary. Sites allocated to the enhanced webpage had mean total site costs £1.91/patient higher (95% CI: -14, 18.74; p = 0.819) than sites allocated to the basic webpage. Sites allocated to the email list had costs £2.87/patient lower (95% CI: -19.70, 13.95; p = 0.731) than sites allocated to no email list. Most of these costs were staff time for mailing information and handling patients' queries. Most site staff reported no concerns about how they had shared results (88%) and no challenges (76%). Most (83%) found it easy to answer queries from patients about the results and thought the way they were allocated to share results with participants would be an acceptable standard approach (76%), with 79% saying they would follow the same approach for future trials. There were no significant effects of the randomised interventions on these outcomes. Site staff emphasised the importance of preparing patients to receive the results, including giving opt-in/opt-out options, and the need to offer further support, particularly if the results could confuse or distress some patients. CONCLUSIONS: Adding a printed summary to a webpage (which significantly improved participant satisfaction) may increase costs to sites by ~£14/patient, which is modest in relation to the cost of trials. The Show RESPECT communication interventions were feasible to implement. This information could help future trials ensure they have sufficient resources to share results with participants

Testing approaches to sharing trial results with participants : The Show RESPECT cluster randomised, factorial, mixed methods trial

Funding: The Show RESPECT study was funded by the Medical Research Council through core grants to MRS at the MRC CTU at UCL for Trial Conduct Methodology (MC_UU12023/24 and MC_UU_00004/08) https://mrc.ukri.org/. The funder had no role in the study design, the collection, analysis and interpretation of data, the writing of the report and the decision to submit the article for publication. All authors had full access to the study data, including statistical reports and tables, and can take responsibility for the integrity of the data and the accuracy of the data analysis. Acknowledgments We are very thankful to the patients who participated in this study and the people who contributed to our Patient and Public Involvement activities. We are very grateful for the work of the Show RESPECT site teams in carrying out this study. A list of team members from sites can be found in S10 Table. We thank Eva Burnett, who is a patient representative on the Study Steering Group for Show RESPECT and ICON8, for her input on the design and conduct of this study and for her comments on this manuscript, and Amanda Hunn for her contributions to the steering group. We also acknowledge the hard work and diligence of Sierra Santana and Ania Spurdens, who were data managers for Show RESPECT. We also wish to thank the ICON8 trial team for their support of this project, particularly Andrew Clamp, Babasola Popoola, Francesca Schiavone, Jonathan Badrock, and Rick Kaplan. We also thank Julia Bailey for her advice and guidance on the qualitative aspect of this study.Peer reviewedPublisher PD

Hemocyanin facilitates lignocellulose digestion by wood-boring marine crustaceans

Woody (lignocellulosic) plant biomass is an abundant renewable feedstock, rich in polysaccharides that are bound into an insoluble fiber composite with lignin. Marine crustacean woodborers of the genus Limnoria are among the few animals that can survive on a diet of this recalcitrant material without relying on gut resident microbiota. Analysis of fecal pellets revealed that Limnoria targets hexose-containing polysaccharides (mainly cellulose, and also glucomannans), corresponding with the abundance of cellulases in their digestive system, but xylans and lignin are largely unconsumed. We show that the limnoriid respiratory protein, hemocyanin, is abundant in the hindgut where wood is digested, that incubation of wood with hemocyanin markedly enhances its digestibility by cellulases, and that it modifies lignin. We propose that this activity of hemocyanins is instrumental to the ability of Limnoria to feed on wood in the absence of gut symbionts. These findings may hold potential for innovations in lignocellulose biorefining

Subchronic toxicity, immunoregulation and anti-breast tumor effect of Nordamnacantal, an anthraquinone extracted from the stems of Morinda citrifolia L.

Background: Morinda citrifolia L. that was reported with immunomodulating and cytotoxic effects has been traditionally used to treat multiple illnesses including cancer. An anthraquinone derived from fruits of Morinda citrifolia L., nordamnacanthal, is a promising agent possessing several in vitro biological activities. However, the in vivo anti-tumor effects and the safety profile of nordamnacanthal are yet to be evaluated. Methods: In vitro cytotoxicity of nordamnacanthal was tested using MTT, cell cycle and Annexin V/PI assays on human MCF-7 and MDA-MB231 breast cancer cells. Mice were orally fed with nordamnacanthal daily for 28 days for oral subchronic toxicity study. Then, the in vivo anti-tumor effect was evaluated on 4T1 murine cancer cells-challenged mice. Changes of tumor size and immune parameters were evaluated on the untreated and nordamnacanthal treated mice. Results: Nordamnacanthal was found to possess cytotoxic effects on MDA-MB231, MCF-7 and 4T1 cells in vitro. Moreover, based on the cell cycle and Annexin V results, nordamnacanthal managed to induce cell death in both MDA-MB231 and MCF-7 cells. Additionally, no mortality, signs of toxicity and changes of serum liver profile were observed in nordamnacanthal treated mice in the subchronic toxicity study. Furthermore, 50 mg/kg body weight of nordamncanthal successfully delayed the progression of 4T1 tumors in Balb/C mice after 28 days of treatment. Treatment with nordamnacanthal was also able to increase tumor immunity as evidenced by the immunophenotyping of the spleen and YAC-1 cytotoxicity assays. Conclusion: Nordamnacanthal managed to inhibit the growth and induce cell death in MDA-MB231 and MCF-7 cell lines in vitro and cease the tumor progression of 4T1 cells in vivo. Overall, nordamnacanthal holds interesting anti-cancer properties that can be further explored

Developing an online, searchable database to systematically map and organise current literature on retention research (ORRCA2)

Background: Addressing recruitment and retention challenges in trials is a key priority for methods research, but navigating the literature is difficult and time-consuming. In 2016, ORRCA (www.orrca.org.uk) launched a free, searchable database of recruitment research that has been widely accessed and used to support the update of systematic reviews and the selection of recruitment strategies for clinical trials. ORRCA2 aims to create a similar database to map the growing volume and importance of retention research.  Methods: Searches of Medline (Ovid), CINAHL, PsycINFO, Scopus, Web of Science Core Collection and the Cochrane Library, restricted to English language and publications up to the end of 2017. Hand searches of key systematic reviews were undertaken and randomised evaluations of recruitment interventions within the ORRCA database on 1 October 2020 were also reviewed for any secondary retention outcomes. Records were screened by title and abstract before obtaining the full text of potentially relevant articles. Studies reporting or evaluating strategies, methods and study designs to improve retention within healthcare research were eligible. Case reports describing retention challenges or successes and studies evaluating participant reported reasons for withdrawal or losses were also included. Studies assessing adherence to treatments, attendance at appointments outside of research and statistical analysis methods for missing data were excluded. Eligible articles were categorised into one of the following evidence types: randomised evaluations, non-randomised evaluations, application of retention strategies without evaluation and observations of factors affecting retention. Articles were also mapped against a retention domain framework. Additional data were extracted on research outcomes, methods and host study context.  Results: Of the 72,904 abstracts screened, 4,364 full texts were obtained, and 1,167 articles were eligible. Of these, 165 (14%) were randomised evaluations, 99 (8%) non-randomised evaluations, 319 (27%) strategies without evaluation and 584 (50%) observations of factors affecting retention. Eighty-four percent (n = 979) of studies assessed the numbers of participants retained, 27% (n = 317) assessed demographic differences between retained and lost participants, while only 4% (n = 44) assessed the cost of retention strategies. The most frequently reported domains within the 165 studies categorised as ‘randomised evaluations of retention strategies’ were participant monetary incentives (32%), participant reminders and prompts (30%), questionnaire design (30%) and data collection location and method (26%).  Conclusion: ORRCA2 builds on the success of ORRCA extending the database to organise the growing volume of retention research. Less than 15% of articles were randomised evaluations of retention strategies. Mapping of the literature highlights several areas for future research such as the role of research sites, clinical staff and study design in enhancing retention. Future studies should also include cost–benefit analysis of retention strategies

Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer

Colon tumors from four independent mouse models and 100 human colorectal cancers all exhibited striking recapitulation of embryonic colon gene expression from embryonic days 13.5-18.5