The overlap between randomised evaluations of recruitment and retention interventions:An updated review of recruitment (Online Resource for Recruitment in Clinical triAls) and retention (Online Resource for Retention in Clinical triAls) literature

Background: The Online Resource for Recruitment in Clinical triAls (ORRCA) and the Online Resource for Retention in Clinical triAls (ORRCA2) were established to organise and map the literature addressing participant recruitment and retention within clinical research. The two databases are updated on an ongoing basis using separate but parallel systematic reviews. However, recruitment and retention of research participants is widely acknowledged to be interconnected. While interventions aimed at addressing recruitment challenges can impact retention and vice versa, it is not clear how well they are simultaneously considered within methodological research. This study aims to report the recent update of ORRCA and ORRCA2 with a special emphasis on assessing crossover of the databases and how frequently randomised studies of methodological interventions measure the impact on both recruitment and retention outcomes. Methods: Two parallel systematic reviews were conducted in line with previously reported methods updating ORRCA (recruitment) and ORRCA2 (retention) with publications from 2018 and 2019. Articles were categorised according to their evidence type (randomised evaluation, non-randomised evaluation, application and observation) and against the recruitment and retention domain frameworks. Articles categorised as randomised evaluations were compared to identify studies appearing in both databases. For randomised studies that were only in one database, domain categories were used to assess whether the methodological intervention was likely to impact on the alternate construct. For example, whether a recruitment intervention might also impact retention. Results: In total, 806 of 17,767 articles screened for the recruitment database and 175 of 18,656 articles screened for the retention database were added as result of the update. Of these, 89 articles were classified as ‘randomised evaluation’, of which 6 were systematic reviews and 83 were randomised evaluations of methodological interventions. Ten of the randomised studies assessed recruitment and retention and were included in both databases. Of the randomised studies only in the recruitment database, 48/55 (87%) assessed the content or format of participant information which could have an impact on retention. Of the randomised studies only in the retention database, 6/18 (33%) assessed monetary incentives, 4/18 (22%) assessed data collection location and methods and 3/18 (17%) assessed non-monetary incentives, all of which could have an impact on recruitment. Conclusion: Only a small proportion of randomised studies of methodological interventions assessed the impact on both recruitment and retention despite having a potential impact on both outcomes. Where possible, an integrated approach analysing both constructs should be the new standard for these types of evaluations to ensure that improvements to recruitment are not at the expense of retention and vice versa.</p

The overlap between randomised evaluations of recruitment and retention interventions:An updated review of recruitment (Online Resource for Recruitment in Clinical triAls) and retention (Online Resource for Retention in Clinical triAls) literature

Background: The Online Resource for Recruitment in Clinical triAls (ORRCA) and the Online Resource for Retention in Clinical triAls (ORRCA2) were established to organise and map the literature addressing participant recruitment and retention within clinical research. The two databases are updated on an ongoing basis using separate but parallel systematic reviews. However, recruitment and retention of research participants is widely acknowledged to be interconnected. While interventions aimed at addressing recruitment challenges can impact retention and vice versa, it is not clear how well they are simultaneously considered within methodological research. This study aims to report the recent update of ORRCA and ORRCA2 with a special emphasis on assessing crossover of the databases and how frequently randomised studies of methodological interventions measure the impact on both recruitment and retention outcomes. Methods: Two parallel systematic reviews were conducted in line with previously reported methods updating ORRCA (recruitment) and ORRCA2 (retention) with publications from 2018 and 2019. Articles were categorised according to their evidence type (randomised evaluation, non-randomised evaluation, application and observation) and against the recruitment and retention domain frameworks. Articles categorised as randomised evaluations were compared to identify studies appearing in both databases. For randomised studies that were only in one database, domain categories were used to assess whether the methodological intervention was likely to impact on the alternate construct. For example, whether a recruitment intervention might also impact retention. Results: In total, 806 of 17,767 articles screened for the recruitment database and 175 of 18,656 articles screened for the retention database were added as result of the update. Of these, 89 articles were classified as ‘randomised evaluation’, of which 6 were systematic reviews and 83 were randomised evaluations of methodological interventions. Ten of the randomised studies assessed recruitment and retention and were included in both databases. Of the randomised studies only in the recruitment database, 48/55 (87%) assessed the content or format of participant information which could have an impact on retention. Of the randomised studies only in the retention database, 6/18 (33%) assessed monetary incentives, 4/18 (22%) assessed data collection location and methods and 3/18 (17%) assessed non-monetary incentives, all of which could have an impact on recruitment. Conclusion: Only a small proportion of randomised studies of methodological interventions assessed the impact on both recruitment and retention despite having a potential impact on both outcomes. Where possible, an integrated approach analysing both constructs should be the new standard for these types of evaluations to ensure that improvements to recruitment are not at the expense of retention and vice versa.</p

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

Plasticity of the Phonotactic Selectiveness of Four Species of Chirping Crickets (Gryllidae): Implications for Call Recognition

Earlier studies of phonotaxis by female crickets describe this selective behavioural response as being important in the females\u27 choices of conspecific males, leading to reproduction. In the present study, moderate (30+) to very large data sets of phonotactic behaviour by female Acheta domesticus L., Gryllus bimaculatus DeGeer, Gryllus pennsylvanicus Burmeister and Gryllus veletis Alexander demonstrate substantially greater plasticity in the behavioural choices, as made by females of each species, for the syllable periods (SP) of model calling songs (CS) than has been previously described. Phonotactic choices by each species range from the very selective (i.e. responding to only one or two SPs) to very unselective (i.e. responding to all SPs presented). Some females that do not respond to all SPs prefer a range that includes either the longest or shortest SP tested, which fall outside the range of SPs produced by conspecific males. Old female A. domesticus and G. pennsylvanicus are more likely to be unselective for SPs than are young females. Each species includes females that do not respond to a particular SP when responding to CSs with longer and shorter SPs. The results suggest that the plasticity of phonotactic behaviour collectively exhibited by the females of each species does not ensure that choices of a male\u27s CS effectively focus the female\u27s phonotactic responses on CSs that represent the conspecific male. The phonotactic behaviour collectively exhibited by females of each species does not readily fit any of the models for selective processing by central auditory neurones that have been proposed to underlie phonotactic choice. © 2010 The Authors. Journal compilation © 2010 The Royal Entomological Society

The overlap between randomised evaluations of recruitment and retention interventions: An updated review of recruitment (ORRCA) and retention (ORRCA2) literature

Background: The Online Resource for Recruitment in Clinical triAls (ORRCA) and the Online Resource for Retention in Clinical triAls (ORRCA2) were established to organise and map the literature addressing participant recruitment and retention within clinical research. The two databases are updated on an ongoing basis using separate but parallel systematic reviews. However, recruitment and retention of research participants is widely acknowledged to be interconnected. Whilst interventions aimed at addressing recruitment challenges can impact retention and vice versa, it is not clear how well they are simultaneously considered within methodological research. This study aims to report the recent update of ORRCA and ORRCA2 with a special emphasis on assessing crossover of the databases and how frequently randomised studies of methodological interventions measure the impact on both recruitment and retention outcomes. Methods: Two parallel systematic reviews were conducted in line with previously reported methods updating ORRCA (recruitment) and ORRCA2 (retention) with publications from 2018 and 2019. Articles were categorised according to their evidence type (randomised evaluation, non-randomised evaluation, application and observation) and against the recruitment and retention domain frameworks. Articles categorised as randomised evaluations were compared to identify studies appearing in both databases. For randomised studies that were only in one database, domain categories were used to assess whether the methodological intervention was likely to impact on the alternate construct. For example, whether a recruitment intervention might also impact retention. Results: 806 of 17,767 articles screened for the recruitment database and 175 of 18,656 articles screened for the retention database were added as result of the update. 89 articles were classified as ‘randomised evaluation’, of which 6 were systematic reviews and 83 were randomised evaluations of methodological interventions. 10/83 (12%) of randomised studies assessed recruitment and retention and were included in both databases. 48/55 (87%) of the randomised studies only in the recruitment database assessed the content or format of participant information which could have an impact on retention. Of the randomised studies only in the retention database, 6/18 (33%) assessed monetary incentives, 4/18 (22%) assessed data collection location and methods and 3/18 (17%) assessed non-monetary incentives, all of which could have an impact on recruitment. Conclusion: Only a small proportion of randomised studies of methodological interventions assessed the impact on both recruitment and retention despite having a potential impact on both outcomes. Where possible, an integrated approach analysing both constructs should be the new standard for these types of evaluations to ensure that improvements to recruitment are not at the expense of retention and vice versa.<br/

A phase II single arm feasibility trial of neoadjuvant chemotherapy (NAC) with oxaliplatin/fluorouracil (OxMdG) then short-course preoperative radiotherapy (SCPRT) then immediate surgery in operable rectal cancer (ORC): COPERNICUS (NCT01263171)

Background: Feasibility was assessed of giving NAC prior to SCPRT then immediate surgery in ORC at high risk of metastatic relapse. Methods: Patients (pts) had non-metastatic rectal adenocarcinoma. Pre-treatment pelvic MRI showed resection margin was not at risk (disease > 1mm from mesorectal fascia) but adverse risk factors were present (disease > T3b or node positive or extramural vascular invasion). Pts received 4x2-weekly cycles of oxaliplatin 85mg/m² + levofolinic acid 175 mg, fluorouracil (FU) 400 mg/m² (bolus), then FU 2400 mg/m² (continuous IV in 46 hr). Within 14 days pts had pelvic SCPRT to 25 Gy in 5 daily fractions. Definitive surgery then occurred within a week. Post surgery pts received 16 weeks of OxMdG or oxaliplatin/capecitabine. The primary endpoint was the proportion of pts completing protocol treatment including surgery. Results: 60 UK pts were recruited May 2012-June 2014. At baseline: male 44 (73%), median age 63 (IQR: 56.5-70), WHO PS 0/1 55/5. On pre-treatment MRI tumour was T2/3x/3a/3b/3c/3d/4 in 2/2/16/24/12/1/3 and N0/1/2 in 7/40/13 pts. All pts commenced OxMdG with 57(95%) receiving all 4 cycles. 20 pts (33%) needed a dose reduction and 22 (37%) a dose delay. 58 pts commenced SCPRT (all received full dose) and 57 underwent surgery: anterior resection in 43 (75%), abdominoperineal resection in 11 (19%), Hartmanns in 3 (5%). Three pts withdrew prior to surgery: one lost to follow up after SCPRT, one pt choice and one due to cardiospasm during NAC. Median gap between OxMdG and starting SCPRT was 10 days (IQR: 5-15) and between completing SCPRT and surgery 10 days (IQR: 5-13). Postoperative histology was T0/1/2/3a/3b/3c/4a in 7/3/19/8/9/10/1 pts, N0/1/2 in 39/13/5 pts and ypT0ypN0 in 7/57 pts (12%). All 57 resected pts had a clear (R0) resection margin with no 30 day postoperative mortality. Conclusions: This is the first trial to report on giving NAC prior to SCPRT then surgery within a short time interval in ORC, which proved feasible with good compliance and promising efficacy. The UK NCRI intend to include a similar regimen in a future phase III trial. Clinical trial information: NCT0126317

Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequence normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 4-fold in all individuals, except for one showing a 31-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C > A changes. Different mutation rates and signatures between individuals are likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing