Trial participants' self-reported understanding of randomisation phrases in participation information leaflets can be high, but acceptability of some descriptions is low, especially those linked to gambling and luck.

BACKGROUND: Evidence indicates that trial participants often struggle to understand participant information leaflets (PILs) for clinical trials, including the concept of randomisation. We analysed the language used to describe randomisation in PILs and determine the most understandable and acceptable description through public and participant feedback. METHODS: We collected 280 PILs/informed consent forms and one video animation from clinical research facilities/clinical trial units in Ireland and the UK. We extracted text on how randomisation was described, plus trial characteristics. We conducted content analysis to group the randomisation phrases inductively. We then excluded phrases that appeared more than once or were very similar to others. The final list of randomisation phrases was then presented to an online panel of participants and the public. Panel members were asked to rate each phrase on a 5-point Likert scale in terms of their understanding of the phrase, confidence in their understanding and acceptability of the phrase. RESULTS: Two hundred and eighty PILs and the transcribed text from one video animation represented 229 ongoing or concluded trials. The pragmatic content analysis generated five inductive categories: (1) explanation of why randomisation is required in trials; (2) synonyms for randomisation; (3) comparative randomisation phrases; (4) elaborative phrases for randomisation (5) and phrases that describe the process of randomisation. We had 48 unique phrases, which were shared with 73 participants and members of the public. Phrases that were well understood were not necessarily acceptable. Participants understood, but disliked, comparative phrases that referenced gambling, e.g. toss of a coin, like a lottery, roll of a die. They also disliked phrases that attributed decision-making to computers or automated systems. Participants liked plain language descriptions of what randomisation is and those that did not use comparative phrases. CONCLUSIONS: Potential trial participants are clear on their likes and dislikes when it comes to describing randomisation in PILs. We make five recommendations for practice.

The Impact of Malnutrition on the Developing Lung and Long-Term Lung Health: A Narrative Review of Global Literature.

Worldwide, over 2 billion children under the age of 5 experience stunting, wasting, or are underweight. Malnutrition contributes to 45% of all deaths in this age group (approximately 3.1 million deaths) [1]. Poverty, food insecurity, suboptimal feeding practices, climate change, and conflict are all contributing factors. Malnutrition causes significant respiratory problems, including increased risk of respiratory infections, impaired lung function, and increased risk of subsequent adult respiratory disease, including asthma, COPD, and lung cancer. Childhood malnutrition not only has serious consequences for children's health but it also has numerous consequences on wellbeing and educational attainment. Childhood malnutrition is a complex and multifaceted problem. However, by understanding and addressing the underlying causes, and investing in prevention and treatment programs, it is possible to maximize children's health and wellbeing on a global scale. This narrative review will focus on the impact of childhood malnutrition on lung development, the consequent respiratory disease, and what actions can be taken to reduce the burden of malnutrition on lung health.

Opening up ideas: an advent calendar for patient and public engagement in clinical trials research.

The involvement of patients and the public in research is now an expectation in research with funders requesting a clear plan of involvement and engagement. In the United Kingdom involvement typically focuses on research prioritisation, design and delivery, in contrast activities that share the results of research or research methods more generally are considered to be engagement. Clinical trials tend to concentrate on involvement activities with less emphasis on engagement. To promote engagement activities in the context of clinical trials we asked people attending the 2022 International Clinical Trials Methodology Conference to share ideas on how we can best engage with patients and the public. Responses were reviewed and 22 themes identified. One suggestion was to create an advent calendar and so these 22 themes plus two from the authors were used as a daily tweet from the 1st to the 24th December 2022. Here we share these ideas and draw comparisons between engagement activities in research and traditions of the Christmas period. The ideas shared are not intended as a definitive list but instead a novel way to start discussions between experts by experience, researchers, health professionals and communities to facilitate co-production of meaningful engagement strategies.

Patient and public involvement and engagement are terms used to describe specific activities that have a variety of goals from information giving through topublic co-production of research. Involvement and engagement are important as they can help reduce waste in research by ensuring that the research is relevant, conducted well and that the results are shared to those that will use them to make decisions about treatments, including patients. In the United Kingdom the term "engagement" usually refers to activities that focus mainly on information giving, for example sharing the results of research or information about how research is done in general. In this commentary we share ideas for engagement activities that were collected from people attending the International Clinical Trials Methodology Conference in 2022. One of the ideas shared was to have an advent calendar and we have used this to draw comparisons between traditions surrounding the Christmas period and engagement of patients and the public. We share 24 different ideas in the form of a printable advent calendar and invite the clinical trials community, including experts by experience, to reflect on these to generate more ideas for meaningful engagement activities so that everyone who will use the results of research has the opportunity to shape, share, and benefit from research.

Core outcome measurement instruments for use in clinical and research settings for adults with post-COVID-19 condition: an international Delphi consensus study.

Post-COVID-19 condition (also known as long COVID) is a new, complex, and poorly understood disorder. A core outcome set (COS) for post-COVID-19 condition in adults has been developed and agreement is now required on the most appropriate measurement instruments for these core outcomes. We conducted an international consensus study involving multidisciplinary experts and people with lived experience of long COVID. The study comprised a literature review to identify measurement instruments for the core outcomes, a three-round online modified Delphi process, and an online consensus meeting to generate a core outcome measurement set (COMS). 594 individuals from 58 countries participated. The number of potential instruments for the 12 core outcomes was reduced from 319 to 19. Consensus was reached for inclusion of the modified Medical Research Council Dyspnoea Scale for respiratory outcomes. Measures for two relevant outcomes from a previously published COS for acute COVID-19 were also included: time until death, for survival, and the Recovery Scale for COVID-19, for recovery. Instruments were suggested for consideration for the remaining nine core outcomes: fatigue or exhaustion, pain, post-exertion symptoms, work or occupational and study changes, and cardiovascular, nervous system, cognitive, mental health, and physical outcomes; however, consensus was not achieved for instruments for these outcomes. The recommended COMS and instruments for consideration provide a foundation for the evaluation of post-COVID-19 condition in adults, which should help to optimise clinical care and accelerate research worldwide. Further assessment of this COMS is warranted as new data emerge on existing and novel measurement instruments.

Patient-reported outcomes for people with diabetes: what and how to measure? A narrative review.

Patient-reported outcomes (PROs) are valuable for shared decision making and research. Patient-reported outcome measures (PROMs) are questionnaires used to measure PROs, such as health-related quality of life (HRQL). Although core outcome sets for trials and clinical practice have been developed separately, they, as well as other initiatives, recommend different PROs and PROMs. In research and clinical practice, different PROMs are used (some generic, some disease-specific), which measure many different things. This is a threat to the validity of research and clinical findings in the field of diabetes. In this narrative review, we aim to provide recommendations for the selection of relevant PROs and psychometrically sound PROMs for people with diabetes for use in clinical practice and research. Based on a general conceptual framework of PROs, we suggest that relevant PROs to measure in people with diabetes are: disease-specific symptoms (e.g. worries about hypoglycaemia and diabetes distress), general symptoms (e.g. fatigue and depression), functional status, general health perceptions and overall quality of life. Generic PROMs such as the 36-Item Short Form Health Survey (SF-36), WHO Disability Assessment Schedule (WHODAS 2.0), or Patient-Reported Outcomes Measurement Information System (PROMIS) measures could be considered to measure commonly relevant PROs, supplemented with disease-specific PROMs where needed. However, none of the existing diabetes-specific PROM scales has been sufficiently validated, although the Diabetes Symptom Self-Care Inventory (DSSCI) for measuring diabetes-specific symptoms and the Diabetes Distress Scale (DDS) and Problem Areas in Diabetes (PAID) for measuring distress showed sufficient content validity. Standardisation and use of relevant PROs and psychometrically sound PROMs can help inform people with diabetes about the expected course of disease and treatment, for shared decision making, to monitor outcomes and to improve healthcare. We recommend further validation studies of diabetes-specific PROMs that have sufficient content validity for measuring disease-specific symptoms and consider generic item banks developed based on item response theory for measuring commonly relevant PROs.

The ex vivo pharmacology of HIV-1 antiretrovirals differs between macaques and humans.

Non-human primates (NHP) are widely used for the pre-clinical assessment of antiretrovirals (ARVs) for HIV treatment and prevention. However, the utility of these models is questionable given the differences in ARV pharmacology between humans and macaques. Here, we report a model based on ex vivo ARV exposure and the challenge of mucosal tissue explants to define pharmacological differences between NHPs and humans. For colorectal and cervicovaginal explants in both species, high concentrations of tenofovir (TFV) and maraviroc were predictive of anti-viral efficacy. However, their combinations resulted in increased inhibitory potency in NHP when compared to human explants. In NHPs, higher TFV concentrations were measured in colorectal versus cervicovaginal explants (p = 0.042). In humans, this relationship was inverted with lower levels in colorectal tissue (p = 0.027). TFV-resistance caused greater loss of viral fitness for HIV-1 than SIV. This, tissue explants provide an important bridge to refine and appropriately interpret NHP studies.

A core outcome set for post-COVID-19 condition in adults for use in clinical practice and research: an international Delphi consensus study.

Health consequences that persist beyond the acute infection phase of COVID-19, termed post-COVID-19 condition (also commonly known as long COVID), vary widely and represent a growing global health challenge. Research on post-COVID-19 condition is expanding but, at present, no agreement exists on the health outcomes that should be measured in people living with the condition. To address this gap, we conducted an international consensus study, which included a comprehensive literature review and classification of outcomes for post-COVID-19 condition that informed a two-round online modified Delphi process followed by an online consensus meeting to finalise the core outcome set (COS). 1535 participants from 71 countries were involved, with 1148 individuals participating in both Delphi rounds. Eleven outcomes achieved consensus for inclusion in the final COS: fatigue; pain; post-exertion symptoms; work or occupational and study changes; survival; and functioning, symptoms, and conditions for each of cardiovascular, respiratory, nervous system, cognitive, mental health, and physical outcomes. Recovery was included a priori because it was a relevant outcome that was part of a previously published COS on COVID-19. The next step in this COS development exercise will be to establish the instruments that are most appropriate to measure these core outcomes. This international consensus-based COS should provide a framework for standardised assessment of adults with post-COVID-19 condition, aimed at facilitating clinical care and research worldwide.

A Randomized, Open-Label, Crossover Phase 1 Safety and Pharmacokinetic Study of Oral Maraviroc and Maraviroc 1% Gel (the CHARM-03 Study).

The Combination HIV Antiretroviral Rectal Microbicide-3 (CHARM-03) study was a randomized, open-label, crossover Phase 1 safety and pharmacokinetic (PK) study of oral maraviroc (MVC) and MVC 1% gel. At a single site, healthy HIV-uninfected men and women were enrolled and randomized to an open label crossover sequence of eight consecutive daily exposures to MVC 300 mg dosed orally, MCV 1% gel dosed rectally, and MVC 1% gel dosed vaginally. Male participants received oral and rectal dosing and female participants received oral, rectal, and vaginal dosing. Assessments were undertaken at baseline and following each 8-day period and included collection of plasma, rectal/cervical tissue (CT), and rectal/endocervical/vaginal fluids. Eleven men and nine women were enrolled. Two participants withdrew from the study before receiving study product. There were 25 adverse events, of which 24 were Grade 1 (G1) and one was G2 (unrelated). After eight doses, MVC was quantifiable in all samples following oral, rectal, or vaginal product administration. The highest drug concentrations in plasma, rectal tissue (RT), and CT were associated with oral, rectal, and vaginal drug delivery, respectively. There were significant reductions in tissue drug concentrations when rectal and cervical biopsies were incubated in media before tissue processing for PK (p < .0001). Only oral MVC was associated with limited protection in the rectal explant HIV challenge model (p < .05). There were no immunological changes in RT, and all products were acceptable to participants. In conclusion, all products were found to be safe and acceptable and did not induce local inflammation. The lack of ex vivo efficacy demonstrated in study samples may be due to rapid disassociation of MVC from the explant tissue. ClinicalTrials.gov Identifier: NCT02346084.

Identifying a core outcome set for pulmonary sarcoidosis research - the Foundation for Sarcoidosis Research - Sarcoidosis Clinical OUtcomes Taskforce (SCOUT).

Background: Pulmonary sarcoidosis is a rare granulomatous disease of unknown aetiology. Heterogeneity in the outcomes measured in trials of treatment for pulmonary sarcoidosis has impacted on the ability to systematically compare findings, contributing to research inefficiency. The FSR-SCOUT study has aimed to address this heterogeneity by developing a core outcome set that represents a patient and health professional consensus on the most important outcomes to measure in future research for the treatment of pulmonary sarcoidosis. Research design and methods: systematic review of trial registries, narrative synthesis of published qualitative literature on the patient experience and results of a patient survey contributed to the development of a comprehensive list of outcomes that were rated in a two round online Delphi survey. The Delphi survey was completed by patients/carers and health professionals and the results discussed and ratified at an online consensus meeting. Results: 259 patients/carers and 51 health professionals completed both rounds of the Delphi survey. A pre-agreed definition of consensus was applied and the results discussed at an online consensus meeting attended by 17 patients and 7 health professionals). Fifteen outcomes, across five domains (physiological/clinical, treatment, resource use, quality of life, and death), reached the definition of consensus and were included in the core outcome set. Conclusions: The core outcome set represents a patient and health professional consensus on the most important outcomes for pulmonary sarcoidosis research. The use of the core outcome set in future trials, and efforts to validate its components, will enhance the relevance of trials to stakeholders and will increase the opportunity for the research to contribute to evidence synthesis.

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.

Scout - sarcoidosis outcomes taskforce. A systematic review of outcomes to inform the development of a core outcome set for pulmonary sarcoidosis.

BACKGROUND: Clinical trials evaluating different management strategies for pulmonary sarcoidosis may measure different outcomes. This heterogeneity in outcomes can lead to waste in research due to the inability to compare and combine data. Core outcome sets (COS) have the potential to address this issue and here we describe a systematic review of outcomes as the first step in the development of a COS for pulmonary sarcoidosis research. METHODS: A search of clinical trial registries for phase II, III and IV trials of pulmonary sarcoidosis was undertaken along with a rapid review of the patient perspective literature. Each study was screened for eligibility and outcomes extracted verbatim from the registry entry or publication then reviewed, grouped and categorised using the COMET taxonomy. RESULTS: 36 trial registry entries and 6 studies on patients' perspective of pulmonary sarcoidosis were included reporting 56 and 82 unique outcomes respectively across 23 domains. The most frequently reported outcome domain was "respiratory, thoracic and mediastinal outcomes". However, the patients' perspective literature identified outcomes in the "personal circumstances" and "societal/carer burden" domains that were not reported in any of the included trial registrations. CONCLUSIONS: Using both clinical trial registry data and published literature on patients' perspective has allowed rapid review of outcomes measured and reported in pulmonary sarcoidosis research. The use of multiple sources has led to the development of a comprehensive list of outcomes that represents the first step in the development of a COS for use in future pulmonary sarcoidosis research.

Characterization of the Ovine Vaginal Microbiome and Inflammation Patterns as an Improved Testing Model of Human Vaginal Irritation.

The development of therapies targeted to improve the health of women has utilized direct vaginal delivery as a more effective and less toxic method of protection from HIV and other pathogens. Vaginal applicants and delivery devices that provide sustained effects have been met with increasing acceptability, but the efficacy and toxicity outcomes have not been successfully predicted by preclinical in vitro studies and animal modeling. We have explored the utilization of sheep as a model for testing the safety of vaginal applicants and devices based on spatial and structural similarities to the human vagina. As recently noted by the FDA, an additional safety measure is an impact on the vaginal microbiome (VMB) that is known to contribute to vaginal health and influence pathogen susceptibility and drug metabolism. To advance the utility of the sheep vaginal model, we completed a thorough molecular characterization of the ovine VMB utilizing both next-generation sequencing (NGS) and PCR methods. The process also created a custom PCR array to quantify ovine VMB community profiles in an affordable, higher throughput fashion. The results from vaginal swabs (>475 samples) collected from non-pregnant crossbred Dorset and Merino ewes treated with selected vaginal applicants or collected as sham samples established 16 VMB community types (VMB CTs). To associate VMB CTs with eubiosis or dysbiosis, we also completed custom ELISAs for six cytokines identifying IL1B, IL8, TNFa, and CXCL10 as useful markers to support the characterization of ovine vaginal inflammation. The results indicated that Pasteurella, Actinobacillus, Pseudomonas, Bacteroides, Leptotrichia, and E. coli were common markers of eubiosis (low inflammatory marker expression), and that Haemophilus, Ureaplasma, and Corynebacterium were associated with dysbiosis (high cytokine levels). Utilizing the optimized workflow, we also confirmed the utility of three commonly used vaginal applicants for impact on the VMB and inflammatory state, producing a dataset that supports the recommendation for the use of sheep for testing of vaginal applicants and devices as part of preclinical pipelines.

Development of Gram Stain Scoring System Based on Pro-Inflammatory Cytokines in the Sheep Model for Testing Toxicity of Vaginal Products.

Background: Development of safe, effective products to prevent the sexual transmission of HIV remains a priority. Prior to clinical testing, the products must undergo strict safety evaluations to avoid mucosal drug toxicity, inflammation, and vaginal microbiome (VMB) shifts. Based on the Food and Drug Administration (FDA) guidance, we designed a study to measure the inflammatory markers and VMB changes after intravaginal treatment with products that have been associated with toxicity, with the objective to develop a Gram stain slide scoring system, similar to Nugent scoring, correlated with the proinflammatory cytokines in sheep. Methods: Non-pregnant Dorset ewes (n = 34) were randomized to receive 5 ml intravaginal 4% nonoxynol-9 (N9) contraceptive gel, positive control (0.2% benzalkonium chloride), placebo control [hydroxethyl cellulose (HEC)], or no application daily for 10 days, with 11-day post-treatment follow-up. The vaginal swabs were collected for the cytokines, VMB, and Gram-stained slides. An enzyme-linked immunosorbent assay (ELISA) analysis of cytokines interleukin (IL)-1ß, IL-8, CXCL10, and tumor necrosis factor-α (TNF-α) was used to determine inflammatory state of the sample. Vaginal microbiome community types (CT) were utilized to create five equivalent slide subsets for iterative development of a Gram-stained slide scoring system with comparisons with inflammatory state based on the cytokine levels. Results: Digital images of the Gram-stained slides were scored based on Gram staining and morphology of bacteria, presence of sheep epithelial cells, and immune cells. The scoring system was modified in an iterative fashion with weighting based on cytokine categorization of inflamed samples, with three of four cytokine values above the mean indicating that the sample was inflamed. The parameters in the final version of the scoring system included mature epithelial cells, Gram-negative rods, and Gram-positive diplococci indicating normal and immune cells indicating inflammation. The area under the receiver operator characteristic curve (ROC AUC) was 0.725 (ROC AUCs range between 0.5 and 1.0) with a greater area indicating higher diagnostic ability of a test with a binary outcome: inflamed or normal. Conclusion: The scoring system, derived from the advanced VMB and cytokine analyses, provides a validated, practical method for quantification of Gram-stained slides that can be performed in most laboratories, increasing the potential for standardization. The training plan can assist laboratories to determine the safety of intravaginal products in their sheep studies or the methodological approach can be applied to other animal models where such data are also needed.

Can harmonisation of outcomes bridge the translation gap for pre-clinical research? A systematic review of outcomes measured in mouse models of type 2 diabetes.

BACKGROUND: In pre-clinical research, systematic reviews have the potential to mitigate translational challenges by facilitating understanding of how pre-clinical studies can inform future clinical research. Yet their conduct is encumbered by heterogeneity in the outcomes measured and reported, and those outcomes may not always relate to the most clinically important outcomes. We aimed to systematically review outcomes measured and reported in pre-clinical in vivo studies of pharmacological interventions to treat high blood glucose in mouse models of type 2 diabetes. METHODS: A systematic review of pre-clinical in vivo studies of pharmacological interventions aimed at addressing elevated blood glucose in mouse models of type 2 diabetes was completed. Studies were screened for eligibility and outcomes extracted from the included studies. The outcomes were recorded verbatim and classified into outcome domains using an existing outcome taxonomy. Outcomes were also compared to those identified in a systematic review of registered phase 3/4 clinical trials for glucose lowering interventions in people with type 2 diabetes. RESULTS: Review of 280 included studies identified 532 unique outcomes across 19 domains. No single outcome, or domain, was measured in all studies and only 132 (21%) had also been measured in registered phase 3/4 clinical trials. A core outcome set, representing the minimum that should be measured and reported, developed for type 2 diabetes effectiveness clinical trials includes 18 core outcomes, of these 12 (71%) outcomes were measured and reported in one or more of the included pre-clinical studies. CONCLUSIONS: There is heterogeneity of outcomes reported in pre-clinical research. Harmonisation of outcomes across the research pathway using a core outcome set may facilitate interpretation, evidence synthesis and translational success, and may contribute to the refinement of the use of animals in research. Systematic review registration: The study was prospectively registered on the PROSPERO Database, registration number CRD42018106831.

Development of a core outcome set for use in routine orthodontic clinical trials.

INTRODUCTION: A diverse range of outcomes is used in orthodontic research with a focus on measuring outcomes important to clinicians and little consistency in outcome selection and measurement. We aimed to develop a core outcome set for use in clinical trials of orthodontic treatment not involving cleft or orthognathic patient groups. METHODS: A list of outcomes measured in previous orthodontic research was identified through a scoping literature review. Additional outcomes of importance to patients were obtained using qualitative interviews and focus groups with adolescents aged 10-16 years. Rating of outcomes was carried out in a 2-round electronic Delphi process involving health care professionals and patients using a 9-point scale. A face-to-face meeting was subsequently held with stakeholders to discuss the results before refining the core outcome set. RESULTS: After triangulation, a final list of 34 outcomes grouped under 10 domains was obtained for rating in the e-Delphi surveys. Fifteen outcomes were voted "in" after the second Delphi round involving 274 participants with a further outcome being included after the consensus meeting. These were subsequently refined into a final set of 7 core outcomes, including the impact of self-perceived esthetics, alignment and/or occlusion, skeletal relationship, stability, patient-related adherence, breakages, and adverse effects on teeth or teeth-supporting structures. CONCLUSIONS: A bespoke orthodontic core outcome set encompassing both clinician- and patient-focused outcomes was developed. Incorporating this is the first step into providing a more holistic assessment of the impact of treatment while allowing for meaningful comparisons and synthesis of results from individual trials.

Core outcome sets through the healthcare ecosystem: the case of type 2 diabetes mellitus.

BACKGROUND: It is increasingly accepted that insufficient attention has been given to the patient health outcomes that are important to measure in comparative effectiveness research that will inform decision-making. The relationship between outcomes chosen for comparative effectiveness research, outcomes used in decision-making in routine care, and outcome data recorded in electronic health records (EHR) is also poorly understood. The COMET Initiative (http://www.comet-initiative.org/. Accessed 3 Apr 2020) supports and encourages the development and use of 'core outcome sets' (COS), which represent the minimum set of patient health outcomes that should be measured and reported for a specific condition. There is growing interest in identifying how COS might fit into the different stages of the healthcare research and delivery ecosystem, and whether inclusion in the EHR might facilitate this. METHODS: We sought to determine the degree of overlap between outcomes within COS for research and routine care, EMA, FDA and NICE guidelines, NICE quality statements/indicators, EHR and a point-of-care randomised clinical trial, using type 2 diabetes (T2D) as a case study. RESULTS: There is substantial agreement about important patient outcomes for T2D for research and healthcare, with associated coverage within the UK general practice EHR. CONCLUSIONS: This case study has demonstrated the potential for efficient research and value-based healthcare when the EHR can include COS for both research and care, where the COS comprises outcomes of importance to all relevant stakeholders. However, this concordance may not hold more generally, as the focus on patient-centred outcomes may well be greater in T2D than in other conditions. Work is ongoing to examine other clinical areas, in order to highlight any current inefficiencies when health outcomes in research and healthcare do not agree with core outcomes identified by patients, clinicians and other key stakeholders.

Effectiveness of home or hospital initiation of treatment at diagnosis for children with type 1 diabetes (DECIDE trial): a multicentre individually randomised controlled trial.

OBJECTIVE: To determine whether, in children with newly diagnosed type 1 diabetes who were not acutely unwell, management at home for initiation of insulin treatment and education of the child and family, would result in improved clinical and psychological outcomes at 2 years postdiagnosis. DESIGN: A multicentre randomised controlled trial (January 2008/October 2013). SETTING: Eight paediatric diabetes centres in England, Wales and Northern Ireland. PARTICIPANTS: 203 clinically well children aged under 17 years, with newly diagnosed type 1 diabetes and their carers. INTERVENTION: Management of the initiation period from diagnosis at home, for a minimum of 3 days, to include at least six supervised injections and delivery of pragmatic educational care. MAIN OUTCOME MEASURES: Primary outcome was glycosylated haemoglobin (HbA1c) concentration at 24 months postdiagnosis. Secondary outcomes included coping, anxiety, quality of life and use of NHS resources. RESULTS: 203 children, newly diagnosed, were randomised to commence management at home (n=101) or in hospital (n=102). At the 24 month primary end point, there was one withdrawal and a follow-up rate of 194/202 (96%). Mean HbA1c in the home treatment arm was 72.1 mmol/mol and in the hospital treated arm 72.6 mmol/mol. There was a negligible difference between the mean HbA1c levels in the two arms adjusted for baseline (1.01, 95% CI 0.93 to 1.09). There were mostly no differences in secondary outcomes at 24 months, apart from better child self-esteem in the home-arm. No home-arm children were admitted to hospital during initiation and there were no adverse events at that time. The number of investigations was higher in hospital patients during the follow-up period. There were no differences in insulin regimens between the two arms. CONCLUSIONS: There is no evidence of a difference between home-based and hospital-based initiation of care in children newly diagnosed with type 1 diabetes across relevant outcomes. TRIAL REGISTRATION NUMBER: ISRCTN78114042.

Designing and using incentives to support recruitment and retention in clinical trials: a scoping review and a checklist for design.

BACKGROUND: Recruitment and retention of participants are both critical for the success of trials, yet both remain significant problems. The use of incentives to target participants and trial staff has been proposed as one solution. The effects of incentives are complex and depend upon how they are designed, but these complexities are often overlooked. In this paper, we used a scoping review to 'map' the literature, with two aims: to develop a checklist on the design and use of incentives to support recruitment and retention in trials; and to identify key research topics for the future. METHODS: The scoping review drew on the existing economic theory of incentives and a structured review of the literature on the use of incentives in three healthcare settings: trials, pay for performance, and health behaviour change. We identified the design issues that need to be considered when introducing an incentive scheme to improve recruitment and retention in trials. We then reviewed both the theoretical and empirical evidence relating to each of these design issues. We synthesised the findings into a checklist to guide the design of interventions using incentives. RESULTS: The issues to consider when designing an incentive system were summarised into an eight-question checklist. The checklist covers: the current incentives and barriers operating in the system; who the incentive should be directed towards; what the incentive should be linked to; the form of incentive; the incentive size; the structure of the incentive system; the timing and frequency of incentive payouts; and the potential unintended consequences. We concluded the section on each design aspect by highlighting the gaps in the current evidence base. CONCLUSIONS: Our findings highlight how complex the design of incentive systems can be, and how crucial each design choice is to overall effectiveness. The most appropriate design choice will differ according to context, and we have aimed to provide context-specific advice. Whilst all design issues warrant further research, evidence is most needed on incentives directed at recruiters, optimal incentive size, and testing of different incentive structures, particularly exploring repeat arrangements with recruiters.

Timing Of Primary Surgery for cleft palate (TOPS): protocol for a randomised trial of palate surgery at 6 months versus 12 months of age.

INTRODUCTION: Cleft palate is among the most common birth abnormalities. The success of primary surgery in the early months of life is crucial for successful feeding, speech, hearing, dental development and facial growth. Over recent decades, age at palatal surgery in infancy has reduced. This has led to palatal closure in one-stage procedures being carried out around the age of 12 months, but in some cases as early as 6 months. The primary objective of the Timing Of Primary Surgery for Cleft Palate (TOPS)trial is to determine whether surgery for cleft palate performed at 6 or 12 months of age is most beneficial for speech outcomes. METHODS AND ANALYSIS: Infants with a diagnosis of non-syndromic isolated cleft palate will be randomised to receive standardised primary surgery (Sommerlad technique) for closure of the cleft at either 6 months or 12 months, corrected for gestational age. The primary outcome will be perceived insufficient velopharyngeal function at 5 years of age. Secondary outcomes measured across 12 months, 3 years and 5 years will include growth, safety of the procedure, dentofacial development, speech, hearing level and middle ear function. Video and audio recordings of speech will be collected in a standardised age-appropriate manner and analysed independently by multiple speech and language therapists. The trial aims to recruit and follow-up 300 participants per arm. Data will be analysed according to the intention-to-treat principle using a 5% significance level. All analyses will be prespecified within a full and detailed statistical analysis plan. ETHICS AND DISSEMINATION: Ethical approval has been sought in each participating country according to country-specific procedures. Trial results will be presented at conferences, published in peer-reviewed journals and disseminated through relevant patient support groups. TRIAL REGISTRATION NUMBER: NCT00993551; Pre-results.

A Multiple Dose Phase 1 Assessment of Rilpivirine Long Acting in a Model of Preexposure Prophylaxis Against HIV.

The MWRI-01 study characterized the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of rilpivirine (RPV) long acting (LA) in a model of preexposure prophylaxis (PrEP). Prospective, open-label Phase 1 study. The safety and acceptability of three repeated doses of RPV LA were monitored. Blood, tissue (rectal, cervical, and vaginal), and biological fluids (vaginal and endocervical) were collected at baseline and at 1- to 2-month intervals throughout the study for PK and PD assessment. Eight women and four men received three intramuscular doses of 1,200 mg of RPV LA given 8 weeks apart. There were a total of 195 adverse events (AEs) reported, of which 138 (70.8%) were Grade 1 and 55 (28.2%) were Grade 2. The most common AE was injection site pain. Geometric mean (90% confidence interval) plasma RPV concentrations at 56 days after the first and third doses were 39 (33-45) ng/mL (female)/29 (17-40) ng/mL (male) and 59 (45-62) ng/mL (female)/40 (30-51) ng/mL (male), respectively. Exposure to RPV LA was associated with significant inhibition of HIV-1BaL viral replication in the ex vivo rectal explant model (p < .0001) that persisted for up to 4 months after the third dose of RPV LA. In contrast, no viral suppression was seen in cervicovaginal tissue. Multiple dose administration of RPV LA was safe and well tolerated, and was associated with prolonged suppression of viral replication in rectal explant tissue.