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Abstract Background We conducted an NIHR-funded evidence synthesis project, reviewing evidence relating to interventions for perceptual disorders following stroke. This related paper describes how people with lived experience of stroke-related perceptual disorders contributed to and influenced the project, and identifies lessons for future review projects. Methods We planned our patient and public involvement and engagement (PPIE) activities within a study protocol, described according to the domains of the ACTIVE framework; these were founded on principles for good practice in PPIE. Activities occurred across the lifespan of the project, consisting primarily of group discussions and voting to determine if there was consensus. To assess impact and individual experiences, we sought feedback using an evaluation form after each discussion, and conducted an online meeting at the end of the project to allow further reflection. Results We recruited five people to a Lived Experience Group, including two stroke survivors and three carers. Members attended one face-to-face meeting during the development of the review. Subsequent activities were all held online due to the COVID-19 pandemic; with six online meetings, plus email interactions. Positive impacts of the Lived Experience Group on the reviews included clear definitions of key terms, selection of outcome measures, agreement on implications of review findings, and identification of research recommendations. Key challenges identified related to the complexity of the topic and challenges in the use of new online technology as a consequence of the COVID-pandemic. Conclusions A number of lessons were learned during this project. Specific recommendations for future PPIE are to ensure that those involved have an opportunity to get to know one another, and to provide optional sessions to increase familiarity with online meeting software, clear explanations of the purpose of involvement and specific feedback after each activity. These lessons should be considered when planning the PPIE within future reviews.

Abstract Background Health guideline developers engage with interested people and groups to ensure that guidelines and their recommendations are relevant and useful to those who will be affected by them. These ‘interest‐holders’ include patients, payers/purchasers of health services, payers of health research, peer review editors, product makers, programme managers, policymakers, providers, principal investigators, and the public. The Guidelines International Network (GIN) and McMaster University Guideline Development Checklist describes 146 steps of the guideline process organized into 18 topics. While one topic focuses on engagement, it does not describe how to engage with interest‐holders. In addition, interest‐holder input could be sought throughout the guideline development process. This scoping review is part of a series of four related reviews. The three other reviews address barriers and facilitators to engagement in guideline development, managing conflicts of interest in guideline development, and assessing the impact of interest‐holder engagement on guideline development. The four reviews will inform the development of guidance for multi‐interest‐holder engagement in guideline development; the GIN‐McMaster Guideline Development Checklist Extension for Engagement. Objectives The objective of this scoping review is to identify, describe, and summarise existing guidance and methods for multi‐interest‐holder engagement throughout the health guideline development process. Search Methods We conducted one comprehensive search for studies of engagement in guidelines to meet the inclusion criteria of one or more of the four systematic reviews in this series. We searched MEDLINE (OVID), CINAHL (EBSCO), EMBASE (OVID), PsycInfo (OVID) and SCOPUS databases up to September 2022. We did not include limits for date, study design, or language. We searched websites of agencies and organizations that engage interest‐holder groups, such as the Agency for Healthcare Research and Quality (AHRQ), CIHR Strategy for Patient‐Oriented Research (SPOR), National Institute for Health and Care Research (NIHR) Be Part of Research, Guidelines International Network (G‐I‐N), the National Institute for Health and Care Excellence, and the PatientCentred Outcomes Research Institute (PCORI). We handsearched the websites of guideline producing agencies. We solicited additional grey literature from the members of the MuSE Consortium. Selection Criteria Studies were included in this review if they reported on engagement of any of our identified groups, patients, payers/funders of research, payers/purchasers of health services, policymakers, programme managers, providers, principal investigators/researchers, peer review editors, product makers in the development of a health guideline. Titles and abstracts of identified citations were screened independently, in duplicate. The full text of potentially relevant papers were screened for eligibility into one or more of the four reviews in the series. Screening was done independently, by two reviewers. The team held weekly meetings with all reviewers involved in screening to discuss and resolve conflicts. Data Collection and Analysis Two reviewers extracted relevant data into a pilot‐tested data extraction form using Excel. We used the GIN‐McMaster guideline development checklist as a framework for extracting the available guidance for each of our identified interest‐holder groups throughout the development process. We presented descriptive statistics of the number of papers reporting guidance for each groups across the steps of the guideline process. We synthesized the relevant text using a qualitative meta‐summary approach. Main Results We included 16 papers (from 17 reports). These papers were from Australia, Denmark, the Netherlands, the UK, and the USA, and eight papers were international (countries not specified). The papers provided guidance for at least one of our interest‐holder groups for at least one stage of guideline development. We mapped this guidance to the GIN‐McMaster Guideline Development Checklist to identify the available guidance for each of our interest‐holder groups across all stages of the guideline development process. Guidance was available for patient engagement in 15 of the 16 papers. At least two papers provided guidance for each of the 18 topics of the GIN‐McMaster Guideline Development Checklist. For healthcare providers, 9 papers provided guidance for their engagement across 10 of the 18 guideline development topics. Guidance for engaging with the public was provided for 14 of the 18 topics and reported in 4 of our included papers. For payers/purchasers of health services, policymakers, product makers, programme managers, and principal investigators, 2–3 papers provided guidance for these groups across 4–7 topics of the GIN‐McMaster checklist. We did not identify any specific guidance for payers of health research or for editors of peer‐reviewed journals. Authors' Conclusions Guidance for interst‐holder engagement in guidelines is available but has focused primarily on patients. We will utilize the guidance identified in this scoping review to inform the GIN‐McMaster Guideline Development Checklist Extension for engagement. Combined with the information obtained from the other systematic reviews in this series, we will address the gaps in guidance for the other identified interest‐holder groups.

Background Stroke often affects recognition and interpretation of information from our senses, resulting in perceptual disorders. Evidence to inform treatment is unclear. Objective To determine the breadth and effectiveness of interventions for stroke-related perceptual disorders and identify priority research questions. Methods We undertook a scoping review and then Cochrane systematic review. Definitions, outcome prioritisation, data interpretation and research prioritisation were coproduced with people who had perceptual disorders post stroke and healthcare professionals. We systematically searched electronic databases (including MEDLINE, EMBASE, inception to August 2021) and grey literature. We included studies (any design) of interventions for people with hearing, smell, somatosensation, taste, touch or visual perception disorders following stroke. Abstracts and full texts were independently dual reviewed. Data were tabulated, synthesised narratively and mapped by availability, sense and interventions. Research quality was not evaluated. Our Cochrane review synthesised the randomised controlled trial data, evaluated risk of bias (including randomisation, blinding, reporting) and meta-analysed intervention comparisons (vs. controls or no treatment) using RevMan 5.4. We judged certainty of evidence using grading of recommendations, assessment, development and evaluation. Activities of daily living after treatment was our primary outcome. Extended activities of daily living, quality of life, mental health and psychological well-being perceptual functional and adverse event data were also extracted. Results Scoping review We included 80 studies (n = 893): case studies (36/80) and randomised controlled trials (22/80). No stroke survivor or family stakeholder involvement was reported. Studies addressed visual (42.5%, 34/80), somatosensation (35%, 28/80), auditory (8.7%, 7/80) and tactile (7.5%, 6/80) perceptual disorders; some studies focused on ‘mixed perceptual disorders’ (6.2%, 5/80 such as taste–smell disorders). We identified 93 pharmacological, non-invasive brain stimulation or rehabilitation (restitution, substitution, compensation or mixed) interventions. Details were limited. Studies commonly measured perceptual (75%, 60/80), motor-sensorimotor (40%, 32/80) activities of daily living (22.5%, 18/80) or sensory function (15%, 12/80) outcomes. Cochrane systematic review We included 18 randomised controlled trials (n = 541) addressing tactile (3 randomised controlled trials; n = 70), somatosensory (7 randomised controlled trials; n = 196), visual (7 randomised controlled trials; n = 225) and mixed tactile-somatosensory (1 randomised controlled trial; n = 50) disorders. None addressed hearing, taste or smell disorders. One non-invasive brain stimulation, one compensation, 25 restitution and 4 mixed interventions were described. Risk of bias was low for random sequence generation (13/18), attrition (14/18) and outcome reporting (16/18). Perception was the most commonly measured outcome (11 randomised controlled trials); only 7 randomised controlled trials measured activities of daily living. Limited data provided insufficient evidence to determine the effectiveness of any intervention. Confidence in the evidence was low–very low. Our clinical (n = 4) and lived experience (n = 5) experts contributed throughout the project, coproducing a list of clinical implications and research priorities. Top research priorities included exploring the impact of, assessment of, and interventions for post-stroke perceptual disorders. Limitations Results are limited by the small number of studies identified and the small sample sizes, with a high proportion of single-participant studies. There was limited description of the perceptual disorders and intervention(s) evaluated. Few studies measured outcomes relating to functional impacts. There was limited investigation of hearing, smell, taste and touch perception disorders. Conclusion Evidence informing interventions for perceptual disorders after stroke is limited for all senses. Future work Further research, including high-quality randomised controlled trials, to inform clinical practice are required. Study registration This study is registered as PROSPERO CRD42019160270. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128829) and is published in full in Health Technology Assessment; Vol. 28, No. 69. See the NIHR Funding and Awards Website for further award information. Plain language summary After a stroke, individuals may have difficulty understanding information gathered through their sense of sight, hearing, smell, taste, touch or somatosensation (body position, temperature, etc.), known as perceptual problems. We estimate perceptual problems affect around 240,000 stroke survivors in the UK, limiting their ability to understand the world around them, affecting everyday activities and reducing quality of life. Healthcare professionals may offer different treatments; medicine, brain stimulation, or rehabilitation activities including puzzles, strategies or physical therapy. We wanted to find the best treatments for stroke-related perceptual problems. We searched for all research on sight, hearing, smell, taste, touch and somatosensation perceptual treatments to find out (1) how well they worked, (2) what the research means for stroke survivors and healthcare professionals and (3) what research is needed next. People with stroke-related perceptual problems and healthcare experts produced this research together. We found 80 studies, involving 893 stroke survivors, describing 93 treatments. Eighteen of these studies used higher-quality randomised controlled trial designs; 535 stroke survivors took part, testing 32 treatments. Randomised controlled trials are important as one-half of those involved receive treatment and one-half do not; they provide the best evidence about whether a treatment works. Most treatments were for visual or somatosensation problems. Each study was small, provided few details about the participants or their treatment, and tested very different treatments. Few measured the effect of treatment on everyday life: only seven measured stroke survivors’ ability to take part in everyday activities. No trial asked stroke survivors about their experiences with the treatments offered. We do not have enough research to identify which treatments benefit the lives of people with stroke-related perceptual problems. We need more research into perceptual problems, especially the impact it has on stroke survivors’ lives, as well as bigger studies into well-described treatments, that measure the impact of the treatment on people’s lives. Scientific summary Background Perception is the synthesis and interpretation of information gathered through the senses: hearing, taste, touch, smell, visual and information on temperature, pressure, vibration and body position, known as somatosensation. Up to a fifth of stroke survivors experience perceptual disorders after stroke, limiting their ability to perceive and process sensory information and reducing their ability to take part in daily activities. To date, the effectiveness of perceptual disorder interventions after stroke is unclear. Clinical guidelines offer limited recommendations. Stroke survivors, carers and healthcare professionals have stated that improving research into perception is important to them. Further, it is important to systematically identify evidence gaps and future research priorities. Objectives We aimed to: Identify all published and unpublished research evaluating interventions for perceptual disorders after stroke, providing a comprehensive report on the scope and nature of the evidence to date and highlighting the research gaps identified. Synthesise and appraise the quality of randomised controlled trial (RCT) evidence of the effectiveness of perceptual disorder interventions after stroke. Understand the implications of our findings for stroke survivors and HCPs working in this area and to determine future research priorities. Methods Our project included a scoping review, the revision and expansion of a Cochrane systematic review and we worked with a Lived Experience Group and a Clinical Expert Group to co-create research recommendations and identify research priorities. Our scoping review of the literature was based on a systematic search of several electronic databases including MEDLINE, EMBASE and CINAHL (inception to August 2021), as well as searches of grey literature, contacting experts and forward citation tracking. We included studies of any design which explored interventions for stroke survivors with hearing, smell, somatosensation, taste, touch or visual perception disorders. Eligible abstracts and full texts were independently reviewed by two reviewers; data were extracted, tabulated and narratively synthesised. Data availability and outcome measures used were mapped. In keeping with scoping review methodology, we did not formally assess research quality. We updated a Cochrane systematic review, including RCTs of adult stroke survivors with perceptual disorders. We assessed the risk of bias, conducted meta-analyses to explore effectiveness of interventions and judged our confidence in the findings using grading quality of evidence and strength of recommendations (GRADE). Outcomes were measured using activities of daily living (ADLs) with extended activities of daily living (EADLs), quality of life, mental health, perceptual function and adverse events data also collated. Using structured involvement and priority setting approaches we worked in partnership with our Lived Experience and Clinical Expert Groups to agree clinical implications and to future research priorities. Results This project was coproduced with people with lived experience of stroke and perceptual disorders (n = 5) and relevant multidisciplinary clinical expertise (n = 4). Working in partnership with the core research team, these groups informed the project throughout, agreeing definitions of perception, relevant outcome measures, clinical implications and priorities for future research. Scoping review Of 91,869 records screened, we included 80 studies (including 36 case reports; 22 RCTs) in the scoping review, most (64%) of which were published in the previous decade. Participants (n = 893) were predominately adults and male; five children were included. Studies generally had small sample sizes, with RCTs accounting for most participants (70.5%; 630/893). The perceptual disorders represented included visual (43%), somatosensory (35%), auditory (9%), tactile (8%) or ‘mixed’ disorders (5%) which included one study on taste–smell disorders. We identified 93 interventions including rehabilitation (84%), pharmacological (6.5%) and non-invasive brain stimulation (NIBS) interventions (7.5%); no surgical or assessment-based interventions were identified. Intervention details were limited. Outcome measures commonly included perceptual function (75%), motor/sensorimotor (40%), ADLs (23%) or sensation (15%). No data on discharge destination, health economic, feasibility, educational (children), psychological well-being and mental health, quality of life, or activity and participation were reported. Time points were typically immediately after the intervention (39%) or within 3 months follow-up with just 15% of studies capturing outcomes beyond that time point. Cochrane systematic review Drawing on the scoping review results, the trials identified in a previous Cochrane Review and an updated search of bibliographic databases, 2575 records were identified. From these, 114 full texts were considered and 18 RCTs (n = 541) were included. All but six were stroke survivors, between 19 days and 4.3 years from onset. The interventions included targeted visual (seven RCTs; n = 225), tactile (three RCTs; n = 70), somatosensory (seven RCTs; n = 196) and one mixed tactile-somatosensory disorders (one RCT; n = 50). No RCT evaluated interventions for stroke-related hearing, taste or smell disorders. Interventions included 1 NIBS, 1 compensatory, 25 restitution, 4 mixed and 1 unclear intervention approach. Seven included RCTs (39%) measured participants’ ADLs though others captured perception (11 RCTs), adverse events (6 RCTs), mobility (4 RCTs) and EADLs (1 RCT). None measured activity and participation, quality of life or psychological well-being and mental health outcomes. We identified 11 ongoing RCTs. The risk of bias of the included RCTs varied, with 72% describing adequate generate of the randomisation sequence and outcome assessor blinding, but concealment of allocation was considered adequate for only a third. Most trials adequately reported participant attrition (78%) and the outcome data gathered (89%). Other sources of bias were noted including an imbalance between the groups at baseline and altered eligibility criteria mid-RCT. With limited data there was insufficient evidence to determine the effectiveness of any one intervention compared to no intervention or an alternative intervention. Based on the small number of RCTs, the small sample sizes and the limited comparisons available, our confidence in the evidence was, using GRADE, judged to be low–very low. Strengths Throughout this project, a Lived Experience and Clinical Expert Group were centrally involved in the development of definitions, categorisation, outcome measurement selection, interpretation of data and research prioritisation, supporting clinical relevance and validity. The consensus working definitions and categorisations developed may support future research on this topic area. Our scoping and systematic reviews were conducted to the highest research conduct and reporting standards. Limitations Despite large numbers of people experiencing one or more perceptual disorder after stroke, there is a striking lack of relevant research to inform interventions. What little has been reported is often based on a single participant or small sample sizes. There is limited description of the perceptual disorder, the intervention(s) evaluated and a focus on perception outcomes rather than measures that reflect the functional impacts described by the Lived Experience Group, for example ADLs. We also found evidence of under-researched subpopulations including children and people with hearing, taste and smell perceptual disorders. The project team, Lived Experience and Clinical Expert Groups are UK-based, and it is unclear whether our priorities (outlined below) capture the wider international picture. Priority setting Our clinical expert (n = 4) and lived experience (n = 5) stakeholders’ input was pivotal throughout the project. Together with the core research team, these groups agreed the clinical implications and research priorities emerging from the findings. Implications for health care Clinical recommendations include the facilitation of improved awareness of stroke-related perceptual disorders, assessment and information provision and holistic intervention approaches and support. While the research evidence was insufficient to support clinical decision-making relating to the choice of intervention approach, the scoping review provides an important information resource for clinicians developing best practice until sufficient evidence becomes available. Recommendations for research The evidence informing interventions for perceptual disorders after stroke is limited, and absent for smell, taste and tactile disorders. Future research should prioritise (1) exploration of the lived experience of people with stroke-related perceptual disorders, (2) improving assessments of stroke-related perceptual disorders, (3) exploring interventions in a way that reflects real-world needs, (4) exploring current clinical practices that address perceptual disorders following stroke and (5) establishing the prevalence of perceptual disorders after stroke. Conclusions Healthcare professionals lack high-quality evidence of effective interventions to inform their provision of advice, treatment and education of stroke survivors with perceptual disorders and their families. Evidence informing these research priority topic areas is urgently required. Study registration This study is registered as PROSPERO CRD42019160270. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128829) and is published in full in Health Technology Assessment; Vol. 28, No. 69. See the NIHR Funding and Awards Website for further award information.

Abstract Background Involving collaborators and partners in research may increase relevance and uptake, while reducing health and social inequities. Collaborators and partners include people and groups interested in health research: health care providers, patients and caregivers, payers of health research, payers of health services, publishers, policymakers, researchers, product makers, program managers, and the public. Evidence syntheses inform decisions about health care services, treatments, and practice, which ultimately affect health outcomes. Our objectives are to: A. Identify, map, and synthesize qualitative and quantitative findings related to engagement in evidence syntheses B. Explore how engagement in evidence synthesis promotes health equity C. Develop equity-oriented guidance on methods for conducting, evaluating, and reporting engagement in evidence syntheses Methods Our diverse, international team will develop guidance for engagement with collaborators and partners throughout multiple sequential steps using an integrated knowledge translation approach: 1. Reviews. We will co-produce 1 scoping review, 3 systematic reviews and 1 evidence map focusing on (a) methods, (b) barriers and facilitators, (c) conflict of interest considerations, (d) impacts, and (e) equity considerations of engagement in evidence synthesis. 2. Methods study, interviews, and survey. We will contextualise the findings of step 1 by assessing a sample of evidence syntheses reporting on engagement with collaborators and partners and through conducting interviews with collaborators and partners who have been involved in producing evidence syntheses. We will use these findings to develop draft guidance checklists and will assess agreement with each item through an international survey. 3. Consensus. The guidance checklists will be co-produced and finalised at a consensus meeting with collaborators and partners. 4. Dissemination. We will develop a dissemination plan with our collaborators and partners and work collaboratively to improve adoption of our guidance by key organizations. Conclusion Our international team will develop guidance for collaborator and partner engagement in health care evidence syntheses. Incorporating partnership values and expectations may result in better uptake, potentially reducing health inequities.

Background Up to 30% of children have constipation at some stage in their life. Although often short-lived, in one-third of children it progresses to chronic functional constipation, potentially with overflow incontinence. Optimal management strategies remain unclear. Objective To determine the most effective interventions, and combinations and sequences of interventions, for childhood chronic functional constipation, and understand how they can best be implemented. Methods Key stakeholders, comprising two parents of children with chronic functional constipation, two adults who experienced childhood chronic functional constipation and four health professional/continence experts, contributed throughout the research. We conducted pragmatic mixed-method reviews. For all reviews, included studies focused on any interventions/strategies, delivered in any setting, to improve any outcomes in children (0–18 years) with a clinical diagnosis of chronic functional constipation (excluding studies of diagnosis/assessment) included. Dual reviewers applied inclusion criteria and assessed risk of bias. One reviewer extracted data, checked by a second reviewer. Scoping review: We systematically searched electronic databases (including Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature) (January 2011 to March 2020) and grey literature, including studies (any design) reporting any intervention/strategy. Data were coded, tabulated and mapped. Research quality was not evaluated. Systematic reviews of the evidence of effectiveness: For each different intervention, we included existing systematic reviews judged to be low risk of bias (using the Risk of Bias Assessment Tool for Systematic Reviews), updating any meta-analyses with new randomised controlled trials. Where there was no existing low risk of bias systematic reviews, we included randomised controlled trials and other primary studies. The risk of bias was judged using design-specific tools. Evidence was synthesised narratively, and a process of considered judgement was used to judge certainty in the evidence as high, moderate, low, very low or insufficient evidence. Economic synthesis: Included studies (any design, English-language) detailed intervention-related costs. Studies were categorised as cost-consequence, cost-effectiveness, cost-utility or cost-benefit, and reporting quality evaluated using the consensus health economic criteria checklist. Systematic review of implementation factors: Included studies reported data relating to implementation barriers or facilitators. Using a best-fit framework synthesis approach, factors were synthesised around the consolidated framework for implementation research domains. Results Stakeholders prioritised outcomes, developed a model which informed evidence synthesis and identified evidence gaps. Scoping review 651 studies, including 190 randomised controlled trials and 236 primary studies, conservatively reported 48 interventions/intervention combinations. Effectiveness systematic reviews studies explored service delivery models (n = 15); interventions delivered by families/carers (n = 32), wider children’s workforce (n = 21), continence teams (n = 31) and specialist consultant-led teams (n = 42); complementary therapies (n = 15); and psychosocial interventions (n = 4). One intervention (probiotics) had moderate-quality evidence; all others had low to very-low-quality evidence. Thirty-one studies reported evidence relating to cost or resource use; data were insufficient to support generalisable conclusions. One hundred and six studies described implementation barriers and facilitators. Conclusions Management of childhood chronic functional constipation is complex. The available evidence remains limited, with small, poorly conducted and reported studies. Many evidence gaps were identified. Treatment recommendations within current clinical guidelines remain largely unchanged, but there is a need for research to move away from considering effectiveness of single interventions. Clinical care and future studies must consider the individual characteristics of children. Study registration This study is registered as PROSPERO CRD42019159008. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 128470) and is published in full in Health Technology Assessment; Vol. 28, No. 5. See the NIHR Funding and Awards website for further award information. Plain language summary Between 5% and 30% of children experience constipation at some stage. In one-third of these children, this progresses to chronic functional constipation. Chronic functional constipation affects more children with additional needs. We aimed to find and bring together published information about treatments for chronic functional constipation, to help establish best treatments and treatment combinations. We did not cover assessment or diagnosis of chronic functional constipation. This project was guided by a ‘stakeholder group’, including parents of children with constipation, people who experienced constipation as children, and healthcare professionals/continence experts. We carried out a ‘scoping review’ and a series of ‘systematic reviews’. Our ‘scoping review’ provides an overall picture of research about treatments, with 651 studies describing 48 treatments. This helps identify important evidence gaps. ‘Systematic reviews’ are robust methods of bringing together and interpreting research evidence. Our stakeholder group decided to structure our systematic reviews to reflect who delivered the interventions. We brought together evidence about how well treatments worked when delivered by families/carers (32 studies), the wider children’s workforce (e.g. general practitioner, health visitor) (21 studies), continence teams (31 studies) or specialist consultant-led teams (42 studies). We also considered complementary therapies (15 studies) and behavioural strategies (4 studies). Care is affected by what is done and how it is done. We brought together evidence about different models of delivering care (15 studies), barriers and facilitators to implementation of treatments (106 studies) and costs (31 studies). Quality of evidence was mainly low to very low. Despite numerous studies, there was often insufficient information to support generalisable conclusions. Our findings generally agreed with current clinical guidelines. Management of childhood chronic functional constipation should be child-centred, multifaceted and adapted according to the individual child, their needs, the situation in which they live and the health-care setting in which they are looked after. Research is needed to address our identified evidence gaps. Scientific summary Background Chronic functional constipation (CFC) in childhood is common; it is estimated to affect 5–30% of school-aged children, becoming chronic in around one-third of cases. CFC has negative effects on quality of life (QoL) of children, families and carers, with increasing impact as the child gets older. Although rarely life-threatening, CFC is an unpleasant and distressing condition, associated with a wide range of complications, including physical discomfort, missed school, poor school performance, social isolation and reduced involvement in group activities. More than a third of children with CFC will present clinically with behavioural problems as a result of the constipation. The healthcare costs of childhood CFC are significant. Treatments are usually directed at symptom control since limited diagnostics mean no underlying cause is identified in more than 95% of cases, thus limiting ability to stratify treatments. There are a number of different interventions available for the management of CFC; however, the optimal strategy for combining and implementing interventions for individual circumstances remain unclear. National Institute for Health and Care Research (NIHR) commissioned this work to address the question: ‘What are the most effective interventions, and combinations and sequences of interventions, for childhood chronic functional constipation (CFC), and how can they best be implemented?’ Objectives Specific research questions (RQs) answered by this project were: RQ1: What is the current evidence relating to management strategies for childhood CFC? (Scoping review). RQ2: What are the most effective childhood CFC strategies and combinations of strategies in relation to outcomes of importance to stakeholders and/or cost to the patient/NHS? [Systematic review (SR) of evidence of effectiveness and cost effectiveness]. RQ3: What factors are associated with implementation success or failure of childhood CFC strategies and combinations of strategies for different subgroups? (SR of factors affecting implementation). RQ4: What are the evidence gaps in childhood CFC management strategies? Design We conducted a three-stage pragmatic mixed-method study. In stage 1, we completed a broad, comprehensive scoping review. In stage 2, we conducted focused SRs evaluating effectiveness, cost effectiveness and factors affecting implementation. In stage 3, we integrated findings, generating interactive evidence maps, exploring complementarity between our findings and published clinical guidelines, and identifying evidence gaps. Methods Patient and public involvement Stakeholder involvement was central to our project. We formed a stakeholder group (SG) from across the UK, comprising people with lived experience of childhood CFC, parents of children with CFC, healthcare professionals and representatives of relevant charities. We adhered to key principles for research co-production. The SG provided continuous project oversight and completed specific activities. These activities included development of an intervention taxonomy and logic model, agreement on outcomes for the review, identifying evidence gaps and reaching consensus on clinical implications. Scoping review Our scoping review was based on a systematic search of several electronic databases including medical literature analysis and retrieval system online (MEDLINE), excerpta medica database (EMBASE) and Cumulative Index to Nursing and Allied Health Literature (CINAHL; January 2011 to March 2020), as well as searches of grey literature, contacting experts and forward citation tracking. We included papers, regardless of study design, which investigated, reported or discussed any strategy, delivered in any setting, aimed at improving any outcomes in children (aged 0–18 years) with a clinical diagnosis of CFC. We did not include studies of assessment/diagnosis. We included studies involving children with or without additional needs but excluded those with a recognisable cause of constipation such as anorectal malformation, Hirschsprung’s disease, intestinal nerve abnormalities, metabolic or endocrine causes. Eligible abstracts and full texts were independently reviewed by two reviewers. Data were extracted by one reviewer and cross-checked by a second. Two reviewers independently applied descriptive codes to categorise the type of study, aim/focus of the study, outcomes, types of interventions/intervention combinations, and availability of data relating to effectiveness, economics or implementation factors. In keeping with scoping review methodology, we did not formally assess research quality. Data were summarised within an evidence gap map. Systematic reviews of evidence of effectiveness For our SRs of evidence of effectiveness, we considered all studies identified in the scoping review and ‘tagged’ them as studies of effectiveness. We included any studies investigating effectiveness of any intervention, or combination of interventions, aimed at improving outcomes in children with CFC. Informed by our stakeholders, we grouped studies according to whether the intervention was one that would be delivered by families/carers (‘Level 0’), the wider children’s workforce (e.g. general practitioner, health visitor) (‘Level 1’), continence teams (‘Level 2’) or specialist consultant-led teams (‘Level 3’). We also considered different models of service delivery, and complementary and psychosocial therapies. For each different intervention, we adopted a hierarchical, step-wise approach to inclusion of different study designs. If there was a comprehensive SR, judged to be low risk of bias (ROB) [using risk of bias assessment tool for systematic reviews (ROBIS) criteria, assessed by two independent reviewers], this was also included. Where we included a SR, we also included any randomised controlled trials (RCTs) published after the date of the search in the review. Where there was no SR, we included RCTs and other primary studies of intervention effectiveness. Data were extracted on study methods, participant characteristics, intervention characteristics [using template for intervention description and replication (TIDieR) framework], outcomes and key findings. ROB was judged using tools appropriate to the study design [e.g. Cochrane ROB tool for RCTs, critical appraisals skills programme (CASP) tools for cohort studies, Joanna Briggs Institute (JBI) tools for qualitative evidence, Ways of Evaluating Important and Relevant Data (WEIRD) tool for other study designs]. Relevant meta-analyses within included SRs were updated with any new RCTs following the methods reported in the SR. A narrative synthesis of evidence of effectiveness for each intervention, delivered within ‘level’ 0 to 3 was presented, with a process of considered judgement used to judge certainty in the evidence as high, moderate, low, very low or insufficient evidence. Economic evaluation For our SR of economic studies, we considered any economic evidence identified in our scoping review and conducted additional searching of electronic databases and citation tracking following best practice guidance. We included all types of study detailing costs related to interventions aimed at children with CFC that were published in English, regardless of study design. One reviewer extracted data, including details of economic evaluations, and these were checked by a second reviewer. Studies were categorised as cost-consequence, cost-effectiveness, cost-utility or cost-benefit and their quality evaluated using the consensus health economic criteria (CHEC) checklist, and data were brought together into a narrative synthesis. Systematic review of factors affecting implementation For our SR of factors affecting implementation, we included studies which were identified in the scoping review as explicitly reporting data relating to key participant variables, barriers, facilitators, equity factors and adherence. One reviewer systematically identified, extracted and coded [using the consolidated framework for implementation research (CFIR)] barriers and facilitators, and a second reviewer checked this. We used a best fit framework synthesis approach combining deductive and inductive thematic approaches to identify barriers and facilitators. Data were brought together in a narrative synthesis organised around the CFIR domains. Integration of findings Our integration of findings from the SRs was informed by decisions taken by our stakeholders, including development of a logic model. We explored agreements between our findings and recommendations within previously published guidelines. We brought our findings together within interactive evidence maps, and systematically identified evidence gaps. Results The scoping review included 651 studies, including 190 RCTs and 236 primary studies. Forty-eight interventions (or combinations of interventions) were reported. Studies were mainly conducted in high-income countries; no studies from low-income countries were identified. The most frequently reported interventions were delivered by carers, prior to healthcare professional involvement (22%); these were primarily lifestyle interventions focused on diet. The least frequently reported were psychosocial interventions (3%). Children were recruited from a variety of settings including hospitals, clinical outpatients, and other community settings. Interventions were generally delivered face to face either at home or within a variety of hospital settings such as the emergency department. Interventions were rarely delivered in education settings (e.g. school-based settings) (n = 5) or residential care/looked after population (n = 1) settings. The most frequently reported outcome measurement was defaecation frequency, which was reported in one-third of studies within the scoping review. School attendance or absenteeism was the least frequently reported outcome (n = 8 studies). Our SRs of effectiveness included 32 studies (including 2 SRs) which explored effectiveness of interventions delivered by families/carers (‘Level 0’); 21 studies (including 2 SRs) which explored effectiveness of interventions delivered by wider children’s workforce (‘Level 1’); 31 studies (including 1 SR) which explored effectiveness of interventions delivered by continence teams (‘Level 2’); 42 studies (no SRs) which explored effectiveness of interventions delivered by specialist consultant-led teams (‘Level 3’); 15 studies (no SRs) which explored effectiveness of different models of service delivery; 15 studies (2 SRs) which explored effectiveness of complementary therapies; and 4 studies (1 SR) which explored effectiveness of psychosocial interventions. Interventions for which there was some evidence of potential benefit included, within Level 0: a trial of cows’ milk-free diet, educational interventions for parents, selenium supplements. Within Level 1: laxatives, physical exercise focused on pelvic floor muscle, combined pharmacological, diet and behaviour programme. Within Level 2: combined oral and enema therapy, transanal irrigation, biofeedback (for children with abnormal defaecation dynamics), combined treatment programmes. Within Level 3: botulinum toxin, antegrade continence enema (ACE)/Malone antegrade continence enema (MACE), sacral modulation. Models of care delivery which may be beneficial included nurse-led clinics, an algorithm, or care pathway, used in primary care settings, specialist (Level 2) services and web-based information, following an appointment with a specialist. Complementary therapies for which there was some evidence of effectiveness included: connective tissue manipulation (CTM) for children with cerebral palsy (CP), and some herbal/traditional medicines. There was some evidence in favour of behavioural therapy. Interventions which evidence suggests may not be beneficial include, probiotics, additional dietary fibre, increased fluid intake and biofeedback (for children with normal defaecation dynamics). Evidence relating to probiotics was judged to be moderate quality, but for all other interventions was considered low to very low quality. There was insufficient evidence to support conclusions relating to several other interventions. We identified 31 studies which reported some evidence relating to cost or resource use, of which 20 were cost-of-illness studies. Fewer than 30% of the studies employed a formal economic evaluation study design. Most studies were poorly reported with limited details. Data included in this review were insufficient to support any generalisable conclusions relating to cost or resource use. One hundred and six studies described multiple barriers and facilitators across the five domains of the CFIR framework. The most commonly reported factors related to ‘successfulness’ of an intervention included; whether the intervention was adaptable, flexible and offered an advantage over an alternative solution; understanding the tension for change (i.e. why clinicians and families felt that the changes were needed now); the taboo nature of constipation and the reluctance of children, families, healthcare professionals and wider society to openly engage in discussion about constipation; a lack of understanding of what children and their families need; self-efficacy, coupled with individual knowledge and beliefs; and engagement of champions to support children. Research gaps were identified through evidence maps and stakeholder discussions. Key topics considered priorities for future research relate to recognition of CFC; information provision; diet; laxatives and combinations of laxatives; behavioural therapy and psychological support. Future research studies should address what works for which individual child, and when, including children with and without additional needs. Research to explore the optimal delivery of services, including identification of key components and features of effective teams and criteria for referring children from one ‘level’ to the next, is needed. Conclusions We conducted a comprehensive review of all evidence relating to interventions, and combinations of interventions, for children with CFC. The finding from our review are generally in agreement with the current guideline recommendations, where recommendations exist. A significant proportion of interventions for which we found evidence had not been addressed within current guidelines. This project has highlighted that research in this field often does not adhere to recognised standards for conduct and reporting or consider the complexities of interventions for CFC. We found no evidence which gave us high certainty in the findings; and we only had moderate certainty relating to one intervention (probiotics, with evidence demonstrating that probiotics may not have any beneficial – or harmful – effect). Our certainty about all other findings was low to very low or, in many cases, we judged that the evidence was insufficient to support any generalised conclusions. The current evidence base rarely measured outcomes deemed of highest priority to children and families, and many studies failed to describe the complex nature of the treatments that a child may be receiving. This limits the conclusions that can be made from the current evidence. Further, the limitations within the evidence base reduce confidence in recommendations and create a barrier to implementation of best practice, impairing progress in efforts to improve outcomes for this group of children. Our findings do not indicate that changes are necessarily needed to the treatment recommendations within current clinical guidelines. However, management of childhood CFC is complex, and there is no simple ‘one size fits all’ approach. Clinical care and future studies must consider the individual characteristics of each child with constipation, and the context – or environment – within which they live. Key goals of successful management of CFC should be early recognition of symptoms and delivery of interventions by families/carers, achieved by providing children and families/carers with effective education and support from members of the wider children’s workforce (primary care services). Development, evaluation and implementation of strategies to enhance the delivery of services focused on individualised care, combining lifestyle and behavioural strategies with laxatives are a priority. To avoid further research waste, it is essential that future research addresses the questions which are of the highest priority to key stakeholders and has the highest possible standards of conduct and reporting. Future research studies should address what works for which individual child, and when, including children with and without additional needs. Future research into any interventions for childhood CFC should take into account relevant evidence relating to the development and evaluation of complex interventions. Study registration This study is registered as PROSPERO CRD42019159008. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 128470) and is published in full in Health Technology Assessment; Vol. 28, No. 5. See the NIHR Funding and Awards website for further award information.

Abstract Established in 2015, the Multi-Stakeholder Engagement (MuSE) Consortium is an international network of over 120 individuals interested in stakeholder engagement in research and guidelines. The MuSE group is developing guidance for stakeholder engagement in the development of health and healthcare guideline development. The development of this guidance has included multiple meetings with stakeholders, including patients, payers/purchasers of health services, peer review editors, policymakers, program managers, providers, principal investigators, product makers, the public, and purchasers of health services and has identified a number of key issues. These include: (1) Definitions, roles, and settings (2) Stakeholder identification and selection (3) Levels of engagement, (4) Evaluation of engagement, (5) Documentation and transparency, and (6) Conflict of interest management. In this paper, we discuss these issues and our plan to develop guidance to facilitate stakeholder engagement in all stages of the development of health and healthcare guideline development.

Abstract This is the protocol for a Campbell systematic review. The objectives are as follows: to identify, describe, and summarize existing guidance and methods for multistakeholder engagement throughout the health guideline development process.