Effective interventions to increase representation of under-served groups in randomised trials in UK and Ireland: a scoping literature review.

Background: Participants in clinical trials often do not reflect the populations that could benefit from the treatments being investigated. There are known barriers to trial participation for under-served groups, but limited evidence on strategies to alleviate these barriers to improve representation. This scoping review aimed to identify effective interventions and design features that improve the representation `of under-served groups in trials, focusing on the UK and Ireland. Methods: We included methodological research studies that reported interventions to improve representation of ethnic minority groups, socioeconomically disadvantaged groups, older people, or those with impaired capacity to consent to randomised controlled trials, conducted in the UK and Ireland, published between 2000-2021. Systematic searches were conducted in November 2021 and data were independently extracted by two authors and narratively synthesised. Results: Seven studies were included: one randomised controlled study embedded in five trials, one mixed-methods study, and five studies reporting 'lessons learnt' from one trial. We categorised the 47 reported interventions or strategies into nine broad themes: Recruitment sites, recruitment settings, community engagement, and communication with participants, incentives, inclusion criteria, flexibility, patient documentation, and the consent process. Only 28/47 interventions were evaluated, 23 of which were comparison of recruitment pathways.The randomised study found that a £100 incentive mentioned in the invitation letter increased positive responses overall across drug trials in cardiovascular disease and hypertension, but not for older people or those living in the most deprived areas. Invitation letters via GPs and working with communities were reported as successful recruitment pathways in recruiting different under-served populations. Conclusions: Interventions aiming to improve the recruitment of under-served groups in the UK and Ireland were reported across seven papers, but their effectiveness was rarely rigorously evaluated. Included studies were context specific. Using a variety of recruitment methods is likely to help achieve a more diverse cohort.

Not all people are included in medical research, even though they should be. This is especially true for people from certain groups, called 'under-served groups', and there has been a recent focus on improving inclusion of these groups in clinical trials. Researchers have developed tools to help plan studies that include under-served groups. These tools help researchers to consider who should be included in a study, identify barriers to including certain groups, and develop strategies to overcome those barriers. A team of researchers reviewed existing research to see what strategies have been successful in increasing the participation of under-served groups in clinical trials in the UK and Ireland. They looked at ethnic minority groups, people experiencing disadvantages in income, education, housing and/or employment (socioeconomic disadvantage), older people, and people with limited decision-making abilities (impaired capacity to consent). They found seven studies that provided helpful insights. Two of these studies were designed specifically to test different methods for recruiting under-served groups. The other five studies were based on lessons learned from trials that included these groups. One study found that offering a £100 incentive in recruitment letters led to an increase in responses, but not specifically for older people or people experiencing socioeconomic disadvantage. Another study found that letters from general practitioners were most effective for recruiting older adults. One study found that community engagement was successful for recruiting an ethnic minority group. Overall, the review concluded that there is little evidence for strategies that will increase the inclusion of under-served groups in clinical trials in the UK and Ireland. However, there are several promising approaches that could overcome barriers and make research more inclusive.

Using online methods to recruit participants into mental health clinical trials: considerations and recommendations from the RE-MIND study.

BACKGROUND: Ensuring diversity in clinical trials can be a challenge, which may be exacerbated when recruiting vulnerable populations, such as participants with mental health illness. As recruitment continues to be the major cause of trial delays, researchers are turning to online recruitment strategies, e.g. social media, to reach a wider population and reduce recruitment time and costs. There is mixed evidence for the use of online recruitment strategies; therefore, the REcruitment in Mental health trials: broadening the 'net', opportunities for INclusivity through online methoDs (RE-MIND) study aimed to identify evidence and provide guidance for use of online strategies in recruitment to mental health trials, with a focus on whether online strategies can enhance inclusivity. This commentary, as part of the RE-MIND study, focusses on providing recommendations for recruitment strategy selection in future research with the aim to improve trial efficiency. A mixed-methods approach was employed involving three work packages: (I) an evidence review of a cohort of 97 recently published randomised controlled trials/feasibility or pilot studies in mental health to assess the impact of online versus offline recruitment; (II) a qualitative study investigating the experiences of n = 23 key stakeholders on use of an online recruitment approach in mental health clinical trials; (III) combining the results of WP1 and WP2 to produce recommendations on the use of an online recruitment strategy in mental health clinical trials. The findings from WP1 and 2 have been published elsewhere; this commentary represents the results of the third work package. CONCLUSION: For external validity, clinical trial participants should reflect the populations that will ultimately receive the interventions being tested, if proven effective. To guide researchers on their options for inclusive recruitment strategies, we have developed a list of considerations and practical recommendations on how to maximise the use of online recruitment methods.

Comments, Suggestions and Criticisms of the PRECIS-2 Design Tool: A Citation Analysis.

INTRODUCTION: The Pragmatic Explanatory Continuum Indicator Summary (PRECIS) tool, initially published in 2009 and revised in 2015, was created to assist trialists to align their design choices with the intended purpose of their randomised controlled trial (RCT): either to guide real-world decisions between alternative interventions (pragmatic) or to test hypotheses about intervention mechanisms by minimising sources of variation (explanatory). There have been many comments, suggestions and criticisms of PRECIS-2. This summary will be used to facilitate the development of to the next revision, PRECIS-3. METHODS: We used Web of Science to identify all publication types citing PRECIS-2, published between May 2015 and July 2023. Citations were eligible if they contained 'substantive' suggestions, comments or criticism of the PRECIS-2 tool. We defined 'substantive' as comments explicitly referencing at least one PRECIS-2 domain, or a concept directly linked to an existing or newly proposed domain Two reviewers independently extracted comments, suggestions and criticisms, noting their implications for the update. These were discussed amongst authors to achieve consensus on the interpretation of each comment and its implications for PRECIS-3. RESULTS: The search yielded 885 publications, and after full-text review, 89 articles met the inclusion criteria. Comments pertained to new domains, changes in existing domains, or were relevant across several or all domains. Proposed new domains included assessment of the comparator arm and a domain to describe blinding. There were concerns about scoring eligibility and recruitment domains for cluster trials. Suggested areas for improvement across domains included the need for more scoring guidance for explanatory design choices. DISCUSSION: Published comments recognise PRECIS-2's success in aiding trialists with pragmatic or explanatory design choices. Enhancing its implementation and widespread use will involve adding new domains, refining domain definitions, and addressing overall tool issues. This citation review offers valuable user feedback, pivotal for shaping the upcoming version of the PRECIS tool, PRECIS-3.

Health and social care experience and research perception of different ethnic minority populations in the East Midlands, United Kingdom (REPRESENT study).

INTRODUCTION: Ethnic minority populations experience significant health and social care disparities; despite experiencing a greater burden of diseases, these groups are underrepresented in health and social care research. Consequently, related research can be less applicable to these population groups. The REPRESENT study aims to explore the health and social care experiences of ethnic minorities and other minoritised populations, their research interests and appropriate research practices. METHODS: Focus groups and semistructured interviews were conducted between May and September 2022 with members of a number of ethnic minority communities in England. Data were audio recorded, transcribed and thematically coded using NVivo 12. Rigour was determined through extensive sampling, iterative data collection and analysis. FINDINGS: Fifty-two ethnic minority members were engaged in group interviews and one-to-one interviews. Participants included representatives of the following groups: African Caribbean, Eastern European, Gypsy Travellers, Lesbian, Gay, Bisexual, Transgender, Queer, Intersex and Asexual+, Refugee/Asylum Seekers, Somali and South Asian communities. Interviews were also conducted with ethnic minority healthcare providers and researchers. Three overarching categories were identified: health information, medical service experiences, health and social care concerns and health research. Health and social care services challenges were mostly attributed to discrimination, delayed services, poor cultural relevance and language and cultural barriers. The most influential information sources were local community organisations and word-of-mouth. The main health and social care concerns were chronic long-term health conditions, mental health, maternal health and child development. Recommendations for research involved understanding the motivations for participation, improving communication and empowering communities. Top research priorities were long-term health conditions, health promotion and education, early care interventions and understanding community needs. INTERPRETATION: Discrimination and bias in health and social care provision have severe implications for worsening ethnic health inequalities. Healthcare commissioning authorities and policymakers can leverage the preference of ethnic minority groups for pharmacy services and community organisations to improve access to care. Improving research interest and engagement requires understanding individual community needs, community sensitivity, research relevance and cultural appropriateness. PATIENT OR PUBLIC CONTRIBUTION: Members of ethnic minority Patient and Public Involvement and Engagement group and Community Advisory Board supported the REPRESENT study design, conceptualisation and report development.

Bridging Formal Shape Models and Deep Learning: A Novel Fusion for Understanding 3D Objects.

This article describes a novel fusion of a generative formal model for three-dimensional (3D) shapes with deep learning (DL) methods to understand the geometric structure of 3D objects and the relationships between their components, given a collection of unorganized point cloud measurements. Formal 3D shape models are implemented as shape grammar programs written in Procedural Shape Modeling Language (PSML). Users write PSML programs to describe complex objects, and DL networks estimate the configured free parameters of the program to generate 3D shapes. Users write PSML programs to enforce fundamental rules that define an object class and encode object attributes, including shapes, components, size, position, etc., into a parametric representation of objects. This fusion of the generative model with DL offers artificial intelligence (AI) models an opportunity to better understand the geometric organization of objects in terms of their components and their relationships to other objects. This approach allows human-in-the-loop control over DL estimates by specifying lists of candidate objects, the shape variations that each object can exhibit, and the level of detail or, equivalently, dimension of the latent representation of the shape. The results demonstrate the advantages of the proposed method over competing approaches.

Reporting and representation of underserved groups in intervention studies for patients with multiple long-term conditions: a systematic review.

OBJECTIVES: Globally, there is a growing number of people who are living with multiple long-term conditions (MLTCs). Due to complex management needs, it is imperative that research consists of participants who may benefit most from interventions. It is well documented that ethnic minority groups and lower socioeconomic status (SES) groups are at an increased risk of developing MLTCs. Therefore, the aim of this systematic review was to determine the level of reporting and representation of underserved groups (ethnic minority and low SES) in intervention studies addressing MLTCs. DESIGN: Systematic review. Four databases including Cochrane Library, MEDLINE, CINAHL and Scopus were searched for intervention studies from North America or Europe published between January 1990 and July 2023. SETTING: Hospital and community-based interventions. We included interventional studies focusing on improving MLTC-related outcomes. PARTICIPANTS: Patients with MLTCs. MAIN OUTCOME MEASURES: Total number of studies reporting on ethnicity and SES. Number and proportion of studies reporting by ethnic/SES group. RESULTS: Thirteen studies met the inclusion criteria. Only 4 of 13 studies (31%) recorded and reported ethnicity information. Of these four studies that reported on ethnicity, three studies consisted of primarily White participants. Ethnic minority groups were underrepresented, but one study included a majority of African American participants. Moreover, 12 of 13 studies (92%) reported on SES with income and educational level being the primary measures used. SES representation of higher deprivation groups was varied due to limited data. CONCLUSIONS: For ethnicity, there was a lack of reporting, and ethnic minority groups were underrepresented in intervention studies. For SES, there was a high level of reporting but the proportion of study samples from across the spectrum of SES varied due to the variety of SES measures used. Findings highlight a need to improve the reporting and representation of ethnic minority groups and provide more detailed information for SES through using consistent measures (e.g. education, income and employment) to accurately determine the distribution of SES groups in intervention studies of people with MLTCs.

Clinicopathological and pedigree investigation of a novel spinocerebellar neurological disease in juvenile Quarter Horses in North America.

BACKGROUND: In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). HYPOTHESIS/OBJECTIVES: To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. ANIMALS: Twelve neurologically affected QH foals and the dams. METHODS: Genomic DNA was isolated and pedigrees were manually constructed. RESULTS: All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma-glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0-18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL IMPORTANCE: EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs <1 month of age in North America that is etiologically distinct from other clinically similar neurological disorders. Once the causative variant for EJSCA is validated, carriers can be identified through genetic testing to inform breeding decisions.

UAV-Borne Mapping Algorithms for Low-Altitude and High-Speed Drone Applications.

This article presents an analysis of current state-of-the-art sensors and how these sensors work with several mapping algorithms for UAV (Unmanned Aerial Vehicle) applications, focusing on low-altitude and high-speed scenarios. A new experimental construct is created using highly realistic environments made possible by integrating the AirSim simulator with Google 3D maps models using the Cesium Tiles plugin. Experiments are conducted in this high-realism simulated environment to evaluate the performance of three distinct mapping algorithms: (1) Direct Sparse Odometry (DSO), (2) Stereo DSO (SDSO), and (3) DSO Lite (DSOL). Experimental results evaluate algorithms based on their measured geometric accuracy and computational speed. The results provide valuable insights into the strengths and limitations of each algorithm. Findings quantify compromises in UAV algorithm selection, allowing researchers to find the mapping solution best suited to their application, which often requires a compromise between computational performance and the density and accuracy of geometric map estimates. Results indicate that for UAVs with restrictive computing resources, DSOL is the best option. For systems with payload capacity and modest compute resources, SDSO is the best option. If only one camera is available, DSO is the option to choose for applications that require dense mapping results.

Cardiovascular disease prevention: Community Based Asset Mapping within religious networks in a rural Sub-Saharan African neighbourhood.

Prevalence of conditions which raise cardiovascular risk, such as hypertension and type 2 diabetes are seeing a dramatic rise in Sub Saharan Africa. A large proportion of these cases remain undiagnosed and there is limited resource to provide patients with self-management support and education once diagnosed. This study aimed to identify and catalogue community-based assets for the purposes of developing and deploying a screening and education programme for cardiometabolic risk factors (diabetes and hypertension) within religious organisations in a local community in a rural Ghanaian context. We utilised a community-based form of participatory research made up of a number of different components including community-based asset mapping and stakeholder consultation, supplemented by 18 in-depth interviews and 10 focus groups with n = 115 service users, to map existing assets with relevance to cardiometabolic health in this setting and context. Thematic analysis of interview and focus group data was performed to identify themes related to successful implementation of health screening. Two stakeholder workshops with local healthcare professionals, faith leaders and health policy makers were delivered to co-produced a prioritised list of recommendations and 'asset map' to aid deployment of mass screening within faith organisations in this context. The findings of this research highlight a number of 'hidden' community assets and motivational mechanisms at an individual, community and institutional levels; these have informed a list of recommendations which have been co-developed with the stakeholder group and local community to support the development of effective screening strategies for cardiometabolic conditions within faith organisations in this context. We have identified key mechanisms and assets which would support a sustainable screening approach designed to engage an underserved community at high CVD risk to promote general community health and well-being.

Widening participation - recruitment methods in mental health randomised controlled trials: a qualitative study.

BACKGROUND: Barriers to mental health research participation are well documented including distrust of services and research; and stigma surrounding mental health. They can contribute to a lack of diversity amongst participants in mental health research, which threatens the generalisability of knowledge. Given the recent widespread use of the internet in medical research, this study aimed to explore the perspectives of key partners on the use of online (e.g. social media) and offline (e.g. in-person) recruitment as an approach to improving diversity in mental health randomised controlled trials (RCTs). METHODS: Face-to-face and online interviews/focus groups with researchers working in mental health and Patient and Public Involvement partners in the United Kingdom. Recordings were transcribed and analysed using a combination of inductive and deductive thematic analysis. RESULTS: Three focus groups and three interviews were conducted with a total N = 23 participants. Four overarching themes were identified: (1) recruitment reach; (2) Demographic factors that affect selection of recruitment method; (3) safety of technology, and; (4) practical challenges. Five main factors were identified that affect the choice of recruitment method: age, complexity of mental health problem and stigma, cultural and ethnicity differences and digital divide. The use of online methods was considered more accessible to people who may feel stigmatised by their mental health condition and with a benefit of reaching a wider population. However, a common view amongst participants was that online methods require closer data monitoring for quality of responders, are not fully secure and less trustworthy compared to offline methods that enable participants to build relationships with health providers. Funding, staff time and experience, organisational support, and technical issues such as spam or phishing emails were highlighted as practical challenges facing online recruitment. All participants agreed that using a hybrid approach tailored to the population under study is paramount. CONCLUSIONS: This study highlighted the importance of offering a flexible and multifaceted recruitment approach by integrating online with offline methods to support inclusivity and widening participation in mental health research. The findings will be used to develop considerations for researchers designing RCTs to improve recruitment in mental health research.

The Effects of Protrusion into the Outflow Vein on Outcomes of Stent Grafts Used to Treat Cephalic Arch Stenoses in Dysfunctional Brachiocephalic Fistulae.

PURPOSE: To assess long-term patency rates of cephalic arch stent grafts in brachiocephalic fistulae and the importance of device position. MATERIALS AND METHODS: This retrospective study reviewed 152 patients with dysfunctional brachiocephalic fistulae and cephalic arch stenosis treated with stent grafts (Viabahn; W. L. Gore) at a single tertiary center between 2012 and 2021. The median age was 67.5 years (range, 25-91 years), and the median follow-up period was 637 days (range, 3-3,368 days). A grading system of protrusion was applied: (a) Grade 0, no protrusion; (b) Grade 1, perpendicular; and (c) Grade 2, in-line protrusion. Subsequent fistulograms were available in 133 (88%) of the 152 patients and were assessed for central vein stenosis within 10 mm of the stent graft. Clinical records were assessed for sequelae of stent graft protrusion. Stent graft primary and cumulative circuit patencies were calculated using the Kaplan-Meier method. RESULTS: Protrusion was documented in 106 (70%) stent grafts-56 Grade 1 and 50 Grade 2. Central vein stenosis was seen in 1 (2%) case of no protrusion (Grade 0) and 38 (40%) cases of protrusion (P < .0001). There was no significant difference in stenosis between Grade 1 and 2 protrusion (P = .15). No adverse clinical sequelae occurred in 147 (97%) patients. Eight patients had a new access subsequently formed in the same arm, and 3 of these 8 patients developed symptoms due to the previous stent graft protrusion (all Grade 2). The primary patency rates of the stent-grafts at 6 and 12 months were 73% and 50%, respectively. The cumulative access circuit patency rates at 1, 2, and 5 years were 84%, 72%, and 54%, respectively. CONCLUSIONS: This study demonstrated that protrusion of a cephalic arch stent graft into the central vein is safe and only clinically relevant when a subsequent ipsilateral access is created.

Trial Forge Guidance 3: randomised trials and how to recruit and retain individuals from ethnic minority groups-practical guidance to support better practice.

Randomised trials, especially those intended to directly inform clinical practice and policy, should be designed to reflect all those who could benefit from the intervention under test should it prove effective. This does not always happen. The UK National Institute for Health and Care Research (NIHR) INCLUDE project identified many groups in the UK that are under-served by trials, including ethnic minorities.This guidance document presents four key recommendations for designing and running trials that include the ethnic groups needed by the trial. These are (1) ensure eligibility criteria and recruitment pathway do not limit participation in ways you do not intend, (2) ensure your trial materials are developed with inclusion in mind, (3) ensure staff are culturally competent and (4) build trusting partnerships with community organisations that work with ethnic minority groups. Each recommendation comes with best practice advice, public contributor testimonials, examples of the inclusion problem tackled by the recommendation, or strategies to mitigate the problem, as well as a collection of resources to support implementation of the recommendations.We encourage trial teams to follow the recommendations and, where possible, evaluate the strategies they use to implement them. Finally, while our primary audience is those designing, running and reporting trials, we hope funders, grant reviewers and approvals agencies may also find our guidance useful.

Randomised controlled trial of an innovative hypoglycaemia pathway for self-care at home and admission avoidance: a partnership approach with a regional ambulance trust.

Background: Hypoglycaemia is a common and potentially life-threatening condition in people with diabetes, commonly caused by medications such as insulin. Hypoglycaemic events often require in-patient treatment and/or follow-up with a diabetes specialist nurse (DSN) or GP to make adjustments to medication. This referral pathway commonly relies on patient self-referral to primary care, and as a result many patients are not actively followed up and go on to experience repeat hypoglycaemic events. Methods: Randomised controlled trial in partnership with East Midlands Ambulance Service NHS Trust. People with diabetes calling out an ambulance for a severe hypoglycaemic episode and meeting the eligibility criteria were randomised to either a novel DSN-led pathway or to their general practice for routine follow-up. Primary outcome was proportion of participants with a documented consultation with a healthcare professional to discuss the management of their diabetes within 28 days of call-out. Results: 162 people were randomised to one of the pathways (73 DSN arm, 89 GP arm) with 81 (50%, 35 DSN, 46 GP) providing full consent to be followed up. Due to lower than anticipated randomisation and consent rates, the recruitment target was not met. In the 81 participants who provided full consent, there were higher rates of consultation following the call-out when referred to a DSN compared to primary care (90% vs. 65%). Of the 81 participants, 26 (32%) had a second call-out within 12 months. Conclusions: Consultation rates following the call-out were high in the DSN-led arm, but there was insufficient power to complete the planned comparative analysis. The study highlighted the difficulty in recruitment and delivery of research in pre-hospital emergency care. Further work is needed to provide more feasible study designs and consent procedures balancing demands on ambulance staff time with the need for robust well-designed evaluation of referral pathways.

Individual, healthcare professional and system-level barriers and facilitators to initiation and adherence to injectable therapies for type 2 diabetes: A systematic review and meta-ethnography.

AIMS: To review and synthesise the contemporary qualitative evidence, relating to the individual, healthcare professional and system-level barriers and facilitators to injectable therapies in people with type 2 diabetes, and evaluate (using an intersectional approach to explore the diverse perspectives of different identities) whether views have changed with treatment and guideline advancements. METHODS: A meta-ethnography approach used. Eight databases searched from the years 2006 (GLP-1 analogues introduced) to February 2021. Study selection (using a pre-defined inclusion criteria), quality appraisal and data extraction, conducted independently by two reviewers. RESULTS: Screened 7143 abstracts, assessed 93 full-text papers for eligibility and included 42 studies-using data from 818 individuals with type 2 diabetes and 160 healthcare professionals. Studies covered a diverse range of views from healthcare professionals and individuals, including those relating to older adults and people from ethnic migrant backgrounds, and 10 studies rated moderate to strong research value. Key themes abstracted: barriers (physical/psychological/social) and facilitators (motivation/capability/opportunity). CONCLUSIONS: The first synthesis of contemporary qualitative data to adopt an intersectionality approach and explore diverse views relating to barriers and facilitators that influence engagement with injectable treatments for type 2 diabetes. A model is presented to help patients, health practitioners and policy makers identify barriers and facilitators and understand the complex interplay of physical, psychological and social factors involved when prescribing injectable therapies. Despite advances in injectable treatments and guidelines, findings highlight the many barriers that still exist and show how strongly held culturally-specific health beliefs of people from diverse socio-economic and ethnic backgrounds can become substantial obstacles to treatment.

Use of a VBX balloon expandable stent-graft for management of right brachiocephalic vein stenosis.

Here we describe the use of a VBX balloon expandable stent-graft (WL Gore, Flagstaff, AZ, USA) to treat a right brachiocephalic vein stenosis in a haemodialysis patient prior to ipsilateral upper limb arterio-venous (AV) fistula formation. Balloon expandable stent-grafts are unsuitable for treating peripheral fistula stenoses due to their susceptibility of being crushed. The right brachiocephalic vein is both relatively short in comparison to the left and is less susceptible to extrinsic compression and the use of such a device to treat stenosis here allows for very accurate placement and restoration of luminal diameter. The advantages and disadvantages of using these devices in haemodialysis access circuits are also discussed herein, in what we believe to be the first report of the application of a dedicated commercially available balloon expandable stent graft in a haemodialysis patient.

Promoting inclusion in clinical trials-a rapid review of the literature and recommendations for action.

BACKGROUND: Without inclusion of diverse research participants, it is challenging to understand how study findings will translate into the real world. Despite this, a lack of inclusion of those from under-served groups in research is a prevailing problem due to multi-faceted barriers acting at multiple levels. Therefore, we rapidly reviewed international published literature, in relation to clinical trials, on barriers relating to inclusion, and evidence of approaches that are effective in overcoming these. METHODS: A rapid literature review was conducted searching PubMed for peer-reviewed articles that discussed barriers to inclusion or strategies to improve inclusion in clinical trial research published between 2010 and 2021. Grey literature articles were excluded. RESULTS: Seventy-two eligible articles were included. The main barriers identified were language and communication, lack of trust, access to trials, eligibility criteria, attitudes and beliefs, lack of knowledge around clinical trials, and logistical and practical issues. In relation to evidence-based strategies and enablers, two key themes arose: [1] a multi-faceted approach is essential [2]; no single strategy was universally effective either within or between trials. The key evidence-based strategies identified were cultural competency training, community partnerships, personalised approach, multilingual materials and staff, communication-specific strategies, increasing understanding and trust, and tackling logistical barriers. CONCLUSIONS: Many of the barriers relating to inclusion are the same as those that impact trial design and healthcare delivery generally. However, the presentation of these barriers among different under-served groups may be unique to each population's particular circumstances, background, and needs. Based on the literature, we make 15 recommendations that, if implemented, may help improve inclusion within clinical trials and clinical research more generally. The three main recommendations include improving cultural competency and sensitivity of all clinical trial staff through training and ongoing personal development, the need to establish a diverse community advisory panel for ongoing input into the research process, and increasing recruitment of staff from under-served groups. Implementation of these recommendations may help improve representation of under-served groups in clinical trials which would improve the external validity of associated findings.

Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy.

Diabetes is a major contributor to the increasing burden of heart failure prevalence globally, at least in part due to a disease process termed diabetic cardiomyopathy. Diabetic cardiomyopathy is characterised by cardiac structural changes that are caused by chronic exposure to the diabetic milieu. These structural changes are a major cause of left ventricular (LV) wall stiffness and the development of LV dysfunction. In the current study, we investigated the therapeutic potential of a cardiac-targeted bone morphogenetic protein 7 (BMP7) gene therapy, administered once diastolic dysfunction was present, mimicking the timeframe in which clinical management of the cardiomyopathy would likely be desired. Following 18 weeks of untreated diabetes, mice were administered with a single tail-vein injection of recombinant adeno-associated viral vector (AAV), containing the BMP7 gene, or null vector. Our data demonstrated, after 8 weeks of treatment, that rAAV6-BMP7 treatment exerted beneficial effects on LV functional and structural changes. Importantly, diabetes-induced LV dysfunction was significantly attenuated by a single administration of rAAV6-BMP7. This was associated with a reduction in cardiac fibrosis, cardiomyocyte hypertrophy and cardiomyocyte apoptosis. In conclusion, BMP7 gene therapy limited pathological remodelling in the diabetic heart, conferring an improvement in cardiac function. These findings provide insight for the potential development of treatment strategies urgently needed to delay or reverse LV pathological remodelling in the diabetic heart.

Characterisation of the Myocardial Mitochondria Structural and Functional Phenotype in a Murine Model of Diabetic Cardiomyopathy.

People affected by diabetes are at an increased risk of developing heart failure than their non-diabetic counterparts, attributed in part to a distinct cardiac pathology termed diabetic cardiomyopathy. Mitochondrial dysfunction and excess reactive oxygen species (ROS) have been implicated in a range of diabetic complications and are a common feature of the diabetic heart. In this study, we sought to characterise impairments in mitochondrial structure and function in a recently described experimental mouse model of diabetic cardiomyopathy. Diabetes was induced in 6-week-old male FVB/N mice by the combination of three consecutive-daily injections of low-dose streptozotocin (STZ, each 55 mg/kg i.p.) and high-fat diet (42% fat from lipids) for 26 weeks. At study end, diabetic mice exhibited elevated blood glucose levels and impaired glucose tolerance, together with increases in both body weight gain and fat mass, replicating several aspects of human type 2 diabetes. The myocardial phenotype of diabetic mice included increased myocardial fibrosis and left ventricular (LV) diastolic dysfunction. Elevated LV superoxide levels were also evident. Diabetic mice exhibited a spectrum of LV mitochondrial changes, including decreased mitochondria area, increased levels of mitochondrial complex-III and complex-V protein abundance, and reduced complex-II oxygen consumption. In conclusion, these data suggest that the low-dose STZ-high fat experimental model replicates some of the mitochondrial changes seen in diabetes, and as such, this model may be useful to study treatments that target the mitochondria in diabetes.

Corrigendum: Characterising an Alternative Murine Model of Diabetic Cardiomyopathy.

[This corrects the article DOI: 10.3389/fphys.2019.01395.].