A web-based self-management programme for people with type 2 diabetes : the HeLP-Diabetes research programme including RCT

Background: In the UK, 6% of the UK population have diabetes mellitus, 90% of whom have type 2 diabetes mellitus (T2DM). Diabetes mellitus accounts for 10% of NHS expenditure (£14B annually). Good self-management may improve health outcomes. NHS policy is to refer all people with T2DM to structured education, on diagnosis, to improve their self-management skills, with annual reinforcement thereafter. However, uptake remains low (5.6% in 2014–15). Almost all structured education is group based, which may not suit people who work, who have family or other caring commitments or who simply do not like group-based formats. Moreover, patient needs vary with time and a single education session at diagnosis is unlikely to meet these evolving needs. A web-based programme may increase uptake. / Objectives: Our aim was to develop, evaluate and implement a web-based self-management programme for people with T2DM at any stage of their illness journey, with the goal of improving access to, and uptake of, self-management support, thereby improving health outcomes in a cost-effective manner. Specific objectives were to (1) develop an evidence-based theoretically informed programme that was acceptable to patients and health-care professionals (HCPs) and that could be readily implemented within routine NHS care, (2) determine the clinical effectiveness and cost-effectiveness of the programme compared with usual care and (3) determine how best to integrate the programme into routine care. / Design: There were five linked work packages (WPs). WP A determined patient requirements and WP B determined HCP requirements for the self-management programme. WP C developed and user-tested the Healthy Living for People with type 2 Diabetes (HeLP-Diabetes) programme. WP D was an individually randomised controlled trial in primary care with a health economic analysis. WP E used a mixed-methods and case-study design to study the potential for implementing the HeLP-Diabetes programme within routine NHS practice. / Setting: English primary care. / Participants: People with T2DM (WPs A, D and E) or HCPs caring for people with T2DM (WPs B, C and E). / Intervention: The HeLP-Diabetes programme; an evidence-based theoretically informed web-based self-management programme for people with T2DM at all stages of their illness journey, developed using participatory design principles. / Main outcome measures: WPs A and B provided data on user ‘wants and needs’, including factors that would improve the uptake and accessibility of the HeLP-Diabetes programme. The outcome for WP C was the HeLP-Diabetes programme itself. The trial (WP D) had two outcomes measures: glycated haemoglobin (HbA1c) level and diabetes mellitus-related distress, as measured with the Problem Areas in Diabetes (PAID) scale. The implementation outcomes (WP E) were the adoption and uptake at clinical commissioning group, general practice and patient levels and the identification of key barriers and facilitators. / Results: Data from WPs A and B supported our holistic approach and addressed all areas of self-management (medical, emotional and role management). HCPs voiced concerns about linkage with the electronic medical records (EMRs) and supporting patients to use the programme. The HeLP-Diabetes programme was developed and user-tested in WP C. The trial (WP D) recruited to target (n = 374), achieved follow-up rates of over 80% and the intention-to-treat analysis showed that there was an additional improvement in HbA1c levels at 12 months in the intervention group [mean difference –0.24%, 95% confidence interval (CI) –0.44% to –0.049%]. There was no difference in overall PAID score levels (mean difference –1.5 points, 95% CI –3.9 to 0.9 points). The within-trial health economic analysis found that incremental costs were lower in the intervention group than in the control group (mean difference –£111, 95% CI –£384 to £136) and the quality-adjusted life-years (QALYs) were higher (mean difference 0.02 QALYs, 95% CI 0.000 to 0.044 QALYs), meaning that the HeLP-Diabetes programme group dominated the control group. In WP E, we found that the HeLP-Diabetes programme could be successfully implemented in primary care. General practices that supported people in registering for the HeLP-Diabetes programme had better uptake and registered patients from a wider demographic than those relying on patient self-registration. Some HCPs were reluctant to do this, as they did not see it as part of their professional role. / Limitations: We were unable to link the HeLP-Diabetes programme with the EMRs or to determine the effects of the HeLP-Diabetes programme on users in the implementation study. / Conclusions: The HeLP-Diabetes programme is an effective self-management support programme that is implementable in primary care. / Future work: The HeLP-Diabetes research team will explore the following in future work: research to determine how to improve patient uptake of self-management support; develop and evaluate a structured digital educational pathway for newly diagnosed people; develop and evaluate a digital T2DM prevention programme; and the national implementation of the HeLP-Diabetes programme. / Trial registration: Research Ethics Committee reference number 10/H0722/86 for WPs A–C; Research Ethics Committee reference number 12/LO/1571 and UK Clinical Research Network/National Institute for Health Research (NIHR) Portfolio 13563 for WP D; and Research Ethics Committee 13/EM/0033 for WP E. In addition, for WP D, the study was registered with the International Standard Randomised Controlled Trial Register as reference number ISRCTN02123133. / Funding details: This project was funded by the NIHR Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 6, No. 5. See the NIHR Journals Library website for further project information

Tuft cell-derived acetylcholine regulates epithelial fluid secretion and helminth clearance

Thesis (Ph.D.)--University of Washington, 2023Helminth, or parasitic worm, infection afflicts nearly one third of humans worldwide, resulting in massive suffering and comorbidity. The arm of the immune system responsible for combatting helminth infection, called “Type 2” immunity, is also responsible for causing a variety of allergic diseases. Understanding how Type 2 immunity is regulated has the potential to inform both better treatment for helminth infection as well as allergic disease.Mucosal barrier tissues are the site of exposure to Type 2 stimuli and the locus of the ensuing immune response. Both the airways and the gastrointestinal tract are protected by a gradient of mucus, antimicrobial peptides, and fluid secreted by epithelial cells that contribute to host defense and enable key physiological functions of the tissues. The Type 2 immune response triggers epithelial remodeling that increases fluid and mucus secretion as well as contractility of underlying smooth muscle in order to flush away helminths and allergens. Acetylcholine is a key regulator of both epithelial secretion and muscle contraction. Collectively this response is known as “weep and sweep” and familiar to anyone who experiences seasonal allergies. While the effects of Type 2 immunity have been well understood for decades, the initiation of the response remained a mystery until recently, when tuft cells were discovered as the key sensors of intestinal helminth infection. Tuft cells are epithelial cells that possess chemosensory machinery linking sensing of lumenal stimuli via a suite of receptors to basolateral secretion of immune- and neuro-modulating factors including IL-25, leukotrienes, and acetylcholine (ACh). In response to small intestinal (SI) helminth infection or succinate, a metabolite produced by protist and bacterial colonization, tuft cells secrete IL-25 and leukotrienes to activate Group 2 innate lymphoid cells (ILC2s) that produce the hallmark Type 2 cytokines IL-5 and IL-13. IL-13 signals on the intestinal stem cell compartment to drive preferential differentiation of mucus-producing goblet cells and, intriguingly, tuft cells, which rapidly remodels the epithelium in a matter of days. This remodeling, and thus tuft cells, are required for helminth clearance. Additional functions of SI tuft cells or tuft-derived ACh are not known. We show that in response to sensing of succinate or direct activation of the chemosensory ion channel TRPM5, SI tuft cells secrete ACh to induce epithelial fluid secretion in the intestine and airways, independently of neurons. Unlike other tissues where nearly 100% of tuft cells express the enzyme Chat required for ACh synthesis, the frequency of Chat+ SI tuft cells occurred in a gradient from the proximal to distal SI, increasing from approximately 40% to 80% of tuft cells. Succinate-induced fluid secretion was restricted to the distal SI where Chat+ frequency and SUCNR1 expression was highest. Consistent with their high expression of Sucnr1, tuft cells in the trachea also responded to succinate by inducing ACh-dependent fluid secretion. In the proximal SI and colon tuft cell activation via the TRPM5 agonist Class 8 induced fluid secretion, but the exact ligands sensed by tuft cells in these tissues remains to be determined. Oral administration of Class 8 induced fluid secretion in vivo as measured by fecal water content. During Type 2 tissue remodeling, Chat+ tuft cells increase in number, enhancing the fluid secretion response. Upon helminth infection, mice with Chat-deficient tuft cells experience delayed helminth clearance despite normal tuft-ILC2 circuit activation. We conclude that tuft cell-derived ACh regulates epithelial fluid secretion, and that this effector function can contribute to Type 2 immune responses during helminth infection. By coupling chemosensing to rapid epithelial fluid secretion, tuft cells coordinate an epithelium-intrinsic effector unit that can flush offending agents away from the tissue

A Uniform System for the Annotation of Vertebrate microRNA Genes and the Evolution of the Human microRNAome

Although microRNAs (miRNAs) are among the most intensively studied molecules of the past 20 years, determining what is and what is not a miRNA has not been straightforward. Here, we present a uniform system for the annotation and nomenclature of miRNA genes. We show that less than a third of the 1,881 human miRBase entries, and only approximately 16% of the 7,095 metazoan miRBase entries, are robustly supported as miRNA genes. Furthermore, we show that the human repertoire of miRNAs has been shaped by periods of intense miRNA innovation and that mature gene products show a very different tempo and mode of sequence evolution than star products. We establish a new open access database-MirGeneDB (http://mirgenedb.org)-to catalog this set of miRNAs, which complements the efforts of miRBase but differs from it by annotating the mature versus star products and by imposing an evolutionary hierarchy upon this curated and consistently named repertoire.</p