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BackgroundThe COVID-19 health crisis has disproportionately impacted populations who have been historically marginalized in health care and public health, including low-income and racial and ethnic minority groups. Members of marginalized communities experience undue barriers to accessing health care through virtual care technologies, which have become the primary mode of ambulatory health care delivery during the COVID-19 pandemic. Insights generated during the COVID-19 pandemic can inform strategies to promote health equity in virtual care now and in the future. ObjectiveThe aim of this study is to generate insights arising from literature that was published in direct response to the widespread use of virtual care during the COVID-19 pandemic, and had a primary focus on providing recommendations for promoting health equity in the delivery of virtual care. MethodsWe conducted a narrative review of literature on health equity and virtual care during the COVID-19 pandemic published in 2020, describing strategies that have been proposed in the literature at three levels: (1) policy and government, (2) organizations and health systems, and (3) communities and patients. ResultsWe highlight three strategies for promoting health equity through virtual care that have been underaddressed in this literature: (1) simplifying complex interfaces and workflows, (2) using supportive intermediaries, and (3) creating mechanisms through which marginalized community members can provide immediate input into the planning and delivery of virtual care. ConclusionsWe conclude by outlining three areas of work that are required to ensure that virtual care is employed in ways that are equity enhancing in a post–COVID-19 reality.

BackgroundThe rapid virtualization of health services during the COVID-19 pandemic has drawn increasing attention to the impact of virtual care technologies on health equity. In some circumstances, virtual care initiatives have been shown to increase health disparities, as individuals from underserved communities are less likely to benefit from such initiatives. ObjectiveThe purpose of this paper is to describe a protocol for a scoping review of reviews that aims to map review-level evidence that describes challenges and strategies for promoting effective engagement with virtual care technologies among underserved communities. MethodsOur methodology was adapted from seminal scoping review guidelines provided by Arksey and O’Malley, Levac at al, Colquhoun et al, and the Joanna Briggs Institute. Our search strategy was developed for the following databases: MEDLINE (on Ovid), EMBASE (on Ovid), CINAHL (on EBSCO), Scopus, and Epistemonikos. Supplementary searches will include the use of Google Scholar and reference tracking. Each citation will be independently screened by 2 researchers at the title and abstract level, and full-text screening will be performed in accordance with our eligibility criteria. The eligibility criteria focused on the inclusion of methods-driven reviews (ie, systematic reviews, scoping reviews, meta-analyses, realist reviews, and critical interpretative syntheses) to enhance rigor and quality. Other inclusion criteria included a focus on virtual care services that facilitate bidirectional patient-provider communication (ie, video, telephone, and asynchronous messaging visits) for underserved populations (ie, those who experience social disadvantage due to race, age, income, and other factors related to the social determinants of health). ResultsThis scoping review of reviews will provide a broad overview of identified challenges associated with the accessibility of virtual health care services among underserved communities. In addition, strategies for improving the access to, uptake of, and engagement with virtual care technologies among underserved communities will be identified. The knowledge synthesized from this review will aid in developing and implementing virtual services that acknowledge the unique needs of populations who experience barriers to care and disproportionately worse health outcomes. The results will also inform gaps in current research. ConclusionsThe rapid shift toward virtual health services has highlighted the urgent need to critically examine the intersection of virtual care and health equity. Although technology-driven innovations in health care generally aim to improve access, quality, and health outcomes, it is also possible for these innovations to produce intervention-generated inequities. Assessing current review-level evidence on the key challenges and strategies for improving the application of virtual care in underserved communities is imperative for ensuring that virtual care benefits all populations. International Registered Report Identifier (IRRID)PRR1-10.2196/22847

BackgroundImplementing digital health technologies is complex but can be facilitated by considering the features of the tool that is being implemented, the team that will use it, and the routines that will be affected. ObjectiveThe goal of this study was to assess the implementation of a remote-monitoring initiative for patients with chronic obstructive pulmonary disease in Ontario, Canada using the Tool+Team+Routine framework and to refine this approach to conceptualize the adoption of technologies in health care. MethodsThis study was a qualitative research project that took place alongside a randomized controlled trial comparing a technology-enabled self-monitoring program with a technology-enabled self- and remote-monitoring program in patients with chronic obstructive pulmonary disease and with standard care. This study included interviews with 5 remote-monitoring patients, 3 self-monitoring patients, 2 caregivers, 5 health care providers, and 3 hospital administrators. The interview questions were structured around the 3 main concepts of the Tool+Team+Routine framework. ResultsFindings emphasized that (1) technologies can alter relationships between providers and patients, and that these relationships drove the development of a new service arising from the technology, in our case, and (2) technologies can create additional work that is not visible to management as a result of not being considered within the scope of the service. ConclusionsLiterature on the implementation of digital health technologies has still not reconciled the importance of interpersonal relationships to conventional implementation strategies. By acknowledging the centrality of such relationships, implementation teams can better plan for the adaptations required in order to make new technologies work for patients and health care providers. Further work will need to address how specific individuals administering a remote-monitoring program work to build relationships, and how these relationships and other sources of activity might lead to technological scope creep—an unanticipated expanding scope of work activities in relation to the function of the tool.

BackgroundChronic obstructive pulmonary disease (COPD) is a leading cause of mortality and leads to frequent hospital admissions and emergency department (ED) visits. COPD exacerbations are an important patient outcome, and reducing their frequency would result in significant cost savings. Remote monitoring and self-monitoring could both help patients manage their symptoms and reduce the frequency of exacerbations, but they have different resource implications and have not been directly compared. ObjectiveThis study aims to compare the effectiveness of implementing a technology-enabled self-monitoring program versus a technology-enabled remote monitoring program in patients with COPD compared with a standard care group. MethodsWe conducted a 3-arm randomized controlled trial evaluating the effectiveness of a remote monitoring and a self-monitoring program relative to standard care. Patients with COPD were recruited from outpatient clinics and a pulmonary rehabilitation program. Patients in both interventions used a Bluetooth-enabled device kit to monitor oxygen saturation, blood pressure, temperature, weight, and symptoms, but only patients in the remote monitoring group were monitored by a respiratory therapist. All patients were assessed at baseline and at 3 and 6 months after program initiation. Outcomes included self-management skills, as measured by the Partners in Health (PIH) Scale; patient symptoms measured with the St George’s Respiratory Questionnaire (SGRQ); and the Bristol COPD Knowledge Questionnaire (BCKQ). Patients were also asked to self-report on health system use, and data on health use were collected from the hospital. ResultsA total of 122 patients participated in the study: 40 in the standard care, 41 in the self-monitoring, and 41 in the remote monitoring groups. Although all 3 groups improved in PIH scores, BCKQ scores, and SGRQ impact scores, there were no significant differences among any of the groups. No effects were observed on the SGRQ activity or symptom scores or on hospitalizations, ED visits, or clinic visits. ConclusionsDespite regular use of the technology, patients with COPD assigned to remote monitoring or self-monitoring did not have any improvement in patient outcomes such as self-management skills, knowledge, or symptoms, or in health care use compared with each other or with a standard care group. This may be owing to low health care use at baseline, the lack of structured educational components in the intervention groups, and the lack of integration of the action plan with the technology. Trial RegistrationClinicalTrials.gov NCT03741855; https://clinicaltrials.gov/ct2/show/ NCT03741855

Artificial intelligence (AI) is seen as a strategic lever to improve access, quality, and efficiency of care and services and to build learning and value-based health systems. Many studies have examined the technical performance of AI within an experimental context. These studies provide limited insights into the issues that its use in a real-world context of care and services raises. To help decision makers address these issues in a systemic and holistic manner, this viewpoint paper relies on the health technology assessment core model to contrast the expectations of the health sector toward the use of AI with the risks that should be mitigated for its responsible deployment. The analysis adopts the perspective of payers (ie, health system organizations and agencies) because of their central role in regulating, financing, and reimbursing novel technologies. This paper suggests that AI-based systems should be seen as a health system transformation lever, rather than a discrete set of technological devices. Their use could bring significant changes and impacts at several levels: technological, clinical, human and cognitive (patient and clinician), professional and organizational, economic, legal, and ethical. The assessment of AI’s value proposition should thus go beyond technical performance and cost logic by performing a holistic analysis of its value in a real-world context of care and services. To guide AI development, generate knowledge, and draw lessons that can be translated into action, the right political, regulatory, organizational, clinical, and technological conditions for innovation should be created as a first step.

BackgroundPhysiotherapy is essential for the successful rehabilitation of common shoulder injuries and following shoulder surgery. Patients may receive some training and supervision for shoulder physiotherapy through private pay or private insurance, but they are typically responsible for performing most of their physiotherapy independently at home. It is unknown how often patients perform their home exercises and if these exercises are performed correctly without supervision. There are no established tools for measuring this. It is, therefore, unclear if the full benefit of shoulder physiotherapy treatments is being realized. ObjectiveThe proposed research will (1) validate a smartwatch and machine learning (ML) approach for evaluating adherence to shoulder exercise participation and technique in a clinical patient population with rotator cuff pathology; (2) quantify the rate of home physiotherapy adherence, determine the effects of adherence on recovery, and identify barriers to successful adherence; and (3) develop and pilot test an ethically conscious adherence-driven rehabilitation program that individualizes patient care based on their capacity to effectively participate in their home physiotherapy. MethodsThis research will be conducted in 2 phases. The first phase is a prospective longitudinal cohort study, involving 120 patients undergoing physiotherapy for rotator cuff pathology. Patients will be issued a smartwatch that will record 9-axis inertial sensor data while they perform physiotherapy exercises both in the clinic and in the home setting. The data collected in the clinic under supervision will be used to train and validate our ML algorithms that classify shoulder physiotherapy exercise. The validated algorithms will then be used to assess home physiotherapy adherence from the inertial data collected at home. Validated outcome measures, including the Disabilities of the Arm, Shoulder, and Hand questionnaire; Numeric Pain Rating Scale; range of motion; shoulder strength; and work status, will be collected pretreatment, monthly through treatment, and at a final follow-up of 12 months. We will then relate improvement in patient outcomes to measured physiotherapy adherence and patient baseline variables in univariate and multivariate analyses. The second phase of this research will involve the evaluation of a novel rehabilitation program in a cohort of 20 patients. The program will promote patient physiotherapy engagement via the developed technology and support adherence-driven care decisions. ResultsAs of December 2019, 71 patients were screened for enrollment in the noninterventional validation phase of this study; 65 patients met the inclusion and exclusion criteria. Of these, 46 patients consented and 19 declined to participate in the study. Only 2 patients de-enrolled from the study and data collection is ongoing for the remaining 44. ConclusionsThis study will provide new and important insights into shoulder physiotherapy adherence, the relationship between adherence and recovery, barriers to better adherence, and methods for addressing them. International Registered Report Identifier (IRRID)DERR1-10.2196/17841

BackgroundHigh-level policy barriers impede widespread adoption for even the most well-positioned innovations. Most of the work in this field assumes rather than analyzes the driving forces of health innovation. Objective: The aim of this study was to explore the challenges and opportunities experienced by health system stakeholders in the implementation of digital health innovation in Ontario. ObjectiveThe aim of this study was to explore the challenges and opportunities experienced by health system stakeholders in the implementation of digital health innovation in Ontario. MethodsWe completed semistructured interviews with 10 members of senior leadership across key organizations that are engaged in health care–related digital health activities. Data were analyzed using qualitative description. ResultsA total of 6 key policy priorities emerged, including the need for (1) a system-level definition of innovation, (2) a clear overarching mission, and (3) clearly defined organizational roles. Operationally, there is a need to (4) standardize processes, (5) shift the emphasis to change management, and (6) align funding structures. ConclusionsThese findings emphasize the critical role of the government in developing a vision and creating the foundation upon which innovation activities will be modeled.

BackgroundAs the increasing prevalence of type 2 diabetes mellitus has put pressure on health systems to appropriately manage these patients, there have been a growing number of mobile apps designed to improve the self-management of diabetes. One such app, BlueStar, has been shown to significantly reduce hemoglobin A1c (HbA1c) levels in small studies and is the first app in the United States to receive Food and Drug Administration approval as a mobile prescription therapy. However, the impact of the app across real-world population among different clinical sites and health systems remains unclear. ObjectiveThe primary objective of this study was to conduct a pragmatic randomized controlled trial of the BlueStar mobile app to determine if app usage leads to improved HbA1c levels among diverse participants in real-life clinical contexts. We hypothesized that this mobile app would improve self-management and HbA1c levels compared with controls. MethodsThe study consisted of a multicenter pragmatic randomized controlled trial. Overall, 110 participants randomized to the immediate treatment group (ITG) received the intervention for 6 months, and 113 participants randomized to the wait-list control (WLC) group received usual care for the first 3 months and then received the intervention for 3 months. The primary outcome was glucose control measured by HbA1c levels at 3 months. Secondary outcomes assessed intervention impact on patient self-management, experience of care, and self-reported health utilization using validated scales, including the Problem Areas in Diabetes, the Summary of Diabetes Self-Care Activities, and the EuroQol-5D. Intervention usage data were collected directly from the app. ResultsThe results of an analysis of covariance controlling for baseline HbA1c levels did not show evidence of intervention impact on HbA1c levels at 3 months (mean difference [ITG−WLC] −0.42, 95% CI −1.05 to 0.21; P=.19). Similarly, there was no intervention effect on secondary outcomes measuring diabetes self-efficacy, quality of life, and health care utilization behaviors. An exploratory analysis of 57 ITG participants investigating the impact of app usage on HbA1c levels showed that each additional day of app use corresponded with a 0.016-point decrease in participants’ 3-month HbA1c levels (95% CI −0.03 to −0.003). App usage varied significantly by site, as participants from 1 site logged in to the app a median of 36 days over 14 weeks (interquartile range [IQR] 10.5-124); those at another site used the app significantly less (median 9; IQR 6-51). ConclusionsThe results showed no difference between intervention and control arms for the primary clinical outcome of glycemic control measured by HbA1c levels. Although there was low usage of the app among participants, results indicate contextual factors, particularly site, had a significant impact on overall usage. Future research into the patient and site-specific factors that increase app utilization are needed. Trial RegistrationClinicaltrials.gov NCT02813343; https://clinicaltrials.gov/ct2/show/NCT02813343 (Archived by WebCite at https://clinicaltrials.gov/ct2/show/NCT02813343)

Aims/hypothesis: The aim of this study was to investigate insulin secretion, insulin sensitivity, disposition index and insulin clearance by glucose tolerance status in individuals with cystic fibrosis (CF) and exocrine pancreatic insufficiency., Methods: In a cross-sectional study, we conducted an extended (ten samples) OGTT in individuals with pancreatic-insufficient CF (PI-CF). Participants were divided into normal glucose tolerance (NGT), early glucose intolerance (EGI), impaired glucose tolerance (IGT) and CF-related diabetes (CFRD) groups. We used three different oral minimal models to assess insulin secretion, insulin sensitivity and insulin clearance during the OGTT. We evaluated insulin secretion using total secretion (Φ total), first-phase secretion (Φ dynamic) and second-phase secretion (Φ static) from the model, and we estimated the disposition index by multiplying Φ total and insulin sensitivity., Results: Among 61 participants (NGT 21%, EGI 33%, IGT 16%, CFRD 30%), insulin secretion indices (Φ total, dynamic and static) were significantly lower in the CFRD group compared with the other groups. Insulin sensitivity declined with worsening in glucose tolerance (p value for trend <0.001) and the disposition index declined between NGT and EGI and between IGT and CFRD. Those with CFRD had elevated insulin clearance compared with NGT (p=0.019) and low insulin secretion (Φ total) was also associated with high insulin clearance (p<0.001)., Conclusions/interpretation: In individuals with PI-CF, disposition index declined with incremental impairment in glucose tolerance due to a reduction in both insulin secretion and insulin sensitivity. Moreover in CF, reduced insulin secretion was associated with higher insulin clearance., (© 2024. The Author(s).)

CF-related diabetes (CFRD) is a prevalent comorbidity in people with Cystic Fibrosis (CF), significantly impacting morbidity and mortality rates. This review article critically evaluates the current understanding of CFRD molecular mechanisms, including the role of CFTR protein, oxidative stress, unfolded protein response (UPR) and intracellular communication. CFRD manifests from a complex interplay between exocrine pancreatic damage and intrinsic endocrine dysfunction, further complicated by the deleterious effects of misfolded CFTR protein on insulin secretion and action. Studies indicate that ER stress and subsequent UPR activation play critical roles in both exocrine and endocrine pancreatic cell dysfunction, contributing to β-cell loss and insulin insufficiency. Additionally, oxidative stress and altered calcium flux, exacerbated by CFTR dysfunction, impair β-cell survival and function, highlighting the significance of antioxidant pathways in CFRD pathogenesis. Emerging evidence underscores the importance of exosomal microRNAs (miRNAs) in mediating inflammatory and stress responses, offering novel insights into CFRD's molecular landscape. Despite insulin therapy remaining the cornerstone of CFRD management, the variability in response to CFTR modulators underscores the need for personalized treatment approaches. The review advocates for further research into non-CFTR therapeutic targets, emphasizing the need to address the multifaceted pathophysiology of CFRD. Understanding the intricate mechanisms underlying CFRD will pave the way for innovative treatments, moving beyond insulin therapy to target the disease's root causes and improve the quality of life for individuals with CF., Competing Interests: Declaration of competing interest All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: The HypoCOMPaSS multi-centre trial achieved improvement in hypoglycaemia awareness and 20-fold reduction in severe hypoglycaemia (SH) in a cohort with long-standing type 1 diabetes (T1D). All participants received 'my hypo compass' (MHC) brief structured psycho-educational intervention in addition to optimisation of insulin delivery/glucose monitoring. In this 24-week, prospective, single-centre feasibility RCT, we piloted MHC as a sole intervention in comparison to standard clinical care alone (CON)., Methods: Participants with T1D and impaired hypoglycaemia awareness (IAH) (Clarke score ≥4) were recruited. MHC comprised a group/individual 1-2 h face-to-face session followed by a telephone call and second face-to-face session at 4 weeks. Outcome measures at 24 weeks were compared with baseline., Results: Fifty-two individuals provided consent for screening with 39 fulfilling eligibility criteria. Fifteen withdrew before any study intervention. Twenty-four adults with (mean ± SD) T1D duration 41.0 ± 15.1 years commenced/completed the study (100% visit attendance); 12 randomised to MHC and 12 to CON. All had IAH at baseline and at 24 weeks. Annualised SH rate following MHC was 3.8 ± 19.0 (24 weeks) versus 12.6 ± 3.5 (Baseline) and in CON group 2.0 ± 19.0 (24 weeks) versus 4.6 ± 11.5 (Baseline). 'Immediate Action' for and 'Worry' about hyperglycaemia measured by the Hyperglycaemia Avoidance Scale appeared lower following MHC. Participants attended all study visits and reflected positively on the MHC intervention., Conclusions: Feasibility of MHC implementation without additional intervention has been demonstrated. MHC education was associated with positive changes in attitudes and behaviours with the potential to reduce SH risk. MHC provides a validated, simple, well-received programme to fulfil the educational component within RCTs targeting problematic hypoglycaemia and as part of holistic clinical care., (© 2024 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aims: Impaired awareness of hypoglycaemia (IAH) increases the risk of severe hypoglycaemia in people with type 1 diabetes mellitus (T1DM). IAH can be reversed through meticulous avoidance of hypoglycaemia. Diabetic autonomic neuropathy (DAN) has been proposed as an underlying mechanism contributing to IAH; however, data are inconsistent. The aim of this study was to examine the effects of cardiac autonomic neuropathy (CAN) on IAH reversibility inT1DM., Methods: Participants with T1DM and IAH (Gold score ≥4) recruited to the HypoCOMPaSS (24-week 2 × 2 factorial randomised controlled) trial were included. All underwent screening for cardiac autonomic function testing at baseline and received comparable education and support aimed at avoiding hypoglycaemia and improving hypoglycaemia awareness. Definite CAN was defined as the presence of ≥2 abnormal cardiac reflex tests. Participants were grouped according to their CAN status, and changes in Gold score were compared., Results: Eighty-three participants (52 women [62.7%]) were included with mean age (SD) of 48 (12) years and mean HbA1c of 66 (13) mmol/mol (8.2 [3.3] %). The mean duration of T1DM was 29 (13) years. The prevalence of CAN was low with 5/83 (6%) participants having definite autonomic neuropathy with 11 (13%) classified with possible/early neuropathy. All participants, regardless of the autonomic function status, showed a mean improvement in Gold score of ≥1 (mean improvement -1.2 [95% CI -0.8, -1.6]; p < 0.001)., Conclusions: IAH can be improved in people with T1DM, and a long duration of disease, with and without cardiac autonomic dysfunction. These data suggest that CAN is not a prime driver for modulating IAH reversibility., (© 2024 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Intra-islet crosstalk has become a focus area to fully understand the regulation of insulin secretion and impaired β-cell function in type 2 diabetes (T2D). Here, we put forward evidence for insulin-like growth factor binding protein 7 (IGFBP7) as a potential protein involved in autocrine and paracrine β-cell regulation. We showed presence of IGFBP7 in granules of both human α- and β-cells and measured elevated gene expression as well as IGFBP7 protein in T2D. Insulin secretion was reduced in human islets, and the human β-cell line EndoC-βH1, after 72-h incubation with IGFBP7. Mechanistically reduced insulin secretion by IGFBP7 is attributed to reduced p21-activated kinase 1 (PAK1) protein, and decreased oxygen consumption and ATP-production. Knockdown of IGFBP7 in EndoC-βH1 cells verified reduced IGFBP7 levels in the medium, as well as improved insulin secretion. Finally, IGFBP7 knockdown in islets from T2D donors improved insulin secretion, making IGFBP7 a potential drug target in diabetes., Competing Interests: The authors declare no relationships or activities related to personal gain, financial or otherwise, that are in a conflict of interest with this work., (© 2024 The Author(s).)

Competing Interests: The authors declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Severe hypoglycemia is a common and feared complication of medications used to lower blood glucose levels in individuals with diabetes. Psychoeducational interventions can prevent severe hypoglycemia in individuals with type 1 diabetes (T1D). We aim to determine the effectiveness of this approach among adults with type 2 diabetes (T2D) at elevated risk for severe hypoglycemia., Methods: Preventing Hypoglycemia in Type 2 diabetes (PHT2) is a two-arm, parallel, randomized controlled trial. Participants are eligible if they are adults with T2D receiving care at an integrated group practice in Washington state and have experienced one or more episodes of severe hypoglycemia in the prior 12 months or have impaired awareness of hypoglycemia (Gold score ≥ 4). Participants are randomized to proactive nurse care management with or without my hypo compass, an evidence-based, psychoeducational intervention combining group and individual self-management training. For this study, my hypo compass was adapted to be suitable for adults with T2D and from an in-person to a virtual intervention over videoconference and telephone. The primary outcome is any self-reported severe hypoglycemia in the 12 months following the start of the intervention. Secondary outcomes include biochemical measures of hypoglycemia, self-reported hypoglycemia awareness, fear of hypoglycemia, and emergency department visits and hospitalizations for severe hypoglycemia. The study includes a process evaluation to assess implementation fidelity and clarify the causal pathway., Conclusion: The PHT2 trial will compare the effectiveness of two approaches for reducing severe hypoglycemia in adults with T2D., Trial Registration: clinicaltrials.gov, # NCT04863872., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. JDR reported receiving grants from National Institutes of Health (NIH) and Agency for Healthcare Research and Quality (AHRQ). AJK reported receiving grants from NIH (R01 AG063391; P30 DK092924; R01 DK134446), PCORI (CDR-2019C1–16,126), the Leona M and Harry B Helmsley Charitable Trust outside the submitted work. JAMS reported receiving honoraria for consultancy with Mogrify and grants from the Cystic Fibrosis Trust and the Medical Research Council. The research group of JSp (ACBRD) has received unrestricted educational grants from Abbott Diabetes Care, Medtronic, and Sanofi Diabetes; sponsorship to host, attend, or present at educational meetings from Lilly, Medtronic, Merck Sharp & Dohme, Novo Nordisk, Roche Diabetes Care, and Sanofi Diabetes; and consultancy income from Abbott Diabetes Care, AstraZeneca, Insulet, Roche Diabetes Care, and Sanofi Diabetes. JSp owns the copyright of the HypoA-Q., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: To determine the frequency, severity, burden, and utility of hypoglycaemia symptoms among adults with type 1 diabetes (T1D) and impaired awareness of hypoglycaemia (IAH) at baseline and week 24 following the HypoCOMPaSS awareness restoration intervention., Methods: Adults (N = 96) with T1D (duration: 29 ± 12 years; 64% women) and IAH completed the Hypoglycaemia Burden Questionnaire (HypoB-Q), assessing experience of 20 pre-specified hypoglycaemia symptoms, at baseline and week 24., Results: At baseline, 93 (97%) participants experienced at least one symptom (mean ± SD 10.6 ± 4.6 symptoms). The proportion recognising each specific symptom ranged from 15% to 83%. At 24 weeks, symptom severity and burden appear reduced, and utility increased., Conclusions: Adults with T1D and IAH experience a range of hypoglycaemia symptoms. Perceptions of symptom burden or utility are malleable. Although larger scale studies are needed to confirm, these findings suggest that changing the salience of the symptomatic response may be more important in recovering protection from hypoglycaemia through regained awareness than intensifying symptom frequency or severity., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: Donor hyperglycaemia following brain death has been attributed to reversible insulin resistance. However, our islet and pancreas transplant data suggest that other mechanisms may be predominant. We aimed to determine the relationships between donor insulin use and markers of beta-cell death and beta-cell function in pancreas donors after brain death., Methods: In pancreas donors after brain death, we compared clinical and biochemical data in 'insulin-treated' and 'not insulin-treated donors' (IT vs. not-IT). We measured plasma glucose, C-peptide and levels of circulating unmethylated insulin gene promoter cell-free DNA (INS-cfDNA) and microRNA-375 (miR-375), as measures of beta-cell death. Relationships between markers of beta-cell death and islet isolation outcomes and post-transplant function were also evaluated., Results: Of 92 pancreas donors, 40 (43%) required insulin. Glycaemic control and beta-cell function were significantly poorer in IT donors versus not-IT donors [median (IQR) peak glucose: 8 (7-11) vs. 6 (6-8) mmol/L, p = .016; C-peptide: 3280 (3159-3386) vs. 3195 (2868-3386) pmol/L, p = .046]. IT donors had significantly higher levels of INS-cfDNA [35 (18-52) vs. 30 (8-51) copies/ml, p = .035] and miR-375 [1.050 (0.19-1.95) vs. 0.73 (0.32-1.10) copies/nl, p = .05]. Circulating donor miR-375 was highly predictive of recipient islet graft failure at 3 months [adjusted receiver operator curve (SE) = 0.813 (0.149)]., Conclusions: In pancreas donors, hyperglycaemia requiring IT is strongly associated with beta-cell death. This provides an explanation for the relationship of donor IT with post-transplant beta-cell dysfunction in transplant recipients., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The field of transplantation has witnessed the emergence of Advanced Therapy Medicinal Products (ATMPs) as highly promising solutions to address the challenges associated with organ and tissue transplantation. ATMPs encompass gene therapy, cell therapy, and tissue-engineered products, hold immense potential for breakthroughs in overcoming the obstacles of rejection and the limited availability of donor organs. However, the development and academic research access to ATMPs face significant bottlenecks that hinder progress. This opinion paper emphasizes the importance of addressing bottlenecks in the development and academic research access to ATMPs by implementing several key strategies. These include the establishment of streamlined regulatory processes, securing increased funding for ATMP research, fostering collaborations and partnerships, setting up centralized ATMP facilities, and actively engaging with patient groups. Advocacy at the policy level is essential to provide support for the development and accessibility of ATMPs, thereby driving advancements in transplantation and enhancing patient outcomes. By adopting these strategies, the field of transplantation can pave the way for the introduction of innovative and efficacious ATMP therapies, while simultaneously fostering a nurturing environment for academic research., Competing Interests: Authors MM, KP-K, and PK were employed by Kugelmeiers Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Piemonti, Scholz, de Jongh, Kerr-Conte, van Apeldoorn, Shaw, Engelse, Bunnik, Mühlemann, Pal-Kutas, Scott, Magalon, Kugelmeier and Berishvili.)

Associations between islet graft function and well-being in islet transplant recipients requiring exogenous insulin remain unclear. This cross-sectional analysis compared person-reported outcome measures in 15 adults with type 1 diabetes whose islet transplants were classified according to Igls criteria as "Good" ( n = 5), "Marginal" ( n = 4) and "Failed" ( n = 6) graft function. At a mean of 6.2 years post-first islet transplant, 90% reduction in severe hypoglycaemia was maintained in all groups, with HbA1c (mean ± SD mmol/mol) 49 ± 4 in recipients with "Good" function; 56 ± 5 ("Marginal"); and 69 ± 25 ("Failed"). Self-reported impaired awareness of hypoglycaemia persisted in all groups but those with "Good" function were more likely to experience symptoms during hypoglycaemia. "Marginal" function was associated with greater fear of hypoglycaemia (HFS-II score: "Marginal": 113 [95, 119]; "Failed": 63 [42, 93] ( p = 0.082); "Good": 33 [29, 61]) and severe anxiety (GAD7: "Marginal"): 21 [17, 21]; "Failed": 6 [6, 6] "Good": 6 [3, 11]; ( p = 0.079)), diabetes distress and low mood. Despite clear evidence of ongoing clinical benefit, Igls criteria 'Marginal' function is associated with sub-optimal well-being, including greater fear of hypoglycaemia and severe anxiety. This study provides person-reported validation that "Good" and "Marginal" graft function are differentiated by general and diabetes-specific subjective well-being, suggesting those with "Marginal" function may benefit from further intervention, including re-transplantation., Competing Interests: JSp has served on advisory boards for Janssen, Medtronic, Omnipod, Roche Diabetes Care, and Sanofi Diabetes; received unrestricted educational grants and in-kind support from Abbott Diabetes Care, AstraZeneca, Medtronic, Roche Diabetes Care, and Sanofi Diabetes; received sponsorship to attend educational meetings from Medtronic, Roche Diabetes Care and Sanofi Diabetes, and consultancy income or speaker fees from Abbott Diabetes Care, AstraZeneca, Insulet, Medtronic, Novo Nordisk, Roche Diabetes Care and Sanofi Diabetes. In all cases, JSp’s research group (ACBRD) has been the beneficiary. JAMS has served on an Advisory Board for Mogrify. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bond, Malik, Bashir, Stocker, Buckingham, Speight and Shaw.)

Aims: The purpose of the study was to further elucidate the pathophysiology of cystic fibrosis (CF)-related diabetes (CFRD) and potential drivers of hypoglycaemia. Hence, we aimed to describe and compare beta cell function (insulin and proinsulin) and alpha cell function (glucagon) in relation to glucose tolerance in adults with CF and to study whether hypoglycaemia following oral glucose challenge may represent an early sign of islet cell impairment., Methods: Adults with CF (≥18 years) were included in a cross-sectional study using an extended (-10, -1, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min) or a standard (-1, 30, 60, and 120 min) oral glucose tolerance test (OGTT). Participants were classified according to glucose tolerance status and hypoglycaemia was defined as 3-hour glucose <3.9 mmol/L in those with normal glucose tolerance (NGT) and early glucose intolerance (EGI)., Results: Among 93 participants, 67 underwent an extended OGTT. In addition to worsening in insulin secretion, the progression to CFRD was associated with signs of beta cell stress, as the fasting proinsulin-to-insulin ratio incrementally increased (p-value for trend=0.013). The maximum proinsulin level (pmol/L) was positively associated with the nadir glucagon, as nadir glucagon increased 6.2% (95% confidence interval: 1.4-11.3%) for each unit increase in proinsulin. Those with hypoglycaemia had higher 60-min glucose, 120-min C-peptide, and 180-min glucagon levels (27.8% [11.3-46.7%], 42.9% [5.9-92.85%], and 80.3% [14.9-182.9%], respectively) and unaltered proinsulin-to-insulin ratio compared to those without hypoglycaemia., Conclusions: The maximum proinsulin concentration was positively associated with nadir glucagon during the OGTT, suggesting that beta cell stress is associated with abnormal alpha cell function in adults with CF. In addition, hypoglycaemia seemed to be explained by a temporal mismatch between glucose and insulin levels rather than by an impaired glucagon response., Competing Interests: Author TA holds stocks in the company Novo Nordisk. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nielsen, Mathiesen, Møller, Krogh-Madsen, Katzenstein, Pressler, Shaw, Ritz, Rickels, Stefanovski, Almdal and Faurholt-Jepsen.)

Aims/hypothesis: The aims of this study were to assess cognitions relating to hypoglycaemia in adults with type 1 diabetes and impaired awareness of hypoglycaemia before and after the multimodal HypoCOMPaSS intervention, and to determine cognitive predictors of incomplete response (one or more severe hypoglycaemic episodes over 24 months)., Methods: This analysis included 91 adults with type 1 diabetes and impaired awareness of hypoglycaemia who completed the Attitudes to Awareness of Hypoglycaemia (A2A) questionnaire before, 24 weeks and 24 months after the intervention, which comprised a short psycho-educational programme with optimisation of insulin therapy and glucose monitoring., Results: The age and diabetes duration of the participants were 48±12 and 29±12 years, respectively (mean±SD). At baseline, 91% reported one or more severe hypoglycaemic episodes over the preceding 12 months; this decreased to <20% at 24 weeks and after 24 months (p=0.001). The attitudinal barrier 'hyperglycaemia avoidance prioritised' (η 2 p =0.250, p=0.001) decreased from baseline to 24 weeks, and this decrease was maintained at 24 months (mean±SD=5.3±0.3 vs 4.3±0.3 vs 4.0±0.3). The decrease in 'asymptomatic hypoglycaemia normalised' from baseline (η 2 p =0.113, p=0.045) was significant at 24 weeks (1.5±0.3 vs 0.8±0.2). Predictors of incomplete hypoglycaemia response (one or more further episodes of severe hypoglycaemia) were higher baseline rates of severe hypoglycaemia, higher baseline scores for 'asymptomatic hypoglycaemia normalised', reduced change in 'asymptomatic hypoglycaemia normalised' scores at 24 weeks, and lower baseline 'hypoglycaemia concern minimised' scores (all p<0.05)., Conclusions/interpretation: Participation in the HypoCOMPaSS RCT was associated with improvements in hypoglycaemia-associated cognitions, with 'hyperglycaemia avoidance prioritised' most prevalent. Incomplete prevention of subsequent severe hypoglycaemia episodes was associated with persistence of the cognition 'asymptomatic hypoglycaemia normalised'. Understanding and addressing cognitive barriers to hypoglycaemia avoidance is important in individuals prone to severe hypoglycaemia episodes., Clinical Trials Registration: www.isrctn.org : ISRCTN52164803 and https://eudract.ema.europa.eu : EudraCT2009-015396-27., (© 2022. The Author(s).)

Appropriate glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells is an essential component of blood glucose homeostasis. Configuration of β-cells as 3D pseudoislets (PI) improves the GSIS response compared to 2D monolayer (ML) culture. The aim of this study was to determine the underlying mechanisms. MIN6 β-cells were grown as ML or PI for 5 days. Human islets were isolated from patients without diabetes. Function was assessed by GSIS and metabolic capacity using the Seahorse bioanalyser. Connexin 36 was downregulated using inducible shRNA. Culturing MIN6 as PI improved GSIS. MIN6 PI showed higher glucose-stimulated oxygen consumption (OCR) and extracellular acidification (ECAR) rates. Further analysis showed the higher ECAR was, at least in part, a consequence of increased glycolysis. Intact human islets also showed glucose-stimulated increases in both OCR and ECAR rates, although the latter was smaller in magnitude compared to MIN6 PI. The higher rates of glucose-stimulated ATP production in MIN6 PI were consistent with increased enzyme activity of key glycolytic and TCA cycle enzymes. There was no impact of connexin 36 knockdown on GSIS or ATP production. Configuration of β-cells as PI improves GSIS by increasing the metabolic capacity of the cells, allowing higher ATP production in response to glucose.

Aims: Many individuals with type 1 diabetes retain residual β-cell function, with increased endogenous insulin secretion associated with reduced hyperglycaemia, hypoglycaemia and glycaemic variability. However, it is unknown when these improvements occur during the day. Dysglycaemia is common in overnight and postprandial periods and associated with diabetes complications. Therefore, this study aimed to determine the influence of residual β-cell function upon nocturnal and postprandial glycaemic control in established type 1 diabetes., Methods: Under free-living conditions, 66 participants wore a blinded continuous glucose monitor (CGM), kept a food diary, and completed a stimulated urine C-peptide creatinine (UCPCR) test. Nocturnal, and postprandial CGM outcomes (participant means and discrete event analysis) were compared between UCPCR groups: undetectable (Cpep und ), low (Cpep low : 0.001-0.19 nmol/mmol) and high (Cpep high : ≥0.2 nmol/mmol)., Results: Greater β-cell function was associated with incremental improvements in glycaemia. Cpep high spent significantly greater time in normoglycaemia than Cpep und overnight (76 ± 20% vs. 58 ± 20%, p = 0.005) and 0-300 mins postprandially (68 ± 22% vs. 51 ± 22%, p = 0.045), while also having reducing nocturnal variability (SD 1.12 ± 0.41 vs. 1.52 ± 0.43 mmol/L, p = 0.010). Analysis of individual events, controlling for diabetes duration, BMI, basal insulin, use of a continuous or flash glucose monitor and (for postprandial) meal type, carbohydrate and bolus insulin intake, replicated the group findings, additionally demonstrating Cpep und had increased hyperglycaemia versus Cpep low overnight and increased postprandial hypoglycaemic events compared with Cpep high . For all participants, breakfast had a significantly higher incremental area under the curve than lunch and dinner., Conclusions: Residual β-cell function is associated with improved nocturnal and postprandial glycaemic control. These data may be of clinical importance for identifying specific periods and individuals where further glycaemic management strategies would be beneficial., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C-peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3-8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C-peptide at 12 months (p < .01). Despite 1.9-fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291-15 417] vs. 6442 [5156-7639] IEQ/kg; p < .0001), stimulated C-peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta -0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function., (© 2021 The Authors. American Journal of Transplantation published by Wiley periodicals LLC on behalf of the The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Pancreas and islet transplantation outcomes are negatively impacted by injury to the endocrine cells from acute stress during donor death, organ procurement, processing, and transplant procedures. Here, we report a novel electron microscopy scoring system, the Newcastle Pancreas Endocrine Stress Score (NPESS)., Methods: NPESS was adapted and expanded from our previously validated method for scoring pancreatic exocrine acinar cells, yielding a 4-point scale (0-3) classifying ultrastructural pathology in endocrine cell nuclei, mitochondria, endoplasmic reticulum, cytoplasmic vacuolization, and secretory granule depletion, with a maximum additive score of 15. We applied NPESS in a cohort of deceased organ donors after brainstem (DBD) and circulatory (DCD) death with a wide range of cold ischemic times (3.6-35.9 h) including 3 donors with type 1 and 3 with type 2 diabetes to assess islets in situ (n = 30) in addition to pancreata (n = 3) pre- and postislet isolation., Results: In DBD pancreata, NPESS correlated with cold ischemic time (head: r = 0.55; P  = 0.02) and mirrored exocrine score (r = 0.48; P  = 0.01). When stratified by endocrine phenotype, cells with granules of heterogeneous morphology had higher scores than α, β, and δ cells ( P  < 0.0001). Cells of mixed endocrine-exocrine morphology were observed in association with increased NPESS ( P  = 0.02). Islet isolation was associated with improved NPESS (in situ: 8.39 ± 0.77 [Mean ± SD]; postisolation: 5.44 ± 0.31; P  = 0.04)., Conclusions: NPESS provides a robust method for semiquantitative scoring of subcellular ultrastructural changes in human pancreatic endocrine cells in situ and following islet isolation with utility for unbiased evaluation of acute stress in organ transplantation research., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic β-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost β-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring β-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived β-like cells to restore β-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of β-cell replacement therapies., Competing Interests: Declaration of interests LDS holds a licensed patent on nanoparticles for autoimmune tolerance, with patent applications pending on scaffolds for islet transplantation and local immune monitoring. MOH receives funding and consulting fees from Crinetics. JAMS has received hororaria for chairing academic meetings organised by Novo Nordisk and for participating in a Medtronic Scientific Advisory Board. NAJK declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet β cell loss and dysfunction resulting in insulin deficiency and hyperglycemia. During a presymptomatic phase of established β cell autoimmunity, β cell loss may first be evident through assessment of β cell secretory capacity, a measure of functional β cell mass. Reduction in pancreatic islet β cell reserve eventually manifests as impaired first-phase insulin response to glucose and abnormal glucose tolerance, which progresses until the functional capacity for β cell secretion can no longer meet the demand for insulin to control glycemia. A functional β cell mass of ∼25% of normal may be required to avoid symptomatic T1D but is already associated with dysregulated glucagon secretion. With symptomatic T1D, stimulated C-peptide levels >0.60 ng/mL (0.200 pmol/mL) indicate the presence of clinically meaningful residual β cell function for contributing to glycemic control, although even higher residual C-peptide appears necessary for evidencing glucose-dependent islet β and α cell function that may contribute to maintaining (near)normal glycemia. β cell replacement by islet transplantation can restore a physiologic reserve capacity for insulin secretion, confirming thresholds for functional β cell mass required for independence from insulin therapy., (© 2021 New York Academy of Sciences.)

Background: The pancreas is small and irregular in shape in people with type 2 diabetes. If these abnormalities are caused by the disease state itself rather than being a predisposing factor, remission of type 2 diabetes should restore normal pancreas morphology. The objective of this study was to determine whether changes in pancreas volume and shape occurred during 2 years of remission., Methods: For this post-hoc analysis, we included a subset of adult participants of the Diabetes Remission Clinical Trial (DiRECT), who had type 2 diabetes and were randomly assigned to a weight management intervention or routine diabetes management. Intervention group participants were categorised as responders (HbA 1c <6·5% [48 mmol/mol] and fasting blood glucose <7·0 mmol/L, off all anti-diabetes medication) and non-responders, who were classified as remaining diabetic. Data on pancreas volume and irregularity of pancreas border at baseline, 5 months, 12 months, and 24 months after intervention were compared between responders and non-responders; additional comparisons were made between control group participants with type 2 diabetes and a non-diabetic comparator (NDC) group, who were matched to the intervention group by age, sex, and post-weight-loss weight, to determine the extent of any normalisation. We used a mixed-effects regression model based on repeated measures ANOVA with correction for potential confounding. Magnetic resonance techniques were employed to quantify pancreas volume, the irregularity of the pancreas borders, and intrapancreatic fat content. β-cell function and biomarkers of tissue growth were also measured., Findings: Between July 25, 2015, and Aug 5, 2016, 90 participants with type 2 diabetes in the DiRECT subset were randomly assigned to intervention (n=64) or control (n=26) and were assessed at baseline; a further 25 non-diabetic participants were enrolled into the NDC group. At baseline, mean pancreas volume was 61·7 cm 3 (SD 16·0) in all participants with type 2 diabetes and 79·8 cm 3 (14·3) in the NDC group (p<0·0001). At 24 months, pancreas volume had increased by 9·4 cm 3 (95% CI 6·1 to 12·8) in responders compared with 6·4 cm 3 (2·5 to 10·3) in non-responders (p=0·0008). Pancreas borders at baseline were more irregular in participants with type 2 diabetes than in the NDC group (fractal dimension 1·138 [SD 0·027] vs 1·097 [0·025]; p<0·0001) and had normalised by 24 months in responders only (1·099 [0·028]). Intrapancreatic fat declined by 1·02 percentage points (95% CI 0·53 to 1·51) in 32 responders and 0·51% (-0·17 to 1·19) in 13 non-responders (p=0·23)., Interpretation: These data show for the first time, to our knowledge, reversibility of the abnormal pancreas morphology of type 2 diabetes by weight loss-induced remission., Funding: Diabetes UK., (Copyright © 2020 Elsevier Ltd. All rights reserved.)