Predicting risk of severe hypoglycaemia in type 2 diabetes.

For many, the extent to which blood glucose control can be lowered is limited by risk of hypoglycaemia. Hypoglycaemia is feared and carries fiscal, social and medical costs, with risk of death being associated with severe hypoglycaemia in patients with type 2 diabetes at high cardiovascular risk. In this issue of Diabetologia, Chow et al (DOI: 10.1007/s00125-015-3512-0 ) report that patients with type 2 diabetes who suffered severe hypoglycaemia during attempts to lower blood glucose intensively were more likely to be insulin deficient and/or carry markers of autoimmunity more usually associated with type 1 diabetes. This opens the question of whether biomarkers might help clinicians identify those patients at greater or lower risk of treatment-induced hypoglycaemia, allowing therapeutic targets to be modified accordingly.SN is supported by the NIHR Cambridge Biomedical Centre.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00125-015-3550-

Prediction and Detection of Hypoglycaemia in Type 1 Diabetes

Patients with Type 1 Diabetes still suffer from recurrent and troublesome hypoglycaemia despite improvements in glucose monitoring, insulin delivery and structured education. The key objectives of my thesis were to explore ways to identify patients at greater risk to develop hypoglycaemia and to investigate novel ways to prevent hypoglycaemic episodes by detecting this early and with ease. This might ultimately translate into reduction in overall risk of hypoglycaemia occurrence in those with Type 1 Diabetes. I investigated potential factors that could predict persistent presence of severe hypoglycaemia in the HypoCOMPaSS study, a multi-centre UK study examining clinical strategies to reduce burden of hypoglycaemia. Looking at a subset of these participants who underwent detailed hypoglycaemic clamp studies, I found no obvious parameters predicting persistent risk of severe hypoglycaemia. I then examined whether individual genetic factors might contribute to risk of persistent severe hypoglycaemia, exploring the association between polymorphisms in Angiotensin Converting Enzyme ACE gene and severe hypoglycaemia in 77 participants in HypoCOMPaSS study. Interestingly, I found that the homozygous DD ACE gene polymorphism was associated with a significantly increased risk of severe hypoglycaemia. Considering then practical approaches to trying to minimise hypoglycaemia risk, I examined the efficacy and safety of a novel implantable Continuous Glucose Monitoring Senseonics CGM System in 10 subjects with Type 1 Diabetes from the Cambridge cohort of the pivotal European PRECISE 1 study. In keeping with the global data, I found in Cambridge participants that this novel system was safe and its efficacy was comparable to commercially available Continuous Glucose Monitoring. This device was useful in detecting hypoglycaemia early with high device satisfaction among the users. I also explored alternative non-invasive methods to measure blood glucose and detect hypoglycaemia easily using breath sample in Type 1 Diabetes participants during experimental hypoglycaemia. The concentration of Isoprene exhaled in breath was significantly raised during hypoglycaemia. Finally, I looked at the stability of ‘diluted insulin aspart (NovoRapid®)’ in ambient temperature and CSII over 30 days. Both neat and diluted insulin aspart were stable beyond 30 days and could potentially be used by patients with T1D requiring very low insulin doses to avoid hypoglycaemia.NIHR Cambridge Biomedical research centre, Diabetes UK, University of East Anglia Senseonics Inc. Dr Frank Waldron-Lync

Continuous glucose monitoring in older people with diabetes and memory problems:a mixed-methods feasibility study in the UK

OBJECTIVES: Older people with diabetes are at increased risk of harm from hypoglycaemia, particularly where there are coexisting memory problems. Continuous glucose monitoring (CGM) offers important benefits in terms of detecting hypoglycaemia, but the feasibility of use and extent of data capture has not been tested in this patient group. Our objective was to investigate the feasibility of trialling a CGM intervention in the community setting in older people with diabetes and memory problems. DESIGN: Mixed-methods feasibility study. SETTING: Community dwellings in the UK. PARTICIPANTS: Patients aged ≥65 with diabetes and abbreviated mental test score ≤8 or known dementia. INTERVENTION: FreeStyle Libre CGM. PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility criteria were numbers of eligible patients, recruitment, attrition, extent of capture of glucose readings and adverse events. Qualitative interview. RESULTS: We identified 49 eligible participants; 17 consented, but 5 withdrew before recording of data because they or their carers felt unable to manage study procedures. 12 participants (mean age 85 years) completed the study without adverse events. Data capture across 14 days ranged between 3% and 92% (mean 55%); 6 participants had <60% capture. Hypoglycaemic events were recorded in six out of nine insulin users. Qualitative interviews found: the device does not interfere with daily activities, usability and comfort was positive, and it was helpful for carers in monitoring participants' glucose concentrations. CONCLUSIONS: The device was acceptable to participants, and carers reported greater ease in monitoring the participant's glucose concentrations. However, completeness of data capture varied considerably with this device due to the need for users to conduct ≥3 scans per day. Real-time devices with automated data transfer may be more suitable in older people with memory problems

Accuracy and Longevity of an Implantable Continuous Glucose Sensor in the PRECISE Study: A 180-Day, Prospective, Multicenter, Pivotal Trial

It is known that continuous glucose monitoring (CGM) systems can lower mean glucose compared with episodic self-monitoring of blood glucose. Implantable CGM systems may provide additional benefits. We studied the Eversense (Senseonics Inc.) implantable CGM sensor in 71 participants aged 18 years and older with type 1 and type 2 diabetes in a 180-day multinational, multicenter pivotal trial. Participants used the CGM system at home and in the clinic. CGM accuracy was assessed during eight in-clinic visits with the mean absolute relative difference (MARD) for venous reference glucose values >4.2 mmol/L as the primary end point. Secondary end points included Clarke Error Grid Analysis and alarm performance. The primary safety outcome was device-related serious adverse events. This trial is registered with ClinicalTrials.gov, number NCT02154126. The MARD value against reference glucose values >4.2 mmol/L was 11.1% (95% CI 10.5, 11.7). Clarke Error Grid Analysis showed 99.2% of samples in the clinically acceptable error zones A and B. Eighty-one percent of hypoglycemic events were detected by the CGM system within 30 min. No device-related serious adverse events occurred during the study. Our results indicate the safety and accuracy of this new type of implantable CGM system and support it as an alternative for transcutaneous CG

Exhaled Breath Isoprene Rises During Hypoglycemia in Type 1 Diabetes.

Work was supported by the NIHR Cambridge Biomedical Research Centre including salary support for SN. Hormonal assays were performed by Keith Burling and colleagues in the NIHR Cambridge Biomedical Research Centre Core Biochemical Assay Laboratory. Clamp studies were performed in the Cambridge NIHR/ Wellcome Trust Clinical Research Facility.This is the author accepted manuscript. The final version is available from the American Diabetes Association via http://dx.doi.org/10.2337/dc16-046

Acceptability of Implantable Continuous Glucose Monitoring Sensor

Real-time continuous glucose monitoring is associated with significant benefits for diabetes management. Implantable sensors could overcome some challenges reportedly associated with device visibility, psychosocial functioning and sensor durability. A psychosocial assessment was conducted to determine acceptability and impact of an implantable continuous glucose monitoring (CGM) sensor as part of the PRECISE trial. Questionnaires were administered to participants comprising the Diabetes Distress Scale, the CGM impact scale, and bespoke device satisfaction. Fifty-one participants across the United Kingdom (n = 10) and Germany (n = 41) completed the questionnaires. Of these, 90% had T1D, 50% followed an insulin pump therapy regimen, and 45% of the participants were previous CGM users. CGM Impact Scale results show 86% (n = 44) of participants reported feeling better (14% neutral) about their diabetes control with 90% CGM naïve participants and 81% previous CGM users reporting increased confidence about their diabetes management. Furthermore, 73% (n = 37) felt more safe (27% neutral) while sleeping and 78% (n = 39) more confident (22% neutral) about avoiding serious hypoglycemia. Responses correspond with an average improvement in HbA1c from 7.51 to 7.05 ( P < .0001) over the 90 days use of the CGM. Overall, the system was rated highly on ease of use, convenience and comfort. 84% would choose to be inserted again with 93% of CGM naïve participants (86% previous CGM users) reporting minimized burden of diabetes. Implantable CGM devices are acceptable to users and are evaluated favorably. The considerable majority of participants (93% of first time users and 77% previous CGM users) would like to continue using the system to help manage their diabetes more effectivel

Estimating the cost‐effectiveness of intermittently scanned continuous glucose monitoring in adults with type 1 diabetes in England

We previously showed that intermittently scanned continuous glucose monitoring (isCGM) reduces HbA1c at 24 weeks compared with self-monitoring of blood glucose with finger pricking (SMBG) in adults with type 1 diabetes and high HbA1c levels (58-97 mmol/mol [7.5%-11%]). We aim to assess the economic impact of isCGM compared with SMBG. Participant-level baseline and follow-up health status (EQ-5D-5L) and within-trial healthcare resource-use data were collected. Quality-adjusted life-years (QALYs) were derived at 24 weeks, adjusting for baseline EQ-5D-5L. Participant-level costs were generated. Using the IQVIA CORE Diabetes Model, economic analysis was performed from the National Health Service perspective over a lifetime horizon, discounted at 3.5%. Within-trial EQ-5D-5L showed non-significant adjusted incremental QALY gain of 0.006 (95% CI: -0.007 to 0.019) for isCGM compared with SMBG and an adjusted cost increase of £548 (95% CI: 381-714) per participant. The lifetime projected incremental cost (95% CI) of isCGM was £1954 (-5108 to 8904) with an incremental QALY (95% CI) gain of 0.436 (0.195-0.652) resulting in an incremental cost-per-QALY of £4477. In all subgroups, isCGM had an incremental cost-per-QALY better than £20,000 compared with SMBG; for people with baseline HbA1c >75 mmol/mol (9.0%), it was cost-saving. Sensitivity analysis suggested that isCGM remains cost-effective if its effectiveness lasts for at least 7 years. While isCGM is associated with increased short-term costs, compared with SMBG, its benefits in lowering HbA1c will lead to sufficient long-term health-gains and cost-savings to justify costs, so long as the effect lasts into the medium term. [Abstract copyright: © 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

Flash glucose monitoring with the FreeStyle Libre 2 compared with self-monitoring of blood glucose in suboptimally controlled type 1 diabetes: the FLASH-UK randomised controlled trial protocol.

INTRODUCTION: Optimising glycaemic control in type 1 diabetes (T1D) remains challenging. Flash glucose monitoring with FreeStyle Libre 2 (FSL2) is a novel alternative to the current standard of care self-monitoring of blood glucose (SMBG). No randomised controlled trials to date have explored the potential benefits of FSL2 in T1D. We aim to assess the impact of FSL2 in people with suboptimal glycaemic control T1D in comparison with SMBG. METHODS: This open-label, multicentre, randomised (via stochastic minimisation), parallel design study conducted at eight UK secondary and primary care centres will aim to recruit 180 people age ≥16 years with T1D for >1 year and glycated haemoglobin (HbA1c) 7.5%-11%. Eligible participants will be randomised to 24 weeks of FSL2 (intervention) or SMBG (control) periods, after 2-week of blinded sensor wear. Participants will be assessed virtually or in-person owing to the COVID-19 pandemic. HbA1c will be measured at baseline, 12 and 24 weeks (primary outcome). Participants will be contacted at 4 and 12 weeks for glucose optimisation. Control participants will wear a blinded sensor during the last 2 weeks. Psychosocial outcomes will be measured at baseline and 24 weeks. Secondary outcomes include sensor-based metrics, insulin doses, adverse events and self-report psychosocial measures. Utility, acceptability, expectations and experience of using FSL2 will be explored. Data on health service resource utilisation will be collected. ANALYSIS: Efficacy analyses will follow intention-to-treat principle. Outcomes will be analysed using analysis of covariance, adjusted for the baseline value of the corresponding outcome, minimisation factors and other known prognostic factors. Both within-trial and life-time economic evaluations, informed by modelling from the perspective of the National Health Service setting, will be performed. ETHICS: The study was approved by Greater Manchester West Research Ethics Committee (reference 19/NW/0081). Informed consent will be sought from all participants. TRIAL REGISTRATION NUMBER: NCT03815006. PROTOCOL VERSION: 4.0 dated 29 June 2020.Diabetes U

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pmed.100213

Developing a static website and deploying it to Heroku

The thesis aimed to develop a website and deploy it to a cloud platform, Heroku. This proposal demonstrates in detail the procedure and devices for web application improvement and developments and accordingly can be utilized as an expert guide for comparative purposes. The theory also shows the hypothesis of a cloud platform as help and particularly the accompanying three principal types: PaaS, IaaS, and SaaS. Accordingly, the Heroku cloud stage PaaS was chosen to have an exhibition adaptation of the site, and to fabricate, convey, test, screen, and scale. Heroku is a cloud platform to build, monitor and scale the app. Heroku has different functionalities, such as accessibility, reliability, and feasibility. Deploying a static website to Heroku was very effective. However, there were a lot of challenges during the process of website deployment such as to use the programming language which is supported by Heroku, using the Git bash terminal, use of commands, changing a static website to a web app. Though it was a challenge throughout the process, Blogs and different YouTube tutorials were beneficial and helpful