Assessing the effect of closed-loop insulin delivery from onset of type 1 diabetes in youth on residual beta-cell function compared to standard insulin therapy (CLOuD study): a randomised parallel study protocol.

INTRODUCTION:Management of newly diagnosed type 1 diabetes (T1D) in children and adolescents is challenging for patients, families and healthcare professionals. The objective of this study is to determine whether continued intensive metabolic control using hybrid closed-loop (CL) insulin delivery following diagnosis of T1D can preserve C-peptide secretion, a marker of residual beta-cell function, compared with standard multiple daily injections (MDI) therapy. METHODS AND ANALYSIS:The study adopts an open-label, multicentre, randomised, parallel design, and aims to randomise 96 participants aged 10-16.9 years, recruited within 21 days of diagnosis with T1D. Following a baseline mixed meal tolerance test (MMTT), participants will be randomised to receive 24 months treatment with conventional MDI therapy or with CL insulin delivery. A further 24-month optional extension phase will be offered to all participants to continue with the allocated treatment. The primary outcome is the between group difference in area under the stimulated C-peptide curve (AUC) of the MMTT at 12 months post diagnosis. Analyses will be conducted on an intention-to-treat basis. Key secondary outcomes are between group differences in time spent in target glucose range (3.9-10 mmol/L), glycated haemoglobin (HbA1c) and time spent in hypoglycaemia (<3.9 mmol/L) at 12 months. Secondary efficacy outcomes include between group differences in stimulated C-peptide AUC at 24 months, time spent in target glucose range, glucose variability, hypoglycaemia and hyperglycaemia as recorded by periodically applied masked continuous glucose monitoring devices, total, basal and bolus insulin dose, and change in body weight. Cognitive, emotional and behavioural characteristics of participants and parents will be evaluated, and a cost-utility analysis performed to support adoption of CL as a standard treatment modality following diagnosis of T1D. ETHICS AND DISSEMINATION:Ethics approval has been obtained from Cambridge East Research Ethics Committee. The results will be disseminated by peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER:NCT02871089; Pre-results

Time spent in hypoglycemia according to age and time-of-day: Observations during closed-loop insulin delivery.

OBJECTIVE We aimed to assess whether percentage of time spent in hypoglycemia during closed-loop insulin delivery differs by age-group and time-of-day. METHODS We retrospectively analyzed data from hybrid closed-loop studies involving young children (2-7 years), children and adolescents (8-18 years), adults (19-59 years), and older adults (≥60 years) with type 1 diabetes. Main outcome was time spent in hypoglycemia <3.9mmol/l. Eight weeks of data for 88 participants were analyzed. RESULTS Median time spent in hypoglycemia over the 24-hour period was highest in children and adolescents (4.4%; [IQR 2.4-5.0]) and very young children (4.0% [3.4-5.2]), followed by adults (2.7% [1.7-4.0]), and older adults (1.8% [1.2-2.2]); p<0.001 for difference between age-groups. Time spent in hypoglycemia during nighttime (midnight-05:59) was lower than during daytime (06:00-23:59) across all age-groups. CONCLUSION Time in hypoglycemia was highest in the pediatric age-group during closed-loop insulin delivery. Hypoglycemia burden was lowest overnight across all age-groups

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Pyrosequencing-Based Comparative Genome Analysis of Vibrio vulnificus Environmental Isolates

Between 1996 and 2006, the US Centers for Disease Control reported that the only category of food-borne infections increasing in frequency were those caused by members of the genus Vibrio. The Gram-negative bacterium Vibrio vulnificus is a ubiquitous inhabitant of estuarine waters, and is the number one cause of seafood-related deaths in the US. Many V. vulnificus isolates have been studied, and it has been shown that two genetically distinct subtypes, distinguished by 16S rDNA and other gene polymorphisms, are associated predominantly with either environmental or clinical isolation. While local genetic differences between the subtypes have been probed, only the genomes of clinical isolates have so far been completely sequenced. In order to better understand V. vulnificus as an agent of disease and to identify the molecular components of its virulence mechanisms, we have completed whole genome shotgun sequencing of three diverse environmental genotypes using a pyrosequencing approach. V. vulnificus strain JY1305 was sequenced to a depth of 33×, and strains E64MW and JY1701 were sequenced to lesser depth, covering approximately 99.9% of each genome. We have performed a comparative analysis of these sequences against the previously published sequences of three V. vulnificus clinical isolates. We find that the genome of V. vulnificus is dynamic, with 1.27% of genes in the C-genotype genomes not found in the E- genotype genomes. We identified key genes that differentiate between the genomes of the clinical and environmental genotypes. 167 genes were found to be specifically associated with environmental genotypes and 278 genes with clinical genotypes. Genes specific to the clinical strains include components of sialic acid catabolism, mannitol fermentation, and a component of a Type IV secretory pathway VirB4, as well as several other genes with potential significance for human virulence. Genes specific to environmental strains included several that may have implications for the balance between self-preservation under stress and nutritional competence

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Closed-Loop Therapy and Preservation of C-Peptide Secretion in Type 1 Diabetes.

BACKGROUND: Whether improved glucose control with hybrid closed-loop therapy can preserve C-peptide secretion as compared with standard insulin therapy in persons with new-onset type 1 diabetes is unclear. METHODS: In a multicenter, open-label, parallel-group, randomized trial, we assigned youths 10.0 to 16.9 years of age within 21 days after a diagnosis of type 1 diabetes to receive hybrid closed-loop therapy or standard insulin therapy (control) for 24 months. The primary end point was the area under the curve (AUC) for the plasma C-peptide level (after a mixed-meal tolerance test) at 12 months after diagnosis. The analysis was performed on an intention-to-treat basis. RESULTS: A total of 97 participants (mean [±SD] age, 12±2 years) underwent randomization: 51 were assigned to receive closed-loop therapy and 46 to receive control therapy. The AUC for the C-peptide level at 12 months (primary end point) did not differ significantly between the two groups (geometric mean, 0.35 pmol per milliliter [interquartile range, 0.16 to 0.49] with closed-loop therapy and 0.46 pmol per milliliter [interquartile range, 0.22 to 0.69] with control therapy; mean adjusted difference, -0.06 pmol per milliliter [95% confidence interval {CI}, -0.14 to 0.03]). There was not a substantial between-group difference in the AUC for the C-peptide level at 24 months (geometric mean, 0.18 pmol per milliliter [interquartile range, 0.06 to 0.22] with closed-loop therapy and 0.24 pmol per milliliter [interquartile range, 0.05 to 0.30] with control therapy; mean adjusted difference, -0.04 pmol per milliliter [95% CI, -0.14 to 0.06]). The arithmetic mean glycated hemoglobin level was lower in the closed-loop group than in the control group by 4 mmol per mole (0.4 percentage points; 95% CI, 0 to 8 mmol per mole [0.0 to 0.7 percentage points]) at 12 months and by 11 mmol per mole (1.0 percentage points; 95% CI, 7 to 15 mmol per mole [0.5 to 1.5 percentage points]) at 24 months. Five cases of severe hypoglycemia occurred in the closed-loop group (in 3 participants), and one occurred in the control group; one case of diabetic ketoacidosis occurred in the closed-loop group. CONCLUSIONS: In youths with new-onset type 1 diabetes, intensive glucose control for 24 months did not appear to prevent the decline in residual C-peptide secretion. (Funded by the National Institute for Health and Care Research and others; CLOuD ClinicalTrials.gov number, NCT02871089.)

The effect of closed-loop glucose control on C-peptide secretion in youth with newly diagnosed type 1 diabetes: the CLOuD RCT

Background We assessed whether a sustained period of intensive glucose control with hybrid closed-loop for 12 months following diagnosis of type 1 diabetes in children and adolescents can preserve C-peptide secretion compared to standard insulin therapy. Methods In an open-label, multicentre, randomised, parallel trial, youth aged 10–16.9 years were randomised within 21 days of type 1 diabetes diagnosis to hybrid closed-loop or standard insulin therapy (control). Primary end point was the difference in mixed-meal C-peptide area under the curve 12 months post diagnosis. Key secondary end points included time spent in target glucose range, glycated haemoglobin and time spent below target glucose range at 12 months. Analysis was by intention to treat. The Closed Loop from Onset in Type 1 Diabetes consortium secured external funding for participants to continue on beyond 12 months, but the funding by National Institute for Health and Care Research and the results reported here refer only to the 12 months follow-up. Results We randomised 97 participants (mean ± standard deviation age 12 ± 2 years), 51 to closed-loop and 46 to control therapy. There was no difference in C-peptide area under the curve at 12 months between groups [geometric mean (interquartile range) closed-loop (n = 46): 0.35 pmol/ml (0.16, 0.49) vs. control (n = 37): 0.46 pmol/ml (0.22, 0.69); mean adjusted difference –0.06 (95% confidence interval –0.14 to 0.03); p = 0.19]. The proportion of time in target range 3.9–10.0 mmol/l based on 14-day masked LibrePro (Abbott Diabetes Care, Maidenhead, UK) sensor glucose data at 12 months was 10 percentage points (95% confidence interval 2 to 17) higher in the closed-loop group (64 ± 14%) compared to control group (54 ± 23%). Arithmetic mean glycated haemoglobin A1c was lower in the closed-loop group by 4 mmol/mol (0.4%) [95% confidence interval 0 to 8 mmol/mol (0.0% to 0.7%)] at 12 months. The mean difference in time spent < 3.9 mmol/l between groups was 0.9 percentage points (95% confidence interval –1.0 to 2.8). Three severe hypoglycaemic events occurred in the closed-loop group (two participants), and one in the control group; one diabetic ketoacidosis occurred in the closed-loop group. Conclusions A sustained period of hybrid closed-loop glucose control following diagnosis of type 1 diabetes in children and adolescents does not slow down the decline in residual C-peptide secretion compared with standard insulin therapy. Despite the lack of effect on C-peptide, glycaemic control was sustained in the closed-loop group, whereas glycaemic control deteriorated in the control group 6 to 9 months after diagnosis and closed-loop safely accommodated the variability in exogenous insulin requirements which occur with beta-cell recovery post diagnosis. Limitations of the study included no central measurement of auto-antibodies at diagnosis. There was imbalance in the rate of diabetic ketoacidosis at diagnosis which is associated with a more rapid decline in C-peptide secretion, but this was adjusted for in the analyses. This highlights the need for improved therapies to allow youth to achieve recommended glycaemic targets from onset of type 1 diabetes irrespective of the lack of effect on residual C-peptide secretion. Future work includes ongoing follow-up of the study population for up to 4 years after diagnosis to observe how any differences in glycaemic control between treatment groups develop over time. Trial registration This trial is registered as Clinicaltrials.gov NCT02871089. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 14/23/09), the Helmsley Trust (2016PG-T1D045 and 2016PG-T1D046), and JDRF (22-2013-266 and 2-RSC-2019-828-M-N), and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 8. See the NIHR Funding and Awards website for further award information. Additional support for the artificial pancreas work was from the NIHR Cambridge Biomedical Research Centre and NIHR Oxford Biomedical Research Centre. Abbott Diabetes Care supplied free glucose monitoring devices, and Dexcom supplied discounted continuous glucose monitoring devices. Medtronic supplied discounted insulin pumps, phone enclosures, continuous glucose monitoring devices, and pump consumables. Plain language summary In type 1 diabetes the body’s immune system attacks and destroys the cells that make insulin in the pancreas. At diagnosis, there are usually a small number of cells left which still make insulin. Over time, people with type 1 diabetes lose the ability to make insulin themselves. Good glucose control in the early years after diagnosis might help to preserve insulin production. Even making a small amount of insulin can help with more stable glucose control and reduced risk of diabetes-related complications. Closed-loop systems have been shown to be safe and improve glucose control in people with type 1 diabetes. A closed-loop system is made up of a glucose sensor which continuously measures glucose levels, an insulin pump and a computer algorithm on a smartphone that automatically adjusts the amount of insulin given by the pump, depending on the glucose levels. The Closed Loop from Onset in Type 1 Diabetes study aimed to find out if a closed-loop system can preserve insulin production compared to standard insulin treatment in children and young people recently diagnosed with type 1 diabetes. The Closed Loop from Onset in Type 1 Diabetes consortium secured external funding for participants to continue on beyond 12 months but the funding by National Institute for Health and Care Research and the results reported here refer only to the 12 months follow-up. A total of 97 people were included in the study; 51 were assigned to use the closed-loop system and 46 used normal insulin treatment (control group). Every 6 months we measured how much insulin was being made by the pancreas. We also compared glucose control between the two groups and we asked participants using the closed-loop system how it affected their quality of life, using questionnaires and interviews. We showed that, although the group using the closed-loop system had better glucose control than the control group at 12 months, there was no difference between the two groups in the amount of insulin being made. This suggests that in young people recently diagnosed with type 1 diabetes, closed-loop glucose control does not preserve insulin production. Scientific summary Background Type 1 diabetes is characterised by autoimmune destruction of pancreatic beta-cells. At clinical diagnosis most people have residual pancreatic beta-cells which can continue to secrete insulin for several additional years. The Diabetes Control and Complications Trial (DCCT) showed that in adults, persistence of residual functioning beta-cells, measured by C-peptide secretion, is associated with improved glycaemic control, reduced risk of hypoglycaemia and lower incidence of microvascular complications. Interventions which can preserve endogenous insulin secretion prior to and following clinical diagnosis of type 1 diabetes are clinically important. Previous studies have investigated whether an early period of intensive glycaemic control following diagnosis of type 1 diabetes can prevent the decline in endogenous insulin secretion, with conflicting results. An early exploratory study in adolescents reported improved C-peptide secretion at 12 months following a period of intensive insulin treatment in hospital for 2 weeks after diagnosis. A more recent study applying a short period of hybrid closed-loop within 7 days of diagnosis, followed by sensor-augmented pump therapy, did not alter C-peptide secretion at 12 months compared with standard care, but there was no difference in glucose control between the two treatment groups over the 12-month study period. It has yet to be determined whether sustained intensive glycaemic control following diagnosis can ameliorate the decline in endogenous insulin secretion in youth with type 1 diabetes. Hybrid closed-loop systems have been shown to improve glucose control in youth and can accommodate variability in exogenous insulin requirements. We hypothesised that a sustained period of intensive glucose control with hybrid closed-loop following diagnosis of type 1 diabetes in children and adolescents can preserve C-peptide secretion compared to standard insulin therapy. Objectives The primary objective was to assess residual C-peptide secretion 12 months after diagnosis of type 1 diabetes in participants receiving either closed-loop insulin delivery or standard insulin therapy. The Closed Loop from Onset in Type 1 Diabetes (CLOuD) consortium secured external funding for participants to continue on beyond 12 months, but the funding by the National Institute for Health and Care Research (NIHR) and the results reported here refer only to the 12 months follow-up. Secondary objectives included: biochemical assessment of how closed-loop insulin delivery affects glucose control in terms of safety and efficacy human factors assessments of emotional and behavioural characteristics of participants and family members and their response to closed-loop insulin delivery. Methods In this open-label, multicentre, randomised, single-period, parallel design trial, youth aged 10–16.9 years were recruited within 21 days of type 1 diabetes diagnosis from seven paediatric diabetes clinics in the UK (Cambridge, Edinburgh, Leeds, Liverpool, Nottingham, Oxford, Southampton). Participants and their families received structured diabetes education and training on the multiple daily injection regimen as per standard clinical practice. Following recruitment, participants underwent a baseline mixed-meal tolerance test (MMTT) and were randomised to hybrid closed-loop or standard insulin therapy (control). Participants randomised to the closed-loop group were trained to use the study insulin pump and glucose sensor prior to starting closed-loop insulin delivery within 6 weeks of diagnosis. Participants continued with closed-loop therapy at home with no remote monitoring or study-related restrictions. Participants randomised to standard insulin therapy received additional training to complement the core training and to match contact time with the closed-loop group. Participants could switch to insulin pump therapy and/or use flash/continuous glucose monitoring (CGM) or approved closed-loop systems if clinically indicated, applying National Institute for Health and Care Excellence (NICE) criteria. Participants were followed up at 3-monthly intervals. At each follow-up visit, glycated haemoglobin A1c (HbA1c) was measured and participants wore a masked glucose sensor for 14 days. MMTTs were conducted at 6, 12 and 24 months post diagnosis following an overnight fast. The primary end point was the difference in mixed-meal C-peptide area under the curve (AUC) 12 months post diagnosis. Key secondary end points included time in target glucose range 3.9–10.0 mmol/l, glycated haemoglobin (HbA1c), and time in hypoglycaemia ( 10.0 mmol/l was 11 percentage points (95% CI 3 to 19 percentage points) lower in the CL group compared to the control group at 12 months. Glucose variability measured by standard deviation (SD) was similar between CL and control groups, while coefficient of variation of glucose was 4 percentage points higher in the CL group at 12 months (95% CI 1 to 8 percentage points). The primary end point was similar in a per-protocol analysis using data from randomised participants in the CL group with at least 60% CL use and those in the control group who did not start insulin pump therapy. Total daily insulin dose was similar between treatment groups, but there was a greater proportion of basal insulin (mean ± SD closed-loop 0.52 ± 0.31 U/kg/day, control 0.37 ± 0.26 U/kg/day) to bolus insulin (mean ± SD closed-loop 0.44 ± 0.22 U/kg/day, control 0.46 ± 0.23 U/kg/day) in the CL group at 12 months. Blood pressure, lipid profile and BMI percentile were similar between treatment groups. In the CL group, median CL use was 66% (IQR 44–80) over the 12-month period. In the control group, 10% of participants (n = 4) were using insulin pump therapy and 57% (n = 21) were using a flash or real-time continuous glucose sensor at 12 months post diagnosis. Three severe hypoglycaemic events occurred in the CL group (two participants), and one in the control group; one DKA occurred in the CL group and none in the control group. The number of other AEs (CL group 34, control group 37) and SAEs (CL group 2, control group 4) was similar between groups. Responses to the Pediatric Quality of Life Inventory (PedsQL), hypoglycaemia fear survey (HFS), problem areas in diabetes (PAID) and Strengths and Difficulties Questionnaires (SDQs) were similar between treatment groups in both children and parents at 12 months. Scores for the INSPIRE (INsulin Dosing Systems: Perceptions, Ideas, Reflections and Expectations) questionnaire were high in children, teenagers and parents, suggesting positive expectancies regarding automated insulin delivery in this population. In-depth interviews of 18 youths and 21 parents with ≥ 12 months’ experience of using CL technology were undertaken. Interviews explored the impact of using CL systems on diabetes management practices and everyday family life. As reported by Lawton et al. Participants reported very few disruptions to their lives when using a closed-loop system. Reports of family conflict were minimal as the closed-loop enabled dietary flexibility and glucose levels to be checked effortlessly. Adolescents described doing ‘normal’ activities without worrying about high or low glucose, and parents reported allowing them to do so unsupervised because the closed-loop would regulate their glucose and keep them safe. Some adolescents expressed concerns about the visibility of components and, to avoid stigma, described curtailing activities such as swimming. Participants described how the closed-loop enabled adolescents to be in control of, or create distance from, their diabetes. Lawton J, Kimbell B, Rankin D, Ashcroft NL, Varghese L, Allen JM, et al.; CLOuD Consortium. Health professionals’ views about who would benefit from using a closed-loop system: a qualitative study. Diabet Med: J Br Diabet Assoc 2020;37(6):1030–7. Interviews of multidisciplinary healthcare professionals (n = 22) providing support to trial participants explored the benefits, issues and challenges arising from introducing and using CL systems to support diabetes self-management. Lawton et al. reported that interviewees described how, compared with other insulin regimens, teaching and supporting individuals to use a closed-loop system could be initially more time-consuming. However, they also noted that after an initial adjustment period, users had less need for initiating contact with the clinical team compared with people using pumps or multiple daily injections. Interviewees highlighted how a lessened need for ad hoc clinical input could result in new challenges; specifically, they had fewer opportunities to reinforce users’ diabetes knowledge and skills and detect potential psychosocial problems. Lawton et al. (2020) We explored health professionals’ views about who would benefit from using a CL system. Interviewees described holding strong assumptions about the types of people who would use the technology effectively prior to the trial. Interviewees described changing their views as a result of observing individuals engaging with the CL system in ways they had not anticipated. This included educated, technologically competent individuals who over-interacted with the system in ways which could compromise glycaemic control. Other individuals, who health professionals assumed would struggle to understand and use the technology, were reported to have benefited from it because they stood back and allowed the system to operate without interference. Interviewees concluded that individual, family and psychological attributes cannot be used as pre-selection criteria and ideally all individuals should be given the chance to try the technology. Conclusions The CLOuD study demonstrates that CL glucose control over a period of 12 months does not slow the decline in C-peptide secretion in children and adolescents with new-onset type 1 diabetes. Mean time in range was 10 percentage points higher and mean HbA1c was 0.4% (4 mmol/mol) lower in the CL group compared with the control group at 12 months, but these end points did not reach the pre-specified significance thresholds and it is possible that a greater improvement in glucose control with attainment of normoglycaemia could prevent the decline in C-peptide secretion. Further work may be needed to definitively rule out a role of glycaemic burden in the decline of C-peptide secretion. Total daily exogenous insulin requirements, a surrogate marker of residual insulin secretion, were similar between groups at all time points after diagnosis. This comparison may be hampered by any between-group differences in glycaemic control. It is likely that factors other than glycaemic control, such as autoimmune response, determine the rate of C-peptide decline following diagnosis of type 1 diabetes. It is possible that other factors act in concert with dysglycaemia on C-peptide secretion. The present study demonstrates that hybrid CL is effective in new-onset type 1 diabetes in youth and can safely accommodate the variability in exogenous insulin requirements which occur with beta-cell recovery post diagnosis. Glycaemic control was sustained over 12 months in the CL group, whereas glycaemic control started to deteriorate in the control group at 6 to 9 months after diagnosis. At 12 months post diagnosis, only 56% of youth in the control group (78% in the CL group) were able to achieve a HbA1c of < 58 mmol/mol (< 7.5%) which is above the current national and international glycaemic targets. This highlights the need for improved therapies to allow youth to achieve recommended glycaemic targets from onset of type 1 diabetes irrespective of the lack of effect on residual C-peptide secretion. Strengths of this study include the multicentre,

Evaluating the Impact of Applying Personal Glucose Targets in a Closed-Loop System for People With Type 1 Diabetes

Peer reviewed: TrueFunder: JDRF; FundRef: https://doi.org/10.13039/100008871Funder: National Institute for Health Research Cambridge Biomedical Research CentreBackground: CamAPS FX is a hybrid closed-loop smartphone app used to manage type one diabetes. The closed-loop algorithm has a default target glucose of 5.8 mmol/L (104.5 mg/dL), but users can select personal glucose targets (adjustable between 4.4 mmol/L and 11.0 mmol/L [79 mg/dL and 198 mg/dL, respectively]). Method: In this post-hoc analysis, we evaluated the impact of personal glucose targets on glycemic control using data from participants in five randomized controlled trials. Results: Personal glucose targets were widely used, with 20.3% of all days in the data set having a target outside the default target bin (5.5-6.0 mmol/L [99-108 mg/dL]). Personal glucose targets >6.5 mmol/L (117 mg/dL) were associated with significantly less time in target range (3.9-10.0 mmol/L [70-180 mg/dL]; 6.5-7.0 mmol/L [117-126 mg/dL]: mean difference = −3.2 percentage points [95% CI: −5.3 to −1.2; P 6.5 mmol/L (117 mg/dL) were associated with significantly lower time (<3.9 mmol/L [<70 mg/dL]; 6.5-7.0 mmol/L [117-126 mg/dL]: −1.85 percentage points [95% CI: −2.37 to −1.34; P < .001]; 7.0-7.5 mmol/L [126-135 mg/dL]: −2.68 percentage points [95% CI: −3.49 to −1.86; P < .001]). Conclusions: Discrete study populations showed differences in glucose control when applying similar personal targets