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The US Food and Drug Administration's (FDA) approval of teplizumab to delay the onset of type 1 diabetes could be seen as symbolic, because it came a century after the first use of insulin. Teplizumab, an anti-CD3 monoclonal antibody, is now approved in the USA for people at high risk of type 1 diabetes. This approval is a highly welcome development for this population and all those involved in the care and wellbeing of people with type 1 diabetes. However, in our opinion, the approval of teplizumab should be interpreted with caution. A global health perspective must consider evidence, cost, patient preferences, and equity...

OBJECTIVE: To evaluate the impact of CamAPS FX hybrid closed-loop (HCL) automated insulin delivery in very young children with type 1 diabetes (T1D) on caregivers' well-being, fear of hypoglycemia, and sleepiness. RESEARCH DESIGN AND METHODS: We conducted a multinational, open-label, randomized crossover study. Children (age 1-7 years) with T1D received treatment for two 4-month periods in random order, comparing HCL with sensor augmented pump (control). At baseline and after each treatment period, caregivers were invited to complete World Health Organization-Five Well-Being Index, Hypoglycemia Fear Survey, and Epworth Sleepiness Scale questionnaires. RESULTS: Caregivers of 74 children (mean ± SD age 5 ± 2 years and baseline HbA1c 7.3 ± 0.7%; 42% female) participated. Results revealed significantly lower scores for hypoglycemia fear (P < 0.001) and higher scores for well-being (P < 0.001) after HCL treatment. A trend toward a reduction in sleepiness score was observed (P = 0.09). CONCLUSIONS: Our results suggest better well-being and less hypoglycemia fear in caregivers of very young children with T1D on CamAPS FX HCL.

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

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disorder characterized by high cholesterol and if left untreated leads to premature cardiovascular disease, such as heart attacks. Treatment that begins early in life, particularly in childhood, is highly efficacious in preventing cardiovascular disease and cost-effective, thus early detection of FH is crucial. However, in Europe, less than 10% of people living with FH are diagnosed and even less receive life-saving treatment. The Prague Declaration is a call to action for national and European Union policymakers and decision-makers and a result of the Czech EU Presidency meeting on FH Paediatric Screening (early detection of inherited high cholesterol) at the Czech Senate in Prague on 6th September 2022. It builds on a considerable body of evidence which was discussed at the Technical Meeting under the auspices of the Slovenian EU Presidency in October 2021. The Prague meeting addressed the outstanding barriers to the systematic implementation of FH paediatric screening across Europe. In this article, we present the key points from the Prague meeting and concrete actions needed to move forward.

This is the peer reviewed version of the following article: "COVID-19 outbreak and pediatric diabetes: perceptions of health care professionals worldwide". Pediatric Diabetes (2020): 20 July, which has been published in final form at 10.1111/pedi.13084. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions, Coronavirus diasease (COVID-19) is an infectious disease that startedin Wuhan, China in late 2019 and later spread around the world. Diabetes has beenrecognized as a possible risk factor for COVID-19 complications.Objective: International Society for Pediatric and Adolescent Diabetes (ISPAD) investi-gated perceptions, challenges and experience of health care professionals (HCP) takingcare of children and young people with diabetes worldwide during COVID-19 pandemic.Methods: From 21st April to 17th May 2020, during COVID-19 pandemic, a web-based survey was sent to ISPAD members and former participants of ISPAD confer-ences by email.Results: Responders from 215 diabetes centers from 75 countries completed the sur-vey. Majority were from UK (35; 16.3%), USA (20; 9.3%), and India (15; 7%). HCPwere mostly pediatric endocrinologists (64%). During COVID-19 pandemic, 16.5% ofresponders continued face-to-face consultation while most changed to telephone(32%) or video (18%) consultations. 19% reported a shortage of medical supplies.22% reported a delay in diagnosis of patients with new-onset diabetes, while 15%reported a higher incidence of DKA. 12% reported having one or more patients withCOVID-19. Most of the 86 children and adolescents with diabetes and COVID-19had only mild/moderate symptoms, while 5 required admission to an intensive careunit. No deaths were reported.Conclusions: This large global survey during COVID-19 pandemic showed that manyHCP adapted to the pandemic by resorting to telemedicine. One fourth of HCPreported delays in diagnosis and an increased rate of DKA. The emergence ofCOVID-19 pandemic had an important impact on family's behavior that might haveled to increase in diabetic ketoacidosis presentation

Funder: National Institute for Health Research Cambridge Biomedical Research Centre, AIMS: To explore parents' experiences of using remote monitoring technology when caring for a very young child with type 1 diabetes during a clinical trial. METHODS: Interviews were conducted with parents of 30 children (aged 1-7 years) participating in a trial (the KidsAP02 study) comparing hybrid closed-loop insulin delivery with sensor-augmented pump therapy. In both arms, parents had access to remote monitoring technology. Data analysis focused on identification of descriptive themes. RESULTS: Remote monitoring technology gave parents improved access to data which helped them pre-empt and manage glucose excursions. Parents observed how, when children were in their own care, they could be more absent while present, as their attention could shift to non-diabetes-related activities. Conversely, when children were others' care, remote monitoring enabled parents to be present while absent, by facilitating oversight and collaboration with caregivers. Parents described how remote monitoring made them feel more confident allowing others to care for their children. Parents' confidence increased when using a hybrid closed-loop system, as less work was required to keep glucose in range. Benefits to children were also highlighted, including being able to play and sleep uninterrupted and attend parties and sleepovers without their parents. While most parents welcomed the increased sense of control remote monitoring offered, some noted downsides, such as lack of respite from caregiving responsibilities. CONCLUSIONS: Remote monitoring can offer manifold benefits to both parents and very young children with type 1 diabetes. Some parents, however, may profit from opportunities to take 'time out'.

Aims: To explore parents’ experiences of using remote monitoring technology when caring for a very young child with type 1 diabetes during a clinical trial. Methods: Interviews were conducted with parents of 30 children (aged 1-7 years) participating in a trial (the KidsAP02 study) comparing hybrid closed-loop insulin delivery with sensor-augmented pump therapy. In both arms, parents had access to remote monitoring technology. Data analysis focused on identification of descriptive themes.Results: Remote monitoring technology gave parents improved access to data which helped them pre-empt and manage glucose excursions. Parents observed how, when children were in their own care, they could be more absent while present, as their attention could shift to non-diabetes-related activities. Conversely, when children were others’ care, remote monitoring enabled parents to be present while absent, by facilitating oversight and collaboration with caregivers. Parents described how remote monitoring made them feel more confident allowing others to care for their children. Parents’ confidence increased when using a hybrid closed-loop system, as less work was required to keep glucose in range. Benefits to children were also highlighted, including being able to play and sleep uninterrupted and attend parties and sleepovers without their parents. While most parents welcomed the increased sense of control remote monitoring offered, some noted downsides, such as lack of respite from caregiving responsibilities. Conclusions: Remote monitoring can offer manifold benefits to both parents and very young children with type 1 diabetes. Some parents, however, may profit from opportunities to take ‘time out’.

CamAPS FX (CamDiab, Cambridge, UK) is a hybrid closed-loop app hosting the Cambridge closed-loop algorithm on an Android smartphone, and is approved in the EU for use in children ≥1 year, and adults (including during pregnancy) with type 1 diabetes (T1D). The interoperable CamAPS FX app receives glucose data from a compatible CGM system (Dexcom G6; Dexcom, San Diego, CA), connects to a compatible insulin pump (Dana Diabecare RS and DANA-i; Sooil, Seoul, South Korea) to direct glucose-responsive insulin delivery every 8-12 minutes, includes a bolus calculator allowing discrete bolusing via the app, and streams data in real-time to cloud-based diabetes data repositories (Diasend/Glooko, Gothenburg, Sweden).

IntroductionDiabetes management in very young children remains challenging. Glycaemic targets are achieved at the expense of high parental diabetes management burden and frequent hypoglycaemia, impacting quality of life for the whole family. Our objective is to assess whether automated insulin delivery can improve glycaemic control and alleviate the burden of diabetes management in this particular age group.Methods and analysisThe study adopts an open-label, multinational, multicentre, randomised, crossover design and aims to randomise 72 children aged 1–7 years with type 1 diabetes on insulin pump therapy. Following screening, participants will receive training on study insulin pump and study continuous glucose monitoring devices. Participants will be randomised to 16-week use of the hybrid closed-loop system (intervention period) or to 16-week use of sensor-augmented pump therapy (control period) with 1–4 weeks washout period before crossing over to the other arm. The order of the two study periods will be random. The primary endpoint is the between-group difference in time spent in the target glucose range from 3.9 to 10.0 mmol/L based on sensor glucose readings during the 16-week study periods. Analyses will be conducted on an intention-to-treat basis. Key secondary endpoints are between group differences in time spent above and below target glucose range, glycated haemoglobin and average sensor glucose. Participants’ and caregivers’ experiences will be evaluated using questionnaires and qualitative interviews, and sleep quality will be assessed. A health economic analysis will be performed.Ethics and disseminationEthics approval has been obtained from Cambridge East Research Ethics Committee (UK), Ethics Committees of the University of Innsbruck, the University of Vienna and the University of Graz (Austria), Ethics Committee of the Medical Faculty of the University of Leipzig (Germany) and Comité National d’Ethique de Recherche (Luxembourg). The results will be disseminated by peer-reviewed publications and conference presentations.Trial registration numberNCT03784027.

OBJECTIVE: To evaluate the experiences of families with very young children aged 1 to 7 years (inclusive) with type 1 diabetes using day-and-night hybrid closed-loop insulin delivery. METHODS: Parents/caregivers of 20 children aged 1 to 7 years with type 1 diabetes completed a closed-loop experience survey following two 3-week periods of unrestricted day-and-night hybrid closed-loop insulin therapy using Cambridge FlorenceM system at home. Benefits, limitations, and improvements of closed-loop technology were explored. RESULTS: Responders reported reduced burden of diabetes management, less time spent managing diabetes, and improved quality of sleep with closed-loop. Ninety percent of the responders felt less worried about their child's glucose control using closed-loop. Size of study devices, battery performance and connectivity issues were identified as areas for improvement. Parents/caregivers wished for more options to input information to the system such as temporary glucose targets. CONCLUSIONS: Parents/caregivers of very young children reported important quality of life benefits associated with using closed-loop, supporting adoption of this technology in this population.

OBJECTIVE: To quantify age-related variability of insulin needs during day and night closed-loop insulin delivery. RESEARCH DESIGN AND METHODS: We retrospectively analyzed data from hybrid closed-loop studies involving young children (1-6 years old, n = 20), children (7-12 years, n = 21), adolescents (13-17 years, n = 15), and adults (>18 years, n = 58) with type 1 diabetes. The coefficient of variation quantified variability of insulin needs during 3 weeks of unrestricted-living hybrid closed-loop use. RESULTS: Data from 2,365 nights and 2,367 days in 114 participants were analyzed. The coefficient of variation of insulin delivery was higher in young children compared with adults (mean difference at nighttime 10.7 percentage points [95% CI 2.9-18.4], P = 0.003; daytime 6.4 percentage points [95% CI 2.0-10.9], P = 0.002) and compared with adolescents (mean difference at nighttime 10.2 percentage points [95% CI 0.0-20.4], P = 0.049; daytime 7.0 percentage points [95% CI 1.1-12.8], P = 0.014). CONCLUSIONS: Diabetes management in young children is complicated by higher variability in insulin requirements, supporting fast-track clinical practice adoption of closed-loop in this vulnerable population.

Sleep Diaries. (DOC 77 kb)

Questionnaires for parents. (DOC 158 kb)

Trial Protocol. (DOCX 46 kb)

Sleep Diaries. (DOC 81 kb)

Case Report Forms. (DOC 81 kb)

Case Report Forms. (DOC 88 kb)

Case Report Forms. (DOC 70 kb)

Figure S1. Scheme summarising the different control experiments, the titration experiments and their outcomes. a) Tracing non-human sRNA sequences to contaminants on spin columns by variation of different steps in the isolation protocol and analysis by qPCR assays. Modifications to the steps named at the top are listed below the workflow and the outcomes are summarised at the right hand side. b) Workflow of the titration experiment to determine a minimal safe input volume for all contaminant sequences. UCP column ultra-clean column. (PDF 86Â kb)

Sleep Diaries. (DOC 78 kb)

Questionnaires for children. (DOC 146 kb)

Patient Information and consent form. (DOCX 233 kb)

Questionnaires for parents. (DOC 119 kb)

IRB approval. (PDF 118 kb)

Case Report Forms. (DOC 105 kb)

Case Report Forms. (DOC 80 kb)

Questionnaires for children. (DOC 152 kb)

Spirit Checklist. (DOC 114 kb)

Figure S3. Detection of contaminants in eluates of regular and ultra-clean RNeasy columns. Two batches of regular miRNeasy columns and four batches of ultra-clean RNeasy columns were compared. Results are based on sRNA sequencing data of mock extracts, normalised to the detected levels of spike-in synthetic RNAs. The different shadings represent reads mapping to the human genome with 2, 1, or 0 mismatches and the different column batches are coloured in the same colours as in main Fig. 3, as indicated in the legends. (PDF 16Â kb)

Figure S2. Detection of contaminants in published datasets. Heatmap showing the relative abundances of the confirmed contaminant sequences in published sRNA sequencing data of low-biomass samples. Only samples for which any of the confirmed contaminants were detected are shown. Extraction methods: Q regular QIAGEN miRNeasy; T TRIZOL. rpm reads per million. (PDF 106Â kb)

BackgroundStudies have shown that overnight closed-loop insulin delivery can improve glucose control and reduce the risk of hypoglycemia and hence may improve metabolic outcomes and reduce burden for children with type 1 diabetes and their families. However, research so far has not reported insulin levels while comparing closed-loop to open-loop insulin delivery in children. Therefore, in this study we obtained glucose levels as well as plasma insulin levels in children with type 1 diabetes to evaluate the efficacy of a model-based closed-loop algorithm compared to an open-loop administration.MethodsFifteen children with type 1 diabetes, 6-12 years, participated in this open-label single center study. We used a randomized cross over design in which we compared overnight closed-loop insulin delivery with sensor augmented pump therapy for two nights in both the hospital and at home (i.e., 1 night in-patient stay and at home per treatment condition). Only during the in-patient stay, hourly plasma insulin and blood glucose levels were assessed and are reported in this paper.ResultsResults of paired sample t-tests revealed that although plasma insulin levels were significantly lower during the closed-loop than in the open-loop (Mean difference 36.51 pmol/l; t(13) = 2.13, p = .03, effect size d = 0.57), blood glucose levels did not vary between conditions (mean difference 0.76 mmol/l; t(13) = 1.24, p = .12, d = 0.37). The administered dose of insulin was significantly lower during the closed-loop compared with the open-loop (mean difference 0.10 UI; t(12) = 2.45, p = .02, d = 0.68).ConclusionsLower insulin doses were delivered in the closed-loop, resulting in lower plasma insulin levels, whereby glucose levels were not affected negatively. This suggests that the closed-loop administration is better targeted and hence could be more effective.

Aims/hypothesis The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study was designed to establish whether weaning to a highly hydrolysed formula in infancy subsequently reduces the risk of type 1 diabetes. Methods The study population comprises newborn infants who have first-degree relatives with type 1 diabetes and meet the increased risk HLA inclusion, but not exclusion criteria. The study is being performed in 15 countries in three continents. First-degree relatives of patients with type 1 diabetes were identified from diabetes clinics, diabetes registries, and from other endocrinology or obstetrics offices and websites. HLA typing was performed at birth from cord or heel stick blood, and the results sent to the study’s Data Management Unit within 2 weeks for communication of eligibility to the clinical study centre. All mothers recruited were encouraged to breastfeed. The intervention lasted for 6 to 8 months, and weaning formulas based on hydrolysed casein and standard cow’s milk were compared. Results TRIGR recruited 5,606 infants, of whom 2,160 were enrolled as eligible participants, 6% more than the target of 2,032. Of those enrolled, 80% were exposed to the study formula. The overall retention rate over the first 5 years is 87%, with protocol compliance at 94%. The randomisation code will be opened when the last recruited child turns 10 years of age, i.e. in 2017. Conclusions/interpretation The TRIGR experience demonstrates the feasibility and successful implementation of an international dietary intervention study. TRIGR is the first ever primary prevention trial for type 1 diabetes and, if completed successfully, will provide a definite answer to the research question. Trial registration ClinicalTrials.gov NCT00179777 Funding The study was funded by the National Institute of Child Health and Development (NICHD) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (grant numbers HD040364, HD042444 and HD051997), Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation International and the Commission of the European Communities (specific RTD programme ‘Quality of Life and Management of Living Resources’, contract number QLK1-2002-00372 ‘Diabetes Prevention’. Other funding came from the EFSD/JDRF/Novo Nordisk Focused Research Grant, Academy of Finland, Dutch Diabetes Research Foundation and Finnish Diabetes Research Foundation). Electronic supplementary material The online version of this article (doi:10.1007/s00125-010-1964-9) includes details of the TRIGR Writing Group, plus a complete list of investigators and other TRIGR staff members, and is available to authorised users.

Objective: To document current practices using continuous subcutaneous insulin infusion (CSII) by downloading electronically the 90-d pump data held within the pump memory and relating that to clinical data from children and adolescents in different pediatric diabetes centers from Europe and Israel.Methods: Data of patients (1-18 yr) treated with CSII in 23 centers from nine European countries and Israel were recorded with the ENCAPTURE software (PEC International, Frankfurt, Germany). The number of patients who participated was 377 (48% female; mean diabetes duration +/- SD: 6.8 +/- 3.7 yr; age: 12.9 +/- 3.8 yr, preschool n = 33; prepubertal n = 95; adolescent n = 249; CSII duration: 1.6 +/- 1.2 yr; local HbA1c: 8.1 +/- 1.2%).Results: The total insulin dose was lower than previously reported for injection therapy (0.79 +/- 0.20 U/kg/d). Covariance coefficient of daily total insulin was high in all age groups (adolescents 19 +/- 9%, prepubertal 18 +/- 8 and preschool 17 +/- 8). The distribution of basal insulin infusion rates over 24 hr (48 +/- 12% of total dose) varied significantly between centers and age groups. The number of boluses per day (7 +/- 3) was not significantly different between the age groups (average daily bolus amount: 0.42 +/- 0.16 U/kg). The rate of severe hypoglycemia (coma/convulsions) was 12.4 episodes per 100 patient-years and the number of diabetes-related hospital days was 124 per 100 patient-years.Discussion: Pediatric CSII patients show a high variability in their insulin therapy. This relates both to age-dependent differences in the distribution of basal insulin as to the age-independent day-to-day variation in prandial insulin.

Figure S4. Relative abundance of potential exogenous sRNAs in datasets derived from a plasma sample of one healthy individual. Detected levels of the 21 potential exogenous sRNA sequences in preparations using 45 to 1115 μL human plasma and regular or ultra-clean RNeasy spin columns and in controls without plasma, including no library, mock extractions and water controls (n = 33). cpm counts per million. Error bars indicate one standard deviation; data points are available in Additional file 2: Table S11. (PDF 11 kb)

Figure S4. Relative abundance of potential exogenous sRNAs in datasets derived from a plasma sample of one healthy individual. Detected levels of the 21 potential exogenous sRNA sequences in preparations using 45 to 1115 μL human plasma and regular or ultra-clean RNeasy spin columns and in controls without plasma, including no library, mock extractions and water controls (n = 33). cpm counts per million. Error bars indicate one standard deviation; data points are available in Additional file 2: Table S11. (PDF 11 kb)