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Background and Aims: Following recent reports of increased numbers of adolescents being diagnosed with the adult or type 2 form of diabetes we aimed to describe the prevalence of both [...]

AIMS: Primary Care Trusts (PCTs) are now responsible for the planning and delivery of health-care services throughout England and Wales. As the 25 PCTs throughout Yorkshire are representative of the national distribution in terms of population structure and socio-economic status, we aimed to address the paucity of information describing the burden of childhood diabetes in primary care and to evaluate the cost implications of insulin pump therapy on individual PCTs. METHODS: We extracted information from a population-based register in Yorkshire, including 1952 patients diagnosed under the age of 15 years from 1990 to 2003. Each patient's postcode was linked to an individual PCT. Incidence rates (per 100 000 patient years) were derived and assessed for evidence of heterogeneity across PCTs and within Strategic Health Authorities (SHAs). RESULTS: Incidence rates were lower in West Yorkshire (19.1, 95% CI 18.0-20.2) than North-east Yorkshire (20.3, 18.9-21.6), although this difference was not significant (P = 0.20). No significant evidence of heterogeneity in incidence rates was observed across PCTs (P = 0.46). Ninety per cent of all PCTs would expect four to seven newly diagnosed children per year, corresponding to a single general practitioner (GP) referring an individual for diagnosis once every 15 years on average. Assuming 1% of current patients under the age of 15 years with diabetes were to move onto insulin pump therapy, this would impose an additional cost of pound400-1300 per year for each PCT. The average cost was 15% lower for PCTs in West Yorkshire than North and East Yorkshire. CONCLUSIONS: The additional resources required to pay for insulin pump therapy for a small proportion of the diabetes population would be minimal given the potential benefits to these patients of improved control and anticipated reduction in long-term morbidity. [ABSTRACT FROM AUTHOR]

Background: Eltrombopag is a new, orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis. We evaluated its ability to increase platelet counts and facilitate treatment for hepatitis C virus (HCV) infection in patients with thrombocytopenia associated with HCV-related cirrhosis.Methods: Seventy-four patients with HCV-related cirrhosis and platelet counts of 20,000 to less than 70,000 per cubic millimeter were randomly assigned to receive eltrombopag (30, 50, or 75 mg daily) or placebo daily for 4 weeks. The primary end point was a platelet count of 100,000 per cubic millimeter or more at week 4. Peginterferon and ribavirin could then be initiated, with continuation of eltrombopag or placebo for 12 additional weeks.Results: At week 4, platelet counts were increased to 100,000 per cubic millimeter or more in a dose-dependent manner among patients for whom these data were available: in 0 of the 17 patients receiving placebo, in 9 of 12 (75%) receiving 30 mg of eltrombopag, in 15 of 19 (79%) receiving 50 mg of eltrombopag, and in 20 of 21 (95%) receiving 75 mg of eltrombopag (P<0.001). Antiviral therapy was initiated in 49 patients (in 4 of 18 patients receiving placebo, 10 of 14 receiving 30 mg of eltrombopag, 14 of 19 receiving 50 mg of eltrombopag, and 21 of 23 receiving 75 mg of eltrombopag) while the administration of eltrombopag or placebo was continued. Twelve weeks of antiviral therapy, with concurrent receipt of eltrombopag or placebo, were completed by 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, and 75 mg of eltrombopag, respectively, and by 6% of patients in the placebo group. The most common adverse event during the initial 4 weeks was headache; thereafter, the adverse events were those expected with interferon-based therapy.Conclusions: Eltrombopag therapy increases platelet counts in patients with thrombocytopenia due to HCV-related cirrhosis, thereby permitting the initiation of antiviral therapy. (ClinicalTrials.gov number, NCT00110799.) [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the longer-term safety and efficacy of hybrid closed-loop (CL) therapy in very young children with type 1 diabetes (T1D)., Research Design and Methods: Following a 16-week multinational, randomized crossover trial comparing hybrid CL with sensor-augmented pump (SAP) therapy in 74 very young children aged 1-7 years with T1D, participants were invited to an extension phase using CL for a further 18 months. Outcomes were compared with the primary-phase SAP period and primary-phase CL period., Results: After the primary study phase, 60 participants were eligible to enroll in the extension. Of these, 49 consented (mean ± SD age 6.6 ± 1.5 years) to continue use of CL for 18 months. Percentage time in range (TIR) 3.9-10.0 mmol/L was 8.4 percentage points (95% CI 6.7-10.1; P < 0.001) higher, while HbA1c was 0.4% ([5.0 mmol/mol], 95% CI 0.3-0.6 [3.7-6.2]; P < 0.001) lower during the CL extension phase compared with primary-phase SAP period. At 18 months, mean HbA1c was 6.7 ± 0.5% and TIR was 70 ± 7%, compared with 6.7 ± 0.5% and 71 ± 6% in the primary-phase CL period. Time in hypoglycemia (<3.9 mmol/L) was similar between CL extension phase and both primary-phase SAP (P = 0.31) and CL periods (P = 0.70). There were two severe hypoglycemia events and one other serious adverse event during the extension phase. One unexpected serious adverse device effect occurred., Conclusions: Use of the Cambridge hybrid CL system led to sustained improvements in glycemic control lasting more than 18 months in very young children with T1D., (© 2024 by the American Diabetes Association.)

Background: A diagnosis of type 1 diabetes in a young person can create vulnerability for sleep. Historically it has been rare for young people to be offered a closed-loop system soon after diagnosis meaning that studies examining sleep under these circumstances in comparison with standard treatment have not been possible. In this study, we examine sleep in young people (and their parents) who were provided with hybrid closed-loop therapy at diagnosis of type 1 diabetes versus those who receive standard treatment over a 2-year period., Methods: The sample comprised 97 participants (mean age = 12.0 years; SD = 1.7) from a multicenter, open-label, randomized, parallel trial, where young people were randomized to either hybrid closed-loop insulin delivery or standard care at diagnosis. Sleep was measured using actigraphy and the Pittsburgh Sleep Quality Index (PSQI) in the young people, and using the PSQI in parents., Results: Sleep in young people using hybrid closed-loop insulin delivery did not differ significantly compared with those receiving standard care (although there were nonsignificant trends for better sleep in the closed-loop group for 4 of the 5 sleep actigraphy measures and PSQI). Similarly, there were nonsignificant differences for sleep between the groups at 24 months (with mixed direction of effects)., Conclusions: This study assessed for the first time sleep in young people using a closed-loop system soon after diagnosis. Although sleep was not significantly different for young people using closed-loop insulin delivery as compared with those receiving standard care, the direction of effects of the nonsignificant results indicates a possible tendency for better sleep quality in the hybrid closed-loop insulin delivery group at the beginning of the treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EMS has received research support from Medical Research Council, Diabetes UK, National Institute for Health Research (NIHR), Abbott Diabetes Care and speaker honoraria: from Abbott Diabetes Care, Ypsomed, and Lilly Diabetes Care. CKB has received consulting fees from CamDiab and speaker honoraria from Ypsomed. JW has received speaker honoraria from Ypsomed and Novo Nordisk. MEW reports patents related to closed-loop and being a consultant at CamDiab. SH serves as a member of Medtronic advisory board, is a director of Ask Diabetes Ltd providing training and research support in health care settings, and reports having received training honoraria from Medtronic and Sanofi and consulting fees for CamDiab. TR receives consultancy fees from Abbott Diabetes care and has received honoraria from NovoNordisk for delivering educational meetings. REJB reports receiving speaker honoraria from Eli Lilly and Springer Healthcare, and reports sitting on the NovoNordisk UK Foundation Research Selection Committee on a voluntary basis. She acted as an independent advisor for Provent Bio, and received speaking honoraria from Sanofi and Medcape, which were donated to an education research fund. RH reports receiving speaker honoraria from Eli Lilly, Dexcom and Novo Nordisk, receiving license and/or consultancy fees from BBraun and Abbott Diabetes Care; patents related to closed-loop, and being director at CamDiab. AMG is an advisor for a project initially sponsored by Johnson’s Baby. She was a consultant for Perrigo (2021+). She receives royalties for two books Nodding Off (Bloomsbury Sigma, 2018) and The Sleepy Pebble (Flying Eye, 2019) and a sleep gift (The Gift of Sleep, Laurence King Publishers, 2023). She was previously a CEO of Sleep Universal LTD (2022). She is a regular contributor to BBC Focus Magazine and has contributed to other outlets (such as The Conversation, The Guardian, and Balance Magazine). She occasionally receives sample products related to sleep (eg, blue light–blocking glasses) and has given a paid talk to a business (Investec). She is a specialist subject editor at JCPP (sleep) for which she receives a small honorarium. She has contributed a paid article to Neurodiem.JJM-V, JMA, AT, AG, DE, NT, and FMC declare no competing financial interests.

Objective: We evaluated the effect of long-term intensive metabolic control with hybrid closed-loop (CL) on residual C-peptide secretion and glucose control compared with standard insulin therapy in youth with type 1 diabetes over 48 months., Research Design and Methods: Following the 24-month primary phase of a multicenter, randomized, parallel trial of 96 newly diagnosed youth aged 10 to 16.9 years, participants were invited to an extension phase using treatment allocated at randomization. They continued with hybrid CL using the Cambridge algorithm or standard insulin therapy (control) until 48 months after diagnosis. Analysis was by intention-to-treat., Results: At 24 months after diagnosis, 81 participants (mean ± SD age 14 ± 2 years) continued in the extension phase (47 CL, 34 control). There was no difference in fasting C-peptide corrected for fasting glucose at 48 months between groups (CL: 5 ± 9 vs. control: 6 ± 14 pmol/L per mmol/L; mean adjusted difference -2 [95% CI -7, 4; P = 0.54]). Central laboratory HbA1c remained lower in the CL group by 0.9% (10 mmol/mol [95% CI 0.2, 1.5; 3, 17 mmol/mol); P = 0.009). Time in target range of 3.9 to 10.0 mmol/L was 12 percentage points (95% CI 3, 20; P = 0.008) higher in the CL group compared with control. There were 11 severe hypoglycemic events (6 CL, 5 control) and 7 diabetic ketoacidosis events (3 CL, 4 control) during the extension phase., Conclusions: Improved glycemic control was sustained over 48 months after diagnosis with CL insulin delivery compared with standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion., (© 2024 by the American Diabetes Association.)

Objective: Many hybrid closed-loop (HCL) systems struggle to manage unusually high glucose levels as experienced with intercurrent illness or pre-menstrually. Manual correction boluses may be needed, increasing hypoglycemia risk with overcorrection. The Cambridge HCL system includes a user-initiated algorithm intensification mode ("Boost"), activation of which increases automated insulin delivery by approximately 35%, while remaining glucose-responsive. In this analysis, we assessed the safety of "Boost" mode., Methods: We retrospectively analyzed data from closed-loop studies involving young children (1-7 years, n = 24), children and adolescents (10-17 years, n = 19), adults (≥24 years, n = 13), and older adults (≥60 years, n = 20) with type 1 diabetes. Outcomes were calculated per participant for days with ≥30 minutes of "Boost" use versus days with no "Boost" use. Participants with <10 "Boost" days were excluded. The main outcome was time spent in hypoglycemia <70 and <54 mg/dL., Results: Eight weeks of data for 76 participants were analyzed. There was no difference in time spent <70 and <54 mg/dL between "Boost" days and "non-Boost" days; mean difference: -0.10% (95% confidence interval [CI] -0.28 to 0.07; P = .249) time <70 mg/dL, and 0.03 (-0.04 to 0.09; P = .416) time < 54 mg/dL. Time in significant hyperglycemia >300 mg/dL was 1.39 percentage points (1.01 to 1.77; P < .001) higher on "Boost" days, with higher mean glucose and lower time in target range ( P < .001)., Conclusions: Use of an algorithm intensification mode in HCL therapy is safe across all age groups with type 1 diabetes. The higher time in hyperglycemia observed on "Boost" days suggests that users are more likely to use algorithm intensification on days with extreme hyperglycemic excursions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RH reports having received speaker honoraria from Eli Lilly, Dexcom, and Novo Nordisk; receiving license fees from BBraun; patents related to closed-loop; and being director at CamDiab. JW reports receiving speaker honoraria from Ypsomed. YR is a consultant at CamDiab. MEW is a consultant at CamDiab and reports patents related to closed-loop. CKB reports receiving consultancy fees from CamDiab and speaker honoraria from Ypsomed. SH reports speaker and advisory board fees from Dexcom, Medtronic, Sanofi, and Ypsomed; being director at ASK Diabetes Ltd; and receiving consulting/training fees from CamDiab. LB reports receiving research support from Dexcom and CamDiab. REJB reports receiving speaking honoraria from Eli Lilly and Springer Healthcare, and sitting as a voluntary unpaid member of the NovoNordisk UK Foundation Research Selection committee. FMC reports receiving speaker honoraria from Eli Lilly, Dexcom, and Novo Nordisk and Insulet, and consultancy fees from Abbott Diabetes Care. EF-R reports having received speaker honoraria from Eli Lilly and Novo Nordisk, serving on advisory boards for Eli Lilly and Sanofi. MLE is a clinical triallist with or has served on advisory boards or received speakers or writers fees from Medtronic, Dexcom, Abbott Diabetes Care, Roche, AstraZeneca, Novo Nordisk, Eli Lilly, Zucara, Pila Pharma, and Imcyse Pharma. SEH has received speaker honoraria by Eli Lilly, Vertex, Minimed Medtronic, Insulet, Ypsomed, and Sanofi. TMK reports having received speaker honoraria from Eli Lilly and Novo. LL has received personal fees from Abbott Diabetes Care, Dexcom, Insulet, Medtronic, Novo Nordisk, Sanofi, and Diabetes Care. JKM is a member on the advisory board of Boehringer Ingelheim, Becton-Dickinson, Eli Lilly, Medtronic, Prediktor A/S, Roche Diabetes Care, and Sanofi-Aventis, and received speaker honoraria from Abbott Diabetes Care, AstraZeneca, Becton-Dickinson, Dexcom, Eli Lilly, Mercke Sharp & Dohme, NovoNordisk, Roche Diabetes Care, Sanofi, Servier, and Ypsomed. TR reports receiving speaker honoraria from Novo Nordisk and consultancy fees from Abbott Diabetes Care. HT reports receiving research support from Dexcom and speaker honoraria from Eli Lilly. MT reports having received speaker honoraria from Eli Lilly, Novo Nordisk, and Medtronic and advisory board fees from Abbott Diabetes Care. BR-M has received speaker honoraria from Abbott Diabetes Care, Eli Lilly, Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi, and Menarini and has been on the advisory boards of Eli Lilly, Roche Diabetes Care, and Abbott Diabetes Care. CdB has received speaker honoraria from Minimed Medtronic, and has been member of their European Psychology and e-learning Advisory Board. JMA reports training fees from CamDiab. DE, WMM, PN, TP, AG, AT, KD, and NT have no disclosures.

Background: 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 < .001]; 7.0-7.5 mmol/L [126-135 mg/dL]: -10.8 percentage points [95% CI: -14.1 to -7.6; P < .001]). Personal targets >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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C.K.B. has received consulting fees from CamDiab and speaker honoraria from Ypsomed. J.W. has received speaker honoraria from Ypsomed. J.M.A. has received consulting fees from CamDiab. S.H. serves as a member of Sigma (Dexcom) and Medtronic advisory boards; is a consultant for CamDiab and a director of Ask Diabetes Ltd., providing training and research support in healthcare settings; and reports having received training honoraria from Medtronic, Sanofi, and Ypsomed. M.E.W. reports receiving license fees from B. Braun, patents related to closed-loop systems, and being a consultant at CamDiab. C.d.B. reports having received speaker honoraria from Medtronic and has served on the EU psychology e-learning board of Medtronic. E.F.-R. reports having received speaker honoraria from Medtronic, Eli Lilly and Company, Novo Nordisk, and Sanofi and serving on the advisory board for Eli Lilly and Company. S.E.H. has received speaker honoraria from Medtronic, Eli Lilly, Ypsomed, and Insulet. T.M.K. reports having received speaker honoraria from Eli Lilly, Merck Serono, and Novo Nordisk. B.R.-M. has received speaker honoraria from Abbott Diabetes Care, Eli Lilly, Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi, and Menarini and has been on the advisory boards of Eli Lilly, Roche Diabetes Care, and Abbott Diabetes Care. T.L.R. has received consultancy fees from Abbott Diabetes Care and speaker honoraria from Novo Nordisk. R.E.J.B. reports having received speaking honoraria from Eli Lilly and Springer Healthcare and sits as an unpaid member of the Novo Nordisk UK Research Foundation grant and selection committee. L.D. has received honoraria for taking part in an Interactive Advisory and Advocacy Forum on CGM Use in Pediatric Clinical Practice from Dexcom and has received conference fees from Novo Nordisk. H.T. reports having received research support from Dexcom and speaker honoraria from Eli Lilly and Dexcom. L.L. reports having received speaker honoraria from Animas, Abbott, Insulet, Medtronic, Novo Nordisk, Roche, and Sanofi; was on advisory panels for Animas, Abbott, Novo Nordisk, Dexcom, Medtronic, Sanofi, and Roche; and received research support from Novo Nordisk and Dexcom. M.L.E. reports having received speaker honoraria from Eli Lilly and Company, Novo Nordisk, Abbott Diabetes Care, Medtronic, AstraZeneca, and Ypsomed and acting on advisory boards for Medtronic, Novo Nordisk, Zucara Therapeutics, Pila Pharma, and Abbott Diabetes Care. J.K.M. is a member of the advisory boards of Abbott Diabetes Care, BD, Boehringer Ingelheim, Eli Lilly and Company, Medtronic, Novo Nordisk AS, Prediktor A/S, Roche Diabetes Care, and Sanofi; received speaker honoraria from Abbott Diabetes Care, AstraZeneca, Dexcom, Eli Lilly and Company, Menarini Diagnostics, Novo Nordisk A/S, Roche Diabetes Care, Servier, and Ypsomed; and is a cofounder and shareholder of decide Clinical Software Ltd. R.H. reports having received speaker honoraria from Eli Lilly and Company, Dexcom, and Novo Nordisk; receiving license fees from Medtronic; receiving patents related to closed-loop systems; and being the director at CamDiab. M.F., A.T., F.M.C., A.G., D.E., N.T., N.D., and L.B. have no conflict of interest to disclose.

The presence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) is associated with higher glycated hemoglobin levels over time. We evaluated whether hybrid-closed loop (HCL) therapy from onset of T1D could prevent the adverse impact of DKA at diagnosis on long-term glycemic outcomes. This was a posthoc analysis from 51 adolescents using HCL from diagnosis of T1D as part of the CLOuD trial (NCT02871089). We compared glycemic and insulin metrics between adolescents with ( n  = 17) and without ( n  = 34) DKA at diagnosis. Participants with and without DKA at diagnosis had similar time in target glucose range 3.9-10.0 mmol/L (70-180 mg/dL), time below range (<3.9 mmol/L, <70 mg/dL) and HbA1c at 6, 12, and 24 months. While insulin requirements at 6 months were higher in those with DKA at diagnosis, this was not statistically significant after adjusting for bodyweight. Residual C-peptide secretion was similar between groups. We conclude that HCL therapy may mitigate against the negative glycemic effects of DKA at T1D diagnosis.

Objective: Hearing loss has a detrimental impact on cognitive function. However, there is a lack of consensus on the impact of cochlear implants on cognition. This review systematically evaluates whether cochlear implants in adult patients lead to cognitive improvements and investigates the relations of cognition with speech recognition outcomes., Data Sources: A literature review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies evaluating cognition and cochlear implant outcomes in postlingual, adult patients from January 1996 to December 2021 were included. Of 2510 total references, 52 studies were included in qualitative analysis and 11 in meta-analyses., Review Methods: Proportions were extracted from studies of (1) the significant impacts of cochlear implantation on 6 cognitive domains and (2) associations between cognition and speech recognition outcomes. Meta-analyses were performed using random effects models on mean differences between pre- and postoperative performance on 4 cognitive assessments., Results: Only half of the outcomes reported suggested cochlear implantation had a significant impact on cognition (50.8%), with the highest proportion in assessments of memory & learning and inhibition-concentration. Meta-analyses revealed significant improvements in global cognition and inhibition-concentration. Finally, 40.4% of associations between cognition and speech recognition outcomes were significant., Conclusion: Findings relating to cochlear implantation and cognition vary depending on the cognitive domain assessed and the study goal. Nonetheless, assessments of memory & learning, global cognition, and inhibition-concentration may represent tools to assess cognitive benefit after implantation and help explain variability in speech recognition outcomes. Enhanced selectivity in assessments of cognition is needed for clinical applicability., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Introduction: Bepirovirsen (GSK3228836) is an antisense oligonucleotide that induced rapid and prolonged hepatitis B surface antigen (HBsAg) reduction with a favorable safety profile following 4 weeks of treatment in participants with chronic hepatitis B virus (HBV) infection. The objective of the phase 2b study B-Clear is to access the efficacy and safety of bepirovirsen in participants with chronic HBV infection., Methods: B-Clear is a phase 2b, multicenter, randomized, partial-blind (sponsor/participant-blinded, investigator-unblinded) study in participants with chronic HBV infection receiving stable nucleos(t)ide analogue (On-NA) or not currently receiving NA therapy (Not-on-NA). Eligibility criteria included HBsAg > 100 IU/mL, HBV DNA < 90 IU/mL (On-NA) or > 2000 IU/mL (Not-on-NA), and alanine aminotransferase ≤ 2 × upper limit of normal (ULN; On-NA) or < 3 × ULN (Not-on-NA). Participants were randomized 3:3:3:1 to one of four treatment arms, with treatment administered weekly as subcutaneous injections with or without loading doses (LD) on days 4 and 11: bepirovirsen 300 mg (with 300 mg LD) for 24 weeks; bepirovirsen 300 mg (with 300 mg LD) for 12 weeks then bepirovirsen 150 mg for 12 weeks; bepirovirsen 300 mg (with 300 mg LD) for 12 weeks then placebo for 12 weeks; placebo for 12 weeks (with placebo LD) then bepirovirsen 300 mg without LD for 12 weeks., Planned Outcomes: The primary endpoint of the study was HBsAg < lower limit of detection and HBV DNA < lower limit of quantification for 24 weeks after the end of bepirovirsen treatment in the absence of rescue medication. The study enrolled 457 participants (On-NA, n = 227; Not-on-NA, n = 230) and the last patient visit occurred in March 2022. The novel design of the B-Clear study will allow assessment of HBsAg and HBV DNA seroclearance post bepirovirsen treatment discontinuation in the presence and absence of background NA therapy., Trial Registration Number: ClinicalTrials.gov (NCT04449029; GSK study 209668)., (© 2023. The Author(s).)

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 <3.9 mmol/L (<70 mg/dL). Eight weeks of data for 88 participants were analyzed. Results: Median time spent in hypoglycemia over the 24-h period was highest in children and adolescents (4.4% [interquartile range 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.

Background: Although guidelines have been published on treatment of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL), there has been no comprehensive analysis of BIA-ALCL treatment variation based on the available literature. The authors sought to assess current treatment strategies of BIA-ALCL relative to current guidelines., Methods: Database searches were conducted in June of 2020. Included articles were case reports and case series with patient-level data. Collected variables included clinicopathologic features, implant characteristics, diagnostic tests, ALCL characteristics, treatment, and details of follow-up and outcome. Treatment data from before and after 2017 were compared with National Cancer Center Network guidelines., Results: A total of 89 publications were included and 178 cases of BIA-ALCL were identified. Most patients presented with seroma ( n = 114, 70.4 percent), followed by a mass ( n = 14, 8.6 percent), or both ( n = 23, 14.2 percent). Treatment included en bloc capsulectomy of the affected implant in 122 out of 126 cases with treatment details provided (96.8 percent). Radiation therapy was given in 38 cases (30.2 percent) and chemotherapy was given in 71 cases (56.3 percent). Practitioners used less chemotherapy for local disease after treatment guideline publication in 2017 ( p < 0.001), whereas treatment for advanced disease remained unchanged ( p = 0.3). There were 10 recurrences and eight fatalities attributable to BIA-ALCL, which were associated with advanced presentation (29 versus 2.1 percent; OR, 19.4; 95 percent CI, 3.9 to 96.3; p < 0.001)., Conclusions: BIA-ALCL remains a morbid but treatable condition. Current guidelines focus treatment for local disease and reduce nonsurgical interventions with radiation or chemotherapy. Patients presenting with advanced BIA-ALCL experience higher rates of recurrence and mortality., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Background & Aims: Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection., Methods: This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic findings from Part 1 informed Part 2 dosing. In Part 2, patients with chronic hepatitis B on nucleos(t)ide analogue therapy were randomised 11:2 to GSK3389404 (30, 60, 120 mg weekly or 120 mg bi-weekly) or placebo until Day 85. Coprimary endpoints included HBsAg response (≥1.5 log 10 IU/ml reduction from baseline) rate, safety and pharmacokinetics., Results: Parts 1 and 2 included 12 (9 GSK3389404, 3 placebo) and 66 patients (56 GSK3389404, 10 placebo), respectively. In Part 2, one patient each in the 60 mg weekly, 120 mg weekly and 120 mg bi-weekly arms achieved a HBsAg response. HBsAg reductions were dose-dependent (Day 85: mean 0.34 [60 mg weekly] to 0.75 log 10 IU/ml [120 mg weekly]) and occurred in hepatitis B e antigen-positive and -negative patients. No patient achieved HBsAg seroclearance. 43/56 (77%) GSK3389404- and 9/10 (90%) placebo-treated patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in 2 GSK3389404-treated patients (120 mg weekly, 120 mg bi-weekly); both were associated with decreased HBsAg, but neither was considered a responder. GSK3389404 plasma concentrations peaked 2-4 hours post dose; mean plasma half-life was 3-5 hours., Conclusions: GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified., Clinical Trial Number: NCT03020745., Lay Summary: Hepatitis B virus (HBV) can result in chronic HBV infection, which may ultimately lead to chronic liver disease, primary liver cancer and death; HBV proteins may prevent the immune system from successfully controlling the virus. GSK3389404 is an investigational agent that targets HBV RNA, resulting in reduced viral protein production. This study assessed the safety of GSK3389404 and its ability to reduce the viral proteins in patients with chronic HBV infection. GSK3389404 showed dose-dependent reduction in hepatitis B surface antigen, with an acceptable safety profile. While no clear optimal dose was identified, the findings from this study may help in the development of improved treatment options for patients with chronic HBV infections., Competing Interests: Conflict of interest MFY has been an advisor for and received consulting fees from AbbVie, Arbutus, Bristol-Myers Squibb (BMS), Dicerna, GSK, Gilead, Janssen, Merck Sharp & Dohme (MSD), Clear B Therapeutics, Springbank and Roche; and received grants from Assembly biosciences, Arrowhead, BMS, Fujirebio, Gilead, MSD, Springbank and Sysmex. JHeo, YS, QX, JJ, YK, JLT, WX, ZD, S-JP, RK, Y-OK and HJY report no conflicts of interest. HK has received teaching fees from MSD, Gilead, AbbVie, Eisei and Dainippon Sumitomo. FS has received teaching fees from AbbVie and Gilead. JLHou has received consulting fees from Aligos, Assembly, Gilead Sciences, Johnson & Johnson, Roche; lecturer fees from Gilead, Johnson & Johnson, Roche and grants from BMS. KC has received grants from AbbVie and Dainippon Sumitomo; and has received teaching fees from MSD, BMS and Gilead. MI received grants and teaching fees from BMS. S-GL has been an advisor for and received grants from Abbott Diagnostics, Gilead, Roche and MSD; and has been an advisor for Kaleido Bioscience, Arbutus, Assembly Grifols, Janssen, Fibronostics and GSK. YTanaka received grants from Gilead, Janssen and Chugai; and teaching fees from Gilead and Fujirebio, Inc. J-HY received grants from GSK, Dicerna Pharmaceuticals, Roche, AstraZeneca, Daewoong and Hanmi. MK was an advisor for Gilead and GSK; and received speaking fees from Gilead, AbbVie, MSD, Eisai, Chugai and Bayer. MEL has been an advisor for and received speaking fees for Abbott Diagnostics, Hi-Eisai, Menarini, Mylan and Roche. YTao, JC, RE, MD, SB-B, KH, FMC, MP and DT are employees of GSK and hold GSK stocks/options. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2022 by the American Diabetes Association.)

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.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: Several studies have suggested that increased oxidative stress during pregnancy may be associated with adverse maternal and foetal outcomes. As selenium is an essential mineral with an antioxidant role, our aim was to perform a systematic review of the existing literature reporting the effects of selenium supplementation during pregnancy on maternal and neonatal outcomes., Materials and Methods: Six electronic databases (Medline, Embase, Cochrane Library, Web of Science, Scopus, and PubMed) were searched for studies reporting the effects of selenium supplementation during pregnancy and the postpartum period on maternal and neonatal outcomes. Only randomised controlled trials on human subjects reported in English and published up to October 2021 were included. Quality assessments were conducted using the modified Downs and Black quality assessment tool. Data were extracted using a narrative synthesis., Results: Twenty-two articles were included in our systematic review (seventeen reported on maternal outcomes, two on newborn outcomes, and three on both). Maternal studies reported the effects of selenium supplementation in the prevention of thyroid dysfunction, gestational diabetes, pregnancy-induced hypertension/preeclampsia, oxidative stress, postpartum depression, premature rupture of membranes, intrauterine growth retardation, breastmilk composition, and HIV-positive women. Newborn studies reported the effects of maternal selenium supplementation on foetal oxidation stress, foetal lipid profile, neonatal hyperbilirubinemia, and newborn outcomes in HIV-positive mothers. The majority of studies were inappropriately designed to establish clinical or scientific utility. Of interest, four studies reported that selenium supplementation reduced the incidence of thyroid dysfunction and permanent hypothyroidism during the postpartum period by reducing thyroid peroxidase and thyroglobulin antibody titres., Conclusion: The evidence supporting selenium supplementation during pregnancy is poor and there is a need for appropriately designed randomised controlled trials before routine use can be recommended., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Koushik Biswas et al.)

Background: Closed-loop insulin delivery systems have the potential to address suboptimal glucose control in children and adolescents with type 1 diabetes. We compared safety and efficacy of the Cambridge hybrid closed-loop algorithm with usual care over 6 months in this population., Methods: In a multicentre, multinational, parallel randomised controlled trial, participants aged 6-18 years using insulin pump therapy were recruited at seven UK and five US paediatric diabetes centres. Key inclusion criteria were diagnosis of type 1 diabetes for at least 12 months, insulin pump therapy for at least 3 months, and screening HbA 1c levels between 53 and 86 mmol/mol (7·0-10·0%). Using block randomisation and central randomisation software, we randomly assigned participants to either closed-loop insulin delivery (closed-loop group) or to usual care with insulin pump therapy (control group) for 6 months. Randomisation was stratified at each centre by local baseline HbA 1c . The Cambridge closed-loop algorithm running on a smartphone was used with either (1) a modified Medtronic 640G pump, Medtronic Guardian 3 sensor, and Medtronic prototype phone enclosure (FlorenceM configuration), or (2) a Sooil Dana RS pump and Dexcom G6 sensor (CamAPS FX configuration). The primary endpoint was change in HbA 1c at 6 months combining data from both configurations. The primary analysis was done in all randomised patients (intention to treat). Trial registration ClinicalTrials.gov, NCT02925299., Findings: Of 147 people initially screened, 133 participants (mean age 13·0 years [SD 2·8]; 57% female, 43% male) were randomly assigned to either the closed-loop group (n=65) or the control group (n=68). Mean baseline HbA 1c was 8·2% (SD 0·7) in the closed-loop group and 8·3% (0·7) in the control group. At 6 months, HbA 1c was lower in the closed-loop group than in the control group (between-group difference -3·5 mmol/mol (95% CI -6·5 to -0·5 [-0·32 percentage points, -0·59 to -0·04]; p=0·023). Closed-loop usage was low with FlorenceM due to failing phone enclosures (median 40% [IQR 26-53]), but consistently high with CamAPS FX (93% [88-96]), impacting efficacy. A total of 155 adverse events occurred after randomisation (67 in the closed-loop group, 88 in the control group), including seven severe hypoglycaemia events (four in the closed-loop group, three in the control group), two diabetic ketoacidosis events (both in the closed-loop group), and two non-treatment-related serious adverse events. There were 23 reportable hyperglycaemia events (11 in the closed-loop group, 12 in the control group), which did not meet criteria for diabetic ketoacidosis., Interpretation: The Cambridge hybrid closed-loop algorithm had an acceptable safety profile, and improved glycaemic control in children and adolescents with type 1 diabetes. To ensure optimal efficacy of the closed-loop system, usage needs to be consistently high, as demonstrated with CamAPS FX., Funding: National Institute of Diabetes and Digestive and Kidney Diseases., Competing Interests: Declaration of interests MT reports receiving speaker honoraria from Novo Nordisk. RPW reports receiving grants and contract support from Tandem Diabetes Care and Dexcom, consulting fees from Beta Bionics, and honoraria and travel support from Tandem Diabetes. BAB declares grant support from JDRF and National Institutes of Health (NIH), honoraria from Lilly, reports receiving grant support and advisory board fees from ConvaTec, grant support and honoraria from Insulet, advisory board fees from Medtronic MiniMed, grant support from Tandem Diabetes Care, Data Safety Monitoring Board role for ConvaTec, NovoNordisk, and Medtronic, advisory board fees from Arecor, advisory board role for ConvaTec, Medtronic and NovoNordisk, and patents (US 6,572,545 B2, PCT/US 2020/017997, US 2010/0174228 A1). LADM reports grants from Medtronic, leadership/fiduciary role regarding ISPAD Guidelines and Editorial Board, and receipt of equipment from Dexcom. NM reports receiving grants, contracts and payment, and honoraria from Novo Nordisk. SAW reports receiving consulting fees from Zealand Pharma, speaker honoraria from Dexcom, Insulet, Medtronic, Tandem Diabetes Care, and Abbott, and is a Data and Safety Monitoring Board member for two AID studies (NCT04492566, NCT04510506), and study supply receipt from Medtronic. RWB reports receiving grant support from NIH, Tandem Diabetes Care, Beta Bionics, and Dexcom; donated supplies from Tandem Diabetes Care, Beta Bionics, Dexcom, Medtronic, Ascencia, Roche, Eli Lilly, and Novo Nordisk; and consulting fees from Novo Nordisk, Bigfoot Biomedical, Eli Lilly, and Insulet. RH reports receiving speaker honoraria from Eli Lilly, Dexcom, and Novo Nordisk, receiving license fees from B Braun and Medtronic, declares consulting fees from Abbott Diabetes Care; patent issued in closed-loop field (Glucose monitoring and control using multi-model approach, patent number CA2702345C) with University of Cambridge and patent issued in closed-loop field (methods for reducing false hypoglycaemia alarm occurrence during closed-loop, patent number US9579456B2) with University of Cambridge and Abbott Diabetes Care, being director and stockholder at CamDiab, and leadership/fiduciary role for ATTD. MEW reports patents related to closed-loop (US9402953B2, US9579456B2) and being a consultant at CamDiab. REJB declares a leadership and fiduciary role for NovoNordisk. JW declares support for attending meetings from the YDEF Lilly Scholarship. KKH declares consulting fees for Cecelia Health, Insulet, and Lifescan Diabetes Institute. LK, CKo, CKB, JMA, AT, JS, LD, FMC, ND, AG, and DSF declare no competing financial interests exist., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The possible advantage of hybrid closed-loop therapy (i.e., artificial pancreas) over sensor-augmented pump therapy in very young children with type 1 diabetes is unclear., Methods: In this multicenter, randomized, crossover trial, we recruited children 1 to 7 years of age with type 1 diabetes who were receiving insulin-pump therapy at seven centers across Austria, Germany, Luxembourg, and the United Kingdom. Participants received treatment in two 16-week periods, in random order, in which the closed-loop system was compared with sensor-augmented pump therapy (control). The primary end point was the between-treatment difference in the percentage of time that the sensor glucose measurement was in the target range (70 to 180 mg per deciliter) during each 16-week period. The analysis was conducted according to the intention-to-treat principle. Key secondary end points included the percentage of time spent in a hyperglycemic state (glucose level, >180 mg per deciliter), the glycated hemoglobin level, the mean sensor glucose level, and the percentage of time spent in a hypoglycemic state (glucose level, <70 mg per deciliter). Safety was assessed., Results: A total of 74 participants underwent randomization. The mean (±SD) age of the participants was 5.6±1.6 years, and the baseline glycated hemoglobin level was 7.3±0.7%. The percentage of time with the glucose level in the target range was 8.7 percentage points (95% confidence interval [CI], 7.4 to 9.9) higher during the closed-loop period than during the control period (P<0.001). The mean adjusted difference (closed-loop minus control) in the percentage of time spent in a hyperglycemic state was -8.5 percentage points (95% CI, -9.9 to -7.1), the difference in the glycated hemoglobin level was -0.4 percentage points (95% CI, -0.5 to -0.3), and the difference in the mean sensor glucose level was -12.3 mg per deciliter (95% CI, -14.8 to -9.8) (P<0.001 for all comparisons). The time spent in a hypoglycemic state was similar with the two treatments (P = 0.74). The median time spent in the closed-loop mode was 95% (interquartile range, 92 to 97) over the 16-week closed-loop period. One serious adverse event of severe hypoglycemia occurred during the closed-loop period. One serious adverse event that was deemed to be unrelated to treatment occurred., Conclusions: A hybrid closed-loop system significantly improved glycemic control in very young children with type 1 diabetes, without increasing the time spent in hypoglycemia. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT03784027.)., (Copyright © 2022 Massachusetts Medical Society.)

Advanced glycation end products (AGEs) are a heterogeneous group of molecules produced, non-enzymatically, from the interaction between reducing sugars and the free amino groups of proteins, nucleic acids, and lipids. AGEs are formed as a normal consequence of metabolism but can also be absorbed from the diet. They have been widely implicated in the complications of diabetes affecting cardiovascular health, the nervous system, eyes, and kidneys. Increased levels of AGEs are also detrimental to metabolic health and may contribute to the metabolic abnormalities induced by the Western diet, which is high in processed foods and represents a significant source of AGEs. While increased AGE levels are a consequence of diabetic hyperglycaemia, AGEs themselves activate signaling pathways, which compromise insulin signaling and pancreatic β-cell function, thus, contributing to the development of type 2 diabetes mellitus (T2DM). Furthermore, AGEs may also contribute to the obesogenic effects of the Western diet by promoting hypothalamic inflammation and disrupting the central control of energy balance. Here, the role of dietary AGEs in metabolic dysfunction is reviewed with a focus on the mechanisms underpinning their detrimental role in insulin resistance, pancreatic β-cell dysfunction, hypothalamic control of energy balance, and the pathogenesis of T2DM and obesity., (© 2020 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Objectives: This systematic review aims to summarize the body of available literature on pediatric extracorporeal cardiopulmonary resuscitation in order to delineate current utilization, practices, and outcomes, while highlighting gaps in current knowledge., Data Sources: PubMed, Embase, Scopus, Cochrane Library, and ClinicalTrials.gov databases., Study Selection: We searched for peer-reviewed original research publications on pediatric extracorporeal cardiopulmonary resuscitation (patients < 18 yr old) and were inclusive of all publication years., Data Extraction: Our systematic review used the structured Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Our initial literature search was performed on February 11, 2019, with an updated search performed on August 28, 2019. Three physician reviewers independently assessed the retrieved studies to determine inclusion in the systematic review synthesis. Using selected search terms, a total of 4,095 publications were retrieved, of which 96 were included in the final synthesis. Risk of bias in included studies was assessed using the Risk of Bias in Non-Randomized Studies of Interventions-I tool., Data Synthesis: There were no randomized controlled trials of extracorporeal cardiopulmonary resuscitation use in pediatrics. A vast majority of pediatric extracorporeal cardiopulmonary resuscitation publications were single-center retrospective studies reporting outcomes after in-hospital cardiac arrest. Most pediatric extracorporeal cardiopulmonary resuscitation use in published literature is in cardiac patients. Survival to hospital discharge after extracorporeal cardiopulmonary resuscitation for pediatric in-hospital cardiac arrest ranged from 8% to 80% in included studies, and there was an association with improved outcomes in cardiac patients. Thirty-one studies reported neurologic outcomes after extracorporeal cardiopulmonary resuscitation, of which only six were prospective follow-up studies. We summarize the available literature on: determination of candidacy, timing of activation of extracorporeal cardiopulmonary resuscitation, staffing/logistics, cannulation strategies, outcomes, and the use of simulation for training., Conclusions: This review highlights gaps in our understanding of best practices for pediatric extracorporeal cardiopulmonary resuscitation. We summarize current studies available and provide a framework for the development of future studies.

Aims: To assess the efficacy of insulin pumps with automated insulin suspension systems in a real-world setting., Methods: We analysed anonymized data uploaded to CareLink ™ by people (n=920) with Type 1 diabetes using the MiniMed Paradigm Veo system and the MiniMed 640G system (Medtronic International Trading Sàrl, Tolochanez, Switzerland) with SmartGuard technology, with or without automated insulin suspension enabled, between February 2016 and June 2018. Users with ≥15 days of sensor data and ≥70% sensor-wear time were classified as sensor-augmented pump alone, sensor-integrated pump with low glucose suspend enabled or sensor-integrated pump with predictive low glucose management enabled., Results: The median (25 th -75 th percentile) system use was 161 (58-348) days. The median time spent with sensor glucose values ≤3 mmol/l was 0.8 (0.3-1.7)% in the sensor-augmented pump group, 0.3 (0.1-0.7)% in the sensor-integrated pump with low glucose suspend group, and 0.3 (0.1-0.5)% in the sensor-integrated pump with predictive low glucose management group. In individuals switching from sensor-augmented pump to sensor-integrated pump with low glucose suspend (n=31), there were significant reductions in the monthly rate of hypoglycaemic events <3 mmol/l (rate ratio 0.63, 95% CI 0.45-0.89; P=0.009) and in the percentage of time with glucose values ≤3 mmol/l [sensor-augmented pump: 0.63% (95% CI 0.34-1.29), sensor-integrated pump with low glucose suspend: 0.33% (95% CI 0.16-0.64); P=0.001]. The monthly rate of hypoglycaemic events decreased further in individuals (n=139) switching from sensor-integrated pump with low glucose suspend to sensor-integrated pump with predictive low glucose management [rate ratio 0.82 (95% CI 0.69-0.98); P<0.0274]. Similar results were seen for events <3.9 mmol/l. There was no difference in median time spent in target glucose range., Conclusion: Real-world UK data show that increasing automation of insulin suspension reduces hypoglycaemia exposure in people with Type 1 diabetes., (© 2019 Diabetes UK.)

Background: The rise in global obesity makes it crucial to understand how diet drives obesity-related health conditions, such as premature cognitive decline and Alzheimer's disease (AD). In AD hippocampal-dependent episodic memory is one of the first types of memory to be impaired. Previous studies have shown that in mice fed a high-fat diet (HFD) episodic memory is rapidly but reversibly impaired., Methods: In this study we use hippocampal proteomics to investigate the effects of HFD in the hippocampus. Mice were fed either a low-fat diet (LFD) or HFD containing either 10% or 60% (Kcal) from fat for 3 days, 1 week or 2 weeks. One group of mice were fed the HFD for 1 week and then returned to the LFD for a further week. Primary hippocampal cultures were challenged with palmitic acid (PA), the most common long-chain saturated FA in the Western diet, and with the anti-inflammatory, n-3 polyunsaturated FA, docosahexaenoic acid (DHA), or a combination of the two to ascertain effects of these fatty acids on dendritic structure., Results: HFD-induced changes occur in hippocampal proteins involved in metabolism, inflammation, cell stress, cell signalling, and the cytoskeleton after 3 days, 1 week and 2 weeks of HFD. Replacement of the HFD after 1 week by a low-fat diet (LFD) for a further week resulted in partial recovery of the hippocampal proteome. Microtubule-associated protein 2 (MAP2), one of the earliest proteins changed, was used to investigate the impact of fatty acids (FAs) on hippocampal neuronal morphology. PA challenge resulted in shorter and less arborised dendrites while DHA had no effect when applied alone but counteracted the effects of PA when FAs were used in combination. Dendritic morphology recovered when PA was removed from the cell culture media., Conclusion: This study provides evidence for the rapid and reversible effects of diet on the hippocampal proteome and the impact of PA and DHA on dendritic structure., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Background: Prolonged over-consumption of a high-fat diet (HFD) commonly leads to obesity and insulin resistance. However, even 3 days of HFD consumption has been linked to inflammation within the key homeostatic brain region, the hypothalamus., Methods: Mice were fed either a low-fat diet (LFD) or HFD containing 10% or 60% (Kcal) respectively from fat for 3 days. Mice were weighed, food intake measured and glucose tolerance calculated using intraperitoneal glucose tolerance tests (IPGTT). Proteomic analysis was carried out to determine if hypothalamic proteins were changed by a HFD. The direct effects of dietary fatty acids on mitochondrial morphology and on one of the proteins most changed by a HFD, dihydropyrimidinase-related protein 2 (DRP-2) a microtubule-associated protein which regulates microtubule dynamics, were also tested in mHypoE-N42 (N42) neuronal cells challenged with palmitic acid (PA) and oleic acid (OA)., Results: Mice on the HFD, as expected, showed increased adiposity and glucose intolerance. Hypothalamic proteomic analysis revealed changes in 104 spots after 3 days on HFD, which, when identified by LC/MS/MS, were found to represent 78 proteins mainly associated with cytoskeleton and synaptic plasticity, stress response, glucose metabolism and mitochondrial function. Over half of the changed proteins have also been reported to be changed in neurodegenerative conditions such as Alzheimer's disease. Also,in N42 neurons mitochondrial morphology and DRP-2 levels were altered by PA but not by OA., Conclusion: These results demonstrate that within 3 days, there is a relatively large effect of HFD on the hypothalamic proteome indicative of cellular stress, altered synaptic plasticity and mitochondrial function, but not inflammation. Changes in N42 cells show an effect of PA but not OA on DRP-2 and on mitochondrial morphology indicating that long-chain saturated fatty acids damage neuronal function., Competing Interests: All studies involving animals were licensed under the Animal (Scientific Procedures) Act of 1986 and in accordance with the European Directive on the Protection of Animals used for Scientific Purposes 2010/63/E following ARRIVE guidelines and had received prior approval from the Rowett Institute of Nutrition and Health’s Ethical Review Committee.N/AThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Objective: To explore individuals' experiences of daytime use of a day-and-night hybrid closed-loop system, their information and support needs, and their views about how future systems could be improved., Research Design and Methods: Twenty-four adults, adolescents, and parents were interviewed before using a hybrid day-and-night closed-loop system and 3 months later, data were analyzed thematically., Results: Participants praised the closed loop's ability to respond to high and low blood glucose in ways which extended beyond their own capabilities and to act as a safety net and mop up errors, such as when a mealtime bolus was forgotten or unplanned activity was undertaken. Participants also described feeling less burdened by diabetes as a consequence and more able to lead flexible, spontaneous lives. Contrary to their initial expectations, and after trust in the system had been established, most individuals wanted opportunities to collaborate with the closed loop to optimize its effectiveness. Such individuals expressed a need to communicate information, such as when routines changed or to indicate different intensities of physical activity. While individuals valued frequent contact with staff in the initial month of use, most felt that their long-term support needs would be no greater than when using an insulin pump., Conclusions: While participants reported substantial benefits to using the closed loop during the day, they also identified ways in which the technology could be refined and education and training tailored to optimize effective use. Our findings suggest that mainstreaming this technology will not necessarily lead to increased demands on clinical staff.

Background: Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus., Results: Mouse global array data identified serpinA3N as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed serpinA3N expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (α 1 AC), the protein encoded by serpinA3 , is localised to neurons and revealed that it is secreted into the media. SerpinA3N expression in N42 neurons is upregulated by palmitic acid and by leptin, together with IL-6 and TNFα , and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of serpinA3 in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of serpinA3N expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout ( IL-1R1 -/- ) mice., Conclusions: These data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation., Competing Interests: The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background and Objective: Outcomes of using flash glucose monitoring have been reported in adults. This trial evaluated use in children and teenagers with type 1 diabetes., Methods: Prospective, single arm, non-inferiority multicenter study to demonstrate equivalence of time in range (TIR [70-180 mg/dL]) by comparing 14-day masked sensor wear (baseline) with self-monitored blood glucose (SMBG) testing to the final 14-days of 8-week open-label system use for diabetes self-management including insulin dosing., Results: A total of 76 children and teenagers (46.1% male; age 10.3 ± 4.0 years, type 1 diabetes duration 5.4 ± 3.7 years; mean ± SD) from 10 sites participated. TIR improved significantly by 0.9 ± 2.8 h/d (P = 0.005) vs SMBG baseline. Time in hyperglycemia (>180 mg/dL) reduced by -1.2 ± 3.3 h/d (P = 0.004). HbA1c reduced by -0.4% (-4.4 mmol/mol), from 7.9 ± 1.0% (62.9 ± 11.2 mmol/mol) baseline to 7.5 ± 0.9% (58.5 ± 9.8 mmol/mol) study end (P < 0.0001) with reductions across all age-subgroups (4-6, 7-12 and 13-17 years). Time in hypoglycemia (<70 mg/dL) was unaffected. Throughout the treatment phase system utilization was 91% ± 9; sensor scanning was 12.9 ± 5.7/d with SMBG dropping to 1.6 ± 1.9 from 7.7 ± 2.5/d. Diabetes Treatment Satisfaction Questionnaire "Total Treatment Satisfaction" score improved for parents (P < 0.0001) and teenagers (P < 0.0001). No adverse events (n = 121) were associated with sensor accuracy, 42 participants experienced sensor insertion signs and symptoms. Three participants experienced three mild device-related (sensor wear) symptoms, resolving quickly (without treatment [n = 2], non-prescription antihistamines [n = 1])., Conclusions: Children with diabetes improved glycemic control safely and effectively with short-term flash glucose monitoring compared to use of SMBG in a single arm study., (© 2018 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

Alzheimer's disease is a leading cause of morbidity and mortality with no cure and only limited treatment available. Obesity and type 2 diabetes are positively associated with the development of premature cognitive decline and Alzheimer's disease, linking diet with these conditions. Here we demonstrate that in mice episodic memory, together with spatial and contextual associative memory, is compromised after only one day of high-fat diet. However, object memory remains intact. This shows not only a more rapid effect than previously reported but also that more complex memories are at higher risk of being compromised by a high-fat diet. In addition, we show that these memory deficits are rapidly reversed by switching mice from a high-fat diet back to a low-fat diet. These findings have important implications for the contribution of nutrition to the development of cognitive decline and Alzheimer's disease.

Introduction: The paper presents a case study that critically assesses the role of global strategy 'Public Health on the Frontline 2014-2015' ('the Strategy') in supporting Merlin and Save the Children's organisational change and future programme of the combined organisation in Myanmar., Materials and Methods: Research was undertaken in 2014 in Myanmar. Twenty-six individual and three group interviews were conducted with stakeholders, and 10 meetings relevant to the country organisational transition process were observed. A conceptual framework was developed to assess the role of the global strategy in supporting the country change process., Results: Several positive aspects of the global strategy were found, as well as critical shortcomings in its support to the organisational change process at country level. The strategy was useful in signalling Save the Children's intention to scale up humanitarian health provision. However, it had only limited influence on the early change process and outcomes in Myanmar., Conclusions: Results highlight several aspects that would enhance the role of a global strategy at country level. Lessons can be applied by organisations undertaking a similar process. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Objective: Celiac disease (CD) has a recognized association with type 1 diabetes. We examined international differences in CD prevalence and clinical characteristics of youth with coexisting type 1 diabetes and CD versus type 1 diabetes only., Research Design and Methods: Data sources were as follows: the Prospective Diabetes Follow-up Registry (DPV) (Germany/Austria); the T1D Exchange Clinic Network (T1DX) (U.S.); the National Paediatric Diabetes Audit (NPDA) (U.K. [England/Wales]); and the Australasian Diabetes Data Network (ADDN) (Australia). The analysis included 52,721 youths <18 years of age with a clinic visit between April 2013 and March 2014. Multivariable linear and logistic regression models were constructed to analyze the relationship between outcomes (HbA 1c , height SD score [SDS], overweight/obesity) and type 1 diabetes/CD versus type 1 diabetes, adjusting for sex, age, and diabetes duration., Results: Biopsy-confirmed CD was present in 1,835 youths (3.5%) and was diagnosed at a median age of 8.1 years (interquartile range 5.3-11.2 years). Diabetes duration at CD diagnosis was <1 year in 37% of youths, >1-2 years in 18% of youths, >3-5 years in 23% of youths, and >5 years in 17% of youths. CD prevalence ranged from 1.9% in the T1DX to 7.7% in the ADDN and was higher in girls than boys (4.3% vs. 2.7%, P < 0.001). Children with coexisting CD were younger at diabetes diagnosis compared with those with type 1 diabetes only (5.4 vs. 7.0 years of age, P < 0.001) and fewer were nonwhite (15 vs. 18%, P < 0.001). Height SDS was lower in those with CD (0.36 vs. 0.48, adjusted P < 0.001) and fewer were overweight/obese (34 vs. 37%, adjusted P < 0.001), whereas mean HbA 1c values were comparable: 8.3 ± 1.5% (67 ± 17 mmol/mol) versus 8.4 ± 1.6% (68 ± 17 mmol/mol)., Conclusions: CD is a common comorbidity in youth with type 1 diabetes. Differences in CD prevalence may reflect international variation in screening and diagnostic practices, and/or CD risk. Although glycemic control was not different, the lower height SDS supports close monitoring of growth and nutrition in this population., (© 2017 by the American Diabetes Association.)

Background: The feasibility, safety, and efficacy of prolonged use of an artificial beta cell (closed-loop insulin-delivery system) in the home setting have not been established., Methods: In two multicenter, crossover, randomized, controlled studies conducted under free-living home conditions, we compared closed-loop insulin delivery with sensor-augmented pump therapy in 58 patients with type 1 diabetes. The closed-loop system was used day and night by 33 adults and overnight by 25 children and adolescents. Participants used the closed-loop system for a 12-week period and sensor-augmented pump therapy (control) for a similar period. The primary end point was the proportion of time that the glucose level was between 70 mg and 180 mg per deciliter for adults and between 70 mg and 145 mg per deciliter for children and adolescents., Results: Among adults, the proportion of time that the glucose level was in the target range was 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8) greater with the use of the closed-loop system day and night than with control therapy (P<0.001). The mean glucose level was lower during the closed-loop phase than during the control phase (difference, -11 mg per deciliter; 95% CI, -17 to -6; P<0.001), as were the area under the curve for the period when the glucose level was less than 63 mg per deciliter (39% lower; 95% CI, 24 to 51; P<0.001) and the mean glycated hemoglobin level (difference, -0.3%; 95% CI, -0.5 to -0.1; P=0.002). Among children and adolescents, the proportion of time with the nighttime glucose level in the target range was higher during the closed-loop phase than during the control phase (by 24.7 percentage points; 95% CI, 20.6 to 28.7; P<0.001), and the mean nighttime glucose level was lower (difference, -29 mg per deciliter; 95% CI, -39 to -20; P<0.001). The area under the curve for the period in which the day-and-night glucose levels were less than 63 mg per deciliter was lower by 42% (95% CI, 4 to 65; P=0.03). Three severe hypoglycemic episodes occurred during the closed-loop phase when the closed-loop system was not in use., Conclusions: Among patients with type 1 diabetes, 12-week use of a closed-loop system, as compared with sensor-augmented pump therapy, improved glucose control, reduced hypoglycemia, and, in adults, resulted in a lower glycated hemoglobin level. (Funded by the JDRF and others; AP@home04 and APCam08 ClinicalTrials.gov numbers, NCT01961622 and NCT01778348.).

Background and Aim: Thrombocytopenia is frequently observed in patients with chronic hepatitis C virus (HCV) infection and cirrhosis, although it can also be observed in patients without cirrhosis by a virus-mediated phenomenon. This study assessed the prevalence, characteristics, and outcomes of antiviral therapy in patients with chronic HCV infection and thrombocytopenia not associated with cirrhosis., Methods: The study included 1268 patients with HCV infection and thrombocytopenia enrolled in the phase 3 ENABLE studies that assessed the impact of eltrombopag on achieving a sustained virologic response to pegylated interferon and ribavirin. The study population was subdivided according to baseline FibroSURE test results into patients with non-cirrhosis (FibroSURE < 0.4) and cirrhosis-related (FibroSURE ≥ 0.75) thrombocytopenia., Results: Compared with patients with cirrhosis-related thrombocytopenia (n = 995; 78.5%), non-cirrhotic patients with thrombocytopenia (n = 59; 4.6%) were younger (mean age [95% confidence interval (CI)]: 43.9 [40.7-47.2] vs 52.7 [52.2-53.3] years; P < 0.0001), predominantly female (64% [51-76] vs 30% [27-33]; P < 0.0001), and less frequently had a Model for End-Stage Liver Disease score ≥ 10 (24% [14-37] vs 45% [42-49]; P = 0.0012), low albumin levels (≤ 35 g/L; 2% [0-9] vs 32% [29-35]; P < 0.0001), and prevalence of diabetes mellitus (3% [0-12] vs 21% [19-24]; P = 0.0005). The sustained virologic response rate was higher in non-cirrhotic patients with thrombocytopenia (46% [95% CI, 33-59] vs 16% [14-18]; P < 0.0001)., Conclusions: Patients with thrombocytopenia associated with HCV who have lower FibroSURE test results may have better preserved liver function and higher sustained virologic response rates than patients with cirrhosis., (© 2015 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

High-fat (HF) diet-induced obesity and insulin insensitivity are associated with inflammation, particularly in white adipose tissue (WAT). However, insulin insensitivity is apparent within days of HF feeding when gains in adiposity and changes in markers of inflammation are relatively minor. To investigate further the effects of HF diet, C57Bl/6J mice were fed either a low (LF) or HF diet for 3 days to 16 weeks, or fed the HF-diet matched to the caloric intake of the LF diet (PF) for 3 days or 1 week, with the time course of glucose tolerance and inflammatory gene expression measured in liver, muscle and WAT. HF fed mice gained adiposity and liver lipid steadily over 16 weeks, but developed glucose intolerance, assessed by intraperitoneal glucose tolerance tests (IPGTT), in two phases. The first phase, after 3 days, resulted in a 50% increase in area under the curve (AUC) for HF and PF mice, which improved to 30% after 1 week and remained stable until 12 weeks. Between 12 and 16 weeks the difference in AUC increased to 60%, when gene markers of inflammation appeared in WAT and muscle but not in liver. Plasma proteomics were used to reveal an acute phase response at day 3. Data from PF mice reveals that glucose intolerance and the acute phase response are the result of the HF composition of the diet and increased caloric intake respectively. Thus, the initial increase in glucose intolerance due to a HF diet occurs concurrently with an acute phase response but these effects are caused by different properties of the diet. The second increase in glucose intolerance occurs between 12-16 weeks of HF diet and is correlated with WAT and muscle inflammation. Between these times glucose tolerance remains stable and markers of inflammation are undetectable.

Background & Aims: Thrombocytopenia is common among patients with hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis, limiting initiation and dose of peginterferon-alfa (PEG) and ribavirin (RBV) therapy. The phase 3 randomized, controlled studies, Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE)-1 and ENABLE-2, investigated the ability of eltrombopag to increase the number of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV., Methods: Patients with HCV infection and thrombocytopenia (platelet count <75,000/μL) who participated in ENABLE-1 (n = 715) or ENABLE-2 (n = 805), from approximately 150 centers in 23 countries, received open-label eltrombopag (25-100 mg/day) for 9 weeks or fewer. Patients whose platelet counts reached the predefined minimal threshold for the initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were assigned randomly (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary end point was sustained virologic response (SVR) 24 weeks after completion of antiviral therapy., Results: More patients who received eltrombopag than placebo achieved SVRs (ENABLE-1: eltrombopag, 23%; placebo, 14%; P = .0064; ENABLE-2: eltrombopag, 19%; placebo, 13%; P = .0202). PEG was administered at higher doses, with fewer dose reductions, in the eltrombopag groups of each study compared with the placebo groups. More patients who received eltrombopag than placebo maintained platelet counts of 50,000/μL or higher throughout antiviral treatment (ENABLE-1, 69% vs 15%; ENABLE-2, 81% vs 23%). Adverse events were similar between groups, with the exception of hepatic decompensation (both studies: eltrombopag, 10%; placebo, 5%) and thromboembolic events, which were more common in the eltrombopag group of ENABLE-2., Conclusions: Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV and advanced fibrosis and cirrhosis, allowing otherwise ineligible or marginal patients to begin and maintain antiviral therapy, leading to significantly increased rates of SVR. Clinical trial no: NCT00516321, NCT00529568., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)