Randomized Trial of Closed-Loop Control in Very Young Children with Type 1 Diabetes.

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.).

Reduced burden of diabetes and improved quality of life: Experiences from unrestricted day-and-night hybrid closed-loop use in very young children with type 1 diabetes.

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.

Skin Malignancy in the Military: A Number Needed to Biopsy Analysis.

INTRODUCTION: Skin malignancy has increased in prevalence over the last 15 years and effective diagnosis is required for adequate treatment. Retrospective data analysis of skin biopsy data has shown correlation between various independent variables, but no studies have been shown to directly assess skin malignancy risks for military personnel. Assessing correlation could lead to more effective, targeted screening programs that could lead to decreased mortality from skin malignancies. We present a 1-year analysis of the number needed to biopsy (NNB) to detect skin cancer and analysis of military-specific risk factors in a military dermatology training program. The present study aims to (1) compare skin biopsy yields to civilian institutions and patient populations and (2) determine significance of exposure variables including age, gender, military beneficiary status, branch of service, and military rank. MATERIALS AND METHODS: We performed a retrospective observational study over 1 year by identifying all skin biopsies performed in the Walter Reed National Military Medical Center dermatology clinic from August 2015 to July 2016. Utilizing the pathology reports, we manually excluded biopsies performed for the purpose of ruling out inflammatory/immunologic conditions or cosmeses and focused only on encounters performed to rule out basal cell carcinoma, squamous cell carcinoma, or melanoma. We decided to exclude malignant diagnoses that were exceedingly rare or could mimic inflammatory conditions, such as cutaneous T-cell lymphoma. For uncertain diagnoses with vague context per pathology report, previous office clinic notes and pre-biopsy differential were referenced and included only if melanoma or non-melanoma skin cancer (NMSC) diagnosis was the intended indication. RESULTS: A total of 3,098 biopsies were included in the study, diagnostic for 1,084 total skin malignancy and 54 melanoma diagnoses. Melanoma comprised 4.98% of all skin malignancy diagnosed. The NNB for all skin malignancy was 2.86 (95% CI 2.76-2.96) and NNB for melanoma and NMSC was 20.93 (95% CI 19.70-22.15) and 1.91 (95% CI 1.83-2.00), respectively. Patient age, gender, and military rank significantly impacted NNB values (P < .001). CONCLUSIONS: The proportion of melanoma skin cancers is notably increased in our population compared to published population statistics with comparable total biopsy yields. Skin biopsy for purpose of screening for malignancy should be performed in the military population and consideration should be made for gender, age, and rank. Our findings can further expand on military risk factors for skin cancer and aid in further multivariant modeling.

Cambridge Hybrid Closed-Loop System in Very Young Children With Type 1 Diabetes Reduces Caregivers' Fear of Hypoglycemia and Improves Their Well-Being.

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.

Type 1 diabetes mellitus presenting with diabetic ketoacidosis in a child with Patau syndrome (trisomy 13) and persistent fetal haemoglobin.

A 35-month-old boy with non-mosaic Patau syndrome presented in diabetic ketoacidosis and was diagnosed with type 1 diabetes mellitus. A decision to treat this unanticipated medical problem was made in conjunction with the child's parent, and he improved with fluid resuscitation and insulin treatment. Acute kidney injury with hypernatraemia complicated his treatment, but this resolved with careful intravenous fluid management. The child survived and was followed up in the diabetes clinic where ongoing management was complicated by persistent fetal haemoglobin, which meant that glycated haemoglobin could not be used to gauge his glucose control.

Assessing the efficacy, safety and utility of closed-loop insulin delivery compared with sensor-augmented pump therapy in very young children with type 1 diabetes (KidsAP02 study): an open-label, multicentre, multinational, randomised cross-over study protocol.

INTRODUCTION: Diabetes 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 ANALYSIS: The 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 DISSEMINATION: Ethics 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 NUMBER: NCT03784027.

Psychological Well-Being of Parents of Very Young Children With Type 1 Diabetes - Baseline Assessment.

Background: Type 1 diabetes in young children is a heavy parental burden. As part of pilot phase of the KIDSAP01 study, we conducted a baseline assessment in parents to study the association between hypoglycemia fear, parental well-being and child behavior. Methods: All parents were invited to fill in baseline questionnaires: hypoglycemia fear survey (HFS), WHO-5, Epworth Sleepiness Scale and Strength and Difficulties Questionnaire (SDQ). Results: 24 children (median age: 5-year, range 1-7 years, 63% male, mean diabetes duration: 3 ± 1.7 years) participated. 23/24 parents filled out the questionnaires. We found a higher score for the hypoglycemia fear behavior 33.9 ± 5.6 compared to hypoglycemia worry 34.6 ± 12.2. Median WHO-5 score was 16 (8 - 22) with poor well-being in two parents. Median daytime sleepiness score was high in five parents (>10). For six children a high total behavioral difficulty score (>16) was reported. Pro social behavior score was lower than normal in six children (<6). Parental well-being was negatively associated with HFS total (r = - 0.50, p <.05) and subscale scores (r = - 0.44, p <.05 for HFS-Worry and HFS-Behavior), child behavior (r = - 0.45, p = .05) and positively with child age and diabetes duration (r = 0.58, p <.01, r = 0.6, p <.01). HFS, parental well-being nor daytime sleepiness are associated with the HbA1c. Conclusion: Regular screening of parental well-being, hypoglycemia fear and child behavior should be part of routine care to target early intervention.

Home Use of Day-and-Night Hybrid Closed-Loop Insulin Delivery in Very Young Children: A Multicenter, 3-Week, Randomized Trial.

OBJECTIVE: We aimed to assess the feasibility and safety of hybrid closed-loop insulin delivery in children with type 1 diabetes aged 1-7 years as well as evaluate the role of diluted insulin on glucose control. RESEARCH DESIGN AND METHODS: In an open-label, multicenter, multinational, randomized crossover study, 24 children with type 1 diabetes on insulin pump therapy (median age 5 years [interquartile range 3-6] and mean ± SD HbA1c 7.4 ± 0.7% [57 ± 8 mmol/mol] and total insulin 13.2 ± 4.8 units/day) underwent two 21-day periods of unrestricted living and we compared hybrid closed-loop with diluted insulin (U20) and hybrid closed-loop with standard strength insulin (U100) in random order. During both interventions, the Cambridge model predictive control algorithm was used. RESULTS: The proportion of time that sensor glucose was in the target range between 3.9 and 10 mmol/L (primary end point) was not different between interventions (mean ± SD 72 ± 8% vs. 70 ± 7% for closed-loop with diluted insulin vs. closed-loop with standard insulin, respectively; P = 0.16). There was no difference in mean glucose levels (8.0 ± 0.8 vs. 8.2 ± 0.6 mmol/L; P = 0.14), glucose variability (SD of sensor glucose 3.1 ± 0.5 vs. 3.2 ± 0.4 mmol/L; P = 0.16), or the proportion of time spent with sensor glucose <3.9 mmol/L (4.5 ± 1.7% vs. 4.7 ± 1.4%; P = 0.47) or <2.8 mmol/L (0.6 ± 0.5% vs. 0.6 ± 0.4%; P > 0.99). Total daily insulin delivery did not differ (17.3 ± 5.6 vs. 18.9 ± 6.9 units/day; P = 0.07). No closed-loop-related severe hypoglycemia or ketoacidosis occurred. CONCLUSIONS: Unrestricted home use of day-and-night closed-loop in very young children with type 1 diabetes is feasible and safe. The use of diluted insulin during closed-loop does not provide additional benefits compared with standard strength insulin.

Closing the Loop in Adults, Children and Adolescents With Suboptimally Controlled Type 1 Diabetes Under Free Living Conditions: A Psychosocial Substudy.

OBJECTIVE: The objective was to explore psychosocial experiences of closed loop technology for adults, children, and adolescents with type 1 diabetes and their parents taking part in two multicenter, free-living, randomized crossover home studies. METHODS: Participants using insulin pump therapy were randomized to either 12 weeks of automated closed-loop glucose control, then 12 weeks of sensor augmented insulin pump therapy (open loop), or vice versa. Closed loop was used for 24 hours by adults and overnight only by children and adolescents. Participants completed the Diabetes Technology Questionnaire (DTQ) periodically and shared their views in semistructured interviews. This analysis characterizes the impact of the technology, positive and negative aspects of living with the device, alongside participants' expectations, hopes, and anxieties. RESULTS: Participants were 32 adults, age 38.6 ± 9.6 years, 55% male, and 26 children, mean age 12 years (range 6-18 years), 54% male. DTQ results indicated moderately favorable impact of, and satisfaction with, both open and closed loop interventions, but little evidence of a comparative advantage of either. Key positive themes included perceived improved blood glucose control, improved general well-being, particularly on waking, improved sleep, reduced burden of diabetes, and visibility of data. Key negative themes included having to carry around the equipment and dislike of the pump and second cannula (ie, sensor) inserted. CONCLUSIONS: Overall, participants reported a positive experience of the closed loop technology. Results are consistent with previous research with size of equipment continuing to be a problem. Progress is being made in the usability of the closed-loop system.

Applications of monoclonal anti-human inhibin alpha subunit in endometrial curettings.

AIMS: Using archival material, we studied the immunoreactivity and utility of monoclonal anti-human inhibin alpha subunit in the identification of chorionic villi (CV) and trophoblastic subpopulations in endometrial curettings (EC) from patients who had intra-uterine, ectopic, molar and, particularly, probable intra-uterine pregnancies. We also compared its expression with those of betaHCG, HPL and CAM 5.2. METHODS: The four groups of EC investigated included: Group 1, 15 patients with intra-uterine pregnancies (IUP); Group 2, 15 patients with tubal pregnancies (TP); Group 3, 15 patients with hydatidiform moles (HM); and Group 4, 20 patients with purported history of intra-uterine pregnancies (PIUP). Positive and negative control cases were from Groups 1 and 3 and Group 2, respectively. The test cases were from Group 4. Immunohistochemistry was performed on each case testing for expression of inhibin alpha, betaHCG, HPL and CAM 5.2. RESULTS: Trophoblastic populations, which included syncytiotrophoblast (ST), cytotrophoblast (CT) and intermediate trophoblast (IT), were absent in all 15 negative control cases (Group 2). The 30 positive control cases (Groups 1 and 3) revealed the following: (a) ST, CT and IT were identified in all cases and were positive for CAM 5.2, (b) inhibin alpha, betaHCG and HPL (except one case) were reactive for all cases with ST, but not CT, and (c) IT positivity for betaHCG, HPL and inhibin alpha was 67, 80-93 and 100%, respectively. From the 20 test cases (Group 4), the findings were: (a) CT was absent in all cases, (b) scattered ST cells, which were identified only in 10 cases, were positive for all antibodies, (c) scattered IT cells were present in 17 cases and showed 100% CAM 5.2 positivity, and (d) IT positivity for betaHCG, inhibin alpha and HPL was 58.8% (10/17), 76.5% (13/17) and 82.4% (14/17), respectively. Background staining was observed in 22 of 65 cases (33.8%) stained with betaHCG and HPL; half of these cases came from Group 3. Inhibin alpha and CAM 5.2 staining did not show this problem. CONCLUSIONS: We suggest that inhibin alpha is a useful antibody in diagnosing IUP and HM and in documenting intra-uterine gestations in cases with PIUP because it is a sensitive marker in immunolabelling IT and ST. Combined application of inhibin alpha and CAM 5.2 might be more useful than betaHCG and HPL because the latter showed background staining in one third of the cases.

The significance of cerebral mantle thickness in fetal ventriculomegaly at autopsy.

AIMS: To confirm the validity of the method of diagnosing fetal ventriculomegaly at autopsy by measuring cerebral mantle thickness at the frontal lobe and to further evaluate whether taking three measurements at three separate sites is even more reliable. METHODS: The thickness of the cerebral mantle was measured at three sites: the frontal lobe, posterior-frontal lobe and occipital lobe, in 10 human fetuses which were clinically diagnosed by ultrasound to have ventriculomegaly, and in 120 control fetuses. Most fetuses were obtained during the second trimester. The mantle thicknesses were charted against foot length and crown-rump length in each case. RESULTS: Fetal cerebral mantle thickness was reduced in the three sites examined in eight of ten fetuses with a pre-autopsy diagnosis of ventriculomegaly. The mantle thickness was in the normal range in a growth-restricted fetus of 19 weeks gestational age with trisomy 21, mild ventriculomegaly, hydrops and cerebral oedema, when correlated with crown-rump and foot lengths. In a 32-week growth-retarded fetus with a prenatal ultrasound diagnosis of ventriculomegaly, cerebral mantle thickness was also within the normal range relative to crown-rump and foot lengths. CONCLUSION: Measurement at autopsy of cerebral mantle thickness is a reproducible and reliable method of confirming the diagnosis of ventriculomegaly in second trimester fetuses. Fetal cerebral mantle thickness measurement taken at the three sites must be correlated with crown-rump and foot length. In most cases where ventriculomegaly was established, the mantle thickness was reduced in fetuses in all three sites examined. The relative thickness of the cerebral mantle in different areas was often abnormal in the presence of ventriculomegaly. Our study of small numbers of cases also suggested that the method of measurement may not be reliable in some cases where there is only mild ventriculomegaly, cerebral oedema or growth retardation.

Early myocardial fibrosis is associated with depletion of vasoactive intestinal peptide in rat heart.

In this study we sought to determine whether early myocardial fibrosis is associated with depletion of vasoactive intestinal peptide (VIP) in the heart, thereby suggesting a possible pathogenetic role for depletion of myocardial VIP levels in the development of fibrosis in the heart. Spontaneously hypertensive rats (SHRs) and normotensive control Wistar-Kyoto rats (WKYs) were assigned randomly to low, intermediate or high sodium diets and their blood pressure was recorded twice weekly for 4 weeks. At the end of this period the rats were anaesthetised, blood was sampled for plasma VIP concentration and the hearts were harvested for histology and determination of the concentration of VIP in the heart. The degree of myocardial fibrosis increased with increasing dietary sodium intake in both the WKYs (P < 0.001) and the SHRs (P < 0.01). Myocardial VIP concentration decreased with increasing dietary sodium intake in the WKYs (P < 0.01) and in the SHRs (P < 0.01). There was a negative correlation between myocardial VIP concentration and the degree of myocardial fibrosis in both the WKYs (P < 0.0005) and the SHRs (P < 0.005). Dietary sodium intake induces myocardial fibrosis in a dose-dependent manner. Further, in early myocardial fibrosis resulting from increasing dietary sodium intake in both normotensive and hypertensive rats the concentration of VIP in the heart was negatively correlated with the degree of fibrosis. This suggests a possible role for depletion of VIP in the myocardium in the pathogenesis of myocardial fibrosis.