Safety Evaluation of the MiniMed 670G System in Children 7-13 Years of Age with Type 1 Diabetes.

OBJECTIVE: To evaluate the safety of in-home use of the MiniMed™ 670G system with SmartGuard™ technology in children with type 1 diabetes (T1D). METHODS: Participants (N = 105, ages 7-13 years, mean age 10.8 ± 1.8 years) were enrolled at nine centers (eight in the United States and one in Israel) and completed a 2-week baseline run-in phase in Manual Mode followed by a 3-month study phase with Auto Mode enabled. Sensor glucose (SG), glycated hemoglobin (HbA1c), percentage of SG values across glucose ranges, and SG variability, during the run-in and study phases were compared. Participants underwent frequent sample testing with i-STAT® venous reference measurement during a hotel period (6 days/5 nights) to evaluate the system's continuous glucose monitoring performance. RESULTS: Auto Mode was used a median of 81% of the time. From baseline to end of study, overall SG dropped by 6.9 ± 17.2 mg/dL (P < 0.001), HbA1c decreased from 7.9% ± 0.8% to 7.5% ± 0.6% (P < 0.001), percentage of time in target glucose range (70-180 mg/dL) increased from 56.2% ± 11.4% to 65.0% ± 7.7% (P < 0.001), and the SG coefficient of variation decreased from 39.6% ± 5.4% to 38.5% ± 3.8% (P = 0.009). The percentage of SG values within target glucose range was 68.2% ± 9.1% and that of i-STAT reference values was 65.6% ± 17.7%. The percentage of values within 20%/20 of the i-STAT reference was 85.2%. There were no episodes of severe hypoglycemia or diabetic ketoacidosis during the study phase. CONCLUSION: In-home use of MiniMed 670G system Auto Mode for 3 months by children with T1D, similar to MiniMed 670G system use by adolescents and adults with T1D, was safe and associated with reduced HbA1c levels and increased time in target glucose range, compared with baseline.

In-Clinic Evaluation of the MiniMed 670G System "Suspend Before Low" Feature in Children with Type 1 Diabetes.

BACKGROUND: The Medtronic predictive low-glucose management (PLGM) algorithm automatically stops insulin delivery when sensor glucose (SG) is predicted to reach or fall below a preset low-glucose value within the next 30 min, and resumes delivery after hypoglycemia recovery. The present study evaluated the PLGM algorithm performance of the MiniMed™ 670G system SmartGuard™ "suspend before low" feature in children aged 7-13 years with type 1 diabetes (T1D). METHOD: Participants (N = 105, mean ± standard deviation of 10.8 ± 1.8 years) underwent an overnight in-clinic evaluation of the "suspend before low" feature with a preset low limit of 65 mg/dL. After exercise, frequent sample testing (FST) was conducted every 5 min if values were <70 mg/dL; every 15 min if 70-80 mg/dL; and every 30 min if >80 mg/dL. First-day performance of the Guardian™ Sensor 3 glucose sensor and continuous glucose monitoring system was also evaluated. RESULTS: Activation of the "suspend before low" feature occurred in 79 of the 105 participants, 79.7% (63/79) did not result in SG falling below 65 mg/dL. Mean glucose at activation was 102 ± 19 mg/dL and the initial insulin suspension duration was 87.5 ± 32.7 min. Four hours after insulin resumption, mean reference glucose was 130 ± 42 mg/dL. Mean absolute relative difference between the FST reference glucose and SG values on the first day of sensor wear was 11.4%. For the 26 participants in whom the "suspend before low" feature did not activate, none involved a reference glucose value ≤65 mg/dL, suggesting that the PLGM algorithm performed as intended. CONCLUSION: In children aged 7-13 years with T1D, the "suspend before low" feature of the MiniMed 670G system demonstrated a hypoglycemia prevention rate of nearly 80% after exercise and did not involve rebound hyperglycemia. There were no events of severe hypoglycemia during the evaluation.

Accuracy of a Fourth-Generation Continuous Glucose Monitoring System in Children and Adolescents with Type 1 Diabetes.

BACKGROUND: This study evaluated the safety and performance of the Guardian™ continuous glucose monitoring (CGM) system in children and adolescents with type 1 diabetes (T1D). MATERIALS AND METHODS: Subjects 2-18 years of age (mean ± standard deviation [SD] 13.1 ± 3.9 years) with T1D and duration of diagnosis ≥1 year were enrolled at 11 sites in the United States and wore two Guardian Sensor 3 sensors in the abdomen and/or buttock. Sensors were connected to a transmitter paired with either a Guardian Connect system (i.e., mobile device with software application allowing display of sensor glucose [SG] values) or a Guardian Link 3 transmitter used as a Glucose Sensor Recorder (GSR). There were 145 participants who underwent a 6-h in-clinic frequent sample testing (FST) on day 1 (n = 54), day 3 (n = 48), or day 7 (n = 43) postsensor insertion. During FST, SG values were compared with a Yellow Springs Instrument (YSI) plasma reference every 5-15 min (n = 124, 7-18 years of age; n = 2, 2-6 years of age), or to a self-monitoring of blood glucose (SMBG) reference every 5-30 min (n = 19, 2-6 years of age). RESULTS: The overall mean absolute relative difference (ARD ± SD) between SG and reference values (YSI or SMBG) when calibrating approximately every 12 h, was 10.9% ± 10.7% (3102 paired points) for sensors communicating with the Guardian Connect system and 11.1% ± 10.6% (2624 paired points) for sensors connected to the GSR. The overall percentage of SG values within ±20% of reference values >80 mg/dL or within 20 mg/dL of reference values ≤80 mg/dL was 87.8% for the Guardian Connect system and 86.7% for the GSR, respectively. There was one device-related adverse event of contact dermatitis, but no serious device-related adverse events. CONCLUSIONS: The Guardian CGM system demonstrated good accuracy in children and adolescents. These findings support its use in sensor-integrated insulin pump platforms, as well as a standalone technology, for managing diabetes in pediatric populations.

IMPROVED HBA1C, TOTAL DAILY INSULIN DOSE, AND TREATMENT SATISFACTION WITH INSULIN PUMP THERAPY COMPARED TO MULTIPLE DAILY INSULIN INJECTIONS IN PATIENTS WITH TYPE 2 DIABETES IRRESPECTIVE OF BASELINE C-PEPTIDE LEVELS.

OBJECTIVE: Fasting C-peptide levels are used to differentiate type 1 from type 2 diabetes (T2D), thereby determining eligibility for coverage of continuous subcutaneous insulin infusion (CSII) for patients with T2D. METHODS: A total of 168 patients (74 female/94 male, aged 55.5 ± 9.7 years) were randomized to CSII, and 163 patients (77 female/86 male, aged 56.4 ± 9.5 years) were randomized to multiple daily injections (MDI) of insulin and grouped by baseline C-peptide level: group A (≤183 pmol/L [≤0.55 ng/mL]); group B (>183 pmol/L [>0.55 ng/mL]). At 6 months, the MDI group crossed over to CSII. Within- and between-group comparisons were recorded at 6 and 12 months in the entire group and separately for those patients aged ≥65 years. RESULTS: CSII reduced hemoglobin A1c (A1c) equally in groups A ( P = .0006, P = .0022) and B ( P<.0001, P<.0001) at 6 and 12 months, respectively. There was an increase in weight in group A versus group B at 6 months but not 12 months ( P<.03). CSII therapy reduced total daily dose (TDD) of insulin and improved treatment satisfaction similarly in groups A and B. The results for patients aged ≥65 years displayed a similar trend as the entire group. CONCLUSION: A1c, TDD of insulin, and treatment satisfaction improved for T2D patients using CSII versus MDI therapy, irrespective of baseline C-peptide level. A subgroup of patients aged ≥65 years displayed a similar trend. These results support abandoning C-peptide as a criterion for reimbursing CSII therapy in patients with diabetes. ABBREVIATIONS: A1c = hemoglobin A1c; CMS = Centers for Medicare and Medicaid Services; CSII = continuous subcutaneous insulin infusion; DTSQ = Diabetes Treatment Satisfaction Questionnaire; MDI = multiple daily injections; RCT = randomized controlled trials; T1D = type 1 diabetes; T2D = type 2 diabetes; TDD = total daily dose.

Accuracy of a Fourth-Generation Subcutaneous Continuous Glucose Sensor.

BACKGROUND: This study evaluated the accuracy and performance of a fourth-generation subcutaneous glucose sensor (Guardian™ Sensor 3) in the abdomen and arm. METHODS: Eighty-eight subjects (14-75 years of age, mean ± standard deviation [SD] of 42.0 ± 19.1 years) with type 1 or type 2 diabetes participated in the study. Subjects wore two sensors in the abdomen that were paired with either a MiniMed™ 640G insulin pump, or an iPhone® or iPod® touch® running a glucose monitoring mobile application (Guardian Connect system) and a third sensor in the arm, which was connected to a glucose sensor recorder (GSR). Subjects were also asked to undergo in-clinic visits of 12-14 h on study days 1, 3, and 7 for frequent blood glucose sample testing using a Yellow Springs Instrument (YSI) reference. RESULTS: The overall mean absolute relative difference (MARD ± SD) between abdomen sensor glucose (SG) and YSI reference values was 9.6% ± 9.0% and 9.4% ± 9.8% for the MiniMed 640G insulin pump and Guardian Connect system, respectively; and 8.7% ± 8.0% between arm SG and YSI reference values. The percentage of SG values within 20% agreement of the YSI reference value (for YSI >80 mg/dL) was 90.7% with the MiniMed 640G insulin pump, 91.8% with the Guardian Connect system, and 93.1% for GSR-connected arm sensors. Mean functional sensor life, when calibrating 3-4 times/day, was 145.9 ± 39.3 h for sensors paired with the MiniMed 640G insulin pump, 146.1 ± 41.6 h for sensors paired with the Guardian Connect system, and 147.6 ± 40.4 h for sensors connected to the GSR. Responses to survey questions regarding sensor comfort and ease of use were favorable. CONCLUSIONS: The Guardian Sensor 3 glucose sensor, whether located in abdomen or the arm, provided accurate glucose readings when compared with the YSI reference and demonstrated functional life commensurate with the intended 7-day use. ClinicalTrials.gov : NCT02246582.

RNAi Screening of the Glucose-Regulated Chaperones in Cancer with Self-Assembled siRNA Nanostructures.

The emerging field of RNA nanotechnology has been used to design well-programmed, self-assembled nanostructures for applications in chemistry, biology, and medicine. At the forefront of its utility in cancer is the unrestricted ability to self-assemble multiple siRNAs within a single nanostructure formulation for the RNAi screening of a wide range of oncogenes while potentiating the gene therapy of malignant tumors. In our RNAi nanotechnology approach, V- and Y-shape RNA templates were designed and constructed for the self-assembly of discrete, higher-ordered siRNA nanostructures targeting the oncogenic glucose regulated chaperones. The GRP78-targeting siRNAs self-assembled into genetically encoded spheres, triangles, squares, pentagons and hexagons of discrete sizes and shapes according to TEM imaging. Furthermore, gel electrophoresis, thermal denaturation, and CD spectroscopy validated the prerequisite siRNA hybrids for their RNAi application. In a 24 sample siRNA screen conducted within the AN3CA endometrial cancer cells known to overexpress oncogenic GRP78 activity, the self-assembled siRNAs targeting multiple sites of GRP78 expression demonstrated more potent and long-lasting anticancer activity relative to their linear controls. Extending the scope of our RNAi screening approach, the self-assembled siRNA hybrids (5 nM) targeting of GRP-75, 78, and 94 resulted in significant (50-95%) knockdown of the glucose regulated chaperones, which led to synergistic effects in tumor cell cycle arrest (50-80%) and death (50-60%) within endometrial (AN3CA), cervical (HeLa), and breast (MDA-MB-231) cancer cell lines. Interestingly, a nontumorigenic lung (MRC5) cell line displaying normal glucose regulated chaperone levels was found to tolerate siRNA treatment and demonstrated less toxicity (5-20%) relative to the cancer cells that were found to be addicted to glucose regulated chaperones. These remarkable self-assembled siRNA nanostructures may thus encompass a new class of potent siRNAs that may be useful in screening important oncogene targets while improving siRNA therapeutic efficacy and specificity in cancer.

Synthesis, characterization and anti-cancer activity of a peptide nucleolipid bioconjugate.

The synthesis, characterization and anti-cancer activity of a novel peptide nucleolipid bioconjugate is reported in this study. The prerequisite 5'-carboxy derived nucleolipid was synthesized following a five-step solution-phase approach and then coupled to the cytotoxic D-(KLAKLAK)2 sequence by solid-phase bioconjugation. The biophysical and structural properties of the peptide-nucleolipid bioconjugate were evaluated and compared to the peptide controls. These characterization studies revealed that the amphiphilic peptides favored helical-type secondary structures and well-defined nanoparticle formulations that were found to be contributive towards their biological activity. The peptide-nucleolipid bioconjugate displayed greater lethality in comparison to the native D-(KLAKLAK)2AK sequence when treated within the human A549 non-small cell lung carcinoma cell line. Thus, the amphiphilic peptide-nucleolipid forms a new class of anti-cancer peptides that may be developed into promising leads in the fight against cancer.

The effects of lowering nighttime and breakfast glucose levels with sensor-augmented pump therapy on hemoglobin A1c levels in type 1 diabetes.

OBJECTIVE: This study determined the association of continuous glucose monitoring glucose (CGM-glucose) levels at different times of the day with improvement in glycated hemoglobin (HbA1c) levels. The potential application of these data is to focus effort to improve glucose control in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Data were analyzed from 196 patients with type 1 diabetes who were randomized to receive sensor-augmented pump therapy in the 1-year STAR 3 trial. CGM-glucose values and HbA1c levels from baseline and after 1 year were evaluated to determine associations of improvement in CGM-glucose at different times of the day with longitudinal improvement in HbA1c. RESULTS: Improvement in HbA1c levels after 1 year was related to improvement in mean CGM-glucose levels in daytime (6 a.m.-midnight), overnight (midnight-6 a.m.), and each mealtime period (P<0.0001 for each). In multivariable analysis, only improvement in breakfast meal period was associated with improvement in HbA1c after 1 year, explaining 59% of the HbA1c improvement using the partial R(2) test. Moreover, among those patients who only improved CGM-glucose in the overnight period there was an associated improvement in breakfast meal period CGM-glucose of 26 ± 22 mg/dL (P<0.01). CONCLUSIONS: Breakfast period glucose improvement had the greatest effect on lowering HbA1c levels in patients with type 1 diabetes. Improving glucose control overnight resulted in subsequent improvement in the breakfast period. Although glucose control should be improved at all times, methods to improve overnight and post-breakfast glucose levels may be of primary importance in improving glucose control in patients with type 1 diabetes.

Accuracy performance of the Medtronic NexSensor™ for 6 days in an inpatient setting using abdomen and buttocks insertion sites.

BACKGROUND: Users of continuous glucose monitoring are concerned with product accuracy and choice of insertion site. The Medtronic NexSensor™ was evaluated for accuracy during 6 days of wear when inserted in the abdomen and buttocks areas. METHODS: Adults (ages 18-75) with type 1 diabetes wore two sensors simultaneously for 6 days, one each inserted in the abdomen and buttocks. Subjects underwent a frequent blood sampling study for 12 hours, during which time reference blood glucose values were obtained every 15 minutes and compared to sensor values. RESULTS: Sixty-three subjects were enrolled, and 61 subjects completed the study. The mean agreement rate between sensor and blood glucose values was 75.5% [95% confidence interval (CI), 69.5, 81.4] at the abdomen site, 73.8% (95% CI, 68.8, 78.8) at the buttocks site, and 75.6% (95% CI, 70.8, 80.4) when sensor and reference data were combined between sites. Over 90% of paired sensor-reference values on Clarke error grids were within the A and B ranges. The mean absolute relative differences were 17.1% at the abdomen site, 16.5% at the buttocks site, and 16.8% when sites were combined. CONCLUSION: The NexSensor was accurate for inpatient, frequent-sample testing for 6 days when inserted into the abdomen and buttocks. The results of this study also provide evidence that both the abdomen and buttocks are suitable as sensor insertion sites.

Parental concentration of dichlorodiphenyl dichloroethene and polychlorinated biphenyls in Michigan fish eaters and sex ratio in offspring.

Contamination of fish in the Great Lakes generated three surveys assessing polychlorinated biphenyls (PCB) serum concentration in Michigan anglers: 1973 to 1974, 1979 to 1982, and 1989 to 1991. This cohort provided 1177 individuals with PCB determinations. In 2000, we conducted telephone interviews with parents on their children's birth characteristics. We estimated the sex odds ratio for parental PCB and dichlorodiphenyl dichloroethene concentrations using generalized estimation equations. We identified 208 offspring, within 101 families, born after 1963, with paternal measurements of both PCB and dichlorodiphenyl dichloroethene. When controlling for maternal exposure and parental dichlorodiphenyl dichloroethene, the sex odds ratio was increased if paternal PCB concentrations exceeded 8.1 micrograms/L (sex ratio, 2.29; 95% confidence interval, 1.11 to 4.74). Thus, paternal exposure was linked to a higher proportion of male offspring. These findings are opposite those reported for the Seveso study and are in accordance with those for dioxin exposure in the American veterans study.