Extensive assessment of blood glucose monitoring during postprandial period and its impact on closed-loop performance

[EN] Background: Closed-loop (CL) systems aims to outperform usual treatments in blood glucose control and continuous glucose monitors (CGM) are a key component in such systems. Meals represents one of the main disturbances in blood glucose control, and postprandial period (PP) is a challenging situation for both CL system and CGM accuracy. Methods: We performed an extensive analysis of sensor¿s performance by numerical accuracy and precision during PP, as well as its influence in blood glucose control under CL therapy. Results: During PP the mean absolute relative difference (MARD) for both sensors presented lower accuracy in the hypoglycemic range (19.4 ± 12.8%) than in other ranges (12.2 ± 8.6% in euglycemic range and 9.3 ± 9.3% in hyperglycemic range). The overall MARD was 12.1 ± 8.2%. We have also observed lower MARD for rates of change between 0 and 2 mg/dl. In CL therapy, the 10 trials with the best sensor spent less time in hypoglycemia (PG < 70 mg/dl) than the 10 trials with the worst sensors (2 ± 7 minutes vs 32 ± 38 minutes, respectively). Conclusions: In terms of accuracy, our results resemble to previously reported. Furthermore, our results showed that sensors with the lowest MARD spent less time in hypoglycemic range, indicating that the performance of CL algorithm to control PP was related to sensor accuracy.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project has been partially supported by the Spanish Government through Grants DPI 2013-46982-C2-1-R, DPI 2016-78831-C2-1-R, DPI 2013-46982-C2-2-R, and DPI 2016-78831-C2-2-R, the National Council of Technological and Scientific Development, CNPq Brazil through Grants 202050/2015-7 and 207688/2014-1.Biagi, L.; Hirata-Bertachi, A.; Conget, I.; Quirós, C.; Giménez, M.; Ampudia-Blasco, F.; Rossetti, P.... (2017). Extensive assessment of blood glucose monitoring during postprandial period and its impact on closed-loop performance. Journal of Diabetes Science and Technology. 11(6):1089-1095. https://doi.org/10.1177/1932296817714272S10891095116Doyle, F. J., Huyett, L. M., Lee, J. B., Zisser, H. C., & Dassau, E. (2014). Closed-Loop Artificial Pancreas Systems: Engineering the Algorithms. Diabetes Care, 37(5), 1191-1197. doi:10.2337/dc13-2108Cengiz, E., & Tamborlane, W. V. (2009). A Tale of Two Compartments: Interstitial Versus Blood Glucose Monitoring. Diabetes Technology & Therapeutics, 11(S1), S-11-S-16. doi:10.1089/dia.2009.0002Cobelli, C., Schiavon, M., Dalla Man, C., Basu, A., & Basu, R. (2016). Interstitial Fluid Glucose Is Not Just a Shifted-in-Time but a Distorted Mirror of Blood Glucose: Insight from an In Silico Study. Diabetes Technology & Therapeutics, 18(8), 505-511. doi:10.1089/dia.2016.0112Castle, J. R., & Ward, W. K. (2010). Amperometric Glucose Sensors: Sources of Error and Potential Benefit of Redundancy. Journal of Diabetes Science and Technology, 4(1), 221-225. doi:10.1177/193229681000400127Basu, A., Dube, S., Veettil, S., Slama, M., Kudva, Y. C., Peyser, T., … Basu, R. (2014). Time Lag of Glucose From Intravascular to Interstitial Compartment in Type 1 Diabetes. Journal of Diabetes Science and Technology, 9(1), 63-68. doi:10.1177/1932296814554797Keenan, D. B., Grosman, B., Clark, H. W., Roy, A., Weinzimer, S. A., Shah, R. V., & Mastrototaro, J. J. (2011). Continuous Glucose Monitoring Considerations for the Development of a Closed-Loop Artificial Pancreas System. Journal of Diabetes Science and Technology, 5(6), 1327-1336. doi:10.1177/193229681100500603Van Bon, A. C., Jonker, L. D., Koebrugge, R., Koops, R., Hoekstra, J. B. L., & DeVries, J. H. (2012). Feasibility of a Bihormonal Closed-Loop System to Control Postexercise and Postprandial Glucose Excursions. Journal of Diabetes Science and Technology, 6(5), 1114-1122. doi:10.1177/193229681200600516Rossetti, P., Quirós, C., Moscardó, V., Comas, A., Giménez, M., Ampudia-Blasco, F. J., … Vehí, J. (2017). Closed-Loop Control of Postprandial Glycemia Using an Insulin-on-Board Limitation Through Continuous Action on Glucose Target. Diabetes Technology & Therapeutics, 19(6), 355-362. doi:10.1089/dia.2016.0443Bailey, T., Zisser, H., & Chang, A. (2009). New Features and Performance of a Next-Generation SEVEN-Day Continuous Glucose Monitoring System with Short Lag Time. Diabetes Technology & Therapeutics, 11(12), 749-755. doi:10.1089/dia.2009.0075Zschornack, E., Schmid, C., Pleus, S., Link, M., Klötzer, H.-M., Obermaier, K., … Freckmann, G. (2013). Evaluation of the Performance of a Novel System for Continuous Glucose Monitoring. Journal of Diabetes Science and Technology, 7(4), 815-823. doi:10.1177/193229681300700403Pleus, S., Schmid, C., Link, M., Zschornack, E., Klötzer, H.-M., Haug, C., & Freckmann, G. (2013). Performance Evaluation of a Continuous Glucose Monitoring System under Conditions Similar to Daily Life. Journal of Diabetes Science and Technology, 7(4), 833-841. doi:10.1177/193229681300700405Zisser, H. C., Bailey, T. S., Schwartz, S., Ratner, R. E., & Wise, J. (2009). Accuracy of the SEVEN® Continuous Glucose Monitoring System: Comparison with Frequently Sampled Venous Glucose Measurements. Journal of Diabetes Science and Technology, 3(5), 1146-1154. doi:10.1177/193229680900300519Obermaier, K., Schmelzeisen-Redeker, G., Schoemaker, M., Klötzer, H.-M., Kirchsteiger, H., Eikmeier, H., & del Re, L. (2013). Performance Evaluations of Continuous Glucose Monitoring Systems: Precision Absolute Relative Deviation is Part of the Assessment. Journal of Diabetes Science and Technology, 7(4), 824-832. doi:10.1177/193229681300700404Clarke, W. L., Cox, D., Gonder-Frederick, L. A., Carter, W., & Pohl, S. L. (1987). Evaluating Clinical Accuracy of Systems for Self-Monitoring of Blood Glucose. Diabetes Care, 10(5), 622-628. doi:10.2337/diacare.10.5.622Martin Bland, J., & Altman, D. (1986). STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENT. The Lancet, 327(8476), 307-310. doi:10.1016/s0140-6736(86)90837-8Breton, M., & Kovatchev, B. (2008). Analysis, Modeling, and Simulation of the Accuracy of Continuous Glucose Sensors. Journal of Diabetes Science and Technology, 2(5), 853-862. doi:10.1177/193229680800200517Kropff, J., Bruttomesso, D., Doll, W., Farret, A., Galasso, S., Luijf, Y. M., … DeVries, J. H. (2014). Accuracy of two continuous glucose monitoring systems: a head‐to‐head comparison under clinical research centre and daily life conditions. Diabetes, Obesity and Metabolism, 17(4), 343-349. doi:10.1111/dom.12378Reddy, M., Herrero, P., Sharkawy, M. E., Pesl, P., Jugnee, N., Pavitt, D., … Oliver, N. S. (2015). Metabolic Control With the Bio-inspired Artificial Pancreas in Adults With Type 1 Diabetes. Journal of Diabetes Science and Technology, 10(2), 405-413. doi:10.1177/1932296815616134Pleus, S., Schoemaker, M., Morgenstern, K., Schmelzeisen-Redeker, G., Haug, C., Link, M., … Freckmann, G. (2015). Rate-of-Change Dependence of the Performance of Two CGM Systems During Induced Glucose Swings. Journal of Diabetes Science and Technology, 9(4), 801-807. doi:10.1177/193229681557871

Closed-Loop Control of Postprandial Glycemia Using an Insulin-on-Board Limitation Through Continuous Action on Glucose Target

This is a copy of an article published in the Diabetes Technology & Therapeutics © 2017 [copyright Mary Ann Liebert, Inc.]; Diabetes Technology & Therapeutics is available online at: https://www.liebertpub.com/.[EN] Background: Postprandial (PP) control remains a challenge for closed-loop (CL) systems. Few studies with inconsistent results have systematically investigated the PP period. Objective: To compare a new CL algorithm with current pump therapy (open loop [OL]) in the PP glucose control in type 1 diabetes (T1D) subjects. Methods: A crossover randomized study was performed in two centers. Twenty T1D subjects (F/M 13/7, age 40.7 -10.4 years, disease duration 22.6 +/- 9.9 years, and A1c 7.8% +/- 0.7%) underwent an 8-h mixed meal test on four occasions. In two (CL1/CL2), after meal announcement, a bolus was given followed by an algorithmdriven basal infusion based on continuous glucose monitoring (CGM). Alternatively, in OL1/OL2 conventional pump therapy was used. Main outcome measures were as follows: glucose variability, estimated with the coefficient of variation (CV) of the area under the curve (AUC) of plasma glucose (PG) and CGM values, and from the analysis of the glucose time series; mean, maximum (C-max), and time to C-max glucose concentrations and time in range (180 mg/dL). Results: CVs of the glucose AUCs were low and similar in all studies (around 10%). However, CL achieved greater reproducibility and better PG control in the PP period: CL1 = CL2 0.05) nor the need for oral glucose was significantly different (CL 40.0% vs. OL 22.5% of meals; P = 0.054). Conclusions: This novel CL algorithm effectively and consistently controls PP glucose excursions without increasing hypoglycemia. Study registered at ClinicalTrials.gov: study number NCT02100488.This work was supported by the Spanish Ministry of Economy and Competitiveness through Grants DPI2013-46982-C2-1-R and DPI2013-46982-C2-2-R, and the EU through FEDER funds. C.Q. is the recipient of a grant from the Hospital Clinic i Universitari of Barcelona ("Ajut a la recerca Josep Font 2014-2017").Rossetti, P.; Quirós, C.; Moscardo-Garcia, V.; Comas, A.; Giménez, M.; Ampudia-Blasco, F.; León, F.... (2017). Closed-Loop Control of Postprandial Glycemia Using an Insulin-on-Board Limitation Through Continuous Action on Glucose Target. Diabetes Technology & Therapeutics. 19(6):355-362. https://doi.org/10.1089/dia.2016.0443S35536219

The Antidiabetic Effect of MSCs Is Not Impaired by Insulin Prophylaxis and Is Not Improved by a Second Dose of Cells

Type 1 diabetes mellitus (T1D) is due to autoimmune destruction of pancreatic beta-cells. Previously, we have shown that intravenously administered bone marrow-derived multipotent mesenchymal stromal cells (MSCs) allows pancreatic islet recovery, improves insulin secretion and reverts hyperglycemia in low doses streptozotocin (STZ)-induced diabetic mice. Here we evaluate whether insulin prophylaxis and the administration of a second dose of cells affect the antidiabetic therapeutic effect of MSC transplantation. Insulitis and subsequent elimination of pancreatic beta-cells was promoted in C57BL/6 mice by the injection of 40 mg/kg/day STZ for five days. Twenty-four days later, diabetic mice were distributed into experimental groups according to if they received or not insulin and/or one or two doses of healthy donor-derived MSCs. Three and half months later: glycemia, pancreatic islets number, insulinemia, glycated hemoglobin level and glucose tolerance were determined in animals that did not received exogenous insulin for the last 1.5 months. Also, we characterized MSCs isolated from mice healthy or diabetic. The therapeutic effect of MSC transplantation was observed in diabetic mice that received or not insulin prophylaxis. Improvements were similar irrespective if they received one or two doses of cells. Compared to MSCs from healthy mice, MSCs from diabetic mice had the same proliferation and adipogenic potentials, but were less abundant, with altered immunophenotype and no osteogenic potential

Adventage of mesenchymal stem cells (MSC) expansion directly from purified bone marrow CD105^+ and CD271^+ cells

Mesenchymal Stem Cells (MSC) are employed in gene and cellular therapies. Routinely MSC are isolated from bone marrow mononuclear cells (MNC) by plastic adherence. Here we compared new isolation strategies of bone marrow MSC including immunodepletion of hematopoietic cells and immunomagnetic isolation of CD105+ and CD271+ populations. Four fractions were obtained: MNC MSC, RosetteSep-isolated MSC, CD105+ and CD271+ sorted MSC. We evaluated i) number of CFU-F colonies, ii) cell phenotype, iii) in vitro differentiation of expanded cells and iv) expression of osteo/adipogenesis related genes. Results: Average number of day 9 CFU-F colonies was the highest for CD271 positive fraction. Real-Time PCR analysis revealed expression of RUNX2, PPARgamma and N-cadherin in isolated cells, particularly high in CD271+ cells. Expression of CD105, CD166, CD44, CD73 antigens was comparable for all expanded populations (over 90%). We observed various levels of hematopoietic contamination with the highest numbers of CD45+ cells in MNC-MSC fraction and the lowest in CD105+ and CD271+ fractions. Cells of all the fractions were CD34 antigen negative. Expanded CD105 and CD271 populations showed higher level of RUNX2, osteocalcin, PTHR, leptin, PPARgamma2 and aggrecan1 genes except for alpha1 collagen. After osteogenic differentiation CD105+ and CD271+ populations showed lower expression of RUNX, PPARgamma2 and also lower expression of osteocalcin and PTHR than MNC, with comparable alpha1-collagen expression. Chondrogenic and adipogenic gene expression was higher in MNC. More clonogenic CD105+ and particularly CD271+ cells, which seem to be the most homogenous fractions based on Real-Time PCR and immunostaining data, are better suited for MSC expansion

Expansion and Harvesting of hMSC-TERT

The expansion of human mesenchymal stem cells as suspension culture by means of spinner flasks and microcarriers, compared to the cultivation in tissue culture flasks, offers the advantage of reducing the requirements of large incubator capacities as well as reducing the handling effort during cultivation and harvesting. Nonporous microcarriers are preferable when the cells need to be kept in viable condition for further applications like tissue engineering or cell therapy. In this study, the qualification of Biosilon, Cytodex 1, Cytodex 3, RapidCell and P102-L for expansion of hMSC-TERT with an associated harvesting process using either trypsin, accutase, collagenase or a trypsin-accutase mixture was investigated. A subsequent adipogenic differentiation of harvested hMSC-TERT was performed in order to observe possible negative effects on their (adipogenic) differentiation potential as a result of the cultivation and harvesting method. The cultivated cells showed an average growth rate of 0.52 d-1. The cells cultivated on Biosilon, RapidCell and P102-L were harvested succesfully achieving high cell yield and vitalities near 100%. This was not the case for cells on Cytodex 1 and Cytodex 3. The trypsin-accutase mix was most effective. After spinner expansion and harvesting the cells were successfully differentiated to adipocytes

Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement?

BACKGROUND: Mefloquine is a clinically important antimalaria drug, which is often not well tolerated. We critically reviewed 516 published case reports of mefloquine adverse effects, to clarify the phenomenology of the harms associated with mefloquine, and to make recommendations for safer prescribing. PRESENTATION: We postulate that many of the adverse effects of mefloquine are a post-hepatic syndrome caused by primary liver damage. In some users we believe that symptomatic thyroid disturbance occurs, either independently or as a secondary consequence of the hepatocellular injury. The mefloquine syndrome presents in a variety of ways including headache, gastrointestinal disturbances, nervousness, fatigue, disorders of sleep, mood, memory and concentration, and occasionally frank psychosis. Previous liver or thyroid disease, and concurrent insults to the liver (such as from alcohol, dehydration, an oral contraceptive pill, recreational drugs, and other liver-damaging drugs) may be related to the development of severe or prolonged adverse reactions to mefloquine. IMPLICATIONS: We believe that people with active liver or thyroid disease should not take mefloquine, whereas those with fully resolved neuropsychiatric illness may do so safely. Mefloquine users should avoid alcohol, recreational drugs, hormonal contraception and co-medications known to cause liver damage or thyroid damage. With these caveats, we believe that mefloquine may be safely prescribed in pregnancy, and also to occupational groups who carry out safety-critical tasks. TESTING: Mefloquine's adverse effects need to be investigated through a multicentre cohort study, with small controlled studies testing specific elements of the hypothesis