bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biofouling of Polymer Hydrogel Materials and its Effect on Diffusion and Enzyme-Based Luminescent Glucose Sensor Functional Characteristics
Authors: Roberts Jason R. , Park Jaebum , Helton Kristen , Wisniewski Natalie , McShane Michael J. 
Published: January 2014

Background: Continuous glucose monitoring is crucial to developing a successful artificial pancreas. However, biofouling and host response make in vivo sensor performance difficult to predict. We investigated changes in glucose diffusivity and sensor response of optical enzymatic glucose sensors due to biological exposure. Method: Three hydrogel materials, poly(2-hydroxyethyl methacrylate) (pHEMA), poly(acrylamide) (pAM), and poly(2-hydroxyethyl methacrylate)-co-poly(acrylamide) (p(HEMA-co-AM)), were tested for glucose diffusivity before and after exposure to serum or implantation in rats for 1 month. Luminescent sensors based on these materials were measured to compare the response to glucose before and after serum exposure. Results: Glucose diffusivity through the pHEMA [(8.1 ± 0.38) × 10−8 cm2/s] slabs was much lower than diffusivity through pAM [(2.7 ± 0.15) × 10−6 cm2/s] and p(HEMA-co-AM) [(2.5 ± 0.08) × 10−6]. As expected from these differences, sensor response was highly dependent on material type. The pHEMA sensors had a maximum sensitivity of 2.5%/(mg/dl) and an analytical range of 4.2–356 mg/dl, while the p(HEMA-co-AM) sensors had a higher sensitivity [14.9%/(mg/dl)] and a narrower analytical range (17.6–70.5 mg/dl). After serum exposure, the pHEMA sensors were unaffected, whereas the p(HEMA-co-AM) sensors exhibited significantly decreased sensitivity and increased analytical range. Conclusions: Decreases in glucose diffusivity in the polymers resulting from in vitro serum exposure and residence in vivo were shown to be similar, suggesting that serum incubation was a reasonable approximation of in vivo fouling. While biofouling is expected to affect the response of flux-based sensors, we have shown that this depended on the type of sensor and matrix used. Therefore, proper design and materials selection may minimize response alterations occurring upon implantation.
Application of Adaptive Design Methodology in Development of a Long-Acting Glucagon-like Peptide-1 Analog (Dulaglutide): Statistical Design and Simulations
Authors: Skrivanek Zachary , Berry Scott , Berry Don , Chien Jenny , Geiger Mary Jane , Anderson James H. , Gaydos Brenda 
Published: January 2014

Background: Dulaglutide (dula, LY2189265), a long-acting glucagon-like peptide-1 analog, is being developed to treat type 2 diabetes mellitus. Methods: To foster the development of dula, we designed a two-stage adaptive, dose-finding, inferentially seamless phase 2/3 study. The Bayesian theoretical framework is used to adaptively randomize patients in stage 1 to 7 dula doses and, at the decision point, to either stop for futility or to select up to 2 dula doses for stage 2. After dose selection, patients continue to be randomized to the selected dula doses or comparator arms. Data from patients assigned the selected doses will be pooled across both stages and analyzed with an analysis of covariance model, using baseline hemoglobin A1c and country as covariates. The operating characteristics of the trial were assessed by extensive simulation studies. Results: Simulations demonstrated that the adaptive design would identify the correct doses 88% of the time, compared to as low as 6% for a fixed-dose design (the latter value based on frequentist decision rules analogous to the Bayesian decision rules for adaptive design). Conclusions: This article discusses the decision rules used to select the dula dose(s); the mathematical details of the adaptive algorithm—including a description of the clinical utility index used to mathematically quantify the desirability of a dose based on safety and efficacy measurements; and a description of the simulation process and results that quantify the operating characteristics of the design.
Prevention of Diabetes in Rural India with a Telemedicine Intervention
Authors: Mohan Viswanathan , Deepa Mohan , Pradeepa Rajendra , Prathiba Venkat , Datta Manjula , Ravikumar Sethuraman , Rakesh Hari , Sucharita Yarlagadda , Webster Premila , Allender Steven , Kapur Anil , Anjana Ranjit Mohan 
Published: January 2014

Background: Diabetes care is not presently available, accessible, or affordable to people living in rural areas in developing countries, such as India. The Chunampet Rural Diabetes Prevention Project (CRDPP) was conceived with the aim of implementing comprehensive diabetes screening, prevention, and treatment using a combination of telemedicine and personalized care in rural India. Methods: This project was undertaken in a cluster of 42 villages in and around the Chunampet village in the state of Tamil Nadu in southern India. A telemedicine van was used to screen for diabetes and its complications using retinal photography, Doppler imaging, biothesiometry, and electrocardiography using standardized techniques. A rural diabetes center was set up to provide basic diabetes care. Results: Of the total 27,014 adult population living in 42 villages, 23,380 (86.5%) were screened for diabetes, of which 1138 (4.9%) had diabetes and 3410 (14.6%) had prediabetes. A total of 1001 diabetes subjects were screened for complications (response rate of 88.0%). Diabetic retinopathy was detected in 18.2%, neuropathy in 30.9%, microalbuminuria in 24.3%, peripheral vascular disease in 7.3%, and coronary artery disease in 10.8%. The mean hemoglobin A1c levels among the diabetes subjects in the whole community decreased from 9.3 ± 2.6% to 8.5 ± 2.4% within 1 year. Less than 5% of patients needed referral for further management to the tertiary diabetes hospital in Chennai. Conclusions: The Chunampet Rural Diabetes Prevention Project is a successful model for screening and for delivery of diabetes health care and prevention to underserved rural areas in developing countries such as India.
Evaluation of a Continuous Blood Glucose Monitoring System Using Central Venous Microdialysis
Authors: Schierenbeck Fanny , Franco-Cereceda Anders , Liska Jan 
Published: January 2014

Background: Glycemic control in critically ill patients has been shown to be beneficial. In this prospective study, we evaluated the accuracy and technical feasibility of a continuous glucose monitoring system using intravascular microdialysis. Method: Fifty patients undergoing cardiac surgery were monitored using a 4 Fr intravenous microdialysis catheter (Eirus SLC™, Dipylon Medical AB, Solna, Sweden) percutaneously placed with the tip of the catheter positioned in the superior vena cava. The catheter was connected to the Eirus™ monitoring system, and the patients were monitored for up to 48 h postoperatively in the intensive care unit (ICU). As reference, arterial blood samples were taken every hour and analyzed in a blood gas analyzer. Results: Data were available from 48 patients. A total of 994 paired (arterial blood gas microdialysis) samples were obtained. Glucose correlation coefficient ( R2) was 0.85. Using Clarke error grid analysis, 100% of the paired samples were in region AB, and 99% were in region A. Mean glucose level was 8.3 mmol/liter (149 mg/dl), mean relative difference was 0.2%, and mean absolute relative difference was 5%. A total of 99.2% of the paired samples were correct according to International Organization for Standardization (ISO) criteria. Bland-Altman analysis showed that bias ± limits of agreement were 0.02 ± 1.1 mmol/liter (0.36 ± 20 mg/dl). Conclusions: Central venous microdialysis using the Eirus monitoring system is a highly accurate and reliable method for continuous blood glucose monitoring up to 48 h in ICU patients undergoing cardiac surgery. The system may thus be useful in critically ill ICU patients.
Use of a Food and Drug Administration-Approved Type 1 Diabetes Mellitus Simulator to Evaluate and Optimize a Proportional-Integral-Derivative Controller
Authors: Laxminarayan Srinivas , Reifman Jaques , Steil Garry M. 
Published: January 2014

Background: Clinical studies have shown that the Medtronic proportional-integral-derivative (PID) control with insulin feedback (IFB) provides stable 24 h glucose control, but with high postprandial glucose. We coupled this algorithm to a Food and Drug Administration-approved type 1 diabetes mellitus simulator to determine whether a proportional-derivative controller with preprogrammed basal rates (PDBASAL) would have better performance. Methods: We performed simulation studies on 10 adult subjects to (1) obtain the basal profiles for the PDBASAL controller; (2) define the pharmacokinetic/pharmacodynamic profile used to effect IFB, (3) optimize the PID and PDBASAL control parameters, (4) evaluate improvements obtained with IFB, and (5) develop a method to simulate changes in insulin sensitivity and assess the ability of each algorithm to respond to such changes. Results: PDBASAL control significantly reduced peak postprandial glucose [252 (standard error = 11) versus 279 (14) mg/dl; p < .001] and increased nadir glucose [102 (3) versus 92 (3) mg/dl; p < .001] compared with PID control (both implemented with IFB). However, with PDBASAL control, fasting glucose remained elevated following a 30% decrease in insulin sensitivity [156 (6) mg/dl; different from the target of 110 mg/dl; p < .001] and remained below target following a 30% increase in insulin sensitivity [84 (2) mg/dl; p < .001]. In both cases, PID control returned glucose levels to target. Conclusions: PDBASAL provides better postprandial glucose control than PID but is not appropriate for subjects whose basal requirements change with insulin sensitivity. Simulations used to compare different control strategies should assess this variability.
Improving the Computational Effort of Set-Inversion-Based Prandial Insulin Delivery for Its Integration in Insulin Pumps
Authors: León-Vargas Fabian , Calm Remei , Bondia Jorge , Vehí Josep 
Published: January 2014

Objective: Set-inversion-based prandial insulin delivery is a new model-based bolus advisor for postprandial glucose control in type 1 diabetes mellitus (T1DM). It automatically coordinates the values of basal-bolus insulin to be infused during the postprandial period so as to achieve some predefined control objectives. However, the method requires an excessive computation time to compute the solution set of feasible insulin profiles, which impedes its integration into an insulin pump. In this work, a new algorithm is presented, which reduces computation time significantly and enables the integration of this new bolus advisor into current processing features of smart insulin pumps. Methods: A new strategy was implemented that focused on finding the combined basal-bolus solution of interest rather than an extensive search of the feasible set of solutions. Analysis of interval simulations, inclusion of physiological assumptions, and search domain contractions were used. Data from six real patients with T1DM were used to compare the performance between the optimized and the conventional computations. Results: In all cases, the optimized version yielded the basal-bolus combination recommended by the conventional method and in only 0.032% of the computation time. Simulations show that the mean number of iterations for the optimized computation requires approximately 3.59 s at 20 MHz processing power, in line with current features of smart pumps. Conclusions: A computationally efficient method for basal-bolus coordination in postprandial glucose control has been presented and tested. The results indicate that an embedded algorithm within smart insulin pumps is now feasible. Nonetheless, we acknowledge that a clinical trial will be needed in order to justify this claim.
Continuous Monitoring of Glucose in Subcutaneous Tissue Using Microfabricated Differential Affinity Sensors
Authors: Huang Xian , Leduc Charles , Ravussin Yann , Li Siqi , Davis Erin , Song Bing , Wang Qian , Accili Domenico , Leibel Rudolph , Lin Qiao 
Published: January 2014

Objective: We describe miniaturized differential glucose sensors based on affinity binding between glucose and a synthetic polymer. The sensors possess excellent resistance to environmental disturbances and can potentially allow wireless measurements of glucose concentrations within interstitial fluid in subcutaneous tissue for long-term, stable continuous glucose monitoring (CGM). Methods: The sensors are constructed using microelectromechanical systems (MEMS) technology and exploit poly(N-hydroxy-ethyl acrylamide- ran-3-acrylamidophenylboronic acid) (PHEAA- ran-PAAPBA), a glucose-binding polymer with excellent specificity, reversibility, and stability. Two sensing approaches have been investigated, which respectively, use a pair of magnetically actuated diaphragms and perforated electrodes to differentially measure the glucose-binding-induced changes in the viscosity and permittivity of the PHEAA- ran-PAAPBA solution with respect to a reference, glucose-unresponsive polymer solution. Results: In vivo characterization of the MEMS affinity sensors were performed by controlling blood glucose concentrations of laboratory mice by exogenous glucose and insulin administration. The sensors experienced an 8–30 min initialization period after implantation and then closely tracked commercial capillary glucose meter readings with time lags ranging from 0–15 min during rapid glucose concentration changes. Clarke error grid plots obtained from sensor calibration suggest that, for the viscometric and dielectric sensors, respectively, approximately 95% (in the hyperglycemic range) and 84% (ranging from hypoglycemic to hyperglycemic glucose concentrations) of measurement points were clinically accurate, while 5% and 16% of the points were clinically acceptable. Conclusions: The miniaturized MEMS sensors explore differential measurements of affinity glucose recognition. In vivo testing demonstrated excellent accuracy and stability, suggesting that the devices hold the potential to enable long-term and reliable CGM in clinical applications.
Blood Glucose Self-Monitoring with a Long-Term Subconjunctival Glucose Sensor
Authors: Müller Achim Josef , Knuth Monika , Nikolaus Katharina Sibylle , Krivánek Roland , Küster Frank , Hasslacher Christoph , Auffarth Gerd Uwe 
Published: January 2014

Background: To evaluate the feasibility of an implantable subconjunctival glucose monitoring system (SGMS) for long-term glucose monitoring, we investigated the in vivo performance of the system. Method: The SGMS consists of an implantable ocular mini implant (OMI) and a handheld fluorescence photometer. A clinical study was performed on 47 diabetes patients split into two cohorts. Two different types of OMI were used, with and without a biocompatible surface coating. Duration of the study was 1 year. Correlation between capillary blood glucose and SGMS-derived interstitial fluid glucose was investigated during the first 6 months of the study. Results: Both OMI types were tolerated well in the eyes of the patients. At the beginning of the study, the SGMS of both cohorts revealed a high accuracy with mean absolute relative difference (MARD) values of 7–12%. The performance of the uncoated OMIs deteriorated within 3 months of wearing time, exhibiting a MARD value of 20%. The performance of the surface-coated OMIs was preserved longer. Glucose correlation measurement with reasonable results (MARD of 14%) could be performed for up to 6 months of wear. Conclusions: The biocompatible surface coating on the OMIs enabled a longer duration of action of up to 6 months compared with 3 months for uncoated implants in a clinical trial.
Gel Encapsulation of Glucose Nanosensors for Prolonged In Vivo Lifetime
Authors: Balaconis Mary K. , Clark Heather A. 
Published: January 2014

Background: Fluorescent glucose-sensitive nanosensors have previously been used in vivo to track glucose concentration changes in interstitial fluid. However, this technology was limited because of loss of fluorescence intensity due to particle diffusion from the injection site. In this study, we encapsulated the nanosensors into injectable gels to mitigate nanosensor migration in vivo. Methods: Glucose-sensitive nanosensors were encapsulated in two different commercially available gelling agents: gel 1 and gel 2. Multiple formulations of each gel were assessed in vitro for their nanosensor encapsulation efficiency, permeability to glucose, and nanosensor retention over time. The optimal formulation for each gel, as determined from the in vitro assessment, was then tested in mice, and the lifetime of the encapsulated nanosensors was compared with controls of nanosensors without gel. Results: Five gel formulations had encapsulation efficiencies of the nanosensors greater than 90%. Additionally, they retained up to 20% and 40% of the nanosensors over 24 h for gel 1 and gel 2, respectively. In vivo, both gels prevented diffusion of glucose nanosensors at least three times greater than the controls. Conclusions: Encapsulating glucose nanosensors in two injectable gels prolonged nanosensor lifetime in vivo; however, the lifetime must still be increased further to be applicable for diabetes monitoring.
A Novel Fasting Blood Test for Insulin Resistance and Prediabetes
Authors: Cobb Jeff , Gall Walter , Adam Klaus-Peter , Nakhle Pamela , Button Eric , Hathorn James , Lawton Kay , Milburn Michael , Perichon Regis , Mitchell Matthew , Natali Andrea , Ferrannini Ele 
Published: January 2014

Background: Insulin resistance (IR) can precede the dysglycemic states of prediabetes and type 2 diabetes mellitus (T2DM) by a number of years and is an early marker of risk for metabolic and cardiovascular disease. There is an unmet need for a simple method to measure IR that can be used for routine screening, prospective study, risk assessment, and therapeutic monitoring. We have reported several metabolites whose fasting plasma levels correlated with insulin sensitivity. These metabolites were used in the development of a novel test for IR and prediabetes. Methods: Data from the Relationship between Insulin Sensitivity and Cardiovascular Disease Study were used in an iterative process of algorithm development to define the best combination of metabolites for predicting the M value derived from the hyperinsulinemic euglycemic clamp, the gold standard measure of IR. Subjects were divided into a training set and a test set for algorithm development and validation. The resulting calculated M score, MQ, was utilized to predict IR and the risk of progressing from normal glucose tolerance to impaired glucose tolerance (IGT) over a 3 year period. Results: MQ correlated with actual M values, with an r value of 0.66. In addition, the test detects IR and predicts 3 year IGT progression with areas under the curve of 0.79 and 0.70, respectively, outperforming other simple measures such as fasting insulin, fasting glucose, homeostatic model assessment of IR, or body mass index. Conclusions: The result, Quantose™, is a simple test for IR based on a single fasting blood sample and may have value as an early indicator of risk for the development of prediabetes and T2DM.
Insulin Depot Formation in Subcutaneous Tissue
Authors: Jockel James P. Leuenberger , Roebrock Philipp , Shergold Oliver A. 
Published: January 2014

Background: The size and geometry of an insulin depot that is formed during subcutaneous administration by an insulin pump is evaluated. A novel method is used to visualize accurately the depot formation for small volumes of insulin (of the order of 10–100 μl) at a given point in time. Conventional visualization methods such as magnetic resonance imaging are unable to provide such accurate measurements because of their coarse imaging resolution and long measurement time. Methods: The described method consists of subcutaneously infusing dyed insulin into porcine tissue and subsequently shock freezing it with liquid nitrogen. The frozen sample is then sliced into thin layers using a cryomicrotome. A digital image of each layer is taken and then processed with proprietary software, which identifies the dyed areas on each layer and reconstructs a three-dimensional model of the insulin depot with a planar resolution of 30 × 30 μm2 and a depth resolution of 100 μm. Since this process is not viable for living organisms, porcine tissue was used immediately following slaughter of the animal. Results: To date, it is most often assumed that the insulin depot takes the shape of a sphere around the tip of the cannula (e.g., 50 μl insulin equates to a spherical radius of 2.3 mm). However, in practice, such a depot form is never observed. Instead, the insulin depot initially spreads laterally (i.e., parallel) to the skin surface and in the collagen matrix that binds the adipose cells together. The depot outreach increases with larger infused volumes, e.g., maximum outreach measured at 5.0/5.7/7.1 mm (quartiles, n = 17) for 50 μl of infused insulin. Beyond a given infused volume (approximately 100 μl), the insulin also starts to spread perpendicular to the skin surface. Conclusions: It is concluded that formation of the insulin depot depends on the opening of channels at the boundaries between adipose cells. Hence the insulin follows a path of least resistance and depot formation is determined by the local structure of the subcutaneous tissue.
Understanding Heterogeneity in Response to Antidiabetes Treatment: A Post Hoc Analysis Using SIDES, a Subgroup Identification Algorithm
Authors: Hardin Dana S. , Rohwer Rachelle D. , Curtis Bradley H. , Zagar Anthony , Chen Lei , Boye Kristina S. , Jiang Honghua H. , Lipkovich Ilya A. 
Published: January 2014

Background: Treatment response in patients with type 2 diabetes mellitus (T2DM) varies because of different genotypic and phenotypic characteristics. Results of clinical trials are based largely on aggregated estimates of treatment effect rather than individualized outcomes. This research assessed heterogeneity and differential treatment response using the subgroup identification based on differential effect search (SIDES) algorithm with data from a large multinational study. Methods: This was a retrospective analysis of the DURABLE trial, a randomized, open-label, two-arm, parallel study. The trial enrolled 2091 insulin-naïve T2DM patients aged 30 to 80 years. Patients received twice-daily insulin lispro mix 75/25 (LM75/25) or once-daily insulin glargine (insulin glargine). The SIDES methodology was used to find subgroups where the treatment effect was substantially different from what was observed in the full population of the clinical trial. A subgroup identification tool implementing the SIDES algorithm was used to examine data for 1092 patients (584 LM75/25 and 508 insulin glargine), achieving at-goal 12- or 24-week glycated hemoglobin A1c (A1C) (≤7.0%). Results: The overall at-goal population treatment difference (A1C reduction) was not clinically meaningful, but a clinically meaningful difference was observed (A1C reduction 2.31% ± 0.06% LM75/25 versus 2.01% ± 0.07% insulin glargine; p = .001) in patients with a baseline fasting insulin level >11.4 μIU/ml and age ≤56 years. Conclusion: The observation that younger patients with higher levels of fasting insulin may benefit from a regimen that includes short-acting insulin targeting postprandial glycemia helps explain the heterogeneity in response and warrants further investigation.