bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoglycemia Detection in Critical Care Using Continuous Glucose Monitors: An in Silico Proof of Concept Analysis
Authors: Pretty Christopher G. , Chase J. Geoffrey , Compte Aaron Le , Shaw Geoffrey M. , Signal Matthew 
Published: January 2014

Background: Tight glycemic control (TGC) in critical care has shown distinct benefits but has also been proven difficult to obtain. The risk of severe hypoglycemia (<40 mg/dl) has been increased significantly in several, but not all, studies, raising significant concerns for safety. Continuous glucose monitors (CGMs) offer frequent measurement and thus the possibility of using them for early detection alarms to prevent hypoglycemia. Methods: This study used retrospective clinical data from the Specialized Relative Insulin Nutrition Titration TGC study covering seven patients who experienced severe hypoglycemic events. Clinically validated metabolic system models were used to recreate a continuous blood glucose profile. In silico analysis was enabled by using a conservative single Gaussian noise model based on reported CGM clinical data from a critical care study [mean absolute percent error (MAPE) 17.4%]. A novel median filter was implemented and further smoothed with a least mean squares-fitted polynomial to reduce sensor noise. Two alarm approaches were compared. An integral-based method is presented that examined the area between a preset threshold and filtered simulated CGM data. An alarm was raised when this value became too low. A simple glycemic threshold method was also used for comparison. To account for random noise skewing the results, each patient record was Monte Carlo simulated 100 times with a different random noise profile for a total of 700 runs. Different alarm thresholds were analyzed parametrically. Results are reported in terms of detection time before the clinically measured event and any false alarms. These retrospective clinical data were used with approval from the New Zealand South Island Regional Ethics Committee. Results: The median filter reduced MAPE from 17.4% [standard deviation (SD) 13%] to 9.3% (SD 7%) over the cohort. For the integral-based alarm, median per-patient detection times ranged, t, from −35 minutes (before event) to −170 minutes, with zero to two false alarms per patient over the cohort and different alarm parameters. For a simple glycemic threshold alarm (three consecutive values below threshold), median per-patient alarm times were −10 to −75 minutes and false alarms were zero to seven; however, in one case, five of seven subjects never alarmed at all, despite the hypoglycemic event. Conclusions: A retrospective study used clinical hypoglycemic events from a TGC study to develop and analyze an integral-based hypoglycemia alarm for use in critical care TGC studies. The integral-based approach was accurate, provided significant lead time before a hypoglycemic event, alarmed at higher glycemic levels, was robust to sensor noise, and had minimal false alarms. The approach is readily generalizable to similar scenarios, and results would justify a pilot clinical trial to verify this study.
Individuals Achieve More Accurate Results with Meters That Are Codeless and Employ Dynamic Electrochemistry
Authors: Rao Anoop , Wiley Meg , Iyengar Sridhar , Nadeau Dan , Carnevale Julie 
Published: January 2014

Background: Studies have shown that controlling blood glucose can reduce the onset and progression of the long-term microvascular and neuropathic complications associated with the chronic course of diabetes mellitus. Improved glycemic control can be achieved by frequent testing combined with changes in medication, exercise, and diet. Technological advancements have enabled improvements in analytical accuracy of meters, and this paper explores two such parameters to which that accuracy can be attributed. Methods: Four blood glucose monitoring systems (with or without dynamic electrochemistry algorithms, codeless or requiring coding prior to testing) were evaluated and compared with respect to their accuracy. Results: Altogether, 108 blood glucose values were obtained for each system from 54 study participants and compared with the reference values. The analysis depicted in the International Organization for Standardization table format indicates that the devices with dynamic electrochemistry and the codeless feature had the highest proportion of acceptable results overall (System A, 101/103). Results were significant when compared at the 10% bias level with meters that were codeless and utilized static electrochemistry ( p = .017) or systems that had static electrochemistry but needed coding ( p = .008). Conclusions: Analytical performance of these blood glucose meters differed significantly depending on their technologic features. Meters that utilized dynamic electrochemistry and did not require coding were more accurate than meters that used static electrochemistry or required coding.
Noninvasive Glucose Monitoring: Increasing Accuracy by Combination of Multi-Technology and Multi-Sensors
Authors: Harman-Boehm Ilana , Gal Avner , Raykhman Alexander M. , Naidis Eugene , Mayzel Yulia 
Published: January 2014

Background: The main concern in noninvasive (NI) glucose monitoring methods is to achieve high accuracy results despite the fact that no direct blood or interstitial fluid glucose measurement is performed. An alternative approach to increase the accuracy of NI glucose measurement was previously suggested through a combination of three NI methods: Ultrasonic, electromagnetic, and thermal. This paper provides further explanation about the nature of the implemented technologies, and multi-sensors are presented, as well as a detailed elaboration on the novel algorithm for data analysis. Methods: Clinical trials were performed on two different days. During the first day, calibration and six subsequent measurements were performed. During the second day, a “full day” session of about 10 hours took place. During the trial, type 1 and 2 diabetes patients were calibrated and evaluated with GlucoTrack® glucose monitor against HemoCue® (Glucose 201+). Results: A total of 91 subjects were tested during the trial period. Clarke error grid (CEG) analysis shows 96% of the readings (on both days 1 and 2) fall in the clinically accepted A and B zones, of which 60% are within zone A. The absolute relative differences (ARDs) yield mean and median values of 22.4% and 15.9%, respectively. The CEG for day 2 of the trial shows 96% of the points in zones A and B, with 57% of the values in zone A. Mean and median ARD values for the readings on day 2 are 23.4% and 16.5%, respectively. The intervals between day 1 (calibration and measurements) and day 2 (measurements only) were 1–22 days, with a median of 6 days. Conclusions: The presented methodology shows that increased accuracy was indeed achieved by combining multi-technology and multi-sensors. The approach of integration contributes to increasing the signal-to-noise ratio (glucose to other contributors). A combination of several technologies allows compensation of a possible aberration in one modality by the others, while multi-sensor implementation enables corrections for interference contributions. Furthermore, clinical trials indicate the ability of using the device for a wide range of demography, showing clearly that the calibration is valid for long term.
Comparison Pharmacokinetics of Two Concentrations (0.7% and 1.0%) of Nasulin™, an Ultra-Rapid-Acting Intranasal Insulin Formulation
Authors: Stote Robert , Marbury Thomas , Shi Leon , Miller Michael , Strange Poul 
Published: January 2014

Background: This pharmacokinetic (PK) study was designed to characterize the dose response of two concentrations (0.7% and 1%) of a nasal spray of recombinant regular human insulin in combination with cyclopentadecalactone (CPE-215), a compound that enhances absorption of molecules across mucous membranes (Nasulin™, CPEX Pharmaceuticals). Nasulin has been effective in lowering blood glucose in both normal subjects and diabetes patients, and additional dosing options would allow greater titration flexibility. Method: A five-period crossover study of 24 healthy, nonsmoking subjects (ages 18–50, basal metabolic index <33 kg/m2, weight >70 kg) were studied. Subjects were in a fasted state for 5 h before and 45 min after administration for PK assessment and were then given a meal. Each spray contained 100 μl. Doses tested were 25, 35, 50, 70, and 100 U. Maximum concentration (Cmax) and area under the curve (AUC) were estimated for each dose group. Glucose measurements were also performed. Results: A dose response (slope of the natural log response versus dose) was demonstrated by baseline-adjusted Cmax of 22, 27, 56, 62, and 84 μU/ml for the 25, 35, 50, 70, and 100 U doses ( p < .0001), respectively, and by baseline-adjusted AUC(0–45 min) values of 491, 592, 1231, 1310, and 1894 μU/ml/min ( p < .0001). Glucose AUC(0–45 min) determinations also demonstrated a pharmacodynamic (PD) dose response. Conclusions: Proportional and linear dose responses for both PK and PD parameters were demonstrated for the two concentrations, making multiple doses available for clinical development.
Near Infrared Wound Monitor Helps Clinical Assessment of Diabetic Foot Ulcers
Authors: Neidrauer Michael , Zubkov Leonid , Weingarten Michael S. , Pourrezaei Kambiz , Papazoglou Elisabeth S. 
Published: January 2014

Background: The efficacy of using diffuse near infrared spectroscopy (NIRS) in predicting wound healing in diabetic foot ulcers was demonstrated by conducting a pilot human study. Method: Sixteen chronic diabetic wounds were followed and assessed for subsurface oxyhemoglobin concentration using the NIRS device. Weekly measurements were conducted until there was wound closure, limb amputation, or 20 completed visits without healing. Wound size and degree of wound contraction were measured by image analysis of digital photographs, and results were compared to NIRS results. Results: In the 16 patients followed, seven wounds healed, six limbs were amputated, and three wounds remained opened after 20 visits. Initial values of subsurface hemoglobin concentration, in all wounds, were higher than in nonwound control sites. Healed wounds exhibited a consistent reduction of hemoglobin concentration several weeks prior to closure, and the absolute hemoglobin concentration approached the value at the control site. In wounds that did not heal or ended in amputations, the hemoglobin concentration remained elevated throughout the study. A negative slope for the rate of change of hemoglobin concentration was indicative of healing across all wounds. Conclusions: Evaluation of diabetic foot ulcers using NIRS may provide an effective and more complete measurement of wound healing compared to current clinical approaches.
Making a Case: Nanofabrication Techniques in Encapsulated Cell Therapy for People with Diabetes
Authors: Gimi Barjor 
Published: January 2014

A nanoporous immunoisolative case/capsule that encases/encapsulates insulin-secreting cells vastly expands the source of therapeutic cells available for grafting in people with diabetes, including cells from animal sources, stem cells, and genetically engineered cells. These encapsulated cellular grafts potentially provide an endogenous, renewable, and long-term source of insulin without the need for pharmacological immunosuppression. Micro- and nanofabrication techniques used principally in the semiconductor industry can play a positive role in encapsulated cell therapy. Many of these techniques do not have direct applicability in cell encapsulation, but can be leveraged to develop processes suitable for this application. This commentary highlights the salient features of an effective cell encapsulation system, enumerates limitations of existing encapsulation schemes, and touches upon progress in key areas of encapsulation technology; one example of how micro- and nanofabrication technology may be used to develop a more effective platform for cell encapsulation is presented. This commentary urges further exploration and expansion of techniques used traditionally in electronics and optics for cell-based therapy in people with diabetes.
Guidelines for Insulin Dosing in Continuous Subcutaneous Insulin Infusion Using New Formulas from a Retrospective Study of Individuals with Optimal Glucose Levels
Authors: Walsh John , Roberts Ruth , Bailey Timothy 
Published: January 2014

Background: Successful insulin pump therapy depends on correct insulin doses based on an optimal total daily dose (TDD) and optimal pump settings for basal infusion, carbohydrate factor (CarbF), and glucose correction factor (CorrF) based on the TDD. There are limited data in the literature to guide providers and patients regarding methods to optimize these critical parameters for glucose control. Methods: Anonymous data downloads from 1020 insulin pumps used throughout the United States and overseen by a variety of clinicians were analyzed retrospectively to find insulin doses that provided the best glucose control. A subset of 396 pumps was chosen for glucose data reliability, with over 85% of their glucose data directly entered from a meter. This subset was divided into tertiles based on glucose levels, and the low glucose tertile was analyzed to derive formulas for optimal insulin pump settings. Results: An inconsistent clustering of pump settings was found for the CarbF and the CorrF. This was less pronounced when CarbFs and CorrFs were determined from the actual bolus doses delivered once adjustments were made to the initial dose calculations by users and, to a larger extent, internally by the bolus calculator itself. Common beliefs that hyperglycemia is related to less carb counting, fewer carb boluses, or delivery of less insulin per day were not substantiated in this data. New or verified insulin dosing formulas presented include basal U/day = TDD x 0.48; CarbF = [2.6 x Wt(lb)]/TDD; and CorrF = 1960/TDD. Conclusions: Insulin pump users cannot reap full benefit from their pump bolus calculator if the settings on which bolus doses are based are less than optimal. Our data show that CarbFs and CorrFs tend to be unevenly distributed, suggesting that these factors are not selected in a systematic manner through use of formulas. Poor glucose outcomes among insulin pump users appear to be related to pump setting errors and being relatively underinsulinized, even though those in poor control use more total insulin per day. We have developed a model with the hypothesis that improved glucose outcomes will result from the use of formulas to derive appropriate pump settings. Prospective validation of these concepts is needed.
Accuracy and Reliability of the Nova StatStrip® Glucose Meter for Real-Time Blood Glucose Determinations during Glucose Clamp Studies
Authors: Rabiee Atoosa , Magruder J. Trent , Grant Crystal , Salas-Carrillo Rocio , Gillette Audrey , DuBois Jeffrey , Shannon Richard P. , Andersen Dana K. , Elahi Dariush 
Published: January 2014

Aims/Hypothesis: The Andres clamp technique, which requires accurate and timely determination of glucose, utilizes the Beckman or Yellow Springs Instruments (YSI) glucose analyzers. Both instruments require maintenance, a dedicated operator, preparation of a plasma sample, and a duplicate measurement that takes ≥2 minutes. The Nova StatStrip glucose meter was evaluated for accuracy, reliability, and near-real-time availability of glucose. Methods: Blood samples from 24 patients who underwent 6-hour clamp studies and 12 patients who had a standardized meal tolerance test (SMT) were measured. Specimens were analyzed simultaneously and immediately upon collection by Beckman, YSI, and Nova. Results: Of 1004 data pairs for the Nova device versus Beckman, the Nova data points ranged from 32 to 444, while Beckman ranged from 42 to 412. The coefficient for the slope of Beckman versus Nova was 1.009 ( r = 0.978). Using error grid analysis, the number and percentage of values for Nova were 976 (97.2%) in the A zone and 28 (2.8%) in the B zone. Of 399 data pairs for the Nova device versus YSI, the Nova data points ranged from 46 to 255, whereas YSI ranged from 47 to 231. The coefficient for the slope of YSI versus Nova was 1.023 ( r = 0.989). All Nova readings fell in the A zone. Time required for final reading, in duplicate, was 15 seconds for Nova and 120–180 seconds for Beckman and YSI. Conclusions: The simplicity of Nova and its reliability, accuracy, and speed make it an acceptable replacement device for Beckman and YSI in the conduct of clamps, especially when perturbations require rapid glucose determination.
Efficacy Determinants of Subcutaneous Microdose Glucagon during Closed-Loop Control
Authors: Russell Steven J. , El-Khatib Firas H. , Nathan David M. , Damiano Edward R. 
Published: January 2014

Background: During a previous clinical trial of a closed-loop blood glucose (BG) control system that administered insulin and microdose glucagon subcutaneously, glucagon was not uniformly effective in preventing hypoglycemia (BG <70 mg/dl). After a global adjustment of control algorithm parameters used to model insulin absorption and clearance to more closely match insulin pharmacokinetic (PK) parameters observed in the study cohort, administration of glucagon by the control system was more effective in preventing hypoglycemia. We evaluated the role of plasma insulin and plasma glucagon levels in determining whether glucagon was effective in preventing hypoglycemia. Methods: We identified and analyzed 36 episodes during which glucagon was given and categorized them as either successful or unsuccessful in preventing hypoglycemia. Results: In 20 of the 36 episodes, glucagon administration prevented hypoglycemia. In the remaining 16, BG fell below 70 mg/dl (12 of the 16 occurred during experiments performed before PK parameters were adjusted). The (dimensionless) levels of plasma insulin (normalized relative to each subject's baseline insulin level) were significantly higher during episodes ending in hypoglycemia (5.2 versus 3.7 times the baseline insulin level, p = .01). The relative error in the control algorithm's online estimate of the instantaneous plasma insulin level was also higher during episodes ending in hypoglycemia (50 versus 30%, p = .003), as were the peak plasma glucagon levels (183 versus 116 pg/ml, p = .007, normal range 50–150 pg/ml) and mean plasma glucagon levels (142 versus 75 pg/ml, p = .02). Relative to mean plasma insulin levels, mean plasma glucagon levels tended to be 59% higher during episodes ending in hypoglycemia, although this result was not found to be statistically significant (p = .14). The rate of BG descent was also significantly greater during episodes ending in hypoglycemia (1.5 versus 1.0 mg/dl/min, p = .02). Conclusions: Microdose glucagon administration was relatively ineffective in preventing hypoglycemia when plasma insulin levels exceeded the controller's online estimate by >60%. After the algorithm PK parameters were globally adjusted, insulin dosing was more conservative and microdose glucagon administration was very effective in reducing hypoglycemia while maintaining normal plasma glucagon levels. Improvements in the accuracy of the controller's online estimate of plasma insulin levels could be achieved if ultrarapid-acting insulin formulations could be developed with faster absorption and less intra- and intersubject variability than the current insulin analogs available today.
Optimization of the Native Glucagon Sequence for Medicinal Purposes
Authors: Chabenne Joseph R. , DiMarchi Maria A. , Gelfanov Vasily M. , DiMarchi Richard D. 
Published: January 2014

Background: Glucagon is a life-saving medication used in the treatment of hypoglycemia. It possesses poor solubility in aqueous buffers at or near physiological pH values. At low and high pH, at which the peptide can be formulated to concentrations of a milligram or more per milliliter, the chemical integrity of the hormone is limited, as evidenced by the formation of multiple degradation-related peptides. Consequently, the commercial preparation is provided as a lyophilized solid with an acidic diluent and directions for rendering it soluble at the time of use. Any unused material is recommended for disposal immediately after initial use. Methods: A set of glucagon analogs was prepared by solid-phase peptide synthesis to explore the identification of a glucagon analog with enhanced solubility and chemical stability at physiological pH. The physical properties of the peptide analogs were studied by solubility determination, high-performance chromatography, and mass spectral analysis. The biochemical properties were determined in engineered human embryonic kidney cell line 293 (HEK293) cells that overexpressed either the human glucagon or glucagon-like peptide-1 (GLP-1) receptors linked to a luciferase reporter gene. Results: We observed the previously characterized formation of glucagon degradation products upon incubation of the peptide in dilute acid for extended periods or elevated temperature. Lowering the isoelectric point of the hormone through the substitution of asparagine-28 with aspartic acid significantly increased the solubility at physiological pH. Similarly, the C-terminal extension (Cex) of the hormone with an exendin-based, 10-residue, C-terminal sequence yielded a peptide of dramatically enhanced solubility. These two glucagon analogs, D28 and Cex, maintained high potency and selectivity for the glucagon receptor relative to GLP-1 receptor. Conclusions: Glucagon presents unique structural challenges to the identification of an analog of high biological activity and selectivity that also possesses sufficient aqueous solubility and stability such that it might be developed as a ready-to-use medicine. The glucagon analogs D28 and Cex demonstrated all of the chemical, physical, and biochemical properties supportive of further study as potential clinical candidates for treatment of hypoglycemia.
The Minimum Frequency of Glucose Measurements from Which Glycemic Variation Can Be Consistently Assessed
Authors: Baghurst Peter A. , Rodbard David , Cameron Fergus J. 
Published: January 2014

Aims: While there has been much debate about the clinical importance of glycemic variation (GV), little attention has been directed to the properties of data sets from which it is measured. The purpose of this study is to assess the minimum frequency of glucose measurements from which GV can be consistently and meaningfully measured. Methods: Forty-eight 72 h continuous glucose monitoring traces from children with type 1 diabetes were assessed. Measures of GV included standard deviation (SD), mean amplitude of glycemic excursion (MAGE), and continuous overlapping net glycemic action (CONGA1–4). Measures of GV calculated using 5 min sampling were designated as the 100% or “best estimate” value. Calculations were then repeated for each patient using glucose values spaced at increasing intervals. For each of the specified sampling frequencies, the ratio (%) of the between-subject SD based on the reduced subset of data to the estimate of the SD based on the full 5 min sampling data set was calculated. Results: As the interval between observations increased, so did the variability of the estimators of GV. Standard deviation exhibited the least systematic change at all measurement intervals, and MAGE exhibited the greatest systematic change. Conclusions: In patients with type 1 diabetes, GV as measured by SD or CONGA4, becomes unreliable if observations are more than 2–4 h apart, and estimates of MAGE become unreliable if glucose measurements are more than 1 h apart. MAGE is more unstable and prone to random measurement error than either SD or CONGA. The frequency of glycemic measurements is thus pivotal when selecting a parameter for measurement of GV.