bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Silico Preclinical Trials: A Proof of Concept in Closed-Loop Control of Type 1 Diabetes
Authors: Kovatchev Boris P. , Breton Marc , Dalla Man Chiara , Cobelli Claudio 
Published: January 2014

Arguably, a minimally invasive system using subcutaneous (s.c.) continuous glucose monitoring (CGM) and s.c. insulin delivery via insulin pump would be a most feasible step to closed-loop control in type 1 diabetes mellitus (T1DM). Consequently, diabetes technology is focusing on developing an artificial pancreas using control algorithms to link CGM with s.c. insulin delivery. The future development of the artificial pancreas will be greatly accelerated by employing mathematical modeling and computer simulation. Realistic computer simulation is capable of providing invaluable information about the safety and the limitations of closed-loop control algorithms, guiding clinical studies, and out-ruling ineffective control scenarios in a cost-effective manner. Thus computer simulation testing of closed-loop control algorithms is regarded as a prerequisite to clinical trials of the artificial pancreas. In this paper, we present a system for in silico testing of control algorithms that has three principal components: (1) a large cohort of n = 300 simulated “subjects” ( n = 100 adults, 100 adolescents, and 100 children) based on real individuals' data and spanning the observed variability of key metabolic parameters in the general population of people with T1DM; (2) a simulator of CGM sensor errors representative of Freestyle Navigator™, Guardian RT, or Dexcom™ STS™, 7-day sensor; and (3) a simulator of discrete s.c. insulin delivery via OmniPod Insulin Management System or Deltec Cozmo® insulin pump. The system has been shown to represent adequate glucose fluctuations in T1DM observed during meal challenges, and has been accepted by the Food and Drug Administration as a substitute to animal trials in the preclinical testing of closed-loop control strategies.
Treatment with Sitagliptin or Metformin Does Not Increase Body Weight despite Predicted Reductions in Urinary Glucose Excretion
Authors: Waters Steven B. , Topp Brian G. , Siler Scott Q. , Alexander Charles M. 
Published: January 2014

Background: We used a mathematical model to estimate the contribution of urinary glucose excretion (UGE) to reported changes in body weight (BW) following oral antihyperglycemic agent (AHA) therapy. This modeling approach was used to gain novel insight into the mechanisms by which oral AHA affects BW. Methods: Twenty-four hour glucose profiles were used to predict UGE before and after treatment with oral AHA. Model-predicted changes in BW due to reduced UGE were compared with reported changes in BW to quantify non-UGE-dependent effects (fluid retention, food intake, and energy expenditure). Results: In type 2 diabetes patients [hemoglobin A1c (HbA1c) >7.3%], the energy lost to UGE is predicted to decrease an average of 100 kcal/day for each 1% decrease in HbA1c. This effect, alone, is predicted to increase BW 1.4 kg after 6 months. Differences from this value reported for changes in BW with oral AHA therapy (+1.4 kg for pioglitazone and rosiglitazone; −0.4 kg for glyburide; −0.9 kg for sitagliptin and vildagliptin; −2.3 kg for metformin) are therefore predicted to be due to additional, non-UGE-dependent mechanisms. Conclusions: Weight gain following thiazolidinedione therapy is predicted to result from both reduced UGE and non-UGE-dependent mechanisms. Reduced UGE alone is predicted to account for most of the weight gain reported following sulfonylurea therapy. Weight loss observed in response to metformin and weight maintenance observed in response to dipeptidyl peptidase-4 inhibitors may result from an increase in satiety, energy expenditure, or both.
Coordinated Basal—Bolus Infusion for Tighter Postprandial Glucose Control in Insulin Pump Therapy
Authors: Bondia Jorge , Dassau Eyal , Zisser Howard , Calm Remei , Vehí Josep , Jovanovič Lois , Doyle Francis J. 
Published: January 2014

Background: Basal and bolus insulin determination in intensive insulin therapy for type 1 diabetes mellitus (T1DM) are currently considered independently of each other. A new strategy that coordinates basal and bolus insulin infusion to cope with postprandial glycemia in pump therapy is proposed. Superior performance of this new strategy is demonstrated through a formal analysis of attainable performances in an in silico study. Methods: The set inversion via interval analysis algorithm has been applied to obtain the feasible set of basal and bolus doses that, for a given meal, mathematically guarantee a postprandial response fulfilling the International Diabetes Federation (IDF) guidelines (i.e., no hypoglycemia and 2 h postprandial glucose below 140 mg/dl). Hypoglycemia has been defined as a glucose value below 70 mg/dl. A 5 h time horizon has been considered for a 70 kg in silico T1DM subject consuming meals in the range of 30 to 80 g of carbohydrates. Results: The computed feasible sets demonstrate that current separated basal/bolus strategy dramatically limits the attainable performance. For a nominal basal of 0.8 IU/h leading to a basal glucose of approximately 100 mg/dl, IDF guidelines cannot be fulfilled for meals greater than 50 g of carbohydrates, independent of the bolus insulin computed. However, coordinating the basal and bolus insulin delivery can achieve this. A decrement of basal insulin during the postprandial period is required together with an increase in bolus insulin, in appropriate percentages, which is meal dependent. After 3 h, basal insulin can be restored to its nominal value. Conclusions: The new strategy meets IDF guidelines in a typical day, contrary to the standard basal/bolus strategy, yielding a mean 2 h postprandial glucose reduction of 36.4 mg/dl without late hypoglycemia. The application of interval analysis for the computation of feasible sets is demonstrated to be a powerful tool for the analysis of attainable performance in glucose control.
Clinical Evaluation of a Transcutaneous Interrogated Fluorescence Lifetime-Based Microsensor for Continuous Glucose Reading
Authors: Nielsen Jannik K. , Christiansen Jens S. , Kristensen Jesper S. , Toft Hans O. , Hansen Lars Lundby , Aasmul Søren , Gregorius Klaus 
Published: January 2014

Background: Continuous glucose monitoring is presently used worldwide. Accuracy, precision, durability, invasiveness, and lack of drift of sensors and lag time are key parameters essential to these systems. This article describes a new online minimally invasive biodegradable microsensor for optical, transcutaneous interrogation, which has at least 14 days of functionality. Method: Studies were performed in vitro and in vivo on pigs, as well as on type 1 diabetic humans. Functionality has been ensured in laboratory settings, and precision and durability have been tested in vivo. During in vivo studies, venous blood samples were used as reference. Results were based on one single point calibration per experiment. Results: Excellent stability was found in 14-day in vitro trials as well as in vivo in up to 70-hour trials. The overall median relative absolute difference of type 1 diabetic patients was 11.4%. Error grid analysis showed 97.7% of all values in the A+B zone. Comparable results were found in animal studies. No sensor drift was observed in any trial. Conclusion: Results point toward the possibility of developing a stable and precise minimally invasive glucose reader for at least 2 weeks of continuous use.
An Automated Discontinuous Venous Blood Sampling System for Ex Vivo Glucose Determination in Humans
Authors: Schaller Roland , Feichtner Franz , Köhler Hans , Bodenlenz Manfred , Plank Johannes , Wutte Andrea , Mader Julia K. , Ellmerer Martin , Hainisch Reinhard , Pieber Thomas R. , Schaupp Lukas 
Published: January 2014

Background: Intensive insulin therapy reduces mortality and morbidity in critically ill patients but places great demands on medical staff who must take frequent blood samples for the determination of glucose levels. A cost-effective solution to this resourcing problem could be provided by an effective and reliable automated blood sampling (ABS) system suitable for ex vivo glucose determination. Method: The primary study aim was to compare the performance of a prototype ABS system with a manual reference system over a 30 h sampling period under controlled conditions in humans. Two venous cannulae were inserted to connect the ABS system and the reference system. Blood samples were taken with both systems at 15, 30, and 60 min intervals and analyzed using a Beckman glucose analyzer. During the study, blood glucose levels were altered through four meal ingestions. Results: The median Pearson coefficient of correlation between manually and automatically withdrawn blood samples was 0.976 (0.953–0.996). The system error was −3.327 ± 5.546% (−6.03–0.49). Through Clark error grid analysis, 420 data pairs were analyzed, showing that 98.6% of the data were in zone A and 1.4% were in zone B. Insulin titration error grid analysis revealed an acceptable treatment in 100% of cases. A 17.5-fold reduction in the occurrence of blood-withdrawal failures through occluded catheters was moreover achieved by the added implementation in the ABS system of a “keep vein open” saline infusion. Conclusions: Our study showed that the ABS system described provides a user-friendly, reliable automated means for reproducible and accurate blood sampling from a peripheral vein for blood glucose determination and thus represents a promising alternative to frequent manual blood sampling.
Smart Home-Based Health Platform for Behavioral Monitoring and Alteration of Diabetes Patients
Authors: Helal Abdelsalam , Cook Diane J. , Schmalz Mark 
Published: January 2014

Background: Researchers and medical practitioners have long sought the ability to continuously and automatically monitor patients beyond the confines of a doctor's office. We describe a smart home monitoring and analysis platform that facilitates the automatic gathering of rich databases of behavioral information in a manner that is transparent to the patient. Collected information will be automatically or manually analyzed and reported to the caregivers and may be interpreted for behavioral modification in the patient. Method: Our health platform consists of five technology layers. The architecture is designed to be flexible, extensible, and transparent, to support plug-and-play operation of new devices and components, and to provide remote monitoring and programming opportunities. Results: The smart home-based health platform technologies have been tested in two physical smart environments. Data that are collected in these implemented physical layers are processed and analyzed by our activity recognition and chewing classification algorithms. All of these components have yielded accurate analyses for subjects in the smart environment test beds. Conclusions: This work represents an important first step in the field of smart environment-based health monitoring and assistance. The architecture can be used to monitor the activity, diet, and exercise compliance of diabetes patients and evaluate the effects of alternative medicine and behavior regimens. We believe these technologies are essential for providing accessible, low-cost health assistance in an individual's own home and for providing the best possible quality of life for individuals with diabetes.
Near-Infrared Microspectroscopic Analysis of Rat Skin Tissue Heterogeneity in Relation to Noninvasive Glucose Sensing
Authors: Alexeeva Natalia V. , Arnold Mark A. 
Published: January 2014

Background: Noninvasive glucose measurements are possible by analysis of transmitted near-infrared light over the 4000- to 5000-cm−1 spectral range. Such measurements are highly sensitive to the exact position of the fiber-optic interface on the surface of the skin sample. A critical question is the degree of heterogeneity of the major chemical components of the skin matrix in relation to the size of the fiber-optic probed used to collect noninvasive spectra. Microscopic spectral mapping is used to map the chemical distribution for a set of excised sections of rat skin. Method: A Fourier transform near-infrared microspectrometer was used to collect transmission spectra from 16 tissue samples harvested from a set of four healthy Harlan-Sprague male rats. A reference point in the center of the tissue sample was probed regularly to track dehydration, changes in tissue composition, and changes in instrument performance. Amounts of the major skin constituents were determined by fitting microspectra to a set of six pure component absorbance spectra corresponding to water, type I collagen protein, keratin protein, fat, an offset term, and a slope term. Results: Microspectroscopy provides spectra with root mean square noise levels on 100% lines between 418 and 1475 microabsorbance units, which is sufficient for measuring the main chemical components of skin. The estimated spatial resolution of the microscope is 220 μm. The amounts of each tissue matrix component were determined for each 480 × 360-μm2 location of a 4.8 × 3.6-mm2 rectangular block of skin tissue. These spectra were used to generate two-dimensional distribution maps for each of the principal skin components. Conclusions: Distribution of the chemical components of rat skin is significant relative to the dimensions of noninvasive glucose sensing. Chemical distribution maps reveal that variations in the chemical composition of the skin samples are on the same length scale as the fiber-optic probe used to collect noninvasive near-infrared spectra. Analysis of variance between tissue slices collected for one animal and analysis of variations between animals indicate that animal-to-animal variation for all four chemical components is significantly higher than variations between samples for a given animal. These findings justify the collection and interpretation of near-infrared microspectroscopic maps of human skin to establish chemical heterogeneity and its impact on noninvasive glucose sensing for the management of diabetes.
Noninvasive Glucose Monitoring: A Novel Approach
Authors: Harman-Boehm Ilana , Gal Avner , Raykhman Alexander M. , Zahn Jeffrey D. , Naidis Eugene , Mayzel Yulia 
Published: January 2014

Background: The main concern in noninvasive (NI) glucose measurement is achieving high accuracy readings, although no blood (or other fluid) is involved in the process. Using methods based on different physical properties of a measured object can ensure the independence of each of the readings and therefore improve the validity of the end result. By using a combination of (three) independent technologies—ultrasonic, electromagnetic, and thermal—GlucoTrack™ presents a unique approach for a real-time, truly NI blood glucose spot measurement. Methods: Clinical trials were performed in two stages. Stage 1 was an initial method validation and performance verification of the device. In this stage, 50 type 1 and 2 diabetic patients, as well as healthy subjects, were evaluated with GlucoTrack against Ascensia Elite® (Bayer). In the second stage, 85 additional diabetic subjects were evaluated in half and full daytime sessions using a GlucoTrack comparison with HemoCue® (Glucose 201+). Results: A total of 135 subjects were tested during the trial period, producing 793 data pairs. Using Clarke error grid analysis, 92% of the readings fell in the clinically acceptable zones A and B, with 50% in the A zone. Mean and median relative absolute differences were 29.9 and 19.9%, respectively. Conclusions: Integrating several modalities for NI assessment of glucose level enables more accurate readings, while a possible aberration in one modality is bypassed by the others. The present generation of GlucoTrack gives promising results; however, further improvement of the accuracy of the device is needed.
Comparison of Intuitiveness, Ease of Use, and Preference in Two Insulin Pens
Authors: Asakura Toshinari , Jensen Klaus H. 
Published: January 2014

Background: The intuitiveness, instruction time, and handling of the Levemir® (insulin detemir) FlexPen® and the Lantus® OptiClik® pen (with insulin glargine) were investigated. Methods: This randomized open-label crossover study involved two groups of insulin-device-naive Japanese patients with type 2 diabetes [mean (SD) age 61.9 ± 12.3 years, 57% male]. Patients were evaluated on the ease-of-use of each insulin pen without instruction [intuitiveness group ( n = 32)], or with instruction [instruction time group ( n = 29)]. Patient preferences for the respective devices were assessed by questionnaire. Results and Discussion: FlexPen required significantly less instruction time ( p < .001) and was objectively more intuitive to use ( p < .001) than OptiClik. Nevertheless, few patients in the intuitiveness group felt confident injecting either pen prior to instruction (FlexPen, 31%; OptiClik, 16%). No patients in the instruction time group found FlexPen difficult to learn, whereas 45% of patients found OptiClik difficult or very difficult to learn. FlexPen was rated simpler to use (77% versus 12%; p < .001), easier to inject (67% versus 13%; p < .001), and more convenient (71% versus 12%; p < .001) compared with OptiClik. More patients would trust FlexPen to deliver insulin injections ( p < .01) and would prefer to use FlexPen compared with OptiClik (82% versus 13%; p < .001). Conclusions: FlexPen was faster to teach, simpler to use, and more trusted by patients compared with OptiClik. Mean injection time was significantly shorter for FlexPen than OptiClik, with or without instruction. This study highlights not only how easy it is for patients to learn to use FlexPen, but also how easily health care providers can teach patients to use it.
The Role of Immunomodulation Therapy in Autoimmune Diabetes
Authors: Ludvigsson Johnny 
Published: January 2014

Type 1 diabetes (T1DM) is characterized by loss of virtually all endogenous insulin secretion. If residual insulin secretion is preserved, this will lead to improved metabolic balance, less acute and late complications, improved quality of life, and, in case of pronounced improvement of residual insulin secretion, complete remission and even cure of the disease. Immune suppression or immune modulation have been demonstrated as a proof of principle to stop/decrease the destructive process and thereby preserve beta-cell function. Several methods to save residual beta-cell function have been tried for more than three decades with little or no evidence of efficacy. Positive effects have been seen mainly in adult patients but have been minimal or absent in children with diabetes. Furthermore, the safety of these immune interventions and/or their benefit to risk relationships have not been found to justify clinical use. More specific immune modulation with anti-CD3 monoclonal antibodies has resulted in more encouraging postponement of C-peptide decline, but with frequent and serious adverse effects. Still more promising are the autoantigen therapies, of which glutamic acid decarboxylase (GAD) vaccination has shown significant preservation of residual insulin secretion in 10–18-year-old type 1 diabetes patients with recent onset. Efficacy was most impressive in the subgroup of patients with diabetes of short duration (<3 months). The treatment was simple, well tolerated, and showed no treatment-related adverse events. If these results can be confirmed, there is a realistic hope that GAD vaccination, perhaps in combination with vaccinations with other autoantigens and/or other therapies, will result in remission for some patients. The prospects of cure and prevention of T1DM will become less remote.
A Review of Variant Hemoglobins Interfering with Hemoglobin A1c Measurement
Authors: Little Randie R. , Roberts William L. 
Published: January 2014

Hemoglobin A1c (HbA1c) is used routinely to monitor long-term glycemic control in people with diabetes mellitus, as HbA1c is related directly to risks for diabetic complications. The accuracy of HbA1c methods can be affected adversely by the presence of hemoglobin (Hb) variants or elevated levels of fetal hemoglobin (HbF). The effect of each variant or elevated HbF must be examined with each specific method. The most common Hb variants worldwide are HbS, HbE, HbC, and HbD. All of these Hb variants have single amino acid substitutions in the Hb β chain. HbF is the major hemoglobin during intrauterine life; by the end of the first year, HbF falls to values close to adult levels of approximately 1%. However, elevated HbF levels can occur in certain pathologic conditions or with hereditary persistence of fetal hemoglobin. In a series of publications over the past several years, the effects of these four most common Hb variants and elevated HbF have been described. There are clinically significant interferences with some methods for each of these variants. A summary is given showing which methods are affected by the presence of the heterozygous variants S, E, C, and D and elevated HbF. Methods are divided by type (immunoassay, ion-exchange high-performance liquid chromatography, boronate affinity, other) with an indication of whether the result is artificially increased or decreased by the presence of a Hb variant. Laboratorians should be aware of the limitations of their method with respect to these interferences.
Beyond Health Information Technology: Critical Factors Necessary for Effective Diabetes Disease Management
Authors: Ciemins Elizabeth L. , Coon Patricia J. , Fowles Jinnet Briggs , Min Sung-Joon 
Published: January 2014

Background: Electronic health records (EHRs) have been implemented throughout the United States with varying degrees of success. Past EHR implementation experiences can inform health systems planning to initiate new or expand existing EHR systems. Key “critical success factors,” e.g., use of disease registries, workflow integration, and real-time clinical guideline support, have been identified but not fully tested in practice. Methods: A pre/postintervention cohort analysis was conducted on 495 adult patients selected randomly from a diabetes registry and followed for 6 years. Two intervention phases were evaluated: a “low-dose” period targeting primary care provider (PCP) and patient education followed by a “high-dose” EHR diabetes management implementation period, including a diabetes disease registry and office workflow changes, e.g., diabetes patient preidentification to facilitate real-time diabetes preventive care, disease management, and patient education. Results: Across baseline, “low-dose,” and “high-dose” postintervention periods, a significantly greater proportion of patients (a) achieved American Diabetes Association (ADA) guidelines for control of blood pressure (26.9 to 33.1 to 43.9%), glycosylated hemoglobin (48.5 to 57.5 to 66.8%), and low-density lipoprotein cholesterol (33.1 to 44.4 to 56.6%) and (b) received recommended preventive eye (26.2 to 36.4 to 58%), foot (23.4 to 40.3 to 66.9%), and renal (38.5 to 53.9 to 71%) examinations or screens. Conclusions: Implementation of a fully functional, specialized EHR combined with tailored office workflow process changes was associated with increased adherence to ADA guidelines, including risk factor control, by PCPs and their patients with diabetes. Incorporation of previously identified “critical success factors” potentially contributed to the success of the program, as did use of a two-phase approach.