bluuebunny/crossref_metadata_2025 huggingface dataset:
Intra-Individual Variability of the Metabolic Effect of a Novel Rapid-Acting Insulin (VIAject™) in Comparison to Regular Human Insulin
Authors: Hompesch Marcus , McManus Laura , Pohl Roderike , Simms Patrick , Pfützner Andreas , Bülow Elena , Flacke Frank , Heinemann Lutz , Steiner Solomon S.
Published: January 2014

Background:

The variability of the metabolic action of insulin after subcutaneous (sc) injection hampers optimal insulin therapy. Insulin formulations with a reduced tendency to form hexamers might exhibit a reduced variability of absorption from the sc insulin depot into the blood stream.

Methods:

We investigated the within-subject variability of pharmacodynamic and pharmacokinetic properties of an ultra-fast insulin (UFI) formulation and regular human insulin (RHI) in patients with type 1 diabetes. Fourteen patients participated in six 10-hour euglycemic glucose clamp experiments. In this double-blind, crossover study, subjects were randomly assigned to a sequence of two experimental blocks: Each block consisted of three doses of 0.1 IU/kg UFI or RHI, respectively, administered on separate days by abdominal sc injection.

Results:

Ultra-fast insulin has an earlier onset of action and shorter time to maximal plasma insulin concentration when compared to RHI (tGIRmax 99 ± 36 min vs. 154 ± 74 min, p = 0.002; tCmax 33 ± 16 min vs. 97 ± 39 min, p = 0.00001). The within-subject variability of plasma insulin tCmax ( p = 0.027) and of tGIRmax ( p = 0.022) was less for UFI than for RHI.

Conclusions:

In patients with type 1 diabetes, this UFI showed reduced within-subject variability when compared with RHI.
Thrombosis and Inflammation in Intraportal Islet Transplantation: A Review of Pathophysiology and Emerging Therapeutics
Authors: Wilson John T. , Chaikof Elliot L.
Published: January 2014

With the inception of the Edmonton Protocol, intraportal islet transplantation (IPIT) has re-emerged as a promising cell-based therapy for type 1 diabetes. However, current clinical islet transplantation remains limited, in part, by the need to transplant islets from 2–4 donor organs, often through several separate infusions, to reverse diabetes in a single patient. Results from clinical islet transplantation and experimental animal models now indicate that the majority of transplanted islets are destroyed in the immediate post-transplant period, a process largely facilitated by deleterious inflammatory responses triggered by islet-derived procoagulant and proinflammatory mediators. Herein, mechanisms that underlie the pathophysiology of thrombosis and inflammation in IPIT are reviewed, and emerging approaches to improve islet engraftment through attenuation of inflammatory responses are discussed.
An Electronic Protocol for Translation of Research Results to Clinical Practice: A Preliminary Report
Authors: Morris Alan H. , Orme James , Rocha Beatriz H. , Holmen John , Clemmer Terry , Nelson Nancy , Allen Jode , Jephson Al , Sorenson Dean , Sward Kathy , Warner Homer ,   for the Reengineering Critical Care Clinical Research Investigators6
Published: January 2014

Introduction:

We evaluated the feasibility of using an electronic protocol developed for research use (Research-eProtocol-insulin) for blood glucose management in usual intensive care unit clinical practice.

Methods:

We implemented the rules of Research-eProtocol-insulin in the electronic medical record of the Intermountain Healthcare hospital system (Clinical-eProtocol-insulin) for use in usual clinical practice. We evaluated the performance of Clinical-eProtocol-insulin rules in the intensive care units of seven Intermountain Healthcare hospitals and compared this performance with the performance of Research-eProtocol-insulin at the LDS Hospital Shock/Trauma/Respiratory Intensive Care Unit.

Results:

Clinician (nurse or physician) compliance with computerized protocol recommendations was 95% (of 21,325 recommendations) with Research-eProtocol-insulin and 92% (of 109,458 recommendations) with Clinical-eProtocol-insulin. The blood glucose distribution in clinical practice (Clinical-eProtocol-insulin) was similar to the research use distribution (Research-eProtocol-insulin); however, the mean values (119 mg/dl vs 113 mg/dl) were statistically different ( P = 0.0001). Hypoglycemia rates in the research and practice settings did not differ: the percentage of measurements ≤40 mg/dl (0.11% vs 0.1%, P = 0.65) and the percentage of patients with at least one blood glucose ≤40 mg/dl (4.2% vs 3%, P = 0.23) were not statistically significantly different.

Conclusion:

Our electronic blood glucose protocol enabled translation of a research decision-support tool (Research-eProtocol-insulin) to usual clinical practice (Clinical-eProtocol-insulin).
The DURABLE Trial Study Design: Comparing the Safety, Efficacy, and Durability of Insulin Glargine to Insulin Lispro Mix 75/25 Added to Oral Antihyperglycemic Agents in Patients with Type 2 Diabetes
Authors: Fahrbach Jessie , Jacober Scott , Jiang Honghua , Martin Sherry
Published: January 2014

Background:

While studies have compared the safety and efficacy of starter insulin regimens in type 2 diabetes, none have evaluated regimen durability (length of time a patient can maintain glycemic control) or the safety and efficacy of subsequent intensification regimens in a large, multinational cohort.

Methods:

The DURABLE (Assessing the DURAbility of Basal vs Lispro Mix 75/25 Insulin Efficacy) trial will compare the ability of glargine once daily vs lispro mix 75/25 (75% insulin lispro protamine suspension, 25% lispro) twice daily added to oral antihyperglycemic agents to achieve and maintain hemoglobin A1c (HbA1c) goals. This randomized, open label, parallel study will enroll over 2000 insulin-naïve patients with type 2 diabetes from 11 countries, ages 30 to 80, with HbA1c >7.0% on at least two oral antihyperglycemic agents. At the completion of the 6-month initiation phase, safety and efficacy of the two regimens will be compared. Patients who achieve an HbA1c ≤7.0% at 6 months will continue into the 24-month maintenance phase to evaluate durability. In a substudy, patients not achieving HbA1c ≤7.0% at 6 months may be randomized to one of two intensification comparisons: patients previously on glargine will receive lispro mix 75/25 twice daily or basal/bolus therapy (glargine + thrice-daily mealtime lispro) and patients previously on lispro mix 75/25 will receive lispro mix 50/50 (50% insulin lispro protamine suspension, 50% lispro) thrice daily or basal/bolus therapy.

Results:

Upon completion, this trial will provide new information about starter insulin durability, defined as the length of time patients can maintain HbA1c control (HbA1c ≤7.0%, or >7.0% but with an increase of <0.4% from the most recent HbA1c ≤7.0%). Additionally, the study will provide comparative data on HbA1c, blood glucose profiles, 1,5-anhydroglucitol, hypoglycemic episodes, weight change, and insulin dose for starter insulin regimens following 6 and 24 months of treatment, as well as intensified insulin via the 6-month substudy.

Conclusion:

This trial aims to broaden clinicians' understanding of the ability of starter insulin and insulin intensification regimens to achieve and maintain glycemic control in patients with type 2 diabetes.
Definition of Information Technology Architectures for Continuous Data Management and Medical Device Integration in Diabetes
Authors: Hernando M. Elena , Pascual Mario , Salvador Carlos H. , García-Sáez Gema , Rodríguez-Herrero Agustín , Martínez-Sarriegui Iñaki , Gómez Enrique J.
Published: January 2014

The growing availability of continuous data from medical devices in diabetes management makes it crucial to define novel information technology architectures for efficient data storage, data transmission, and data visualization. The new paradigm of care demands the sharing of information in interoperable systems as the only way to support patient care in a continuum of care scenario. The technological platforms should support all the services required by the actors involved in the care process, located in different scenarios and managing diverse information for different purposes. This article presents basic criteria for defining flexible and adaptive architectures that are capable of interoperating with external systems, and integrating medical devices and decision support tools to extract all the relevant knowledge to support diabetes care.
A Review of Glycated Albumin as an Intermediate Glycation Index for Controlling Diabetes
Authors: Roohk H. Vernon , Zaidi Asad R.
Published: January 2014

Introduction:

This article reviews glycated albumin (GA) as a potential intermediate-term glycation index to fill the gap between self-monitoring of blood glucose (SMBG) and hemoglobin A1c testing in diabetes management. The introduction gives an assessment of available short-, medium-, and long-term glycemic indicators.

Methodologies and Utility:

Methods of GA measurement are summarized, and the variance of normal and diabetic GA values are discussed. Greatest uniformity in GA measurement is generally associated with immunoassay and the newer affinity chromatography methodologies utilized by reference laboratories. Utility of GA measurement includes its value as a marker for glycation, its substantial relationship to diabetes complications such as nephropathy and coronary artery disease, and as an unambiguous indicator of glycemic control in diabetes patients undergoing hemodialysis. Studies support the utility of GA in detecting short-term changes in glycemic control, and GA testing has been strongly recommended for gestational diabetes.

Results and Discussion:

The results of a survey with mailings to over 3500 diabetes care professionals primarily in the United States are outlined and analyzed (margin of error: +/-6.5%, 95% confidence). Respondents strongly supported the need for a test for intermediate glycemic control as well as the utility of a rapid GA test as a monthly glycemic indicator.

Conclusions:

Such a test, as yet unavailable, could increase compliance and enhance empowerment among diabetes patients. It also has the potential to reduce the number of recommended SMBG tests, which may result in significant health care cost savings.
Trust: Need for an Improved Communication between the Public World and the Pharmaceutical Companies
Authors: Heinemann Lutz
Published: January 2014

In the industrialized world, the negative image that many people (including politicians) have of pharmaceutical companies not only makes the life for those working in this field more difficult, in a sense it is a road block. Without an improvement in communication between the public world and the pharmaceutical industry, one can foresee this industry steadily becoming a more difficult environment to work in. There is a clear need for knowing more about all the work done inside these companies before a new drug is approved (it is not all about marketing…). That society has no understanding of the ever-increasing costs of new drugs is also related to this lack of understanding of how tricky and cumbersome the process is to take a new idea for treating a certain disease to production of a marketed drug. With a relatively small investment of money, but with an investment of much good will, brain power, and trust, it should be possible to bring all relevant parties together and make a change.
Temporal and Geographic Patterns of Hypoglycemia among Hospitalized Patients with Diabetes Mellitus
Authors: Bailon Rachel M. , Cook Curtiss B. , Hovan Michael J. , Hull Bryan P. , Seifert Karen M. , Miller-Cage Victoria , Beer Karen A. , Boyle Mary E. , Littman Stephanie D. , Magallanez Janice M. , Fischenich Joanne M. , Harris Jana K. , Scoggins Susie S. , Uy Josephine
Published: January 2014

Background:

Hypoglycemia is often cited as a barrier to achieving inpatient glycemic targets. We sought to characterize hypoglycemic events in our institution by work-shift cycle and by specific treatment area.

Methods:

Capillary (bedside) and blood (laboratory) glucose values of <70 mg/dl for patients with either a known diagnosis of diabetes or with evidence of hyperglycemia were abstracted from our laboratory database for hospitalizations between October 1, 2007, and February 3, 2008. Hypoglycemic events were analyzed by 12 h nursing work-shift cycles (day shift, 07:00 to 18:59; night shift, 19:00 to 06:59) and by the six medical, surgical, and intensive care areas in the hospital (designated areas 1 to 6).

Results:

We identified 206 individual patients with either diabetes or hyperglycemia (mean age, 67 years; 56% men; 83% white) who had 423 hypoglycemic events. There were 78% more hypoglycemic events during the night shift ( n = 271 events in 128 individual patients) than during the day shift ( n = 152 events in 96 individual patients). Most of the night-shift hypoglycemic measurements were detected between 04:00 and 04:59 or 06:00 and 06:59. The mean hypoglycemic level was comparable between shifts ( p = .79) and across the six inpatient areas. The number of hypoglycemic events per person increased with lengths of hospital stay >5 days. The prevalence of hypoglycemia varied across patient care areas within the hospital, with most (28%) detected in one area of the hospital.

Conclusion:

There are temporal and geographic patterns in the occurrence of hypoglycemia among patients with diabetes or hyperglycemia in our hospital. Further study should focus on the reasons underlying these variations so that specific interventions can address the risk of hypoglycemia during peak times and places.
In Silico Preclinical Trials: Methodology and Engineering Guide to Closed-Loop Control in Type 1 Diabetes Mellitus
Authors: Patek Stephen D. , Bequette B. Wayne , Breton Marc , Buckingham Bruce A. , Dassau Eyal , Doyle Francis J. , Lum John , Magni Lalo , Zisser Howard
Published: January 2014

This article sets forth guidelines for in silico (simulation-based) proof-of-concept testing of artificial pancreas control algorithms. The goal was to design a test procedure that can facilitate regulatory approval [e.g., Food and Drug Administration Investigational Device Exemption] for General Clinical Research Center experiments without preliminary testing on animals. The methodology is designed around a software package, based on a recent meal simulation model of the glucose-insulin system. Putting a premium on generality, this document starts by specifying a generic, rather abstract, meta-algorithm for control. The meta-algorithm has two main components: (1) patient assessment and tuning of control parameters, i.e., algorithmic processes for collection and processing patient data prior to closed-loop operation, and (2) controller warm-up and run-time operation, i.e., algorithmic processes for initializing controller states and managing blood glucose. The simulation-based testing methodology is designed to reveal the conceptual/mathematical operation of both main components, as applied to a large population of in silico patients with type 1 diabetes mellitus.
A Nanoporous, Transparent Microcontainer for Encapsulated Islet Therapy
Authors: Gimi Barjor , Kwon Joonbum , Kuznetsov Andrey , Vachha Behroze , Magin Richard L. , Philipson Louis H. , Lee Jeong-Bong
Published: January 2014

Present-day islet encapsulation techniques such as polymer microcapsules and microelectromechanical system (MEMS)-based biocapsules have shown promise in insulin replacement therapy, but they each have limitations—the permeability characteristics of existing polymeric capsules cannot be strictly controlled because of tortuosity and the large size of present-day MEMS biocapsules leads to necrotic regions within the encapsulation volume. We report on a new microcontainer to encapsulate and immunoprotect islets/β cells that may be used for allo- or xenotransplantation in cell-based therapy. The microcontainers have membranes containing nanoslots to permit the bidirectional transport of nutrients, secretagogues, and cellular products while immunoprotecting the encapsulated cells. The 300-μm microcontainers were fabricated from an epoxy-based polymer, SU-8, with 50-μm-thick walls. Arrays of 25-nm wide slots were created in the SU-8 microcontainer lid. Isolated mouse islets were encapsulated in the microcontainer, and their physiological response to glucose was studied with fluorescence and two-photon imaging over 48 hours. The physiological response of the encapsulated islets was indistinguishable from controls. An agarose-filled microcontainer was imaged with magnetic resonance imaging to demonstrate the feasibility of future noninvasive, in vivo imaging. The SU-8 microcontainers maintained mechanical integrity upon islet loading and mechanical manipulation. Islet encapsulation, as well as the ability to visualize islet function within these transparent microcontainers, was demonstrated.
Fabrication of Polymer Microneedles Using a Two-Photon Polymerization and Micromolding Process
Authors: Gittard Shaun D. , Ovsianikov Aleksandr , Monteiro-Riviere Nancy A. , Lusk Jason , Morel Pierre , Minghetti Paola , Lenardi Cristina , Chichkov Boris N. , Narayan Roger J.
Published: January 2014

Background:

Microneedle-mediated drug delivery is a promising method for transdermal delivery of insulin, incretin mimetics, and other protein-based pharmacologic agents for treatment of diabetes mellitus. One factor that has limited clinical application of conventional microneedle technology is the poor fracture behavior of microneedles that are created using conventional materials and methods. In this study polymer microneedles for transdermal delivery were created using a two-photon polymerization (2PP) microfabrication and subsequent polydimethylsiloxane (PDMS) micromolding process.

Methods:

Solid microneedle arrays, fabricated by means of 2PP, were used to create negative molds from PDMS. Using these molds microneedle arrays were subsequently prepared by molding eShell 200, a photo-reactive acrylate-based polymer that exhibits water and perspiration resistance.

Results:

The eShell 200 microneedle array demonstrated suitable compressive strength for use in transdermal drug delivery applications. Human epidermal keratinocyte viability on the eShell 200 polymer surfaces was similar to that on polystyrene control surfaces. In vitro studies demonstrated that eShell 200 microneedle arrays fabricated using the 2PP microfabrication and PDMS micromolding process technique successfully penetrated human stratum corneum and epidermis.

Conclusions:

Our results suggest that a 2PP microfabrication and subsequent PDMS micromolding process may be used to create microneedle structures with appropriate structural, mechanical, and biological properties for transdermal drug delivery of insulin and other protein-based pharmacologic agents for treatment of diabetes mellitus.
Diabetes Connected Health: A Pilot Study of a Patient- and Provider-Shared Glucose Monitoring Web Application
Authors: Watson Alice J. , Kvedar Joseph C. , Rahman Basmah , Pelletier Alexandra C. , Salber Gregory , Grant Richard W.
Published: January 2014

Background:

Real-time sharing of blood glucose results with providers could improve communication and lead to more timely medication titration. New technology platforms are available to support the delivery of innovative models of care delivery.

Methods:

In the Diabetes Connected Health (DCH) pilot study, patients with diabetes received access to an online application that stored and graphed glucose readings uploaded from a standard glucometer. Both patients and providers had access to this Web site, where data could be viewed, analyzed, and discussed. To examine the impact of the DCH program, we assessed adoption of the program, patient and provider satisfaction, frequency of use, and changes in glucose levels over a period of 3 months.

Results:

The mean age of the 7 pilot participants was 51 (range 35–65). Participants sent in an average of 50 readings in Month 1 and 38 readings in Month 3 and made, on average, 6 comments in Months 1 and 12 comments in Month 3. The mean blood glucose range decreased in Month 3 versus Month 1 (141.1 and 146.5, respectively). Self-reported HbA1c fell from 6.8% at the start of the study to 5.8% at the end. Five/seven participants described the site as excellent or good. Qualitative data analysis highlighted key benefits of the program as well as areas for improvement.

Conclusions:

This pilot study of a shared glucose monitoring Web application was well received by patients. Programs like this may lead to improvements in the quality of clinical care delivered to people with type 2 diabetes.
Unlocking the Potential of Continuous Glucose Monitoring: A New Guideline Supports the Development of Continuous Glucose Monitoring Devices
Authors: D'Archangelo Melissa J.
Published: January 2014

Continuous glucose monitoring (CGM) is a new technology that allows patients to measure glucose levels continuously over several days. It has several advantages over traditional glucose meters in that it does not involve repeated finger sticks and can measure trends and track changes in glucose levels over time. The Clinical and Laboratory Standards Institute, working with the Diabetes Technology Society, published Performance Metrics for Continuous Interstitial Glucose Monitoring; Approved Guideline, which provides recommendations for methods for determining analytical and clinical metrics of CGMs. The document provides guidance on how CGM data should be presented, compared between devices, and compared between measurement technologies. The document serves as a roadmap for the testing of CGM devices and will ultimately advance the potential of this exciting technology. Performance Metrics for Continuous Interstitial Glucose Monitoring; Approved Guideline represents the consensus view on preparing and presenting CGM data.
Eating for Life: Designing Foods for Appetite Control
Authors: Wilde Peter J.
Published: January 2014

We are all well aware that rising levels of obesity in developed countries is having a significant impact on the health of the population. This is despite the availability of a wide range of low-calorie foods and an awareness of how important it is to adopt a healthy lifestyle. A new and emerging approach is to design foods that enhance the physiological regulatory mechanisms controlling appetite and energy intake. This is achieved through either promoting gastric distension or slowing intestinal transit in order to promote satiety-enhancing neuroendocrine feedback responses. This commentary explores the background and mechanisms involved in developing these strategies.
Use of Serial Patient Hemoglobin A1c Differences to Determine Long-Term Imprecision of Immunoassay and High-Performance Liquid Chromatography Analyzers
Authors: Tran David V. , Lyon Andrew W. , Higgins Trefor N. , Wesenberg James C. , Vandergouwe Lisa , Wiley Carmen L. , Cembrowski George S.
Published: January 2014

Background:

The quality of the HbA1c assay is inversely proportional to the variation of the assay. Most published measures of HbA1c variation are limited by the data collection period, the statistical treatment of outliers, and even the noncommutability of the products used to generate the variation measurements. We have used an alternate approach to derive HbA1c variation, using serial patient data.

Methods:

HbA1c measurements of outpatient blood sample pairs drawn within 30 days of each other were made on three different immunoassay systems: the Roche INTEGRA® 700, the Roche INTEGRA® 400, and the Dade Dimension® RxL; and two high-performance liquid chromatography assays: the Tosoh G7 and the Tosoh 2.2+. The standard deviation of duplicates was calculated for the following time intervals: 1 to 3 days, 4 to 6 days, 7 to 9 days, …, 28 to 30 days. These intra-individual variations were then plotted; extrapolation to time zero yields the long term total random error which consists of both analytic and pre-analytic error. Data collection periods were usually 2 years.

Results:

At the mean HbA1cs of 7.08%, 7.14%, 7.20%, 6.96%, and 7.51% for populations tested on the Roche INTEGRA 700, Roche INTEGRA 400, Dade Dimension RxL, Tosoh 2.2+, and Tosoh G7, respectively, the total analytic imprecisions (coefficient of variation) were 2.56%, 2.29%, 2.25%, 1.66%, and 1.14%, respectively.

Conclusion:

Assessment of the HbA1c long term total imprecisions shows that while the three immunoassay systems are acceptable, the Tosoh HbA1c analyzers demonstrate superior analytic performance.
Value of Self-Monitoring Blood Glucose Pattern Analysis in Improving Diabetes Outcomes
Authors: Parkin Christopher G. , Davidson Jaime A.
Published: January 2014

Self-monitoring of blood glucose (SMBG) is an important adjunct to hemoglobin A1c (HbA1c) testing. This action can distinguish between fasting, preprandial, and postprandial hyperglycemia; detect glycemic excursions; identify and monitor resolution of hypoglycemia; and provide immediate feedback to patients about the effect of food choices, activity, and medication on glycemic control.

Pattern analysis is a systematic approach to identifying glycemic patterns within SMBG data and then taking appropriate action based upon those results. The use of pattern analysis involves: (1) establishing pre- and postprandial glucose targets; (2) obtaining data on glucose levels, carbohydrate intake, medication administration (type, dosages, timing), activity levels and physical/emotional stress; (3) analyzing data to identify patterns of glycemic excursions, assessing any influential factors, and implementing appropriate action(s); and (4) performing ongoing SMBG to assess the impact of any therapeutic changes made.

Computer-based and paper-based data collection and management tools can be developed to perform pattern analysis for identifying patterns in SMBG data. This approach to interpreting SMBG data facilitates rational therapeutic adjustments in response to this information. Pattern analysis of SMBG data can be of equal or greater value than measurement of HbA1c levels.
Do Race and Ethnicity Impact Hemoglobin A1c Independent of Glycemia?
Authors: Herman William H.
Published: January 2014

Hemoglobin A1c (HbA1c) is widely used as an index of mean glycemia, a measure of risk for the development of diabetes complications, and a measure of the quality of diabetes care. Emerging literature suggests that, although HbA1c levels change little over time within persons without diabetes, they vary considerably among individuals, suggesting that factors other than glycemia may impact HbA1c. Racial and ethnic differences in HbA1c have been described that do not appear to be explained by differences in glycemia. It is imperative that the nonglycemic factors that affect HbAlc be more clearly defined. Even more important, it must be determined whether differences among individuals or groups correlate with susceptibility to complications or merely reflect variation in hemoglobin glycation.
The Case for Personalized Medicine
Authors: Abrahams Edward , Silver Mike
Published: January 2014

Personalized medicine may be considered an extension of traditional approaches to understanding and treating disease, but with greater precision. Physicians may now use a patient's genetic variation or expression profile as well as protein and metabolic markers to guide the selection of certain drugs or treatments. In many cases, the information provided by molecular markers predicts susceptibility to conditions. The added precision introduces the possibility of a more preventive, effective approach to clinical care and reductions in the duration and cost of clinical trials. Here, we make the case, through real-world examples, that personalized medicine is delivering significant value to individuals, to industry, and to the health care system overall and that it will continue to grow in importance if we can lift the barriers that impede its adoption and build incentives to encourage its practice.
Validation of a Multimarker Model for Assessing Risk of Type 2 Diabetes from a Five-Year Prospective Study of 6784 Danish People (Inter99)
Authors: Urdea Mickey , Kolberg Janice , Wilber Judith , Gerwien Robert , Moler Edward , Rowe Michael , Jorgensen Paul , Hansen Torben , Pedersen Oluf , Jørgensen Torben , Borch-Johnsen Knut
Published: January 2014

Background:

Improved identification of subjects at high risk for development of type 2 diabetes would allow preventive interventions to be targeted toward individuals most likely to benefit. In previous research, predictive biomarkers were identified and used to develop multivariate models to assess an individual's risk of developing diabetes. Here we describe the training and validation of the PreDx™ Diabetes Risk Score (DRS) model in a clinical laboratory setting using baseline serum samples from subjects in the Inter99 cohort, a population-based primary prevention study of cardiovascular disease.

Methods:

Among 6784 subjects free of diabetes at baseline, 215 subjects progressed to diabetes (converters) during five years of follow-up. A nested case-control study was performed using serum samples from 202 converters and 597 randomly selected nonconverters. Samples were randomly assigned to equally sized training and validation sets. Seven biomarkers were measured using assays developed for use in a clinical reference laboratory.

Results:

The PreDx DRS model performed better on the training set (area under the curve [AUC] = 0.837) than fasting plasma glucose alone (AUC = 0.779). When applied to the sequestered validation set, the PreDx DRS showed the same performance (AUC = 0.838), thus validating the model. This model had a better AUC than any other single measure from a fasting sample. Moreover, the model provided further risk stratification among high-risk subpopulations with impaired fasting glucose or metabolic syndrome.

Conclusions:

The PreDx DRS provides the absolute risk of diabetes conversion in five years for subjects identified to be “at risk” using the clinical factors.
Factors Affecting Blood Glucose Monitoring: Sources of Errors in Measurement
Authors: Ginsberg Barry H.
Published: January 2014

Glucose monitoring has become an integral part of diabetes care but has some limitations in accuracy. Accuracy may be limited due to strip manufacturing variances, strip storage, and aging. They may also be due to limitations on the environment such as temperature or altitude or to patient factors such as improper coding, incorrect hand washing, altered hematocrit, or naturally occurring interfering substances. Finally, exogenous interfering substances may contribute errors to the system evaluation of blood glucose.

In this review, I discuss the measurement of error in blood glucose, the sources of error, and their mechanism and potential solutions to improve accuracy in the hands of the patient. I also discuss the clinical measurement of system accuracy and methods of judging the suitability of clinical trials and finally some methods of overcoming the inaccuracies. I have included comments about additional information or education that could be done today by manufacturers in the appropriate sections. Areas that require additional work are discussed in the final section.
Computerized Prompting and Feedback of Diabetes Care: A Review of the Literature
Authors: Boren Suzanne Austin , Puchbauer Aaron M. , Williams Faustine
Published: January 2014

Background:

The objective of this study was to assess published literature on computerized prompting and feedback of diabetes care as well as to identify opportunities to strengthen diabetes care processes.

Methods:

Medline (1970–2008), Cumulative Index to Nursing and Allied Health Literature (1982–2008), and Cochrane Central Register of Controlled Trials (4th quarter 2008) were searched, and reference lists from included articles were reviewed to identify additional studies. Patient sample, clinician sample, setting, duration of the trial, intervention description, control description, and results were abstracted from each study.

Results:

Fifteen trials were included in this review. The following elements were observed in the interventions: general prompt for a particular patient to be seen for diabetes-related follow-up (5 studies), specific prompt reminding clinicians of particular tests or procedures related to diabetes (13 studies), feedback to clinicians in addition to prompting (5 studies), and patient reminders in addition to clinician prompts (5 studies). Twelve of the 15 studies (80%) measured a significant process or outcome from the intervention.

Conclusions:

The majority of trials identified at least one process or outcome that was significantly better in the intervention group than in the control group; however, the success of the information interventions varied greatly. Providing and receiving appropriate care is the first step toward better outcomes in chronic disease management.
Identification of Intraday Metabolic Profiles during Closed-Loop Glucose Control in Individuals with Type 1 Diabetes
Authors: Kanderian Sami S. , Weinzimer Stu , Voskanyan Gayane , Steil Garry M.
Published: January 2014

Background:

Algorithms for closed-loop insulin delivery can be designed and tuned empirically; however, a metabolic model that is predictive of clinical study results can potentially accelerate the process.

Methods:

Using data from a previously conducted closed-loop insulin delivery study, existing models of meal carbohydrate appearance, insulin pharmacokinetics, and the effect on glucose metabolism were identified for each of the 10 subjects studied. Insulin's effects to increase glucose uptake and decrease endogenous glucose production were described by the Bergman minimal model, and compartmental models were used to describe the pharmacokinetics of subcutaneous insulin absorption and glucose appearance following meals. The composite model, comprised of only five equations and eight parameters, was identified with and without intraday variance in insulin sensitivity ( SI), glucose effectiveness at zero insulin ( GEZI), and endogenous glucose production ( EGP) at zero insulin.

Results:

Substantial intraday variation in SI, GEZI and EGP was observed in 7 of 10 subjects (root mean square error in model fit greater than 25 mg/dl with fixed parameters and nadir and/or peak glucose levels differing more than 25 mg/dl from model predictions). With intraday variation in these three parameters, plasma glucose and insulin were well fit by the model ( R2 = 0.933 ± 0.00971 [mean ± standard error of the mean] ranging from 0.879–0.974 for glucose; R2 = 0.879 ± 0.0151, range 0.819–0.972 for insulin). Once subject parameters were identified, the original study could be reconstructed using only the initial glucose value and basal insulin rate at the time closed loop was initiated together with meal carbohydrate information (glucose, R2 = 0.900 ± 0.015; insulin delivery, R2 = 0.640 ± 0.034; and insulin concentration, R2 = 0.717 ± 0.041).

Conclusion:

Metabolic models used in developing and comparing closed-loop insulin delivery algorithms will need to explicitly describe intraday variation in metabolic parameters, but the model itself need not be comprised by a large number of compartments or differential equations.
Performance Analysis of the OneTouch® UltraVue™ Blood Glucose Monitoring System
Authors: Chang Anna , Orth Alice , Le Bryan , Menchavez Perla , Miller Lupe
Published: January 2014

Background:

OneTouch® UltraVue™ is a new meter for self-monitoring of blood glucose that includes a color display, used-strip ejector, and no-button interface. The system uses an electrochemical biosensor technology based on glucose oxidase chemistry to detect glucose concentrations from 20 to 600 mg/dl (1.1 to 33.3 mmol/liter).

Methods:

Accuracy and reproducibility were evaluated over a wide range of glucose concentrations according to standard criteria. Clinical accuracy was assessed by health care providers (HCPs) in two studies and by diabetes patients in the second study. Reference glucose levels were determined by a YSI 2300 analyzer. Same-day reproducibility and day-to-day reproducibility were also evaluated.

Results:

In the accuracy studies, 99.7% and 98.7% of tests by HCPs and 97.0% of tests by patients were within ±15 mg/dl (±0.8 mmol/liter) of the YSI reference for blood glucose <75 mg/dl (<4.2 mmol/liter), and within ±20% for blood glucose ≥75 mg/dl (≥4.2 mmol/liter), respectively. Consensus error grid analysis showed that 99.7% and 95.3% of tests by HCPs and 97.0% of tests by patients fell within zone A (i.e., has no effect on clinical action); all other results were in zone B (i.e., altered clinical action, little or no effect on clinical outcome). In the reproducibility studies, the standard deviation was <1.5 mg/dl (<0.1 mmol/liter) for glucose concentrations <100 mg/dl (<5.6 mmol/liter), and the coefficient of variation was <2% for concentrations ≥100 mg/dl (≥5.6 mmol/liter).

Conclusions:

OneTouch UltraVue meets standard acceptability criteria for accuracy and reproducibility across a wide range of glucose concentrations. Its simple interface and lack of contact with used strips make it a viable option for older patients and their caregivers.
An Overview of Preoperative Glucose Evaluation, Management, and Perioperative Impact
Authors: Sheehy Ann M. , Gabbay Robert A.
Published: January 2014

Perioperative hyperglycemia is a common phenomenon affecting patients both with and without a known prior history of diabetes. Despite an exponential rise in publications and studies of inpatient hyperglycemia over the last decade, many questions still exist as to what defines optimal care of these patients. Initial enthusiasm for tight glycemic control has waned as the unanticipated reality of hypoglycemia and mortality has been realized in some prospective studies. The recent dramatic modification of national practice guidelines to endorse more modest inpatient glycemic targets highlights the dynamic nature of current knowledge as the next decade approaches. This review discusses perioperative hyperglycemia and the categories of patients affected by it. It reviews current recommendations for ambulatory diabetes screening and its importance in preoperative patient care. Finally, it concludes with a review of current practice guidelines, as well as a discussion of future direction and goals for inpatient perioperative glycemic control.
Blood Glucose Control in the Trauma Patient
Authors: Eakins James
Published: January 2014

Hyperglycemia can be a significant problem in the trauma population and has been shown to be associated with increased morbidity and mortality. Hyperglycemia in the trauma patient, as in other critically ill patients, is caused by a hypermetabolic response to stress and seems to be an entity of its own rather than simply a marker. Although several early studies in a mixed intensive care unit population indicated that insulin protocols aimed at strict glucose control improved outcome, later studies did not support this and, in fact, encountered increased complications due to hypoglycemia. More recent studies in the trauma population, while supporting the correlation between hyperglycemia and increased mortality, seemed to indicate that protocols aimed at moderate glucose control improved outcome while limiting the incidence of hypoglycemic complications.
Enhanced 911/Global Position System Wizard: A Telemedicine Application for the Prevention of Severe Hypoglycemia—Monitor, Alert, and Locate
Authors: Dassau Eyal , Jovanovic Lois , Doyle Francis J. , Zisser Howard C.
Published: January 2014

Intensive insulin therapy has an inherent risk of hypoglycemia that can lead to loss of consciousness, cardiac arrhythmia, seizure, and death (“dead-in-bed syndrome”). This risk of hypoglycemia is a major concern for patients, families, and physicians. The need for an automated system that can alert in the event of severe hypoglycemia is evident. In engineering systems, where there is a risk of malfunction of the primary control system, alert and safety mechanisms are implemented in layers of protection. This concept has been adopted in the proposed system that integrates a hypoglycemia prediction algorithm with a global position system (GPS) locator and short message service such that the current glucose value with the rate of change (ROC) and the location of the subject can be communicated to a predefined list. Furthermore, if the system is linked to the insulin pump, it can suspend the pump or decrease the basal insulin infusion rate to prevent the pending event. The system was evaluated on clinical datasets of glucose tracings from the DexCom Seven® system. Glucose tracings were analyzed for hypoglycemia events and then a text message was broadcast to a predefined list of people who were notified with the glucose value, ROC, GPS coordinates, and a Google map of the location. In addition to providing a safety layer to a future artificial pancreas, this system also can be easily implemented in current continuous glucose monitors to help provide information and alerts to people with diabetes.
The Business of Intensive Insulin Therapy for Type 2 Diabetes Patients: Where It all Began for Me
Authors: Norton Evan
Published: January 2014

Ideally, it would be easy for physicians with Diabetes Control and Complications Trial data in hand to convince type 2 diabetes mellitus (T2DM) patients on insulin to move toward intensive insulin therapy (IIT), but in actuality, patient compliance remains a significant issue. One of the statistics that best illustrates this point is that 89% of T2DM patients on insulin do not inject themselves outside of the home (according to the National Health and Nutrition Examination Survey). The market has responded to poor compliance by developing insulin pens and different insulin formulations to improve compliance. But the fact remains that most T2DM patients on insulin are out of control. I would suggest that, in addition to better education, an opportunity exists for a medical device approach to better facilitate an easy-to-use, discreet approach to moving from conventional to IIT.
Modeling the Error of Continuous Glucose Monitoring Sensor Data: Critical Aspects Discussed through Simulation Studies
Authors: Facchinetti Andrea , Sparacino Giovanni , Cobelli Claudio
Published: January 2014

Background:

Knowing the statistical properties of continuous glucose monitoring (CGM) sensor errors can be important in several practical applications, e.g., in both open- and closed-loop control algorithms. Unfortunately, modeling the accuracy of CGM sensors is very difficult for both experimental and methodological reasons. It has been suggested that the time series of CGM sensor errors can be described as realization of the output of an autoregressive (AR) model of first order driven by a white noise process. The AR model was identified exploiting several reference blood glucose (BG) samples (collected frequently in parallel to the CGM signal), a procedure to recalibrate CGM data, and a linear time-invariant model of blood-to-interstitium glucose (BG-to-IG) kinetics. By resorting to simulation, this work shows that some assumptions made in the Breton and Kovatchev modeling approach may significantly affect the estimated sensor error and its statistical properties.

Method:

Three simulation studies were performed. The first simulation was devoted to assessing the influence of CGM data recalibration, whereas the second and third simulations examined the role of the BG-to-IG kinetic model. Analysis was performed by comparing the “original” (synthetically generated) time series of sensor errors vs its “reconstructed” version in both time and frequency domains.

Results:

Even small errors either in CGM data recalibration or in the description of BG-to-IG dynamics can severely affect the possibility of correctly reconstructing the statistical properties of sensor error. In particular, even if CGM sensor error is a white noise process, a spurious correlation among its samples originates from suboptimal recalibration or from imperfect knowledge of the BG-to-IG kinetics.

Conclusions:

Modeling the statistical properties of CGM sensor errors from data collected in vivo is difficult because it requires perfect calibration and perfect knowledge of BG-to-IG dynamics. Results suggest that correct characterization of CGM sensor error is still an open issue and requires further development upon the pioneering contribution of Breton and Kovatchev.
Accuracy of a New Real-Time Continuous Glucose Monitoring Algorithm
Authors: Keenan D. Barry , Cartaya Raymond , Mastrototaro John J.
Published: January 2014

Background:

Through minimally invasive sensor-based continuous glucose monitoring (CGM), individuals can manage their blood glucose (BG) levels more aggressively, thereby improving their hemoglobin A1c level, while reducing the risk of hypoglycemia. Tighter glycemic control through CGM, however, requires an accurate glucose sensor and calibration algorithm with increased performance at lower BG levels.

Methods:

Sensor and BG measurements for 72 adult and adolescent subjects were obtained during the course of a 26-week multicenter study evaluating the efficacy of the Paradigm® REAL-Time (PRT) sensor-augmented pump system (Medtronic Diabetes, Northridge, CA) in an outpatient setting. Subjects in the study arm performed at least four daily finger stick measurements. A retrospective analysis of the data set was performed to evaluate a new calibration algorithm utilized in the Paradigm® Veo™ insulin pump (Medtronic Diabetes) and to compare these results to performance metrics calculated for the PRT.

Results:

A total of N = 7193 PRT sensor downloads for 3 days of use, as well as 90,472 temporally and nonuniformly paired data points (sensor and meter values), were evaluated, with 5841 hypoglycemic and 15,851 hyperglycemic events detected through finger stick measurements. The Veo calibration algorithm decreased the overall mean absolute relative difference by greater than 0.25 to 15.89%, with hypoglycemia sensitivity increased from 54.9% in the PRT to 82.3% in the Veo (90.5% with predictive alerts); however, hyperglycemia sensitivity was decreased only marginally from 86% in the PRT to 81.7% in the Veo.

Conclusions:

The Veo calibration algorithm, with sensor error reduced significantly in the 40- to 120-mg/dl range, improves hypoglycemia detection, while retaining accuracy at high glucose levels.
Essential Elements of the Native Glucoregulatory System, Which, If Appreciated, May Help Improve the Function of Glucose Controllers in the Intensive Care Unit Setting
Authors: DeJournett Leon
Published: January 2014

In 2001, Van den Berghe and colleagues were able to show that tight glucose control decreases morbidity and mortality rates in the intensive care unit (ICU) setting. Several large, prospective, randomized controlled trials have failed to confirm these results. All of these studies attempted tight glucose control using expert-designed algorithms to adjust the rate of intravenous insulin. Unfortunately, these studies each had high rates of hypoglycemia, a high percentage of glucose values outside of the target range, and increased glucose variability. These three measurements have been shown to increase mortality rates in ICU patients. In order to achieve a high rate of success with regards to tight glucose control, a closed-loop system will need to be created. The two main elements of such a system are a continuous glucose sensor and a recursive glucose control algorithm. This review highlights the important elements of the native glucoregulatory system, which, if utilized, may help create a successful glucose control algorithm for a closed-loop system.