A Glycemic Status Classification Model Using a Radiofrequency Noninvasive Blood Glucose Monitor.

Despite significant efforts in the development of noninvasive blood glucose (BG) monitoring solutions, delivering an accurate, real-time BG measurement remains challenging. We sought to address this by using a novel radiofrequency (RF) glucose sensor to noninvasively classify glycemic status. The study included 31 participants aged 18-65 with prediabetes or type 2 diabetes and no other significant medical history. During control sessions and oral glucose tolerance test sessions, data were collected from both a RF sensor that rapidly scans thousands of frequencies and concurrently from a venous blood draw measured with an US Food and Drug Administration (FDA)-cleared glucose hospital meter system to create paired observations. We trained a time series forest machine learning model on 80% of the paired observations and reported results from applying the model to the remaining 20%. Our findings show that the model correctly classified glycemic status 93.37% of the time as high, normal, or low.

Detecting Unique Analyte-Specific Radio Frequency Spectral Responses in Liquid Solutions-Implications for Non-Invasive Physiologic Monitoring.

With rising healthcare costs and the rapid increase in remote physiologic monitoring and care delivery, there is an increasing need for economical, accurate, and non-invasive continuous measures of blood analytes. Based on radio frequency identification (RFID), a novel electromagnetic technology (the Bio-RFID sensor) was developed to non-invasively penetrate inanimate surfaces, capture data from individual radio frequencies, and convert those data into physiologically meaningful information and insights. Here, we describe groundbreaking proof-of-principle studies using Bio-RFID to accurately measure various concentrations of analytes in deionized water. In particular, we tested the hypothesis that the Bio-RFID sensor is able to precisely and non-invasively measure and identify a variety of analytes in vitro. For this assessment, varying solutions of (1) water in isopropyl alcohol; (2) salt in water, and (3) commercial bleach in water were tested, using a randomized double-blind trial design, as proxies for biochemical solutions in general. The Bio-RFID technology was able to detect concentrations of 2000 parts per million (ppm), with evidence suggesting the ability to detect considerably smaller concentration differences.

Spatial epidemiology of eastern equine encephalitis in Florida.

BACKGROUND: Eastern Equine Encephalitis virus (EEEV) is an alphavirus with high pathogenicity in both humans and horses. Florida continues to have the highest occurrence of human cases in the USA, with four fatalities recorded in 2010. Unlike other states, Florida supports year-round EEEV transmission. This research uses GIS to examine spatial patterns of documented horse cases during 2005-2010 in order to understand the relationships between habitat and transmission intensity of EEEV in Florida. METHODS: Cumulative incidence rates of EEE in horses were calculated for each county. Two cluster analyses were performed using density-based spatial clustering of applications with noise (DBSCAN). The first analysis was based on regional clustering while the second focused on local clustering. Ecological associations of EEEV were examined using compositional analysis and Euclidean distance analysis to determine if the proportion or proximity of certain habitats played a role in transmission. RESULTS: The DBSCAN algorithm identified five distinct regional spatial clusters that contained 360 of the 438 horse cases. The local clustering resulted in 18 separate clusters containing 105 of the 438 cases. Both the compositional analysis and Euclidean distance analysis indicated that the top five habitats positively associated with horse cases were rural residential areas, crop and pastureland, upland hardwood forests, vegetated non-forested wetlands, and tree plantations. CONCLUSIONS: This study demonstrates that in Florida tree plantations are a focus for epizootic transmission of EEEV. It appears both the abundance and proximity of tree plantations are factors associated with increased risk of EEE in horses and therefore humans. This association helps to explain why there is are spatially distinct differences in the amount of EEE horse cases across Florida.

Application of adaptive design methodology in development of a long-acting glucagon-like peptide-1 analog (dulaglutide): statistical design and simulations.

BACKGROUND: Dulaglutide (dula, LY2189265), a long-acting glucagon-like peptide-1 analog, is being developed to treat type 2 diabetes mellitus. METHODS: To foster the development of dula, we designed a two-stage adaptive, dose-finding, inferentially seamless phase 2/3 study. The Bayesian theoretical framework is used to adaptively randomize patients in stage 1 to 7 dula doses and, at the decision point, to either stop for futility or to select up to 2 dula doses for stage 2. After dose selection, patients continue to be randomized to the selected dula doses or comparator arms. Data from patients assigned the selected doses will be pooled across both stages and analyzed with an analysis of covariance model, using baseline hemoglobin A1c and country as covariates. The operating characteristics of the trial were assessed by extensive simulation studies. RESULTS: Simulations demonstrated that the adaptive design would identify the correct doses 88% of the time, compared to as low as 6% for a fixed-dose design (the latter value based on frequentist decision rules analogous to the Bayesian decision rules for adaptive design). CONCLUSIONS: This article discusses the decision rules used to select the dula dose(s); the mathematical details of the adaptive algorithm-including a description of the clinical utility index used to mathematically quantify the desirability of a dose based on safety and efficacy measurements; and a description of the simulation process and results that quantify the operating characteristics of the design.

Improvement of glycemic control and quality-of-life by insulin lispro therapy: Assessing benefits by ITR-QOL questionnaires.

OBJECTIVE: To investigate the impact of insulin lispro on patients' quality of life (QOL) in diabetic patients who need insulin treatment. METHODS: In this open-label, 12-week study 770 diabetic patients whose medications were switched to insulin lispro from human insulin were evaluated. Main outcome measures were compliance with insulin injection timing, HbA(1c), postprandial blood glucose, frequency and time of onset of hypoglycemia, and QOL measurements. RESULTS: After switching to insulin lispro, approximately 95% of patients "Always" or "Usually" complied with the timing of insulin injections as instructed by their physician. HbA(1c) was improved from 8.2 to 7.8% without increasing the number of hypoglycemic episodes. In terms of QOL, statistically significant improvements were observed in the insulin-therapy-related QOL measure questionnaire (ITR-QOL) total score. Statistically significant correlations were found between compliance with insulin injection timing and glycemic control, as well as glycemic control and QOL. CONCLUSION: The improvement in patient convenience obtained by switching to insulin lispro provided better compliance with insulin injection timing, and this in turn led to better glycemic control and improved QOL. Especially, a better QOL was seen to be clearly related with better glycemic control.

In vivo measurement of cell proliferation in canine brain tumor using C-11-labeled FMAU and PET.

INTRODUCTION: Noncatabolized thymidine analogs are being developed for use in imaging DNA synthesis. We sought to relate a labeling index measured by immunohistochemical staining bromodeoxyuridine (BUdR) technique to the uptake of (11)C 2'-fluoro-5-methyl-1-beta-d-arabinofuranosyluracil (FMAU) measured with positron emission tomography (PET) in a brain tumor model. METHODS: Adult beagles (n=8) with implanted brain tumors received [(11)C]FMAU and dynamic imaging with arterial sampling. Six dogs were then infused with BUdR (200 mg/m(2)) and sacrificed. Tumor time-activity curves (TACs) obtained from computed-tomography-defined regions of interest were corrected for partial volume effects and crosstalk from brain tissue. Tissue was analyzed for the percentage of tumor volume occupied by viable cells and by viable cells in S-phase as identified by BUdR staining. PET/[(11)C]FMAU and BUdR were compared by linear regression analysis and analysis of variance, as well as by a nonparametric rank correlation test. RESULTS: Tumor standardized uptake values (SUVs) and tumor-to-contralateral-brain uptake ratios at 50 min were 1.6+/-0.4 and 5.5+/-1.2 (n=8; mean+/-S.E.M.), respectively. No (11)C-labeled metabolites were observed in the blood through 60 min. Tumor TACs were well described with a three-compartment/four-parameter model (k(4)=0) and by Patlak analysis. Parametric statistical analysis showed that FMAU clearance from plasma into tumor Compartment 3 (K(FMAU)) was significantly correlated with S-phase percent volume (P=.03), while tumor SUV was significantly correlated with both S-phase percent volume and cell percent volume (P=.02 and .03, respectively). Patlak slope, K(FMAU) and tumor SUV were equivalent with regard to rank correlation analysis, which showed that tumor uptake and trapping of FMAU were correlated with the volume density of dividing cells (P=.0003) rather than nondividing cells (P=.3). CONCLUSIONS: Trapping of [(11)C]FMAU correlated with tumor growth rate, as measured by direct tissue analysis with BUdR in a canine brain tumor model, suggesting that [(11)C]FMAU is useful for the imaging of cell proliferation in cancers.

Integrative haptic and visual interaction for simulation of PMMA injection during vertebroplasty.

In vertebroplasty, physician relies on both sight and feel to properly place the bone needle through various tissue types and densities, and to help monitor the injection of PMMA or cement into the vertebra. Incorrect injecting and reflux of the PMMA into areas where it should not go can result in detrimental clinical complication. This paper focuses on the human-computer interaction for simulating PMMA injection in our virtual spine workstation. Fluoroscopic images are generated from the CT patient volume data and simulated volumetric flow using a time varying 4D volume rendering algorithm. The user's finger movement is captured by a data glove. Immersion CyberGrasp is used to provide the variable resistance felt during injection by constraining the user's thumb. Based on our preliminary experiments with our interfacing system comprising simulated fluoroscopic imaging and haptic interaction, we found that the former has a larger impact on the user's control during injection.

Flow visualization for interactive simulation of drugs injection during chemoembolization.

Chemoembolization is an important therapeutic procedure. A catheter was navigated to the artery that feeds the tumor, and chemotherapy drugs and embolus are injected directly into the tumor. There is a risk that embolus may lodge incorrectly and deprive normal tissue of its blood supply. This paper focuses on visualization of the flow particles in simulation of chemotherapy drugs injection for training of hand-eye coordination skills. We assume that the flow follows a defined path in the hepatic vascular system from the catheter tip. The vascular model is constructed using sweeping and blending operations. Quadrilaterals which are aligned to face the viewer are drawn for the trail of each particle. The quadrilateral in the trail is determined using bilinear interpolation. On simulated fluoroscopic image, the flow is rendered as overlaying and semitransparent quadrilaterals representing the particles' trails. This visualization model achieves a good visual approximation of the flow of particles inside the vessels under fluoroscopic imaging.

Measurement of insulin absorption and insulin action.

For the practical implementation of every type of insulin therapy it is necessary to know both the time course of action of therapeutically used short- and long-acting insulin preparations and the factors influencing such time-action profiles. The only reliable way to obtain the required quantitative information about the pharmacokinetic and glucodynamic properties of insulin preparations has been the use of the euglycemic glucose clamp technique. The first studies with each new insulin formulation or insulin application technique should be performed with healthy subjects in order to have the most comparable study conditions. Thereafter, results from such clinical-experimental studies should be verified in similar studies with patients with diabetes. Earlier investigational approaches, which either had been limited to the determination of the pharmacokinetic properties of insulin preparations or had used the quantitative decrease of the blood glucose level as a measure of the pharmacodynamic properties, do not provide valid quantitative results. The proposed glucose clamp technique makes possible the quantitative study of the pharmacokinetic and pharmacodynamic properties of insulin preparations under comparative and reproducible conditions.

Dynamic exercise imaging with an MR-compatible stationary cycle within the general electric open magnet.

Many cases of muscular ischemia do not manifest without increased metabolic demand. Hence, diagnosis of intermittent claudication often requires inducing physiologic challenge, such as by exercise. Cine phase-contrast MRI can concurrently acquire cross-sectional vascular anatomy and through-plane blood velocities, enabling blood flow rate quantification. An MR-compatible stationary cycle was designed, constructed, and tested for flow quantification in large arteries during lower-limb exercise in a General Electric Signa SP 0.5 T open magnet. The cycle demonstrated smooth cycling during image acquisition, has freewheeling capability, is adjustable for subject size and strength, and can quantify workload. A healthy 59-year-old male was imaged at the supraceliac and infrarenal levels of the abdominal aorta at rest and during exercise. An exercise workload of 47.9 W was achieved. His heart rate increased from 52 to 78 bpm, supraceliac flow increased from 1.7 to 3.7 L/min, and infrarenal flow increased from 0.4 to 3.2 L/min from rest to exercise.

Effect of long-term exposure to insulin lispro on the induction of antibody response in patients with type 1 or type 2 diabetes.

OBJECTIVE: To determine the long-term effects of insulin lispro on inducing lispro-specific, insulin-specific, and cross-reactive (reactive with both insulin lispro and human insulin) antibodies. RESEARCH DESIGN AND METHODS: A multinational, multicenter combination of controlled and noncontrolled, open-label studies of 4.5 years' duration was designed to evaluate the long-term immunologic profile of subcutaneously administered insulin lispro. A total of 1,221 patients (men and women; 12-81 years of age) with type 1 or type 2 diabetes were enrolled. Circulating anti-insulin antibodies were measured using radioimmunoassays. RESULTS: Insulin-specific and lispro-specific antibody responses were within the background noise levels of the assays. Significant elevations of antibody were confined to a cross-reactive antibody response. Antibody levels resulting from prior exposure to long- and short-acting insulins changed little after transfer to insulin lispro and remained within or near the baseline levels. De novo exposure to insulin lispro resulted in increases in cross-reactive but not insulin- or lispro-specific antibody levels. Cross-reactive insulin antibodies developed more readily in patients with type 1 diabetes than in those with type 2 diabetes. Long-term antibody responses tended to decrease over time and returned to baseline or near-baseline levels by the end of the long-term studies. No evidence of an anamnestic antibody response could be found in individuals treated intermittently with insulin lispro. CONCLUSIONS: The immunogenic profile of patients treated with insulin lispro was comparable to that of patients treated with recombinant human insulin. Inductions of significant levels of specific or cross-reactive antibodies were not observed in patients who had received insulin previously. No significant antibody-dependent increases in insulin dosage requirements were noted in these patients. The incidence of insulin allergy was not different from that in patients treated with recombinant regular human insulin.

System for robotically assisted prostate biopsy and therapy with intraoperative CT guidance.

RATIONALE AND OBJECTIVES: The purpose of this study was to assess the work-in-progress prototype of an image-guided, robotic system for accurate and consistent placement of transperineal needles into the prostate with intraoperative image guidance inside the gantry of a computed tomographic (CT) scanner. MATERIALS AND METHODS: The coach-mounted system consists of a seven-degrees-of-freedom, passive mounting arm: a remote-center-of-motion robot; and a motorized, radiolucent needle-insertion device to deliver 17-18-gauge implant and biopsy needles into the prostate with the transperineal route. The robot is registered to the image space with a stereotactic adapter. The surgeon plans and controls the intervention in the CT scanner room with a desktop computer that receives DICOM images from the CT scanner. The complete system fits in a carry-on suitcase, does not need calibration, and does not utilize vendor-specific features of the CT scanner. RESULTS: In open air, the average accuracy was better than 1 mm at a 5-8-cm depth. In various phantoms, the average orientation error was 1.3 degrees, and the average distance between the needle tip and the target was 2 mm. CONCLUSION: Results of preliminary experiments indicate that this robotic system may be suitable for transperineal needle placement into the prostate and shows potential in a variety of other percutaneous clinical applications.

The 1st balloon valvuloplasty: an historical note.

Balloon valvuloplasty (BV) is currently the treatment of choice for pulmonic stenosis in humans and dogs. Before permission was obtained to attempt the 1st BV in a child in 1982, the safety and efficacy of the procedure were tested in 1980 in an English Bulldog with spontaneous pulmonic stenosis. A fatal outcome would have caused indefinite postponement of BV in human patients, a procedure that currently benefits over 25,000 patients a year worldwide. This article describes the initial test procedure and its fortunate outcome in spite of unrecognized coronary anomalies in the bulldog. A small balloon was used in the test procedure, and fatal disruption of the anomalous left coronary artery (CA) did not occur as it has in several bulldogs since that time.

Training and pretreatment planning of interventional neuroradiology procedures--initial clinical validation.

A PC based system for simulating image-guided interventional neuroradiological procedures for physician training and patient specific pretreatment planning is described. The system allows physicians to manipulate and interface interventional devices such as catheters, guidewires, stents and coils within 2-D and hybrid surface and volume rendered 3-D patient vascular images in real time. A finite element method is employed to model the interaction of the catheters and guidewires with the vascular system. Fluoroscopic, roadmapping and volume rendered 3-D presentations of the vasculature are provided. System software libraries allow for the use of commonly employed catheters, guidewires, stents and occluding coils of various shapes and sizes. The results of an initial clinical validation suggest that the experience gained from our simulator is comparable with that of using a vascular phantom. We are conducting further validation with the aim of providing patient specific pretreatment planning.