A Model-Based Insulin Dose Optimization Algorithm for People With Type 1 Diabetes on Multiple Daily Injections Therapy.

OBJECTIVE: Multiple daily injections (MDI) therapy is the most common treatment for type 1 diabetes (T1D) including basal insulin doses to keep glucose levels constant during fasting conditions and bolus insulin doses with meals. Optimal insulin dosing is critical to achieving satisfactory glycemia but is challenging due to inter- and intra-individual variability. Here, we present a novel model-based iterative algorithm that optimizes insulin doses using previous-day glucose, insulin, and meal data. METHODS: Our algorithm employs a maximum-a-posteriori method to estimate parameters of a model describing the effects of changes in basal-bolus insulin doses. Then, parameter estimates, their confidence intervals, and the goodness of fit, are combined to generate new recommendations. We assessed our algorithm in three ways. First, a clinical data set of 150 days (15 participants) were used to evaluate the proposed model and the estimation method. Second, 60-day simulations were performed to demonstrate the efficacy of the algorithm. Third, a sample 6-day clinical experiment is presented and discussed. RESULTS: The model fitted the clinical data well with a root-mean-square-error of 1.75 mmol/L. Simulation results showed an improvement in the time in target (3.9-10 mmol/L) from 64% to 77% and a decrease in the time in hypoglycemia (< 3.9 mmol/L) from 8.1% to 3.8%. The clinical experiment demonstrated the feasibility of the algorithm. CONCLUSION: Our algorithm has the potential to improve glycemic control in people with T1D using MDI. SIGNIFICANCE: This work is a step forward towards a decision support system that improves their quality of life.

Intravascular optical coherence tomography to validate finite-element simulation of angioplasty balloon inflation.

Concrete methods are lacking to examine angioplasty simulation results. For the first time, we explored the application of intravascular optical coherence tomography (IVOCT) to experimentally validate results obtained from finite-element simulation of angioplasty balloon deployment. In order to simulate each experimental scenario, IVOCT images were used to create initial geometrical models for the balloon and the phantoms. The study comprised three scenarios. The first scenario involved experimentally monitoring as well as simulating free expansion of the balloon. The second scenario involved experimentally monitoring as well as simulating balloon inflation inside three artery phantoms with different mechanical properties. The third scenario involved experimentally monitoring as well as simulating balloon unfolding and inflation inside a multilayer phantom. Using the first scenario, a constitutive model was developed for the balloon and was tuned to fit the IVOCT balloon inflation monitoring results. This model was used to simulate the balloon's response in simulations involving phantoms corresponding to the second and third scenarios. Diameter values were calculated both from images and simulation results. These values were then compared for each scenario. The obtained results highlight the potentials of IVOCT monitoring to validate simulation procedures.

Computer Simulation Model to Train Medical Personnel on Glucose Clamp Procedures.

OBJECTIVE: A glucose clamp procedure is the most reliable way to quantify insulin pharmacokinetics and pharmacodynamics, but skilled and trained research personnel are required to frequently adjust the glucose infusion rate. A computer environment that simulates glucose clamp experiments can be used for efficient personnel training and development and testing of algorithms for automated glucose clamps. METHODS: We built 17 virtual healthy subjects (mean age, 25±6 years; mean body mass index, 22.2±3 kg/m2), each comprising a mathematical model of glucose regulation and a unique set of parameters. Each virtual subject simulates plasma glucose and insulin concentrations in response to intravenous insulin and glucose infusions. Each virtual subject provides a unique response, and its parameters were estimated from combined intravenous glucose tolerance test-hyperinsulinemic-euglycemic clamp data using the Bayesian approach. The virtual subjects were validated by comparing their simulated predictions against data from 12 healthy individuals who underwent a hyperglycemic glucose clamp procedure. RESULTS: Plasma glucose and insulin concentrations were predicted by the virtual subjects in response to glucose infusions determined by a trained research staff performing a simulated hyperglycemic clamp experiment. The total amount of glucose infusion was indifferent between the simulated and the real subjects (85±18 g vs. 83±23 g; p=NS) as well as plasma insulin levels (63±20 mU/L vs. 58±16 mU/L; p=NS). CONCLUSIONS: The virtual subjects can reliably predict glucose needs and plasma insulin profiles during hyperglycemic glucose clamp conditions. These virtual subjects can be used to train personnel to make glucose infusion adjustments during clamp experiments.

Glucose-responsive insulin and glucagon delivery (dual-hormone artificial pancreas) in adults with type 1 diabetes: a randomized crossover controlled trial.

BACKGROUND: Most patients with type 1 diabetes do not achieve their glycemic targets. We aimed to assess the efficacy of glucose-responsive insulin and glucagon closed-loop delivery for controlling glucose levels in adults with type 1 diabetes. METHODS: We conducted a randomized crossover trial involving 15 adults with type 1 diabetes, comparing standard insulin-pump therapy with dual-hormone, closed-loop delivery. Patients were admitted twice to a clinical research facility and received, in random order, both treatments. Each 15-hour visit (from 1600 to 0700) included an evening exercise session, followed by a medium-sized meal, a bedtime snack and an overnight stay. During visits that involved closed-loop delivery, basal insulin and glucagon miniboluses were delivered according to recommendations based on glucose sensor readings and a predictive dosing algorithm at 10-minute intervals. During visits involving standard insulin-pump therapy (control visits), patients used conventional treatment. RESULTS: Dual-hormone closed-loop delivery increased the percentage of time for which patients' plasma glucose levels were in the target range (median 70.7% [interquartile range (IQR) 46.1%-88.4%] for closed-loop delivery v. 57.3% [IQR 25.2%-71.8%] for control, p = 0.003) and decreased the percentage of time for which plasma glucose levels were in the low range (bottom of target range [< 4.0 mmol/L], 0.0% [IQR 0.0%-3.0%] for closed-loop delivery v. 10.2% [IQR 0.0%-13.0%] for control, p = 0.01; hypoglycemia threshold [< 3.3 mmol/L], 0.0% [IQR 0.0%-0.0%] for closed-loop delivery v. 2.8% [IQR 0.0%-5.9%] for control, p = 0.006). Eight participants (53%) had at least 1 hypoglycemic event (plasma glucose < 3.0 mmol/L) during standard treatment, compared with just 1 participant (7%) during closed-loop treatment (p = 0.02). INTERPRETATION: Dual-hormone, closed-loop delivery guided by advanced algorithms improved short-term glucose control and reduced the risk of hypoglycemia in a group of 15 adults with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01297946.

Intravascular optical coherence tomography to characterize tissue deformation during angioplasty: preliminary experiments with artery phantoms.

We explored the potential of intravascular optical coherence tomography (IVOCT) to assess deformation during angioplasty balloon inflation. Using a semi-compliant balloon and artery phantoms, we considered two experimental scenarios. The goal for the first scenario was to investigate if variation in the elasticity of the structure surrounding the balloon could be sensed by IVOCT monitoring. In this scenario, we used three single-layer phantoms with various mechanical properties. Image analysis was performed to extract the inner and outer diameters of the phantoms at various pressures. The goal for the second scenario was twofold. First, we investigated the IVOCT capability to monitor a more complex balloon inflation process. The balloon was in a folded state prior to inflation. This allowed studying two stages of deformation: during balloon unfolding and during balloon expansion. Second, we investigated IVOCT capability to monitor the deformation in a three-layer phantom used to better mimic a true artery. So, not only were the IVOCT images processed to provide the inner and outer diameters of the phantom, but the layer thicknesses were also determined. In both scenarios, IVOCT monitoring revealed to be very efficient in providing relevant information about the phantom deformation during balloon inflation.

Real-time control of angioplasty balloon inflation based on feedback from intravascular optical coherence tomography: experimental validation on an excised heart and a beating heart model.

We report on real-time control of balloon inflation inside porcine arteries. In the first step, experiments were done in a coronary artery of an excised heart. In the second step, experiments were done in a beating heart setup providing conditions very close to in vivo conditions without the complications. A programmable syringe pump was used to inflate a compliant balloon in arteries, while intravascular optical coherence tomography (IVOCT) monitoring was performed. In a feedback loop, IVOCT images were processed to provide the balloon diameter values in real time to control the pump action in order to achieve a target diameter. In different experiments, various flow rates and target diameters were used. In the excised heart experiment, there was good convergence to target diameters resulting in a satisfactory balloon inflation control. In the beating heart experiment, there were oscillations in the diameter values due to cyclic arterial contractions. In these experiments, the control system maintained diameter averages satisfactorily close to predetermined target values. Real-time control of balloon inflation could not only provide a safer outcome for angioplasty procedures, but could also provide additional information for diagnostics since it implicitly provides information about the artery response to the inflation process.

Estimating postprandial glucose fluxes using hierarchical Bayes modelling.

A new stochastic computational method was developed to estimate the endogenous glucose production, the meal-related glucose appearance rate (R(a meal)), and the glucose disposal (R(d)) during the meal tolerance test. A prior probability distribution was adopted which assumes smooth glucose fluxes with individualized smoothness level within the context of a Bayes hierarchical model. The new method was contrasted with the maximum likelihood method using data collected in 18 subjects with type 2 diabetes who ingested a mixed meal containing [U-¹³C]glucose. Primed [6,6-²H2]glucose was infused in a manner that mimicked the expected endogenous glucose production. The mean endogenous glucose production, R(a meal), and R(d) calculated by the new method and maximum likelihood method were nearly identical. However, the maximum likelihood gave constant, nonphysiological postprandial endogenous glucose production in two subjects whilst the new method gave plausible estimates of endogenous glucose production in all subjects. Additionally, the two methods were compared using a simulated triple-tracer experiment in 12 virtual subjects. The accuracy of the estimates of the endogenous glucose production and R(a meal) profiles was similar [root mean square error (RMSE) 1.0±0.3 vs. 1.4±0.7 µmol/kg/min for EGP and 2.6±1.0 vs. 2.9±0.9 µmol/kg/min for R(a meal); new method vs. maximum likelihood method; P=NS, paired t-test]. The accuracy of R(d) estimates was significantly increased by the new method (RMSE 5.3±1.9 vs. 4.2±1.3; new method vs. ML method; P<0.01, paired t-test). We conclude that the new method increases plausibility of the endogenous glucose production and improves accuracy of glucose disposal compared to the maximum likelihood method.

Real-time control of angioplasty balloon inflation based on feedback from intravascular optical coherence tomography: preliminary study on an artery phantom.

A method is proposed to achieve computerized control of angioplasty balloon inflation, based on feedback from intravascular optical coherence tomography (IVOCT). Controlled balloon inflation could benefit clinical applications, cardiovascular research, and medical device industry. The proposed method was experimentally tested for balloon inflation within an artery phantom. During balloon inflation, luminal contour of the phantom was extracted from IVOCT images in real time. Luminal diameter was estimated from the obtained contour and was used in a feedback loop. Based on the estimated actual diameter and a target diameter, a computer controlled a programmable syringe pump to deliver or withdraw liquid in order to achieve the target diameter. The performance of the control method was investigated under different conditions, e.g., various flow rates and various target diameters. The results were satisfactory, as the control method provided convergence to the target diameters in various experiments.

Optical coherence tomography monitoring of angioplasty balloon inflation in a deployment tester.

We present an innovative integration of an intravascular optical coherence tomography probe into a computerized balloon deployment system to monitor the balloon inflation process. The high-resolution intraluminal imaging of the balloon provides a detailed assessment of the balloon quality and, consequently, a technique to improve the balloon manufacturing process. A custom-built swept-source optical coherence tomography system is used for real-time imaging. A semicompliant balloon with a nominal diameter of 4 mm is fabricated for the experiments. Imaging results correspond to balloon deployment in air and inside an artery phantom. A characterization of the balloon diameter, wall thickness, compliance, and elastic modulus is provided, based on image segmentation. Using the images obtained from the probe pullback, a three-dimensional visualization of the inflated balloon is presented.