An automatic deep reinforcement learning bolus calculator for automated insulin delivery systems.

In hybrid automatic insulin delivery (HAID) systems, meal disturbance is compensated by feedforward control, which requires the announcement of the meal by the patient with type 1 diabetes (DM1) to achieve the desired glycemic control performance. The calculation of insulin bolus in the HAID system is based on the amount of carbohydrates (CHO) in the meal and patient-specific parameters, i.e. carbohydrate-to-insulin ratio (CR) and insulin sensitivity-related correction factor (CF). The estimation of CHO in a meal is prone to errors and is burdensome for patients. This study proposes a fully automatic insulin delivery (FAID) system that eliminates patient intervention by compensating for unannounced meals. This study exploits the deep reinforcement learning (DRL) algorithm to calculate insulin bolus for unannounced meals without utilizing the information on CHO content. The DRL bolus calculator is integrated with a closed-loop controller and a meal detector (both previously developed by our group) to implement the FAID system. An adult cohort of 68 virtual patients based on the modified UVa/Padova simulator was used for in-silico trials. The percentage of the overall duration spent in the target range of 70-180 mg/dL was 71.2 % and 76.2 % , < 70 mg/dL was 0.9 % and 0.1 % , and > 180 mg/dL was 26.7 % and 21.1 % , respectively, for the FAID system and HAID system utilizing a standard bolus calculator (SBC) including CHO misestimation. The proposed algorithm can be exploited to realize FAID systems in the future.

Generative deep learning for the development of a type 1 diabetes simulator.

BACKGROUND: Type 1 diabetes (T1D) simulators, crucial for advancing diabetes treatments, often fall short of capturing the entire complexity of the glucose-insulin system due to the imprecise approximation of the physiological models. This study introduces a simulation approach employing a conditional deep generative model. The aim is to overcome the limitations of existing T1D simulators by synthesizing virtual patients that more accurately represent the entire glucose-insulin system physiology. METHODS: Our methodology utilizes a sequence-to-sequence generative adversarial network to simulate virtual T1D patients causally. Causality is embedded in the model by introducing shifted input-output pairs during training, with a 90-min shift capturing the impact of input insulin and carbohydrates on blood glucose. To validate our approach, we train and evaluate the model using three distinct datasets, each consisting of 27, 12, and 10 T1D patients, respectively. In addition, we subject the trained model to further validation for closed-loop therapy, employing a state-of-the-art controller. RESULTS: The generated patients display statistical similarity to real patients when evaluated on the time-in-range results for each of the standard blood glucose ranges in T1D management along with means and variability outcomes. When tested for causality, authentic causal links are identified between the insulin, carbohydrates, and blood glucose levels of the virtual patients. The trained generative model demonstrates behaviours that are closer to reality compared to conventional T1D simulators when subjected to closed-loop insulin therapy using a state-of-the-art controller. CONCLUSIONS: These results highlight our approach's capability to accurately capture physiological dynamics and establish genuine causal relationships, holding promise for enhancing the development and evaluation of therapies in diabetes.

New therapies and treatments for type 1 diabetes (T1D) are often first tested on specialized computer programs called simulators before being tried on actual patients. Traditionally, these simulators rely on mathematical equations to mimic real-life patients, but they sometimes fail to provide reliable results because they do not consider everything that affects individuals with diabetes, such as lifestyle, eating habits, time of day, and weather. In our research, we suggest using computer programs based on artificial intelligence that can directly learn all these factors from real patient data. We tested our programs using information from different groups of patients and found that they were much better at predicting what would happen with a patient's diabetes. These new programs can understand how insulin, food, and blood sugar levels interact in the body, which makes them valuable for developing therapies for T1D.

An ensemble machine learning approach for the detection of unannounced meals to enhance postprandial glucose control.

BACKGROUND: Hybrid automated insulin delivery systems enhance postprandial glucose control in type 1 diabetes, however, meal announcements are burdensome. To overcome this, we propose a machine learning-based automated meal detection approach; METHODS:: A heterogeneous ensemble method combining an artificial neural network, random forest, and logistic regression was employed. Trained and tested on data from two in-silico cohorts comprising 20 and 47 patients. It accounted for various meal sizes (moderate to high) and glucose appearance rates (slow and rapid absorbing). To produce an optimal prediction model, three ensemble configurations were used: logical AND, majority voting, and logical OR. In addition to the in-silico data, the proposed meal detector was also trained and tested using the OhioT1DM dataset. Finally, the meal detector is combined with a bolus insulin compensation scheme; RESULTS:: The ensemble majority voting obtained the best meal detector results for both the in-silico and OhioT1DM cohorts with a sensitivity of 77%, 94%, 61%, precision of 96%, 89%, 72%, F1-score of 85%, 91%, 66%, and with false positives per day values of 0.05, 0.19, 0.17, respectively. Automatic meal detection with insulin compensation has been performed in open-loop insulin therapy using the AND ensemble, chosen for its lower false positive rate. Time-in-range has significantly increased 10.48% and 16.03%, time above range was reduced by 5.16% and 11.85%, with a minimal time below range increase of 0.35% and 2.69% for both in-silico cohorts, respectively, compared to the results without a meal detector; CONCLUSION:: To increase the overall accuracy and robustness of the predictions, this ensemble methodology aims to take advantage of each base model's strengths. All of the results point to the potential application of the proposed meal detector as a separate module for the detection of meals in automated insulin delivery systems to achieve improved glycemic control.

Artificial Intelligence and Machine Learning for Improving Glycemic Control in Diabetes: Best Practices, Pitfalls, and Opportunities.

OBJECTIVE: Artificial intelligence and machine learning are transforming many fields including medicine. In diabetes, robust biosensing technologies and automated insulin delivery therapies have created a substantial opportunity to improve health. While the number of manuscripts addressing the topic of applying machine learning to diabetes has grown in recent years, there has been a lack of consistency in the methods, metrics, and data used to train and evaluate these algorithms. This manuscript provides consensus guidelines for machine learning practitioners in the field of diabetes, including best practice recommended approaches and warnings about pitfalls to avoid. METHODS: Algorithmic approaches are reviewed and benefits of different algorithms are discussed including importance of clinical accuracy, explainability, interpretability, and personalization. We review the most common features used in machine learning applications in diabetes glucose control and provide an open-source library of functions for calculating features, as well as a framework for specifying data sets using data sheets. A review of current data sets available for training algorithms is provided as well as an online repository of data sources. SIGNIFICANCE: These consensus guidelines are designed to improve performance and translatability of new machine learning algorithms developed in the field of diabetes for engineers and data scientists.

Optimizing Noninvasive Vagus Nerve Stimulation for Systemic Lupus Erythematosus: Protocol for a Multicenter Randomized Controlled Trial.

BACKGROUND: Systemic lupus erythematosus is a chronic, multisystem, inflammatory disease of autoimmune etiology occurring predominantly in women. A major hurdle to the diagnosis, treatment, and therapeutic advancement of this disease is its heterogeneous nature, which presents as a wide range of symptoms such as fatigue, fever, musculoskeletal involvement, neuropsychiatric disorders, and cardiovascular involvement with varying severity. The current therapeutic approach to this disease includes the administration of immunomodulatory drugs that may produce unfavorable secondary effects. OBJECTIVE: This study explores the known relationship between the autonomic nervous system and inflammatory pathways to improve patient outcomes by treating autonomic nervous system dysregulation in patients via noninvasive vagus nerve stimulation. In this study, data including biomarkers, physiological signals, patient outcomes, and patient quality of life are being collected and analyzed. After completion of the clinical trial, a computer model will be developed to identify the biomarkers and physiological signals related to lupus activity in order to understand how they change with different noninvasive vagus nerve stimulation frequency parameters. Finally, we propose building a decision support system with integrated noninvasive wearable technologies for continuous cardiovascular and peripheral physiological sensing for adaptive, patient-specific optimization of the noninvasive vagus nerve stimulation frequency parameters in real time. METHODS: The protocol was designed to evaluate the efficacy and safety of transauricular vagus nerve stimulation in patients with systemic lupus erythematosus. This multicenter, national, randomized, double-blind, parallel-group, placebo-controlled study will recruit a minimum of 18 patients diagnosed with this disease. Evaluation and treatment of patients will be conducted in an outpatient clinic and will include 12 visits. Visit 1 consists of a screening session. Subsequent visits up to visit 6 involve mixing treatment and evaluation sessions. Finally, the remaining visits correspond with early and late posttreatment follow-ups. RESULTS: On November 2022, data collection was initiated. Of the 10 participants scheduled for their initial appointment, 8 met the inclusion criteria, and 6 successfully completed the entire protocol. Patient enrollment and data collection are currently underway and are expected to be completed in December 2023. CONCLUSIONS: The results of this study will advance patient-tailored vagus nerve stimulation therapies, providing an adjunctive treatment solution for systemic lupus erythematosus that will foster adoption of technology and, thus, expand the population with systemic lupus erythematosus who can benefit from improved autonomic dysregulation, translating into reduced costs and better quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT05704153; https://clinicaltrials.gov/study/NCT05704153. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48387.

Safety and performance of a hybrid closed-loop insulin delivery system with carbohydrate suggestion in adults with type 1 diabetes prone to hypoglycemia.

AIMS: To evaluate the safety and performance of a hybrid closed-loop (HCL) system with automatic carbohydrate suggestion in adults with type 1 diabetes (T1D) prone to hypoglycemia. METHODS: A 32-hour in-hospital pilot study, including a night period, 4 meals and 2 vigorous unannounced 45-minute aerobic sessions, was conducted in 11 adults with T1D prone to hypoglycemia. The primary outcome was the percentage of time in range 70-180 mg/dL (TIR). Main secondary outcomes were time below range < 70 mg/dL (TBR < 70) and < 54 (TBR < 54). Data are presented as median (10th-90th percentile ranges). RESULTS: The participants, 6 (54.5%) men, were 24 (22-48) years old, and had 22 (9-32) years of T1D duration. All of them regularly used an insulin pump and a continuous glucose monitoring system. The median TIR was 78.7% (75.6-91.2): 92.7% (68.2-100.0) during exercise and recovery period, 79.3% (34.9-100.0) during postprandial period, and 95.4% (66.4-100.0) during overnight period. The TBR < 70 and TBR < 54 were 0.0% (0.0-6.6) and 0.0% (0.0-1.2), respectively. A total of 4 (3-9) 15-g carbohydrate suggestions were administered per person. No severe acute complications occurred during the study. CONCLUSIONS: The HCL system with automatic carbohydrate suggestion performed well and was safe in this population during challenging conditions in a hospital setting.

Intermittent closed-loop blood glucose control for people with type 1 diabetes on multiple daily injections.

BACKGROUND AND OBJECTIVES: Recent advances in Automated Insulin Delivery systems have been shown to dramatically improve glycaemic control and reduce the risk of hypoglycemia in people with type 1 diabetes. However, they are complex systems that require specific training and are not affordable for most. Attempts to reduce the gap with closed-loop therapies using advanced dosing advisors have so far failed, mainly because they require too much human intervention. With the advent of smart insulin pens, one of the main constraints (having reliable bolus and meal information) disappears and new strategies can be employed. This is our starting hypothesis, which we have validated in a very demanding simulator. In this paper, we propose an intermittent closed-loop control system specifically intended for multiple daily injection therapy to bring the benefits of artificial pancreas to the application of multiple daily injections. METHODS: The proposed control algorithm is based on model predictive control and integrates two patient-driven control actions. Correction insulin boluses are automatically computed and recommended to the patient to minimize the duration of hyperglycemia. Rescue carbohydrates are also triggered to avoid hypoglycemia episodes. The algorithm can adapt to different patient lifestyles with customizable triggering conditions, closing the gap between practicality and performance. The proposed algorithm is compared with conventional open-loop therapy, and its superiority is demonstrated through extensive in silico evaluations using realistic cohorts and scenarios. The evaluations were conducted in a cohort of 47 virtual patients. We also provide detailed explanations of the implementation, imposed constraints, triggering conditions, cost functions, and penalties for the algorithm. RESULTS: The in-silico outcomes combining the proposed closed-loop strategy with slow-acting insulin analog injections at 09:00 h resulted in percentages of time in range (TIR) (70-180 mg/dL) of 69.5%, 70.6%, and 70.4% for glargine-100, glargine-300, and degludec-100, respectively, and injections at 20:00 h resulted in percentages of TIR of 70.5%, 70.3%, and 71.6%, respectively. In all the cases, the percentages of TIR were considerably higher than those obtained from the open-loop strategy, being only 50.7%, 53.9%, and 52.2% for daytime injection and 55.5%, 54.1%, and 56.9% for nighttime injection. Overall, the occurrence of hypoglycemia and hyperglycemia was notably reduced using our approach. CONCLUSIONS: Event-triggering model predictive control in the proposed algorithm is feasible and may meet clinical targets for people with type 1 diabetes.

Bolus Insulin calculation without meal information. A reinforcement learning approach.

In continuous subcutaneous insulin infusion and multiple daily injections, insulin boluses are usually calculated based on patient-specific parameters, such as carbohydrates-to-insulin ratio (CR), insulin sensitivity-based correction factor (CF), and the estimation of the carbohydrates (CHO) to be ingested. This study aimed to calculate insulin boluses without CR, CF, and CHO content, thereby eliminating the errors caused by misestimating CHO and alleviating the management burden on the patient. A Q-learning-based reinforcement learning algorithm (RL) was developed to optimise bolus insulin doses for in-silico type 1 diabetic patients. A realistic virtual cohort of 68 patients with type 1 diabetes that was previously developed by our research group, was considered for the in-silico trials. The results were compared to those of the standard bolus calculator (SBC) with and without CHO misestimation using open-loop basal insulin therapy. The percentage of the overall duration spent in the target range of 70-180 mg/dL was 73.4% and 72.37%, <70 mg/dL was 1.96 and 0.70%, and >180 mg/dL was 23.40 and 24.63%, respectively, for RL and SBC without CHO misestimation. The results revealed that RL outperformed SBC in the presence of CHO misestimation, and despite not knowing the CHO content of meals, the performance of RL was similar to that of SBC in perfect conditions. This algorithm can be incorporated into artificial pancreas and automatic insulin delivery systems in the future.

Generation of Individualized Synthetic Data for Augmentation of the Type 1 Diabetes Data Sets Using Deep Learning Models.

In this paper, we present a methodology based on generative adversarial network architecture to generate synthetic data sets with the intention of augmenting continuous glucose monitor data from individual patients. We use these synthetic data with the aim of improving the overall performance of prediction models based on machine learning techniques. Experiments were performed on two cohorts of patients suffering from type 1 diabetes mellitus with significant differences in their clinical outcomes. In the first contribution, we have demonstrated that the chosen methodology is able to replicate the intrinsic characteristics of individual patients following the statistical distributions of the original data. Next, a second contribution demonstrates the potential of synthetic data to improve the performance of machine learning approaches by testing and comparing different prediction models for the problem of predicting nocturnal hypoglycemic events in type 1 diabetic patients. The results obtained for both generative and predictive models are quite encouraging and set a precedent in the use of generative techniques to train new machine learning models.

A simulator with realistic and challenging scenarios for virtual T1D patients undergoing CSII and MDI therapy.

In silico simulations have become essential for the development of diabetes treatments. However, currently available simulators are not challenging enough and often suffer from limitations in insulin and meal absorption variability, which is unable to realistically reflect the dynamics of people with type 1 diabetes (T1D). Additionally, T1D simulators are mainly designed for the testing of continuous subcutaneous insulin infusion (CSII) therapies. In this work, a simulator is presented that includes a generated virtual patient (VP) cohort and both fast- and long-acting Glargine-100 U/ml (Gla-100), Glargine-300 U/ml (Gla-300), and Degludec-100 U/ml (Deg-100) insulin models. Therefore, in addition to CSII therapies, multiple daily injections (MDI) therapies can also be tested. The Hovorka model and its published parameter probability distributions were used to generate cohorts of VPs that represent a T1D population. Valid patients are filtered through restrictions that guarantee that they are physiologically acceptable. To obtain more realistic scenarios, basal insulin profile patterns from the literature have been used to identify variability in insulin sensitivity. A library of mixed meals identified from real data has also been included. This work presents and validates a methodology for the creation of realistic VP cohorts that include physiological variability and a simulator that includes challenging and realistic scenarios for in silico testing. A cohort of 47 VPs has been generated and in silico simulations of both CSII and MDI therapies were performed in open-loop. The simulation outcome metrics were contrasted with literature results.

A Machine Learning Approach to Minimize Nocturnal Hypoglycemic Events in Type 1 Diabetic Patients under Multiple Doses of Insulin.

Nocturnal hypoglycemia (NH) is one of the most challenging events for multiple dose insulin therapy (MDI) in people with type 1 diabetes (T1D). The goal of this study is to design a method to reduce the incidence of NH in people with T1D under MDI therapy, providing a decision-support system and improving confidence toward self-management of the disease considering the dataset used by Bertachi et al. Different machine learning (ML) algorithms, data sources, optimization metrics and mitigation measures to predict and avoid NH events have been studied. In addition, we have designed population and personalized models and studied the generalizability of the models and the influence of physical activity (PA) on them. Obtaining 30 g of rescue carbohydrates (CHO) is the optimal value for preventing NH, so it can be asserted that this is the value with which the time under 70 mg/dL decreases the most, with almost a 35% reduction, while increasing the time in the target range by 1.3%. This study supports the feasibility of using ML techniques to address the prediction of NH in patients with T1D under MDI therapy, using continuous glucose monitoring (CGM) and a PA tracker. The results obtained prove that BG predictions can not only be critical in achieving safer diabetes management, but also assist physicians and patients to make better and safer decisions regarding insulin therapy and their day-to-day lives.

A Hybrid Automata Approach for Monitoring the Patient in the Loop in Artificial Pancreas Systems.

The use of automated insulin delivery systems has become a reality for people with type 1 diabetes (T1D), with several hybrid systems already on the market. One of the particularities of this technology is that the patient is in the loop. People with T1D are the plant to control and also a plant operator, because they may have to provide information to the control loop. The most immediate information provided by patients that affects performance and safety are the announcement of meals and exercise. Therefore, to ensure safety and performance, the human factor impact needs to be addressed by designing fault monitoring strategies. In this paper, a monitoring system is developed to diagnose potential patient modes and faults. The monitoring system is based on the residual generation of a bank of observers. To that aim, a linear parameter varying (LPV) polytopic representation of the system is adopted and a bank of Kalman filters is designed using linear matrix inequalities (LMI). The system uncertainty is propagated using a zonotopic-set representation, which allows determining confidence bounds for each of the observer outputs and residuals. For the detection of modes, a hybrid automaton model is generated and diagnosis is performed by interpreting the events and transitions within the automaton. The developed system is tested in simulation, showing the potential benefits of using the proposed approach for artificial pancreas systems.

Fault Tolerant Strategies for Automated Insulin Delivery Considering the Human Component: Current and Future Perspectives.

Automated Insulin Delivery (AID) are systems developed for daily use by people with type 1 diabetes (T1D). To ensure the safety of users, it is essential to consider how the human factor affects the performance and safety of these devices. While there are numerous publications on hardware-related failures of AID systems, there are few studies on the human component of the system. From a control point of view, people with T1D using AID systems are at the same time the plant to be controlled and the plant operator. Therefore, users may induce faults in the controller, sensors, actuators, and the plant itself. Strategies to cope with the human interaction in AID systems are needed for further development of the technology. In this paper, we present an analysis of potential faults introduced by AID users when the system is under normal operation. This is followed by a review of current fault tolerant control (FTC) approaches to identify missing areas of research. The paper concludes with a discussion on future directions for the new generation of FTC AID systems.

Probabilistic Model of Transition between Categories of Glucose Profiles in Patients with Type 1 Diabetes Using a Compositional Data Analysis Approach.

The time spent in glucose ranges is a common metric in type 1 diabetes (T1D). As the time in one day is finite and limited, Compositional Data (CoDa) analysis is appropriate to deal with times spent in different glucose ranges in one day. This work proposes a CoDa approach applied to glucose profiles obtained from six T1D patients using continuous glucose monitor (CGM). Glucose profiles of 24-h and 6-h duration were categorized according to the relative interpretation of time spent in different glucose ranges, with the objective of presenting a probabilistic model of prediction of category of the next 6-h period based on the category of the previous 24-h period. A discriminant model for determining the category of the 24-h periods was obtained, achieving an average above 94% of correct classification. A probabilistic model of transition between the category of the past 24-h of glucose to the category of the future 6-h period was obtained. Results show that the approach based on CoDa is suitable for the categorization of glucose profiles giving rise to a new analysis tool. This tool could be very helpful for patients, to anticipate the occurrence of potential adverse events or undesirable variability and for physicians to assess patients' outcomes and then tailor their therapies.

Overview of therapeutic applications of non-invasive vagus nerve stimulation: a motivation for novel treatments for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disorder that commonly affects the skin, joints, kidneys, and central nervous system. Although great progress has been made over the years, patients still experience unfavorable secondary effects from medications, increased economic burden, and higher mortality rates compared to the general population. To alleviate these current problems, non-invasive, non-pharmacological interventions are being increasingly investigated. One such intervention is non-invasive vagus nerve stimulation, which promotes the upregulation of the cholinergic anti-inflammatory pathway that reduces the activation and production of pro-inflammatory cytokines and reactive oxygen species, culpable processes in autoimmune diseases such as SLE. This review first provides a background on the important contribution of the autonomic nervous system to the pathogenesis of SLE. The gross and structural anatomy of the vagus nerve and its contribution to the inflammatory response are described afterwards to provide a general understanding of the impact of stimulating the vagus nerve. Finally, an overview of current clinical applications of invasive and non-invasive vagus nerve stimulation for a variety of diseases, including those with similar symptoms to the ones in SLE, is presented and discussed. Overall, the review presents neuromodulation as a promising strategy to alleviate SLE symptoms and potentially reverse the disease.

Machine Learning Techniques for Hypoglycemia Prediction: Trends and Challenges.

(1) Background: the use of machine learning techniques for the purpose of anticipating hypoglycemia has increased considerably in the past few years. Hypoglycemia is the drop in blood glucose below critical levels in diabetic patients. This may cause loss of cognitive ability, seizures, and in extreme cases, death. In almost half of all the severe cases, hypoglycemia arrives unannounced and is essentially asymptomatic. The inability of a diabetic patient to anticipate and intervene the occurrence of a hypoglycemic event often results in crisis. Hence, the prediction of hypoglycemia is a vital step in improving the life quality of a diabetic patient. The objective of this paper is to review work performed in the domain of hypoglycemia prediction by using machine learning and also to explore the latest trends and challenges that the researchers face in this area; (2) Methods: literature obtained from PubMed and Google Scholar was reviewed. Manuscripts from the last five years were searched for this purpose. A total of 903 papers were initially selected of which 57 papers were eventually shortlisted for detailed review; (3) Results: a thorough dissection of the shortlisted manuscripts provided an interesting split between the works based on two categories: hypoglycemia prediction and hypoglycemia detection. The entire review was carried out keeping this categorical distinction in perspective while providing a thorough overview of the machine learning approaches used to anticipate hypoglycemia, the type of training data, and the prediction horizon.

Artificial Pancreas With Carbohydrate Suggestion Performance for Unannounced and Announced Exercise in Type 1 Diabetes.

OBJECTIVE: To evaluate the safety and performance of a new multivariable closed-loop (MCL) glucose controller with automatic carbohydrate recommendation during and after unannounced and announced exercise in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: A randomized, 3-arm, crossover clinical trial was conducted. Participants completed a heavy aerobic exercise session including three 15-minute sets on a cycle ergometer with 5 minutes rest in between. In a randomly determined order, we compared MCL control with unannounced (CLNA) and announced (CLA) exercise to open-loop therapy (OL). Adults with T1D, insulin pump users, and those with hemoglobin (Hb)A1c between 6.0% and 8.5% were eligible. We investigated glucose control during and 3 hours after exercise. RESULTS: Ten participants (aged 40.8 ± 7.0 years; HbA1c of 7.3 ± 0.8%) participated. The use of the MCL in both closed-loop arms decreased the time spent <70 mg/dL of sensor glucose (0.0%, [0.0-16.8] and 0.0%, [0.0-19.2] vs 16.2%, [0.0-26.0], (%, [percentile 10-90]) CLNA and CLA vs OL respectively; P = 0.047, P = 0.063) and the number of hypoglycemic events when compared with OL (CLNA 4 and CLA 3 vs OL 8; P = 0.218, P = 0.250). The use of the MCL system increased the proportion of time within 70 to 180 mg/dL (87.8%, [51.1-100] and 91.9%, [58.7-100] vs 81.1%, [65.4-87.0], (%, [percentile 10-90]) CLNA and CLA vs OL respectively; P = 0.227, P = 0.039). This was achieved with the administration of similar doses of insulin and a reduced amount of carbohydrates. CONCLUSIONS: The MCL with automatic carbohydrate recommendation performed well and was safe during and after both unannounced and announced exercise, maintaining glucose mostly within the target range and reducing the risk of hypoglycemia despite a reduced amount of carbohydrate intake.Register Clinicaltrials.gov: NCT03577158.

Dynamic Rule-Based Algorithm to Tune Insulin-on-Board Constraints for a Hybrid Artificial Pancreas System.

The artificial pancreas (AP) is a system intended to control blood glucose levels through automated insulin infusion, reducing the burden of subjects with type 1 diabetes to manage their condition. To increase patients' safety, some systems limit the allowed amount of insulin active in the body, known as insulin-on-board (IOB). The safety auxiliary feedback element (SAFE) layer has been designed previously to avoid overreaction of the controller and thus avoiding hypoglycemia. In this work, a new method, so-called "dynamic rule-based algorithm," is presented in order to adjust the limits of IOB in real time. The algorithm is an extension of a previously designed method which aimed to adjust the limits of IOB for a meal with 60 grams of carbohydrates (CHO). The proposed method is intended to be applied on hybrid AP systems during 24 h operation. It has been designed by combining two different strategies to set IOB limits for different situations: (1) fasting periods and (2) postprandial periods, regardless of the size of the meal. The UVa/Padova simulator is considered to assess the performance of the method, considering challenging scenarios. In silico results showed that the method is able to reduce the time spent in hypoglycemic range, improving patients' safety, which reveals the feasibility of the approach to be included in different control algorithms.

Prediction of Nocturnal Hypoglycemia in Adults with Type 1 Diabetes under Multiple Daily Injections Using Continuous Glucose Monitoring and Physical Activity Monitor.

(1) Background: nocturnal hypoglycemia (NH) is one of the most challenging side effects of multiple doses of insulin (MDI) therapy in type 1 diabetes (T1D). This work aimed to investigate the feasibility of a machine-learning-based prediction model to anticipate NH in T1D patients on MDI. (2) Methods: ten T1D adults were studied during 12 weeks. Information regarding T1D management, continuous glucose monitoring (CGM), and from a physical activity tracker were obtained under free-living conditions at home. Supervised machine-learning algorithms were applied to the data, and prediction models were created to forecast the occurrence of NH. Individualized prediction models were generated using multilayer perceptron (MLP) and a support vector machine (SVM). (3) Results: population outcomes indicated that more than 70% of the NH may be avoided with the proposed methodology. The predictions performed by the SVM achieved the best population outcomes, with a sensitivity and specificity of 78.75% and 82.15%, respectively. (4) Conclusions: our study supports the feasibility of using ML techniques to address the prediction of nocturnal hypoglycemia in the daily life of patients with T1D on MDI, using CGM and a physical activity tracker.

Detection and Control of Unannounced Exercise in the Artificial Pancreas Without Additional Physiological Signals.

The purpose of this study was to develop an algorithm that detects aerobic exercise and triggers disturbance rejection actions to prevent exercise-induced hypoglycemia. This approach can provide a solution to poor glycemic control during and after aerobic exercise, a major hindrance in the participation of exercise by patients with type 1 diabetes. This novel exercise-induced hypoglycemia reduction algorithm (EHRA) detects exercise using a threshold on a disturbance term, a parameter estimated from an augmented minimal model using an unscented Kalman filter. After detection, the EHRA triggers the following three actions: First, a carbohydrate suggestion, second, a reduction in basal insulin and the insulin-on-board maximum limit, and finally, a 30% reduction of the next insulin meal bolus. The EHRA was tested in silico using a 15-day scenario with 8 exercise sessions of 50 min at [Formula: see text] on alternating days. The EHRA was able to obtain improved results when compared to strategies with and without exercise announcement. The unannounced, announced, and EHRA strategies all obtained an overall percentage of time in range (70-180 mg/dl) of 94% and a percentage of time 70 mg/dl of 2%, 0%, and 0%, respectively. The EHRA was tested for robustness during exercise sessions of +25% and -25% intensity and results suggest that the EHRA is able to account for variability in exercise intensity, duration, and patient dynamics such as glucose uptake rate and insulin sensitivity.