Insulin Estimation and Prediction A REVIEW OF THE ESTIMATION AND PREDICTION OF SUBCUTANEOUS INSULIN PHARMACOKINETICS IN CLOSED-LOOP GLUCOSE CONTROL

This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO) through grant DPI2013-46982-C2-1-R and the EU through FEDER funds.Bondía Company, J.; Romero Vivó, S.; Ricarte Benedito, B.; Diez, J. (2018). Insulin Estimation and Prediction A REVIEW OF THE ESTIMATION AND PREDICTION OF SUBCUTANEOUS INSULIN PHARMACOKINETICS IN CLOSED-LOOP GLUCOSE CONTROL. IEEE Control Systems. 38(1):47-66. https://doi.org/10.1109/MCS.2017.2766312S476638

Robust strategies for glucose control in type 1 diabetes

[EN] Type 1 diabetes mellitus is a chronic and incurable disease that affects millions of people all around the world. Its main characteristic is the destruction (totally or partially) of the beta cells of the pancreas. These cells are in charge of producing insulin, main hormone implied in the control of blood glucose. Keeping high levels of blood glucose for a long time has negative health effects, causing different kinds of complications. For that reason patients with type 1 diabetes mellitus need to receive insulin in an exogenous way. Since 1921 when insulin was first isolated to be used in humans and first glucose monitoring techniques were developed, many advances have been done in clinical treatment with insulin. Currently 2 main research lines focused on improving the quality of life of diabetic patients are opened. The first one is concentrated on the research of stem cells to replace damaged beta cells and the second one has a more technological orientation. This second line focuses on the development of new insulin analogs to allow emulating with higher fidelity the endogenous pancreas secretion, the development of new noninvasive continuous glucose monitoring systems and insulin pumps capable of administering different insulin profiles and the use of decision-support tools and telemedicine. The most important challenge the scientific community has to overcome is the development of an artificial pancreas, that is, to develop algorithms that allow an automatic control of blood glucose. The main difficulty avoiding a tight glucose control is the high variability found in glucose metabolism. This fact is especially important during meal compensation. This variability, together with the delay in subcutaneous insulin absorption and action causes controller overcorrection that leads to late hypoglycemia (the most important acute complication of insulin treatment). The proposals of this work pay special attention to overcome these difficulties. In that way interval models are used to represent the patient physiology and to be able to take into account parametric uncertainty. This type of strategy has been used in both the open loop proposal for insulin dosage and the closed loop algorithm. Moreover the idea behind the design of this last proposal is to avoid controller overcorrection to minimize hypoglycemia while adding robustness against glucose sensor failures and over/under- estimation of meal carbohydrates. The algorithms proposed have been validated both in simulation and in clinical trials.[ES] La diabetes mellitus tipo 1 es una enfermedad crónica e incurable que afecta a millones de personas en todo el mundo. Se caracteriza por una destrucción total o parcial de las células beta del páncreas. Estas células son las encargadas de producir la insulina, hormona principal en el control de glucosa en sangre. Valores altos de glucosa en la sangre mantenidos en el tiempo afectan negativamente a la salud, provocando complicaciones de diversa índole. Es por eso que los pacientes con diabetes mellitus tipo 1 necesitan recibir insulina de forma exógena. Desde que se consiguiera en 1921 aislar la insulina para poder utilizarla en clínica humana, y se empezaran a desarrollar las primeras técnicas de monitorización de glucemia, se han producido grandes avances en el tratamiento con insulina. Actualmente, las líneas de investigación que se están siguiendo en relación a la mejora de la calidad de vida de los pacientes diabéticos, tienen fundamentalmente 2 vertientes: una primera que se centra en la investigación en células madre para la reposición de las células beta y una segunda vertiente de carácter más tecnológico. Dentro de esta segunda vertiente, están abiertas varias líneas de investigación, entre las que se encuentran el desarrollo de nuevos análogos de insulina que permitan emular más fielmente la secreción endógena del páncreas, el desarrollo de monitores continuos de glucosa no invasivos, bombas de insulina capaces de administrar distintos perfiles de insulina y la inclusión de sistemas de ayuda a la decisión y telemedicina. El mayor reto al que se enfrentan los investigadores es el de conseguir desarrollar un páncreas artificial, es decir, desarrollar algoritmos que permitan disponer de un control automático de la glucosa. La principal barrera que se encuentra para conseguir un control riguroso de la glucosa es la alta variabilidad que presenta su metabolismo. Esto es especialmente significativo durante la compensación de las comidas. Esta variabilidad junto con el retraso en la absorción y actuación de la insulina administrada de forma subcutánea favorece la aparición de hipoglucemias tardías (complicación aguda más importante del tratamiento con insulina) a consecuencia de la sobreactuación del controlador. Las propuestas presentadas en este trabajo hacen especial hincapié en sobrellevar estas dificultades. Así, se utilizan modelos intervalares para representar la fisiología del paciente, y poder tener en cuenta la incertidumbre en sus parámetros. Este tipo de estrategia se ha utilizado tanto en la propuesta de dosificación automática en lazo abierto como en el algoritmo en lazo cerrado. Además la principal idea de diseño de esta última propuesta es evitar la sobreactuación del controlador evitando hipoglucemias y añadiendo robustez ante fallos en el sensor de glucosa y en la estimación de las comidas. Los algoritmos propuestos han sido validados en simulación y en clínica.[CA] La diabetis mellitus tipus 1 és una malaltia crònica i incurable que afecta milions de persones en tot el món. Es caracteritza per una destrucció total o parcial de les cèl.lules beta del pàncrees. Aquestes cèl.lules són les encarregades de produir la insulina, hormona principal en el control de glucosa en sang. Valors alts de glucosa en la sang mantinguts en el temps afecten negativament la salut, provocant complicacions de diversa índole. És per això que els pacients amb diabetis mellitus tipus 1 necessiten rebre insulina de forma exògena. Des que s'aconseguís en 1921 aïllar la insulina per a poder utilitzar-la en clínica humana, i es començaren a desenrotllar les primeres tècniques de monitorització de glucèmia, s'han produït grans avanços en el tractament amb insulina. Actualment, les línies d'investigació que s'estan seguint en relació a la millora de la qualitat de vida dels pacients diabètics, tenen fonamentalment 2 vessants: un primer que es centra en la investigació de cèl.lules mare per a la reposició de les cèl.lules beta i un segon vessant de caràcter més tecnològic. Dins d' aquest segon vessant, estan obertes diverses línies d'investigació, entre les que es troben el desenrotllament de nous anàlegs d'insulina que permeten emular més fidelment la secreció del pàncrees, el desenrotllament de monitors continus de glucosa no invasius, bombes d'insulina capaces d'administrar distints perfils d'insulina i la inclusió de sistemes d'ajuda a la decisió i telemedicina. El major repte al què s'enfronten els investigadors és el d'aconseguir desenrotllar un pàncrees artificial, és a dir, desenrotllar algoritmes que permeten disposar d'un control automàtic de la glucosa. La principal barrera que es troba per a aconseguir un control rigorós de la glucosa és l'alta variabilitat que presenta el seu metabolisme. Açò és especialment significatiu durant la compensació dels menjars. Aquesta variabilitat junt amb el retard en l'absorció i actuació de la insulina administrada de forma subcutània afavorix l'aparició d'hipoglucèmies tardanes (complicació aguda més important del tractament amb insulina) a conseqüència de la sobreactuació del controlador. Les propostes presentades en aquest treball fan especial insistència en suportar aquestes dificultats. Així, s'utilitzen models intervalares per a representar la fisiologia del pacient, i poder tindre en compte la incertesa en els seus paràmetres. Aquest tipus d'estratègia s'ha utilitzat tant en la proposta de dosificació automàtica en llaç obert com en l' algoritme en llaç tancat. A més, la principal idea de disseny d'aquesta última proposta és evitar la sobreactuació del controlador evitant hipoglucèmies i afegint robustesa.Revert Tomás, A. (2015). Robust strategies for glucose control in type 1 diabetes [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/56001TESI

Effect of Model, Observer and Their Interaction on State and Disturbance Estimation in Artificial Pancreas: An In-Silico Study

The state and disturbance estimations are an indispensable part of the state-of-the-art model-based controllers as related to the artificial pancreas, supporting the decision-making and self-tuning of the algorithms. They are not just important when state-feedback kind of controller structure is applied, but also play a crucial role in the estimation of, for example, the amount of the acting drug (insulin) in blood or meal intake estimation which has determining role in the short and long term effectivity of the given therapy. This information is also important for physicians to support them in knowledge-based decision-making to be sure a given therapy or device works well. This article compares three observers – a linear-parameter-varying (LPV) dual Kalman filter (KF), a LPV joint KF, and a nonlinear sliding mode observer (NSMO) – designed with two individualized models – Hovorka and Identifiable Virtual Patient model (IVP). The article also statistically quantifies the effect of the observer algorithm and model structure on the accuracy of the estimation of plasma insulin, rate of glucose appearance, and glucose. Data for the analysis was generated by the UVa-Padova simulator. Results indicated that, for the rate of glucose appearance and the plasma insulin, the type of model and the observer structure explain less than 10% of the variability in the error, while the inter-patient variability contributes to the error more than 50%. This reveals a limiting factor in the estimation accuracy that might be improved by model parameter adaptation

Triboelectric Effect Enabled Self-Powered, Point-of-Care Diagnostics: Opportunities for developing ASSURED and REASSURED devices

The use of rapid point-of-care (PoC) diagnostics in conjunction with physiological signal monitoring has seen tremendous progress in their availability and uptake, particularly in low- and middle-income countries (LMICs). However, to truly overcome infrastructural and resource constraints, there is an urgent need for self-powered devices which can enable on-demand and/or continuous monitoring of patients. The past decade has seen the rapid rise of triboelectric nanogenerators (TENGs) as the choice for high-efficiency energy harvesting for developing self-powered systems as well as for use as sensors. This review provides an overview of the current state of the art of such wearable sensors and end-to-end solutions for physiological and biomarker monitoring. We further discuss the current constraints and bottlenecks of these devices and systems and provide an outlook on the development of TENG-enabled PoC/monitoring devices that could eventually meet criteria formulated specifically for use in LMICs.Ulster Universityhttp://www.mdpi.com/journal/micromachineshj2021Electrical, Electronic and Computer Engineerin

Microfluidic Technology and Application in Urinal Analysis

Microfluidic technology offers numerous advantages in minimizing and integrating the traditional assays. However, the lack of efficient control components of the microfluidic systems has been hindering the widely commercialization of the technology. The research work in this dissertation focused on the development of effective control components for microfluidic applications. A linear peristaltic pump was firstly designed, fabricated, and tested for conventional microfluidics by synchronously compressing the microfluidic channel with a miniature cam-follower system in Chapter 2. The miniature cam-follower system and microfluidic chip was prototyped using three-dimensional (3D) printing technology and soft lithography technology. Results from experimental test showed that the pump is self-priming and tolerant of bubbles. The pumping flowrate and back pressure could be controlled by changing the driving speed of the motor. Then a novel pinch-type valving system that can be used to realize both normally closed and normally open valves for centrifugal microfluidics was demonstrated in Chapter 3. A sliding wedge was actuated by centrifugal force to drive the valves. Experimental test and theoretical predication showed that the burst frequency of the valves could be tuned by changing the physical parameters of the valving system. In Chapter 4, the pinch type valving system was then further improved for better integration of multiple valves in limited space to realize sequential control of microfluidics. A valve chip with grooves on the surface was used to drive multiple valves. A flow switch which is capable of working at low rotation frequency and constant rotation direction is realized. Finally, the microfluidic platform was utilized for automatic urinalysis for the application at point of care (POC) to eliminate the difficulties in control of sample distribution and read-out time in manually conducted colorimetric urinalysis. 3D printed prototype of the microfluidic chip was used to test the proposed system. Commercial urinalysis strips was integrated with the microfluidic system for detecting glucose, specific gravity, PH, and protein from simulated urine sample. The color change of the pads was recorded using smartphone camera and analyzed to quantify the interested parameters

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 405)

This bibliography lists 225 reports, articles and other documents introduced into the NASA Scientific and Technical Information System during Sep. 1995. Subject coverage includes: aerospace medicine and physiology, life support systems and man/system technology, protective clothing, exobiology and extraterrestrial life, planetary biology, and flight crew behavior and performance

Hyperglycaemia, insulin and acute ischaemic stroke

Background: Hyperglycaemia is common in acute stroke and is associated with a poor outcome. Underlying aetiology and mechanism of action is poorly understood. Management remains uncertain. Methods: We undertook a randomised placebo controlled trial to assess the effect of GKI (Glucose-Potassium-Insulin) versus placebo on lesion volume progression and cerebral lactate levels using magnetic resonance imaging (MRI) and spectroscopy (MRS). An observational study of the capillary blood glucose within 48 hours of stroke onset was performed to define the temporal profile of glucose, with a subset followed prospectively to determine the prevalence of abnormal glucose metabolism in patients with stress hyperglycaemia. The association between insular cortex involvement and hyperglycaemia was determined by analysing MRI data sets from two randomised trials. Stroke unit practice for the management of glucose was assessed in a review of the stroke unit trialists’ collaboration data set. Results: • GKI infusion failed to attenuate infarct growth in patients with moderate hyperglycaemia within 24 hours of acute ischaemic stroke. A trend towards attenuation of increased lactate concentration was evident in the GKI treatment arm. Exploratory analyses raised the possibility that GKI may be harmful in patients with persistent arterial occlusion. • Over the 48hour monitoring period 75% of patients developed Hyperglycaemia. Stroke severity was not predictive of admission hyperglycaemia whereas glycosylated haemoglobin was (OR 2.97; 95%CI 1.84-4.78; p<0.001). 50% of patients screened were found to have abnormal glucose metabolism at follow-up. • Insular cortex involvment on MRI was not predictive of admission hyperglycaemia. • Testing for blood glucose concentration in stroke units was infrequent. Of the minority of units that had a protocol in place, the threshold for intervention with insulin was >10mmol/l. Conclusion: We found no evidence that GKI infusion attenuated infarct growth in patients with mild hyperglycaemia following acute ischaemic stroke. In post-hoc analysis the possibility that GKI infusion may be harmful in patients with total occlusion suggests an effect dependent on recanalisation status. A non-significant trend towards attenuation of increased lactate concentration was evident. Stroke severity was not found to be a predictor of post stroke hyperglycaemia. Underlying dysglycaemia was common in non-diabetic patients manifesting hyperglycaemia within 48hours of stroke ictus. Screening of high risk patients with oral glucose tolerance testing is justified and provides a potential opportunity for secondary prevention. Insular cortex involvement did not independently predict hyperglycaemia in acute stroke. Current management of hyperglycaemia is guided by consensus guidelines with little evidence base. Stroke unit practice varies with little change across stroke units over the years