An Intraoperative Glucose Control Benchmark for Formal Verification

Diabetes associated complications are affecting an increasingly large population of hospitalized patients. Since glucose physiology is significantly impacted by patient-specific parameters, it is critical to verify that a clinical glucose control protocol is safe across a wide patient population. A safe protocol should not drive the glucose level into dangerous low (hypoglycemia) or high (hyperglycemia) ranges. Verification of glucose controllers is challenging due to the high-dimensional, non-linear glucose physiological models which contain both unobservable states and unmeasurable patient-specific parameters. This paper presents a hybrid system model of a closed-loop physiological system that includes an existing FDA-accepted high-fidelity physiological model tailored to intraoperative settings and a validated improvement to a clinical glucose control protocol for diabetic cardiac surgery patients. We propose the closed-loop model as a physiological system benchmark for verification and present our initial results on verifying the system using the SMT-based hybrid system verification tool dReach

Model-Based Analysis of User Behaviors in Medical Cyber-Physical Systems

Human operators play a critical role in various Cyber-Physical System (CPS) domains, for example, transportation, smart living, robotics, and medicine. The rapid advancement of automation technology is driving a trend towards deep human-automation cooperation in many safety-critical applications, making it important to explicitly consider user behaviors throughout the system development cycle. While past research has generated extensive knowledge and techniques for analyzing human-automation interaction, in many emerging applications, it remains an open challenge to develop quantitative models of user behaviors that can be directly incorporated into the system-level analysis. This dissertation describes methods for modeling different types of user behaviors in medical CPS and integrating the behavioral models into system analysis. We make three main contributions. First, we design a model-based analysis framework to evaluate, improve, and formally verify the robustness of generic (i.e., non-personalized) user behaviors that are typically driven by rule-based clinical protocols. We conceptualize a data-driven technique to predict safety-critical events at run-time in the presence of possible time-varying process disturbances. Second, we develop a methodology to systematically identify behavior variables and functional relationships in healthcare applications. We build personalized behavior models and analyze population-level behavioral patterns. Third, we propose a sequential decision filtering technique by leveraging a generic parameter-invariant test to validate behavior information that may be measured through unreliable channels, which is a practical challenge in many human-in-the-loop applications. A unique strength of this validation technique is that it achieves high inter-subject consistency despite uncertain parametric variances in the physiological processes, without needing any individual-level tuning. We validate the proposed approaches by applying them to several case studies

Barriers and Facilitators Influencing Compliance with Enhanced Recovery After Surgery Protocol: A Qualitative Study

Standardization in many industries has proven to lead to improved productivity and efficiency, however, standard practice in healthcare has proven difficult due to patient and physician variation. Evidence-based practices provide an opportunity to create more standardization. Enhanced Recovery After Surgery (ERAS) programs are attempting to standardize the surgical pathways of patients by implementing standard evidence-based steps, beginning in the surgeons office and continuing through a patients discharge (Ljungqvist, Scott, & Fearon, 2017). Implementing ERAS to standardize the surgical care of patients has shown to improve patient outcomes, reduce length of stay and reduce readmissions, however, there is a lack of studies detailing the implementation process to be successful. A literature review by Stone et al. (2018) found only 53 papers on ERAS that discussed implementation. The review organized barriers and facilitators using the Consolidated Framework for Implementation Research (CFIR). The CFIR is a framework organized with five domains and constructs within each domain that could affect implementation (Damschroder et al., 2009). The purpose of this research is to detail implementation and identify barriers and facilitators that impact compliance with an ERAS protocol for colorectal surgery. This research begins by detailing seven steps taken prior to implementing ERAS. Compliance with 19 of the ERAS components will be tracked to measure improvements over the implementation timeline. The first objective is to measure if compliance with the process measures increased from the pre-implementation to post-implementation. The second objective is to measure if implementation leads to a decrease in length of stay. The third objective is to identify barriers and facilitators with implementation by conducting semi structured focus groups with nursing, surgeons, anesthesia and leadership. The outcome of these findings will be an implementation framework. The results of this study showed a significant increase in compliance with 10 of the process measures as well as a significant decrease in length of stay, as measured by a t-test. The semistructured focus groups analyzed by the CFIR indicated that inner setting and implementation plan were the most discussed. Key facilitators to implementation were gaining leadership support and engagement, establishing a multidisciplinary team that meets regularly, and showing process measure and outcome data as feedback. These items are essential to implementation of an ERAS protocol

Parameter Invariant Monitoring for Signal Temporal Logic

Signal Temporal Logic (STL) is a prominent specification formalism for real-time systems, and monitoring these specifications, specially when (for different reasons such as learning) behavior of systems can change over time, is quite important. There are three main challenges in this area: (1) full observation of system state is not possible due to noise or nuisance parameters, (2) the whole execution is not available during the monitoring, and (3) computational complexity of monitoring continuous time signals is very high. Although, each of these challenges has been addressed by different works, to the best of our knowledge, no one has addressed them all together. In this paper, we show how to extend any parameter invariant test procedure for single points in time to a parameter invariant test procedure for efficiently monitoring continuous time executions of a system against STL properties. We also show, how to extend probabilistic error guarantee of the input test procedure to a probabilistic error guarantee for the constructed test procedure

Abdominal aortic aneurysm treatment outcomes in the Netherlands

In this thesis, the nationwide trends in abdominal aortic aneurysm treatment outcomes and outcomes of subgroups such as octogenarians following abdominal aortic aneurysm repair are investigated using data from the Dutch Surgical Aneurysm Audit (DSAA). Moreover, the nationwide outcomes of complex EVAR are described, including a volume-outcome association, and new opportunities for feedback and outcome measurement are discussed

Abdominal aortic aneurysm treatment outcomes in the Netherlands

In this thesis, the nationwide trends in abdominal aortic aneurysm treatment outcomes and outcomes of subgroups such as octogenarians following abdominal aortic aneurysm repair are investigated using data from the Dutch Surgical Aneurysm Audit (DSAA). Moreover, the nationwide outcomes of complex EVAR are described, including a volume-outcome association, and new opportunities for feedback and outcome measurement are discussed

Biomatériaux dérivés d’une matrice extracellulaire (MEC) pour l’ingénierie tissulaire et les dispositifs médicaux

Abstract: Tissue engineering involves the production of whole organ or a part of it in vitro or in vivo. Decellularized organs as scaffolds for reconstructing organs have been emerging due to the potential of the ExtraCellular Matrix (ECM). ECM is a complex structure primarily composed of proteins and glycosaminoglycans (GAGs). Most common proteins include collagens, laminins, fibronectins and elastins. Several commercial products have been derived from ECM including tissue papers, 3D-printed scaffolds, and wound dressings. Bioadhesives are currently employed alone or as adjuncts to sutures to seal leaks of air or blood from organs following surgical interventions. ECM-incorporated bioadhesives could be hypothesized to not only seal leaks, but also to regenerate tissues. This thesis aims to investigate the composition and properties of ECMs derived from different porcine organs (bladders, kidneys, livers, lungs, and pancreas) using detergent-based and detergent-free methods. The first experimental work includes the design of a cell culture system to study the effect of detergent-based and detergent-free decellularized bladders on insulin-secreting rat pancreatic cell (INS-1) proliferation and functionality. ECMs were characterized initially for conservation of ultrastructure and removal of dsDNA. CyQUANT proliferation assay indicated cell proliferation following 7 days of culture on detergent-free decellularized bladders. Glucose-stimulated insulin secretion (GSIS) and immunostaining confirmed that cells were functional. The second experimental work involved decellularization of the five porcine organs using the detergent-based and detergent-free methods. Two additional steps were added to the detergent-free approach (pH adjustment and ethylenediaminetetraacetic acid (EDTA) treatment) to aid in the removal of residual hemoglobin from the organs. ECMs were characterized by staining for the removal of cellular content and conservation of ultrastructure. Further, mass spectrometry revealed better conservation of a greater number of key proteins such as collagen IV, laminins, fibronectin, and elastin in the ECM resulting from the detergent-free methods, as compared to that produced using the detergent-based one. Collagen fibers orientation measurement indicated preservation of the fibers orientation in the ECMs as compared to that measured in the native organs. The third experimental work initially screened the INS-1 cell response on different organ ECMs. INS-1 cells were functional on certain detergent-free decellularized organs following 7 days of cell culture. Finally, mouse primary pancreatic islets were seeded on the detergent-free decellularized bladders, revealing functional islets following 48 hours of culture.Le génie tissulaire consiste à construire un organe entier ou une partie de celui-ci in vitro ou in vivo. Les organes décellularisés utilisés comme échafaudages pour la reconstruction d'organes sont de plus en plus populaires en raison, entre autres, du potentiel de la matrice extracellulaire (MEC). La MEC consiste en un ensemble complexe composé principalement de protéines et de glycosaminoglycanes (GAG). Les protéines les plus courantes comprennent les collagènes, les laminines, les fibronectines et l’élastine. Plusieurs produits commerciaux sont composés de MEC, notamment des papiers tissulaires, des encres pour l’impression 3D et des pansements pour le traitement de plaies. Les bio-adhésifs sont actuellement utilisés seuls ou en complément des sutures pour sceller les fuites d'air ou de sang à la suite d’interventions chirurgicales. On pourrait supposer, par exemple, qu’un bio-adhésif incorporant la MEC permettrait non seulement de sceller une fuite, mais qu'il contribuerait également à la régénération tissulaire. Cette thèse a pour objectif général d’évaluer la composition et les propriétés de la MEC dérivée de différents organes porcins (vessie, rein, foie, poumon et pancréas) décellularisés à l'aide de méthodes utilisant un détergent et sans détergent. Également, le projet vise à développer une nouvelle famille de biomatériaux à base de MEC pour des applications en médecine. Le premier travail expérimental comprend la conception d'un système de culture cellulaire pour étudier l'effet des vessies décellularisées, avec ou sans détergent, sur la prolifération et la fonctionnalité des cellules pancréatiques (INS-1 cellules) de rat sécrétant de l'insuline en réponse à des gradients de glucose. Les MECs ont été initialement caractérisées pour la conservation de l'ultrastructure et l'élimination de l'ADN double brin. L'analyse utilisant un test de prolifération CyQUANT a indiqué une prolifération cellulaire après 7 jours de culture sur les vessies décellularisées sans détergent. La sécrétion d'insuline stimulée par le glucose (GSIS) et l'immunomarquage ont confirmé que les cellules étaient également fonctionnelles. Le deuxième travail expérimental visait la décellularisation des cinq organes porcins à l'aide d’une méthode utilisant un détergent et de méthodes sans détergent. Deux étapes supplémentaires ont été ajoutées à la technique sans détergent (ajustement du pH et traitement par éthylènediaminetétraacétate (EDTA)) afin de réduire la présence d'hémoglobine résiduelle dans les organes décellularisés. Les MECs ont été caractérisées en histologie par différentes colorations pour investiguer l'élimination du contenu cellulaire et la conservation de l'ultrastructure. De plus, la spectrométrie de masse a révélé la conservation d'un plus grand nombre de protéines clés telles que le collagène IV, les laminines, la fibronectine et l'élastine dans les MECs produites avec des méthodes sans détergent par rapport à celles résultantes de la méthode utilisant un détergent. Les mesures de l’orientation du collagène ont indiqué une conservation de l'orientation dans les MECs par rapport à la structure native. Le troisième travail expérimental a initialement investigué la réponse des cellules INS-1 exposées aux différentes MEC d'organes. Les cellules INS-1 demeuraient fonctionnelles sur certains organes décellularisés sans détergent après 7 jours de culture. Enfin, des îlots pancréatiques primaires de souris ont été ensemencés sur des vessies décellularisées sans détergent, révélant ainsi que les îlots étaient fonctionnels après 48 heures de culture

Foundations for Safety-Critical on-Demand Medical Systems

In current medical practice, therapy is delivered in critical care environments (e.g., the ICU) by clinicians who manually coordinate sets of medical devices: The clinicians will monitor patient vital signs and then reconfigure devices (e.g., infusion pumps) as is needed. Unfortunately, the current state of practice is both burdensome on clinicians and error prone. Recently, clinicians have been speculating whether medical devices supporting ``plug & play interoperability\u27\u27 would make it easier to automate current medical workflows and thereby reduce medical errors, reduce costs, and reduce the burden on overworked clinicians. This type of plug & play interoperability would allow clinicians to attach devices to a local network and then run software applications to create a new medical system ``on-demand\u27\u27 which automates clinical workflows by automatically coordinating those devices via the network. Plug & play devices would let the clinicians build new medical systems compositionally. Unfortunately, safety is not considered a compositional property in general. For example, two independently ``safe\u27\u27 devices may interact in unsafe ways. Indeed, even the definition of ``safe\u27\u27 may differ between two device types. In this dissertation we propose a framework and define some conditions that permit reasoning about the safety of plug & play medical systems. The framework includes a logical formalism that permits formal reasoning about the safety of many device combinations at once, as well as a platform that actively prevents unintended timing interactions between devices or applications via a shared resource such as a network or CPU. We describe the various pieces of the framework, report some experimental results, and show how the pieces work together to enable the safety assessment of plug & play medical systems via a two case-studies

Quantification of knee extensor muscle forces: a multimodality approach

Given the growing interest of using musculoskeletal (MSK) models in a large number of clinical applications for quantifying the internal loading of the human MSK system, verification and validation of the model’s predictions, especially at the knee joint, have remained as one of the biggest challenges in the use of the models as clinical tools. This thesis proposes a methodology for more accurate quantification of knee extensor forces by exploring different experimental and modelling techniques that can be used to enhance the process of verification and validation of the knee joint model within the MSK models for transforming the models to a viable clinical tool. In this methodology, an experimental protocol was developed for simultaneous measurement of the knee joint motion, torques, external forces and muscular activation during an isolated knee extension exercise. This experimental protocol was tested on a cohort of 11 male subjects and the measurements were used to quantify knee extensor forces using two different MSK models representing a simplified model of the knee extensor mechanism and a previously-developed three-dimensional MSK model of the lower limb. The quantified knee extensor forces from the MSK models were then compared to evaluate the performance of the models for quantifying knee extensor forces. The MSK models were also used to investigate the sensitivity of the calculated knee extensor forces to key modelling parameters of the knee including the method of quantifying the knee centre of rotation and the effect of joint translation during motion. In addition, the feasibility of an emerging ultrasound-based imaging technique (shear wave elastography) for direct quantification of the physiologically-relevant musculotendon forces was investigated. The results in this thesis showed that a simplified model of the knee can be reliably used during a controlled planar activity as a computationally-fast and effective tool for hierarchical verification of the knee joint model in optimisation-based large-scale MSK models to provide more confidence in the outputs of the models. Furthermore, the calculation of knee extensor muscle forces has been found to be sensitive to knee joint translation (moving centre of rotation of the knee), highlighting the importance of this modelling parameter for quantifying physiologically-realistic knee muscle forces in the MSK models. It was also demonstrated how the movement of the knee axis of rotation during motion can be used as an intuitive tool for understanding the functional anatomy of the knee joint. Moreover, the findings in this thesis indicated that the shear wave elastography technique can be potentially used as a novel method for direct quantification of the physiologically-relevant musculotendon forces for independent validation of the predictions of musculotendon forces from the MSK models.Open Acces