Approximate dynamic programming for anemia management.

The focus of this dissertation work is the formulation and improvement of anemia management process involving trial-and-error. A two-stage method is adopted toward this objective. Given a medical treatment process, a discrete Markov representation is first derived as a formal translation of the treatment process to a control problem under uncertainty. A simulative numerical solution of the control problem is then obtained on-the-fly in the form of a control law maximizing the long-term benefit at each decision stage. Approximate dynamic programming methods are employed in the proposed solution. The motivation underlying this choice is that, in reality, some patient characteristics, which are critical for the sake of treatment, cannot be determined through diagnosis and remain unknown until early stages of treatment, when the patient demonstrates them upon actions by the decision maker. A review of these simulative control tools, which are studied extensively in reinforcement learning theory, is presented. Two approximate dynamic programming tools, namely SARSA and Q -learning, are introduced. Their performance in discovering the optimal individualized drug dosing policy is illustrated on hypothetical patients made up as fuzzy models for simulations. As an addition to these generic reinforcement learning methods, a state abstraction scheme for the considered application domain is also proposed. The control methods of this study, capturing the essentials of a drug delivery problem, constitutes a novel computational framework for model-free medical treatment. Experimental evaluation of the dosing strategies produced by the proposed methods against the standard policy, which is being followed actually by human experts in Kidney Diseases Program, University of Louisville, shows the advantages for use of reinforcement learning in the drug dosing problem in particular and in medical decision making in general

Integrated Product and Process Design for Mass Customization: A Road Towards Patient Access to Individualized Pharmaceutical Therapy

Individualized pharmaceutical therapy strives to attain optimal health outcomes a priori in all patients treated with pharmaceutical products by tailoring these products to each patient’s holistic needs. However, existing mass-produced pharmaceutical products are not available in sufficient variety to enable adequate tailoring to the diverse needs of individuals. Consequently, this thesis has, firstly, recognized a potential alternative production approach designed for the provision of affordable variety, namely, mass customization. Thereafter, key product and process design requirements for establishing mass customization opportunities in the pharmaceutical value chain were identified and demonstrated. The foundation and key contribution of this thesis is a proposed patient-centric framework of design requirements for individualization of each oral dosage form feature. Additionally, an overarching product requirement for multifunctional individualization was determined, i.e., the simultaneous, independent individualization of multiple product features, which had not been addressed prior to this thesis. With a primary focus on product modularization, this thesis demonstrates that multifunctional individualization and the enhanced product variety crucial for affordable individualization may be achieved through reconfigurable modularization. Hot melt extrusion and fused deposition modelling were collectively deemed high-potential technologies for the fabrication of individualized products. However, this thesis reveals key material and manufacturing trade-offs between material diversity, dispensing precision, and geometric design flexibility, arising due to strict product and process requirements, which remain unsolved. Throughout, a systems approach is demonstrated to tackle existing interdependencies and, in future, navigate change on the road towards realization of accessible individualized therapy

Reinforcement learning in large, structured action spaces: A simulation study of decision support for spinal cord injury rehabilitation

Reinforcement learning (RL) has helped improve decision-making in several applications. However, applying traditional RL is challenging in some applications, such as rehabilitation of people with a spinal cord injury (SCI). Among other factors, using RL in this domain is difficult because there are many possible treatments (i.e., large action space) and few patients (i.e., limited training data). Treatments for SCIs have natural groupings, so we propose two approaches to grouping treatments so that an RL agent can learn effectively from limited data. One relies on domain knowledge of SCI rehabilitation and the other learns similarities among treatments using an embedding technique. We then use Fitted Q Iteration to train an agent that learns optimal treatments. Through a simulation study designed to reflect the properties of SCI rehabilitation, we find that both methods can help improve the treatment decisions of physiotherapists, but the approach based on domain knowledge offers better performance

Fluorescence Lifetime Nanoscopy of Liposomal Irinotecan Onivyde: From Manufacturing to Intracellular Processing

: Onivyde was approved by the Food and Drug Administration (FDA) in 2015 for the treatment of solid tumors, including metastatic pancreatic cancer. It is designed to encapsulate irinotecan at high concentration, increase its blood-circulation lifetime, and deliver it to cells where it is enzymatically converted into SN-38, a metabolite with 100- to 1000-fold higher anticancer activity. Despite a rewarding clinical path, little is known about the physical state of encapsulated irinotecan within Onivyde and how this synthetic identity changes throughout the process from manufacturing to intracellular processing. Herein, we exploit irinotecan intrinsic fluorescence and fluorescence lifetime imaging microscopy (FLIM) to selectively probe the supramolecular organization of the drug. FLIM analysis on the manufacturer's formulation reveals the presence of two coexisting physical states within Onivyde liposomes: (i) gelated/precipitated irinotecan and (ii) liposome-membrane-associated irinotecan, the presence of which is not inferable from the manufacturer's indications. FLIM in combination with high-performance liquid chromatography (HPLC) and a membrane-impermeable dynamic quencher of irinotecan reveals rapid (within minutes) and complete chemical dissolution of the gelated/precipitated phase upon Onivyde dilution in standard cell-culturing medium with extensive leakage of the prodrug from liposomes. Indeed, confocal imaging and cell-proliferation assays show that encapsulated and nonencapsulated irinotecan formulations are similar in terms of cell-uptake mechanism and cell-division inhibition. Finally, 2-channel FLIM analysis discriminates the signature of irinotecan from that of its red-shifted SN-38 metabolite, demonstrating the appearance of the latter as a result of Onivyde intracellular processing. The findings presented in this study offer fresh insights into the synthetic identity of Onivyde and its transformation from production to in vitro administration. Moreover, these results serve as another validation of the effectiveness of FLIM analysis in elucidating the supramolecular organization of encapsulated fluorescent drugs. This research underscores the importance of leveraging advanced imaging techniques to deepen our understanding of drug formulations and optimize their performance in delivery applications

How can we improve guideline use? A conceptual framework of implementability

BACKGROUND: Guidelines continue to be underutilized, and a variety of strategies to improve their use have been suboptimal. Modifying guideline features represents an alternative, but untested way to promote their use. The purpose of this study was to identify and define features that facilitate guideline use, and examine whether and how they are included in current guidelines. METHODS: A guideline implementability framework was developed by reviewing the implementation science literature. We then examined whether guidelines included these, or additional implementability elements. Data were extracted from publicly available high quality guidelines reflecting primary and institutional care, reviewed independently by two individuals, who through discussion resolved conflicts, then by the research team. RESULTS: The final implementability framework included 22 elements organized in the domains of adaptability, usability, validity, applicability, communicability, accommodation, implementation, and evaluation. Data were extracted from 20 guidelines on the management of diabetes, hypertension, leg ulcer, and heart failure. Most contained a large volume of graded, narrative evidence, and tables featuring complementary clinical information. Few contained additional features that could improve guideline use. These included alternate versions for different users and purposes, summaries of evidence and recommendations, information to facilitate interaction with and involvement of patients, details of resource implications, and instructions on how to locally promote and monitor guideline use. There were no consistent trends by guideline topic. CONCLUSIONS: Numerous opportunities were identified by which guidelines could be modified to support various types of decision making by different users. New governance structures may be required to accommodate development of guidelines with these features. Further research is needed to validate the proposed framework of guideline implementability, develop methods for preparing this information, and evaluate how inclusion of this information influences guideline use

Emerging Technology IS Course Design: Blockchain for Business Example

IS curricula require constant updating to accommodate the emergence of new technologies. Designing and delivering effective emerging technology courses within the constraints of existing programs remains an important challenge faculty face. This paper presents a template for approaching these courses from a learning theory perspective. Results of tests of this template, developed for teaching blockchain, indicate that it successfully strikes the balance needed in an IS program while simplifying the work of designing the structure of an emerging technology course. Additionally, this design was able to deliver this success in an online format, which can be a more challenging format for observing application of knowledge. Blockchain is a disruptive emerging technology opportunity for businesses to unlock value through trusted and “smart” peer-to-peer transactions, wherein smart means businesspeople can custom design processes for verification and transfer of assets. The blockchain example provided here includes a flexible 7-scenario design targeted to enable a constructive, project-based learning approach focused on authentic learning experiences. The template as applied to blockchain may be used directly or adapted for easier development of other emerging technology courses

Clinical Applications of Pharmacogenetics

The rapidly evolving field of Pharmacogenetics aims at identifying the genetic factors implicated in the inter-individual variation of drug response. These factors could enable patient sub-classification based on their treatment needs thus expediting drug development and promoting personalized, safer and more effective treatments. This book presents Pharmacogenetic examples from a broad spectrum of different drugs, for different diseases, which are representative of different stages of evaluation or application. It has been designed so as to serve both the unfamiliar reader through explanations of basic Pharmacogenetic concepts, the clinician with presentation of the latest developments and international guidelines, and the research scientist with examples of Pharmacogenetic applications, discussions on the limitations and an outlook on the new scientific trends in this field

The Rhetoric of the iPhone: A Cultural Gateway Of Our Transforming Digital Paradigm

The metaphors “tipping point” and “paradigm shift” are used to describe the moments surrounding social and scientific changes; however, I argue that in examining changes in culture and communication, the role of technology suggests the need for a new metaphor. Weaving together cultural studies, digital rhetoric and technology theories, I offer a complimentary metaphor, the cultural gateway, defined as specific artifacts that are simultaneously familiar and strange, providing a comfortable bridge between “before and after.” This thesis posits that the iPhone behaves as such a gateway to our current, fully mobile paradigm, and has changed the face of everyday composition. Employing the circuit of culture, I examine evidence found in early media accounts of iPhone’s impact, literacy narratives that name smartphones and iPhones as literacy agents, and early advertising. Investigations suggest that these quotidian artifacts have additional, unintended purposes that are quite human and intrinsic to our ordered realities

Homecare user needs from the perspective of the patient and carers: a review

There is a global shift towards a blending of care delivery within formal and informal environments in direct response to economic and demographic pressures. Homecare is at the hub of this activity, enabling people to age in place and keeping families intact. However, our understanding of patient and carer needs is fragmented; understandably so, given the complexity of these needs. This descriptive review offers a content analysis of papers focused on patients' and carers' needs and homecare published between January 2010 and October 2013. It is evident that homecare is an intensely researched area, yet it is disjointed. Emerging research emphasizes the need to take a holistic approach. Firstly, incorporating emotional psychosocial and cultural elements will help to draw together our current understanding within a more cohesive framework. Secondly, tensions that hinder communication and collaboration between stakeholders must be resolved. Thirdly, information and communications technology is rapidly becoming synonymous with homecare, and offers solutions for facilitating care delivery, collaboration, and training of future professionals. The rate of international activity promises much for future research collaborations to compare, contrast, and identify best practices for the future of homecare as we endeavor to meet the ever-increasing pressures on health and social care systems