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Introduction: Low adherence to chronic treatment regimens is a significant barrier to improving clinical outcomes in patients with chronic diseases. Low adherence is a result of multiple factors., Methods: We review the relevant studies on the prevalence of low adherence and present some potential solutions., Results: This review presents studies on the current measures taken to overcome low adherence, indicating a need for better methods to deal with this problem. The use of first-generation digital systems to improve adherence is mainly based on reminding patients to take their medications, which is one of the reasons they fail to provide a solution for many patients. The establishment of a second-generation artificial intelligence system, which aims to improve the effectiveness of chronic drugs, is described., Conclusion: Improving clinically meaningful outcome measures and disease parameters may increase adherence and improve patients' response to therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Antimicrobial resistance results from the widespread use of antimicrobial agents and is a significant obstacle to the effectiveness of these agents. Numerous methods are used to overcome this problem with moderate success. Besides efforts of antimicrobial stewards, several artificial intelligence (AI)-based technologies are being explored for preventing resistance development. These first-generation systems mainly focus on improving patients' adherence. Chronobiology is inherent in all biological systems. Host response to infections and pathogens activity are assumed to be affected by the circadian clock. This paper describes the problem of antimicrobial resistance and reviews some of the current AI technologies. We present the establishment of a second-generation AI chronobiology-based approach to help in preventing further resistance and possibly overcome existing resistance. An algorithm-controlled regimen that improves the long-term effectiveness of antimicrobial agents is being developed based on the implementation of variability in dosing and drug administration times. The method provides a means for ensuring a sustainable response and improved outcomes. Ongoing clinical trials determine the effectiveness of this second-generation system in chronic infections. Data from these studies are expected to shed light on a new aspect of resistance mechanisms and suggest methods for overcoming them.IMPORTANCE SECTIONThe paper presents the establishment of a second-generation AI chronobiology-based approach to help in preventing further resistance and possibly overcome existing resistance.Key messagesAntimicrobial resistance results from the widespread use of antimicrobial agents and is a significant obstacle to the effectiveness of these agents.We present the establishment of a second-generation AI chronobiology-based approach to help in preventing further resistance and possibly overcome existing resistance.

The constrained disorder principle (CDP) defines systems based on their degree of disorder bounded by dynamic boundaries. The principle explains stochasticity in living and non-living systems. Denis Noble described the importance of stochasticity in biology, emphasizing stochastic processes at molecular, cellular, and higher levels in organisms as having a role beyond simple noise. The CDP and Noble's theories (NT) claim that biological systems use stochasticity. This paper presents the CDP and NT, discussing common notions and differences between the two theories. The paper presents the CDP-based concept of taking the disorder beyond its role in nature to correct malfunctions of systems and improve the efficiency of biological systems. The use of CDP-based algorithms embedded in second-generation artificial intelligence platforms is described. In summary, noise is inherent to complex systems and has a functional role. The CDP provides the option of using noise to improve functionality., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Disorder and noise are inherent in biological systems. They are required to provide systems with the advantages required for proper functioning. Noise is a part of the flexibility and plasticity of biological systems. It provides systems with increased routes, improves information transfer, and assists in response triggers. This paper reviews recent studies on noise at the genome, cellular, and whole organ levels. We focus on the need to use noise in system engineering. We present some of the challenges faced in studying noise. Optimizing the efficiency of complex systems requires a degree of variability in their functions within certain limits. Constrained noise can be considered a method for improving system robustness by regulating noise levels in continuously dynamic settings. The digital pill-based artificial intelligence (AI)-based platform is the first to implement second-generation AI comprising variability-based signatures. This platform enhances the efficacy of the therapeutic regimens. Systems requiring variability and mechanisms regulating noise are mandatory for understanding biological functions., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Patients with rare diseases are a major challenge for healthcare systems. These patients face three major obstacles: late diagnosis and misdiagnosis, lack of proper response to therapies, and absence of valid monitoring tools. We reviewed the relevant literature on first-generation artificial intelligence (AI) algorithms which were designed to improve the management of chronic diseases. The shortage of big data resources and the inability to provide patients with clinical value limit the use of these AI platforms by patients and physicians. In the present study, we reviewed the relevant literature on the obstacles encountered in the management of patients with rare diseases. Examples of currently available AI platforms are presented. The use of second-generation AI-based systems that are patient-tailored is presented. The system provides a means for early diagnosis and a method for improving the response to therapies based on clinically meaningful outcome parameters. The system may offer a patient-tailored monitoring tool that is based on parameters that are relevant to patients and caregivers and provides a clinically meaningful tool for follow-up. The system can provide an inclusive solution for patients with rare diseases and ensures adherence based on clinical responses. It has the potential advantage of not being dependent on large datasets and is a dynamic system that adapts to ongoing changes in patients' disease and response to therapy., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background and Aims: Improving global health requires making current and future drugs more effective and affordable. While healthcare systems around the world are faced with increasing costs, branded and generic drug companies are facing the challenge of creating market differentiators. Two of the problems associated with the partial or complete loss of response to chronic medications are a lack of adherence and compensatory responses to chronic drug administration, which leads to tolerance and loss of effectiveness. Approach and Results: First-generation artificial intelligence (AI) systems do not address these needs and suffer from a low adoption rate by patients and clinicians. Second-generation AI systems are focused on a single subject and on improving patients' clinical outcomes. The digital pill, which combines a personalized second-generation AI system with a branded or generic drug, improves the patient response to drugs by increasing adherence and overcoming the loss of response to chronic medications. By improving the effectiveness of drugs, the digital pill reduces healthcare costs and increases end-user adoption. The digital pill also provides a market differentiator for branded and generic drug companies. Conclusions: Implementing the use of a digital pill is expected to reduce healthcare costs, providing advantages for all the players in the healthcare system including patients, clinicians, healthcare authorities, insurance companies, and drug manufacturers. The described business model for the digital pill is based on distributing the savings across all stakeholders, thereby enabling improved global health.

Introduction: The main obstacle in treating cancer patients is drug resistance. Lenvatinib treatment poses challenges due to loss of response and the common dose-limiting adverse events (AEs). The Constrained-disorder-principle (CDP)- based second-generation artificial intelligence (AI) systems introduce variability into treatment regimens and offer a potential strategy for enhancing treatment efficacy. This proof-of-concept clinical trial aimed to assess the impact of a personalized algorithm-controlled therapeutic regimen on lenvatinib effectiveness and tolerability. Methods: A 14-week open-label, non-randomized trial was conducted with five cancer patients receiving lenvatinib--an AI-assisted application tailored to a personalized therapeutic regimen for each patient, which the treating physician approved. The study assessed changes in tumor response through FDG-PET-CT and tumor markers and quality of life via the EORTC QLQ-THY34 questionnaire, AEs, and laboratory evaluations. The app monitored treatment adherence. Results: At 14 weeks of follow-up, the disease control rate (including the following outcomes: complete response, partial response, stable disease) was 80%. The FDG-PET-CT scan-based RECIST v1.1 and PERCIST criteria showed partial response in 40% of patients and stable disease in an additional 40% of patients. One patient experienced a progressing disease. Of the participants with thyroid cancer, 75% showed a reduction in thyroglobulin levels, and 60% of all the participants showed a decrease in neutrophil-to-lymphocyte ratio during treatment. Improvement in the median social support score among patients utilizing the system supports an ancillary benefit of the intervention. No grade 4 AEs or functional deteriorations were recorded. Summary: The results of this proof-of-concept open-labeled clinical trial suggest that the CDP-based second-generation AI system-generated personalized therapeutic recommendations may improve the response to lenvatinib with manageable AEs. Prospective controlled studies are needed to determine the efficacy of this approach. [ABSTRACT FROM AUTHOR]

Background/Objectives: Gaucher Disease type 1 (GD1) is a recessively inherited lysosomal storage disorder caused by a deficiency in the enzyme β-glucocerebrosidase. Enzyme replacement therapy (ERT) has become the standard of care for patients with GD. However, over 10% of patients experience an incomplete response or partial loss of response to ERT, necessitating the exploration of alternative approaches to enhance treatment outcomes. The present feasibility study aimed to determine the feasibility of using a second-generation artificial intelligence (AI) system that introduces variability into dosing regimens for ERT to improve the response to treatment and potentially overcome the partial loss of response to the enzyme. Methods: This was an open-label, prospective, single-center proof-of-concept study. Five patients with GD1 who received ERT were enrolled. The study used the Altus Care™ cellular-phone-based application, which incorporated an algorithm-based approach to offer random dosing regimens within a pre-defined range set by the physician. The app enabled personalized therapeutic regimens with variations in dosages and administration times. Results: The second-generation AI-based personalized regimen was associated with stable responses to ERT in patients with GD1. The SF-36 quality of life scores improved in one patient, and the sense of change in health improved in two; platelet levels increased in two patients, and hemoglobin remained stable. The system demonstrated a high engagement rate among patients and caregivers, showing compliance with the treatment regimen. Conclusions: This feasibility study highlights the potential of using variability-based regimens to enhance ERT effectiveness in GD and calls for further and longer trials to validate these findings. [ABSTRACT FROM AUTHOR]

There is still controversy surrounding the definition and mechanisms of consciousness. The constrained disorder principle (CDP) defines complex systems by their dynamic borders, limiting their inherent disorder. In line with the CDP, the brain exhibits a disorder bounded by dynamic borders essential for proper function, efficient energy use, and life support under continuous perturbations. The brain's inherent variability contributes to its adaptability and flexibility. Neuronal signal variability challenges the association of brain structures with consciousness and methods for assessing consciousness. The present paper discusses some theories about consciousness, emphasizing their failure to explain the brain's variability. This paper describes how the CDP accounts for consciousness's variability, complexity, entropy, and uncertainty. Using newly developed second-generation artificial intelligence systems, we describe how CDP-based platforms may improve disorders of consciousness (DoC) by accounting for consciousness variability, complexity, entropy, and uncertainty. This platform could be used to improve response to current interventions and develop new therapeutic regimens for patients with DoC in future studies. [ABSTRACT FROM AUTHOR]

The success of artificial intelligence depends on whether it can penetrate the boundaries of evidence-based medicine, the lack of policies, and the resistance of medical professionals to its use. The failure of digital health to meet expectations requires rethinking some of the challenges faced. We discuss some of the most significant challenges faced by patients, physicians, payers, pharmaceutical companies, and health systems in the digital world. The goal of healthcare systems is to improve outcomes. Assisting in diagnosing, collecting data, and simplifying processes is a "nice to have" tool, but it is not essential. Many of these systems have yet to be shown to improve outcomes. Current outcome-based expectations and economic constraints make "nice to have," "assists," and "ease processes" insufficient. Complex biological systems are defined by their inherent disorder, bounded by dynamic boundaries, as described by the constrained disorder principle (CDP). It provides a platform for correcting systems' malfunctions by regulating their degree of variability. A CDP-based second-generation artificial intelligence system provides solutions to some challenges digital health faces. Therapeutic interventions are held to improve outcomes with these systems. In addition to improving clinically meaningful endpoints, CDP-based second-generation algorithms ensure patient and physician engagement and reduce the health system's costs. [ABSTRACT FROM AUTHOR]

Digital twins are computer programs that use real-world data to create simulations that predict the performance of processes, products, and systems. Digital twins may integrate artificial intelligence to improve their outputs. Models for dealing with uncertainties and noise are used to improve the accuracy of digital twins. Most currently used systems aim to reduce noise to improve their outputs. Nevertheless, biological systems are characterized by inherent variability, which is necessary for their proper function. The constrained-disorder principle defines living systems as having a disorder as part of their existence and proper operation while kept within dynamic boundaries. In the present paper, we review the role of noise in complex systems and its use in bioengineering. We describe the use of digital twins for medical applications and current methods for dealing with noise and uncertainties in modeling. The paper presents methods to improve the accuracy and effectiveness of digital twin systems by continuously implementing variability signatures while simultaneously reducing unwanted noise in their inputs and outputs. Accounting for the noisy internal and external environments of complex biological systems is necessary for the future design of improved, more accurate digital twins. [ABSTRACT FROM AUTHOR]

Opioids remain an essential part of the treatment of chronic pain. However, their use and increasing rates of misuse are associated with high morbidity and mortality. The development of tolerance to opioids and analgesics further complicates dosing and the need to reduce side effects. First-generation digital systems were developed to improve analgesics but are not always capable of making clinically relevant associations and do not necessarily lead to better clinical efficacy. A lack of improved clinical outcomes makes these systems less applicable for adoption by clinicians and patients. There is a need to enhance the therapeutic regimens of opioids. In the present paper, we present the use of a digital analgesic that consists of an analgesic administered under the control of a second-generation artificial intelligence system. Second-generation systems focus on improved patient outcomes measured based on clinical response and reduced side effects in a single subject. The algorithm regulates the administration of analgesics in a personalized manner. The digital analgesic provides advantages for both users and providers. The system enables dose optimization, improving effectiveness, and minimizing side effects while increasing adherence to beneficial therapeutic regimens. The algorithm improves the clinicians' experience and assists them in managing chronic pain. The system reduces the financial burden on healthcare providers by lowering opioid-related morbidity and provides a market disruptor for pharma companies. [ABSTRACT FROM AUTHOR]

Diuretics are a mainstay therapy for congestive heart failure (CHF); however, over one-third of patients develop diuretic resistance. Second-generation artificial intelligence (AI) systems introduce variability into treatment regimens to overcome the compensatory mechanisms underlying the loss of effectiveness of diuretics. This open-labeled, proof-of-concept clinical trial sought to investigate the ability to improve diuretic resistance by implementing algorithm-controlled therapeutic regimens. Ten CHF patients with diuretic resistance were enrolled in an open-labeled trial where the Altus Care™ app managed diuretics' dosage and administration times. The app provides a personalized therapeutic regimen creating variability in dosages and administration times within pre-defined ranges. Response to therapy was measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) score, 6-minute walk test (SMW), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and renal function. The second-generation, AI-based, personalized regimen alleviated diuretic resistance. All evaluable patients demonstrated clinical improvement within ten weeks of intervention. A dose reduction (based on a three-week average before and last three weeks of intervention) was achieved in 7/10 patients (70 %, p = 0.042). The KCCQ score improved in 9/10 (90 %, p = 0.002), the SMW improved in 9/9 (100 %, p = 0.006), NT-proBNP was decreased in 7/10 (70 %, p = 0.02), and serum creatinine was decreased in 6/10 (60 %, p = 0.05). The intervention was associated with reduced number of emergency room visits and the number of CHF-associated hospitalizations. The results support that the randomization of diuretic regimens guided by a second-generation personalized AI algorithm improves the response to diuretic therapy. Prospective controlled studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]