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Anticoagulants are a cornerstone of treatment in atrial fibrillation. Nowadays, direct oral anticoagulants (DOACs) are extensively used for this condition in developed countries. However, DOAC treatment may be inappropriate in certain patient populations, such as: patients with chronic kidney disease in whom DOAC concentrations may be dangerously elevated; frail elderly patients with an increased risk of falls; patients with significant drug–drug interactions (DDI) affecting either DOAC concentration or effect; patients at the extremes of body mass in whom an "abnormal" volume of distribution may result in inappropriate drug concentrations; patients with recurrent stroke reflecting an unusually high thromboembolic tendency; and, lastly, patients who experience major hemorrhage on an anticoagulant and in whom continued anticoagulation is deemed necessary. Herein we provide a fictional case-based approach to review the recommendations for the use of DOACs in these special patient populations. [ABSTRACT FROM AUTHOR]

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 SECTION The paper presents the establishment of a second-generation AI chronobiology-based approach to help in preventing further resistance and possibly overcome existing resistance. Antimicrobial 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. [ABSTRACT FROM AUTHOR]

Adropin is a peptide that was suggested to have a role in cirrhosis. The present study aimed to determine the ability to use serumadropin levels to improve their prediction accuracy as an adjunct to the current scores. In a single-center, proof-of-concept study, serum adropin levels were determined in thirty-three cirrhotic patients. The data were analyzed in correlation with Child-Pugh and MELD-Na scores, laboratory parameters, and mortality. Adropin levels were higher among cirrhotic patients that died within 180 days (1,325.7 ng/dL vs. 870.3 ng/dL, p = 0.024) and inversely correlated to the time until death (r² = 0.74). The correlation of adropin serum levels with mortality was better than MELD or Child-Pough scores (r² = 0.32 and 0.38, respectively). Higher adropin levels correlated with creatinine (r² = 0.79. p < 0.01). Patients with diabetes mellitus and cardiovascular diseases had elevated adropin levels. Integrating adropin levels with the Child-Pugh and MELD scores improved their correlation with the time of death (correlation coefficient: 0.91 vs. 0.38 and 0.67 vs. 0.32). The data of this feasibility study suggest that combining serum adropin with the Child-Pugh score and MELD-Na score improves the prediction of mortality in cirrhosis and can serve as a measure for assessing kidney dysfunction in these patients [ABSTRACT FROM AUTHOR]

There are no clear guidelines for diuretic administration in heart failure (HF), and reliable markers are needed to tailor treatment. Continuous monitoring of multiple advanced physiological parameters during diuresis may allow better differentiation of patients into subgroups according to their responses. In this study, 29 HF patients were monitored during outpatient intravenous diuresis, using a noninvasive wearable multi-parameter monitor. Analysis of changes in these parameters during the course of diuresis aimed to recognize subgroups with different response patterns. Parameters did not change significantly, however, subgroup analysis of the last quartile of treatment showed significant differences in cardiac output, cardiac index, stroke volume, pulse rate, and systemic vascular resistance according to gender, and in systolic blood pressure according to habitus. Changes in the last quartile could be differentiated using k-means, a technique of unsupervised machine learning. Moreover, patients' responses could be best clustered into four groups. Analysis of baseline parameters showed that two of the clusters differed by baseline parameters, body mass index, and diabetes status. To conclude, we show that physiological changes during diuresis in HF patients can be categorized into subgroups sharing similar response trends, making noninvasive monitoring a potential key to personalized treatment in HF. [ABSTRACT FROM AUTHOR]

Summary: Adropin is a peptide hormone, which plays a role in energy homeostasis and controls glucose and fatty acid metabolism. Its levels correlate with changes in carbohydrate‐lipid metabolism, metabolic diseases, central nervous system function, endothelial function and cardiovascular disease. Both metabolic pathways and adropin are regulated by the circadian clocks. Here, we review the roles of the autonomic nervous system and circadian rhythms in regulating metabolic pathways and energy homeostasis. The beneficial effects of chronotherapy in various systems are discussed. We suggest a potential role for adropin as a mediator of the metabolic system‐autonomic nervous system axis. We discuss the possibility of establishing an individualized adropin and circadian rhythm‐based platform for implementing chronotherapy, and variability signatures for improving the efficacy of adropin‐based therapies are discussed. [ABSTRACT FROM AUTHOR]

Anticoagulants are a cornerstone of treatment in atrial fibrillation. Nowadays, direct oral anticoagulants (DOACs) are extensively used for this condition in developed countries. However, DOAC treatment may be inappropriate in certain patient populations, such as: patients with chronic kidney disease in whom DOAC concentrations may be dangerously elevated; frail elderly patients with an increased risk of falls; patients with significant drug-drug interactions (DDI) affecting either DOAC concentration or effect; patients at the extremes of body mass in whom an "abnormal" volume of distribution may result in inappropriate drug concentrations; patients with recurrent stroke reflecting an unusually high thromboembolic tendency; and, lastly, patients who experience major hemorrhage on an anticoagulant and in whom continued anticoagulation is deemed necessary. Herein we provide a fictional case-based approach to review the recommendations for the use of DOACs in these special patient populations.

Background and Aims: Metabolic dysfunction-associated steatohepatitis is an advanced form of nonalcoholic fatty liver disease and a leading cause of end-stage liver disease and transplantation. Insulin resistance and inflammation underlie the pathogenesis of the disease., Methods: This double-blind, randomized, placebo-controlled, multicenter feasibility clinical trial aimed to determine the safety of oral 8 mg insulin in patients with metabolic dysfunction-associated steatohepatitis and type 2 diabetes mellitus. Patients were treated twice daily for 12 weeks with an 8 mg insulin (n = 21) or placebo (n = 11) capsule. Safety was monitored throughout the study. MRI-proton density fat fraction assessed liver fat content, and Fibroscan® measured liver fibrosis and steatosis levels at screening and after 12 weeks of treatment., Results: No severe drug-related adverse events were reported during the study. After 12 weeks of treatment, mean percent reductions in whole-liver (-11.2% vs -6.5%, respectively) and liver segment 3 (-11.7% vs +0.1%, respectively) fat content was higher in the insulin than in the placebo arm. Patients receiving insulin showed a median -1.2 kPa and -21.0 dB/m reduction from baseline fibrosis and steatosis levels, respectively, while placebo-treated patients showed median increases of 0.3 kPa and 13.0 dB/m, respectively. At Week 12, oral insulin was associated with a mean of 0.27% reduction and placebo with a 0.23% increase from baseline hemoglobin A1c levels. Mean percent changes from baseline alanine aminotransferase, and aspartate aminotransferase levels were -10% and -0.8%, respectively, in the oral insulin and 3.0% and 13.4%, in the placebo arm., Conclusion: The results of this feasibility study support the safety and potential therapeutic effect of orally delivered insulin on liver fibrosis, fat accumulation, and inflammatory processes (NIH Clinical Trials No. NCT04618744)., (© 2024 The Authors.)

Background: Treatment of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) remains a significant challenge in the face of increased worldwide morbidity and mortality. The acute illness caused by SARS-CoV-2 is initiated by a viral phase, followed by an inflammatory phase. Numerous anti-inflammatory and anti-viral therapies, with a relatively minor clinical effect, have been applied. Developing a safe and efficient direct anti-viral treatment is essential as it can block disease progression before significant complications ensue and potentially prevent transmission., Aim: The present phase 1 study aimed to determine the safety of Codivir, a newly developed anti-viral agent, and to preliminarily assess its anti-viral activity in patients infected by COVID-19., Methods: In vitro studies were conducted to determine the direct anti-viral effect of Codivir using an immunofluorescence-based assay and to assess its cytotoxic effect by tetrazolium assay (MTT). In a phase I clinical trial, Codivir was administered for ten days in 12 patients who were followed for its safety. Patients were followed for clinical manifestations during administration. Sequential nasal viral PCR titers (Cycle Threshold, CT) were determined preceding and during treatment., Results: In vitro, Codivir showed activity against SARS-CoV-2 with 90% viral replication suppression and minimal cytotoxicity. The anti-viral activity was demonstrated at the early stages of infection, post-entry of the virus in the cell. Codivir was safe in all 12 patients in phase I clinical trial and significantly suppressed viral replication in 5/7 fully assessed patients, with an anti-viral effect noted as early as three days., Summary: The present study's data support the safety of Codivir administration in humans and suggest its significant anti-COVID-19 effect. These results support the testing of the drug in more extensive controlled trials in patients with SARS-CoV-2., Competing Interests: Conflict of interests: EF and EN are employees of Code Pharma; YI, SM, and DE are consultants for Code Pharma. NL is a medical advisor and a clinical CRO. The remaining authors have nothing to disclose., (Copyright © 2022, Applied Systems.)

Hepatic encephalopathy (HE) is a common, incapacitating complication of cirrhosis that affects many patients with cirrhosis. Although several therapies have proven effective in the treatment and prevention of this condition, several patients continue to suffer from covert disease or episodes of relapse. The circadian rhythm has been demonstrated to be pivotal for many body functions, including those of the liver. Here, we explore the impact of circadian rhythm-dependent signaling on the liver and discuss the evidence of its impact on liver pathology and metabolism. We describe the various pathways through which circadian influences are mediated. Finally, we introduce a novel method for improving patient response to drugs aimed at treating HE by utilizing the circadian rhythm. A digital system that introduces a customization-based technique for improving the response to therapies is presented as a hypothetical approach for improving the effectiveness of current medications used for the treatment of recurrent and persistent hepatic encephalopathy.