AI-based cluster analysis enables outcomes prediction among patients with increased LVM.

Background: The traditional classification of left ventricular hypertrophy (LVH), which relies on left ventricular geometry, fails to correlate with outcomes among patients with increased LV mass (LVM). Objectives: To identify unique clinical phenotypes of increased LVM patients using unsupervised cluster analysis, and to explore their association with clinical outcomes. Methods: Among the UK Biobank participants, increased LVM was defined as LVM index ≥72 g/m2 for men, and LVM index ≥55 g/m2 for women. Baseline demographic, clinical, and laboratory data were collected from the database. Using Ward's minimum variance method, patients were clustered based on 27 variables. The primary outcome was a composite of all-cause mortality with heart failure (HF) admissions, ventricular arrhythmia, and atrial fibrillation (AF). Cox proportional hazard model and Kaplan-Meier survival analysis were applied. Results: Increased LVM was found in 4,255 individuals, with an average age of 64 ± 7 years. Of these patients, 2,447 (58%) were women. Through cluster analysis, four distinct subgroups were identified. Over a median follow-up period of 5 years (IQR: 4-6), 100 patients (2%) died, 118 (2.8%) were admissioned due to HF, 29 (0.7%) were admissioned due to VA, and 208 (5%) were admissioned due to AF. Univariate Cox analysis demonstrated significantly elevated risks of major events for patients in the 2nd (HR = 1.6; 95% CI 1.2-2.16; p < .001), 3rd (HR = 2.04; 95% CI 1.49-2.78; p < .001), and 4th (HR = 2.64; 95% CI 1.92-3.62; p < .001) clusters compared to the 1st cluster. Further exploration of each cluster revealed unique clinical phenotypes: Cluster 2 comprised mostly overweight women with a high prevalence of chronic lung disease; Cluster 3 consisted mostly of men with a heightened burden of comorbidities; and Cluster 4, mostly men, exhibited the most abnormal cardiac measures. Conclusions: Unsupervised cluster analysis identified four outcomes-correlated clusters among patients with increased LVM. This phenotypic classification holds promise in offering valuable insights regarding clinical course and outcomes of patients with increased LVM.

Oral Insulin Alleviates Liver Fibrosis and Reduces Liver Steatosis in Patients With Metabolic Dysfunction-associated Steatohepatitis and Type 2 Diabetes: Results of Phase II Randomized, Placebo-controlled Feasibility Clinical Trial.

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).

Apoptotic Cell-Based Therapy for the Modification of the Inflammatory Response to Hemorrhagic Shock.

INTRODUCTION: Many trauma patients die from hemorrhagic shock in the military and civilian settings. Although two-thirds of hemorrhagic shock victims die of reasons other than exsanguination, such as the consequent cytokine storm, anti-inflammatory therapies failed to be utilized. Apoptotic cell-based treatments enhance innate ability to exert systemic immunomodulation as demonstrated in several clinical applications and hence might present a novel approach in hemorrhagic shock treatment. MATERIALS AND METHODS: Twenty-two rats underwent a pressure-controlled hemorrhagic shock model and followed up for 24 hours. An infusion of apoptotic cells (Allocetra-OTS, Enlivex Therapeutics Ltd, Nes Ziona, Israel) was administered to the treatment group. Hemodynamics, blood counts, biochemistry findings, and cytokine profile were compared to a saline-resuscitated control group. RESULTS: The treatment group's mean arterial pressure decreased from 94.8 mmHg to 28.2 mmHg, resulting in an 8.13 mg/dL increase in lactate and a 1.9 g/L decrease in hemoglobin, similar to the control group. White blood cells and platelets decreased more profoundly in the treatment group. A similar cytokine profile after 24 hours was markedly attenuated in the treatment group 2 hours after bleeding. Levels of pro-inflammatory cytokines such as interleukin (IL)-1a (28.4 pg/mL vs. 179.1 pg/mL), IL-1b (47.4 pg/mL vs. 103.9 pg/mL), IL-6 (526.2 pg/mL vs. 3492 pg/mL), interferon γ (11.4 pg/mL vs. 427.9 pg/mL), and tumor necrosis factor α (19.0 pg/mL vs. 31.7 pg/mL) were profoundly lower in the treatment group. CONCLUSION: In a pressure-control hemorrhagic shock model in rats, apoptotic cell infusion showed preliminary signs of a uniform attenuated cytokine response. Apoptotic cell-based therapies might serve as a novel immunomodulatory therapy for hemorrhagic shock.

Continuous Monitoring of Advanced Hemodynamic Parameters during Hemodialysis Demonstrated Early Variations in Patients Experiencing Intradialytic Hypotension.

Intradialytic hypotension (IDH) is a severe complication of hemodialysis (HD) with a significant impact on morbidity and mortality. In this study, we used a wearable device for the continuous monitoring of hemodynamic vitals to detect hemodynamic changes during HD and attempted to identify IDH. End-stage kidney disease patients were continuously monitored 15 min before starting the session and until 15 min after completion of the session, measuring heart rate (HR), noninvasive cuffless systolic and diastolic blood pressure (SBP and DBP), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR). Data were analyzed retrospectively and included comparing BP measured by the wearable devices (recorded continuously every 5 s) and the cuff-based devices. A total of 98 dialysis sessions were included in the final analysis, and IDH was identified in 22 sessions (22.5%). Both SBP and DBP were highly correlated (r > 0.62, p < 0.001 for all) between the wearable device and the cuff-based measurements. Based on the continuous monitoring, patients with IDH had earlier and more profound reductions in SBP and DBP during the HD treatment. In addition, nearly all of the advanced vitals differed between groups. Further studies should be conducted in order to fully understand the potential of noninvasive advanced continuous monitoring in the prediction and prevention of IDH events.

Tumor Treating Fields (TTFields) demonstrate antiviral functions in vitro, and safety for application to COVID-19 patients in a pilot clinical study.

Coronaviruses are the causative agents of several recent outbreaks, including the COVID-19 pandemic. One therapeutic approach is blocking viral binding to the host receptor. As binding largely depends on electrostatic interactions, we hypothesized possible inhibition of viral infection through application of electric fields, and tested the effectiveness of Tumor Treating Fields (TTFields), a clinically approved cancer treatment based on delivery of electric fields. In preclinical models, TTFields were found to inhibit coronavirus infection and replication, leading to lower viral secretion and higher cell survival, and to formation of progeny virions with lower infectivity, overall demonstrating antiviral activity. In a pilot clinical study (NCT04953234), TTFields therapy was safe for patients with severe COVID-19, also demonstrating preliminary effectiveness data, that correlated with higher device usage.

Diurnal cardio-respiratory changes in ambulatory individuals deciphered using a multi-parameter wearable device.

Background: Recent technological developments enable big data-driven insights on diurnal changes. This study aimed to describe the trajectory of multiple and advanced parameters using a medical-grade wearable remote patient monitor. Methods: Parameters were monitored for 24 h in 256 ambulatory participants who kept living their normal life. Parameters included heart rate, blood pressure, stroke volume, cardiac index, systemic vascular resistance, blood oxygen saturation, and respiratory rate. Diurnal variations were evaluated, and analyses were stratified based on sex, age, and body mass index. Results: All parameters showed diurnal changes (p < 0.001). Females demonstrated higher heart rate and cardiac index with lower systemic vascular resistance. Obese participants had a higher blood pressure, and lower stroke volume and cardiac index. Systemic vascular resistance was higher among the elderly. Diurnal changes corresponded with awake-sleep hours and differed between sex, age, and body mass index groups. Conclusion: Wearable monitoring platforms could decipher hemodynamic changes in subgroups of individuals, and might help with efforts to provide personalized medicine, pre-symptomatic diagnosis and prevention, and drug development.

Serum Levels of Adropin Improve the Predictability of MELD and Child-Pugh Score in Cirrhosis: Results of Proof-of-Concept Clinical Trial.

Adropin is a peptide that was suggested to have a role in cirrhosis. The present study aimed to determine the ability to use serum adropin 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 (r 2 = 0.74). The correlation of adropin serum levels with mortality was better than MELD or Child-Pough scores (r 2 = 0.32 and 0.38, respectively). Higher adropin levels correlated with creatinine (r 2 = 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.

Implantable cardioverter defibrillator for primary prevention in patients with non-ischemic cardiomyopathy in the era of novel therapeutic agents- meta-analysis.

Background: Evidence regarding the mortality benefit of implantable cardioverter defibrillator (ICD) non-ischemic dilated cardiomyopathy (NIDCM) is inconsistent. The most recent randomized study, the DANISH trial, did not find improved outcomes with ICD. However, based on previous studies and meta-analyses, current guidelines still highly recommend ICD implantation in NIDCM patients. The introduction of novel medications for heart failure improved the clinical outcome dramatically. We aimed in this study to evaluate the effect of Angiotensin Receptor-Neprilysin Inhibitors (ARNi) and sodium-glucose transport protein 2 inhibitors (SGLT2i) on the mortality benefit of ICD in NIDCM. Methods: We used a previous metanalysis algorithm and added an updated comprehensive literature search in PubMed for randomized control trials that examined the mortality benefit of ICD in NIDCM vs. optimal medical treatment. The primary outcome included death from any cause. We did a meta-regression analysis to search for a single independent factor affecting mortality. Using previous data, we evaluated the theoretical effect of ICD implementation on patients treated with SGLT2 inhibitors and ARNi. Results: No new articles were added to the results of the previous meta-analysis. 2,622 patients with NIDCM from 5 cohort studies published between 2002 and 2016 were included in the analysis. 50% of them underwent ICD implantation for primary prevention of sudden cardiac death, and 50% did not. ICD was associated with a significantly decreased risk for death from any cause compared to control (OR = 0.79, 95%CI: 0.66-0.95, p = 0.01, I2 = 0%). The theoretical addition of ARNi and the SGLT2 inhibitor dapagliflozin did not change the significant mortality effect of ICD (OR = 0.82, 95%CI: 0.7-0.9, p = 0.001, I2 = 0%) and (OR = 0.82, 95%CI: 0.7-0.9, p = 0.001, I2 = 0%). A meta-regression revealed no association between death from any cause and left bundle branch block (LBBB), use of amiodarone, use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers, year initiated enrollment, and the year ended enrollment (R2 = 0.0). Conclusion: In patients with NIDCM, the addition of ARNi and SGLT2i did not affect the mortality advantages of ICD for primary prevention. PROSPERO registry number: https://www.crd.york.ac.uk/prospero/, identifier: CRD42023403210.

A second-generation artificial intelligence-based therapeutic regimen improves diuretic resistance in heart failure: Results of a feasibility open-labeled clinical trial.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. SUMMARY: 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.

Low-Dose Colchicine Attenuates Sepsis-Induced Liver Injury: A Novel Method for Alleviating Systemic Inflammation.

Sepsis is a significant public health challenge. The immune system underlies the pathogenesis of the disease. The liver is both an active player and a target organ in sepsis. Targeting the gut immune system using low-dose colchicine is an attractive method for alleviating systemic inflammation in sepsis without inducing immunosuppression. The present study aimed to determine the use of low-dose colchicine in LPS-induced sepsis in mice. C67B mice were injected intraperitoneal with LPS to induce sepsis. The treatment group received 0.02 mg/kg colchicine daily by gavage. Short and extended models were performed, lasting 3 and 5 days, respectively. We followed the mice for biochemical markers of end-organ injury, blood counts, cytokine levels, and liver pathology and conducted proteomic studies on liver samples. Targeting the gut immune system using low-dose colchicine improved mice's well-being measured by the murine sepsis score. Treatment alleviated the liver injury in septic mice, manifested by a significant decrease in their liver enzyme levels, including ALT, AST, and LDH. Treatment exerted a trend to reduce creatinine levels. Low-dose colchicine improved liver pathology, reduced inflammation, and reduced the pro-inflammatory cytokine TNFα and IL1-ß levels. A liver proteomic analysis revealed low-dose colchicine down-regulated sepsis-related proteins, alpha-1 antitrypsin, and serine dehydratase. Targeting the gut immune system using low-dose colchicine attenuated liver injury in LPS-induced sepsis, reducing the pro-inflammatory cytokine levels. Low-dose colchicine provides a safe method for immunomodulation for multiple inflammatory disorders.

Using chronobiology-based second-generation artificial intelligence digital system for overcoming antimicrobial drug resistance in chronic infections.

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.

Direct Oral Anticoagulants in Special Patient Populations.

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.

Management of heart failure with reduced ejection fraction: challenges in patients with atrial fibrillation, renal disease and in the elderly.

Heart failure with reduced ejection fraction (HFrEF) is an increasing global pandemic affecting more than 30 million individuals worldwide. Importantly, HFrEF is frequently accompanied by the presence of cardiac and non-cardiac comorbidities that may greatly influence the management and prognosis of the disease. In this review article, we will focus on three important comorbidities in HFrEF; atrial fibrillation (AF), advanced renal disease, and elderly, which all have a paramount impact on progression of the disease, management strategies, and response to therapy. AF is very common in HFrEF and shares many risk factors. AF aggravates heart failure and contributes to HF-related adverse clinical outcomes; hence it requires special consideration in HFrEF management. The kidney function is largely affected by the reduced cardiac output developed in the setting of HFrEF, and the neurohormonal feedback effects create a complex interplay that pose challenges in the management of HFrEF when renal function is significantly impaired. Cardiorenal syndrome is a challenging sequela with increased morbidity and mortality thereby reflecting the delicate and complex balance between the heart and the kidney in HFrEF and renal failure conditions. Furthermore, patients with advanced renal failure have poor prognosis in the presence of HFrEF with limited treatment options. Finally, aging and frailty are important factors that influence treatment strategies in HFrEF with greater emphasis on tolerability and safety of the various HFrEF therapies in elderly individuals.

Codivir suppresses SARS-Cov-2 viral replication and stabilizes clinical outcome: In vitro and Phase I clinical trial results.

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.

Advanced Hemodynamic Monitoring Allows Recognition of Early Response Patterns to Diuresis in Congestive Heart Failure Patients.

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.

In Search of Clinical Impact: Advanced Monitoring Technologies in Daily Heart Failure Care.

Despite significant advances in the management of heart failure (HF), further improvement in the outcome of this chronic and progressive disease is still considered a major unmet need. Recurrent hospitalizations due to decompensated HF frequently occur, resulting in increased morbidity and mortality rates. Past attempts at early detection of clinical deterioration were mainly based on monitoring of signs and symptoms of HF exacerbation, which have mostly given disappointing results. Extensive research of the pathophysiology of HF decompensation has indicated that hemodynamic alterations start days prior to clinical manifestation. Novel technologies aim to monitor these minute hemodynamic changes, allowing time for therapeutic interventions to prevent hemodynamic derangement and HF exacerbation. The latest noticeable advancements include assessment of lung fluid volume, wearable devices with integrated sensors, and microelectromechanical systems-based implantable devices for continuous measurement of cardiac filling pressures. This manuscript will review the rationale for monitoring HF patients and discuss previous and ongoing attempts to develop clinically meaningful monitoring devices to improve daily HF health care, with particular emphasis on the recent advances and clinical trials relevant to this evolving field.

Role of circadian rhythm and autonomic nervous system in liver function: a hypothetical basis for improving the management of hepatic encephalopathy.

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.

Right-sided endocarditis caused by polyclonal Staphylococcus aureus infection.

We present a case of bacterial endocarditis with both methicillin-sensitive and methicillin-resistant Staphylococcus aureus, which based on typing, originated from two distinct clones. Such a case may be misinterpreted by microbiology lab automation to be a monoclonal multi-drug resistant Staphylococcus aureus, while simple microbiology techniques will instantly reveal distinct clonality.