DFT and molecular simulation validation of the binding activity of PDEδ inhibitors for repression of oncogenic k-Ras.

The development of effective drugs targeting the K-Ras oncogene product is a significant focus in anticancer drug development. Despite the lack of successful Ras signaling inhibitors, recent research has identified PDEδ, a KRAS transporter, as a potential target for inhibiting the oncogenic KRAS signaling pathway. This study aims to investigate the interactions between eight K-Ras inhibitors (deltarazine, deltaflexin 1 and 2, and its analogues) and PDEδ to understand their binding modes. The research will utilize computational techniques such as density functional theory (DFT) and molecular electrostatic surface potential (MESP), molecular docking, binding site analyses, molecular dynamic (MD) simulations, electronic structure computations, and predictions of the binding free energy. Molecular dynamic simulations (MD) will be used to predict the binding conformations and pharmacophoric features in the active site of PDEδ for the examined structures. The binding free energies determined using the MMPB(GB)SA method will be compared with the observed potency values of the tested compounds. This computational approach aims to enhance understanding of the PDEδ selective mechanism, which could contribute to the development of novel selective inhibitors for K-Ras signaling.

Future of Artificial Intelligence in Surgery: A Narrative Review.

Artificial intelligence (AI) is the capability of a machine to execute cognitive processes that are typically considered to be functions of the human brain. It is the study of algorithms that enable machines to reason and perform mental tasks, including problem-solving, object and word recognition, and decision-making. Once considered science fiction, AI today is a fact and an increasingly prevalent subject in both academic and popular literature. It is expected to reshape medicine, benefiting both healthcare professionals and patients. Machine learning (ML) is a subset of AI that allows machines to learn and make predictions by recognizing patterns, thus empowering the medical team to deliver better care to patients through accurate diagnosis and treatment. ML is expanding its footprint in a variety of surgical specialties, including general surgery, ophthalmology, cardiothoracic surgery, and vascular surgery, to name a few. In recent years, we have seen AI make its way into the operating theatres. Though it has not yet been able to replace the surgeon, it has the potential to become a highly valuable surgical tool. Rest assured that the day is not far off when AI shall play a significant intraoperative role, a projection that is currently marred by safety concerns. This review aims to explore the present application of AI in various surgical disciplines and how it benefits both patients and physicians, as well as the current obstacles and limitations facing its seemingly unstoppable rise.

Left Atrial Septal Pouch (LASP) and cryptogenic stroke risk: An updated systematic review and meta-analysis of observational studies.

BACKGROUND: The left atrial septal pouch (LASP) is a small anatomical septal recess in the heart that has been linked with cardioembolic events. A systematic appraisal of the existing literature is necessary to establish a better understanding of the risk as studies continue to indicate a correlation between LASPs and cryptogenic strokes. OBJECTIVES: To determine the level of association between the presence of LASP and the risk of developing cryptogenic stroke. METHODS: We searched PubMed, EMBASE and Scopus for studies comparing the prevalence of LASP in patients with cryptogenic stroke against non-cryptogenic stroke control groups from inception till December, 2023. The Newcastle Ottawa scale was used for quality assessment and Comprehensive Meta-Analysis Version 3.3 was used for data analysis with odds ratio (OR) as the effect measure. RESULTS: Our review included a total of 10 retrospective, observational studies published between 2010 to 2022. A total of 683 cases of cryptogenic strokes were identified, out of which 33.1 % (n = 271) were associated with a LASP. Among the non-cryptogenic stroke controls (n = 2641), LASP was present in 20.6 % cases (n = 476). The aggregate OR for cryptogenic stroke was 1.618 times greater than non-cryptogenic stroke (p < 0.001) among LASP cases, CONCLUSION: The presence of a septal pouch in the left atrium is significantly linked to a higher risk of developing cryptogenic strokes. As a potential site of thrombus formation and subsequent dislodgement, further large-scale studies are necessary to establish the guidelines for management and prophylaxis to prevent embolic events.

The Gut-Brain Axis in Autoimmune Diseases: Emerging Insights and Therapeutic Implications.

The gut-brain axis (GBA) is a two-way communication system that is influenced by signals from the nervous system, hormones, metabolism, the immune system, and microbes. The GBA may play a key role in gastrointestinal and neurological illnesses. Signaling events from the gut can regulate brain function. As a result, mounting data point to a connection between autoimmune disorders (AIDs), both neuroinflammatory and neurodegenerative diseases, and the GBA. Clinical, epidemiological, and experimental studies have shown that a variety of neurological illnesses are linked to alterations in the intestinal environment, which are suggestive of disease-mediated inter-organ communication between the gut and the brain. This review's objective is to draw attention to the clinical and biological relationship between the gut and the brain, as well as the clinical importance of this relationship for AIDs, neurodegeneration, and neuroinflammation. We also discuss the dysbiosis in the gut microbiota that has been linked to various AIDs, and we make some assumptions about how dietary changes such as prebiotics and probiotics may be able to prevent or treat AIDs by restoring the composition of the gut microbiota and regulating metabolites.

Comparison of the Effectiveness of Prolonged Infusion and Intermittent Infusion of Meropenem in Patients With Sepsis: A Meta-Analysis.

The aim of this study was to compare the clinical effectiveness of prolonged infusion and intermittent infusion of meropenem in patients with sepsis. This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines. PubMed, Web of Science, Scopus, and the Cochrane Library were searched without any language or time restrictions, up to September 25, 2023. The primary outcomes assessed in this meta-analysis included clinical success and all-cause mortality. Other outcomes assessed in this study encompassed the mean length of ICU stay. Total eight studies met the eligibility criteria and were included in this meta-analysis. Pooled analysis showed that the clinical success rate was significantly higher in patients receiving prolonged infusion of meropenem compared to intermittent infusion (RR: 1.49, 95% CI: 1.30 to 1.70). All-cause mortality was 24% significantly lower in patients receiving prolonged infusion of meropenem compared to intermittent infusion (RR: 0.76, 95% CI: 0.60 to 0.96). The results suggest that prolonged infusion of meropenem could be a more effective and efficient treatment for sepsis patients. However, more randomized controlled trials are needed to confirm these findings and to establish the optimal dosing and administration schedule for prolonged infusion of meropenem.

Safety and Efficacy of Efpeglenatide in Patients With Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials.

The aim of this study was to assess the efficacy and safety of efpeglenatide in patients with type 2 diabetes (T2D). The study was reported according to the 2020 guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Web of Science, PubMed, and Scopus databases were searched by two authors independently, with no restriction on language and year of publication, using the following key terms: (efpeglenatide) OR (glucagon-like peptide-1 receptor agonist) AND (type 2 diabetes) OR (diabetes) OR (T2DM) AND (HbA1c) OR (FSG) OR (fasting serum glucose) OR (weight) OR (bodyweight) OR (adverse events) OR (safety) OR (AE). Outcomes assessed in this meta-analysis included change in hemoglobin A1C (HbA1C) from baseline (%), change in weight from baseline (Kg), and change in fasting serum glucose (FSG) from baselines. For the safety analysis, we assessed total adverse events and gastrointestinal (GI) adverse events. A total of four studies fulfilled the inclusion and exclusion criteria and were included in this meta-analysis, encompassing six randomized controlled trials (RCTs). Compared with a control group, efpeglenatide lowered the HbA1c (mean difference (MD): -0.81, 95% confidence interval (CI): -1.01 to -0.60), body weight (MD: -1.15, 95% CI: -1.82 to -0.47), and FSG (MD: -0.98, 95% CI: -1.19 to -0.77). However, the risk of GI-related adverse events was significantly higher in the efpeglenatide group compared to the control group.