De-Risking Seizure Liability: Integrating Adverse Outcome Pathways (AOPs), New Approach Methodologies (NAMs) and In Silico Approaches while Highlighting Knowledge Gaps.

Animal studies are commonly used in drug development, chemical, and environmental toxicology to predict human toxicity, but their reliability, particularly in the central nervous system (CNS) is limited. For example, animal models often fail to predict drug-induced seizures, leading to unforeseen convulsions in clinical trials. Evaluating environmental compounds, such as pesticides, also poses challenges due to time and resource constraints, resulting in compounds remaining untested.

Artificial Intelligence and Machine Learning Models for Predicting Drug-Induced Kidney Injury in Small Molecules.

Background/objectives: Drug-Induced Kidney Injury (DIKI) presents a significant challenge in drug development, often leading to clinical-stage failures. The early prediction of DIKI risk can improve drug safety and development efficiency. Existing models tend to focus on physicochemical properties alone, often overlooking drug-target interactions crucial for DIKI.

Safety Implications of Modulating Nuclear Receptors: A Comprehensive Analysis from Non-Clinical and Clinical Perspectives.

The unintended modulation of nuclear receptor (NR) activity by drugs can lead to toxicities amongst the endocrine, gastrointestinal, hepatic cardiovascular, and central nervous systems. While secondary pharmacology screening assays include NRs, safety risks due to unintended interactions of small molecule drugs with NRs remain poorly understood. To identify potential nonclinical and clinical safety effects resulting from functional interactions with 44 of the 48 human-expressed NRs, we conducted a systematic narrative review of the scientific literature, tissue expression data, and used curated databases (OFF-X™) (Off-X, Clarivate) to organize reported toxicities linked to the functional modulation of NRs in a tabular and machine-readable format.

The state of the art in secondary pharmacology and its impact on the safety of new medicines.

Secondary pharmacology screening of investigational small-molecule drugs for potentially adverse off-target activities has become standard practice in pharmaceutical research and development, and regulatory agencies are increasingly requesting data on activity against targets with recognized adverse effect relationships. However, the screening strategies and target panels used by pharmaceutical companies may vary substantially. To help identify commonalities and differences, as well as to highlight opportunities for further optimization of secondary pharmacology assessment, we conducted a broad-ranging survey across 18 companies under the auspices of the DruSafe leadership group of the International Consortium for Innovation and Quality in Pharmaceutical Development.

A 36-Year-Old Woman With an Unexpected Cause of Hypokalemia.

A 36-year-old woman complained of bilateral lower limb weakness for the last 3 days. She could move her upper limb, neck, and facial muscles and had no respiratory or swallowing difficulties. About 4 years ago, she complained of sudden weakness involving her lower limbs.

Artificial Intelligence/Machine Learning-Driven Small Molecule Repurposing via Off-Target Prediction and Transcriptomics.

The process of discovering small molecule drugs involves screening numerous compounds and optimizing the most promising ones, both in vitro and in vivo. However, approximately 90% of these optimized candidates fail during trials due to unexpected toxicity or insufficient efficacy. Current concepts with respect to drug-protein interactions suggest that each small molecule interacts with an average of 6-11 targets.

Utility of rapid atrial pacing before and after TAVR with balloon-expandable valve in predicting permanent pacemaker implantation.

Background: High-grade or complete atrioventricular block (AVB) requiring permanent pacemaker (PPM) implantation is a known complication of transcatheter aortic valve replacement (TAVR). Wenckebach AVB induced by rapid atrial pacing (RAP) after TAVR was previously demonstrated in an observational analysis to be an independent predictor for PPM. We sought to investigate the utility of both pre- and post-TAVR RAP in predicting PPM implantation.

Shocked to death: a case report of cardiogenic shock and death following electrocardioversion for atrial fibrillation.

Background: Atrial fibrillation (AF) is prevalent, especially in patients with heart failure. Their prevalence increases with age and both conditions are interrelated. Electrocardioversion (ECV) is considered a safe and effective procedure and is among one of the recommended therapies to terminate AF back to normal sinus rhythm.

An in-depth appraisal of clinico-biochemical and radiological findings of COVID-19 patients during the COVID-19 pandemic in a dedicated COVID Care Hospital in Eastern India and its outcome in relation to the COVAXIN vaccination status: A 2-year study.

Introduction: COVID-19 pandemic hit Odisha province from April 2020 to December 2020, then from April 2021 to August 2021 and from February 2022 to April 2022 as the first, second, and third waves, respectively, with the most severe form witnessed during the second wave. Kalinga Institute of Medical Sciences hospital in Odisha was declared a Dedicated COVID Hospital (DCH) during those three waves and witnessed 9485 cases of admissions among which there were 1214 deaths. COVAXIN vaccination of the vulnerable population was launched in February 2021 onwards.

AI/ML Models to Predict the Severity of Drug-Induced Liver Injury for Small Molecules.

Drug-induced liver injury (DILI), believed to be a multifactorial toxicity, has been a leading cause of attrition of small molecules during discovery, clinical development, and postmarketing. Identification of DILI risk early reduces the costs and cycle times associated with drug development. In recent years, several groups have reported predictive models that use physicochemical properties or and assay endpoints; however, these approaches have not accounted for liver-expressed proteins and drug molecules.

Serum Electrolytes in Patients Presenting With Acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD) and Their Comparison With Stable COPD Patients.

Introduction Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, which may be further aggravated by episodes of acute exacerbation of COPD (AECOPD). Electrolyte imbalances during these episodes may add to the duration of hospitalization and disease outcome. Aims and objectives This study aims to compare the serum electrolyte levels of patients with AECOPD and stable COPD and correlate them with the severity of exacerbation and disease outcome.

Immunocytochemical Evaluation of TTF-1, Napsin-A, and p-63 for Subtyping of Non-Small Cell Lung Carcinoma and Clinicopathological Correlation.

Background: Carcinoma of lung is the most common cause of cancer-associated mortality worldwide. About 70% of lung cancer cases are unresectable and present in advanced stages. So, cytology and small core needle biopsy specimen are available for diagnostic as well as prognostication workup.

Anterior-Posterior versus anterior-lateral electrodes position for electrical cardioversion of atrial fibrillation: A meta-analysis of randomized controlled trials.

Background: The optimal electrodes position for elective direct current (DC) cardioversion of patients with atrial fibrillation (AF) remains uncertain.

Methods: An electronic search of MEDLINE, EMBASE and COCHRANE databases was performed through March 2022 for randomized trials that examined the outcomes of anterior-posterior (AP) versus anterior-lateral (AL) electrodes position during cardioversion of (AF). The main outcome was the success rate of cardioversion.

Change in hospitalization rates following transcatheter left atrial appendage occlusion.

Introduction: Left atrial appendage occlusion (LAAO) is recommended in patients with non-valvular atrial fibrillation (AF) who have contraindications to or are intolerant of long-term oral anticoagulants (OAC), but its impact on hospitalization rates has not been well described. The objective of our study is to describe the incidence of all-cause, bleeding-related, and thrombosis-related hospitalizations before and after LAAO.

Material And Methods: We used the Nationwide Readmission Database to include patients aged ≥ 18 years with a diagnosis of AF who underwent transcatheter LAAO during the months of February-November in each year between 2016 and 2018.

Same-Day Discharge After Transcatheter Aortic Valve Implantation: Insights from the Nationwide Readmission Database 2015 to 2019.

Background There is a paucity of data on the feasibility of same-day discharge (SDD) following transcatheter aortic valve implantation (TAVI) at a national level. Methods and Results This study used data from the Nationwide Readmission Database from the fourth quarter of 2015 through 2019 and identified patients undergoing TAVI using the claim code 02RF3. A total of 158 591 weighted hospitalizations for TAVI were included in the analysis.

Toward the development of a polarimetric tool to diagnose the fibrotic human ventricular myocardium.

Significance: Optical polarimetry is an emerging modality that effectively quantifies the bulk optical properties that correlate with the anisotropic structural properties of cardiac tissues. We demonstrate the application of a polarimetric tool for characterizing healthy and fibrotic human myocardial tissues efficiently with a high degree of accuracy.

Aim: The study was aimed to characterize the myocardial tissues from the left ventricle and right ventricle of N  =  7 control and N  =  10 diseased subjects.

Prof. B. Ramamurthi - A Glimpse into his Contributions to Neuroscience.

Prof B Ramamurthi was a pioneer of Indian neurosurgery and a major force in the development of Indian neuroscience. Founding the Madras Institute of Neurology and later the A Lakshmipathi Neurosurgical Centre (ALNC), both at Madras (or Chennai as it is now called), he developed centres of excellence in his career that spanned over five decades. During this period of time he made Madras, a destination for neurosurgery and neuroscience.