Sainath Prabhakar

Vitamin D–Vitamin D receptor (VDR) signaling extends beyond calcium-phosphate homeostasis and regulates immune tolerance, inflammation, cellular differentiation, oxidative stress, and endocrine physiology. This systematic review evaluated the relationship between vitamin D–VDR signaling and thyroid disorders, including hypothyroidism, hyperthyroidism, Hashimoto’s thyroiditis, Graves’ disease, thyroid autoimmunity, genetic susceptibility, experimental mechanisms, and therapeutic implications. This study was conducted and reported in accordance with the PRISMA 2020 statement. PubMed/MEDLINE and Scopus were searched for studies published from January 2005 through June 2026, supplemented by backward and forward citation screening of relevant studies and reviews. Eligible evidence included human observational and interventional studies, genetic investigations, and relevant animal and in vitro studies addressing vitamin D status, vitamin D exposure or supplementation, VDR variation, vitamin D metabolism, or vitamin D–VDR mechanisms in relation to thyroid function, thyroid disease, thyroid autoantibodies, or related biological outcomes. A total of 13,623 records were identified, of which 11,730 unique records underwent title and abstract screening, 449 reports were assessed at the full-text stage, and 118 primary studies were included in the final synthesis. Because of substantial heterogeneity in populations, study designs, vitamin D exposures, outcomes, genetic backgrounds, and experimental models, findings were synthesized narratively rather than by quantitative meta-analysis. Lower circulating 25-hydroxyvitamin D [25(OH)D] concentrations were frequently associated with thyroid disease, particularly autoimmune phenotypes, and increased thyroid peroxidase and thyroglobulin antibodies in Hashimoto’s thyroiditis. Interventional evidence suggests that vitamin D supplementation may reduce thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) concentrations in some patients with autoimmune thyroid disease. However, these laboratory changes represent immunological surrogate outcomes and should not be interpreted as evidence of restored thyroid function, prevention of progression to overt hypothyroidism, reduced dependence on thyroid hormone replacement, or sustained clinical remission. Randomized evidence does not establish a general preventive effect of vitamin D supplementation on incident hypothyroidism. Associations between VDR polymorphisms, including FokI/rs2228570, rs1544410, rs731236, and rs7975232, and thyroid autoimmunity were inconsistent across populations. Experimental evidence implicates immune regulation, Th17/Treg balance, inflammatory signaling, vitamin D metabolism, and calcium-phosphate homeostasis. The evidence was limited by substantial clinical, methodological, and biological heterogeneity, frequent reliance on observational studies, population-specific genetic findings, and differences between experimental models and human thyroid physiology. Overall, vitamin D–VDR signaling represents a biologically plausible modifier of thyroid disease, but current evidence does not establish universal causality or therapeutic efficacy.

Pediatric drug therapy remains fundamentally challenged by profound interindividual variability driven by dynamic development, genetic, and environmental factors. Although dosing strategies based on age, body weight, or body surface area remain important starting points in pediatric pharmacotherapy, they may not fully capture ontogeny-dependent variability in drug disposition and response. Consequently, clinically relevant differences in efficacy and toxicity may still occur among children receiving similar weight-adjusted doses. Pharmacogenomics offers a promising framework for individualized therapy; however, its clinical translation in pediatrics is limited by developmental variability in gene expression and enzyme activity. Emerging evidence highlights the pivotal role of epigenetic regulation, including DNA methylation, histone modifications, and microRNAs, in modulating pharmacogenetic expression across developmental stages, thereby reshaping drug response trajectories. Concurrently, advances in artificial intelligence and next-generation sequencing enable integration of multidimensional datasets, facilitating predictive modeling of drug efficacy and toxicity. This narrative review provides a comprehensive synthesis of developmental pharmacology, pharmacogenomics, and epigenetic mechanisms, while critically evaluating current translational gaps and implementation challenges. Importantly, it proposes an integrative precision framework that incorporates genetic, epigenetic, and computational insights to optimize pediatric pharmacotherapy. By bridging mechanistic biology with emerging digital health technologies, this work advances a paradigm shift from empirical prescribing toward predictive, adaptive, and individualized therapeutic strategies. The proposed approach holds significant potential to enhance clinical outcomes, minimize adverse effects, and accelerate the realization of precision medicine in pediatric populations.

Metabolic dysregulation is increasingly recognized as a central feature linking chronic infection, immune dysfunction, and skeletal deterioration; however, these processes are most often investigated in isolation, limiting the development of integrative mechanistic frameworks. In this review, we propose the Metabolic Reprogramming Interface Model (MRIM) as a systems-level, hypothesis-generating construct that conceptualizes metabolism as a shared regulatory axis bridging host–pathogen interactions and bone microenvironment remodeling. Importantly, MRIM is not presented as a unified or experimentally validated disease model, but rather as a structured framework designed to organize and critically evaluate emerging multidisciplinary evidence. At the molecular level, metformin, a widely used metabolic modulator, has been shown to influence mitochondrial bioenergetics, AMP-activated protein kinase (AMPK) signaling, redox balance, and autophagic pathways, all of which are independently implicated in microbial persistence, immune cell function, and skeletal homeostasis. Within MRIM, these observations are integrated to hypothesize that metabolic perturbation may coordinately influence infection dynamics, inflammatory responses, and bone turnover. Nevertheless, most of the supporting evidence remains indirect, arising from in vitro studies, animal models, and observational clinical datasets, thereby limiting causal inference. To address this, the framework explicitly distinguishes between experimentally validated mechanisms, context-dependent biological interactions, and higher-order theoretical integrations. While preliminary findings suggest that metformin may modulate microbial fitness, attenuate excessive inflammation, and influence bone remodeling, these effects appear to be highly context-dependent and have not yet been substantiated in adequately powered prospective clinical trials evaluating combined infectious and skeletal outcomes. This review therefore provides a critical synthesis of current knowledge, highlights key mechanistic and translational uncertainties, and outlines testable hypotheses for future investigation, positioning MRIM as a conceptual scaffold to guide interdisciplinary research rather than a definitive explanatory model.

Cardiometabolic diseases, including hypertension, type 2 diabetes, dyslipidemia, and obesity, along with their cardiovascular complications, remain leading causes of morbidity and mortality worldwide, imposing significant public health, economic, and societal burdens. Conventional pharmacological therapies often show limited efficacy and increased adverse effects because they do not account for the body’s intrinsic circadian rhythms, which regulate organ function, drug absorption, and metabolism. Chronopharmacology, which aligns treatment timing with these biological rhythms, offers a strategy to enhance therapeutic outcomes. This review presents a comprehensive analysis of chronopharmacology principles applied to cardiometabolic disease management, integrating molecular, physiological, and clinical perspectives. It examines how core clock genes and tissue-specific circadian patterns influence drug action and absorption and summarizes evidence-based time-optimized interventions for hypertension, diabetes, dyslipidemia, obesity, and multimorbid patients. Furthermore, the review highlights emerging innovations, including artificial intelligence-guided dosing, circadian-biomarker-informed therapy selection, and wearable digital devices for real-time monitoring of biological rhythms. By synthesizing mechanistic and clinical insights, circadian-aligned treatment strategies are shown to improve drug efficacy, reduce adverse effects, and support the development of precision, rhythm-based therapeutics, offering a practical framework for personalized cardiometabolic disease care.

Metformin, a long-established antidiabetic agent, is undergoing a renaissance as a prototype gerotherapeutic and immunometabolic oncology adjuvant. Mechanistic advances reveal that metformin modulates an integrated network of metabolic, immunological, microbiome-mediated, and epigenetic pathways that impact the hallmarks of aging and cancer biology. Clinical data now demonstrate its ability to reduce cancer incidence, enhance immunotherapy outcomes, delay multimorbidity, and reverse biological age markers. Landmark trials such as UKPDS, CAMERA, and the ongoing TAME study illustrate its broad clinical impact on metabolic health, cardiovascular risk, and age-related disease trajectories. In oncology, trials such as MA.32 and METTEN evaluate its influence on progression-free survival and tumor response, highlighting its evolving role in cancer therapy. This review critically synthesizes the molecular underpinnings of metformin’s polypharmacology, examines results from pivotal clinical trials, and compares its effectiveness with emerging gerotherapeutics and senolytics. We explore future directions, including optimized dosing, biomarker-driven personalization, rational combination therapies, and regulatory pathways, to expand indications for aging and oncology. Metformin stands poised to play a pivotal role in precision strategies that target the shared roots of aging and cancer, offering scalable global benefits across health systems.

Myocardial protection during cardiac surgery is crucial for preventing ischemia-reperfusion injury and preserving myocardial function. Cardioplegia, a solution used to induce electromechanical cardiac arrest, is the fundamental method for myocardial protection during on-pump procedures. Del Nido cardioplegia, developed in the 1990s, has gained increasing popularity in adult cardiac surgeries over the past two decades. Del Nido cardioplegia is a crystalloid-based solution used to achieve depolarized arrest. Its mechanism of action also involves preventing intracellular calcium overload, a key driver of reperfusion injury. Numerous studies have evaluated the safety and efficacy of del Nido cardioplegia in adult cardiac surgeries, including coronary artery bypass grafting and valve procedures. Compared to standard blood cardioplegia, del Nido cardioplegia has demonstrated reduced hemodilution, transfusion requirements and shorter cardiopulmonary bypass times due to its extended arrest duration. Many studies have reported lower levels of myocardial injury biomarkers and improved myocardial functional recovery with del Nido cardioplegia. It has also been associated with reduced defibrillation requirements, which is attributable to the antiarrhythmic effects of lidocaine. While some studies have reported no significant differences in outcomes between del Nido cardioplegia and blood cardioplegia, others have favored del Nido cardioplegia in terms of myocardial protection, postoperative cardiac function, and perioperative morbidity. The choice between cardioplegia solutions remains subjective and dependent on surgeon preference and institutional practices. However, del Nido cardioplegia has emerged as an acceptable alternative to traditional cardioplegia, offering potential advantages in adult cardiac surgeries.

Background: The development of the cardiopulmonary bypass machine for extracorporeal circulation by Dr. John Gibbon marked a significant milestone in the advancement of medical technology. Subsequent enhancements in this equipment and methodologies have refined this ground-breaking invention for better cardiac surgical results. Main body of the The emergence of miniaturized extracorporeal circuits has demonstrated more promising results in various research studies. This narrative article explores the impacts of miniaturized extracorporeal circuits on different organ systems and their potential advantages over traditional bypass systems, focusing on currently commercially available devices to enhance our understanding. Short conclusion: Nevertheless, practical limitations in standard usage and acceptance have hindered its widespread implementation. Hence, this technique is still in the process of acceptance as the standard of care. The information presented in this review has been collected by accessing major databases and recent reviews, meta-analyses and clinical trials on the internet, adhering to the Revised Standards for QUality Improvement Reporting Excellence (SQUIRE 2.0) guidelines.

Objective: In this study, the effects of two myocardial protection systems, Spictra MPS and BL BCD were compared on coefficient of heat exchange in myocardial temperature during delivery of cardioplegia.Methods: This was a single-center observational prospective study conducted with data from 40 patients who underwent cardiopulmonary bypass. BL group (n=20) and Spictra group (n=20) were compared for blood inlet temperature, blood outlet temperature, myocardial temperature and coefficient of heat exchange, during the administration of cardioplegia. The data was measured and calculated.Results: It was observed that there is no significant difference between the blood inlet temperature and blood outlet temperature of both the devices. Significant difference was seen in co-efficiency of heat exchange and myocardial temperature between both the devices in few dosages.Conclusion: In this comparative study conducted, it was noted that there is no significant difference in the parameters between the Spictra and BL devices except for the myocardial temperature during few dosages.

The aphorism “Primum non nocere” underscores the responsibility of healthcare professionals to prioritize patient safety. Perfusionists, experts in extracorporeal circulation, play a pivotal role in maintaining cardiac function during critical situations. However, the evolving landscape of medical technology has not been without challenges, particularly in ensuring equitable access to perfusion training. Easy Flow Cardiopulmonary Bypass Simulation Model stands out as a cost-effective alternative, utilizing routine CPB equipment found in operating theatres. The uniqueness lies in its incorporation of double reservoirs and two pumps, a novel approach not reported before in educational CPB simulation models. The benefits of this model extend beyond skill development to encompass team management, communication enhancement, and disaster management training. Multiple scenarios, from the initiation of CPB to addressing emergencies like massive air embolism, can be simulated. Although the model requires an instructor, this facilitates the integration of essential professional and communication skills into training. The adaptability of the Easy Flow model makes it a practical and sustainable solution. It provides hands-on experience for perfusion students, translating theoretical knowledge into practical competence. The model's simplicity, combined with its use of readily available materials, positions it to be an accessible tool for educational institutions and healthcare centers globally. In conclusion, the Easy Flow CPB Simulation Model not only fills a critical gap in perfusion education but also exemplifies how innovation can bridge disparities, ensuring that quality healthcare education is within reach for all. Its potential impact on global healthcare training is profound, promising a future where knowledge sharing leads to improved patient care.

Doxorubicin is a widely used anticancer drug whose efficacy is limited due to its cardiotoxicity. There is no ideal cardioprotection available against doxorubicin-induced cardiotoxicity. This study aimed to investigate the anticipated cardioprotective potential of metformin and dapagliflozin against doxorubicin-induced acute cardiotoxicity in Wistar rats. At the beginning of the experiment, cardiac screening of experimental animals was done by recording an electrocardiogram (ECG) before allocating them into the groups. Thereafter, a total of thirty healthy adult Wistar rats (150–200 g) were randomly divided into five groups (n = 6) and treated for eight days as follows: group I (normal control), group II (doxorubicin control), group III (metformin 250 mg/kg/day), group IV (metformin 180 mg/kg/day), and group V (dapagliflozin 0.9 mg/kg/day). On the 7th day of the treatment phase, doxorubicin 20 mg/kg was administered intraperitoneal to groups II, III, IV, and V. On the 9th day (immediately after 48 h of doxorubicin administration), blood was collected from anesthetized animals for glucose, lipid profile, CK-MB & AST estimation, and ECG was recorded. Later, animals were sacrificed, and the heart was dissected for histopathological examination. We found that compared to normal control rats, CK-MB, AST, and glucose were significantly increased in doxorubicin control rats. There was a significant reversal of doxorubicin-induced hyperglycemia in the rats treated with metformin 250 mg/kg compared to doxorubicin control rats. Both metformin (180 mg/kg and 250 mg/kg) and dapagliflozin (0.9 mg/kg) significantly altered doxorubicin-induced ECG changes and reduced the levels of cardiac injury biomarkers CK-MB and AST compared to doxorubicin control rats. Metformin and dapagliflozin protected the cellular architecture of the myocardium from doxorubicin-induced myocardial injury. Current study revealed that both metformin and dapagliflozin at the FDA-recommended antidiabetic doses mitigated doxorubicin-induced acute cardiotoxicity in Wistar rats. The obtained data have opened the perspective to perform chronic studies and then to clinical studies to precisely consider metformin and dapagliflozin as potential chemoprotection in the combination of chemotherapy with doxorubicin to limit its cardiotoxicity, especially in patients with comorbid conditions like type II diabetes mellitus.