Recent work has shown that bilirubin has a hormonal function by binding to the peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor that drives the transcription of genes to control adiposity. Our previous in silico work predicted three potential amino acids that bilirubin may interact with by hydrogen bonding in the PPARα ligand-binding domain (LBD), which could be responsible for the ligand-induced function. To further reveal the amino acids that bilirubin interacts with in the PPARα LBD, we harnessed bilirubin’s known fluorescent properties when bound to proteins such as albumin. Our work here revealed that bilirubin interacts with threonine 283 (T283) and alanine 333 (A333) for ligand binding. Mutational analysis of T283 and A333 showed significantly reduced bilirubin binding, reductions of 11.4% and 17.0%, respectively. Fenofibrate competitive binding studies for the PPARα LBD showed that bilirubin and fenofibrate possibly interact with different amino acid residues. Furthermore, bilirubin showed no interaction with PPARγ. This is the first study to reveal the amino acids responsible for bilirubin binding in the ligand-binding pocket of PPARα. Our work offers new insight into the mechanistic actions of a well-known molecule, bilirubin, and new fronts into its mechanisms.

Introduction: YouTube™ has grown into one of the largest disseminators of health care information. We assessed the quality of information on varicoceles and their treatment, available on YouTube™. Methods: Using a YouTube™ search query with the keyword “varicocele,” the quality of the first 50, nonrepeat videos in English were assessed as a representative group for the topic. DISCERN and Patient Education Materials Assessment Tool for Audiovisual Materials (PEMAT-AV) standardized tools were utilized by three independent reviewers to grade the quality of these videos based on content, understandability, and actionability. Results: The average and median DISCERN score was 31.34 (±9.37) and 31 (interquartile range 25–35), respectively, indicating poor quality. The interrater reliability (IRR) scores ranged from 0.51 to 0.93, indicating fair to excellent reliability. The average PEMAT-AV understandability and actionability scores were 69.8% ±15.4% and 11.0% ±24.6%, respectively, indicating mostly understandable but poor actionability. The t-test results showed that international videos scored higher without statistical significance in the DISCERN or PEMAT-AV scores (P = 0.18, 0.59, and 0.20). Conclusions: The current quality of videos on YouTube™ on the topic of varicoceles is of poor quality due to a lack of a holistic approach in explaining the wide range of treatment options available. With the ease of access to produce and disseminate health information, there is a need to create high-quality videos on varicoceles that empower a patient to make an informed decision.

Purpose: Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, with many patients presenting with locally advanced or metastatic disease. Over the past decade, systemic therapy has evolved from cytokine-based regimens to targeted agents and immune checkpoint inhibitors (ICIs). Methods: A comprehensive narrative review was conducted of peer-reviewed literature and clinical trials published between 2008 and 2025, focusing on systemic therapies for advanced ccRCC, mechanisms of resistance, molecular imaging, and translational biomarker development. Results: Combination regimens integrating ICIs with vascular endothelial growth factor (VEGF), tyrosine kinase inhibitors (TKIs), or dual ICI therapies have significantly improved survival and represent current first-line standards. Emerging therapeutic categories include hypoxia-inducible factor-2α (HIF-2α) inhibitors, AXL/TYRO3/MER (TAM) receptor antagonists, radiopharmaceutical and theranostic platforms, and viral or cellular immunotherapies. Advances in molecular imaging, including carbonic anhydrase IX (CAIX) and prostate-specific membrane antigen (PSMA) targeted modalities, are improving detection and characterization of metastatic disease. Systemic and locoregional strategies are also being explored for biologically aggressive subsets, including tumors with inferior vena cava involvement. Despite these advances, resistance to VEGF-TKIs and ICIs persists, driving investigation into metabolic reprogramming, tumor microenvironment modulation, and emerging resistance pathways such as DEPDC1. Circulating tumor DNA (ctDNA), spatial transcriptomics, and artificial intelligence (AI) are increasingly integrated to support adaptive, precision-guided therapy. Conclusions: Modern ICI-based and biomarker-informed strategies have improved outcomes in metastatic ccRCC. Continued integration of translational biomarkers, ctDNA monitoring, and AI-driven analytics is expected to further personalize systemic therapy and enhance long-term disease control.

We systematically reviewed published data on autopsies of patients who died from COVID-19 to identify pathological changes that are consistently reported in autopsies and those that were reported anecdotally, and to compare consistent findings with autopsy findings in similar diseases. The MEDLINE, Google Scholar, and Embase databases were searched for full-text articles in the English language from December 2019 to March 2021 to include publications on autopsy findings in patients whose main cause of death was COVID-19 and COVID-19-related complications. This review included 124 published papers documenting COVID-19 patient autopsies for over 1100 patients. Most frequent and consistently reported pathological findings included diffuse alveolar damage in the lungs, cardiac inflammation, and hypertrophy, vascular microthrombi, shock kidney and acute tubular necrosis, congested liver and spleen, and shock-associated changes in other organs. These findings by themselves were not unique, and were similar to other severe viral infections and septic shock. However, the frequency of diffuse alveolar damage and the extent of microvascular thrombosis were much higher among the autopsies of patients who had died from COVID-19 compared with other severe viral infections. Autopsy data confirm clinical reports of high incidences of diffuse alveolar damage and microvascular thrombosis in the most severe cases of COVID-19 that caused death.