Adrenal incidentalomas are increasingly encountered in routine clinical practice, driven by widespread imaging use and rising cardiometabolic disease burden. Mild autonomous cortisol secretion (MACS), characterized by low-grade, adrenocorticotropic hormone-independent cortisol excess in the absence of overt Cushingoid features, is the most common functional phenotype. Across observational cohorts, MACS is associated with a higher burden of hypertension, dysglycemia, dyslipidemia, obesity, and fractures; importantly, risk increases continuously with rising post-dexamethasone suppression test (DST) cortisol levels, including values traditionally categorized as nonfunctioning. Diagnosis centers on the 1-mg overnight DST, interpreted in clinical context and with careful attention to common interferents. The limitations of cortisol thresholds alone have prompted interest in adjunctive hormonal markers and composite clinical-biochemical risk stratification. Management is individualized, ranging from optimized cardiometabolic therapy to adrenalectomy in selected patients with clinically relevant comorbidities, while medical cortisol-modulating therapies remain investigational. This review synthesizes current evidence on the diagnosis, cardiometabolic implications, and management of MACS; highlights key uncertainties; and outlines future directions aimed at improving risk stratification and informing clinical decision-making for this increasingly prevalent condition.
Barriers to healthy eating lead to substantial health harms, but clinicians have historically had few tools to help patients address them. To fill this gap, food is medicine (FIM) interventions seek to improve the prevention or management of specific clinical conditions through the provision of healthy food resources and other strategies to address barriers to healthy eating. This article describes the rationale for and major types of FIM and reviews key studies and developments in the field. We note that the evidence to date shows promising benefits for FIM, including for both clinical outcomes and health care utilization, but it also has meaningful limitations and unexpected findings. We discuss results from evaluations of large-scale FIM implementation, particularly in Medicaid, and why FIM studies may have been more or less effective in different contexts. We conclude with several implementation learnings that can guide researchers going forward.
Cachexia is a complex, multifactorial syndrome driven by anorexia and systemic inflammation, ultimately resulting in a catabolic state characterized by weight loss, decreased muscle mass, and impaired physical function. Many chronic comorbidities are implicated in the pathophysiology of cachexia, with malignancy being one of the most common. Although approved cachexia-directed therapies are limited to date, the growth differentiation factor 15 (GDF-15)-glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) signaling axis has been identified as a primary mediator of cachexia and is an interesting pathway for cachexia-directed therapies and antibodies. Ponsegromab, a monoclonal antibody that is a highly selective and potent inhibitor of GDF-15, has resulted in improved body weight and other cachexia-related symptoms in patients with cancer. Other anti-GDF-15 and anti-GFRAL therapies are currently under investigation. Through the development of these treatments, many unexpected potential therapeutic applications have been identified, highlighting the broad, systemic impacts of cachexia. As research continues, it is imperative to focus on clear trial design and endpoints.
Eosinophilic esophagitis (EoE) is a chronic allergic disease with a complex pathogenesis driven by an abnormal type 2 immune response to food or environmental allergens in the setting of impaired esophageal epithelial function. The goals of EoE treatment are to reduce esophageal inflammation, improve symptoms, and prevent complications. Traditionally, anti-inflammatory treatments included proton pump inhibitors, swallowed or topical corticosteroids, and food elimination diets, while esophageal dilation was used for strictures. Dupilumab is a human monoclonal antibody that functions as an interleukin-4 receptor-alpha antagonist, leading to blockade of IL-4 and IL-13, which are key factors in EoE pathogenesis. This article discusses the rationale for dupilumab use in EoE, reviews the clinical trial data across the lifespan as well as emerging real-world data, highlights guideline recommendations and the role of dupilumab in the evolving treatment paradigm for EoE, and notes future directions for research.
Peanut allergy is a significant rising public health problem affecting both children and adults. Early peanut introduction has been adopted in multiple westernized nations as a preventative strategic measure to reduce the risk of developing peanut allergy, although implementation faces barriers. Multiple therapies to treat peanut allergy have been developed, including oral immunotherapy and omalizumab as approved treatments to provide protection against reactions from accidental exposure and reduce the risk of anaphylaxis, offering options beyond strict avoidance. Strategies in the developmental pipeline include epicutaneous immunotherapy and sublingual immunotherapy. The future is bright for individuals with peanut allergy, as these breakthroughs can help address the fear, uncertainty, severity, and lack of protection that has become synonymous with this disease. Shared decision-making is needed to ensure that each patient receives the management approach best suited to their needs, preferences, and goals.
Having already revolutionized outcomes for relapsed or refractory B cell malignancies and multiple myeloma, chimeric antigen receptor (CAR) T cell therapy is on the cusp of significantly impacting those with solid tumors. However, antitumor response is frequently associated with acute toxicities due to immune hyperactivation, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, immune effector cell-associated hematotoxicity, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. We discuss the clinical presentations, evaluation, management, risk factors, and pathophysiologies of these toxicities and briefly describe emerging toxicity mitigation strategies.
Immunoglobulin A nephropathy (IgAN) remains the leading primary glomerular disease worldwide, with a majority of patients reaching kidney failure within their lifetimes. IgAN is a heterogeneous glomerular disorder characterized by mesangial deposition of galactose-deficient immunoglobulin A1 containing immune complexes that induce glomerular injury and nephron loss. The primary therapeutic goal in treating IgAN is reduction of nephron loss from the time of diagnosis. Management ideally incorporates interventions targeting both immunologic and nonspecific chronic kidney disease pathomechanisms. Multitargeted approaches that simultaneously target the production of pathogenic immunoglobulin A immune complexes, address the consequences of ongoing nephron loss, halt glomerular inflammation, and inhibit profibrotic signals in the glomerulus and tubulointerstitium will provide maximal benefit. Given significant advances in the understanding of disease pathogenesis and the acceptance of surrogate outcomes (including proteinuria reduction) for accelerated drug approval, there has been a plethora of pharmacological agents recently evaluated and approved to treat IgAN. This review highlights the latest therapeutic developments in the field.
The understanding of myocardial ischemia evolved from early twentieth-century studies showing reversible or irreversible damage depending on ischemia duration. The concept of hibernating myocardium emerged in the 1970s, describing chronically impaired but viable myocardium that could recover after revascularization. Initial observational studies supported revascularization benefits, but randomized trials such as PARR-2, HEART, and STICH showed mixed results, with STICH demonstrating mortality benefits only after extended follow-up. Advances in medical therapy and intervention raised questions about the role of revascularization, leading to recent trials such as ISCHEMIA and REVIVED-BCIS2, which showed limited benefit of revascularization over optimal medical therapy in stable patients.
With the pharmacokinetics, dosing, safety, and manufacturing of approved or investigational drugs already well-characterized, drug repurposing and repositioning offer emerging strategies to rapidly develop effective treatments for various challenging diseases. However, the growing mass of genetic and multiomics data has not been effectively explored by the drug repurposing community due to a lack of accurate approaches. This review aims to be an authoritative, critical, and accessible review and discussion of general interest to the drug repurposing community concerning the use of artificial intelligence (AI) and machine learning (ML) tools. Emerging questions include what is achievable with AI in this domain and what its impact will be, what AI and ML embrace, and how we, as geneticists, pharmacologists, and computational scientists, can contribute to the discovery of new, inexpensive, and affordable repurposable medicines. The fast growth of genetics and multiomics data (genomics, transcriptomics, proteomics, metabolomics, and radiomics) and electronic health records in diverse populations contributes to answering questions, including how to rapidly identify effective repurposable medicines, what a clinically meaningful effect size in trials is, and what the potential implications for precision medicine are. This review discusses AI and ML for drug repurposing in the context of genetics, multiomics, real-world data collection, and crowdsourcing of knowledge. We conclude by considering questions on how AI and ML methodologies can unite the diverse aspects of translational medicine for emerging treatment development in human-challenging diseases.
Diffuse parenchymal lung disease (DPLD) is a group of distinct inflammatory-fibrotic diseases with varied causes, clinical presentations, and outcomes. Complex pathogenesis, patient heterogeneity, and nonspecificity of diagnostic techniques make its management challenging. In the past decade, there have been marked advances in the understanding of the pathophysiology of and management options for DPLD, especially through multidisciplinary collaboration, which has improved the accuracy of diagnosis and aided in personalized treatment strategies, thereby improving patient outcomes. The management of DPLD includes specific therapeutic options, which vary based on the underlying etiology and disease pattern, such as antifibrotics for progressive fibrotic diseases, as well as common strategies focusing on disease monitoring and management of symptoms and comorbidities. This review discusses updates in epidemiology, classification, pathophysiology, and management as well as ongoing research exploring new diagnostic and therapeutic options for different DPLD subtypes.
The past century has witnessed a paradigm shift in our understanding of the immune system's impact on tumor immunogenicity, outgrowth, and therapy. These advances come not only as a consequence of our enhanced appreciation for the mechanisms underlying immune system function but also because of new experimental technologies that made these advancements possible. Among the most impactful advances has been the development of the field of immunogenomics, which uses next-generation sequencing and predictive algorithms to rapidly identify tumor-specific mutant proteins. These mutant proteins serve as immunotherapy targets, enabling the immune system to differentiate cancer cells from normal cells. The ability to identify these so-called somatic mutation-based tumor neoantigens has led tumor immunologists to explore their efficacy in personalized cancer vaccines, first in mouse tumor models and then in human cancer patients. This review highlights the efforts leading to the discovery and use of tumor- and patient-specific neoantigens, summarizes preclinical and clinical studies that established the efficacy of tumor-specific neoantigen cancer vaccines, discusses challenges and opportunities in the therapeutic use of these vaccines in cancer patients, and summarizes current efforts to render these therapies more generalizable to a larger group of cancer patients.
A new era in obesity management is emerging, characterized by the development of more effective treatments and healthcare strategies. A paradigm shift in obesity care calls for a more integrated, community-based approach that bridges the gap between medical management and bariatric surgery. This review explores important pillars related to obesity management, encompassing aspects related to the pathophysiology of the disease; treatments related to behavioral, nutritional, pharmacotherapeutic, and surgical approaches; and stigma mitigation.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease impacting one-third of the adult population worldwide. MASLD has substantial associated morbidity and mortality, including progression to cirrhosis with the need for liver transplantation and development of hepatocellular carcinoma. Individuals with metabolic dysfunction-associated steatohepatitis (MASH), the more aggressive subtype of MASLD that includes hepatocyte injury, and stage 2 fibrosis or above are at the highest risk for adverse liver-related outcomes and overall mortality. Identification of high-risk individuals is key as these patients would benefit from directed pharmacotherapy for MASH. Additional directed pharmacotherapy agents are in development for MASH and hepatic fibrosis across various mechanisms of action. This review focuses on therapeutic options for and approaches to treatment in MASLD, including emerging agents.
Transthyretin amyloid cardiomyopathy (ATTR-CM) has emerged as a significant yet underdiagnosed cause of heart failure. Advancements in the noninvasive imaging that facilitates diagnosis at an earlier stage of disease and treatment have marked a paradigm shift in the management of this previously fatal disease. This review outlines the epidemiology, pathophysiology, diagnosis, and treatment of ATTR-CM, with an emphasis on the recent developments transforming the field, including an ability to diagnose most patients without a biopsy, the shift toward screening or active ascertainment, the development of several new therapies, and a better understanding of how to employ standard heart failure therapies in patients with this disease. Additionally, the review explores questions that have emerged from these developments.
Microscopic colitis (MC), which predominately affects older adults, is a chronic inflammatory bowel disease characterized by watery diarrhea. Diagnosis relies on histological examination, as there are no established biomarkers to facilitate noninvasive diagnosis, and endoscopic findings are typically unremarkable. MC is classified into subtypes of lymphocytic and collagenous colitis. First-line therapy is budesonide (9 mg/day for 6-8 weeks), which induces remission effectively. However, relapse rates are high, necessitating alternative treatment strategies. Long-term maintenance strategies include low-dose budesonide, bile salt binders, antidiarrheals, and advanced therapies for refractory cases.
We take a Paleolithic perspective to account for why nephrolithiasis afflicts so many people and review evidence suggesting that the rapid shift in the human diet 10,000 years ago was a key event that increased stone risk in the modern era. For the past 2 million years, the diet of the hominid family was high in potassium, low in sodium, and high in alkali precursors. A series of technological advances in agriculture, animal husbandry, and industrial-scale food production transformed the human diet to contain more sodium, less potassium, and more acid precursors. This dietary shift was abrupt enough that the kidney was forced to maintain homeostasis at the expense of increasing stone risk. In theory, dietary patterns that resemble the Paleolithic diet should reduce stone risk. Medications like thiazides, alkali, and empagliflozin may improve urinary parameters associated with stone risk, but more clinical trials are needed to test their efficacy for reducing stone recurrence.
Advances in cancer genomics have significantly influenced and improved oncologic treatments in recent years. Somatic genetic testing, which assesses for gene amplification and acquired mutations in tumor tissue, enables the identification of actionable mutations (i.e., biomarkers) to determine patients who may benefit from targeted therapies. Despite the progress made in somatic genetic testing, broad accessibility and adoption have been limited due to multifactorial barriers. Systematically addressing obstacles to somatic genetic testing is required to enhance availability, facilitate cancer treatments, and ultimately improve patient care.
Peripheral artery disease (PAD) is a prevalent and underdiagnosed atherosclerotic condition affecting more than 10 million adults in the United States. PAD is a marker of systemic vascular disease and a strong predictor of myocardial infarction, stroke, and mortality. Despite its clinical importance, PAD remains underrecognized due to variable presentation, limitations in screening, and disparities in diagnosis and treatment. This review examines contemporary PAD epidemiology, diagnostic strategies (including the ankle-brachial index), and evidence-based management approaches, from supervised exercise to surgical revascularization. It also highlights the evolving debate on PAD screening guidelines and presents emerging evidence favoring targeted screening in high-risk populations. Importantly, the review explores structural inequities, racial and ethnic disparities, and geographic variation in PAD-related outcomes, particularly amputation. These disparities persist even after adjustment for comorbidities and socioeconomic factors. Addressing PAD effectively requires comprehensive strategies that include early diagnosis, equitable access to care, and policy initiatives.
For decades, the management of locally advanced rectal cancer has been trimodal therapy with radiotherapy, surgery, and chemotherapy. Collectively, the adoption of total neoadjuvant therapy (TNT), advances in how radiotherapy and chemotherapy are administered, and the introduction of immunotherapy for patients with mismatch repair-deficient tumors have revolutionized the treatment paradigm of locally advanced rectal cancer, most notably by making nonoperative management possible in up to half of patients. Here, we highlight landmark studies that inform the use of TNT. We then discuss ongoing research efforts and future directions in the field with the ultimate goal of improving both survival and quality of life for patients with locally advanced rectal cancer.
Cancer immunotherapy has advanced through immune checkpoint inhibitors and T cell therapies, yet challenges persist in overcoming immune evasion. Neoantigen-based vaccines have shown promise, particularly in tumors with high tumor mutation burden. However, logistical barriers and tumor heterogeneity limit their scalability. Shared oncogenic driver mutations (e.g., KRAS, EGFR, IDH) offer a stable and broadly applicable alternative. Clinical trials demonstrate their immunogenicity and potential in minimal residual disease settings. Advances in vaccine delivery and immune modulation, including adjuvants and cytokine-based therapies, may further enhance efficacy. This review explores the evolution of oncogene-directed vaccines, their clinical impact, and future strategies to optimize their therapeutic potential.
