Stroke is the fifth leading cause of death in the United States and disproportionately affects Black Americans. The Reasons for Geographic and Racial Disparities in Stroke (REGARDS) cohort study is investigating why this disparity exists by comparing Black and White adults age 45+. Seminal findings included that higher stroke incidence in Black than in White persons, but not higher case fatality, drives the disparity. Higher prevalence of stroke risk factors in Black participants, especially hypertension and diabetes, explained 50% of the racial disparity. Elevated lipoprotein(a) was three times more frequent in Black participants and was a race-specific stroke risk factor only among Black participants. Higher interleukin-6 was a strong stroke risk factor in both Black and White participants with a hazard ratio of 2.0 for concentrations in the top versus bottom quartile. In mediation analysis, higher interleukin-6 with presence of stroke risk factors party explained the race disparity in stroke. Findings highlight the potential that prevention of stroke risk factors, treatment of higher Lp(a), and inflammation reduction have in reducing the race disparity in stroke.
The only Food and Drug Administration (FDA)-approved biomarker for prediction of acute kidney injury (AKI) in adults has a false positive rate (FPR) of 50%. We identified insulin-like growth factor-binding protein 1 (IGFBP-1) as a good but not great predictor of severe AKI. IGFBP-1 was cleaved by an enzyme in the urine. We tested the ability of IGFBP-1 cleavage to predict progression to dialysis. Urine from all 12 patients with stage 1 AKI that progressed to require dialysis cleaved the protein (100% sensitivity). FPR was 0% among healthy controls. FPRs among patients with stage 1 AKI at the time of collection were 11% for patients who did not progress beyond stage 1, 15% for patients who progressed to stage 2, and 50% for patients who progressed to stage 3 but did not require dialysis. The sensitivity of a test with these characteristics would be 100% in a typical intensive care unit (ICU) population, and the FPR would be 6%.
Today's first-line tuberculosis regimen was developed in the 1950s to 1970s, followed by a long period of stagnation. New drugs have progressed to market only recently, with long timelines from target discovery to clinical trial success, alongside costly Phase 3 failures. Currently, the tuberculosis drug development pipeline is robust, containing multiple new chemical entities from diverse drug classes, motivating us to optimize this opportunity to advance compounds effectively and efficiently. In this article, we explore how recent innovations in data integration and computational methods are revolutionizing tuberculosis drug development, accelerating development timelines, and heightening the probability of success. We anticipate that these breakthroughs will lead to approval of novel drugs in unprecedented time frames, marking a significant milestone in the fight against this age-old disease. This progress is timely, as resistance to even recently registered drugs is emerging rapidly. Our hope is that these strategies will also be of value in other medical fields.
Given that low testosterone levels predict type 2 diabetes mellitus (T2DM) in men, we sought to dissect the relationship between testosterone and insulin sensitivity in men. We showed a positive correlation between serum testosterone levels and insulin sensitivity in men across the full spectrum of glucose tolerance. Men with hypogonadal testosterone levels were twice as insulin resistant as eugonadal controls. By dissecting the hypothalamic-pituitary-gonadal axis, we demonstrated that the cause of low testosterone was a decrease in testicular responsiveness to luteinizing hormone (LH). Using functional and genetic studies, we provided evidence that hypogonadism may induce insulin resistance by causing mitochondrial dysfunction. We also showed that weight loss can increase testosterone levels and reverse hypogonadism in over 50% of obese men with impaired glucose tolerance. We concluded that the relationship between testosterone and insulin resistance in men is bidirectional. Our data emphasized the importance of lifestyle modification as a key therapeutic step in the management of the hypogonadal male.
Aging is a recent development in human history with nearly half of all median life expectancy gains occurring in the last two to three centuries. Aging is the strongest risk factor for medical conditions that predominately account for morbidity, mortality, and health care costs: cancer, heart disease, stroke, arthritis, and neurodegenerative disease. The geroscience hypothesis postulates that mechanisms of aging simultaneously drive multiple chronic illnesses and functional decline/disability, and intervening in the rate of aging can prevent multiple diseases. Geroscience now relies on 12 identified "hallmarks" or "pillars" of aging that involve alterations in genomic stability/repair, telomere length, epigenetics, proteostasis, macroautophagy, nutrient-sensing, mitochondrial function, cellular senescence, stem cell regeneration, intercellular communication, inflammation, and the microbiome. These pillars are mechanisms/pathways associated with aging, and evidence for causal associations is rapidly becoming more robust. Geroscience-based interventions may reduce illness burden-preserving function and independence-to a greater degree than addressing illnesses one by one. However, the pathway from promise to success is riddled with obstacles and potential pitfalls. Even success can have negative impacts on human populations and our planet that will require major shifts in society. Both the promises and perils of geroscience are likely to shape medical research and ethical debate for years to come.
As the state's land-grant research institution, we implemented a transdisciplinary research strategy in the College of Medicine (COM) forming multiple research teams selected with criteria for success and progress. To assess for key factors, we reviewed the literature and data from studies conducted at the University of Kentucky (UK) that included a quantitative study with a mixed-methods approach to assess team dynamics, collaboration, and research outcomes, as well as a qualitative study (1,2). Team interactions were positively associated with scholarly products. We also experienced an approximate doubling of the COM National Institutes of Health (NIH) funding over four years. Based on these data and experiences, we developed a process for future team building. In summary, we describe a team-based model with consideration of evidential criteria for structure, monitoring, and success metrics, and we developed a process that could be used by leadership to develop transdisciplinary teams across the university for research, education, or service.
Phosphorus metabolism disorders are independent risk factors for cardiovascular disease, kidney disease, and mortality. Given that excessive dietary phosphorus intake is prevalent in the general population and significantly contributes to disruptions in phosphorus balance, there is growing interest in limiting phosphorus intake as a potential strategy to enhance cardiovascular and kidney health. Socioeconomic status is a major determinant of phosphorus intake, as extensive epidemiological research indicates a direct correlation between income, education, and diet quality. Beyond individual socioeconomic indicators like income and education, built environment factors such as the availability of and access to healthy food outlets, as well as the density of fast-food restaurants in certain areas, greatly affect individuals' ability to moderate phosphorus consumption. Given the strong link between the built environment and diet quality, any effective strategy to reduce excess phosphorus intake and improve health outcomes must address built environmental challenges in accessing healthy foods.
Integrins play a critical role in leukocyte recruitment and activation within inflamed tissues. These heterodimeric cell-surface receptors recognize ligands on vascular endothelium or extracellular matrix to initiate intracellular signals leading to leukocyte adhesion, migration, and activation. The best-described role for integrins is in the leukocyte adhesion cascade, which is the process by which leukocytes exit the blood vasculature and enter the tissues in response to infection or injury. During the adhesion cascade, integrin signaling is required for changes in leukocyte cytoskeletal structure required for firm adhesion to endothelial cells, followed by intravascular crawling and transmigration from the bloodstream into the tissues. During this process, integrin signaling augments leukocytes' inflammatory and antimicrobial functions. Mutations in the genes encoding integrins or their downstream signaling molecules result in immunodeficiency and altered tissue repair following injury. Many of these mutations occur in proteins involved in the reorganization of the actin cytoskeleton and have become known as actinopathies, the classic example being Wiskott-Aldrich syndrome. We describe a new actinopathy-type mutation in the integrin signaling molecule SKAP2, which is associated with autoimmunity and type 1 diabetes.
A critical adaptation required for successful extrauterine life is the onset of respiration. The production of pulmonary surfactant by alveolar type II (AT2) cells is required for functional ventilation. Pulmonary surfactant is produced in lamellar bodies in AT2 cells. Key components of pulmonary surfactant include phospholipids and surfactant proteins B (SP-B) and C (SP-C). Phospholipids are transported into lamellar bodies by ATP-binding cassette subfamily A member 3 (ABCA3) where they combine with SP-B and -C to form surfactant that is secreted into alveoli. Recessive loss of function mutations in surfactant protein B (SFTPB) and ABCA3, or monoallelic dominant mutations in surfactant protein C (SFTPC), can cause severe respiratory distress in term newborns, later-onset childhood interstitial lung disease (ChILD), or adult-onset ILD. Currently, no specific treatments for these diseases are available. Genetic therapies, including gene addition and gene editing strategies, offer the possibility to correct these defects in AT2 progenitor cells.
Scientific fraud, particularly within medical journals, is a critical and complex issue due to the potential consequences for public health. Medical research plays a crucial role in informing scientific innovation, guiding clinical practice, and driving advancements in treatments. False or misleading research can influence future discovery, lead to ineffective or harmful treatments, waste valuable resources, and erode public trust. A troubling increase in misconduct, including data fabrication and falsification, has been recently noted, although it's unclear whether this partially reflects the development of better methods of detection. Addressing the issue of scientific fraud in medical journals requires a concerted effort from all stakeholders involved, including researchers, journal editors, peer reviewers, funding agencies, and regulatory bodies. Implementing robust measures for detecting and preventing fraud, promoting transparency and accountability in research practices, and fostering a culture of integrity and ethical conduct are all essential steps toward safeguarding the integrity of medical research.
The scientific research article is a careful balance of factual information and social interaction in which academic writers need to make the results of their research public and persuasive. Although scientific communication through journal articles has a history spanning over 350 years, there remains significant potential for improvement. I hypothesize that compositional strategies employed by artists-particularly landscape artists-can enhance academic scientific writing by promoting interaction and improving persuasive communication. This article explores how principles fundamental to landscape art, such as notan, focal point, element hierarchy, the 80/20 rule, simplification, and repetition, can enhance scientific writing. Awareness and adoption of these artistic techniques can make the scientific writing process more engaging and enjoyable for lovers of science and art alike.
The National Institutes of Health's All of Us Research Program is building one of the most comprehensive research cohorts in the United States. Launched in 2018, the program has enrolled more than 849,000 individuals to empower precision medicine relevant to all populations. Participants in All of Us share complete surveys, share electronic health records, donate biospecimens, and contribute other data, such as wearable device data. To date, All of Us has generated whole genome sequences for more than 414,000 participants and returned actionable genetic health information to more than 100,000. By examining the technological, engagement, and data integration challenges encountered, this paper highlights how All of Us builds on pioneering efforts in biomedical research and points to future directions, including expanded data sharing, international cooperation, and the potential to drive transformative discoveries in personalized health care. Current successes also highlight necessary future directions: even larger and more comprehensive cohorts, better data sharing, and more international cooperation.
I have spent most of my career studying neuroendocrine (NE) tumors or cancers (1-5). NE cancers are a diverse group of tumors that develop in multiple organs throughout the body. During a recent trip to Tasmania, I learned that there is currently an epidemic within the animal kingdom of a transmissible NE cancer. The Tasmanian devil (Sarcophilus harrisii) is only found in Tasmania. Devil facial tumor disease (DFTD) is an aggressive, transmissible, and uniformly fatal NE cancer found exclusively in Tasmanian devils. Tumor cells are transmitted between devils through frequent biting during mating and recognized as a rare clonally transmissible cancer. Tasmanian devils were declared an endangered species in 2008. Several interventions are underway to save this species from this deadly transmissible cancer.
Pericytes are specialized, mural cells essential to vascular integrity and homeostasis, with emerging roles in lung injury, fibrosis, and viral pathology. Situated around capillaries, pericytes can transition into myofibroblast-like cells and contribute to extracellular matrix (ECM) deposition following lung injury. This review delves into pericyte biology in the lung, highlighting their contributions to fibrotic processes, immune response mediation, and potential as viral reservoirs. Experimental insights from murine models and human lung pericytes underscore their dual function in structural repair and immune signaling. Here, we explore the impact of pericyte plasticity on fibrosis and immune dynamics, evaluate their interactions with viruses, and discuss their potential as therapeutic targets in lung disease. A comprehensive understanding of pericyte plasticity and heterogeneity could pave the way for novel treatments targeting fibrosis and virus-induced lung pathology.
Treating breast cancer is both a success story and a lesson in the challenges of tailoring treatment to need. Beginning in the 1980s, multiple initiatives minimized surgical intervention and toxicity, integrated radiation therapy, and began to incorporate increasingly targeted medical therapy. Because of advances in treatment and screening, the U.S. mortality from breast cancer has dropped over 40%. However, these advances have come at a financial, physical, and social cost. It costs nearly $30 billion per year in the United States to achieve these improved outcomes in treating breast cancer, and we know that we overtreat many patients. Moreover, racial disparities in outcome persist, and many patients cannot access modern treatments. Ensuring that we give the right treatment to the right patient, and that we omit therapy when it is safe to do so, will require new strategies.
Programmed death 1 (PD-1) pathway inhibitors have transformed cancer therapy, leading to durable responses in some patients. However, many patients do not benefit from PD-1 blockade therapy, which highlights the critical need to identify new therapeutic targets to complement PD-1 pathway inhibitors. To address this need, we have developed an in vivo clustered regularly interspaced short palindromic repeats (CRISPR)-based screening platform to discover novel regulators of anti-tumor immunity. In this article, I will first discuss the biology of the PD-1 pathway and its role in regulating anti-tumor immunity. Next, I will introduce our innovative CRISPR-based platforms designed for conducting gene screens in mature immune cell lineages and for enabling gene perturbation without stimulating or manipulating immune cells, two approaches that can affect immune cell development and function. In addition, I will illustrate how these platforms facilitate discovery of new targets that can promote anti-tumor immunity and their potential to lead to more effective cancer therapies.
Novel avian influenza viruses continue to circulate in animal species around the world and show a propensity to reassort and acquire virulence factors, which raises the concern that these viruses may adapt to humans. Pandemic preparedness has relied heavily on vaccine stockpiles. However, avian influenza strains genetically drift over time, and stockpiled vaccines often fail to elicit protective immunity for these genetic variants. Various strategies can help overcome immune imprinting and immunological hyporeactivity as well as broaden the immune response to variant viruses. Adjuvants remain a key strategy for improving the immunological response to avian influenza antigens. Today, three vaccines are approved in the United States for H5N1 influenza viruses though continued focus on surveillance and pandemic preparedness is essential to prepare for the possibility of human-to-human spread of this highly pathogenic influenza virus.
Cancer remains a leading cause of mortality in the United States, with significant inequities across racial and ethnic groups. Evidence-based cancer screening and prevention offers one pathway to reducing cancer mortality but can be challenging to implement with high fidelity and equity. In this paper, we describe the development of equitable, evidence-based cancer screening programs in Central Texas as a potential model for other regions and for other conditions for which evidence-based clinical preventive services exist but are not well-implemented or have not been implemented equitably. Key features include basing the program in Federally Qualified Health Centers (FQHCs); developing proactive outreach along with opportunistic in-reach; bilingual, bicultural social work-trained patient navigators for follow-up of abnormal screening; virtual multi-disciplinary conferences for challenging diagnostic and management decisions; and advocacy work to improve the entire screening process, including treatment.
