搜索结果：Transactions of the American Clinical and Climatological Association

The rapid and unprecedented climate changes driven by human-induced greenhouse gas emissions present a critical challenge for society today. However, the link between climate change and health remains inadequately explored in both literature and policy discussions. Thousands of individuals die each year in the United States due to climate-related factors, including extreme temperatures, severe weather, air pollution, and vector-borne diseases, and these health impacts disproportionately affect already vulnerable populations. Climate change is not just an environmental concern but also an imminent threat to individual and population health, as well as a major challenge to health equity. Moreover, the health sector significantly contributes to greenhouse gas emissions. Recognizing their roles as health care providers and contributors to the climate crisis, clinicians and health professionals have a moral obligation to emphasize the profound significance of climate impacts on human health and equity. This lecture provides an overview of efforts by the U.S. National Academy of Medicine and others to address the intersection of climate change and health, with an aim to raise awareness about the immediate threats to patient health and to build a proactive path forward for the health sector. The health sector must unite to collectively tackle these challenges, safeguard patient well-being, and promote the common good in the face of climate-induced health crises.

Otto Warburg sparked the field of cancer metabolism in the 1920s through his observations that human and animal cancer tissues converted significant amounts of glucose to lactate with an elusive underlying mechanism. The discovery of oncogenes led to the notion that neoplasia results from deregulated cell division control with metabolism at the margin, standing by to support cell growth. Studies over the past several decades have linked oncogenes to the direct regulation of metabolism, such as the myelocytomatosis (MYC) oncogene, driving glycolysis and other central metabolic pathways, necessary for cell growth and proliferation. Deregulated oncogenic drive of metabolism renders tumor cells addicted to glucose and other nutrients, such that nutrient deprivation can trigger cancer cell death. The revelation of this addiction stimulated pharmaceutical companies to target metabolism for cancer therapy, but due to several failed clinical studies, this exuberance fizzled commercially. However, the transformative impact of cancer immunotherapy ushered in an interest in understanding the hostile metabolic tumor microenvironment that limits the function of anti-tumor T cells and clinical responses to immunotherapy. This interest drives the convergence of immunometabolism and cancer cell metabolism research to provide a richer understanding of tumor metabolic vulnerability. Herein, I discuss the historical and current context of opportunities and challenges to targeting cancer metabolism.

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.

Calcium-permeable transient receptor potential cation channel subfamily V member 4 (TRPV4) channels, first described in 2000, are activated by osmotic, mechanical, thermal, actinic, and chemical cues; play multiple roles in multiple physiologic processes, organ systems, and diseases; and are expressed in diverse cell lineages, with channel function-expression regulated by metabolic and endocrine state, inflammation, mechanical microenvironment, and other forms of cellular stress. Here, I will focus on TRPV4's role in endothelia, citing three examples that can guide translational efforts and development of TPRV4-focused therapeutics. (i) Peroxynitrite-dependent impairment of endothelial TRPV4 drives obesity-related hypertension. (ii) Blood-brain barrier in MS: TRPV4 drives endothelial inflammation and pro-inflammatory interaction between endothelia and microglia in active lesions. (iii) Gain-of-function spinal cord endothelial TRPV4 causes spinal muscular atrophy via developmental barrier impairment, leakage, and subsequent motoneuron injury. Thus, different pathophysiologic mechanisms need to be met with different strategies when selectively targeting endothelial TRPV4, namely restoration of impaired function (i), versus inhibition of excessive function (ii)-(iii).

Gene-environmental interactions create risk profiles for sporadic cancer development in patients with colorectal cancer (CRC). For instance, a person's socioeconomic status over their lifetime can affect their level of physical activity and type of diet, and their exposure to tobacco and alcohol may affect their gut microbiome and ultimate risk for developing CRC. Metabolic disease can independently or further change the gut microbiome and alter the typical timing of CRC development, such as is observed and linked with early-onset disease. Patients with microsatellite unstable tumors where DNA mismatch repair is defective have altered immune environments as a result of tumor hypermutability and neoantigen generation, allowing for immune checkpoint inhibitor susceptibility; in such cases, the genetics of the tumor changed the environment. The environment can also change the genetics, where interleukin-6-generated inflammation can inactivate MSH3 protein function that is associated with CRCs which are more metastatic, and patients show poor outcomes. Some specific aspects of the local microbial environment that may be influenced by diet and metabolism are associated with CRC risk, such as Fusobacterium nucleatum infection, and may affect the initiation, perpetuation, and spread of CRC. Overall, both the macro- and microenvironments associated with a person play a major role in CRC formation, progression, and metastases.

Early in the pandemic, clinicians recognized an overlap between Long COVID symptoms and dysautonomia, suggesting autonomic nervous system (ANS) dysfunction. Our clinical experience at Johns Hopkins with primary dysautonomia suggested heritability of sympathetic dysfunction, manifesting primarily as hyperhidrosis and as other dysautonomia symptoms. Whole exome sequencing revealed mutations in genes regulating electrical signaling in the nervous system, thus providing a genetic basis for the sympathetic overdrive observed. We hypothesize that dysautonomia in Long COVID requires two molecular hits: a genetic vulnerability to prime the ANS and a SARS-CoV-2 infection, as an immune trigger, to further disrupt ANS function resulting in increased sympathetic activity. Indeed, Long COVID patients show signs of chronic inflammation and autoimmunity. We have translated this two-hit concept to the clinic using ion channel inhibitors to target genetic susceptibility and immunomodulators to treat inflammation. This multi-hit hypothesis shows promise for managing Long COVID and merits further study.

In aggregate, autoimmune diseases affect at least 8% of the U.S. population, making them a significant health problem. Multiple lines of evidence accumulated over the last 20+ years have clearly demonstrated that the pathophysiology leading to autoimmune tissue damage and organ dysfunction occurs over a lengthy and clinically silent time period. As with other chronic diseases, this preclinical phase is an opportunity to identify people at risk and to develop medical and/or lifestyle interventions that can lessen the impact of disease or prevent it entirely. This will require movement away from historical disease definitions that emphasize the clinical features of tissue damage and toward more precise molecular definitions. It is a daunting task that requires large-scale epidemiological studies of immune dysfunction. Ultimately, it creates the opportunity to describe disease "stages" that give patients more clarity about their health and provide researchers, industry, and regulators with a path forward to autoimmune disease prevention.

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.

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 Healthcare Innovation Lab, established by BJC HealthCare and Washington University School of Medicine, has catalyzed care delivery innovations since 2017. Focusing on digital health to enhance care delivery and patient outcomes, the Lab emphasizes predictive analytics, digital point-of-care tools, and remote patient monitoring. The Lab identifies innovative ideas that align with the health system mission and deliver empiric value to its patients and care teams. Since its inception, the Lab has vetted 507 ideas, piloting 98, with a success rate of 40%. Examples include a predictive model to improve palliative care referrals and goal-of-care discussions, a digital approach to non-emergent medical transportation that enhances access and equity, and a COVID-19 home monitoring program that proved essential during the pandemic. These initiatives underscore the importance of integrating digital technology with health care, balancing innovation with practical application, and using a data-informed approach to innovation selection and assessment.

Even before the COVID-19 pandemic, acute respiratory infections represented one of the most common reasons for patients to seek urgent medical care. S. pneumoniae is one of the most frequent bacterial causes of acute respiratory infections, especially community-acquired pneumonia. In the latter part of the twentieth century, the emergence of multidrug resistance among clinical isolates of S. pneumoniae threatened to render standard empiric antibiotic therapy ineffective. One of the biggest drivers of pneumococcal drug resistance is antibiotic overuse, among both adults and children. While the introduction of the pneumococcal conjugate vaccine in 2000 dramatically impacted the overall incidence of pneumococcal pneumonia in both children and adults, the levels of antibiotic resistance have remained significant. To reduce the overuse of antibiotics requires multidimensional interventions targeting patients, clinicians, and health systems. Studies have demonstrated improvement in this area, but the quality gap remains high. Future work will focus on organizational strategies and policies that optimize antibiotic use for patients with antibiotic responsive acute illnesses.

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.

Despite higher per-capita health care spending than any other country, the United States lags far behind in health outcomes. Additionally, there are significant health inequities by race, ethnicity, socioeconomic position, and rurality. One set of potential solutions to improve these outcomes and reduce inequities is through health policy. Policy focused on improving access to care through insurance coverage, such as the Affordable Care Act's Medicaid expansion, has led to better health and reduced mortality. Policy aimed at improving health care delivery, including value-based payment and alternative payment models, has improved quality of care but has had little impact on population health outcomes. Policies that influence broader issues of economic opportunity likely have a strong influence on health, but lack the evidence base of more targeted interventions. To advance health outcomes and equity, further policy change is crucial.

Adrenocortical carcinoma (ACC) is an orphan cancer with 35% five-year survival that has been unchanged for last five decades. Patients often present with severe hypercortisolism or with mass effects. The only Food and Drug Administration (FDA)-approved drug for ACC is mitotane, an insecticide derivative, which provides only limited additional months of survival, but with toxicities. Little progress in the field has occurred due to a lack of preclinical models. We recently developed new human ACC in vitro and in vivo research models. We produced the first two new ACC cell lines for the field, CU-ACC1 and CU-ACC2, which we have distributed for global collaborations. In addition, we developed 10 ACC patient-derived xenograft (PDX) and two humanized ACC-PDX models to test new therapeutics and examine the mechanism of mitotane action in combination with immunotherapy. These new preclinical models allow us to identify novel targets and test new therapeutics for our patients with adrenal cancer.

Genome instability is a hallmark of cancer, allowing for clonal evolution and improved tumor fitness. The mis-repair of DNA double-strand breaks (DSBs) is a major source of genome instability. DNA DSBs are normally repaired by homologous recombination (HR) and nonhomologous end joining (NHEJ). The nucleolytic resection of broken DNA ends generates single-stranded DNA (ssDNA) overhangs that are required for HR, but inhibitory to NHEJ. DNA end resection must be prevented in nondividing cells where NHEJ is the only active DSB repair pathway. Using a novel whole genome gRNA CRISPR/Cas9 screen, we identified the GID complex as functioning to protect DNA ends from nucleolytic resection. The GID complex contains multiple E3 ubiquitin ligase subunits and regulates the expression and function of pro-resection machinery. Thus, by antagonizing DNA end resection GID may prevent homology-mediated joining leading to aberrant DSB repair and genome instability in normal and cancerous nondividing cells.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by epithelial proliferation and progressive cyst enlargement. Using a non-targeted high-resolution metabolomics approach, we analyzed biofluids from 36 ADPKD and 18 healthy controls with estimated glomerular filtration rate (eGFR) > 60 ml/min to identify features specific to ADPKD or that associate with disease severity [eGFR or height-corrected total kidney volume (htTKV)]. Multiple pathways differed between ADPKD subjects and controls, with the histidine pathway being the most highly represented. Plasma histidine, urinary N-methylhistamine, methylimidazole-acetaldehyde, and imidazole-acetaldehyde, as well as 3-methylhistidine and anserine were increased, while plasma N-acetylhistamine and urinary imidazole-acetic acid were decreased in ADPKD compared to controls. In ADPKD, urinary histidine and a histidine derivative, urocanate (a precursor of glutamate), were significantly associated. HtTKV and eGFR were inversely associated with urinary glutamine and plasma 4-imidazolone-5-propionic acid, respectively. Supernatant from cultured human ADPKD renal cystic epithelia demonstrated increased aspartate and glutamate levels at 8 and 24 hours compared to primary tubular epithelia (p < 0.001). Following exposure over 48 hours to &#x3b1;-fluromethylhistidine, an inhibitor of histamine production, primary human PKD1 cyst epithelia proliferation increased significantly from baseline (p < 0.01) and greater than non-cystic epithelia (p < 0.05). The histidine ammonia lyase inhibitor nitromethane reversed &#x3b1;-fluromethylhistidine-induced cyst epithelia proliferation indicating a role for glutamate in cyst growth. In conclusion, histidine metabolism is altered preferentially leading to glutamate production and epithelial proliferation in ADPKD and associates with disease severity.

Housing instability has been shown to negatively impact physical and mental health, with a corresponding increase in health care utilization. In 2019, through a Maryland Medicaid 1115 Health Choice Waiver, 10 Baltimore city hospitals joined with the city of Baltimore and the local nonprofit Health Care for the Homeless to support an innovative program that provides permanent housing and wraparound services to individuals at risk of homelessness. Here, we describe the inception of the program and its subsequent expansion with the investment of the city hospitals. Participants in the program experienced a 48% reduction in all hospital visits and a 51% reduction in emergency department visits in the 12 months following their receipt of housing compared to the 12 months before enrollment. These data suggest the potential health benefits of housing and supportive services as an intervention.

Health care-associated infections (HAIs) remain a major challenge in the U.S. health care system, with Clostridioides difficile (C. difficile or C. diff) being the most prevalent. The use of antibiotics disrupts the gut microbiota, predisposing individuals to infection. Recent research has highlighted the role of the gut microbiome in preventing and treating C. difficile infections (CDI). Strategies such as fecal microbiota transplantation (FMT) and live biotherapeutic products (LBPs) offer promising alternatives to conventional antibiotic treatments. This paper explores the mechanisms underlying CDI, the role of the gut microbiome in infection prevention, and innovative therapeutic approaches.

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.