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The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.
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BACKGROUND: Redlining began in the 1930s with the Home Owners' Loan Corporation (HOLC); this discriminatory practice limited mortgage availability and reinforced concentrated poverty that still exists today. It is important to understand the potential health implications of this federally sanctioned segregation. OBJECTIVE: To examine the relationship between historical redlining policies and present-day nonsuicide firearm fatalities. DESIGN: Maps from the HOLC were overlaid with incidence of nonsuicide firearm fatalities from 2014 to 2022. A multilevel negative binomial regression model tested the association between modern-day firearm fatalities and HOLC historical grading (A ["best"] to D ["hazardous"]), controlling for year, HOLC area-level demographics, and state-level factors as fixed effects and a random intercept for city. Incidence rates (IRs) per 100 000 persons, incidence rate ratios (IRRs), and adjusted IRRs (aIRRs) for each HOLC grade were estimated using A-rated areas as the reference. SETTING: 202 cities with areas graded by the HOLC in the 1930s. PARTICIPANTS: Population of the 8597 areas assessed by the HOLC. MEASUREMENTS: Nonsuicide firearm fatalities. RESULTS: From 2014 to 2022, a total of 41 428 nonsuicide firearm fatalities occurred in HOLC-graded areas. The firearm fatality rate increased as the HOLC grade progressed from A to D. In A-graded areas, the IR was 3.78 (95% CI, 3.52 to 4.05) per 100 000 persons per year. In B-graded areas, the IR, IRR, and aIRR relative to A areas were 7.43 (CI, 7.24 to 7.62) per 100 000 persons per year, 2.12 (CI, 1.94 to 2.32), and 1.42 (CI, 1.30 to 1.54), respectively. In C-graded areas, these values were 11.24 (CI, 11.08 to 11.40) per 100 000 persons per year, 3.78 (CI, 3.47 to 4.12), and 1.90 (CI, 1.75 to 2.07), respectively. In D-graded areas, these values were 16.26 (CI, 16.01 to 16.52) per 100 000 persons per year, 5.51 (CI, 5.05 to 6.02), and 2.07 (CI, 1.90 to 2.25), respectively. LIMITATION: The Gun Violence Archive relies on media coverage and police reports. CONCLUSION: Discriminatory redlining policies from 80 years ago are associated with nonsuicide firearm fatalities today. PRIMARY FUNDING SOURCE: Fred Lovejoy Housestaff Research and Education Fund.
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Armas de Fogo , Ferimentos por Arma de Fogo , Humanos , Armas de Fogo/legislação & jurisprudência , Ferimentos por Arma de Fogo/mortalidade , Estados Unidos/epidemiologia , IncidênciaRESUMO
Understanding the cell-type composition and spatial organization of brain regions is crucial for interpreting brain computation and function. In the thalamus, the anterior thalamic nuclei (ATN) are involved in a wide variety of functions, yet the cell-type composition of the ATN remains unmapped at a single-cell and spatial resolution. Combining single-cell RNA sequencing, spatial transcriptomics, and multiplexed fluorescent in situ hybridization, we identify three discrete excitatory cell-type clusters that correspond to the known nuclei of the ATN and uncover marker genes, molecular pathways, and putative functions of these cell types. We further illustrate graded spatial variation along the dorsomedial-ventrolateral axis for all individual nuclei of the ATN and additionally demonstrate that the anteroventral nucleus exhibits spatially covarying protein products and long-range inputs. Collectively, our study reveals discrete and continuous cell-type organizational principles of the ATN, which will help to guide and interpret experiments on ATN computation and function.
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Núcleos Anteriores do Tálamo , Animais , Camundongos , Núcleos Anteriores do Tálamo/metabolismo , Hibridização in Situ FluorescenteRESUMO
This article draws on Paulo Freire's Pedagogy of the Oppressed to model how health professions education can advance health equity. It first introduces 3 well-known frameworks that can be meaningfully applied as critical pedagogy: structural competency, critical race theory, and participatory action research. It then highlights applications of these frameworks that can prepare trainees for reflection and action that motivate health equity.
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Antirracismo , Equidade em Saúde , Humanos , Pesquisa sobre Serviços de Saúde , Ocupações em SaúdeRESUMO
Importance: Although discharges against medical advice (DAMA) are associated with greater morbidity and mortality, little is known about current racial and ethnic disparities in DAMA from the emergency department (ED) nationally. Objective: To characterize current patterns of racial and ethnic disparities in rates of ED DAMA. Design, Setting, and Participants: This cross-sectional study used data from the Nationwide Emergency Department Sample on all hospital ED visits made between January to December 2019 in the US. Main Outcomes and Measures: The main outcome was odds of ED DAMA for Black and Hispanic patients compared with White patients nationally and in analysis adjusted for sociodemographic factors. Secondary analysis examined hospital-level variation in DAMA rates for Black, Hispanic, and White patients. Results: The study sample included 33â¯147â¯251 visits to 989 hospitals, representing the estimated 143 million ED visits in 2019. The median age of patients was 40 years (IQR, 22-61 years). Overall, 1.6% of ED visits resulted in DAMA. DAMA rates were higher for Black patients (2.1%) compared with Hispanic (1.6%) and White (1.4%) patients, males (1.7%) compared with females (1.5%), those with no insurance (2.8%), those with lower income (<$27 999; 1.9%), and those aged 35 to 49 years (2.2%). DAMA visits were highest at metropolitan teaching hospitals (1.8%) and hospitals that served greater proportions of racial and ethnic minoritized patients (serving ≥57.9%; 2.1%). Odds of DAMA were greater for Black patients (odds ratio [OR], 1.45; 95% CI, 1.31-1.57) and Hispanic patients (OR, 1.16; 95% CI, 1.04-1.29) compared with White patients. After adjusting for sociodemographic characteristics (age, sex, income, and insurance status), the adjusted OR (AOR) for DAMA was lower for Black patients compared with the unadjusted OR (AOR, 1.18; 95% CI, 1.09-1.28) and there was no difference in odds for Hispanic patients (AOR, 1.03; 95% CI, 0.92-1.15) compared with White patients. After additional adjustment for hospital random intercepts, DAMA disparities reversed, with Black and Hispanic patients having lower odds of DAMA compared with White patients (Black patients: AOR, 0.94 [95% CI, 0.90-0.98]; Hispanic patients: AOR, 0.68 [95% CI, 0.63-0.72]). The intraclass correlation in this secondary analysis model was 0.118 (95% CI, 0.104-0.133). Conclusions and Relevance: This national cross-sectional study found that Black and Hispanic patients had greater odds of ED DAMA than White patients in unadjusted analysis. Disparities were reversed after patient-level and hospital-level risk adjustment, and greater between-hospital than within-hospital variation in DAMA was observed, suggesting that Black and Hispanic patients are more likely to receive care in hospitals with higher DAMA rates. Structural racism may contribute to ED DAMA disparities via unequal allocation of health care resources in hospitals that disproportionately treat racial and ethnic minoritized groups. Monitoring variation in DAMA by race and ethnicity and hospital suggests an opportunity to improve equitable access to health care.
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Etnicidade , Alta do Paciente , Feminino , Masculino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Estudos Transversais , Serviço Hospitalar de Emergência , Hospitais de EnsinoRESUMO
Introduction: Graphical abstracts may enhance dissemination of scientific and medical research but are also prone to reductionism and bias. We conducted a systematic content analysis of the Journal of Internal Medicine (JIM) Graphical Abstract Gallery to assess for evidence of bias. Materials and Methods: We analyzed 140 graphical abstracts published by JIM between February 2019 and May 2020. Using a combination of inductive and deductive approaches, we developed a set of codes and code definitions for thematic, mixed-methods analysis. Results: We found that JIM graphical abstracts disproportionately emphasized male (59.5%) and light-skinned (91.3%) bodies, stigmatized large body size, and overstated genetic and behavioral causes of disease, even relative to the articles they purportedly represented. Whereas 50.7% of the graphical surface area was coded as representing genetic factors, just 0.4% represented the social environment. Discussion: Our analysis suggests evidence of bias and reductionism promoting normative white male bodies, linking large bodies with disease and death, conflating race with genetics, and overrepresenting genes while underrepresenting the environment as a driver of health and illness. These findings suggest that uncritical use of graphical abstracts may distort rather than enhance our understanding of disease; harm patients who are minoritized by race, gender, or body size; and direct attention away from dismantling the structural barriers to health equity. Conclusion: We recommend that journals develop standards for mitigating bias in the publication of graphical abstracts that (1) ensure diverse skin tone and gender representation, (2) mitigate weight bias, (3) avoid racial or ethnic essentialism, and (4) attend to sociostructural contributors to disease.
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Background: The discontinuation of the Step 2 Clinical Skills Exam (CS) by the United States Medical Licensing Examination (USMLE) eliminated the need for personal travel to testing centers. The carbon emissions associated with CS have not been previously quantified. Objective: To estimate the annual carbon emissions generated by travel to CS Testing Centers (CSTCs) and to explore differences across geographic regions. Methods: We conducted a cross-sectional, observational study by geocoding medical schools and CSTCs to calculate the distance between them. We obtained data from the 2017 matriculant databases of the Association of American Medical Colleges (AAMC) and the American Association of Colleges of Osteopathic Medicine (AACOM). The independent variable was the location as defined by USMLE geographic regions. The dependent variables were distance traveled to CSTCs and estimated carbon emissions in metric tons CO2 (mtCO2) calculated using three models. In model 1 all students used single occupancy vehicles; in model 2, all carpooled; and in model 3, half traveled by train and half by single occupancy vehicle. Results: Our analysis included 197 medical schools. The mean out-of-town travel distance was 280.67 miles (IQR: 97.49-383.42). The mtCO2 associated with travel was 2,807.46 for model 1; 3,135.55 for model 2; and 635.34 for model 3. The Western region traveled the farthest, while the Northeast traveled significantly less than other regions. Conclusion: The annual estimated carbon emissions from travel to CSTCs was approximately 3,000 mtCO2. Northeastern students traveled the shortest distances; the average US medical student expended 0.13 mtCO2. Medical leaders must consider the environmental impact of medical curricula and pursue accordant reforms.
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Estudantes de Medicina , Humanos , Estados Unidos , Competência Clínica , Estudos Transversais , Avaliação Educacional , Faculdades de MedicinaRESUMO
Abortion is healthcare. Bodily autonomy is a fundamental human right. As chief resident physicians representing family medicine residency programs in the Greater Bay Area and Central California in the University of California San Francisco Family Medicine Alliance, we share a deep commitment to promoting health equity, advancing social justice, and eliminating health disparities. The 2022 Supreme Court decision in Dobbs v. Jackson Women's Health Organization to overturn Roe v. Wade contradicts the inherent rights of patients to make their own reproductive healthcare decisions. This is a clarion call for all people to engage in activities to raise awareness and prompt discussion about abortion, reproductive rights, and maternal mortality.
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OBJECTIVES: The objective was to conduct a scoping review of the literature and develop consensus-derived research priorities for future research inquiry in an effort to (1) identify and summarize existing research related to race, racism, and antiracism in emergency medicine (EM) and adjacent fields and (2) set the agenda for EM research in these topic areas. METHODS: A scoping review of the literature using PubMed and EMBASE databases, as well as review of citations from included articles, formed the basis for discussions with community stakeholders, who in turn helped to inform and shape the discussion and recommendations of participants in the Society for Academic Emergency Medicine (SAEM) consensus conference. Through electronic surveys and two virtual meetings held in April 2021, consensus was reached on terminology, language, and priority research questions, which were rated on importance or impact (highest, medium, lower) and feasibility or ease of answering (easiest, moderate, difficult). RESULTS: A total of 344 articles were identified through the literature search, of which 187 met inclusion criteria; an additional 34 were identified through citation review. Findings of racial inequities in EM and related fields were grouped in 28 topic areas, from which emerged 44 key research questions. A dearth of evidence for interventions to address manifestations of racism in EM was noted throughout. CONCLUSIONS: Evidence of racism in EM emerged in nearly every facet of our literature. Key research priorities identified through consensus processes provide a roadmap for addressing and eliminating racism and other systems of oppression in EM.
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Medicina de Emergência , Racismo , Humanos , Consenso , PrevisõesRESUMO
Recent studies have reported that the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is activated in approximately 40% of patients with muscle-invasive bladder cancer. This led us to investigate pharmacological repression of PPARγ as a possible intervention strategy. Here, we characterize PPARγ antagonists and inverse agonists and find that the former behave as silent ligands, whereas inverse agonists (T0070907 and SR10221) repress downstream PPARγ target genes leading to growth inhibition in bladder cancer cell lines. To understand the mechanism, we determined the ternary crystal structure of PPARγ bound to T0070907 and the corepressor (co-R) peptide NCOR1. The structure shows that the AF-2 helix 12 (H12) rearranges to bind inside the ligand-binding domain, where it forms stabilizing interactions with the compound. This dramatic movement in H12 unveils a large interface for co-R binding. In contrast, the crystal structure of PPARγ bound to a SR10221 analog shows more subtle structural differences, where the compound binds and pushes H12 away from the ligand-binding domain to allow co-R binding. Interestingly, we found that both classes of compound promote recruitment of co-R proteins in biochemical assays but with distinct conformational changes in H12. We validate our structural models using both site-directed mutagenesis and chemical probes. Our findings offer new mechanistic insights into pharmacological modulation of PPARγ signaling.
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PPAR gama , Neoplasias da Bexiga Urinária , Humanos , PPAR gama/metabolismo , Ligantes , Benzamidas/farmacologiaRESUMO
Some clinical algorithms use race as an epidemiological shorthand to "correct" for health determinants that are clinically influential but also variable because they are historical, social, cultural, or economic in origin. Such "correction factors" are both clinically and ethically relevant when their use reinforces racial essentialism and exacerbates racial health inequity. This commentary on a case in which the original vaginal birth after cesarean calculator is used argues that this and similar race-based algorithms should be considered sources of iatrogenic harm by undermining decision sharing in patient-clinician relationships and Black birthing peoples' rights to self-determination.
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Algoritmos , Doença Iatrogênica , Feminino , Humanos , GravidezAssuntos
Buprenorfina , Transtornos Relacionados ao Uso de Opioides , Analgésicos Opioides/uso terapêutico , Buprenorfina/uso terapêutico , Serviço Hospitalar de Emergência , Humanos , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/epidemiologiaRESUMO
Racial essentialism-the belief that socially constructed racial categories reflect "inherent" biological differences-exacerbates learners' racial prejudice and diminishes their empathy. Essentialism hinders health professions education programs' capacity to generate a health care work force that motivates ethics and equity in health care and research. This article suggests how health professions educators and institutions should reform pedagogy on race, when clinically relevant, to emphasize racism as the root cause of health inequity. Publishers of research also have key roles in reform and should enforce appropriate and just references to race in journals and health professions education content.
El esencialismo racial (la creencia de que las categorías raciales construidas socialmente reflejan diferencias biológicas "inherentes") exacerba los prejuicios raciales de los alumnos y disminuye su empatía. El esencialismo dificulta que los programas educativos de las profesiones sanitarias logren producir trabajadores de la salud que motiven la ética y la equidad en la atención y la investigación médicas. Este artículo sugiere cómo los educadores y las instituciones de profesionales sanitarios deberían reformar la pedagogía sobre la raza, cuando sea relevante a nivel clínico, para hacer énfasis en el racismo como la causa de origen de la inequidad sanitaria. Quienes publican investigaciones también tienen un papel clave en la reforma y deben imponer referencias apropiadas y justas a la raza en las publicaciones y el contenido educativo de las profesiones sanitarias.
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Racismo , Empatia , Ocupações em Saúde , HumanosRESUMO
Chronic kidney disease is an important clinical condition beset with racial and ethnic disparities that are associated with social inequities. Many medical schools and health centres across the USA have raised concerns about the use of race - a socio-political construct that mediates the effect of structural racism - as a fixed, measurable biological variable in the assessment of kidney disease. We discuss the role of race and racism in medicine and outline many of the concerns that have been raised by the medical and social justice communities regarding the use of race in estimated glomerular filtration rate equations, including its relationship with structural racism and racial inequities. Although race can be used to identify populations who experience racism and subsequent differential treatment, ignoring the biological and social heterogeneity within any racial group and inferring innate individual-level attributes is methodologically flawed. Therefore, although more accurate measures for estimating kidney function are under investigation, we support the use of biomarkers for determining estimated glomerular filtration rate without adjustments for race. Clinicians have a duty to recognize and elucidate the nuances of racism and its effects on health and disease. Otherwise, we risk perpetuating historical racist concepts in medicine that exacerbate health inequities and impact marginalized patient populations.
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Nefrologia , Racismo , Desigualdades de Saúde , Disparidades nos Níveis de Saúde , Humanos , Justiça Social , Estados UnidosRESUMO
BACKGROUND: Standard equations for estimating glomerular filtration rate (eGFR) employ race multipliers, systematically inflating eGFR for Black patients. Such inflation is clinically significant because eGFR thresholds of 60, 30, and 20 ml/min/1.73m2 guide kidney disease management. Racialized adjustment of eGFR in Black Americans may thereby affect their clinical care. In this study, we analyze and extrapolate national data to assess potential impacts of the eGFR race adjustment on qualification for kidney disease diagnosis, nephrologist referral, and transplantation listing. METHODS: Using population-representative cross-sectional data from the United States National Health and Nutrition Examination Survey (NHANES) from 2015-2018, eGFR values for Black Americans were calculated using the Modification of Diet in Renal Disease (MDRD) equation with and without the 1.21 race-specific coefficient using cohort data on age, sex, race, and serum creatinine. FINDINGS: Without the MDRD eGFR race adjustment, 3.3 million (10.4%) more Black Americans would reach a diagnostic threshold for Stage 3 Chronic Kidney Disease, 300,000 (0.7%) more would qualify for beneficial nephrologist referral, and 31,000 (0.1%) more would become eligible for transplant evaluation and waitlist inclusion. INTERPRETATION: These findings suggest eGFR race coefficients may contribute to racial differences in the management of kidney. We provide recommendations for addressing this issue at institutional and individual levels. FUNDING: No external funding was received for this study.
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Ideas of racial genetic determinism, though unsupported by scientific evidence and atavistic, are common and readily apparent in American medical education. These theories of biologic essentialism have documented negative effects in learners, including increased measures of racial prejudice.
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Empatia , Racismo , Humanos , Faculdades de MedicinaRESUMO
People experiencing homelessness (PEH) suffer higher burdens of chronic illnesses, have higher rates of emergency medicine (ED) use and hospitalization, and ultimately are at increased risk for premature death compared to housed counterparts. Structural racism contributes to a disproportionate burden of homelessness among people of color. PEH experience not only significant medical concerns but also complex social needs that need to be addressed concurrently for effective healing, issues that have been magnified by the COVID-19 pandemic. As health disparities and structural racism intersect among PEH, it is critically important to develop PEH-centered interventions to improve care and health outcomes as part of an effort to dismantle racism. One opportunity to address these disparities in care for PEH is through training ED physicians on methods for identifying and intervening on the unique needs of vulnerable patient groups. The Accreditation Council for Graduate Medical Education has outlined health quality pathways in the clinical learning environment to address health disparities. Community-based participatory research (CBPR) is particularly well suited for this scenario as it allows experiential learning for trainees to work with and understand a diverse group of stakeholders, to deepen their knowledge of local health disparities, and to lead research and measure outcomes of interventions to tackle health disparities. In this paper, we highlight the utility of CBPR in fostering experiential learning for EM residents on tackling health disparities and the importance of community collaboration in trainee-led interventions for comprehensive ED care.