Esr1 but Not CYP19A1 Overexpression in Mammary Epithelial Cells during Reproductive Senescence Induces Pregnancy-Like Proliferative Mammary Disease Responsive to Anti-Hormonals.

Molecular-level analyses of breast carcinogenesis benefit from vivo disease models. Estrogen receptor 1 (Esr1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) overexpression targeted to mammary epithelial cells in genetically engineered mouse models induces largely similar rates of proliferative mammary disease in prereproductive senescent mice. Herein, with natural reproductive senescence, Esr1 overexpression compared with CYP19A1 overexpression resulted in significantly higher rates of preneoplasia and cancer. Before reproductive senescence, Esr1, but not CYP19A1, overexpressing mice are tamoxifen resistant. However, during reproductive senescence, Esr1 mice exhibited responsiveness. Both Esr1 and CYP19A1 are responsive to letrozole before and after reproductive senescence. Gene Set Enrichment Analyses of RNA-sequencing data sets showed that higher disease rates in Esr1 mice were accompanied by significantly higher expression of cell proliferation genes, including members of prognostic platforms for women with early-stage hormone receptor-positive disease. Tamoxifen and letrozole exposure induced down-regulation of these genes and resolved differences between the two models. Both Esr1 and CYP19A1 overexpression induced abnormal developmental patterns of pregnancy-like gene expression. This resolved with progression through reproductive senescence in CYP19A1 mice, but was more persistent in Esr1 mice, resolving only with tamoxifen and letrozole exposure. In summary, genetically engineered mouse models of Esr1 and CYP19A1 overexpression revealed a diversion of disease processes resulting from the two distinct molecular pathophysiological mammary gland-targeted intrusions into estrogen signaling during reproductive senescence.

Overexpression of Estrogen Receptor α in Mammary Glands of Aging Mice Is Associated with a Proliferative Risk Signature and Generation of Estrogen Receptor α-Positive Mammary Adenocarcinomas.

Age is a risk factor for human estrogen receptor-positive breast cancer, with highest prevalence following menopause. While transcriptome risk profiling is available for human breast cancers, it is not yet developed for prognostication for primary or secondary breast cancer development utilizing at-risk breast tissue. Both estrogen receptor α (ER) and aromatase overexpression have been linked to human breast cancer. Herein, conditional genetically engineered mouse models of estrogen receptor 1 (Esr1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) were used to show that induction of Esr1 overexpression just before or with reproductive senescence and maintained through age 30 months resulted in significantly higher prevalence of estrogen receptor-positive adenocarcinomas than CYP19A1 overexpression. All adenocarcinomas tested showed high percentages of ER+ cells. Mammary cancer development was preceded by a persistent proliferative transcriptome risk signature initiated within 1 week of transgene induction that showed parallels to the Prosigna/Prediction Analysis of Microarray 50 human prognostic signature for early-stage human ER+ breast cancer. CYP19A1 mice also developed ER+ mammary cancers, but histology was more divided between adenocarcinoma and adenosquamous, with one ER- adenocarcinoma. Results demonstrate that, like humans, generation of ER+ adenocarcinoma in mice was facilitated by aging mice past the age of reproductive senescence. Esr1 overexpression was associated with a proliferative estrogen pathway-linked signature that preceded appearance of ER+ mammary adenocarcinomas.

The Chicagoland Free Clinics Consortium: A Model for Student-Run Free Clinic Collaboration.

BACKGROUND: While student-run free clinics (SRFCs) play an important role in care for underserved populations, few mechanisms exist to promote collaboration among regional SRFCs. AIMS: To address this gap, the Chicagoland Free Clinics Consortium (CFCC) was formed to (1) facilitate collaboration between Chicagoland SRFCs, (2) provide innovation grant funding, and (3) host an annual conference. SETTING AND PARTICIPANTS: In 2018, students from the Pritzker School of Medicine founded the CFCC and partnered with peers from area schools to implement programming. PROGRAM DESCRIPTION: Between 2018 and 2022, CFCC engaged 23 SRFCs representing all 6 Chicagoland schools, held 4 annual conferences, and distributed $15,423 in grants to 19 projects at 14 SRFC sites. PROGRAM EVALUATION: A total of 176 students from 5 schools attended the 4 conferences. In 2022, 82 unique participants were surveyed, and 66% (54/82) responded. Eighty percent (43/54) reported they were "more likely to collaborate with other Chicagoland free clinics." In 2022, all grant sites were surveyed and 84% (16/19) responded. Most (87%,14/16) agreed the grant "allowed them to implement a project that would not have otherwise been accomplished" and 21% (4/19) were inter-institutional collaborations. DISCUSSION: To our knowledge, CFCC is the first student-led organization to promote sustained collaboration across SRFCs in a metropolitan area.

An Op-Ed Writing Curriculum for Medical Students to Engage in Advocacy Through Public Writing.

BACKGROUND: Op-ed writing can be a powerful and accessible advocacy tool for physicians, but training is lacking in undergraduate medical education. AIM: To train and engage first-year medical students in op-ed writing. SETTING: Midwestern research-intensive medical school. PARTICIPANTS: All students in a required first-year health policy course in 2021 and 2022. PROGRAM DESCRIPTION: For their health policy course's final assignment, students could opt to write an op-ed on a healthcare issue of their choice. All students received written instruction on op-ed writing. Additionally, they could access a seminar, coaching and editing by peers and faculty, and publication guidance. PROGRAM EVALUATION: Of 179 students over 2 years, 105 chose to write op-eds. Fifty-one attended the seminar, 35 attended peer coaching sessions, 33 accessed structured peer editing, and 23 received faculty assistance. Thirty-eight students submitted a total of 42 op-eds for publication. Twenty-two pieces were published in major outlets and 17 in the university's health policy review. Of the 22 in major outlets, 21 received editing from either peers or faculty. DISCUSSION: An op-ed writing curriculum can be integrated into an existing medical school health policy course, resulting in a high level of engagement and in published op-eds by medical students.

US Medical-Legal Partnerships to Address Health-Harming Legal Needs: Closing the Health Injustice Gap.

The medical-legal partnership (MLP) model is emerging across the USA as a powerful tool to address the adverse social conditions underlying health injustice. MLPs embed legal experts into healthcare teams to address health-harming legal needs with civil legal remedies. We conducted a narrative review of peer-reviewed articles published between 2007 and 2022 to characterize the structure and impacts of US MLPs on patients, providers, and healthcare systems. We found that MLPs largely serve vulnerable patient populations by integrating legal experts into community-based clinical settings or children's hospitals, although patient populations and settings varied widely. In most models, healthcare providers were trained to screen patients for legal needs and refer them to legal experts. MLPs provided a wide range of services, such as assistance accessing public benefits (e.g., Social Security, Medicaid, cash assistance) and legal representation for immigration and family law matters. Patients and their families also benefited from increased knowledge about legal rights and systems. Though the evidence base remains nascent, available studies show MLPs to be associated with greater access to care, fewer hospitalizations, and improved physical and mental health outcomes. Medical and legal providers who were engaged in MLPs reported interdisciplinary learning, and healthcare systems often experienced high returns on investment through cost savings and increased Medicaid reimbursement. Many MLPs also conducted advocacy and education to effect broader policy changes related to population health and social needs. To optimize the MLP model, more rigorous research, systematic implementation practices, evaluation metrics, and sustainable funding mechanisms are recommended. Broader integration of MLPs into healthcare systems could help address root causes of health inequity among historically marginalized populations in the USA.

Neighborhood-level factors associated with COVID-19 vaccination rates: a case study in Chicago.

INTRODUCTION: Chicago's deeply-rooted racial and socioeconomic residential segregation is a pattern mirrored in other major cities, making it a prototype for studying the uptake of public health interventions across the US. Residential segregation is related to availability of primary care, sense of community, and trust in the healthcare system, components which are essential in the response to crises like Covid-19 in which vaccine rollout was primarily community-based. We aimed to evaluate the association between rates of access to primary care and community-belonging with Covid-19 vaccination within Chicago's neighborhoods. METHODS: Data from Chicago Department of Public Health (12/2020-6/2022) on Covid-19 vaccination rates, race/ethnicity (% Black and % Hispanic/Latinx residents), age (% >65), gender (% female), socioeconomic status (% below the federal poverty line), access to needed care rate, and rate of self-reported sense of community-belonging on the neighborhood level were analyzed. Linear mixed models (LMMs) were used to study the impact of variables on vaccination; each neighborhood was added as a random effect to account for with-community association. RESULTS: The average Covid-19 vaccination rates across Chicago's neighborhoods was 79%, ranging from 37 to 100%, with median 81%. We found that Covid-19 vaccination rates were positively correlated with access to needed care (p < 0.001) and community-belonging (p < 0.001). Community areas that had lower vaccination rates had greater percentage of Black residents (p < 0.0001) and greater poverty rates (p < 0.0001). After adjusting for poverty, race, gender and age in the models, the association between vaccination rates and access to care or community-belonging were no longer significant, but % Black residents and poverty remained significant. CONCLUSIONS: Though access to needed primary care and community-belonging are correlated with vaccination rates, this association was not significant when controlling for demographic factors. The association between poverty, race and vaccination status remained significant, indicating that socioeconomic and racial disparities across Chicago drive Covid-19 vaccine recommendation adherence regardless of care access. Understanding how poverty, and its intersectional relation to race and primary care access, affects vaccination should be a priority for public health efforts broadly.

Insufficient Reporting of Race and Ethnicity in Breast Cancer Clinical Trials.

BACKGROUND: Reporting race and ethnicity in clinical trial publications is critical for determining the generalizability and effectiveness of new treatments. This is particularly important for breast cancer, in which Black women have been shown to have between 40 and 100% higher mortality rate yet are underrepresented in trials. Our objective was to describe changes over time in the reporting of race/ethnicity in breast trial publications. PATIENTS AND METHODS: We searched ClinicalTrials.gov to identify the primary publication linked to trials with results posted from May 2010-2022. Statistical analysis included summed frequencies and a linear regression model of the proportion of articles reporting race/ethnicity and the proportion of non-White enrollees over time. RESULTS: A proportion of 72 of the 98 (73.4%) studies that met inclusion criteria reported race/ethnicity. In a linear regression model of the proportion of studies reporting race/ethnicity as a function of time, there was no statistically significant change, although we detected a signal toward a decreasing trend (coefficient for quarter = -2.2, p = 0.2). Among all studies reporting race and ethnicity over the study period, the overall percentage of non-White enrollees during the study period was 21.9%, [standard error (s.e.) 1.8, 95% confidence interval (CI) 18.4, 25.5] with a signal towards a decreasing trend in Non-White enrollment [coefficient for year-quarter = -0.8 (p = 0.2)]. CONCLUSION: Our data demonstrate that both race reporting and overall representation of minority groups in breast cancer clinical trials did not improve over the last 12 years and may have, in fact, decreased. Increased reporting of race and ethnicity data forces the medical community to confront disparities in access to clinical trials. This may improve efforts to recruit and retain members of minority groups in clinical trials, and over time, reduce racial disparities in oncologic outcomes.

Neonatal cutaneous inflammatory syndrome associated with homozygous epidermal growth factor receptor mutation.

The epidermal growth factor receptor (EGFR) is a transmembrane protein with tyrosine kinase signaling activity regulating many essential cellular functions, and loss of function mutations in EGFR result in a life-threatening neonatal syndrome. We present the case of a preterm boy born with intrauterine growth restriction who developed multisystem disease due to a homozygous mutation in the EGFR gene. He experienced a tumultuous and complex clinical course with recurrent skin infections and sepsis, nephrocalcinosis, failure to thrive, severe electrolyte imbalances, rectal perforation, and thrombus formation, and died after 11 months due to renal failure. This case report builds on work recently published in 2020 describing a case series of 18 similar patients and adds to the growing literature describing the severe phenotype and multisystem disease associated with loss of EGFR mutation in the Roma population.

Reducing barriers through education: A scoping review calling for structured disability curricula in surgical training programs.

BACKGROUND: Patients with disabilities face widespread barriers to accessing surgical care given inaccessible health systems, resulting in poor clinical outcomes and perpetuation of health inequities. One barrier is the lack of education, and therefore awareness, among trainees/providers, of the need for reasonable accommodations for surgical patients with disabilities. METHODS: We conducted a scoping review of the literature on the current state of disabilities curricula in medical education and graduate residency curriculum. RESULTS: While the literature does demonstrate a causal link between reasonable accommodation training and positive patient-provider relationships and improved clinical outcomes, in practice, disability-focused curricula are rare and often limited in time and to awareness-based didactic courses in medical education and surgical training. CONCLUSIONS: The absence of structured curricula to educate on anti-ableism and care for patients with disabilities promotes a system of structural "ableism." Expanding disability curricula for medical students and trainees may be an opportunity to intervene and promote better surgical care for all patients.

Women working in violence intervention and outreach: providing space for emotional vulnerability and empathy.

Introduction: There is a growing presence of violence intervention workers who identify as women, yet their unique strengths and challenges have not been described previously. The purpose of this study was to characterize the intersections of gender and violence intervention work. Methods: We conducted a qualitative study of women working in violence intervention via focus groups. Perceived strengths and risks were explored using a semistructured interviewing technique. Focus groups were transcribed and coded by two separate evaluators. Grounded theory methodology was used for thematic analysis. Results: 17 violence intervention and outreach specialists who identify as women were included in three focus groups. Common challenges include a sense of powerlessness when faced with inequitable structural limitations and vicarious trauma. When discussing the role of their gender identity in the work, the women reported that men seem more willing to be emotionally vulnerable with women, including disclosures of a history of sexual abuse. Women also experience a lack of respect personally and professionally in their role related to gender. The women revealed a need for leadership opportunities to leverage their strengths and for enhanced training, especially for male colleagues who may benefit from the insights of colleagues who are women. Conclusions: Women bring unique strengths to roles as violence intervention specialists to deal with trauma and prevent future violence. These findings suggest a need for specific curricula to support women working in violence intervention and further studies that explore the intersectional role of race as well as gender in violence intervention work. Level of Evidence: 6.

State-Level Analysis of Intimate Partner Violence, Abortion Access, and Peripartum Homicide: Call for Screening and Violence Interventions for Pregnant Patients.

BACKGROUND: Despite representing 4% of the global population, the US has the fifth highest number of intentional homicides in the world. Peripartum people represent a unique and vulnerable subset of homicide victims. This study aimed to understand the risk factors for peripartum homicide. STUDY DESIGN: We used data from the 2018 to 2020 National Violent Death Reporting System to compare homicide rates of peripartum and nonperipartum people capable of becoming pregnant (12 to 50 years of age). Peripartum was defined as currently pregnant or within 1-year postpartum. We additionally compared state-level peripartum homicide rates between states categorized as restrictive, neutral, or protective of abortion. Pearson's chi-square and Wilcoxon rank-sum tests were used. RESULTS: There were 496 peripartum compared with 8,644 nonperipartum homicide victims. The peripartum group was younger (27.4 ± 71 vs 33.0 ± 9.6, p < 0.001). Intimate partner violence causing the homicide was more common in the peripartum group (39.9% vs 26.4%, p < 0.001). Firearms were used in 63.4% of homicides among the peripartum group compared with 49.5% in the comparison (p < 0.001). A significant difference was observed in peripartum homicide between states based on policies regarding abortion access (protective 0.37, neutral 0.45, restrictive 0.64; p < 0.01); the same trend was not seen with male homicides. CONCLUSIONS: Compared with nonperipartum peers, peripartum people are at increased risk for homicide due to intimate partner violence, specifically due to firearm violence. Increasing rates of peripartum homicide occur in states with policies that are restrictive to abortion access. There is a dire need for universal screening and interventions for peripartum patients. Research and policies to reduce violence against pregnant people must also consider the important role that abortion access plays in protecting safety.

Disparities in breast cancer among patients with disabilities: care gaps, accessibility, and best practices.

Pronounced disparities exist in detecting and treating breast cancer in women with disabilities, leading to cancer detection at advanced stages. This paper provides an overview of disparities for women with disabilities related to breast cancer screening and care, primarily focusing on clinically significant mobility disabilities. Current care gaps include screening barriers related to accessibility and inequitable treatment options, with race and ethnicity, socioeconomic status, geographic location, and disability severity factors mediating the disparities for this population. The reasons for these disparities are myriad and stem from both system-level deficiencies and individual-level clinician bias. Although structural changes are warranted, individual healthcare professionals must also be incorporated into the requisite change. Intersectionality is critical to disparities and inequities and should be central to any discussion of strategies for improving care for people with disabilities, many of whom have intersectional identities. Efforts to reduce screening rate disparities for breast cancer in women with mobility-related disabilities should start with improving accessibility through removing structural barriers, establishing comprehensive accessibility standards, and addressing healthcare professional bias. Future interventional studies are needed to implement and assess the value of programs to improve breast cancer screening rates in women with disabilities. Increasing the representation of women with disabilities in clinical trials may provide another avenue for reducing treatment disparities because these trials often provide breakthrough treatment to women with cancer diagnosed at later stages. Ultimately, attention to the specific needs of patients with disabilities should be improved across the United States to promote inclusive and effective cancer screening and treatment.

Diversity, Equity, and Inclusion in Clinical Trials.

Minority groups are vastly underrepresented in clinical trial participants and leadership. Because these studies provide innovative and revolutionary treatment options to patients with cancer and have the potential to extend survival, it is imperative that public and private stakeholders, as well as hospital and clinical trial leadership, prioritize equity and inclusion of diverse populations in clinical trial development and recruitment strategies. Achieving equity in clinical trials could be an important step in reducing the overall cancer burden and mortality disparities in vulnerable populations.

The outcome of frailty in older people with diabetes as a function of glycaemic control and hypoglycaemic therapy: a review.

INTRODUCTION: Frailty is an emerging and newly recognized complication of diabetes in older people. However, frailty is not thoroughly investigated in diabetes outcome studies. AREAS COVERED: This manuscript reviews the effect of glycemic control and hypoglycemic therapy on the incidence of frailty in older people with diabetes. EXPERT OPINION: Current studies show that both low glycemia and high glycemia are associated with frailty. However, most of the studies, especially low glycemia studies, are cross-sectional or retrospective, suggesting association, rather than causation, of frailty. In addition, frail patients in the low glycemia studies are characterized by lower body weight or lower body mass index (BMI), contrary to those in the high glycemia studies, who are either overweight or obese. This may suggest that frailty has a heterogeneous metabolic spectrum, starting with an anorexic malnourished (AM) phenotype at one end, which is associated with low glycemia and a sarcopenic obese (SO) phenotype on the other end, which is associated with high glycemia. The current little evidence suggests that poor glycemic control increases the risk of frailty, but there is a paucity of evidence to suggest that tight glycemic control would reduce the risk of incident frailty. Metformin is the only well-studied hypoglycemic agent, so far, to have a protective effect against frailty independent of glycemic control in the non-frail older people with diabetes. However, once frailty is developed, the choice of the best hypoglycemic agent for these patients will be affected by the metabolic phenotype of frailty. For example, sodium glucose transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are appropriate in the SO phenotype due to their weight losing properties, while insulin therapy may be considered early in the AM phenotype due to its anabolic and weight gaining benefits. Future studies are still required to further investigate the metabolic effects of frailty on older people with diabetes, determine the most appropriate HbA1c target, and explore the most suitable hypoglycemic agent in each metabolic phenotype of frailty.

Metabolic Characteristics of Frail Older People with Diabetes Mellitus-A Systematic Search for Phenotypes.

Frailty in older people with diabetes is viewed as one homogeneous category. We previously suggested that frailty is not homogeneous and spans across a metabolic spectrum that starts with an anorexic malnourished (AM) frail phenotype and ends with a sarcopenic obese (SO) phenotype. We aimed to investigate the metabolic characteristics of frail older people with diabetes reported in the current literature to explore whether they fit into two distinctive metabolic phenotypes. We performed systematic review of studies published over the last 10 years and reported characteristics of frail older people with diabetes mellitus. A total of 25 studies were included in this systematic review. Fifteen studies reported frail patients' characteristics that could fit into an AM phenotype. This phenotype is characterised by low body weight, increased prevalence of malnutrition markers such as low serum albumin, low serum cholesterol, low Hb, low HbA1c, and increased risk of hypoglycaemia. Ten studies reported frail patients' characteristics that describe a SO phenotype. This phenotype is characterised by increased body weight, increased serum cholesterol, high HbA1c, and increased blood glucose levels. Due to significant weight loss in the AM phenotype, insulin resistance decreases, leading to a decelerated diabetes trajectory and reduced hypoglycaemic agent use or deintensification of therapy. On the other hand, in the SO phenotype, insulin resistance increases leading to accelerated diabetes trajectory and increased hypoglycaemic agent use or intensification of therapy. Current literature suggests that frailty is a metabolically heterogeneous condition that includes AM and SO phenotypes. Both phenotypes have metabolically distinctive features, which will have a different effect on diabetes trajectory. Therefore, clinical decision-making and future clinical studies should consider the metabolic heterogeneity of frailty.

Trauma as a Public Health Moment: Addressing Vaccine Uptake in Trauma Patients.

Objective: Our objective was to identify factors associated with COVID-19 vaccination in trauma patients and to provide an opportunity for patients to engage in conversations about vaccination. Background: The trauma surgery service offers a unique opportunity to promote preventative health interventions in hard-to-reach populations. Methods: Trauma inpatients in Chicago, IL were recruited for this mixed-methods study from February 2022 to April 2022. Participants completed a survey on demographics, COVID-19 vaccination status, and Experiences of Discrimination Scale adapted for medical settings. Differences between vaccinated and unvaccinated patients were analyzed using the Wilcoxon-rank sum test. A semistructured, qualitative interview was completed. Qualitative data was transcribed and analyzed using Grounded Theory Methodology. Results: Fifty-eight trauma patients were surveyed, representing 88% of patients approached. Only 23 (40%) patients reported full vaccination to COVID-19. Previous vaccination (at least 1 dose) was associated with greater concern for COVID-19 (OR 3.47, 95% CI 1.987-6.964, P < 0.001) and higher income (OR 1.21, 95% CI 1.02-1.44, P = 0.03). Higher Experiences of Discrimination Scale scores were associated with decreased likelihood of prior vaccination (OR 0.97, 95% CI 0.95-0.99, P = 0.04). On qualitative analysis, recurrent themes included vaccination motivated by either community-based or personal health-related values, and disinterest in vaccination based on perceived low need or skepticism of experimentation. Fifteen patients (26%) eligible for a vaccine dose consented to onsite vaccination after the survey. Conclusions: Trauma patients who have experienced more discrimination in medical settings have lower rates of COVID-19 vaccination. Vaccination rates in our population were over 2 times lower than citywide rates, but admission to the trauma service can increase comprehensive care.

Trauma of abortion restrictions and forced pregnancy: urgent implications for acute care surgeons.

In the aftermath of the Supreme Court's Dobbs vs. Jackson Women's Health decision, acute care surgeons face an increased likelihood of seeing patients with complications from both self-managed abortions and forced pregnancy in underserved areas of reproductive and maternity care throughout the USA. Acute care surgeons have an ethical and legal duty to provide care to these patients, especially in obstetrics and gynecology deserts, which already exist in much of the country and are likely to be exacerbated by legislation banning abortion. Structural inequities lead to an over-representation of poor individuals and people of color among patients seeking abortion care, and it is imperative to make central the fact that people of color who can become pregnant will be disproportionately affected by this legislation in every respect. Acute care surgeons must take action to become aware of and trained to treat both the direct clinical complications and the extragestational consequences of reproductive injustice, while also using their collective voices to reaffirm the right to abortion as essential healthcare in the USA.

Selfish evolution of placental hormones.

We hypothesize that some placental hormones-specifically those that arise by tandem duplication of genes for maternal hormones-may behave as gestational drivers, selfish genetic elements that encourage the spontaneous abortion of offspring that fail to inherit them. Such drivers are quite simple to evolve, requiring just three things: a decrease in expression or activity of some essential maternal hormone during pregnancy; a compensatory increase in expression or activity of the homologous hormone by the placenta; and genetic linkage between the two effects. Gestational drive may therefore be a common selection pressure experienced by any of the various hormones of mammalian pregnancy that have arisen by tandem gene duplication. We examine the evolution of chorionic gonadotropin in the human lineage in light of this hypothesis. Finally, we postulate that some of the difficulties of human pregnancy may be a consequence of the action of selfish genes.