Dual and opposing roles for the kinesin-2 motor, KIF17, in Hedgehog-dependent cerebellar development.

While the kinesin-2 motors KIF3A and KIF3B have essential roles in ciliogenesis and Hedgehog (HH) signal transduction, potential role(s) for another kinesin-2 motor, KIF17, in HH signaling have yet to be explored. Here, we investigated the contribution of KIF17 to HH-dependent cerebellar development, where Kif17 is expressed in both HH-producing Purkinje cells and HH-responding cerebellar granule neuron progenitors (CGNPs). Germline Kif17 deletion in mice results in cerebellar hypoplasia due to reduced CGNP proliferation, a consequence of decreased HH pathway activity mediated through decreased Sonic HH (SHH) protein. Notably, Purkinje cell-specific Kif17 deletion partially phenocopies Kif17 germline mutants. Unexpectedly, CGNP-specific Kif17 deletion results in the opposite phenotype-increased CGNP proliferation and HH target gene expression due to altered GLI transcription factor processing. Together, these data identify KIF17 as a key regulator of HH-dependent cerebellar development, with dual and opposing roles in HH-producing Purkinje cells and HH-responding CGNPs.

Synthesizing Best Practices to Promote Health Equity for Older Adults Through Community-Engaged Research.

Achieving health equity requires creating evidence that reflects the nuance and diversity of experiences among populations disproportionately impacted by age- and race-related disparities. Community-engaged research (CEnR) is one way to pursue equity in research on health and aging to ensure the relevance and translational potential of findings. The current review synthesizes best practices regarding CEnR that promote health equity among older adults, including an overview of CEnR, benefits, and fundamental principles, and three research exemplars from the authors' CEnR. Finally, we discuss these best practices and considerations for advancing CEnR to reduce health disparities experienced by historically underserved older adults and their families. [Research in Gerontological Nursing, 17(1), 9-16.].

Team Science: Advancing Women and Black, Indigenous, and other People of Color on the Pathway of Conducting Clinical Research.

Introduction: Innovative discovery begins with diverse perspectives; research teams should harness this model. Black, Indigenous, and other People of Color (BIPOC) and women are underrepresented as researchers. Team science leverages collaborative and cross-disciplinary approaches to diversify the research workforce, and introduces academic (and non-academic) faculty with limited research exposure/experience to clinical research. Methods: In 2020, two Black women academic physicians implemented an academic collaborative - COVID-19 Characteristics, Readmissions, Outcomes, and Social Determinants of Health (CROSS) - to investigate COVID-19 health inequities, with intentional recruitment of BIPOC and women. The 37 CROSS team members were of diverse races, ethnicities, sex, specialties, and disciplines, and represented eight hospitals. Team members were electronically surveyed to determine their interest, desired activities, and level of participation in research activities; concurrently, self-identified demographics (including race, ethnicity, sex, and language(s) spoken) were obtained. Results: All team members completed the survey: 78.4% (n = 29) were BIPOC and 78.4% (n = 29) were women. Team members spoke 18 languages (including English). Academic medical ranks included Assistant Professor (32.4%; n = 12), Associate Professor (16.2%; n = 6), and Full Professor (2.7%; n = 1). Each member identified desired activities (data collection, data analytics, manuscript development, abstract development/poster presentation, serving as a consultant) and the percentage of time they intended to allocate to each. Between June 2020 and February 2023, the team produced five original peer-reviewed manuscripts (including this article); five members served as first or senior authors. Twenty-one abstracts were presented at local conferences, and 10 at national and regional conferences. Five members achieved academic promotion, and team members were awarded three intramural grants resulting directly from team collaborations. Conclusion: Intentional recruitment and assessment of team members' desired levels of participation in an integrated clinical research team is an effective strategy to engage BIPOC and women. The CROSS Collaborative is a model for diversity and inclusion in team science and clinical research.

A Quality Framework to Address Racial and Ethnic Disparities in Emergency Department Care.

The emergency department serves as a vital source of health care for residents in the United States, including as a safety net. However, patients from minoritized racial and ethnic groups have historically experienced disproportionate barriers to accessing health care services and lower quality of services than White patients. Quality measures and their application to quality improvement initiatives represent a critical opportunity to incentivize health care systems to advance health equity and reduce health disparities. Currently, there are no nationally recognized quality measures that track the quality of emergency care delivery by race and ethnicity and no published frameworks to guide the development and prioritization of quality measures to reduce health disparities in emergency care. To address these gaps, the American College of Emergency Physicians (ACEP) convened a working group of experts in quality measurement, health disparities, and health equity to develop guidance on establishing quality measures to address racial and ethnic disparities in the provision of emergency care. Based on iterative discussion over 3 working group meetings, we present a summary of existing emergency medicine quality measures that should be adapted to track racial and ethnic disparities, as well as a framework for developing new measures that focus on disparities in access to emergency care, care delivery, and transitions of care.

CDON contributes to Hedgehog-dependent patterning and growth of the developing limb.

Hedgehog (HH) signaling is a major driver of tissue patterning during embryonic development through the regulation of a multitude of cell behaviors including cell fate specification, proliferation, migration, and survival. HH ligands signal through the canonical receptor PTCH1 and three co-receptors, GAS1, CDON and BOC. While previous studies demonstrated an overlapping and collective requirement for these co-receptors in early HH-dependent processes, the early embryonic lethality of Gas1;Cdon;Boc mutants precluded an assessment of their collective contribution to later HH-dependent signaling events. Specifically, a collective role for these co-receptors during limb development has yet to be explored. Here, we investigate the combined contribution of these co-receptors to digit specification, limb patterning and long bone growth through limb-specific conditional deletion of Cdon in a Gas1;Boc null background. Combined deletion of Gas1, Cdon and Boc in the limb results in digit loss as well as defects in limb outgrowth and long bone patterning. Taken together, these data demonstrate that GAS1, CDON and BOC are collectively required for HH-dependent patterning and growth of the developing limb.

Differences in diabetes control in telemedicine vs. in-person only visits in ambulatory care setting.

There is limited information regarding how telemedicine visits compare with in-person visits regarding diabetes outcomes in an ambulatory care setting. Our objective was to compare proportions of patients in ambulatory setting with uncontrolled diabetes among those with telemedicine visits versus in-person only visits and examine differences by age, race, gender, ethnicity, and insurance status. Adults with diabetes who attended an ambulatory primary or specialty clinic visit between May 2020 and May 2021 were included. Demographics including age, race, ethnicity, gender, insurance, and comorbidities were extracted from the electronic medical record. Patients were compared among three visit groups: those with in-person only visits, those with only one telemedicine visit, and those with 2 + telemedicine visits. The primary outcome was uncontrolled diabetes, defined as HbA1c ≥ 9.0 %. Multivariable logistic regression was used to assess differences in uncontrolled diabetes between visit groups following risk adjustment. A total of 18,148 patients met inclusion criteria and 2,101 (11.6 %) had uncontrolled diabetes. There was no difference in proportion of patients with uncontrolled diabetes between visit groups (in-person only visits: 834 (11.6 %); one telemedicine visit: 558 (11.8 %); 2 + telemedicine visits: 709 (11.4 %); p = 0.80)). Patients with 2 + telemedicine visits had significantly lower odds of uncontrolled diabetes compared to in-person only visits after risk adjustment (OR: 0.88; 95 % CI: 0.79-0.99, p = 0.03). Compared with in-person ambulatory visits, telemedicine visits were associated with a lower odds of uncontrolled diabetes. Further work is warranted to explore the relationship between telemedicine visits and diabetes outcomes.

Plexins promote Hedgehog signaling through their cytoplasmic GAP activity.

Hedgehog signaling controls tissue patterning during embryonic and postnatal development and continues to play important roles throughout life. Characterizing the full complement of Hedgehog pathway components is essential to understanding its wide-ranging functions. Previous work has identified neuropilins, established semaphorin receptors, as positive regulators of Hedgehog signaling. Neuropilins require plexin co-receptors to mediate semaphorin signaling, but the role of plexins in Hedgehog signaling has not yet been explored. Here, we provide evidence that multiple plexins promote Hedgehog signaling in NIH/3T3 mouse fibroblasts and that plexin loss of function in these cells results in significantly reduced Hedgehog pathway activity. Catalytic activity of the plexin GTPase-activating protein (GAP) domain is required for Hedgehog signal promotion, and constitutive activation of the GAP domain further amplifies Hedgehog signaling. Additionally, we demonstrate that plexins promote Hedgehog signaling at the level of GLI transcription factors and that this promotion requires intact primary cilia. Finally, we find that plexin loss of function significantly reduces the response to Hedgehog pathway activation in the mouse dentate gyrus. Together, these data identify plexins as novel components of the Hedgehog pathway and provide insight into their mechanism of action.

COVID-19 Vaccine Hesitancy Among Health Care Workers in Four Health Care Systems in Atlanta.

Coronavirus disease 2019 (COVID-19) vaccine hesitancy among health care workers (HCWs) undermines community vaccine confidence. Predictors and reasons for HCW hesitancy in the Atlanta region were evaluated using a survey between May and June 2021. Vaccine hesitancy was highest in younger and less educated HCWs. Interventions to address vaccine hesitancy in HCWs are necessary.

Clinical characteristics and social determinants of health associated with 30-day hospital readmissions of patients with COVID-19.

COVID-19 readmissions are associated with increased patient mortality and healthcare system strain. This retrospective cohort study of PCR-confirmed COVID-19 positive adults (>18 years) hospitalized and readmitted within 30 days of discharge from index admission was performed at eight Atlanta hospitals from March to December 2020. The objective was to describe COVID-19 patient-level demographics and clinical characteristics, and community-level social determinants of health (SDoH) that contribute to 30-day readmissions. Demographics, comorbidities, COVID-19 treatment, and discharge disposition data were extracted from the index admission. ZIP codes were linked to a demographic/lifestyle database interpolating to community-level SDoH. Of 7155 patients with COVID-19, 463 (6.5%) had 30-day, unplanned, all-cause hospital readmissions. Statistically significant differences were not found in readmissions stratified by age, sex, race, or ethnicity. Patients with a high-risk Charlson Comorbidity Index had higher odds of readmission (OR 4.8 (95% CI: 2.1 to 11.0)). Remdesivir treatment and intensive care unit (ICU) care were associated with lower odds of readmission (OR 0.5 (95% CI: 0.4 to 0.8) and OR 0.5 (95% CI: 0.4 to 0.7), respectively). Patients residing in communities with larger average household size were less likely to be readmitted (OR 0.7 (95% CI: 0.5 to 0.9). In this cohort, patients who received remdesivir, were cared for in an ICU, and resided in ZIP codes with higher proportions of residents with increased social support had lower odds of readmission. These patient-level factors and community-level SDoH may be used to identify patients with COVID-19 who are at increased risk of readmission.

Unique lingual expression of the Hedgehog pathway antagonist Hedgehog-interacting protein in filiform papillae during homeostasis and ectopic expression in fungiform papillae during Hedgehog signaling inhibition.

BACKGROUND: Hedgehog (HH) signaling is essential for homeostasis in gustatory fungiform papillae (FP) and taste buds. However, activities of HH antagonists in these tissues remain unexplored. We investigated a potential role for HH-interacting protein (HHIP), an endogenous pathway antagonist, in regulating HH signaling during taste organ homeostasis. We found a restricted pattern of Hhip-expressing cells in the anterior epithelium of each nongustatory filiform papilla (FILIF) only. To test for roles in antagonism of HH signaling, we investigated HHIP after pathway inhibition with SMO inhibition via sonidegib and Smo deletion, Gli2 deletion/suppression, or with chorda tympani/lingual nerve cut. RESULTS: In all approaches, the HHIP expression pattern was retained in FILIF suggesting HH-independent regulation of HHIP. Remarkably, after pathway inhibition, HHIP expression was detected also in the conical, FILIF-like atypical FP. We found a close association of de novo expression of HHIP in atypical FP with loss of Gli1+, HH-responding cells. Further, we report that PTCH1 is another potential HH antagonist in FILIF that co-localizes with HHIP. CONCLUSIONS: After HH pathway inhibition the ectopic expression of HHIP correlates with a FILIF-like morphology in atypical FP and we propose that localized expression of the HH antagonist HHIP regulates pathway inhibition to maintain FILIF during tongue homeostasis.

Using Routinely Collected Electronic Health Record Data to Predict Readmission and Target Care Coordination.

ABSTRACT: Patients with chronic renal failure (CRF) are at high risk of being readmitted to hospitals within 30 days. Routinely collected electronic health record (EHR) data may enable hospitals to predict CRF readmission and target interventions to increase quality and reduce readmissions. We compared the ability of manually extracted variables to predict readmission compared with EHR-based prediction using multivariate logistic regression on 1 year of admission data from an academic medical center. Categorizing three routinely collected variables (creatinine, B-type natriuretic peptide, and length of stay) increased readmission prediction by 30% compared with paper-based methods as measured by C-statistic (AUC). Marginal effects analysis using the final multivariate model provided patient-specific risk scores from 0% to 44.3%. These findings support the use of routinely collected EHR data for effectively stratifying readmission risk for patients with CRF. Generic readmission risk tools may be evidence-based but are designed for general populations and may not account for unique traits of specific patient populations-such as those with CRF. Routinely collected EHR data are a rapid, more efficient strategy for risk stratifying and strategically targeting care. Earlier risk stratification and reallocation of clinician effort may reduce readmissions. Testing this risk model in additional populations and settings is warranted.

Age, Comorbid Conditions, and Racial Disparities in COVID-19 Outcomes.

BACKGROUND: Black patients are disproportionately affected by COVID-19. The purpose of this study was to compare risks of hospitalization of Black and non-Black COVID-19 patients presenting to the emergency department and, of those hospitalized, to compare mortality and acute kidney injury. METHODS: A retrospective cohort of 831 adult COVID-19 patients (68.5% Black) who presented to the emergency departments of four academic hospitals, March 1, 2020-May 31, 2020. The primary outcome was risk of hospitalization among Blacks vs. non-Blacks. Secondary outcomes were mortality and acute kidney injury, among hospitalized patients. RESULTS: The crude odds of hospitalization were not different in Black vs. non-Black patients; however, with adjustment for age, Blacks had 55% higher odds of hospitalization. Mortality differed most in the model adjusted for age alone. Acute kidney injury was more common in the Black hospitalized patients, regardless of adjustment. Stratified analyses suggested that disparities in the risk of hospitalization and of in-hospital acute kidney injury were highest in the youngest patients. CONCLUSIONS: Our report shows that Black and non-Black patients presenting to the emergency department with COVID-19 had similar risks of hospitalization and, of those who were hospitalized, similar mortality when adjusted for multiple factors. Blacks had higher risk of acute kidney injury. Our results suggest that examination of disparities without exploration of the individual effects of age and comorbidities may mask important patterns. While stratified analyses suggest that disparities in outcomes may differ substantially by age and comorbid conditions, further exploration among these important subgroups is needed to better target interventions to reduce disparities in COVID-19 clinical outcomes.

The Time Is Now: Racism and the Responsibility of Emergency Medicine to Be Antiracist.

The COVID-19 pandemic has shed light on the ongoing pandemic of racial injustice. In the context of these twin pandemics, emergency medicine organizations are declaring that "Racism is a Public Health Crisis." Accordingly, we are challenging emergency clinicians to respond to this emergency and commit to being antiracist. This courageous journey begins with naming racism and continues with actions addressing the intersection of racism and social determinants of health that result in health inequities. Therefore, we present a social-ecological framework that structures the intentional actions that emergency medicine must implement at the individual, organizational, community, and policy levels to actively respond to this emergency and be antiracist.

The impact of emergency department observation units on a health system.

IMPORTANCE: Protocol driven ED observation units (EDOU) have been shown to improve outcomes for patients and payers, however their impact on an entire health system is unknown. Two thirds of US hospitals do not have such units. OBJECTIVE: To determine the impact of a protocol-driven EDOU on health system length of stay, cost, and resource utilization. METHODS: A retrospective, observational, cross-sectional study of observation patients managed over 25 consecutive months in a four-hospital academic health system. Patients were identified using the "admit to observation" order and limited to adult, emergent / urgent, non-obstetric patients. Data was retrieved from a cost accounting database. The primary study exposure was the setting for observation care which was broken into three discrete groups: EDOUs (n = 3), hospital medicine observation units (HMSOU, n = 2), and a non-observation unit (NOU) bed located anywhere in the hospital. Outcomes included observation-to-inpatient admission rate, length of stay (LoS), total direct cost, and inpatient bed days saved. Unadjusted outcomes were compared, and outcomes were adjusted using multiple study variables. LoS and cost were compared using quantile regressions. Inpatient admit rate was compared using logistic regressions. RESULTS: The sample consisted of 48,145 patients who were 57.4% female, 48% Black, 46% White, median age of 58, with some variation in most common diagnoses and payer groups. The median unadjusted outcomes favored EDOU over NOU settings for admission rate (13.1% vs 37.1%), LoS [17.9 vs 35.6 h), and cost ($1279 vs $2022). The adjusted outcomes favored EDOU over NOU settings for admission rates [12.3% (95% CI 9.7-15.3) vs 26.4% (CI 21.3-32.3)], LoS differences [11.1 h (CI 10.6-11.5 h)] and cost differences [$127.5 (CI $105.4 - $149.5)]. Adjusted differences were similar and favored EDOU over HMSOU settings. For the health system, the total adjusted annualized savings of the EDOUs was 10,399 bed days and $1,329,443 in total direct cost per year. CONCLUSION: Within an academic medical center, EDOUs were associated with improved resource utilization and reduced cost. This represents a significant opportunity for hospitals to improve efficiency and contain costs.

A Framework for Mobilizing Health Care to Respond to the Community Within the COVID-19 Pandemic.

Cultural mistrust of government with regard to health issues has pressed the need to engage trusted community leaders with influence and reach in disproportionately affected communities to ensure that essential public health activities related to COVID-19 occur among populations experiencing disproportionate impact from the pandemic. In April of 2020, a Georgia-based integrated academic health care system created a Community Outreach and Health Disparities Collaborative to unite trusted community leaders from faith-based, civic, and health-sector organizations to work with the health system and Emory University to develop tailored approaches and mobilize support within the context of the communities' cultural and individual needs to reduce the burden of COVID-19. We describe the framework used to join health care and academic collaborators with community partners to mobilize efforts to address the disproportionate impact of COVID-19 on racial, ethnic, and socioeconomic minority groups. The framework outlines a series of steps taken that led to a community-driven collaboration designed to engage local influential community leaders as partners in improving access to care for disproportionately affected communities, collaborations that could be replicated by other large health care systems. This framework can also be applied to other chronic diseases or future public health emergencies to improve communication, education, and health care access for communities experiencing disproportionate impact.

Fast track dialysis: Improving emergency department and hospital throughput for patients requiring hemodialysis.

OBJECTIVE: To describe the impact of a novel communication and triage pathway called fast track dialysis (FTD) on the length of stay (LOS), resource utilization, and charges for unscheduled hemodialysis for end stage renal disease (ESRD) patients presenting to the emergency department (ED). METHODS: Prospective and retrospective cohorts of ESRD patients meeting requirements of routine or urgent hemodialysis at a tertiary academic hospital from September 25th, 2016 to September 25th, 2018 in 1 year cohorts. Two sample t-tests were used to compare most outcomes of the cohorts with a Mann-Whitney U test used for skewed data. Nephrology group outcomes were analyzed by two-way ANOVA and Kruskal-Wallis and chi-square tests. RESULTS: There were 98 encounters in the historical cohort and 143 encounters in the fast track dialysis cohort. FTD had significantly lowered median ED LOS (4.05 h, vs 5.3 h, p < 0.001), median hospital LOS (12.8 h vs 27 h, p < 0.001), time to hemodialysis (4.78 h vs 7.29 h, p < 0.001), and median hospital charges ($26,040 vs $30,747, p < 0.016). The FTD cohort had increased 30 day ED return for each encounter compared to the historical cohort (1.85 visits vs 0.73 visits, p < 0.001), however no significant increase in 1 year ED visits (6.52 visits vs 5.80, p = 0.4589) or 1 year readmissions (5.89 readmissions vs 4.81 readmissions, p = 0.3584). Most nephrology groups had significantly lower time to hemodialysis order placement and time to start hemodialysis. CONCLUSION: A multidisciplinary approach with key stakeholders using a standard pathway can lead to improved efficiency in throughput, reduced charges, and hospital resource utilization for patients needing urgent or routine hemodialysis. A study with a dedicated geographic observation unit for protocolized short stay patients including conditions ranging from low risk chest pain to transient ischemic events that incorporates FTD patients under this protocol should be considered.

The Changing Role of Chest Pain in the Emergency Department Observation Unit.

BACKGROUND: This study objective was to describe changes in the utilization of a protocol-driven emergency department observation unit (EDOU) for chest pain over time. METHODS: This is a retrospective serial cross-sectional study of data from a clinical data warehouse of a single integrated healthcare system. We estimated long-term trends (2009-2019) in EDOU visits at 4 system hospitals, using monthly proportions as the main outcome, and month of visit as the exposure variable, accounting for age and sex. Rate changes associated with compulsory use of the History, EKG, Age, Risk factors, Troponin (HEART) score in 2016 were analyzed. RESULTS: There were 83,168 EDOU admissions among 1.3 million ED visits during the study interval, with an average admission rate of 5.9% of ED visits. The most common conditions were chest pain (41.2%), transient ischemic attack (7.8%), dehydration (6.3%), syncope (5.8%), and abdominal pain (5.2%). In each hospital, there was a temporal annual decline in the proportion of EDOU visits for chest pain protocols ranging from -7.9% to -2.8%, an average rate of -3.3% per year (95% CI, -4.6% to -2.0%) or a 54% (from 54% to 25%) relative decline in over the 11-year study interval. This decline was significantly steeper in younger middle-aged patients (ages 39-49). The HEART score intervention had a small impact on baseline decline of -3.1% at the 2 intervention hospitals, reducing it by -1.5% (95% CI, -2.2% to -0.8%). CONCLUSIONS: Utilization of the EDOU for chest pain decreased over time, with corresponding increases in other conditions. This decline preceded the introduction of the HEART score.

Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment. EXPERIMENTAL DESIGN: We used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytometry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC. RESULTS: We found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression. CONCLUSIONS: Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.

Overcoming barriers to promotion for women and underrepresented in medicine faculty in academic emergency medicine.

Equity in the promotion of women and underrepresented minorities (URiM) is essential for the advancement of academic emergency medicine and the specialty as a whole. Forward-thinking healthcare organizations can best position themselves to optimally care for an increasingly diverse patient population and mentor trainees by championing increased diversity in senior faculty ranks, leadership, and governance roles. This article explores several potential solutions to addressing inequities that hinder the advancement of women and URiM faculty. It is intended to complement the recently approved American College of Emergency Physicians (ACEP) policy statement aimed at overcoming barriers to promotion of women and URiM faculty in academic emergency medicine. This policy statement was jointly released and supported by the Society for Academic Emergency Medicine (SAEM), American Academy of Emergency Medicine (AAEM), and the Association of Academic Chairs of Emergency Medicine (AACEM).