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UNLABELLED: Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. SIGNIFICANCE: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.

Objective: Ocular ischemic syndrome is a rare blinding condition generally caused by disease of the carotid artery. We describe a 69-year-old female with a 50 pack-year smoking history with aortic arch syndrome causing bilateral ocular ischemic syndrome. Methods: The patient presented with progressive visual loss and temple pain. Slit lamp biomicroscopy revealed bilateral iris neovascularization. This finding prompted a cardiovascular work up. Panretinal photocoagulation with retrobulbar block was performed in the right eye. Results: A temporal artery biopsy was negative. The carotid duplex sound showed only a 1–39% stenosis. MRA revealed a more proximal occlusion of the aortic branch for which she underwent subclavian carotid bypass surgery. At the one month follow up, the right eye suffered profound vision loss secondary to a central retinal artery occlusion. Conclusion: Ocular neovascularization may be one of the clinical manifestations of aortic arch syndrome. This case also illustrates the limitations of relying solely on carotid duplex ultrasound testing. We caution against overly aggressive panretinal photocoagulation utilizing retrobulbar anesthesia.

Scholars and students of comparative education routinely, and often reflexively, categorize places with labels that have complex and problematic histories, connotations and associations. Both comparative education classrooms and scholarship will benefit from reflecting on the dynamics of labeling places. We seek to provide a framework for analyzing the main issues and risks associated with labeling with a heuristic we call the 3P framework. It invites students and scholars to consider the ways in which power, perspective, and plurality are expressed through the terms we apply to places. Through this framework, we identify common pitfalls in labeling. We provide a table with open access resources that critically examine many of the most important and common geographic labels in our field. To illustrate how these issues are manifested in particular contexts, we provide two vignettes, on South Asia and Estonia. The vignettes show how issues of power, perspective and plurality are manifested through the labels used and applied in specific places where we conduct research. Finally, we examine how the labeling process is situated in specific contexts and how meaning is culturally rooted; in doing so, we explain how the exclusive use of English-language labels in this piece is necessarily incomplete. The piece concludes with recommendations for teaching with this framework and for producing comparative education scholarship that deploys labels with greater reflexivity and intentionality.

BACKGROUND: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies. METHODS: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer. RESULTS: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer. CONCLUSIONS: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.

Pain and vaso-occlusive crises (VOC) are hallmark complications of sickle cell disease (SCD) and result in significant physical and psychosocial impairment. The variability in SCD pain frequency and triggers for the transition from steady state to VOC are not well understood. This paper summarizes the harmful physiological effects of pain and emotional stressors on autonomically-mediated vascular function in individuals with SCD and the effects of a cognitive, neuromodulatory intervention (i.e. hypnosis) on microvascular blood flow. We reviewed recent studies from the authors vascular physiology laboratory that assessed microvascular responses to laboratory stressors in individuals with SCD. Results indicate that participants with SCD exhibit marked neurally mediated vascular reactivity in response to pain, pain-related fear, and mental stress. Further, pilot study results show that engagement in hypnosis may attenuate harmful microvascular responses to pain. The collective results demonstrate that autonomically-mediated vascular responses to pain and mental stress represent an important SCD intervention target. This ongoing work provides physiological justification for the inclusion of cognitive, neuromodulatory and complementary treatments in SCD disease management and may inform the development of targeted, integrative interventions that prevent the enhancement of autonomic vascular dysfunction in SCD.

Sickle cell disease (SCD) is a monogenetic disease that results in the formation of hemoglobin S. Due to more rapid oxidation of hemoglobin S due to intracellular heme and adventitious iron in SCD, it has been thought that an inherent property of SCD red cells would be an imbalance in antioxidant defenses and oxidant production. Less deformable and fragile RBC in SCD results in intravascular hemolysis and release of free hemoglobin (PFHb) in the plasma, which might be expected to produce oxidative stress in the plasma. Thus, we aimed to characterize intracellular and vascular oxidative stress in whole blood and plasma samples from adult SCD patients and controls recruited into a large study of SCD at Children's Hospital of Los Angeles. We evaluated the cellular content of metHb and several components of the antioxidant system in RBC as well as oxidation of GSH and Prx-2 oxidation in RBC after challenge with hydroperoxides. Plasma markers included PFHb, low molecular weight protein bound heme (freed heme), hemopexin, isoprostanes, and protein carbonyls. While GSH was slightly lower in SCD RBC, protein carbonyls, NADH, NAD+ and total NADP+ + NADPH were not different. Furthermore, GSH or Prx-2 oxidation was not different after oxidative challenge in SCD vs. Control. Elevated freed heme and PFHb had a significant negative, non-linear association with hemopexin. There appeared to be a threshold effect for hemopexin (200 μg/ml), under which the freed heme rose acutely. Plasma F2-isoprostanes were not significantly elevated in SCD. Despite significant release of Hb and elevation of freed heme in SCD when hemopexin was apparently saturated, there was no clear indication of uncompensated vascular oxidative stress. This somewhat surprising result, suggests that oxidative stress is well compensated in RBCs and plasma during a period of relative health.

This article contributes to a growing appreciation and understanding of both the ways to include exposure to Comparative and International Education (CIE) in undergraduate teacher education as well as to how students take up and respond creatively to opportunities for comparative exploration. In order to make space for comparative education in the already oversubscribed pre-service teacher's program of study, we (1) explore a strategy to use a required undergraduate social foundations' class for pre-service teachers at a large public university as a platform for comparative education, and (2) share the lessons learned from creating space for students to express their international and comparative curiosities. We open the article by introducing the "grafting" strategy to make space for the comparative; we then turn to the ways we employed a pedagogical tool we call "drawing out" to allow students to make comparative connections by responding to our deliberate, comparative prompts. We found that by embracing the grafting approach we created opportunities for students to make their own conclusions about the value of comparative considerations and to express their organic interest in the international to better understand domestic developments and options.

Background: Racial and ethnic disparities are evident in the accessibility of treatment for opioid use disorder (OUD). Even when medications for OUD (MOUD) are accessible, racially and ethnically minoritized groups have higher attrition rates from treatment. Existing literature has primarily identified the specific racial and ethnic groups affected by these disparities, but has not thoroughly examined interventions to address this gap. Recovery peer navigators (RPNs) have been shown to improve access and overall retention on MOUD. Patients and Methods: In this retrospective cohort study, we evaluate the role of RPNs on patient retention in clinical care at an outpatient program in a racially and ethnically diverse urban community. Charts were reviewed of new patients seen from January 1, 2019 through December 31, 2019. Sociodemographic and clinical visit data, including which providers and services were utilized, were collected, and the primary outcome of interest was continuous retention in care. Bivariate analysis was done to test for statistically significant associations between variables by racial/ethnic group and continuous retention in care using Student's t-test or Pearson's chi-square test. Variables with p value ≤0.10 were included in a multivariable regression model. Results: A total of 131 new patients were included in the study. RPNs improved continuous retention in all-group analysis (27.6% pre-RPN compared to 80.2% post-RPN). Improvements in continuous retention were observed in all racial/ethnic subgroups but were statistically significant in the non-Hispanic Black (NHB) group (p < 0.001). Among NHB, increases in continuous retention were observed post-RPN in patients with male sex (p < 0.001), public health insurance (p < 0.001), additional substance use (p < 0.001), medical comorbidities (p < 0.001), psychiatric comorbidities (p=0.001), and unstable housing (p=0.005). Multivariate logistic regression demonstrated that patients who lacked insurance had lower odds of continuous retention compared to patients with public insurance (aOR = 0.17, 95% CI 0.039-0.70, p=0.015) Conclusions: RPNs can improve clinical retention for patients with OUD, particularly for individuals experiencing several sociodemographic and clinical factors that are typically correlated with discontinuation of care. [ABSTRACT FROM AUTHOR]

Introduction: Undifferentiated chest pain in the emergency department (ED) is a diagnostic challenge. One approach includes a dedicated chest computed tomography (CT) for pulmonary embolism or dissection followed by a cardiac stress test (TRAD). An alternative strategy is a coronary CT angiogram with concurrent chest CT (Triple Rule Out, TRO). The objective of this study was to describe the ED patient course and short-term safety for these evaluation methods.Methods: This was a retrospective observational study of adult patients presenting to a large, community ED for acute chest pain who had non-diagnostic electrocardiograms (ECGs) and normal biomarkers. We collected demographics, ED length of stay, hospital costs, and estimated radiation exposures. We evaluated 30-day return visits for major adverse cardiac events.Results: A total of 829 patients underwent TRAD, and 642 patients had TRO. Patients undergoing TRO tended to be younger (mean 52.3 vs 56.5 years) and were more likely to be male (42.4% vs. 30.4%). TRO patients tended to have a shorter ED length of stay (mean 14.45 vs. 21.86 hours), to incur less cost (median $449.83 vs. $1147.70), and to be exposed to less radiation (median 7.18 vs. 16.6mSv). No patient in either group had a related 30-day revisit.Conclusion: Use of TRO is feasible for assessment of chest pain in the ED. Both TRAD and TRO safely evaluated patients. Prospective studies investigating this diagnostic strategy are needed to further assess this approach to ED chest pain evaluation.