Elucidating Harm Reduction Principles in a Client-Centered Representative Payee Program.

Harm Reduction seeks to mitigate harms associated with health behaviors without the expectation that these behaviors be extinguished completely. Client-Centered Representative Payee (CCRP) is an intervention that modifies the US Social Security Administration's (SSA) Representative Payee policy by incorporating relational harm reduction. We used Human-Centered Design (HCD) methods to elucidate ways that harm reduction principles are present in and integral to CCRP and to create a blueprint for replication. Thirteen individuals familiar with CCRP brainstormed 88 statements, which were parsed, consolidated, and then independently assigned by a subgroup of participants to six principles of harm reduction. After refining the data, 29 statements aligning with harm reduction principles remained. Delineating harm reduction within CCRP, which can empower and establish trust with clients, may help other providers identify how to offer representative payee services that are respectful, compassionate, rooted in harm reduction, and ultimately improve client outcomes.

The Unbearable Whiteness of Citational Practice in US Medical Anthropology.

In this article, we examine the citational practices of US medical anthropology and seek to decenter Western-centric theory to minimize its theoretical dominance in the field. We call for a robust engagement with a broader variety of texts, genres of evidence, methodologies, and interdisciplinary forms of expertise and epistemology in response to the unbearable whiteness of the citational practices we critique. The practices are unbearable in that they do not support or scaffold the work we need to do as anthropologists. We hope this article invites readers to move in different citational directions to build foundations and epistemologies that support and enrich the capacity for anthropological analysis.

Community Support Persons and Mitigating Obstetric Racism During Childbirth.

PURPOSE: We undertook a study to assess whether presence of community support persons (CSPs), with no hospital affiliation or alignment, mitigates acts of obstetric racism during hospitalization for labor, birth, and immediate postpartum care. METHODS: We conducted a cross-sectional cohort study, measuring 3 domains of obstetric racism as defined for, by, and with Black birthing people: humanity (violation of safety and accountability, autonomy, communication and information exchange, and empathy); kinship (denial or disruption of community and familial bonds that support Black birthing people); and racism in the form of anti-Black racism and misogynoir (weaponization of societal stereotypes and scripts in service provision that reproduce gendered anti-Black racism in the hospital). We used a novel, validated instrument, the Patient-Reported Experience Measure of Obstetric Racism (the PREM-OB Scale suite), and linear regression analysis to determine the association between CSP presence during hospital births and obstetric racism. RESULTS: Analyses were based on 806 Black birthing people, 720 (89.3%) of whom had at least 1 CSP present throughout their labor, birth, and immediate postpartum care. The presence of CSPs was associated with fewer acts of obstetric racism across all 3 domains, with statistically significant reductions in scores in the CSP group of one-third to two-third SD units relative to the no-CSP group. CONCLUSIONS: Our findings suggest that CSPs may be an effective way to reduce obstetric racism as part of quality improvement initiatives, emphasizing the need for democratizing the birthing experience and birth space, and incorporating community members as a way to promote the safety of Black birthing people in hospital settings.Annals "Online First" article.

Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma.

PURPOSE: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. PATIENTS AND METHODS: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS). RESULTS: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs. CONCLUSIONS: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167.

Destigmatizing and Democratizing Postpartum Care: A "Black Woman-Person First" Approach.

Optimizing postpartum care highlights the need for care coordination, enhancement, and expansion of health care services after childbirth. Yet the prioritization of disease surveillance, management, and mitigation during birth and beyond within the American College of Obstetrics and Gynecology facilitates the medicalization and pathologization of Black bodies, voices, and power. Thus, we offer the Building and Bridging Black Futures Beyond Birth Model: A 12-Step Black Woman-Person First Approach, as a more humane and holistic model of culturally affirming and clinically responsive care. Destigmatizing and democratizing care bridges the gap between intent and impact in postpartum care optimization, particularly for Black women, girls, and gender expansive people and their communities.

Loss of Claudin-4 Reduces DNA Damage Repair and Increases Sensitivity to PARP Inhibitors.

High-grade serous ovarian cancer is the deadliest gynecologic malignancy due to progression to resistant disease. Claudin-4 is classically defined as a tight junction protein and is often associated with epithelial cancers. Claudin-4 is aberrantly expressed in nearly 70% of all ovarian cancer tumors and conveys a worse overall prognosis. Elevated claudin-4 expression correlates to increased DNA repair activity and resistance to DNA damaging agents. PARP inhibitors are emerging as an effective therapeutic option for patients with ovarian cancer and function by promoting DNA damage. The study examines the relationship between claudin-4 expression and the response to PARP inhibitors using both genetic and pharmacologic inhibition of claudin-4 in in vitro and ex vivo models of ovarian cancer to examine DNA repair markers and functional activity. Genetic inhibition of claudin-4 results in the downregulation of several DNA damage repair effectors, including 53BP1 and XRCC1. Claudin-4 knockdown did not change homology-directed repair but inhibited nonhomologous end-joining and reduced 53BP1 foci formation. In 15 primary ovarian cancer tumors, higher claudin-4 expression significantly correlated to a dampened PARP inhibitor-mediated antiproliferation response. Further, claudin-4 inhibition in high claudin-4 tumors sensitized tumor sections to PARP inhibition. These data highlight that claudin-4 expression in ovarian cancer tumors could serve as both a marker of PARP inhibitor response and a therapeutic target to improve PARP inhibitor response.

Psychometric validation of a patient-reported experience measure of obstetric racism© (The PREM-OB Scale™ suite).

BACKGROUND: Perinatal quality improvement lacks valid tools to measure adverse hospital experiences disproportionately impacting Black mothers and birthing people. Measuring and mitigating harm requires using a framework that centers the lived experiences of Black birthing people in evaluating inequitable care, namely, obstetric racism. We sought to develop a valid patient-reported experience measure (PREM) of Obstetric Racism© in hospital-based intrapartum care designed for, by, and with Black women as patient, community, and content experts. METHODS: PROMIS© instrument development standards adapted with cultural rigor methodology. Phase 1 included item pool generation, modified Delphi method, and cognitive interviews. Phase 2 evaluated the item pool using factor analysis and item response theory. RESULTS: Items were identified or written to cover 7 previously identified theoretical domains. 806 Black mothers and birthing people completed the pilot test. Factor analysis concluded a 3 factor structure with good fit indices (CFI = 0.931-0.977, RMSEA = 0.087-0.10, R2  > .3, residual correlation < 0.15). All items in each factor fit the IRT model and were able to be calibrated. Factor 1, "Humanity," had 31 items measuring experiences of safety and accountability, autonomy, communication, and empathy. A 12-item short form was created to ease respondent burden. Factor 2, "Racism," had 12 items measuring experiences of neglect and mistreatment. Factor 3, "Kinship," had 7 items measuring hospital denial and disruption of relationships between Black mothers and their child or support system. CONCLUSIONS: The PREM-OB Scale™ suite is a valid tool to characterize and quantify obstetric racism for use in perinatal improvement initiatives.

Circulating CD8+ mucosal-associated invariant T cells correlate with improved treatment responses and overall survival in anti-PD-1-treated melanoma patients.

OBJECTIVES: While much of the research concerning factors associated with responses to immune checkpoint inhibitors (ICIs) has focussed on the contributions of conventional peptide-specific T cells, the role of unconventional T cells, such as mucosal-associated invariant T (MAIT) cells, in human melanoma remains largely unknown. MAIT cells are an abundant population of innate-like T cells expressing a semi-invariant T-cell receptor restricted to the MHC class I-like molecule, MR1, presenting vitamin B metabolites derived from bacteria. We sought to characterise MAIT cells in melanoma patients and determined their association with treatment responses and clinical outcomes. METHODS: In this prospective clinical study, we analysed the frequency and functional profile of circulating and tumor-infiltrating MAIT cells in human melanoma patients. Using flow cytometry, we compared these across metastatic sites and between ICI responders vs. non-responders as well as healthy donors. RESULTS: We identified tumor-infiltrating MAIT cells in melanomas across metastatic sites and found that the number of circulating MAIT cells is reduced in melanoma patients compared to healthy donors. However, circulating MAIT cell frequencies are restored by ICI treatment in responding patients, correlating with treatment responses, in which patients with high frequencies of MAIT cells exhibited significantly improved overall survival. CONCLUSION: Our results suggest that MAIT cells may be a potential predictive marker of responses to immunotherapies and provide rationale for testing MAIT cell-directed therapies in combination with current and next-generation ICIs.

Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling.

The mitochondrial calcium uniporter (MCU) regulates metabolic reprogramming in lung macrophages and the progression of pulmonary fibrosis. Fibrosis progression is associated with apoptosis resistance in lung macrophages; however, the mechanism(s) by which apoptosis resistance occurs is poorly understood. Here, we found a marked increase in mitochondrial B-cell lymphoma-2 (Bcl-2) in lung macrophages from subjects with idiopathic pulmonary fibrosis (IPF). Similar findings were seen in bleomycin-injured wild-type (WT) mice, whereas Bcl-2 was markedly decreased in mice expressing a dominant-negative mitochondrial calcium uniporter (DN-MCU). Carnitine palmitoyltransferase 1a (Cpt1a), the rate-limiting enzyme for fatty acid ß-oxidation, directly interacted with Bcl-2 by binding to its BH3 domain, which anchored Bcl-2 in the mitochondria to attenuate apoptosis. This interaction was dependent on Cpt1a activity. Lung macrophages from IPF subjects had a direct correlation between CPT1A and Bcl-2, whereas the absence of binding induced apoptosis. The deletion of Bcl-2 in macrophages protected mice from developing pulmonary fibrosis. Moreover, mice had resolution when Bcl-2 was deleted or was inhibited with ABT-199 after fibrosis was established. These observations implicate an interplay between macrophage fatty acid ß-oxidation, apoptosis resistance, and dysregulated fibrotic remodeling.

Structural Features of a Family of Coumarin-Enamine Fluorescent Chemodosimeters for Ion Pairs.

A family of coumarin-enamine chemodosimeters is evaluated for their potential use as fluorescent molecular probes for multiple analytes [cadmium(II), cobalt(II), copper(II), iron(II), nickel(II), lead(II), and zinc(II)], as their chloride and acetate salts. These fluorophores displayed excellent optical spectroscopic modulation when exposed to ion pairs with different Lewis acidic and basic properties in dimethyl sulfoxide (DMSO). The chemodosimeters were designed to undergo excited-state intramolecular proton transfer (ESIPT), which leads to significant Stokes shifts (ca. 225 nm) and lower-energy fluorescence emission (ca. 575 nm). A more basic anion, e.g., acetate, inhibited the ESIPT mechanism by deprotonation of the enol, producing a binding pocket (N^O- chelate) that can coordinate to an appropriate metal ion. Coordination of the metal ions enhances the fluorescent intensity via the chelation-enhanced fluorescence emission mechanism. Subjecting the spectroscopic data to linear discriminant analysis provided insights into the source of these systems' markedly different behavior toward ion pairs, despite the subtle structural differences in the organic framework. These compounds are examples of versatile, low-molecular-weight, dual-channel fluorescent sensors for ion-pair recognition. This study paves the way for using these probes as practical components of a sensing array for different metal ions and their respective anions.

Post-translational regulation of PGC-1α modulates fibrotic repair.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with mitochondrial oxidative stress. Mitochondrial reactive oxygen species (mtROS) are important for cell homeostasis by regulating mitochondrial dynamics. Here, we show that IPF BAL cells exhibited increased mitochondrial biogenesis that is, in part, due to increased nuclear expression of peroxisome proliferator-activated receptor-É£ (PPARÉ£) coactivator (PGC)-1α. Increased PPARGC1A mRNA expression directly correlated with reduced pulmonary function in IPF subjects. Oxidant-mediated activation of the p38 MAPK via Akt1 regulated PGC-1α activation to increase mitochondrial biogenesis in monocyte-derived macrophages. Demonstrating the importance of PGC-1α in fibrotic repair, mice harboring a conditional deletion of Ppargc1a in monocyte-derived macrophages or mice administered a chemical inhibitor of mitochondrial division had reduced biogenesis and increased apoptosis, and the mice were protected from pulmonary fibrosis. These observations suggest that Akt1-mediated regulation of PGC-1α maintains mitochondrial homeostasis in monocyte-derived macrophages to induce apoptosis resistance, which contributes to the pathogenesis of pulmonary fibrosis.

More Than a Means to an End: Alignment of Social Service Organizations' Missions with Representative Payee Program Goals.

Although nearly 5 million Social Security Income and Social Security Disability Insurance beneficiaries receive entitlements through representative payee programs and approximately 5% of these receive representative payee services from social service agencies, few studies have assessed ways that these services align with their organizations' missions. We conducted nine qualitative interviews with 15 staff members of organizations in Pennsylvania that provide representative payee services in addition to other social or supportive services, with some interviews conducted with multiple representatives within an organization. The purpose of the interviews was to explore the goals of representative payee services for these organizations, whether these providers incorporated representative payee services into their organizational missions, and the extent to which organizations incorporate client-centered approaches in their representative payee services. We identified three main goals of the representative payee programs, which were in alignment with the organizations' missions: financial and housing stability, financial literacy, and improving health outcomes. In addition, participants discussed challenges related to representative payee services that were encountered within their organizations and with clients. Findings indicate that organizations view representative payee services as not just financial management but also a means to improve clients' knowledge and skills and assist them with achieving their goals. Client-centered practices were emphasized as a means of reducing paternalism and to support clients' goals. Given that participants discussed the importance of incorporating client-centeredness into the provision of representative payee services and there are currently no published guidelines or best practices on how this can be achieved, we suggest that guidance on how to effectively provide client-centered representative payee services to improve client outcomes is essential.

"Support People the Way in Which They Want to Be Supported": Best Practices for Incorporating Client-Centeredness in Representative Payee Programs.

Nearly 1 million Social Security beneficiaries have representative payees to manage their funds. Although coercion and paternalism are historically associated with payee services, a recent study showed high satisfaction in a payee program incorporating client-centered practices. Separately we reported ways organizations align payee services with their missions to empower clients and improve outcomes. Here we share results from nine provider qualitative interviews describing client-centered best practices and exploring beliefs regarding their value. We identified four best practices: Shared Decision-Making on Bills and Spending, Non-Paternalistic Substance Use Policies, Client Advocacy, and Additional Service Policies, (changing fee structures, termination policies, incorporating opting in or out, and "graduation"). Results indicate prioritizing clients' goals and agency may improve the quality of life of beneficiaries and reduce the paternalism and coercion historically associated with payee. Creating a client-centered payee toolkit and a payee collaborative may empower organizations to refine their services and provide opportunities for shared learning and support.

Reproducing while Black: The crisis of Black maternal health, obstetric racism and assisted reproductive technology.

Black women bear the burden of a number of crises related to reproduction. Historically, their reproduction has been governed in relation to the slave economy, and connected to this, they have been experimented upon and subjected to exploitative medical interventions and policies. Even now, they are more likely to experience premature births and more likely to die from pregnancy-related complications. Their reproductive lives have been beleaguered by racism. This reality, as this article points out, shapes the use of assisted reproductive technology (ART) by Black women. Using the framework of obstetric racism, I suggest that, in addition to the crisis of adverse maternal health outcomes, such as premature birth, low-birthweight infants and maternal death, Black women also face the crisis of racism in their medical encounters as they attempt to conceive through ART. Obstetric racism is enacted on racialized bodies that have historically experienced subjugation, especially, but not solely, reproductive subjugation. In my prior work, I delineated four dimensions of obstetric racism: diagnostic lapses; neglect, dismissiveness or disrespect; intentionally causing pain; and coercion. In this article, I extend that framework and explore three additional dimensions of obstetric racism: ceremonies of degradation; medical abuse; and racial reconnaissance. This article is based on ethnographic work from 2011 to 2019, during which time I collected narratives of US-based Black women and documented the circumstances under which they experienced obstetric racism in their interactions with medical personnel while attempting conception through ART.

High-Dimensional Analysis of Postsplenectomy Peripheral Immune Cell Changes.

Although the consequences of splenectomy are well understood in mice, much less is known about the immunologic changes that occur following splenectomy in humans. We sought to characterize the circulating immune cell populations of patients before and after elective splenectomy to determine if these changes are related to postsplenectomy survival outcomes. Retrospective clinical information was collected from 95 patients undergoing elective splenectomy compared with 91 patients undergoing pancreaticoduodenectomy (Whipple procedure). We further analyzed peripheral blood from five patients in the splenectomy group, collected before and after surgery, using single-cell cytometry by time-of-flight mass spectrometry. We compared pre- and postsplenectomy data to characterize both the major and minor immune cell populations in significantly greater detail. Compared with patients undergoing a Whipple procedure, splenectomized patients had significant and long-lasting elevated counts of lymphocytes, monocytes, and basophils. Cytometry by time-of-flight mass spectroscopy analysis demonstrated that the elevated lymphocytes primarily consisted of naive CD4+ T cells and a population of activated CD25+CD56+CD4+ T cells, whereas the elevated monocyte counts were mainly mature, activated monocytes. We also observed a significant increase in the expression of the chemokine receptors CCR6 and CCR4 on several cellular populations. Taken together, these data indicate that significant immunological changes take place following splenectomy. Whereas other groups have compared splenectomized patients to healthy controls, this study compared patients undergoing elective splenectomy to those undergoing a similar major abdominal surgery. Overall, we found that splenectomy results in significant long-lasting changes in circulating immune cell populations and function.

IL-6 and IL-8 Are Linked With Myeloid-Derived Suppressor Cell Accumulation and Correlate With Poor Clinical Outcomes in Melanoma Patients.

We sought to identify tumor-secreted factors that altered the frequency of MDSCs and correlated with clinical outcomes in advanced melanoma patients. We focused our study on several of the many factors involved in the expansion and mobilization of MDSCs. These were identified by measuring circulating concentrations of 13 cytokines and growth factors in stage IV melanoma patients (n = 55) and healthy controls (n = 22). Based on these results, we hypothesized that IL-6 and IL-8 produced by melanoma tumor cells participate in the expansion and recruitment of MDSCs and together would be predictive of overall survival in melanoma patients. We then compared the expression of IL-6 and IL-8 in melanoma tumors to the corresponding plasma concentrations and the frequency of circulating MDSCs. These measures were correlated with clinical outcomes. Patients with high plasma concentrations of either IL-6 (40%) or IL-8 (63%), or both (35%) had worse median overall survival compared to patients with low concentrations. Patients with low peripheral concentrations and low tumoral expression of IL-6 and IL-8 showed decreased frequencies of circulating MDSCs, and patients with low frequencies of MDSCs had better overall survival. We have previously shown that IL-6 is capable of expanding MDSCs, and here we show that MDSCs are chemoattracted to IL-8. Multivariate analysis demonstrated an increased risk of death for subjects with both high IL-6 and IL-8 (HR 3.059) and high MDSCs (HR 4.265). Together these results indicate an important role for IL-6 and IL-8 in melanoma patients in which IL-6 potentially expands peripheral MDSCs and IL-8 recruits these highly immunosuppressive cells to the tumor microenvironment. This study provides further support for identifying potential therapeutics targeting IL-6, IL-8, and MDSCs to improve melanoma treatments.

Increased flux through the mevalonate pathway mediates fibrotic repair without injury.

Macrophages are important in mounting an innate immune response to injury as well as in repair of injury. Gene expression of Rho proteins is known to be increased in fibrotic models; however, the role of these proteins in idiopathic pulmonary fibrosis (IPF) is not known. Here, we show that BAL cells from patients with IPF have a profibrotic phenotype secondary to increased activation of the small GTPase Rac1. Rac1 activation requires a posttranslational modification, geranylgeranylation, of the C-terminal cysteine residue. We found that by supplying more substrate for geranylgeranylation, Rac1 activation was substantially increased, resulting in profibrotic polarization by increasing flux through the mevalonate pathway. The increased flux was secondary to greater levels of acetyl-CoA from metabolic reprogramming to ß oxidation. The polarization mediated fibrotic repair in the absence of injury by enhancing macrophage/fibroblast signaling. These observations suggest that targeting the mevalonate pathway may abrogate the role of macrophages in dysregulated fibrotic repair.

NOX4 modulates macrophage phenotype and mitochondrial biogenesis in asbestosis.

Macrophage activation is implicated in the development of pulmonary fibrosis by generation of profibrotic molecules. Although NADPH oxidase 4 (NOX4) is known to contribute to pulmonary fibrosis, its effects on macrophage activation and mitochondrial redox signaling are unclear. Here, we show that NOX4 is crucial for lung macrophage profibrotic polarization and fibrotic repair after asbestos exposure. NOX4 was elevated in lung macrophages from subjects with asbestosis, and mice harboring a deletion of NOX4 in lung macrophages were protected from asbestos-induced fibrosis. NOX4 promoted lung macrophage profibrotic polarization and increased production of profibrotic molecules that induce collagen deposition. Mechanistically, NOX4 further augmented mitochondrial ROS production and induced mitochondrial biogenesis. Targeting redox signaling and mitochondrial biogenesis prevented the profibrotic polarization of lung macrophages by reducing the production of profibrotic molecules. These observations provide evidence that macrophage NOX4 is a potentially novel therapeutic target to halt the development of asbestos-induced pulmonary fibrosis.