Challenges and gaps in immunosafety evaluation of therapeutics: An IQ DruSafe survey.

Immunotoxicology/immunosafety science is rapidly evolving, with novel modalities and immuno-oncology among the primary drivers of new tools and technologies. The Immunosafety Working Group of IQ/DruSafe sought to better understand some of the key challenges in immunosafety evaluation, gaps in the science, and current limitations in methods and data interpretation. A survey was developed to provide a baseline understanding of the needs and challenges faced in immunosafety assessments, the tools currently being applied across the industry, and the impact of feedback received from regulatory agencies. This survey also focused on current practices and challenges in conducting the T-cell-dependent antibody response (TDAR) and the cytokine release assay (CRA). Respondents indicated that ICH S8 guidance was insufficient for the current needs of the industry portfolio of immunomodulators and novel modalities and should be updated. Other challenges/gaps identified included translation of nonclinical immunosafety assessments to the clinic, and lack of relevant nonclinical species and models in some cases. Key areas of emerging science that will add future value to immunotoxicity assessments include development of additional in vitro and microphysiological system models, as well as application of humanized mouse models. Efforts are ongoing in individual companies and consortia to address some of these gaps and emerging science.

Designing Effective Mentorship for Underrepresented Faculty in Academic Medicine.

BACKGROUND AND OBJECTIVES: A dearth of training and resources exists for mentors to address the unique needs of faculty from racial/ethnic groups that are underrepresented in medicine (URiM). Mentoring Underrepresented Faculty for Academic Excellence (MUFAE) was a multi-institutional mentoring program designed to provide mentors where there were none. METHODS: In 2020, 25 early career URiM faculty mentees each were paired with advanced faculty, and pairs met individually for monthly calls for 1 year. Mentees completed pre- and postassessment surveys regarding their experience in the program. Mentees and mentors also participated in virtual group check-ins where they gave feedback on their experience to program leaders while also networking with fellow participants. RESULTS: Twenty-two of the 25 mentor-mentee pairs (88%) completed the program, and 17 of the 22 (77%) mentees completed the pre- and postsurveys. Survey responses showed significant increases in mentees reports of feeling they received mentorship focused on their needs as URiM faculty members, feeling equipped to advance in their careers, and feeling supported in their efforts to complete antiracism/health-equity programs. Feedback at the check-ins indicated that URiM mentors appreciated the opportunities to talk about their own frustrations and that White mentors appreciated having an increased understanding of challenges that their URIM colleagues faced. CONCLUSIONS: MUFAE is a model for academic societies to address the lack of mentors for URiM faculty. Mentees and mentors found the experience a meaningful one that fills a need in academic mentoring.

A global comparative study of wealth-pain gradients: Investigating individual- and country-level associations.

Pain is a significant yet underappreciated dimension of population health. Its associations with individual- and country-level wealth are not well characterized using global data. We estimate both individual- and country-level wealth inequalities in pain in 51 countries by combining data from the World Health Organization's World Health Survey with country-level contextual data. Our research concentrates on three questions: 1) Are inequalities in pain by individual-level wealth observed in countries worldwide? 2) Does country-level wealth also relate to pain prevalence? 3) Can variations in pain reporting also be explained by country-level contextual factors, such as income inequality? Analytical steps include logistic regressions conducted for separate countries, and multilevel models with random wealth slopes and resultant predicted probabilities using a dataset that pools information across countries. Findings show individual-level wealth negatively predicts pain almost universally, but the association strength differs across countries. Country-level contextual factors do not explain away these associations. Pain is generally less prevalent in wealthier countries, but the exact nature of the association between country-level wealth and pain depends on the moderating influence of country-level income inequality, measured by the Gini index. The lower the income inequality, the more likely it is that poor countries experience the highest and rich countries the lowest prevalence of pain. In contrast, the higher the income inequality, the more nonlinear the association between country-level wealth and pain reporting such that the highest prevalence is seen in highly nonegalitarian middle-income countries. Our findings help to characterize the global distribution of pain and pain inequalities, and to identify national-level factors that shape pain inequalities.

Cooperative CAR targeting to selectively eliminate AML and minimize escape.

Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal hematopoietic stem/progenitor cells (HSPCs). Here we expound a CAR strategy intended to efficiently target AML while minimizing HSPC toxicity. Quantification of target expression in relapsed/refractory patient samples and normal HSPCs reveals a therapeutic window for gated co-targeting of ADGRE2 and CLEC12A: We combine an attenuated ADGRE2-CAR with a CLEC12A-chimeric costimulatory receptor (ADCLEC.syn1) to preferentially engage ADGRE2posCLEC12Apos leukemic stem cells over ADGRE2lowCLEC12Aneg normal HSPCs. ADCLEC.syn1 prevents antigen escape in AML xenograft models, outperforms the ADGRE2-CAR alone and eradicates AML despite proximate myelopoiesis in humanized mice. Off-target HSPC toxicity is similar to that of a CD19-CAR and can be mitigated by reducing CAR T cell-derived interferon-γ. Overall, we demonstrate the ability of target density-adapted cooperative CAR targeting to selectively eliminate AML and potentially obviate the need for hematopoietic rescue.

No struggle, no progress: Taking the anti-racism conversation to a deeper level.

In order to promote ongoing dialogues about how to address racism in health care, the 2021 Forum on Behavioral Science included a workshop on how to take antiracism activities and conversations to a deeper level than what is typically offered. The workshop followed up on a previous antiracism plenary presentation at the 2020 Forum and was intentionally created to keep the importance of antiracism efforts on the forefront of behavioral science and medical education. The currently described presentation provided some background on how health inequity evolved in the United States. It also included information on the role that racism has played in the development of inequities in health care, the profession of medicine and medical education. Presenters included several activities specifically chosen to promote honest, open conversations about power imbalances that promote discrimination on the micro and macrosystem level. Participants were encouraged to start working on specific goals and ideas on how to conduct these activities and challenging conversations in their home institutions.

A global study of pain prevalence across 52 countries: examining the role of country-level contextual factors.

ABSTRACT: There is wide variation in population-level pain prevalence estimates in studies of survey data around the world. The role of country-level social, economic, and political contextual factors in explaining this variation has not been adequately examined. We estimated the prevalence of unspecified pain in adults aged 25+ years across 52 countries using data from the World Health Survey 2002 to 2004. Combining data sources and estimating multilevel regressions, we compared country-level pain prevalence and explored which country-level contextual factors explain cross-country variations in prevalence, accounting for individual-level demographic factors. The overall weighted age- and sex-standardized prevalence of pain across countries was estimated to be 27.5%, with significant variation across countries (ranging from 9.9% to 50.3%). Women, older persons, and rural residents were significantly more likely to report pain. Five country-level variables had robust and significant associations with pain prevalence: the Gini Index, population density, the Gender Inequality Index, life expectancy, and global region. The model including Gender Inequality Index explained the most cross-country variance. However, even when accounting for country-level variables, some variation in pain prevalence remains, suggesting a complex interaction between personal, local, economic, and political impacts, as well as inherent differences in language, interpretations of health, and other difficult to assess cultural idiosyncrasies. The results give new insight into the high prevalence of pain around the world and its demonstrated association with macrofactors, particularly income and gender inequalities, providing justification for regarding pain as a global health priority.

Racism and persistent disparities: Difficult conversations on the road to equity.

The convergence of the major social events of the COVID 19 epidemic and the racial protests around the George Floyd killing spurred many conversations and calls to action for racial justice. The Behavioral Science Forum of 2020 invited a plenary presentation to discuss guidelines for medical education institutions to improve their anti-racism curricula. The plenary aimed to put forward the personal experiences of family medicine faculty contributing to dismantling racism in their institutions. Presenters provided (1) a breakdown of the step by step process of addressing these issues with faculty, residents, and staff, (2) guidelines for improving recruitment and retention of diverse student populations, and (3) small group breakouts and a subsequent discussion forum for participants to bring their experiences into the conversation and develop their personal call to action. The wrap-up discussion and "Zoom chat" yielded emotional responses and specific ideas for participants and other faculty in medical education to do their part in developing anti-racism curricula.

War across the life course: examining the impact of exposure to conflict on a comprehensive inventory of health measures in an aging Vietnamese population.

BACKGROUND: The majority of evidence indicates that exposure to war and other traumatic events continue to have negative impacts on health across the life course. However, existing research on health effects of war exposure primarily concentrates on short-term impacts among veterans in high-income countries sent elsewhere to battle. Yet, most wars situate in lower- and middle-income countries, where many are now or will soon be entering old age. Consequently, the current burden of exposure to war has ignored an important global population. METHODS: The Vietnam Health and Aging Study (VHAS) is a longitudinal study designed to examine historical exposure to highly stressful events during the American War. Two modes of data collection, involving a sample of 2447 individuals aged 60+ years in northern Vietnam, took place between May and August 2018. Using this first wave of data, we generate indexed measures of war exposure and analyze their associations with a set of 12 health outcomes, accounting for confounding variables. RESULTS: Results indicate that greater exposure to three types of war exposure (death and injury, stressful living conditions, and fearing death and/or injury) in earlier life is associated with worse health in later-life across a large number of health outcomes, such as number of diagnosed health conditions, mental distress, somatic symptoms, physical functioning, post-traumatic stress symptoms and chronic pain. CONCLUSIONS: Findings support a life course theory of health and point to long-term effects of war on health that require detailed attention.

"It was Like Magic": Relationships Supporting Compassion, Creativity, and Sense of Coherence in Nutrition Students.

The purpose of this exploratory research was to understand the experiences and learnings of dietetic and nutrition students following a 3-week intensive summer course designed to enhance students' understandings of compassion, creativity, and sense of coherence as they apply to personal growth and socially just professional practice. Seven of 15 students participated in one-on-one, semi-structured interviews. Data analysis was conducted using inductive thematic analysis, resulting in 3 meta-themes: (i) personal meaning and sense making, (ii) relational and power dynamics, and (iii) disruption; participants contextualized these themes via a dynamic interplay within and among the domains of self, pedagogy, and practice. As a result of taking this course, participants developed an enhanced sense of coherence, self-compassion, well-being, and a more equity-focused understanding of health. Student development may have been achieved through attending to student experience and a relational pedagogical epistemology that allowed students to make personal, interpersonal, and systemic connections among their own subjective experiences, the experiences of peers, and broader social impacts on health. Given nutrition classrooms are largely positivist, it is important to consider how these environments as relational contexts may support or undermine compassion, sense of coherence, and ultimately the health and well-being of students.

Canadian Dietitians' Understandings of, Attitudes Toward, and Engagement in Social Justice and Advocacy.

Purpose: To explore Canadian dietitians' understandings of, attitudes towards, and engagement in socially just dietetic practice and advocacy.Methods: An online semi-qualitative survey sent to Canadian dietitians.Results: Respondents' understanding of social justice and socially just dietetics practice highlights the unique ways that social injustice and health inequities may be addressed by dietitians. Overall, respondents had a positive attitude toward dietitians' roles in social justice advocacy. Support for dietitians' advocacy roles was highest for food-related concerns, but it declined for concerns with indirect connections to dietitians' food and nutrition expertise (e.g., environment). However, respondents still had uncertainty and divided perspectives concerning if and how social justice fits within dietitians' scope of practice. They also had concerns about barriers that they felt limit dietitians' ability to perform socially just practice. Respondents shared efforts to engage in socially just practice at intrapersonal, interpersonal, and structural levels.Conclusions: Dietitians could be a critical influence on the determinants of health. This research points strongly to the need for a framework for socially just dietetic practice and advocacy that delineates what social justice looks like across the array of settings in which dietitians practice and within the array of fora that dietitians advocate to support nutrition and health.

Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens.

The immune system adapts to constitutive antigens to preserve self-tolerance, which is a major barrier for anti-tumor immunity. Antigen-specific reversal of tolerance constitutes a major goal to spur therapeutic applications. Here, we show that robust, iterative, systemic stimulation targeting tissue-specific antigens in the context of acute infections reverses established CD8+ T cell tolerance to self, including in T cells that survive negative selection. This strategy results in large numbers of circulating and resident memory self-specific CD8+ T cells that are widely distributed and can be co-opted to control established malignancies bearing self-antigen without concomitant autoimmunity. Targeted expansion of both self- and tumor neoantigen-specific T cells acts synergistically to boost anti-tumor immunity and elicits protection against aggressive melanoma. Our findings demonstrate that T cell tolerance can be re-adapted to responsiveness through robust antigenic exposure, generating self-specific CD8+ T cells that can be used for cancer treatment.

Immune Pharmacodynamic Responses of the Novel Cancer Immunotherapeutic Imprime PGG in Healthy Volunteers.

Imprime PGG (Imprime) is an i.v. administered, yeast ß-1,3/1,6 glucan in clinical development with checkpoint inhibitors. Imprime-mediated innate immune activation requires immune complex formation with naturally occurring IgG anti-ß glucan Abs (ABA). We administered Imprime to healthy human volunteers to assess the necessity of ABA for Imprime-mediated immunopharmacodynamic (IPD) changes. Imprime (4 mg/kg) was administered i.v. in single and multiple infusions. Subsets of subjects were premedicated with antihistamine and corticosteroid. Peripheral blood was measured before, during and after Imprime administration for IPD changes (e.g., ABA, circulating immune complexes, complement activation, complete blood counts, cytokine/chemokine, and gene expression changes). IPD changes were analyzed based on pretreatment serum ABA levels: low-ABA (<20 µg/ml), mid-ABA (≥20-50 µg/ml), and high-ABA (≥50 µg/ml). At the end of infusion, free serum ABA levels decreased, circulating immune complex levels increased, and complement activation was observed. At ∼1-4 h after end of infusion, increased expression of cytokines/chemokines, a 1.5-4-fold increase in neutrophil and monocyte counts and a broad activation of innate immune genes were observed. Low-ABA subjects typically showed minimal IPD changes except when ABA levels rose above 20 µg/ml after repeated Imprime dosing. Mild-to-moderate infusion-related reactions occurred in subjects with ABA ≥20 µg/ml. Premedications alleviated some of the infusion-related reactions, but also inhibited cytokine responses. In conclusion, ABA levels, being critical for Imprime-mediated immune activation may provide a plausible, mechanism-based biomarker to identify patients most likely to respond to Imprime-based anticancer immunotherapy.

CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses.

This study examines the extent to which memory CD4+ T cells share immunosurveillance strategies with CD8+ resident memory T cells (TRM). After acute viral infection, memory CD4+ T cells predominantly used residence to survey nonlymphoid tissues, albeit not as stringently as observed for CD8+ T cells. In contrast, memory CD4+ T cells were more likely to be resident within lymphoid organs than CD8+ T cells. Migration properties of memory-phenotype CD4+ T cells in non-SPF parabionts were similar, generalizing these results to diverse infections and conditions. CD4+ and CD8+ TRM shared overlapping transcriptional signatures and location-specific features, such as granzyme B expression in the small intestine, revealing tissue-specific and migration property-specific, in addition to lineage-specific, differentiation programs. Functionally, mucosal CD4+ TRM reactivation locally triggered both chemokine expression and broad immune cell activation. Thus, residence provides a dominant mechanism for regionalizing CD4+ T cell immunity, and location enforces shared transcriptional, phenotypic, and functional properties with CD8+ T cells.

Exploring Social Justice Advocacy in Dietetic Education: A Content Analysis.

PURPOSE: To explore the extent to which knowledge- and skill-based learning regarding social justice and/or social justice advocacy is included in the course descriptions of required courses of accredited, English-speaking dietitian training programs in Canada. METHODS: This study is a mixed-methods content analysis of required course descriptions sampled from university academic calendars for accredited, English-speaking dietitian training programs across Canada. RESULTS: Quantitative analysis showed that required course descriptions (n = 403) included few instances of social justice-related terminology (n = 63). Two themes emerged from the qualitative analysis: competing conceptualizations of social issues and dietitians' roles; prioritization of science-based knowledge and ways of knowing. CONCLUSIONS: Accredited, English-speaking dietitian training programs in Canada appear to include little knowledge- or skill-based learning regarding social justice issues and advocacy. Supporting future dietitians to pursue leadership roles in redressing social injustices and socially just dietetic practice may require more explicit education and training about social justice issues and advocacy skills.

Addressing Racism in Medical Education An Interactive Training Module.

BACKGROUND AND OBJECTIVES: Education of health care clinicians on racial and ethnic disparities has primarily focused on emphasizing statistics and cultural competency, with minimal attention to racism. Learning about racism and unconscious processes provides skills that reduce bias when interacting with minority patients. This paper describes the responses to a relationship-based workshop and toolkit highlighting issues that medical educators should address when teaching about racism in the context of pernicious health disparities. METHODS: A multiracial, interdisciplinary team identified essential elements of teaching about racism. A 1.5-hour faculty development workshop consisted of a didactic presentation, a 3-minute video vignette depicting racial and gender microaggression within a hospital setting, small group discussion, large group debrief, and presentation of a toolkit. RESULTS: One hundred twenty diverse participants attended the workshop at the 2016 Society of Teachers of Family Medicine Annual Spring Conference. Qualitative information from small group facilitators and large group discussions identified some participants' emotional reactions to the video including dismay, anger, fear, and shame. A pre/postsurvey (N=72) revealed significant changes in attitude and knowledge regarding issues of racism and in participants' personal commitment to address them. DISCUSSION: Results suggest that this workshop changed knowledge and attitudes about racism and health inequities. Findings also suggest this workshop improved confidence in teaching learners to reduce racism in patient care. The authors recommend that curricula continue to be developed and disseminated nationally to equip faculty with the skills and teaching resources to effectively incorporate the discussion of racism into the education of health professionals.

Raising voices: A commentary on "Say their names" by Sandhira Wijayaratne.

Comments on a poem by Sandhira Wijayaratne (see record 2018-12809-007). This poem uses the power of language to speak to the consequences of silence and complacency and points to the role of healers in the social narrative. In his work, Wijayaratne highlights the structural and systemic racism that plagues our nation today, and affects our work as healthcare providers. "Say Their Names" represents a timely contribution to this field and echoes much of the current national discourse around racial oppression. It highlights the role of systemic racism in setting the stage for health disparities, disease, and trauma. (PsycINFO Database Record

Normalizing the environment recapitulates adult human immune traits in laboratory mice.

Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice--like newborn, but not adult, humans--lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.

IL-15-Independent Maintenance of Tissue-Resident and Boosted Effector Memory CD8 T Cells.

IL-15 regulates central and effector memory CD8 T cell (TCM and TEM, respectively) homeostatic proliferation, maintenance, and longevity. Consequently, IL-15 availability hypothetically defines the carrying capacity for total memory CD8 T cells within the host. In conflict with this hypothesis, previous observations demonstrated that boosting generates preternaturally abundant TEM that increases the total quantity of memory CD8 T cells in mice. In this article, we provide a potential mechanistic explanation by reporting that boosted circulating TEM do not require IL-15 for maintenance. We also investigated tissue-resident memory CD8 T cells (TRM), which protect nonlymphoid tissues from reinfection. We observed up to a 50-fold increase in the total magnitude of TRM in mouse mucosal tissues after boosting, suggesting that the memory T cell capacity in tissues is flexible and that TRM may not be under the same homeostatic regulation as primary central memory CD8 T cells and TEM Further analysis identified distinct TRM populations that depended on IL-15 for homeostatic proliferation and survival, depended on IL-15 for homeostatic proliferation but not for survival, or did not depend on IL-15 for either process. These observations on the numerical regulation of T cell memory indicate that there may be significant heterogeneity among distinct TRM populations and also argue against the common perception that developing vaccines that confer protection by establishing abundant TEM and TRM will necessarily erode immunity to previously encountered pathogens as the result of competition for IL-15.

Interleukin-2-Dependent Allergen-Specific Tissue-Resident Memory Cells Drive Asthma.

Exposure to inhaled allergens generates T helper 2 (Th2) CD4(+) T cells that contribute to episodes of inflammation associated with asthma. Little is known about allergen-specific Th2 memory cells and their contribution to airway inflammation. We generated reagents to understand how endogenous CD4(+) T cells specific for a house dust mite (HDM) allergen form and function. After allergen exposure, HDM-specific memory cells persisted as central memory cells in the lymphoid organs and tissue-resident memory cells in the lung. Experimental blockade of lymphocyte migration demonstrated that lung-resident cells were sufficient to induce airway hyper-responsiveness, which depended upon CD4(+) T cells. Investigation into the differentiation of pathogenic Trm cells revealed that interleukin-2 (IL-2) signaling was required for residency and directed a program of tissue homing migrational cues. These studies thus identify IL-2-dependent resident Th2 memory cells as drivers of lung allergic responses.