Sex contextualism in laboratory research: Enhancing rigor and precision in the study of sex-related variables.

Understanding sex-related variation in health and illness requires rigorous and precise approaches to revealing underlying mechanisms. A first step is to recognize that sex is not in and of itself a causal mechanism; rather, it is a classification system comprising a set of categories, usually assigned according to a range of varying traits. Moving beyond sex as a system of classification to working with concrete and measurable sex-related variables is necessary for precision. Whether and how these sex-related variables matter-and what patterns of difference they contribute to-will vary in context-specific ways. Second, when researchers incorporate these sex-related variables into research designs, rigorous analytical methods are needed to allow strongly supported conclusions. Third, the interpretation and reporting of sex-related variation require care to ensure that basic and preclinical research advance health equity for all.

Considering hormones as sex- and gender-related factors in biomedical research: Challenging false dichotomies and embracing complexity.

The inclusion of sex and gender considerations in biomedicine has been increasing in light of calls from research and funding agencies, governmental bodies, and advocacy groups to direct research attention to these issues. Although the inclusion of both female and male participants is often an important element, overreliance on a female-male binary tends to oversimplify the interactions between sex- and gender-related factors and health, and runs a risk of being influenced by cultural stereotypes about sex and gender. When biomedical researchers are examining how hormones associated with gender and sex may influence pathways of interest, it is of crucial importance to approach this work with a critical lens on the rhetoric used, and in ways that acknowledge the complexity of hormone physiology. Here, we document the ways in which discourses around sex, gender and hormones shape our scientific thinking and practice in biomedical research, and review how the existing scientific knowledge about hormones reflects a complex and dynamic reality that is often not reflected outside of specialist niches of hormone biology. Where biomedical scientists take up sex- and gender-associated hormones as a way of addressing sex and gender considerations, it is valuable for us to bring a critical lens to the rhetoric and discourses used, to employ a sex contextualist approach in designing experimentation, and be rigorous and reflexive about the approaches used in analysis and interpretation of data. These strategies will allow us to design experimentation that goes beyond binaries, and grapples more directly with the material intricacies of sex, gender, and hormones.

First steps for integrating sex and gender considerations into basic experimental biomedical research.

In recent decades there has been an increasing recognition of the need to account for sex and gender in biology and medicine, in order to develop a more comprehensive understanding of biological phenomena and to address gaps in medical knowledge that have arisen due to a generally masculine bias in research. We have noted that as basic experimental biomedical researchers, we face unique challenges to the incorporation of sex and gender in our work, and that these have remained largely unarticulated, misunderstood, and unaddressed in the literature. Here, we describe some of the specific challenges to the incorporation of sex and gender considerations in research involving cell cultures and laboratory animals. In our view, the mainstreaming of sex and gender considerations in basic biomedical research depends on an approach that will allow scientists to address these issues in ways that do not undermine our ability to pursue our fundamental scientific interests. To that end, we suggest a number of strategies that allow basic experimental researchers to feasibly and meaningfully take sex and gender into account in their work.

Accounting for social accountability: developing critiques of social accountability within medical education.

BACKGROUND: The concept of the social accountability of medical schools has garnered many followers, in response to a broad desire for greater social justice in health care. As its use has spread, the term 'social accountability' has become a meta-narrative for social justice and an inevitable and unquestionable good, while at the same time becoming increasingly ambiguous in its meaning and intent. In this article, we use the lenses of postmodernism and critical reflexivity to unpack the multiple meanings of social accountability. In our view, subjecting the concept of 'social accountability' to critique will enhance the ability to appraise the ways in which it is understood and enacted. DISCUSSION: We contend that critical reflexivity is necessary for social accountability to achieve its aspirations, and hence we must be prepared to become accountable not only for our actions, but also for the ideologies and discourses underlying them.

Conceptualizing Physicians' Roles in Addressing Intimate Partner Violence: A Critical Discourse Analysis of Resources for Canadian Physicians.

Resources addressing intimate partner violence (IPV) play a role in shaping how physicians conceptualize and perform their roles in caring for affected patients. This study combines environmental scanning with critical discourse analysis (CDA) to parse how roles of physicians were represented in 28 education materials and policy documents about IPV, taking the Canadian training milieu as an example. We developed a cyclical model of three core physician roles in addressing IPV-learning about IPV, identifying patients experiencing IPV, and responding to patients' disclosures of IPV. The construction of these physician roles is suggestive of an ongoing process of medicalization of IPV.

A brief report of aspiring medical student perceptions and behaviours concerning research experiences for selection into Canadian medical schools.

Background: Aspiring medical students behave based on their perception of what is valued in the selection process. While research experience is not explicitly considered in most Canadian admissions policies, it is commonly held as valuable within aspiring medical student communities. The purpose of this study is to describe the perceptions and behaviours of aspiring medical students with respect to gaining research experience in support of their medical school applications. Methods: We surveyed prospective applicants of Canadian medical schools between August 2021 and November 2021, then compiled descriptive statistics pertaining to their perceptions and behaviours. Results: Respondents affirmed the belief that research experience is valued in medical school admissions processes. They reported spending approximately 13 hours per week engaged in research, which usually did not yield publication or presentation recognition. Conclusion: Aspiring medical students invest substantial time and energy in research experiences to benefit their applications. There is room for medical schools to be more transparent about the value of research experience in their admissions processes.

Contexte: Le comportement des candidats aux études de médecine est déterminé par leur perception de ce qui est valorisé dans le processus de sélection. Tandis que la plupart des établissements canadiens ne mentionnent pas explicitement l'expérience en recherche comme prérequis d'admission, les futurs candidats, eux, voient une telle expérience comme un atout précieux. L'objectif de cette étude est de décrire les perceptions et les comportements des futurs étudiants en médecine par rapport à l'acquisition d'une expérience en recherche en appui à leur demande d'admission dans une école de médecine. Méthodes: Nous avons interrogé des postulants potentiels aux programmes de médecine au Canada entre août 2021 et novembre 2021, et nous avons compilé des statistiques descriptives relatives à leurs perceptions et à leurs comportements. Résultats: Les répondants ont affirmé croire que l'expérience en recherche est valorisée dans les processus d'admission aux facultés de médecine. Ils ont déclaré consacrer environ 13 heures par semaine à la recherche, qui, le plus souvent, n'a pas mené à des publications ou des présentations. Conclusion: Les futurs candidats aux études de médecine investissent beaucoup de temps et d'énergie dans des activités de recherche afin d'améliorer leur dossier de candidature. Les facultés de médecine devraient se prononcer de manière transparente sur l'importance attribuée à l'expérience en recherche dans le cadre de leur processus d'admission.

Transcending the Male-Female Binary in Biomedical Research: Constellations, Heterogeneity, and Mechanism When Considering Sex and Gender.

Accounting for the influences of sex- and gender-related factors on health is one of the most interesting and important challenges in contemporary health research. In biomedical research, models, experimental designs, and statistical analyses create particular challenges in attempting to incorporate the complex, dynamic, and context-dependent constructs of sex and gender. Here, we offer conceptual elaborations of the constructs of sex and gender and discuss their application in biomedical research, including a more mechanism-oriented and context-driven approach to experimental design integrating sex and gender. We highlight how practices of data visualization, statistical analysis, and rhetoric can be valuable tools in expanding the operationalization of sex and gender biomedical science and reducing reliance on a male-female binary approach.

Sex, Gender and Health: Mapping the Landscape of Research and Policy.

Including sex and gender considerations in health research is considered essential by many funders and is very useful for policy makers, program developers, clinicians, consumers and other end users. While longstanding confusions and conflations of terminology in the sex and gender field are well documented, newer conceptual confusions and conflations continue to emerge. Contemporary social demands for improved health and equity, as well as increased interest in precision healthcare and medicine, have made obvious the need for sex and gender science, sex and gender-based analyses (SGBA+), considerations of intersectionality, and equity, diversity and inclusion initiatives (EDI) to broaden representation among participants and diversify research agendas. But without a shared and precise understanding of these conceptual areas, fields of study, and approaches and their inter-relationships, more conflation and confusion can occur. This article sets out these areas and argues for more precise operationalization of sex- and gender-related factors in health research and policy initiatives in order to advance these varied agendas in mutually supportive ways.

Air pollution as a potential contributor to the 'epidemic' of autoimmune disease.

There has been remarkable progress over the past 20 years in pushing forward our understanding of many facets of autoimmune disease. Indeed, knowledge of the genetic basis of autoimmunity and the molecular and cellular pathways involved in its pathogenesis has reached an unprecedented level. Yet this knowledge has not served to prevent autoimmune disease nor to curtail the dramatic rise in its incidence over the same interval. Population-level genetic changes cannot explain this trend; thus, environmental factors are strongly implicated. Among the possible environmental contributors to autoimmune disease, air pollution exposure has received very little attention. Although there is only a small amount of published data directly examining a possible causal relationship between air pollution exposure and autoimmunity, data from related fields suggests that it could facilitate autoimmunity as well. If correct, this hypothesis could prove to have sizeable public health implications.

Alcohol fixation of induced sputum samples for applications in rural communities.

BACKGROUND: Sputum induction is a tool recommended for the assessment of airway inflammation and disease management. Currently, its use is limited because samples need to be processed within 3 h of induction (ie, while cells are viable); therefore, this procedure is unavailable to most clinicians. OBJECTIVE: To develop a fixation method for induced sputum samples that allows for a delay in processing while maintaining sample integrity and not altering the standard processing method. METHODS: Sputum samples were collected and split into three portions: a fresh sample processed using the routine method (within 3 h, using dithiothreitol); fixation in alcohol followed by delayed processing using the routine method (within 48 h to 72 h, using dithiothreitol); and fixation in formaldehyde followed by delayed processing using an alternative method (within 48 h to 72 h, using proteolysis). For each method, cytospins were prepared and differential cell counts were performed. RESULTS: Fixation in alcohol provides accurate measures of eosinophils and macrophages, but not neutrophils. Formaldehyde fixation provides accurate measures of neutrophils and macrophages, but not eosinophils. DISCUSSION: Alcohol fixation is a superior method for eosinophil quantification. It requires alteration of standardized methods for sputum sample processing and should be recommended for monitoring eosinophilic airway disease in settings where immediate processing of a sputum sample is not possible.

Sulforaphane-stimulated phase II enzyme induction inhibits cytokine production by airway epithelial cells stimulated with diesel extract.

Airborne particulate pollutants, such as diesel exhaust particles, are thought to exacerbate lung and cardiovascular diseases through induction of oxidative stress. Sulforaphane, derived from cruciferous vegetables, is the most potent known inducer of phase II enzymes involved in the detoxification of xenobiotics. We postulated that sulforaphane may be able to ameliorate the adverse effects of pollutants by upregulating expression of endogenous antioxidant enzymes. Stimulation of bronchial epithelial cells with the chemical constituents of diesel particles result in the production of proinflammatory cytokines. We first demonstrated a role for phase II enzymes in regulating diesel effects by transfecting the airway epithelial cell line (BEAS-2B) with the sentinel phase II enzyme NAD(P)H: quinine oxidoreductase 1 (NQO1). IL-8 production in response to diesel extract was significantly reduced in these compared with untransfected cells. We then examined whether sulforaphane would stimulate phase II induction and whether this would thereby ablate the effect of diesel extracts on cytokine production. We verified that sulforaphane significantly augmented expression of the phase II enzyme genes GSTM1 and NQO1 and confirmed that sulforaphane treatment increased glutathione S-transferase activity in epithelial cells without inducing cell death or apoptosis. Sulforaphane pretreatment inhibited IL-8 production by BEAS-2B cells upon stimulation with diesel extract. Similarly, whereas diesel extract stimulated production of IL-8, granulocyte-macrophage colony-stimulating factor, and IL-1beta from primary human bronchial epithelial cells, sulforaphane pretreatment inhibited diesel-induced production of all of these cytokines. Our studies show that sulforaphane can mitigate the effect of diesel in respiratory epithelial cells and demonstrate the chemopreventative potential of phase II enzyme enhancement.

On the generation of allergic airway diseases: from GM-CSF to Kyoto.

The sharp increase in the prevalence of asthma over the past three decades suggests an important contribution of environmental factors in the generation of this disease, and compels a search for molecular pathways by which such factors could facilitate Th2 immune-inflammatory airway responses; granulocyte-macrophage colony-stimulating factor (GM-CSF) might be one such signal. In this review, we appraise the evidence with respect to the presence of GM-CSF in asthma, the roles played by GM-CSF in these immune responses and environmental triggers that can induce GM-CSF expression. Further, we propose a paradigm that unites these divergent observations, and postulate that GM-CSF produced in response to environmental agents can establish an airway microenvironment that promotes the initiation, influences the evolution and supports the maintenance of an aeroallergen-specific adaptive Th2 immune response.

Granulocyte macrophage colony-stimulating factor-driven respiratory mucosal sensitization induces Th2 differentiation and function independently of interleukin-4.

The development of T helper (Th)2 responses is a key step in the pathogenesis of asthma. Interleukin (IL)-4 is thought to be important, although not strictly necessary, for Th2 differentiation, although triggers of IL-4-independent Th2 polarization have not been identified. We examined whether IL-4 is necessary for Th2-polarized responses during granulocyte macrophage colony-stimulating factor (GM-CSF)-driven respiratory mucosal sensitization. Balb/c wild type (WT) or IL-4 knockout (4KO) mice were exposed to aerosolized ovalbumin (OVA) in the context of airway GM-CSF expression. We examined the extent of Th2 polarization using real-time quantitative polymerase chain reaction on lymph node mRNA, flow cytometric analysis of lung Th cells, and measurement of cells, cytokines, and immunoglobulins in bronchoalveolar lavage (BAL) and serum. GATA-3 and CCR3, -4, and -8 were expressed in the lymph nodes of WT and 4KO mice at similar levels, as were IL-5 and IL-13 levels in the BAL, T1/ST2 on lung Th cells, and BAL eosinophils after recall challenge. With the exception of immunoglobulin production, expression of GATA-3, CCR-3, -4, -8, IL-5, and T1/ST2, and the generation of blood eosinophilia, were intact in mice doubly deficient in both IL-4 and IL-13. We conclude that IL-4 is not required for the generation of Th2-polarized responses in the presence of GM-CSF.