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.

A Gender Hypothesis of sex disparities in adverse drug events.

Pharmacovigilance databases contain larger numbers of adverse drug events (ADEs) that occurred in women compared to men. The cause of this disparity is frequently attributed to sex-linked biological factors. We offer an alternative Gender Hypothesis, positing that gendered social factors are central to the production of aggregate sex disparities in ADE reports. We describe four pathways through which gender may influence observed sex disparities in pharmacovigilance databases: healthcare utilization; bias and discrimination in the clinic; experience of a drug event as adverse; and pre-existing social and structural determinants of health. We then use data from the U.S. FDA Adverse Event Reporting System (FAERS) to explore how the Gender Hypothesis might generate novel predictions and explanations of sex disparities in ADEs in existing widely referenced datasets. Analyzing more than 3 million records of ADEs between 2014 and 2022, we find that patient-reported ADEs show a larger female skew than healthcare provider-reported ADEs and that the sex disparity is markedly smaller for outcomes involving death or hospitalization. We also find that the sex disparity varies greatly across types of ADEs, for example, cosmetically salient ADEs are skewed heavily female and sexual dysfunction ADEs are skewed male. Together, we interpret these findings as providing evidence of the promise of the Gender Hypothesis for identifying intervenable mechanisms and pathways contributing to sex disparities in ADEs. Rigorous application of the Gender Hypothesis to additional datasets and in future research studies could yield new insights into the causes of sex disparities in ADEs.

Deep Brain Stimulation for Substance Use Disorders? An Exploratory Qualitative Study of Perspectives of People Currently in Treatment.

OBJECTIVE: Although previous studies have discussed the promise of deep brain stimulation (DBS) as a possible treatment for substance use disorders (SUDs) and collected researcher perspectives on possible ethical issues surrounding it, none have consulted people with SUDs themselves. We addressed this gap by interviewing people with SUDs. METHODS: Participants viewed a short video introducing DBS, followed by a 1.5-hour semistructured interview on their experiences with SUDs and their perspective on DBS as a possible treatment option. Interviews were analyzed by multiple coders who iteratively identified salient themes. RESULTS: We interviewed 20 people in 12-step-based, inpatient treatment programs (10 [50%] White/Caucasian, 7 Black/African American [35%], 2 Asian [10%], 1 Hispanic/Latino [5%], and 1 [5%] Alaska Native/American Indian; 9 women [45%], 11 men [55%]). Interviewees described a variety of barriers they currently faced through the course of their disease that mirrored barriers often associated with DBS (stigma, invasiveness, maintenance burdens, privacy risks) and thus made them more open to the possibility of DBS as a future treatment option. CONCLUSIONS: Individuals with SUDs gave relatively less weight to surgical risks and clinical burdens associated with DBS than previous surveys of provider attitudes anticipated. These differences derived largely from their experiences living with an often-fatal disease and encountering limitations of current treatment options. These findings support the study of DBS as a treatment option for SUDs, with extensive input from people with SUDs and advocates.

Making a 'sex-difference fact': Ambien dosing at the interface of policy, regulation, women's health, and biology.

The U.S. Food and Drug Administration's (FDA) 2013 decision to lower recommended Ambien dosing for women has been widely cited as a hallmark example of the importance of sex differences in biomedicine. Using regulatory documents, scientific publications, and media coverage, this article analyzes the making of this highly influential and mobile 'sex-difference fact'. As we show, the FDA's decision was a contingent outcome of the drug approval process. Attending to how a contested sex-difference fact came to anchor elite women's health advocacy, this article excavates the role of regulatory processes, advocacy groups, and the media in producing perceptions of scientific agreement while foreclosing ongoing debate, ultimately enabling the stabilization of a binary, biological sex-difference fact and the distancing of this fact from its conditions of construction.

The Role of Family Members in Psychiatric Deep Brain Stimulation Trials: More Than Psychosocial Support.

Family members can provide crucial support to individuals participating in clinical trials. In research on the "newest frontier" of Deep Brain Stimulation (DBS)-the use of DBS for psychiatric conditions-family member support is frequently listed as a criterion for trial enrollment. Despite the significance of family members, qualitative ethics research on DBS for psychiatric conditions has focused almost exclusively on the perspectives and experiences of DBS recipients. This qualitative study is one of the first to include both DBS recipients and their family members as interview participants. Using dyadic thematic analysis-an approach that takes both the individuals and the relationship as units of analyses-this study analyzes the complex ways in which family relationships can affect DBS trial participation, and how DBS trial participation in turn influences family relationships. Based on these findings, we propose ways to improve study designs to better take family relationships into account, and better support family members in taking on the complex, essential roles that they play in DBS trials for psychiatric conditions. Supplementary Information: The online version contains supplementary material available at 10.1007/s12152-023-09520-7.

How Cumulative Statistics Can Mislead: The Temporal Dynamism of Sex Disparities in COVID-19 Mortality in New York State.

Overall, men have died from COVID-19 at slightly higher rates than women. But cumulative estimates of mortality by sex may be misleading. We analyze New York State COVID-19 mortality by sex between March 2020 and August 2021, demonstrating that 72.7% of the total difference in the number of COVID-19 deaths between women and men was accrued in the first seven weeks of the pandemic. Thus, while the initial surge in COVID-19 mortality was characterized by stark sex disparities, this article shows that disparities were greatly attenuated in subsequent phases of the pandemic. Investigating changes over time could help illuminate how contextual factors contributed to the development of apparent sex disparities in COVID-19 outcomes.

Why "sex as a biological variable" conflicts with precision medicine initiatives.

Policies that require male-female sex comparisons in all areas of biomedical research conflict with the goal of improving health outcomes through context-sensitive individualization of medical care. Sex, like race, requires a rigorous, contextual approach in precision medicine. A "sex contextualist" approach to gender-inclusive medicine better aligns with this aim.

Sex disparities in COVID-19 outcomes in the United States: Quantifying and contextualizing variation.

This paper presents the first longitudinal study of sex disparities in COVID-19 cases and mortalities across U.S. states, derived from the unique 13-month dataset of the U.S. Gender/Sex COVID-19 Data Tracker. To analyze sex disparities, weekly case and mortality rates by sex and mortality rate ratios were computed for each U.S. state, and a multilevel crossed-effects conditional logistic binomial regression model was fitted to estimate the variation of the sex disparity in mortality over time and across states. Results demonstrate considerable variation in the sex disparity in COVID-19 cases and mortalities over time and between states. These data suggest that the sex disparity, when present, is modest, and likely varies in relation to context-sensitive variables, which may include health behaviors, preexisting health status, occupation, race/ethnicity, and other markers of social experience.

The future of sperm: a biovariability framework for understanding global sperm count trends.

The past 50 years have seen heated debate in the reproductive sciences about global trends in human sperm count. In 2017, Levine and colleagues published the largest and most methodologically rigorous meta-regression analysis to date and reported that average total sperm concentration among men from 'Western' countries has decreased by 59.3% since 1973, with no sign of halting. These results reverberated in the scientific community and in public discussions about men and masculinity in the modern world, in part because of scientists' public-facing claims about the societal implications of the decline of male fertility. We find that existing research follows a set of implicit and explicit assumptions about how to measure and interpret sperm counts, which collectively form what we term the Sperm Count Decline hypothesis (SCD). Using the study by Levine and colleagues, we identify weaknesses and inconsistencies in the SCD, and propose an alternative framework to guide research on sperm count trends: the Sperm Count Biovariability hypothesis (SCB). SCB asserts that sperm count varies within a wide range, much of which can be considered non-pathological and species-typical. Knowledge about the relationship between individual and population sperm count and life-historical and ecological factors is critical to interpreting trends in average sperm counts and their relationships to health and fertility.

Sex Disparities in COVID-19 Mortality Vary Across US Racial Groups.

BACKGROUND: Inequities in COVID-19 outcomes in the USA have been clearly documented for sex and race: men are dying at higher rates than women, and Black individuals are dying at higher rates than white individuals. Unexplored, however, is how sex and race interact in COVID-19 outcomes. OBJECTIVE: Use available data to characterize COVID-19 mortality rates within and between race and sex strata in two US states, with the aim of understanding how apparent sex disparities in COVID-19 deaths vary across race. DESIGN AND PARTICIPANTS: This observational study uses COVID-19 mortality data through September 21, 2020, from Georgia (GA) and Michigan (MI). MAIN MEASURES: We calculate age-specific rates for each sex-race-age stratum, and age-standardized rates for each race-sex stratum. We investigate the sex disparity within race groups and the race disparity within sex groups using age-standardized rate ratios, and rate differences. KEY RESULTS: Within race groups, men have a higher COVID-19 mortality rate than women. Black men have the highest rate of all race-sex groups (in MI: 254.6, deaths per 100,000, 95% CI: 241.1-268.2, in GA:128.5, 95% CI: 121.0-135.9). In MI, the COVID-19 mortality rate for Black women (147.1, 95% CI: 138.7-155.4) is higher than the rate for white men (39.1, 95% CI: 37.3-40.9), white women (29.7, 95% CI: 28.3-31.0), and Asian/Pacific Islander men and women. COVID-19 mortality rates in GA followed the same pattern. In MI, the male:female mortality rate ratio among Black individuals is 1.7 (1.5-2.0) while the rate ratio among White individuals is only 1.3 (1.2-1.5). CONCLUSION: While overall, men have higher COVID-19 mortality rates than women, our findings show that this sex disparity does not hold across racial groups. This demonstrates the limitations of unidimensional reporting and analyses and highlights the ways that race and gender intersect to shape COVID-19 outcomes.

Multi-cellular engineered living systems: building a community around responsible research on emergence.

Ranging from miniaturized biological robots to organoids, multi-cellular engineered living systems (M-CELS) pose complex ethical and societal challenges. Some of these challenges, such as how to best distribute risks and benefits, are likely to arise in the development of any new technology. Other challenges arise specifically because of the particular characteristics of M-CELS. For example, as an engineered living system becomes increasingly complex, it may provoke societal debate about its moral considerability, perhaps necessitating protection from harm or recognition of positive moral and legal rights, particularly if derived from cells of human origin. The use of emergence-based principles in M-CELS development may also create unique challenges, making the technology difficult to fully control or predict in the laboratory as well as in applied medical or environmental settings. In response to these challenges, we argue that the M-CELS community has an obligation to systematically address the ethical and societal aspects of research and to seek input from and accountability to a broad range of stakeholders and publics. As a newly developing field, M-CELS has a significant opportunity to integrate ethically responsible norms and standards into its research and development practices from the start. With the aim of seizing this opportunity, we identify two general kinds of salient ethical issues arising from M-CELS research, and then present a set of commitments to and strategies for addressing these issues. If adopted, these commitments and strategies would help define M-CELS as not only an innovative field, but also as a model for responsible research and engineering.