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Individual differences in biology as well as experience and exposures throughout life may contribute risk or resilience to neurocognitive decline in aging. To investigate the role of sex as a biological variable in cognitive function due to normal aging, we used substantial cohorts of healthy male and female aged outbred rats maintained under similar conditions throughout life to assess whether both sexes display a similar distribution of individual differences in behavioral performance using a water maze task optimized to assess hippocampal-dependent cognition in aging. We found both aged male and female rats performed poorer than young adults overall, but with no performance differences between sex in either young adults or aged groups in memory probe tests. In addition, aged male and female rats had similar distributions of individual differences such that the same proportion of male and female performed on par with (intact memory) or outside of (impaired memory) the benchmark of young rats of their respective sex. The data support the use of this outbred model with biological diversity to study the neurobiology of aging trajectories for variation in cognitive outcomes in both male and females. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Stress is a major risk factor for neurodevelopmental and neuropsychiatric disorders, with the capacity to impact susceptibility to disease as well as long-term neurobiological and behavioral outcomes. Parvalbumin (PV) interneurons, the most prominent subtype of GABAergic interneurons in the cortex, are uniquely responsive to stress due to their protracted development throughout the highly plastic neonatal period and into puberty and adolescence. Additionally, PV + interneurons appear to respond to stress in a sex-specific manner. This review aims to discuss existing preclinical studies that support our overall hypothesis that the sex-and age-specific impacts of stress on PV + interneurons contribute to differences in individual vulnerability to stress across the lifespan, particularly in regard to sex differences in the diagnostic rate of neurodevelopmental and neuropsychiatric diseases in clinical populations. We also emphasize the importance of studying sex as a biological variable to fully understand the mechanistic and behavioral differences between males and females in models of neuropsychiatric disease.

Background: In 2015, the National Institutes of Health (NIH) established a policy on sex as a biological variable (SABV) in an effort to address the overrepresentation of men and male animals in biomedical research and the lack of attention to sex-based responses to medical treatments. However, questions remain regarding how U.S. biomedical researchers perceive the impact of the SABV policy on their own research and on translational science more broadly. Materials and Methods: A national survey of U.S. scientists who use vertebrate animals in their research was conducted. Respondents were asked how they select and use animal species as model organisms as well as how they perceive the impact of the SABV policy on their research practices. Results: Almost all respondents reported that they had previously heard of the NIH SABV policy, and over one-third had altered their study designs to comply with the policy. There were robust differences in perceptions of the SABV policy based on researchers' primary species of model organism. However, there was no significant difference in the likelihood of researchers analyzing their results by sex based on whether they had received recent NIH funding. Conclusions: While many researchers report adhering to the SABV policy requirements, more work needs to be done to ensure that the policy is being evenly applied to researchers using all types of animal models and that researchers adhere to the policy after receiving NIH funding, particularly in terms of reporting on and analyzing SABV in their study findings for publication.

The field of nutrition has evolved from one focused primarily on discovery of the identities, metabolic functions, and requirements for essential nutrients to one focused on the application of that knowledge to the development and implementation of dietary recommendations to promote health and prevent disease. This evolution has produced a deeper appreciation of not only the roles of nutrients, but also factors affecting their functions in increasingly complex global health contexts. The intersection of nutrition with an increasingly more complex global health context necessitates a view of nutritional status as a biological variable (NABV), the study of which includes an appreciation that nutritional status is: 1) not limited to dietary exposure; 2) intimately and inextricably involved in all aspects of human health promotion, disease prevention, and treatment; and 3) both an input and an outcome of health and disease. This expanded view of nutrition will inform future research by facilitating considerations of the contexts and variability associated with the many interacting factors affecting and affected by nutritional status. It will also demand new tools to study multifactorial relations to the end of increasing precision and the development of evidence-based, safe, and effective standards of health care, dietary interventions, and public health programs.

Time-of-day is a crucial, yet often overlooked, biological variable in biomedical research. We examined the top 25 most cited papers in several domains of behavioral neuroscience to determine whether time-of-day information was reported. The majority of studies report behavioral testing conducted during the day, which does not coincide with the optimal time to perform the testing from an functional perspective of the animals being tested. The majority of animal models used in biomedical research are nocturnal rodents; thus, testing during the light phase (i.e. animals' rest period) may alter the results and introduce variability across studies. Time-of-day is rarely considered in analyses or reported in publications; the majority of publications fail to include temporal details when describing their experimental methods, and those few that report testing during the dark rarely report whether measures are in place to protect from exposure to extraneous light. We propose that failing to account for time-of-day may compromise replication of findings across behavioral studies and reduce their value when extrapolating results to diurnal humans.

Background Men have been, and still are, included in more studies than women, in large part because of the lingering belief that ovulatory cycles result in women showing too much variability to be economically viable subjects. This belief has scientific and social consequences, and yet, it remains largely untested. Recent work in rodents has shown either that there is no appreciable difference in overall variability across a wealth of traits, or that in fact males may show more variability than females. Methods We analyzed learning management system logins associated to gender records spanning 2 years from 13,777 students at Northeastern Illinois University. These data were used to assess variability in daily rhythms in a heterogeneous human population. Results At the population level, men are more likely than women to show extreme chronotypes (very early or very late phases of activity). Men were also found to be more variable than women across and within individuals. Variance correlated negatively with academic performance, which also showed a gender difference. Whereas a complaint against using female subjects is that their variance is the driver of statistical sex differences, only 6% of the gender performance difference is potentially accounted for by variance, suggesting that variability is not the driver of sex differences here. Conclusions Our findings do not support the idea that women are more behaviorally variable than men and may support the opposite. Our findings support including sex as a biological variable and do not support variance-based arguments for the exclusion of women as research subjects.

Sex as a biological variable influences almost all aspects of health and disease, yet many research studies use only males or do not consider sex differences. We describe why sex-specific reporting is needed, including in basic and animal research, and we outline recommendations for sex-specific reporting in manuscript abstracts, Methods and Results sections, tables and figures.

Female sex is a leading risk factor for developing Alzheimer’s disease (AD). Sexual dimorphism in AD is gaining attention as clinical data show that women are not only more likely to develop AD but also to experience worse pathology and faster cognitive decline. Pre-clinical AD research in animal models often neglects to address sexual dimorphism in evaluation of behavioral or molecular characteristics and outcomes. This can compromise its translation to a clinical setting. The triple-transgenic AD mouse model (3xTg-AD) is a commonly used but unique AD model because it exhibits both amyloid and tau pathology, essential features of the human AD phenotype. Mounting evidence has revealed important sexually dimorphic characteristics of this animal model that have yet to be reviewed and thus, are often overlooked in studies using the 3xTg-AD model. In this review we conduct a thorough analysis of reports of sexual dimorphism in the 3xTg-AD model including findings of molecular, behavioral, and longevity-related sex differences in original research articles through August 2020. Importantly, we find results to be inconsistent, and that strain source and differing methodologies are major contributors to lack of consensus regarding traits of each sex. We first touch on the nature of sexual dimorphism in clinical AD, followed by a brief summary of sexual dimorphism in other major AD murine models before discussing the 3xTg-AD model in depth. We conclude by offering four suggestions to help unify pre-clinical mouse model AD research inspired by the NIH expectations for considering sex as a biological variable.

Background: Since the National Institutes of Health (NIH) Revitalization Act of 1993, focus on the equitable inclusion of women in clinical research has been ongoing. NIH's 2015 sex as a biological variable (SABV) policy aims to transform research design, analysis, and reporting in the preclinical sphere by including male and female organisms in vertebrate animal research as well as human studies. However, questions remain regarding how researchers and members of research oversight committees perceive the value and need of the SABV policy. Materials and Methods: Based on 62 interviews with animal researchers and oversight personnel, we analyze what the animal research community knows about the policy and sees as the benefits and challenges of implementation. Results: We found that the 62 interviewees disagreed about the need for the policy, with some being supportive and others questioning whether the policy is based on science or is politically motivated. There were also tensions in how interviewees conceptualized the challenges to and resources needed for implementing the SABV policy. For instance, while some thought implementation would require a significant increase in numbers of animals used for each study, others explicitly rejected this claim. Conclusions: We conclude by discussing the practical and social implications of our findings about the views of members of the animal research community regarding the SABV policy.

Maternal morbidity and mortality constitute a national health crisis, and pain is a significant component of maternal morbidity. One important way to reduce maternal morbidity is to reduce the pain associated with pregnancy. Unfortunately, our understanding of how to reduce pain in women is hampered because, historically, mostly male subjects have been used in the study of pain. However, more recently, females increasingly have been included in pain research studies, and astounding differences in how males and females process pain have been uncovered. Moreover, pain in nonpregnant women differs in many ways from pain experienced by pregnant women. We argue here that to better address maternal morbidity, we must better address the pain associated with pregnancy. Furthermore, just as it is important to include both men and women in pain research to better understand pain in both sexes, conducting pain research in pregnant women is essential to finding ways to reduce pain in pregnant women.

In 2016 the US National Institutes of Health introduced a policy mandating consideration of Sex as a Biological Variable (SABV) in preclinical research. In this article, I ask what, precisely, is meant by the designation of sex as a ‘biological variable’, and how has its inclusion come to take the form of a policy mandate? Given the well documented complexity of ‘sex’ and the degree to which it is politically and scientifically contested, its enactment via policy as a biological variable is not a given. I explore how sex is multiply enacted in efforts to legitimate and realize the SABV policy and consider how the analytical lens of co-production sheds light on how and why this occurs. I show that the policy works to reassert scientific and political order by addressing two institutional concerns: the so-called reproducibility crisis in preclinical research, and pervasive gender inequality across the institution of biomedicine. From here, the entity that underpins this effort – sex as a biological variable – becomes more than one thing, with enactments ranging from an assigned category, to an outcome, to a causal biological force in its own right. Sex emerges as simultaneously entangled with yet distinct from gender, and binary (female/male) yet complex in its variation. I suggest that it is in the very attempt to delineate natural from social order, and in the process create the conditions to privilege a particular kind of science and account of embodied difference, that ontological multiplicity becomes readily visible. That this multiplicity goes unrecognized points to the unifying role of an overarching ideological commitment to sex as a presumed binary and biological scientific object, the institutional dominance of which is never guaranteed.

Sex is increasingly being reported as clinically important variable in the outcome of bladder cancer treatment. But the application of the Sex as a Biological Variable research design, analysis and reporting practices remains limited in biomedical research, dominated by the common use of sex-neutral language with regard to research participants. This study aimed to establish the prevalence of the Sex as a Biological Variable principles in bladder cancer research. Preclinical and clinical studies published in three urology journals were reviewed for the reporting of cells, animal or patient sex and the inclusion of sex as a biological variable in both study design and data analysis. A total of 489 articles were screened from which 133 met the inclusion criteria: 2 (2%) preclinical and 131 (98%) clinical studies. Three articles reported separate outcome data for male and female. Where sex of participants was stated 111/133 (83%); 3 manuscripts (97%) reported a larger number of male participants, compared to females. Only 47 (35%) used sex as a variable in data analysis from which 10 (21%) showed statistically significant difference between their male and female bladder cancer patient cohorts. The inclusion of sex as a biological variable is poorly practiced in bladder cancer research and should be more consistently requested.

Cardiovascular disease (CVD) affects individuals of all races and ethnicities; however, its prevalence is highest in non-Hispanic black individuals (BL) relative to other populations. While previous research has provided valuable insight into elevated CVD risk in the BL population, this work has been almost exclusively conducted in men. This is alarming given that BL women suffer from CVD at an equivalent rate to BL men and each has a greater prevalence when compared to all other ethnicities, regardless of sex. The importance of investigating sex differences in mechanisms of cardiovascular function is highlighted by the National Institute of Health requiring sex to be considered as a biological variable in research studies to better our "understanding of key sex influences on health processes and outcomes." The mechanism(s) responsible for the elevated CVD risk in BL women remains unclear and is likely multifactorial. Limited studies in BL women suggest that, while impaired vasodilator capacity is involved, heightened vasoconstrictor tone and/or responsiveness may also contribute. Within this mini-review, we will discuss potential mechanisms of elevated rates of hypertension and other CVDs in BL individuals with a particular focus on young, otherwise healthy, college-aged women. To stimulate academic thought and future research, we will also discuss potential mechanisms for impaired vascular function in BL women, as well as possible divergent mechanisms between BL men and women based on either preliminary data or plausible speculation extending from findings in the existing literature. Last, we will conclude with potential future research directions aimed at better understanding the elevated risk for hypertension and CVD in BL women.

Spinal cord injury (SCI) causes neurodegeneration, impairs locomotor function, and impacts the quality of life particularly in those individuals in whom neuropathic pain develops. Whether the time course of neurodegeneration, locomotor impairment, or neuropathic pain varies with sex, however, remains understudied. Therefore, the objective of this study in male and female C57BL/6 mice was to evaluate the following outcomes for six weeks after a 75-kdyn thoracic contusion SCI: locomotor function using the Basso Mouse Scale (BMS); spinal cord tissue sparing and rostral-caudal lesion length; and mechanical allodynia and heat hyperalgesia using hindpaw application of Von Frey filaments or radiant heat stimuli, respectively. Although motor function was largely similar between sexes, all of the males, but only half of the females, recovered plantar stepping. Rostral-caudal lesion length was shorter in females than in males. Mechanical allodynia and heat hyperalgesia after SCI developed in all animals, regardless of sex; there were no differences in pain outcomes between sexes. We conclude that contusion SCI yields subtle sex differences in mice depending on the outcome measure but no significant differences in behavioral signs of neuropathic pain.

Background: Preclinical and clinical research is largely inclusive of both the female and the male population, but the lack of specific separation of data according to patient sex prevents the detection of the impact of sex on cancer biology and response to medications and treatment. This study aimed to examine the consideration of sex as a biological variable in preclinical and clinical studies in kidney cancer. Methods: Preclinical and clinical studies pertaining to kidney cancer published in three leading urology journals over a two-year period were reviewed for the reporting of cells, animal or patient sex, and the inclusion of sex as a biological variable in both study design and data analysis. Results: 171 clinical studies and 5 preclinical studies were included. While the sex of the participants was disclosed in all but 10 of the 171 clinical studies reviewed, the patient populations were largely maledominated (male to female ratio > 1.5). Only 5 studies contained more female than male patients. Sexspecific reporting was performed in 3% of studies, and only 37% included sex as part of the statistical analysis. 26% of these identified a statistically significant difference in measured outcomes between male and female participants. Conclusion: Kidney cancer research is sex-inclusive, but the female patient population remains underrepresented. The consideration of sex in data analysis is low and could prevent the identification of key sex-specific optimization opportunities for the improved management of the disease.

Consideration of sex differences in biomedical research is crucial to ensure the safety and effectiveness of drugs and devices for both sexes and to improve the rigor and reproducibility of scientific discoveries. Historically, women were underrepresented in clinical research and sex differences typically were not considered. The U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH) have played a role in improving the representation of women in clinical trials and in encouraging the consideration of sex differences. As it is not appropriate for all studies to be reviewed by the FDA nor do all studies have NIH funding, this results in a regulatory gap. We propose that local institutional review boards (IRBs) and institutional animal care and use committees (IACUCs) provide greater oversight by encouraging researchers to consider sex as a biological variable (SABV) during protocol review. In this perspective article, we review how FDA and NIH policies have fostered change and highlight how IRBs and IACUCs could encourage investigators to consider SABV.

Although most patients with chronic pain are women, the preclinical literature regarding pain processing and the pathophysiology of chronic pain has historically been derived overwhelmingly from the study of male rodents. This Review describes how the recent adoption by a number of funding agencies of policies mandating the incorporation of sex as a biological variable into preclinical research has correlated with an increase in the number of studies investigating sex differences in pain and analgesia. Trends in the field are analysed, with a focus on newly published findings of qualitative sex differences: that is, those findings that are suggestive of differential processing mechanisms in each sex. It is becoming increasingly clear that robust differences exist in the genetic, molecular, cellular and systems-level mechanisms of acute and chronic pain processing in male and female rodents and humans. Historically, preclinical pain research has been dominated by studies in male subjects. Jeffrey Mogil describes recent trends towards the inclusion of male and female subjects in research and the subsequent identification of qualitative sex differences in the mechanisms of pain processing.

Sex as a biological variable (SABV) is critical for understanding the broad range of physiological, neurobiological, and behavioral consequences of early life adversity (ELA). The study of the interaction of SABV and ELA ties into several current debates, including the importance of taking into account SABV in research, differing strategies employed by males and females in response to adversity, and the possible evolutionary and developmental mechanisms of altered development in response to adversity. This review highlights the importance of studying both sexes, of understanding sex differences (and similarities) in response to ELA, and provides a context for the debate surrounding whether the response to ELA may be an adaptive process.

Background: The sex-neutral language used in preclinical and clinical research intends to be inclusive of both the female and the male population, but the practice of data pooling prevents the detection of the impact of sex on cancer biology and response to medications and treatment. This study aimed to examine the consideration of sex as biological variable in the evaluation of radiation therapy in preclinical and clinical studies.Methods: Preclinical and clinical studies published over a 12-month period were reviewed for the reporting of cells, animal or patient sex and the inclusion of sex as a biological variable in both study design and data analysis.Results: A total of 321 articles met the inclusion criteria: 41 (13%) preclinical and 280 (87%) clinical studies. Two articles reported separate outcome data for males and females. Where the sex of participants was stated (230/280 (82%), 81% reported a larger number of male participants, compared to females. Less than half (45%) of studies used sex as a variable in data analysis. Sex disparity was not dependent on study location but may be more prominent in certain cancer sites. In preclinical studies, sex was at best stated in those reporting on animals (48% of studies).Conclusion: Referring to a radiotherapy cancer patient, the literature is female inclusive, but a gap does exist when it comes to consideration of sex in data analysis. The pooled analysis of female and male data could introduce statistical biases and prevent the identification of key sex-specific biological subtilities that do affect radiation responses.

The National Institutes of Health leveled new focus on sex as a biological variable with the goal of understanding sex-specific differences in health and physiology. We previously published a functional assessment of the impact of sex, androgens, and prostate size on C57BL/6J mouse urinary physiology (Ruetten H, Wegner KA, Zhang HL, Wang P, Sandhu J, Sandhu S, Mueller B, Wang Z, Macoska J, Peterson RE, Bjorling DE, Ricke WA, Marker PC, Vezina CM. Am J Physiol Renal Physiol 317: F996–F1009, 2019). Here, we measured and compared five characteristics of urethral histology (urethral lumen diameter and area, epithelial cell count, epithelial and rhabdosphincter thickness, epithelial cell area, and total urethral area) in male and female 9-wk-old C57BL/6J mice using hematoxylin and eosin staining. We also compared male mice with castrated male mice, male and female mice treated with the steroid 5α-reductase inhibitor finasteride or testosterone, or male mice harboring alleles ( Pbsn4cre/+; R26RDta/+) that reduce prostate lobe mass. The three methods used to reduce prostate mass (castration, finasteride, and Pbsn4cre/+; R26RDta/+) changed urethral histology, but none feminized male urethral histology (increased urethral epithelial area). Exogenous testosterone caused increased epithelial cell count in intact females but did not masculinize female urethral histology (decrease epithelial area). Our results lay a critical foundation for future studies as we begin to parse out the influence of hormones and cellular morphology on male and female urinary function.

Interest in the role of sex as a biological variable continues to increase, including a mandate for the study of both sexes in NIH-funded research. Choice-based thermal nociceptive tests allow for the study of a more spontaneous response to thermal stimuli and avoidance behavior compared to traditional nociceptive assays, and their usage has been increasing in recent years. However, to date no comparison of naïve male and female responses to such tests has been published. As sex differences are known to exist in both human chronic pain conditions and rodent models of nociception, it is critical to understand the impact of sex on any nociceptive assay. Herein, we examined the effect of sex on two choice-based thermal nociceptive tests, the thermal gradient test and the temperature place preference test, in adult rats. We report that marked sex differences exist in responses to these tests. Namely, the activation of a 10° C-to-47° C thermal gradient results in an increase in time spent in the 10° C zone in females, compared to a reduction in males. In a temperature place preference test pairing a surface temperature of 22° C with either 5° C, 10° C, 47° C, or 50° C, males spent less than 50% of their time in every non-22° C zone, but in females this was only observed when testing 50° C. Together, these results suggest that male rats show more avoidance behavior to non-ambient temperatures when given free access to multiple zones, including at temperatures which are milder than those typically used to evoke a nociceptive response in traditional hot and cold plate tests.

Although sex differences in psychiatric disorders abound, few neuropsychopharmacology (NPP) studies consider sex as a biological variable (SABV). We conducted a scoping review of this literature in humans by systematically searching PubMed to identify peer-reviewed journal articles published before March 2020 that (1) studied FDA-approved medications used to treat psychiatric disorders (or related symptoms) and (2) adequately evaluated sex differences using in vivo neuroimaging methodologies. Of the 251 NPP studies that included both sexes and considered SABV in analyses, 80% used methodologies that eliminated the effect of sex (e.g., by including sex as a covariate to control for its effect). Only 20% (50 studies) adequately evaluated sex differences either by testing for an interaction involving sex or by stratifying analyses by sex. Of these 50 studies, 72% found statistically significant sex differences in at least one outcome. Sex differences in neural and behavioral outcomes were studied more often in drugs indicated for conditions with known sex differences. Likewise, the majority of studies conducted in those drug classes noted sex differences: antidepressants (13 of 16), antipsychotics (10 of 12), sedative-hypnotics (6 of 10), and stimulants (6 of 10). In contrast, only two studies of mood stabilizers evaluated SABV, with one noting a sex difference. By mapping this literature, we bring into sharp relief how few studies adequately evaluate sex differences in NPP studies. Currently, all NIH-funded studies are required to consider SABV. We urge scientific journals, peer reviewers, and regulatory agencies to require researchers to consider SABV in their research. Continuing to ignore SABV in NPP research has ramifications both in terms of rigor and reproducibility of research, potentially leading to costly consequences and unrealized benefits.

As part of an initiative to improve rigor and reproducibility in biomedical research, the U.S. National Institutes of Health now requires the consideration of sex as a biological variable in preclinical studies. This new policy has been interpreted by some as a call to compare males and females with each other. Researchers testing for sex differences may not be trained to do so, however, increasing risk for misinterpretation of results. Using a list of recently published articles curated by Woitowich et al. (eLife, 2020; 9:e56344), we examined reports of sex differences and non-differences across nine biological disciplines. Sex differences were claimed in the majority of the 147 articles we analyzed; however, statistical evidence supporting those differences was often missing. For example, when a sex-specific effect of a manipulation was claimed, authors usually had not tested statistically whether females and males responded differently. Thus, sex-specific effects may be over-reported. In contrast, we also encountered practices that could mask sex differences, such as pooling the sexes without first testing for a difference. Our findings support the need for continuing efforts to train researchers how to test for and report sex differences in order to promote rigor and reproducibility in biomedical research.Biomedical research has a long history of including only men or male laboratory animals in studies. To address this disparity, the United States National Institutes of Health (NIH) rolled out a policy in 2016 called Sex as a Biological Variable (or SABV). The policy requires researchers funded by the NIH to include males and females in every experiment unless there is a strong justification not to, such as studies of ovarian cancer. Since then, the number of research papers including both sexes has continued to grow. Although the NIH does not require investigators to compare males and females, many researchers have interpreted the SABV policy as a call to do so. This has led to reports of sex differences that would otherwise have been unrecognized or ignored. However, researchers may not be trained on how best to test for sex differences in their data, and if the data are not analyzed appropriately this may lead to misleading interpretations. Here, Garcia-Sifuentes and Maney have examined the methods of 147 papers published in 2019 that included both males and females. They discovered that more than half of these studies had reported sex differences, but these claims were not always backed by statistical evidence. Indeed, in a large majority (more than 70%) of the papers describing differences in how males and females responded to a treatment, the impact of the treatment was not actually statistically compared between the sexes. This suggests that sex-specific effects may be over-reported. In contrast, Garcia-Sifuentes and Maney also encountered instances where an effect may have been masked due to data from males and females being pooled together without testing for a difference first. These findings reveal how easy it is to draw misleading conclusions from sex-based data. Garcia-Sifuentes and Maney hope their work raises awareness of this issue and encourages the development of more training materials for researchers.

Sex is a biological concept determined at conception. Gender is a social concept. Medicine recognises sex as a biological variable and recommends including sex as a factor in clinical practice norms and as a topic of bench and clinical research. Sex plays a role in respiratory physiology according to two pathways: hormones and anatomy, with females characterised by smaller dimensions at every level of the respiratory system. Sex hormones also play specific roles in lung inflammatory processes, breathing control and in response to diseases. The literature is extremely controversial because many factors need to be considered to avoid erroneous comparisons. The main difficulty lies in creating homogeneous groups of subjects according to age, body weight, lung/airway size, fluctuations in circulating hormone levels, and exercise protocol. Because almost all of the knowledge available in physiology is based on research in males, medicine for women is therefore less evidence-based than that being applied to men. Finally, the number of transsexual people is increasing and they represent new challenges for clinicians, due to the anatomical and physiological changes that they undergo.

Alcohol drinking is often initiated during adolescence, and this frequently escalates to binge drinking. As adolescence is also a period of dynamic neurodevelopment, preclinical evidence has highlighted that some of the consequences of binge drinking can be long lasting with deficits persisting into adulthood in a variety of cognitive-behavioral tasks. However, while the majority of preclinical work to date has been performed in male rodents, the rapid increase in binge drinking in adolescent female humans has re-emphasized the importance of addressing alcohol effects in the context of sex as a biological variable. Here we review several of the consequences of adolescent ethanol exposure in light of sex as a critical biological variable. While some alcohol-induced outcomes, such as non-social approach/avoidance behavior and sleep disruption, are generally consistent across sex, others are variable across sex, such as alcohol drinking, sensitivity to ethanol, social anxiety-like behavior, and induction of proinflammatory markers.

In this article, I develop a feminist posthumanist account of biomedical policymaking as a material-discursive intervention that shapes the emergence of phenomena in the scientific laboratory. The setting is United States (U.S.) biomedicine, where a recent policy of the National Institutes of Health has mandated the consideration of sex in basic and preclinical research. Called Sex as a Biological Variable (SABV), the mandate configures cell lines and animal models as the next frontier in the project of advancing gender equity in biomedical research. Given sex and gender are increasingly recognised as having complex, entangled, and dynamic effects on human health and illness, how do laboratory animals respond to their attempted enrolment in this regulatory intervention? Through a qualitative analysis of this policy domain, I show how laboratory animals reveal the context-specific character of sex, its multiplicity and elusiveness as a so-called biological variable, and the considerable work needed to shore up human ideologies of sex as a pervasive cross-species form of binary difference. I suggest that while regulatory interventions constrain patterns of mattering, they also serve as agential openings in which laboratory animals can 'kick back' and reconfigure the pursuit of knowledge, particularly as it relates to difference and health.

We measured walking speed in baboons (67 female, 36 male; 5-22 years) to develop regression formulas to predict biological age. The final model strongly predicted age from just speed and sex. Walking speed is a valuable baboon aging biomarker. We present the first male speed data in a nonhuman primate.

The electrical activity in the heart varies significantly between men and women and results in a sex-specific response to drugs. Recent evidence suggests that women are more than twice as likely as men to develop drug-induced arrhythmia with potentially fatal consequences. Yet, the sex-specific differences in drug-induced arrhythmogenesis remain poorly understood. Here we integrate multiscale modeling and machine learning to gain mechanistic insight into the sex-specific origin of drug-induced cardiac arrhythmia at differing drug concentrations. To quantify critical drug concentrations in male and female hearts, we identify the most important ion channels that trigger male and female arrhythmogenesis, and create and train a sex-specific multi-fidelity arrhythmogenic risk classifier. Our study reveals that sex differences in ion channel activity, tissue conductivity, and heart dimensions trigger longer QT-intervals in women than in men. We quantify the critical drug concentration for dofetilide, a high risk drug, to be seven times lower for women than for men. Our results emphasize the importance of including sex as an independent biological variable in risk assessment during drug development. Acknowledging and understanding sex differences in drug safety evaluation is critical when developing novel therapeutic treatments on a personalized basis. The general trends of this study have significant implications on the development of safe and efficacious new drugs and the prescription of existing drugs in combination with other drugs.

An impairment in willingness to exert physical effort in daily activities is a noted aspect of several psychiatric conditions. Previous studies have supported an important role for the lateral habenula (LHb) in dynamic decision-making, including decisions associated with discounting costly high value rewards. It is unknown whether a willingness to exert physical effort to obtain higher rewards is also mediated by the LHb. It also remains unclear whether the LHb is critical to monitoring the task contingencies generally as they change, or whether it also mediates choices in otherwise static reward environments. The present study indicates that the LHb might have an integrative role in effort-based decision-making even when no alterations in choice contingencies occur. Specifically, pharmacological inactivation of the LHb showed differences in motivational behavior by reducing choices for the high effort (30cm barrier) high reward (2 pellets) choice versus the low effort (0 cm) low reward (1 pellet) choice. In sessions where the barrier was removed, rats demonstrated a similar preference for the high reward arm under both control and LHb inactivation. Further, no differences were observed when accounting for sex as a biological variable. These results support that effort to receive a high-value reward is considered on a trial-by-trial basis and the LHb is part of the circuit responsible for integrating this information during decision-making. Therefore, it is likely that previously observed changes in the LHb may be a key contributor to changes in a willingness to exert effort in psychiatric conditions.

Aims To examine the prevalence, temporal changes, and impact of the National Institute of Health (NIH) Sex as a Biological Variable (SABV) policy on sex and gender reporting and analysis in cardiac resynchronization therapy (CRT) cohort studies. Methods and results We searched MEDLINE, EMBASE, and Web of Science for cohort studies reporting the effectiveness and safety of CRT in heart failure patients from January 2000 to June 2020, with no language restrictions. Segmented regression analysis was used for policy analysis. We included 253 studies. Fourteen per cent considered sex in the study design. Outcome data disaggregated by sex were only reported in 17% of the studies. Of the studies with statistical models (n = 173), 57% were adjusted for sex. Sixty‐eight per cent of those reported an effect size for sex on the outcome. Sex‐stratified analyses were conducted in 13% of the studies. Temporal analysis shows an increase in sex reporting in background, statistical models, study design, and discussion. Besides statistical models, NIH SABV policy analysis showed no significant change in the reporting of sex in study sections. Gender was not reported or analysed in any study. Conclusions There is a need to improve the study design, analysis, and completeness of reporting of sex in CRT cohort studies. Inadequate sex integration in study design and analysis may potentially hinder progress in understanding sex disparities in CRT. Deficiencies in the integration of sex in studies could be overcome by implementing guidance that already exists.

Incorporating sex as a biological variable (SABV) into basic and medical research requires a deliberate plan that weaves concepts of basic genetics, cellular and molecular physiology, and pharmacology into translational medicine. An R4 approach (Right content to the Right learner at the Right time with the Right modality) allows for content to be available in a variety of formats that reinforces the concepts at staged levels of integration. Weaving SABV throughout the varied formats of the R4 approach within the Clinical and Translational Research Training Programs, into the mentoring and training of scholars in NIH Building Interdisciplinary Careers in Women's Health (BIRCWH), and into the Career Enhancement Core of the Specialized Centers of Research Excellence (SCORE) on sex differences through curriculum, case-based approach and journal clubs, and workshops ensures that learners grasp its fundamental relevancy to their own research and beyond. In addition, the collaborative work among the BIRCWH and SCORE programs brings collective expertise from centers around the United States to individual programs through development of best practices and materials. These collective efforts assure that the next generation of basic, clinical, and translational scientists will bring the dimension of SABV into their research and clinical practice.

Background: In the last 3 years, the National Institutes of Health (NIH) declared advancement of understanding the role sex as a biological variable has in research a priority. The burden now falls on educators and clinicians to translate into clinical practice the ensuing body of evidence for sex as a biological variable that clearly shows the effect of sex/gender on disease diagnosis and management. The 2018 Sex and Gender Health Education Summit (SGHE) organized an interdisciplinary and interprofessional workshop to (1) analyze common clinical scenarios highlighting the nuances of sex- and gender-based medicine (SGBM) in presentation, diagnosis, or management of illness; (2) utilize valid educational and assessment tools for a multiprofessional audience; and (3) brainstorm standardized learning objectives that integrate both. Materials and Methods: We describe the iterative process used to create these scenarios, as well as an interprofessional forum to develop standardized SGBM case-based objectives. Results: A total of 170 health education professionals representing 137 schools of Medicine, Dentistry, Pharmacy, Public Health, Nursing, Physical, and Occupational Therapy participated in this workshop. After attending the workshop, participants reported a significant increase in comfort level with using diverse educational modalities in the instruction of health profession learners. Recurrent themes included case-based learning, use of sex-neutral cases, simulation, and standardized patient scenarios for educational modalities; and self-assessment, peer assessment, and review of clinical documentation as used assessment tools. Materials created for the workshop included teaching SGBM case scenarios, methods of assessment, and sample standardized objectives. Conclusion: The SGHE Summit provided an interdisciplinary forum to create educational tools and materials for SABV instruction that may be applied to a diverse audience.

Currently, over 300 million people worldwide have depression, and the socioeconomic burden of this debilitating disorder is anticipated to increase markedly over the coming decades against a background of increasing global turmoil. Despite this impending crisis, we are still waiting for improved therapeutic options for this disorder to emerge, which has led to increasing criticism of the role and value of preclinical models of depression. In this Review, we examine this landscape, focusing firstly on issues related to the terminology used in this context and the myriad of preclinical approaches to modelling and assaying aspects of depression in rodents. We discuss the importance of sex as a biological variable and the controversial idea of intergenerational and transgenerational transmission of depressive-like traits. We then examine the technical strategies available to dissect these models and review emerging evidence for putative druggable disease mechanisms. Finally, we propose a brief framework for future research that makes optimal use of these models and will, we hope, accelerate the discovery of improved antidepressants. Rodent models are essential for characterizing the mechanisms underlying depression as well as for the development of fast-acting and innovative antidepressants. Here, Anand Gururajan and colleagues review strategies for inducing depressive-like behaviours and endophenotypes, and discuss how genetic and circuit-dissection techniques might be used to refine existing models and generate new ones.

We are pleased to add this typescript to the Bone Marrow Transplantation Statistics Series. We realize the term cubic splines may be a bit off-putting to some readers, but stay with us and don’t get lost in polynomial equations. What the authors describe is important conceptually and in practice. Have you ever tried to buy a new pair of hiking boots? Getting the correct fit is critical; shoes that are too small or too large will get you in big trouble! Now imagine if hiking shoes came in only 2 sizes, small and large, and your foot size was somewhere in between. You are in trouble. Sailing perhaps? Transplant physicians are often interested in the association between two variables, say pre-transplant measurable residual disease (MRD) test state and an outcome, say cumulative incidence of relapse (CIR). We typically reduce the results of an MRD test to a binary, negative or positive, often defined by an arbitrary cut-point. However, MRD state is a continuous biological variable, and reducing it to a binary discards what may be important, useful data when we try to correlate it with CIR. Put otherwise, we may miss the trees from the forest. Another way to look at splines is a technique to make smooth curves out of irregular data points. Consider, for example, trying to describe the surface of an egg. You could do it with a series of straight lines connecting points on the egg surface but a much better representation would be combining groups of points into curves and then combining the curves. To prove this try drawing an egg using the draw feature in Microsoft Powerpoint; you are making splines. Gauthier and co-workers show us how to use cubic splines to get the maximum information from data points, which may, unkindly, not lend themselves to dichotomization or a best fit line. Please read on. We hope readers will find their typescript interesting and exciting, and that it will give them a new way to think about how to analyse data. And no, a spline is not a bunch of cactus spines. Robert Peter Gale, Imperial College London, and Mei-Jie Zhang, Medical College of Wisconsin and CIBMTR.

Differences in sleep for men and women begin at a very early age, with women reporting poorer sleep and having a higher risk for insomnia compared with men. Women are particularly vulnerable to developing insomnia during times of reproductive hormonal change. Sleep across the woman's lifespan and special treatment considerations for using cognitive behavioral therapy for insomnia (CBT-I) in women will be addressed in this review.

Sex is an important biological variable that impacts diverse physiological and pathological processes, including the progression of diabetic nephropathy. Diabetic nephropathy is one of the most common complications of diabetes mellitus and is the leading cause of end-stage renal disease. The endothelial nitric oxide synthase-deficient (eNOS−/−) db/ db mouse is an appropriate and valuable model to study mechanisms in the development of diabetic nephropathy because of the similarities of the features of diabetic kidney disease in this model to those in humans. The aim of the present study was to determine whether there was a sex difference in renal injury in eNOS−/− db/ db mice. Both male and female eNOS−/− db/ db mice showed hyperglycemia, obesity, and renal hypertrophy. However, there was no significant difference in those variables between male and female mice. Furthermore, both male and female diabetic mice showed progressive albuminuria and significantly greater levels of serum creatinine and blood urea nitrogen compared with the same sex of wild-type mice (nondiabetic controls). Although all three variables in female eNOS−/− db/ db mice had a tendency to be greater than those in male eNOS−/− db/ db mice, those sex differences were not statistically significant. Moreover, both male and female eNOS−/− db/ db mice showed significant mesangial expansion, higher glomerular injury scores, profound renal fibrosis, and substantial accumulation of fibronectin and collagen type IV proteins. However, sex differences in those structural changes were not observed. Similarly, survival rates of male and female eNOS−/− db/ db mice were comparable. Taken together, the results from the present study suggest no sex difference in renal structural and functional damage in eNOS−/− db/ db mice.

PURPOSE OF REVIEW. Summarize sex-specific contributors to the genetic architecture of Alzheimer’s disease (AD). RECENT FINDINGS. There are sex differences in the effects of Apolipoprotein E (APOE), genes along the APOE pathway, and genes along the neurotrophic signaling pathway in predicting AD. Reported sex differences are largely driven by stronger associations among females. Evidence also suggests that genetic predictors of amyloidosis are largely shared across sexes, while sex-specific genetic effects emerge downstream of amyloidosis and drive the clinical manifestation of AD. SUMMARY. There is a lack of comprehensive assessments of sex differences in genome-wide analyses of AD and a need for more systematic reporting a sex-stratified genetic effects. The emerging emphasis on sex as a biological variable provides an opportunity for transdisciplinary collaborations aimed at addressing major analytical challenges that have hampered advancements in the field. Ultimately, sex-specific genetic association studies represent a logical first step towards precision medicine.

Throughout the world, including the United States, men have worse outcomes from COVID-19 than women. SARS-CoV-2, the causative virus of the COVID-19 pandemic, uses angiotensin-converting enzyme 2 (ACE2) to gain cellular entry. ACE2 is a member of the renin-angiotensin system (RAS) and plays an important role in counteracting the harmful effects mediated by the angiotensin type 1 receptor. Therefore, we conducted Ovid MEDLINE and Embase database searches of basic science studies investigating the impact of the biological variable of sex on ACE2 expression and regulation from 2000, the year ACE2 was discovered, through December 31, 2020. Out of 2,131 publications, we identified 853 original research articles on ACE2 conducted in primary cells, tissues, and/or whole mammals excluding humans. The majority (68.7%) of these studies that cited the sex of the animal were conducted in males, while 11.2% were conducted solely in females; 9.26% compared ACE2 between the sexes, while 10.8% did not report the sex of the animals used. General findings are that sex differences are tissue-specific and when present, are dependent upon gonadal state. Renal, cardiac, and adipose ACE2 is increased in both sexes under experimental conditions that model co-morbidities associated with worse COVID-19 outcomes including hypertension, obesity, and renal and cardiovascular diseases; however, ACE2 protein was generally higher in the males. Studies in Ace2 knockout mice indicate ACE2 plays a greater role in protecting the female from developing hypertension than the male. Studying the biological variable of sex in ACE2 research provides an opportunity for discovery in conditions involving RAS dysfunction and will shed light on sex differences in COVID-19 severity.

Integrating sex as an important biological variable is imperative to enhance the accuracy and reproducibility of cell-based studies, which provide basic information for subsequent preclinical and clinical study designs. Recently, international funding agencies and renowned journals have been attempting to integrate sex as a variable in every research step. To understand what progress has been made in reporting of cell sex in the articles published in AJP-Cell Physiology since the analysis in 2013, we examined the sex notation of the cells in relevant articles published in the same journal in 2018. Of the 107 articles reporting cell experiments, 53 reported the sex of the cells, 18 used both male and female cells, 23 used male cells only, and 12 used female cells only. Sex omission was more frequent when cell lines were used than when primary cells were used. In the articles describing experiments performed using rodent primary cells, more than half of the studies used only male cells. Our results showed an overall improvement in sex reporting for cells in AJP-Cell Physiology articles from 2013 (25%) to 2018 (50%). However, sex omission and male bias were often found still. Furthermore, the obtained results were rarely analyzed by sex even when both male and female cells were used in the experiments. To boost sex-considerate research implementation in basic biomedical studies, cooperative efforts of the research community, funders, and publishers are urged.

Males and females have physiological, hormonal, and genetic differences that can cause different responses to medicinal treatments. The role of sex in the pharmacokinetics and pharmacodynamics of drugs is well established in the literature. However, researchers have yet to robustly and consistently consider the impact of sex differences on the pharmacokinetics and pharmacodynamics of nanomedicine formulations when designing nanomedicine therapeutics and/or constructing clinical trials. In this review, we highlight the physiological and anatomical differences between sexes and discuss how these differences can influence the therapeutic efficacy, side effects, and drug delivery safety of nanomedicine products. A deep understanding of the effects of sex on nano-based drug delivery agents will robustly improve the risk assessment process, resulting in safer formulations, successful clinical translation, and improved therapeutic efficacies for both sexes.

Algal atypical proliferation is a consequence of water fertilization (also called eutrophication) and a worldwide environmental concern since water quality and its uses are seriously compromised. Prevention is the most effective measure given that once the algal proliferation starts, it is too difficult and costly to stop the process. This article presents a nonparametric machine learning algorithm that combines the gradient boosted regression tree (GBRT) model and an improved differential evolution algorithm (L-SHADE) for better understanding and control of the algal abnormal proliferation (usually estimated from Chlorophyll-a and Total Phosphorus concentrations) from physicochemical and biological variable values obtained in a northern Spain reservoir. This L-SHADE technique involves the optimization of the GBRT hyperparameters during the training process. Apart from successfully estimating algal atypical growth (coefficients of determination equal to 0.91 and 0.93 for Chlorophyll-a and Total Phosphorus concentrations were obtained, respectively), this hybrid model allows here to establish the ranking of each independent biological and physicochemical variable according to its importance in the algal enhanced growth.