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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.

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.

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.

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.

The importance of sex as a biological variable is being recognized by more and more researchers, including those using Drosophila melanogaster as a model organism. Differences between the two sexes are not confined to well-known reproductive behaviors, but include other behaviors and physiological characteristics that are considered “common” to both sexes. It is possible to categorize sexual dimorphisms into “qualitative” and “quantitative” differences, and this review focuses on recent advances in elucidating genetic and neurophysiological basis of both qualitative and quantitative sex differences in Drosophila behavior. While sex-specific behaviors are often mediated by sexually dimorphic neural circuits, quantitative sexual dimorphism is caused by sex-specific modulation of a common neuronal substrate.

Modern anaesthesia demands the monitoring of many biological variables. It is no longer sufficient to be satisfied by a patient of good colour with a temporal pulse of reasonable character, volume and rate, though in times of power loss and technological malfunction these are skills that may still be relied upon! The journey of a biological variable from patient to monitor requires several distinct processes, often imagined within a singular ‘black box': (i) detection; (ii) transduction; (iii) processing; (iv) display; (v) storage. The aim of this article is to examine each of these elements in turn, to inspect the ways in which different biological variables require distinct handling techniques and to give running examples to portray each step in a way applicable to daily practice.

In animal models, the physiological systems involved in metabolic homeostasis exhibit a sex difference. Investigators often use male rodents because they show metabolic disease better than females. Thus, females are not used precisely because of an acknowledged sex difference that represents an opportunity to understand novel factors reducing metabolic disease more in one sex than the other. The National Institutes of Health (NIH) mandate to consider sex as a biological variable in preclinical research places new demands on investigators and peer reviewers who often lack expertise in model systems and experimental paradigms used in the study of sex differences. This Perspective discusses experimental design and interpretation in studies addressing the mechanisms of sex differences in metabolic homeostasis and disease, using animal models and cells. We also highlight current limitations in research tools and attitudes that threaten to delay progress in studies of sex differences in basic animal research.

Prior work has shown that there is substantial interindividual variation in the spatial distribution of functional networks across the cerebral cortex, orfunctional topography. However, it remains unknown whether there are sex differences in the topography of individualized networks in youth. Here we leveraged an advanced machine learning method (sparsity-regularized nonnegative matrix factorization) to define individualized functional networks in 693 youth (ages 8-23 years) who underwent functional magnetic resonance imaging as part of the Philadelphia Neurodevelopmental Cohort. Multivariate pattern analysis using support vector machines classified participant sex based on functional topography with 83% accuracy (pSIGNIFICANCE STATEMENTWe identify normative developmental sex differences in the functional topography of personalized association networks including the ventral attention network and default mode network. Furthermore, chromosomal enrichment analyses revealed that sex differences in multivariate patterns of functional topography were spatially coupled to the expression of X-linked genes as well as astrocytic and excitatory neuronal cell-type signatures. These results highlight the role of sex as a biological variable in shaping functional brain development in youth.

Clinical blood pressure measurement (BP) is an occasional and imperfect way of estimating this biological variable. Ambulatory blood pressure monitoring (ABPM) is by far the best clinical tool for measuring an individual's blood pressure. Mean values over 24h, through the daytime and at night all make it more possible to predict organic damage and the future development of the disorder. ABPM enables the detection of white-coat hypertension and masked hypertension in both the diagnosis and follow-up of treated patients. Although some of the advantages of ABPM can be reproduced by more automated measurement without the presence of an observer in the clinic or self-measurement at home, there are some other elements of great interest that are unique to ABPM, such as seeing what happens to a patient's BP at night, the night time dipping pattern and short-term variability, all of which relate equally to the patient's prognosis. There is no scientific or clinical justification for denying these advantages, and ABPM should form part of the evaluation and follow-up of practically all hypertensive patients. Rather than continuing unhelpful discussions as to its availability and acceptability, we should concentrate our efforts on ensuring its universal availability and clearly explaining its advantages to both doctors and patients.

Understanding the mechanisms underlying autism spectrum disorders (ASDs) is a challenging goal. Here we review recent progress on several fronts, including genetics, proteomics, biochemistry, and electrophysiology, that raise motivation for forming a viable pathophysiological hypothesis. In place of a traditionally unidirectional progression, we put forward a framework that extends homeostatic hypotheses by explicitly emphasizing autoregulatory feedback loops and known synaptic biology. The regulated biological feature can be neuronal electrical activity, the collective strength of synapses onto a dendritic branch, the local concentration of a signaling molecule, or the relative strengths of synaptic excitation and inhibition. The sensor of the biological variable (which we have termed the homeostat) engages mechanisms that operate as negative feedback elements to keep the biological variable tightly confined. We categorize known ASD-associated gene products according to their roles in such feedback loops and provide detailed commentary for exemplar genes within each module.

In this essay, I explore the usefulness of gender, in examining sustainability concerns about the future of the accounting academy. In doing so, I differentiate between gender as a biological variable and gender as a concept. Gender as a variable focuses our attention on demographic issues such as numbers of women. Gender as a concept directs our attention toward the institutional framework within which accounting academics (men and women) currently operate. Rather than assuming that increasing numbers of women can fundamentally change the academy, gender as a concept allows us to explore the over-emphasis upon the masculine in the gendering of the good academic accountant. This imbalance unduly limits the openness of the academy including its intellectual heterogeneity and the sorts of values that are promoted within it.

Female and male humans are different. As simple and obvious as that statement is, in biomedical research there has been an historical tendency to either not consider sex at all or to only use males in clinical and in preclinical model system studies. The result is a large volume of research that reflects the average biology and pathology of males even though we know that disease risk, presentation, and response to therapies can be different between females and males. This is true, albeit to differing degrees, for virtually all neurological and psychiatric diseases. However, the days of ignoring sex as a biological variable are over – both because of the realization that genetic sex impacts brain function, and because of the 2014 mandate by the U.S. National Institutes of Health that requires that “sex as a biological variable” be addressed in each grant application. This review is written for neuroscientists who may not have considered sex as a biological variable previously but who now are navigating the best way to adapt their research programs to consider this important biology. We first provide a brief overview of the evidence that male versus female differences in the brain are biologically and clinically meaningful. We then present some fundamental principles that have been forged by a dedicated but small group of ground-breaking researchers along with a description of tools and model systems for incorporating a sex differences component into a research project. Finally, we will highlight some key technologies that, in the coming years, are likely to provide critical information about sex differences in the human brain.

While fatigue is one of the mostly commonly reported side effects of cancer therapy, there is significant variability in intensity and persistence of this symptom. Understanding the factors accounting for this variation may provide insight into mechanisms underlying fatigue. An often overlooked issue is the possible influence of sex differences. The few studies that have been conducted employed patient-reported outcome variables. While a number describe more fatigue in female cancer patients, it is unclear if this is due to underlying biological factors or reporting biases. The use of preclinical approaches may provide greater insight into this relationship. Therefore, we initiated a series of studies comparing behavioral fatigue measured by decreases in voluntary wheel running in response to cancer therapy in a murine model of head and neck cancer. In mice implanted with leg tumors, combined cisplatin and radiotherapy resulted in a robust reduction in wheel running with no significant differences between male and female mice. In response to cisplatin alone, female mice showed a slower recovery of wheel running after treatment. Finally, in response to cisplatin and immunotherapy with an anti-PD-1 monoclonal antibody, female mice showed a trend toward a greater reduction in wheel running. Overall our data indicates that female sex may be associated with enhanced vulnerability to fatigue following cancer therapy. Our current research explores the possible immunological mechanism underlying this increased vulnerability.

Although unipolar depression and bipolar depression are considered distinct entities both by clinicians and researchers, it is not clear whether a pathophysiological distinction, which is the bridge between etiology and treatment, exists between these two conditions. The objective of this paper was to systematically review the studies that examined the biological differences between unipolar and bipolar depression. Using computerized Medline and manual searches, we located and reviewed studies that directly compared patients with unipolar depression with bipolar depressed patients on at least one biological variable. The results showed that patients with bipolar depression had lower levels of urinary NE and its metabolites and lower platelet MAO activity, and higher platelet free and stimulated intracellular calcium levels compared with unipolar depressed patients, but none of the variables examined appeared to differentiate the two groups consistently. We discuss some of the methodological flaws that might have contributed to this, and suggest that further studies should control for such confounding variables.

The discovery of clinical and biological variables which correlate with the rate of treatment response is an important aim of outcome research. In this report, such items were assessed in a large group of patients with recurrent depression to determine what variables contribute to stabilization during treatment. Relatively few items were strongly related to time to stabilization aside from age, clinical severity of illness, and number of previous episodes. One biological variable, cortisol nadir, was positively related to the time of stabilization. Similar assessments of non-responders did not yield any specific predictors.

When individuals with high levels of a biological variable are given a treatment to lower these levels, it is important to be able to assess how much of any subsequent decrease is due to the treatment. The fact that individuals selected for their high levels on one occasion will (on average) show lower levels on subsequent occasions even in the absence of treatment is now recognized, and has been termed the ‘regression’ effect. The reverse is true for low levels. This paper presents a method for predicting how much change can be expected from regression, and thus a means of estimating the treatment effect. The analysis is based on measures of within-person and between-person variability, the within-person source being responsible for the regression effect. The effect that within-person variability has on misclassification of people into high-risk groups, and a means of determining how many estimates of one individual's level are required for a given precision of classification, are also derived from the same analytical approach. Examples are given using data on cholesterol levels following treatment with Clofibrate, caloric intake levels in a diet survey, and the relationship between the incidence of ischemic heart disease and systolic blood pressure level.