Precision medicine requires understanding how both sex and gender influence health.

Progress in studying sex as a biological variable (SABV) is slow, and the influence of gendered effects of the social environment on biology is largely unknown. Yet incorporating these concepts into basic science research will enhance our understanding of human health and disease. We provide steps to move this process forward.

Associations of Posttraumatic Stress Disorder Symptom Clusters and Pain Interference in Post-9/11 Veterans: Exploring Sleep Impairment and Physical Activity as Underlying Mechanisms.

BACKGROUND: Posttraumatic stress disorder (PTSD) symptoms and pain are highly prevalent and comorbid, particularly in veterans, but mechanisms explaining their linkage remain unclear. The aims of this study were to determine: (1) whether sleep impairment and physical activity (PA) mediate relations between PTSD symptoms and pain interference (assessed both longitudinally and as residual change) and (2) the unique roles of each PTSD symptom cluster in those relationships. METHODS: The present study is a secondary analysis of a longitudinal observational investigation of 673 post-9/11 veterans (45.8% women). Surveys were administered at baseline and 3-month and 6-month follow-ups. RESULTS: PTSD symptoms were significantly associated with pain interference longitudinally and worsening pain interference over time. Sleep impairment, but not PA, significantly mediated the relationship between PTSD symptoms and subsequent pain interference. Hyperarousal symptoms were found to be the primary driver of the relationship between PTSD symptoms and pain interference and re-experiencing symptoms were associated with change in pain interference via sleep impairment. Men and women did not differ on any of the study variables with the exception of PA. CONCLUSION: Findings underscore the importance of targeting sleep as a key modifiable health factor linking PTSD symptoms to pain interference in post-9/11 veterans.

Obesity Risk Among West Point Graduates Later in Life.

ABSTRACT: Szivak, TK, Thomas, MM, Pietrzak, RH, Nguyen, DR, Ryan, DM, and Mazure, CM. Obesity Risk Among West Point Graduates Later in Life. J Strength Cond Res 37(6): 1284-1291, 2023-The purpose of this investigation was to evaluate sex differences in health and fitness outcomes among United States Military Academy (USMA) graduates (class years 1980-2011). Subjects ( n = 701 men, 641 women, age: 45.7 ± 9.3 years) were surveyed as a part of a larger investigation on risk and resiliency factors among USMA graduates. Physical activity was assessed using the International Physical Activity Questionnaire (IPAQ) short form and calculation of weekly metabolic equivalents (METs). Overweight and obesity status were assessed by body mass index (BMI). Significance for the study was set at p ≤ 0.05. Obesity rates for men (30.1%) were significantly higher than for women (16.6%). Men reported significantly higher ( p = 0.01) vigorous METs·wk -1 (1,214.6 ± 1,171.6) than women (1,046.8 ± 1,133.2) despite significantly higher ( p = 0.00) BMI values (28.75 ± 4.53 kg·m -2 ) than women (25.90 ± 5.48 kg·m -2 ). Women were 89% more likely to have ever been on a diet and reported higher (15.2%) Army Body Composition Program enrollment rates than men (6.3%). Obesity rates among men reflect trends seen in the broader military, Veteran, and U.S. adult populations, whereas obesity rates among women were lower. Men may be at a greater risk for obesity later in life despite higher self-reported physical activity; however, lean body mass and self-report bias should be considered. Because lifetime obesity may be influenced by factors other than physical activity, health initiatives should use a comprehensive approach early in the career of military officers.

Women, opioid use and addiction.

In the midst of the current coronavirus pandemic, the United States continues to struggle with an ongoing opioid epidemic, initially fueled by widespread prescribing of opioid medications during the 1990s. The primary reason for prescribing opioids is to treat pain. Women have more acute and chronic pain and have been prescribed these drugs in significantly greater numbers than men. Comparison of women and men with chronic pain also shows that women receive the majority of prescription opioids, and the use of these prescribed medications became the major pathway to misuse and addiction for women. Yet, recognition of the extent of women's exposure to opioids and the attendant consequences has been limited. Attempts to stem the overall tide of the epidemic focused on reducing the availability of prescription opioids. However, as these medications became more difficult to obtain and treatment opportunities were limited, many turned to other synthetic opioids, such as heroin and fentanyl. Thus, the public health crisis of opioid addiction has endured. This paper highlights the importance of understanding differences among women and men in opioid use and its biological and psychosocial effects to advance the gender-based treatment approaches and effective public health policy.

Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies.

Identifying brain alterations that contribute to suicidal thoughts and behaviors (STBs) are important to develop more targeted and effective strategies to prevent suicide. In the last decade, and especially in the last 5 years, there has been exponential growth in the number of neuroimaging studies reporting structural and functional brain circuitry correlates of STBs. Within this narrative review, we conducted a comprehensive review of neuroimaging studies of STBs published to date and summarize the progress achieved on elucidating neurobiological substrates of STBs, with a focus on converging findings across studies. We review neuroimaging evidence across differing mental disorders for structural, functional, and molecular alterations in association with STBs, which converges particularly in regions of brain systems that subserve emotion and impulse regulation including the ventral prefrontal cortex (VPFC) and dorsal PFC (DPFC), insula and their mesial temporal, striatal and posterior connection sites, as well as in the connections between these brain areas. The reviewed literature suggests that impairments in medial and lateral VPFC regions and their connections may be important in the excessive negative and blunted positive internal states that can stimulate suicidal ideation, and that impairments in a DPFC and inferior frontal gyrus (IFG) system may be important in suicide attempt behaviors. A combination of VPFC and DPFC system disturbances may lead to very high risk circumstances in which suicidal ideation is converted to lethal actions via decreased top-down inhibition of behavior and/or maladaptive, inflexible decision-making and planning. The dorsal anterior cingulate cortex and insula may play important roles in switching between these VPFC and DPFC systems, which may contribute to the transition from suicide thoughts to behaviors. Future neuroimaging research of larger sample sizes, including global efforts, longitudinal designs, and careful consideration of developmental stages, and sex and gender, will facilitate more effectively targeted preventions and interventions to reduce loss of life to suicide.

Mental Health and Wealth: Depression, Gender, Poverty, and Parenting.

Depression is a common and debilitating condition that adversely affects functioning and the capacity to work and establish economic stability. Women are disproportionately burdened by depression, and low-income pregnant and parenting women have particularly high rates of depression and often lack access to treatment. As depression can be treated, it is a modifiable risk factor for poor economic outcomes for women, and thus for children and families. Recent national and state health care policy changes offer the opportunity for community-based psychological and economic interventions that can reduce the number of pregnant and parenting women with clinically significant depressive symptoms. Moreover, there is strong evidence that in addition to benefiting women's well-being, such reforms bolster children's emotional and social development and learning and help families rise out of poverty. This review summarizes the mental health and economic literature regarding how maternal depression perpetuates intergenerational poverty and discusses recommendations regarding policies to treat maternal depression in large-scale social services systems.

Meaningful military engagement among male and female post-9/11 veterans: An examination of correlates and implications for resilience.

OBJECTIVE: Post-9/11 military deployment is commonly reported as stressful and is often followed by psychological distress after returning home. Yet veterans also frequently report experiencing meaningful military engagement (MME) that may buffer detrimental effects of military stressors. Focusing on the under-investigated topic of association of MME with post-deployment psychological adjustment, this study tests gender differences in MME and post-deployment outcomes. METHOD: This cross-sectional study examined the relationship of MME with deployment stressors, subsequent psychological distress (posttraumatic stress symptoms (PTSS) and depression), and gender among 850 recent-era U.S. veterans (41.4% female). RESULTS: On average, both male and female veterans reported high MME. Greater MME was associated with less PTSS and depression following combat and general harassment, and more depression after sexual harassment. For men only, MME associated with less PTSS after sexual harassment. CONCLUSIONS: MME is high among post-9/11 veterans, but its stress-buffering effects depend on gender and specific stressor exposure.

Bidirectionality of Pain Interference and PTSD Symptoms in Military Veterans: Does Injury Status Moderate Effects?

OBJECTIVE: Pain and post-traumatic stress disorder (PTSD) symptoms are strongly correlated in veteran populations. Arguments for which one condition predicts or worsens the other condition have gone in both directions. However, research addressing this issue has been primarily limited to cross-sectional studies rather than examinations of a potential bidirectional relationship between pain interference and PTSD symptoms over time. In addition, no studies have examined deployment injury status as potentially moderating this bidirectional effect in veterans. To address these gaps in the literature, the present longitudinal study examined whether there is a bidirectional relationship between pain interference and PTSD symptoms in a sample of male and female veterans returning from Operation Iraqi Freedom, Operation Enduring Freedom, or Operation New Dawn (N = 729) and whether deployment injury status moderates this relationship. METHODS: Participants completed phone interviews regarding pain interference and PTSD symptoms at three time points, each three months apart. RESULTS: Pain interference at Time 1 predicted worse PTSD symptoms at Time 2 for the subset of veterans who sustained injuries during deployment (n = 381) but not for veterans with pain interference who did not sustain injuries (n = 338). From Time 1 to Time 3, elevations in PTSD symptoms were mediated by pain interference for injured veterans; in contrast, PTSD symptoms did not appear to drive changes in pain interference in either group. CONCLUSIONS: These results indicate that physical symptom management should be a crucial target of psychological intervention for returning veterans with PTSD symptoms and deployment-related injuries.

Trajectories of depressive and anxiety symptoms in older adults: a 6-year prospective cohort study.

OBJECTIVE: Depressive and anxiety symptoms are common in older adults, significantly affect quality of life, and are risk factors for Alzheimer's disease. We sought to identify the determinants of predominant trajectories of depressive and anxiety symptoms in cognitively normal older adults. METHOD: Four hundred twenty-three older adults recruited from the general community underwent Aß positron emission tomography imaging, apolipoprotein and brain-derived neurotrophic factor genotyping, and cognitive testing at baseline and had follow-up assessments. All participants were cognitively normal and free of clinical depression at baseline. Latent growth mixture modeling was used to identify predominant trajectories of subthreshold depressive and anxiety symptoms over 6 years. Binary logistic regression analysis was used to identify baseline predictors of symptomatic depressive and anxiety trajectories. RESULTS: Latent growth mixture modeling revealed two predominant trajectories of depressive and anxiety symptoms: a chronically elevated trajectory and a low, stable symptom trajectory, with almost one in five participants falling into the elevated trajectory groups. Male sex (relative risk ratio (RRR) = 3.23), lower attentional function (RRR = 1.90), and carriage of the brain-derived neurotrophic factor Val66Met allele in women (RRR = 2.70) were associated with increased risk for chronically elevated depressive symptom trajectory. Carriage of the apolipoprotein epsilon 4 allele (RRR = 1.92) and lower executive function in women (RRR = 1.74) were associated with chronically elevated anxiety symptom trajectory. CONCLUSION: Our results indicate distinct and sex-specific risk factors linked to depressive and anxiety trajectories, which may help inform risk stratification and management of these symptoms in older adults at risk for Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd.

Gender differences in psychiatric and medical comorbidity with post-traumatic stress disorder.

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with significant personal and societal burden. The present study examines the gender-specific differences in this burden in terms of the co-occurrence of psychiatric disorders and medical conditions with PTSD in the general population of France. METHODS: The study is based on a cross-sectional general population survey of 21,879 adults. Trained interviewers used a computer-assisted telephone interviewing system to administer the Composite International Diagnostic Interview-Short Form to screen for psychiatric disorders and medical conditions in the previous 12 months. RESULTS: One third of those with moderately severe PTSD (35.3%) and half of those with severe PTSD (54.2%) suffered from comorbid depression. The prevalence of anxiety disorders and substance use disorders was also greater among severe cases of PTSD. Chronic back or neck problems, frequent or severe headaches, arthritis or rheumatism and hypertension were highly prevalent among adults with PTSD. Adjusting for gender, age, education, employment and marital status, moderately severe and severe PTSD diagnoses were associated with significantly greater odds of comorbid psychiatric disorders and medical conditions. With few exceptions, the pattern of gender differences in psychiatric and medical morbidity among those with moderate or severe PTSD were similar to differences observed among those without PTSD. CONCLUSIONS: The findings highlight the burden of co-occurring psychiatric and medical conditions among PTSD sufferers in France and suggest the need for careful consideration of comorbidity in the assessment and service planning for PTSD.

Considerations of Sex and Gender in FDA Tobacco Regulation.

This Viewpoint discusses how sex and gender subpopulations may be differentially affected by tobacco products and suggests that the FDA formulate regulations in clinically meaningful ways.

Brain circuitry associated with the development of substance use in bipolar disorder and preliminary evidence for sexual dimorphism in adolescents.

Substance use disorders and mood disorders are highly comorbid and confer a high risk for adverse outcomes. However, data are limited on the neurodevelopmental basis of this comorbidity. Substance use initiation typically occurs during adolescence, and sex-specific developmental mechanisms are implicated. In this preliminary study, we review the literature and investigate regional gray matter volume (GMV) associated with subsequent substance use problems in adolescents with bipolar disorder (BD) and explore these associations for females and males. Thirty adolescents with DSM-IV-diagnosed BD and minimal alcohol/substance exposure completed baseline structural magnetic resonance imaging scans. At follow-up (on average 6 years post baseline), subjects were administered the CRAFFT interview and categorized into those scoring at high ( ≥ 2: CRAFFTHIGH ) vs. low ( < 2: CRAFFTLOW ) risk for alcohol/substance problems. Lower GMV in prefrontal, insular, and temporopolar cortices were observed at baseline among adolescents with BD reporting subsequent alcohol and cannabis use compared to adolescents with BD who did not (P < 0.005, clusters ≥ 20 voxels). Lower dorsolateral prefrontal GMV was associated with future substance use in both females and males. In females, lower orbitofrontal and insula GMV was associated with future substance use, while in males, lower rostral prefrontal GMV was associated with future use. Lower orbitofrontal, insular, and temporopolar GMV was observed in those who transitioned to smoking tobacco. Findings indicate that GMV development is associated with risk for future substance use problems in adolescents with BD, with results implicating GMV development in regions subserving emotional regulation in females and regions subserving executive processes and attention in males. © 2016 Wiley Periodicals, Inc.

Sex Differences in Smoking Cessation Pharmacotherapy Comparative Efficacy: A Network Meta-analysis.

INTRODUCTION: Converging clinical and biological evidence suggest sex is an important factor when selecting a pharmacological intervention for smoking cessation. The current investigation used network meta-analyses to estimate sex differences in the comparative efficacy of transdermal nicotine (TN), varenicline, and sustained release (SR) bupropion for smoking cessation. METHODS: Systematically searched previously published reviews and databases (Medline, PsycINFO, Embase) of randomized, double-blind, placebo-controlled trials of bupropion-SR, TN, and varenicline for cigarette smoking cessation in primary care/general community samples were included. RESULTS: Thirty-two studies met all criteria and 28 (88%) were included in the final analyses, representing 14 389 smokers (51% female). Results of the full sample (women and men combined) mirrored those from a Cochrane Tobacco Addiction Group network meta-analysis of smoking cessation pharmacotherapy, showing VAR>TN=BUP. All medications improved quit rates over placebo for both women and men. Relative to placebo, varenicline efficacy was similar for women and men. Significant sex differences were evident when comparing varenicline versus TN and varenicline versus bupropion. For women, varenicline was more efficacious than TN (RR = 1.41; 95% CI = 1.12,1.76) and bupropion (RR = 1.38; 95% CI = 1.08,1.77). For men, outcomes for those treated with TN and bupropion were similar to those treated with varenicline. There were no differences in efficacy when comparing bupropion versus TN. CONCLUSIONS: The advantage of varenicline over bupropion SR and TN is greater for women than men. Clinicians should strongly consider varenicline as the first option treatment for women. Among men, the advantage of varenicline over TN or bupropion is less clear. IMPLICATIONS: This study provides information for the sex-informed treatment of nicotine addiction among cigarette smokers. Relative to placebo, women and men achieved similar outcomes when treated with varenicline; however the advantages of varenicline over transdermal patch and bupropion were greater for women compared to men.

Resting-State Functional Connectivity of the Basal Nucleus of Meynert in Cigarette Smokers: Dependence Level and Gender Differences.

INTRODUCTION: Numerous studies have characterized impaired cerebral functioning in nicotine-addicted individuals. Whereas nicotine interacts with multiple neurotransmitters in cortical and subcortical circuits, it directly targets the cholinergic system, sourced primarily from the basal nucleus of Meynert (BNM). However, no studies have examined how this cholinergic system is influenced by cigarette smoking. Here, we addressed this gap of research. METHODS: Using a dataset from the Functional Connectome Projects, we investigated this issue by contrasting seed-based BNM connectivity of 40 current smokers and 170 age- and gender-matched nonsmokers. We followed our data analytic routines in recent work and examined differences between smokers and nonsmokers in men and women combined as well as separately. RESULTS: Compared to nonsmokers, female but not male smokers demonstrated greater positive BNM connectivity to the supplementary motor area, bilateral anterior insula, and right superior temporal/supramarginal gyri as well as greater negative connectivity to the posterior cingulate cortex and precuneus. Further, BNM connectivity to the supplementary motor area is negatively correlated to the Fagerström Test for Nicotine Dependence score in male but not female smokers. CONCLUSIONS: Along with a previous report of upregulated nicotinic acetylcholine receptor in male but not female smokers, these new findings highlight functional changes of the cholinergic systems in cigarette smokers. The results suggest sex-specific differences in cholinergic dysregulation and a need for multiple imaging modalities to capture the neural markers of nicotine addiction. IMPLICATIONS: Nicotine influences cognition via cholinergic projections of the basal forebrain to the cerebral cortex. This study examined changes in resting-state whole-brain functional connectivity of the BNM in cigarette smokers. The new findings elucidate for the first time sex differences in BNM-cerebral connectivity in cigarette smoking.

ß-Amyloid, APOE and BDNF Genotype, and Depressive and Anxiety Symptoms in Cognitively Normal Older Women and Men.

OBJECTIVE: To examine how ß-amyloid (Aß), APOE and BDNF genotypes, and cortisol relate to depressive and anxiety symptoms in cognitively normal older women and men. METHODS: Cross-sectional data were analyzed from 423 older adults from the Australian Imaging Biomarkers and Lifestyle study. Analyses of covariance evaluated associations between Aß, APOE and BDNF genotype, and cortisol in relation to severity of depressive and anxiety symptoms. RESULTS: Among Aß+ older adults, APOE ε4 carriage was associated with greater severity of anxiety symptoms (d = 0.55); and in the full sample, APOE ε4 carriage was linked to greater severity of depressive (d = 0.26) and anxiety (d = 0.21) symptoms. Among Aß+ women, ε4 carriers reported greater anxiety symptoms than non-ε4 carriers (d = 0.83), and female BDNF rs6265 Val66 Met allele carriers reported greater depressive symptoms (d = 0.29). CONCLUSION: Sex moderated the relationship between Aß, APOE genotype, and BDNF genotype in predicting severity of anxiety and depressive symptoms in cognitively normal older adults.

Sex Differences in Varenicline Efficacy for Smoking Cessation: A Meta-Analysis.

INTRODUCTION: Women have lower rates of quitting than men with both bupropion and nicotine replacement. It is unknown whether varenicline demonstrates differential efficacy for men and women. The purpose of this study was to conduct the first comprehensive meta-analysis of clinical trial data examining sex differences in the efficacy of varenicline for smoking cessation. METHODS: Searching MEDLINE, EMBASE, and PsychINFO, 17 of 43 clinical trials of varenicline for smoking cessation published through December 31, 2014 were low-bias randomized double-blind placebo-controlled trials. Data (n = 6710 smokers, 34% female, n = 16 studies, 96% of available data) was analyzed with Metafor program in R. Outcome endpoints were 7-day point-prevalence (PP) and continuous-abstinence (CA) at week 12 (end of treatment), week 24 (6-month follow-up), and week 52 (12-month follow-up). RESULTS: Using placebo, women were less likely than men to quit (PP-12, CA-24; P < .05 for sex). Using varenicline, similar rates of abstinence for men and women were demonstrated for all six outcomes (eg, PP-12 abstinence rates were 53% in both women and men). Varenicline versus placebo outcomes demonstrated that varenicline was more effective for women for short and intermediate outcomes (PP-12, CA-12, CA-24; P < .05 sex × medication interaction). For end-of-treatment PP, varenicline was 46% more effective for women. For continuous abstinence, varenicline was 34% (CA-12) and 31% (CA-24) more effective for women. CONCLUSIONS: Unlike other smoking cessation medications, varenicline demonstrated greater efficacy among women smokers for short and immediate-term outcomes and equal efficacy for 1-year outcomes. Varenicline may be particularly useful for reducing the sex disparity typically seen in rates of smoking cessation. IMPLICATIONS: Varenicline is currently the most effective FDA-approved smoking cessation medication and this is the first demonstration that women compared with men have a preferred therapeutic response for a smoking cessation medication when considering short-term outcomes. Importantly, this is also the first demonstration that women have similar rates of quitting to men when considering longer-term, 1-year outcomes.

Balance of the Sexes: Addressing Sex Differences in Preclinical Research.

Preclinical research is fundamental for the advancement of biomedical sciences and enhancing healthcare. Considering sex differences in all studies throughout the entire biomedical research pipeline is necessary to adequately inform clinical research and improve health outcomes. However, there is a paucity of information to date on sex differences in preclinical work. As of 2009, most (about 80 percent) rodent studies across 10 fields of biology were still conducted with only male animals. In 2016, the National Institutes of Health implemented a policy aimed to address this concern by requiring the consideration of sex as a biological variable in preclinical research grant applications. This perspective piece aims to (1) provide a brief history of female inclusion in biomedical research, (2) describe the importance of studying sex differences, (3) explain possible reasons for opposition of female inclusion, and (4) present potential additional solutions to reduce sex bias in preclinical research.

Associations of Gender, Smoking, and Stress with Transitions in Major Depression Diagnoses.

Using data from the newly available U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; Wave 3; n = 36,309), we evaluated relationships among gender, cigarette smoking status (current, former, non-smoker), life event stress (0-1 vs. 2+ events), and their impact on transitions in major depression diagnosis (MDD; new vs. absent cases; ongoing vs. remit cases). Women who were both current and former cigarette smokers with more than two stressful events had higher rates of new MDD diagnosis compared to men who were current or former smokers with two or more stressful events. Current smoking and experiencing two or more stressful events increased the odds of having an ongoing MDD diagnosis, while being a former smoker decreased these odds. Results suggest that smoking and stress are markers for depression risk in women and should help guide clinical assessment as well as gender-difference research on the biological underpinnings of these conditions.

Targeting the noradrenergic system for gender-sensitive medication development for tobacco dependence.

INTRODUCTION: Tobacco use remains the leading cause of morbidity and mortality for both women and men in the United States, and women often experience poorer smoking cessation outcomes than men. Preliminary evidence suggests there are sex differences in medication effectiveness for smoking cessation. However, current medications do not take into account gender-sensitive treatment development and efficacy, underscoring the importance of this underdeveloped area of research. METHODS: We reviewed preclinical and clinical evidence for gender differences in the inability to quit smoking by examining (a) the effect of increased negative affect and stress reactivity on smoking outcomes in women and (b) smoking for nicotine reinforcement in men. We also reviewed the current literature targeting the noradrenergic system as a novel gender-sensitive treatment strategy for tobacco dependence. RESULTS: We hypothesize that noradrenergic agents that normalize noradrenergic activity may differentially attenuate stress reactivity in women and nicotine-related reinforcement in men, indicating that targeting the noradrenergic system for smoking cessation may be effective for both genders, with benefits operating through sex-specific mechanisms. CONCLUSIONS: Converging lines of preclinical and clinical evidence suggest that gender-sensitive approaches to medication development for smoking cessation are a critical next step for addressing low quit rates and exacerbated health risks among women. Evidence reviewed indicates that smoking activates different brain systems modulated by noradrenergic activity in women versus men, and noradrenergic compounds may preferentially target these gender-sensitive systems.