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Past research has found that sexualized women are often dehumanized (i.e., attributed reduced human qualities). However, the mechanisms contributing to such dehumanization remain poorly understood. In this pre-registered experiment involving a within-subject, placebo-controlled, cross-over design, we tested whether testosterone contributes to men's (N = 120, age range: 18-38 years) dehumanization of women. After administration of intranasal testosterone or placebo gel, men watched a video of a woman wearing either modest (i.e., conservative) or revealing (i.e., sexualized) clothing (between-subjects factor) and then completed three subtle dehumanization tasks, measuring emotion-based, personality-based, and perceptual dehumanization. We hypothesized that testosterone would increase dehumanization, especially for men who watched the "sexualized-clothing" video. Instead, we found that, while men engaged in emotion-based dehumanization toward the sexualized woman both when they had testosterone and placebo, testosterone increased emotion-based dehumanization toward the conservatively dressed woman. Other forms of dehumanization were not affected by testosterone. We also explored whether personality (e.g., dominance) and biological (e.g., CAG repeat polymorphism) traits that have been found to moderate the effects of testosterone on some social behaviors also moderated the effects examined here, but we did not find any significant moderations. Overall, this experiment revealed a novel physiological mechanism affecting emotion-based dehumanization., Competing Interests: Declaration of Competing Interest none., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A behavioral economic reinforcer pathology model theorizes that alcohol problems are influenced by steep delay discounting, overvaluation of alcohol reinforcement, and low reinforcement from alcohol-free activities. Extending this account to the comorbidity of alcohol problems and posttraumatic stress disorder (PTSD), the present study tested the hypothesis that alcohol problems and PTSD symptom severity would interact and be positively associated with indicators from these three domains. High-risk emerging adults from North America (Study 1, n = 1,311, M age = 22.13) and general community adults from Canada (Study 2, n = 1,506, M age = 36.80) completed measures of alcohol problems, PTSD symptoms, delay discounting, alcohol demand, and proportionate alcohol-related reinforcement. Across studies, regression analyses revealed significant main effects of alcohol problems and PTSD symptoms in relation to selected reinforcer pathology indicators, but no significant interactions were present for delay discounting or proportionate alcohol-related reinforcement. Interactions were observed for alcohol consumption at $0 (intensity) and the rate of change in consumption across the demand curve (elasticity; Study 1) and for elasticity and maximum alcohol expenditure ( O max ; Study 2), but not in the predicted directions. Higher synergistic severity was associated with lower alcohol reinforcing value in each case. These findings reveal expected relations between reinforcer pathology indicators and both alcohol problems and PTSD symptomatology in general but did not support the hypothesized synergistic relationship. The relation between alcohol problems and PTSD is more complex than predicted by existing extensions of the reinforcer pathology model, warranting further investigation. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The mating effort questionnaire (MEQ) is a multi-dimensional self-report instrument that captures factors reflecting individual effort in upgrading from a current partner, investment in a current partner, and mate seeking when not romantically paired. In the current studies, we sought to revise the MEQ so that it distinguishes among two facets of mate seeking-mate locating and mate attracting-to enable a more nuanced measurement and understanding of individual mating effort. Moreover, we developed additional items to better measure partner investment. In total, the number of items was increased from 12 to 26. In Study 1, exploratory factor analysis revealed that a four-factor solution, reflecting partner upgrading, mate locating, mate attracting, and partner investment, yielded the best fit. In Study 2, this structure was replicated using confirmatory factor analysis in an independent sample. Based on extant studies documenting the relationships between psychopathy, short-term mating effort, and sexual risk taking, a structural equation model (SEM) indicated that trait psychopathy positively predicted mate locating, mate attracting, and partner upgrading and negatively predicted partner investment. A separate SEM showed that partner upgrading positively predicted risky sexual behaviors, while partner upgrading and mate locating positively predicted acceptance of cosmetic surgery., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aims: Behavioral economic theory predicts that high alcohol demand and high proportionate alcohol-related reinforcement are important determinants of risky alcohol use in emerging adults, but the majority of research to date has been cross-sectional in nature. The present study investigated prospective and dynamic relationships between alcohol demand and proportionate alcohol-related reinforcement in relation to heavy drinking days and alcohol problems., Design: Longitudinal cohort with assessments every 4 months for 20 months., Setting: Ontario, Canada., Participants: Emerging adults reporting regular heavy episodic drinking (n = 636, M age  = 21.44; 55.8% female)., Measurements: Heavy drinking days (HDD; Daily Drinking Questionnaire), alcohol problems (Brief Young Adult Alcohol Consequences Questionnaire), alcohol demand (Alcohol Purchase Task) and proportionate alcohol-related reinforcement (Activity Level Questionnaire)., Findings: Linear mixed effects models revealed that behavioral economic indicators and alcohol-related outcomes significantly decreased over the study, consistent with 'aging out' of risky alcohol use. Random intercept cross-lagged panel models revealed significant between-person relationships, such that higher alcohol demand and alcohol-related reinforcement were positively associated with HDD and alcohol problems (random intercepts = 0.187-0.534, Ps < 0.01). Moreover, alcohol demand indicators (particularly the rate of change in elasticity of the demand curve, as measured by α, and the maximum expenditure, O max ) and proportionate alcohol-related reinforcement significantly forecasted changes in HDD at all time points (|βs| = 0.063-0.103, Ps < 0.05) in cross-lagged relationships, with bidirectional associations noted for the rate of change in elasticity (βs = -0.085 to -0.104, Ps < 0.01). Proportionate alcohol-related reinforcement also significantly forecasted changes in alcohol problems at all time points (βs = 0.072-0.112, Ps < 0.01)., Conclusions: Multiple behavioral economic indicators (demand elasticity, maximum expenditure and reinforcement ratio) forecast changes in heavy episodic drinking and alcohol problems over the course of emerging adulthood. These results further implicate alcohol demand and proportionate alcohol-related reinforcement as etiologically and developmentally important mechanisms in alcohol use trajectories., (© 2024 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

The strategic and targeted use of an anesthetized canine cardiovascular model early in drug discovery enables a comprehensive cardiovascular and electrophysiological assessment of potential safety liabilities and guides compound selection prior to initiation of chronic toxicological studies. An ideal model would enable exposure-response relationships to guide safety margin calculations, have a low threshold to initiate, and have quick delivery of decision quality data. We have aimed to profile compounds with diverse mechanism of actions (MoAs) of "non-QT" cardiovascular drug effects and evaluate the ability of nonclinical in vivo cardiovascular models to detect clinically reported effects. The hemodynamic effects of 11 drugs (atropine, itraconazole, atenolol, ivabradine, milrinone, enalaprilat, fasudil, amlodipine, prazosin, amiloride, and hydrochlorothiazide) were profiled in an anesthetized dog cardiovascular model. Derived parameters included: heart rate, an index of left ventricular contractility, mean arterial pressure, systemic vascular resistance, and cardiac output. Species specific plasma protein data was generated (human, dog) and utilized to calculate free drug concentrations. Using the anesthetized dog cardiovascular model, 10 of the 11 drugs displayed the predicted changes in CV parameters based on their primary MoAs and corresponding clinically described effects. Interestingly but not unexpected, 1 of 11 failed to display their predicted CV pattern which is likely due to a delay in pharmacodynamic effect that is beyond the duration of the experimental model (hydrochlorothiazide). The analysis from the current study supports the strategic use of the anesthetized dog model early in the drug discovery process for a comprehensive cardiovascular evaluation with good translation to human., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

Delay discounting-the extent to which individuals show a preference for smaller immediate rewards over larger delayed rewards-has been proposed as a transdiagnostic neurocognitive process across mental health conditions, but its examination in relation to posttraumatic stress disorder (PTSD) is comparatively recent. To assess the aggregated evidence for elevated delay discounting in relation to posttraumatic stress, we conducted a meta-analysis on existing empirical literature. Bibliographic searches identified 209 candidate articles, of which 13 articles with 14 independent effect sizes were eligible for meta-analysis, reflecting a combined sample size of N = 6897. Individual study designs included case-control (e.g. examination of differences in delay discounting between individuals with and without PTSD) and continuous association studies (e.g. relationship between posttraumatic stress symptom severity and delay discounting). In a combined analysis of all studies, the overall relationship was a small but statistically significant positive association between posttraumatic stress and delay discounting ( r = .135, p < .0001). The same relationship was statistically significant for continuous association studies ( r = .092, p = .027) and case-control designs ( r = .179, p < .001). Evidence of publication bias was minimal. The included studies were limited in that many did not concurrently incorporate other psychiatric conditions in the analyses, leaving the specificity of the relationship to posttraumatic stress less clear. Nonetheless, these findings are broadly consistent with previous meta-analyses of delayed reward discounting in relation to other mental health conditions and provide further evidence for the transdiagnostic utility of this construct.

Objective: Canadian Armed Forces (CAF) members and Veterans are more likely to experience mental health (MH) conditions, such as posttraumatic stress disorder (PTSD), than the general Canadian population. Previous research suggests that an increasing number of individuals are employing cannabis for MH symptom relief, despite a lack of robust evidence for its effectiveness in treating PTSD. This research aimed to: (1) describe the prevalence of current cannabis use among MH treatment-seeking CAF members and Veterans; and (2) estimate the association between current cannabis use and a number of sociodemographic, military, and MH-related characteristics., Method: Using cross-sectional intake data from 415 CAF members and Veterans attending a specialized outpatient MH clinic in Ontario, Canada, between January 2018 and December 2020, we estimated the proportion of CAF members and Veterans who reported current cannabis use for either medical or recreational purposes. We used multivariable logistic regression to estimate adjusted odds ratios for a number of sociodemographic, military, and MH-related variables and current cannabis use., Results: Almost half of the study participants (n = 187; 45.1%) reported current cannabis use. Respondents who reported current cannabis use for medical purposes had a higher median daily dose than those who reported current cannabis use for recreational purposes. The multivariable logistic regression identified younger age, lower income, potentially hazardous alcohol use, and increased bodily pain as statistically significant correlates of current cannabis use among our MH treatment-seeking sample. PTSD severity, depressive severity, sleep quality, and suicide ideation were not statistically associated with current cannabis use., Conclusions: Almost half of our treatment-seeking sample reported current cannabis use for medical or recreational purposes, emphasizing the importance of screening MH treatment-seeking military members and Veterans for cannabis use prior to commencing treatment. Future research building upon this study could explore the potential impact of cannabis use on MH outcomes., (© 2023. The Author(s).)

Few studies have examined changes in posttraumatic-stress disorder (PTSD) symptomatology across an extended time period during the COVID-19 pandemic. This study used a longitudinal cohort design to examine: (1) changes in overall PTSD symptoms and symptom clusters; (2) moderators of change; (3) the clinical significance of observed changes; and (4) correlates of clinically meaningful changes. Community adults (N = 1412) were assessed using the PTSD Checklist for DSM-5 (PCL-5) at 10 timepoints (October 2018 - April 2022). Changes in overall PCL-5 score and symptom clusters were substantially moderated by pre-pandemic clinical severity (i.e., above/below PCL-5 cut-off). Pre-pandemic non-clinical participants exhibited increases in overall scores, Cluster D (negative cognitions), and Cluster E (arousal), while clinically elevated participants exhibited decreases overall and in all clusters. Regarding clinical significance, 12% of pre-pandemic non-clinical participants exhibited clinically meaningful increases, and 4% exhibited decreases. Conversely, 42% of the pre-pandemic elevated group exhibited clinically meaningful decreases, while 6% exhibited increases. Pandemic impacts in numerous psychosocial domains were associated with clinically meaningful change. Collectively, these findings reveal substantively divergent trajectories by pre-pandemic severity and PTSD symptom cluster. The large proportion of pre-pandemic high-severity participants exhibiting sizable decreases was an unexpected notable observation., Competing Interests: Declaration of Competing Interest JM is a principal in Beam Diagnostics, Inc. and has served as a Consultant to Clairvoyant Therapeutics, Inc. These interests have no connection or relevance to the research reported in this manuscript. No other authors have potentially competing interests to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Exclusion from social relationships is a painful experience that may threaten an individual's status and dominance. The steroid hormone testosterone, which fluctuates rapidly in response to such threats, may be implicated in subsequent behavioral action (e.g., aggressive or prosocial responses) that aims to protect or enhance one's status after exclusion. Past research, however, indicates that the link between acute changes in testosterone and behavior depend on context-relevant individual dispositions. In the context of social exclusion, an individual's level of shame proneness-characterized by a tendency to experience shame and to react submissively-is theoretically relevant to the testosterone-induced aggression relationship but has yet to be examined empirically. Here, men (n = 167) were randomly assigned to be socially included or excluded in the virtual ball-tossing game, Cyberball, after which aggressive behavior was examined using the Point Subtraction Aggression Paradigm (PSAP). Testosterone reactivity was measured via salivary hormone samples collected pre- and post-game. Moderated multiple regression analyses were run to examine the extent to which testosterone reactivity and shame proneness moderated the effect of Cyberball condition on aggression. Results revealed a significant two-way interaction between Cyberball condition and testosterone reactivity, as well as a three-way interaction including shame proneness. For individuals low in shame proneness, exclusion was associated with higher post-cyberball aggression among those who experienced a rise in testosterone but was associated with lower post-cyberball aggression among those who experienced a decrease in testosterone. For individuals high in shame proneness, however, exclusion did not meaningfully affect aggressive responses, regardless of whether they experienced an increase or decrease in testosterone. These findings extend our understanding of the moderating roles of context and disposition on the neuroendocrinology of aggression in social interaction., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Neil V. Watson reports a relationship with Natural Sciences and Engineering Research Council of Canada that includes: funding grants., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Secondary pharmacology profiling is routinely applied in pharmaceutical drug discovery to investigate the pharmaceutical effects of a drug at molecular targets distinct from (off-target) the intended therapeutic molecular target (on-target). Data from a randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX, rofecoxib) trial, raised significant concerns about COX-2 inhibition as a primary or secondary target, shaping the screening and decision-making processes of some pharmaceutical companies. COX-2 is often included in off-target screens due to cardiovascular (CV) safety concerns about secondary interactions with this target. Several potential mechanisms of COX-2-mediated myocardial infarctions have been considered including, effects on platelet stickiness/aggregation, vasal tone and blood pressure, and endothelial cell activation. In the present study, we focused on each of these mechanisms as potential effects of COX-2 inhibitors, to find evidence of mechanism using various in vitro and in vivo preclinical models., Methods: Compounds tested in the study, with a range of COX-2 selectivity, included rofecoxib, celecoxib, etodolac, and meloxicam. Compounds were screened for inhibition of COX-2 vs COX-1 enzymatic activity, ex vivo platelet aggregation (using whole blood from multiple species), ex vivo canine femoral vascular ring model, in vitro human endothelial cell activation (with and without COX-2 induction), and in vivo cardiovascular assessment (anesthetized dog)., Results: The COX-2 binding assessment generally confirmed the COX-2 selectivity previously reported. COX-2 inhibitors did not have effects on platelet function (spontaneous aggregation or inhibition of aggregation), cardiovascular parameters (mean arterial pressure, heart rate, and left ventricular contractility), or endothelial cell activation. However, rofecoxib uniquely produced an endothelial mediated constriction response in canine femoral arteries., Conclusion: Our data suggest that rofecoxib-related cardiovascular events in humans are not predicted by COX-2 potency or selectivity. In addition, the vascular ring model suggested possible adverse cardiovascular effects by COX-2 inhibitors, although these effects were not seen in vivo studies. These results may also suggest that COX-2 inhibition alone is not responsible for rofecoxib-mediated adverse cardiovascular outcomes., (Copyright © 2023. Published by Elsevier Inc.)

Background: Differences in healthcare delivery systems and pathways to mental healthcare for Canadian Armed Forces (CAF) members and Veterans may contribute to variations in mental health services use (MHSU) and the factors associated with it. We: (1) estimated the prevalence of past 12-month MHSU (≥1 visit with a medical or mental health professional); and (2) identified sociodemographic, military-, trauma-, and health-related variables associated with MHSU among CAF members and Veterans., Methods: The current study used data from the 2018 CAF Members and Veterans Mental Health Follow-Up Survey (CAFVMHS). Model variables were selected a priori, and their respective associations with MHSU were estimated among (1) CAF members and (2) Veterans using separate multivariable logistic regression models., Results: Similar proportions of CAF members and Veterans reported past 12-month MHSU (26.9 vs. 27.5%, respectively). For both CAF members and Veterans, meeting criteria for at least one past 12-month MH disorder was associated with past 12-month MHSU [adjusted odds ratio (AOR) = 7.80, 95% confidence interval (CI) = 7.18-8.46; and AOR = 11.82, 95% CI: 11.07-12.61, respectively). Past-year suicide ideation, a history of sexual trauma, and endorsement of adverse childhood experiences were also significantly associated with MHSU among CAF members and Veterans., Significance: Similar to previous research, meeting screening criteria for a past 12-month MH disorder was strongly associated with MHSU among both samples. This study extends our existing knowledge about factors associated with MHSU among CAF members and Veterans, and offers direction for future research to increase MHSU., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kate St. Cyr, Aihua Liu, Rachel A. Plouffe, Maede S. Nouri, Callista A. Forchuk, Sonya G. Wanklyn, Brian M. Bird, Alyson L. Mahar Anthony Nazarov, J. Don Richar and Her Majesty the Queen in Right of Canada, as represented by Defence Research and Development Canada for the contribution of Deniz Fikretoglu.)

The Intrasexual Competition Scale (ICS) measures the extent to which individuals view their interaction with same-sex others in competitive terms. Although it is frequently used in studies investigating differences in mating behavior, the factor structure of the ICS has never been confirmed. Researchers have yet to use multiple-group confirmatory factor analysis to test whether the properties of the scale are equivalent between the sexes. In Study 1, we report on an investigation in which participants' responses to the ICS were submitted to exploratory factor analysis (EFA). In Study 2A, we compared the fit of one and two-factor models from the EFA as well as two additional models, using confirmatory factor analysis with an independent sample. The best fit was obtained by a two-factor solution, which reflected: (1) respondents' feelings of frustration when intrasexual competitors are better off (Inferiority Frustration), and (2) respondents' enjoyment of being better than intrasexual competitors (Superiority Enjoyment). This model achieved a high degree of measurement invariance. In Study 2B, we found the ICS had good concurrent validity via associations with sociosexuality, mating effort, and sexual behavior. Together, these analyses suggest that the ICS is a valid measure of intrasexually competitive attitudes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Attractiveness judgements influence desires to initiate and maintain romantic relationships. Testosterone also predicts relationship initiation and maintenance; such effects may be driven by the hormone's modulation of attractiveness judgements, but no studies have investigated causal (and situation-dependent) effects of the hormone on these judgements. Using a placebo-controlled cross-over design, our preregistered analyses revealed order- and relationship- dependent effects: single heterosexual men judged the women as more appealing when testosterone was administered first (and placebo second), but marginally less appealing when placebo was administered first (and testosterone second). In a more complex model incorporating the women's attractiveness (as rated by an independent set of observers), however, we show that testosterone increases the appeal of women -but this effect depends upon the men's relationship status and the women's attractiveness. In partnered men (n = 53) who tend to derogate attractive alternatives (by rating them as less appealing), testosterone countered this effect, boosting the appeal of these attractive alternatives. In single men (n = 53), conversely, testosterone increased the appeal of low-attractive women. These differential effects highlight the possibility of a newly discovered mechanism whereby testosterone promotes male sexual reproduction through different routes depending on relationship status, promoting partner up- rather than down-grading when partnered and reducing choosiness when single. Further, such effects were relatively rapid [within 85 (±5) minutes], suggesting a potential non-genomic mechanism of action., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Despite global efforts to rapidly distribute COVID-19 vaccines, early estimates suggested that 29-35% of the population were hesitant/unwilling to receive them. Countering such vaccine hesitancy is thus an important priority. Across two sets of online studies (total n  = 1584) conducted in the UK before (August-October 2020) and immediately after the first effective vaccine was publicly announced (November 10-19, 2020), brief exposure (<1 min) to vaccination memes boosted the potentially life-saving intention to vaccinate against COVID-19. These intention-boosting effects, however, weakened once a COVID-19 vaccine became a reality (i.e., after the announcement of a safe/effective vaccine), suggesting meme-based persuasion may be context-dependent. These findings thus represent preliminary evidence that naturally circulating memes may-under certain circumstances-influence public intentions to vaccinate, although more research regarding this context-specificity, as well as the potential psychological mechanisms through which memes act, is needed., Competing Interests: None., (© 2022 Published by Elsevier Ltd.)

Introduction: This manuscript presents a successful integration of multi-timepoint biomarker blood sampling (e.g., cytokines) in a conscious dog cardiovascular study using automated blood sampling via vascular access ports in telemetry instrumented dogs. In addition to determining plasma exposure of the test compound, the assessment of biomarkers of interest allows for more comprehensive preclinical evaluation on a traditional conscious dog cardiovascular (CV) telemetry study especially for immunology and immune-oncology molecules. This model system provides a rapid and efficient means to quickly gain understanding of potential effects on key cardiovascular parameters in large species that are commonly used for preclinical safety evaluations while collecting multiple blood samples for drug and cytokine analysis., Methods: Male beagle dogs were chronically implanted with telemetry devices (PhysioTel™ model D70-PCTP) and vascular access ports (SPMID-GRIDAC-5NC). BASi Culex-L automated blood sampling (ABS) (Bioanalytical Systems, Inc) system was used to collect blood samples at multiple time points for cytokine analysis. Four beagles received low-dose lipopolysaccharide solution (LPS) (0.1 and 0.5 μg/mL). The following cytokines were measured by Milliplex® map Canine Cytokine Magnetic Bead Panel: Interleukin (IL) 2, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, TNF-α, MCP-1, KC-like, GM-CSF, IFN gamma, and IP10., Results: Low dose LPS administration induced a pronounced dose-dependent, transient release of key inflammatory cytokines (IL-2, IL-6, IL-10, TNF-α, MCP-1, and KC-like). Cytokine responses were similar to other canine and human endotoxin models. LPS administration led to an increase in body temperature, heart rate, and mean arterial pressure, as well as a decrease in QTcV interval., Conclusion: Successful incorporation of cytokine analysis in telemetry instrumented dogs with vascular access ports allows for translational PK/PD modeling of both efficacy and safety of compounds in the immunology as well as the immune-oncology therapeutic areas designed to modulate the immune system. Remote collection of blood samples simultaneously with CV endpoints is a significant enhancement for assessment of biomarkers that are sensitive to animal handling and excitement associated with room disturbances which are obligatory with manual blood collection. Furthermore, implementing this approach has also refined our animal welfare procedure by reducing the handling during a study and thereby reducing stress (positive refinement 3R impact)., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: A successful integration of automated blood sampling (ABS) into the telemetry instrumented canine cardiovascular model is presented in this study. This combined model provides an efficient means to quickly gain understanding of potential effects on key cardiovascular parameters in dog while providing a complete Pharmacokinetic/Pharmacodynamic (PK/PD) profile for discovery compounds without handling artifacts, reducing the need for a separate pharmacokinetic study., Methods: Male beagle dogs were chronically implanted with telemetry devices (PhysioTel™ model D70-PCTP) and vascular access ports (SPMID-GRIDAC-5NC). BASi Culex-L automated blood sampling (Bioanalytical Systems, Inc) system was used to collect blood samples at multiple time points. A series of four use cases utilizing four different test compounds and analytical endpoints are described to illustrate some of the potential applications of the technique., Results: In the four presented use cases, automated blood sampling in telemetry instrumented dogs provides simultaneous cardiovascular (heart rate, arterial blood pressure, and left ventricular pressure), electrophysiological assessment (QTc, PR, and QRS intervals), body temperature, and animal activity, while collecting multiple blood samples for drug analysis., Conclusion: The combination of automated blood sampling with cardiovascular telemetry monitoring is a novel capability designed to support safety pharmacology cardiovascular assessment of discovery molecules. By combining telemetry and high-fidelity ABS, the model provides an enhanced PK/PD understanding of drug-induced hemodynamic and electrocardiographic effects of discovery compounds in conscious beagles in the same experimental session. Importantly, the model can reduce the need for a separate pharmacokinetic study (positive reduction 3R impact), reduces compound syntheses requirements, and shorten development timelines. Furthermore, implementation of this approach has also improved animal welfare by reducing the animal handling during a study, thereby reducing stress and associated data artifacts (positive refinement 3R impact)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Successful implementation of automated blood sampling (ABS) into a telemetry instrumented canine cardiovascular model provides simultaneous cardiovascular assessment of novel compounds while collecting multiple blood samples for analysis of drug level, cytokines, and biomarkers. Purpose-bred male Beagle dogs ( n = 36) were instrumented with a dual-pressure telemetry transmitter and vascular access port. Modifications to acclimation practices, surgical procedures, and housing were required for implementation of ABS in our established cardiovascular canine telemetry colony. These modifications have increased the use and reproducibility of the model by combining early pharmacokinetic and cardiovascular studies, thus achieving both refinement and reduction from a 3R perspective. In addition, the modified model can shorten timelines and reduce the compound requirement in early stages of drug development. This telemetry-ABS model provides an efficient means to quickly identify potential effects on key cardiovascular parameters in a large animal species and to obtain a more complete pharmacokinetic-pharmacodynamic profile for discovery compounds.

The Challenge Hypothesis (Wingfield et al., 1990) originally focused on adult male avian testosterone elevated in response to same-sex competition in reproductive contexts. The purpose of the present paper is to demonstrate how the Challenge Hypothesis has shaped ideas about human life histories. We conduct a citation analysis, drawing upon 400 Google Scholar citations in the human literature to identify patterns in this body of scholarship. We cover key factors, such as context and personality traits, that help explain variable testosterone responses such as winning/losing to adult competitive behavior. Findings from studies on courtship and sexual behavior indicate some variation in testosterone responses depending on factors such as motivation. A large body of research indicates that male testosterone levels are often lower in contexts of long-term committed partnerships and nurturant fathering and aligned with variation in male mating and parenting effort. As the Challenge Hypothesis is extended across the life course, DHEA and androstenedione (rather than testosterone) appear more responsive to juvenile male competitive behavior, and during reproductive senescence, baseline male testosterone levels decrease just as male life history allocations show decreased mating effort. We discuss how research on testosterone administration, particularly in older men, provides causal insight into effects of testosterone in humans, and how this "natural experiment" can be viewed in light of the Challenge Hypothesis. We synthesize central concepts and findings, such as an expanded array of costs of testosterone that inform life history tradeoffs between maintenance and reproductive effort, and we conclude with directions for future research., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Testosterone is often considered a critical regulator of aggressive behaviour. There is castration/replacement evidence that testosterone indeed drives aggression in some species, but causal evidence in humans is generally lacking and/or-for the few studies that have pharmacologically manipulated testosterone concentrations-inconsistent. More often researchers have examined differences in baseline testosterone concentrations between groups known to differ in aggressiveness (e.g., violent vs non-violent criminals) or within a given sample using a correlational approach. Nevertheless, testosterone is not static but instead fluctuates in response to cues of challenge in the environment, and these challenge-induced fluctuations may more strongly regulate situation-specific aggressive behaviour. Here, we quantitatively summarize literature from all three approaches (baseline, change, and manipulation), providing the most comprehensive meta-analysis of these testosterone-aggression associations/effects in humans to date. Baseline testosterone shared a weak but significant association with aggression (r = 0.054, 95% CIs [0.028, 0.080]), an effect that was stronger and significant in men (r = 0.071, 95% CIs [0.041, 0.101]), but not women (r = 0.002, 95% CIs [-0.041, 0.044]). Changes in T were positively correlated with aggression (r = 0.108, 95% CIs [0.041, 0.174]), an effect that was also stronger and significant in men (r = 0.162, 95% CIs [0.076, 0.246]), but not women (r = 0.010, 95% CIs [-0.090, 0.109]). The causal effects of testosterone on human aggression were weaker yet, and not statistically significant (r = 0.046, 95% CIs [-0.015, 0.108]). We discuss the multiple moderators identified here (e.g., offender status of samples, sex) and elsewhere that may explain these generally weak effects. We also offer suggestions regarding methodology and sample sizes to best capture these associations in future work., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative differentiates torsadogenic risk of 28 drugs affecting ventricular repolarization based on multiple in vitro human derived ionic currents. However, a standardized prospective assessment of the electrophysiologic effects of these drugs in an integrated in vivo preclinical cardiovascular model is lacking. This study questioned whether QTc interval prolongation in a preclinical in vivo model could detect clinically reported QTc prolongation and assign torsadogenic risk for ten CiPA drugs., Methods: An acute intravenous administered ascending dose anesthetized dog cardiovascular model was used to assess QTc prolongation along with other electrocardiographic (PR, QRS intervals) and hemodynamic (heart rate, blood pressures, left ventricular contractility) parameters at plasma concentrations spanning and exceeding clinical exposures. hERG current block potency was characterized using IC 50 values from automated patch clamp., Results: All eight drugs eliciting clinical QTc prolongation also delayed repolarization in anesthetized dogs at plasma concentrations within four-fold clinical exposures. In vitro QTc safety margins (defined based on clinical C max values/plasma concentrations eliciting statistically significant QTc prolongation in dogs) were lower for high vs intermediate torsadogenic risk drugs. In comparison, hERG IC 10 values represented as total drug concentrations were better predictors of preclinical QTc prolongation than hERG IC 50 values., Conclusion: There was good concordance for QTc prolongation in the anesthetized dog model and clinical torsadogenic risk assignment. QTc assessment in the anesthetized dog remains a valuable part of a more comprehensive preclinical integrated risk assessment for delayed repolarization and torsadogenic risk as part of a global cardiovascular evaluation., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Like other animals, humans are sensitive to facial cues of threat. Recent evidence suggests that we use this information to dynamically calibrate competitive decision-making over resources, ceding more to high-threat individuals (who appear more willing/able to retaliate) and keeping more from low-threat individuals. Little is known, however, about the biological factors that support such threat assessment and decision-making systems. In a pre-registered, double-blind, placebo-controlled, cross-over testosterone administration study ( n = 118 men), we show for the first time that testosterone reduces the effects of threat on decision-making: participants ceded more resources to high-threat (versus low-threat) individuals (replicating the 'threat premium'), but this effect was blunted by testosterone, which selectively reduced the amount of resources ceded to those highest in threat. Thus, our findings suggest that testosterone influences competitive decision-making by recalibrating the integration of threat into the decision-making process.

Little is known about the neurobiological pathways through which testosterone promotes aggression or about the people in whom this effect is observed. Using a psychopharmacogenetic approach, we found that testosterone increases aggression in men ( N = 308) with select personality profiles and that these effects are further enhanced among those with fewer cytosine-adenine-guanine (CAG) repeats in exon 1 of the androgen receptor (AR) gene, a polymorphism associated with increased AR efficiency. Testosterone's effects were rapid (~30 min after administration) and mediated, in part, by subjective reward associated with aggression. Testosterone thus appears to promote human aggression through an AR-related mechanism and to have stronger effects in men with the select personality profiles because it more strongly upregulates the subjective pleasure they derive from aggression. Given other evidence that testosterone regulates reward through dopaminergic pathways, and that the sensitivity of such pathways is enhanced among individuals with the personality profiles we identified, our findings may also implicate dopaminergic processes in testosterone's heterogeneous effects on aggression.

The social heuristic hypothesis posits that human cooperation is an intuitive response that is expressed especially under conditions of time-constraint. Conversely, it proposes that for individuals given an opportunity for reflection, cooperation is more likely to be curtailed by an optimizing process calibrated to maximize individual benefit in a given situation. Notably, the steroid hormone testosterone has also been implicated in intuitive decision-making, including both prosocial and anti-social behaviors, with effects strongest in men with particular dispositional characteristics. This raises the possibility that increased testosterone may augment the effects predicted by the social heuristic hypothesis, particularly among men higher in specific dispositional characteristics (dominance, impulsivity, independent self-construal: high risk for testosterone-induced antisocial behavior). Here, in a testosterone administration study with a relatively large sample of men (N = 400), we test this possibility in a double-blind, placebo-controlled paradigm, with men randomly assigned to play a one-shot public goods game either under time-pressure (forced intuition) or with a time delay (forced reflection). Results revealed that within the placebo group, time-pressure (versus forced delay) increased cooperation among low risk men, but decreased cooperation among high risk men. Testosterone further moderated this pattern by abolishing the time-pressure effect in low risk men and-in high risk men-reversing the effect by selectively reducing offers (compared to placebo) under forced delay. This is the first evidence that testosterone and personality can interact with time-pressure and delay to predict human cooperation.

Topic: The Brief Services psychotherapy paradigm has evolved to produce cost-effective and clinically significant outcomes in children's mental health. Though its clinical evaluation is still in its infancy, it has been utilized to a much lesser degree with autism spectrum disorders, which typically require a longer-term approach to psychotherapy treatment., Purpose: The current paper introduces a novel, four-session intervention that aims to decrease anxiety experienced by clients presenting with high-functioning autism. Externalizing Metaphors Therapy is based upon the externalization of problems, transformation of metaphoric imagery, shifting of maladaptive emotional schemas, and the generalization of problems. A case study is utilized to visually aid in the understanding of this new treatment intervention., Source: A composite literature review was conducted with regards to significant works in Narrative Therapy, treatment interventions for anxiety and high functioning autism, evidence-based treatments for anxiety, and practice based approaches in psychotherapy. Works were selected based on their relevance to the research filed of anxiety and autism., Conclusions: This clinical research challenges the children's mental health field in addressing anxiety and high-functioning autism from a brief framework. Further clinical research is needed to clinically evaluate the current model., (© 2018 Wiley Periodicals, Inc.)

Background: Recent evidence suggests that psychedelic use predicts reduced perpetration of intimate partner violence among men involved in the criminal justice system. However, the extent to which this association generalizes to community samples has not been examined, and potential mechanisms underlying this association have not been directly explored., Aims: The present study examined the association between lifetime psychedelic use and intimate partner violence among a community sample of men and women. The study also tested the extent to which the associations were mediated by improved emotion regulation., Methods: We surveyed 1266 community members aged 16-70 (mean age=22.78, standard deviation =7.71) using an online questionnaire that queried substance use, emotional regulation, and intimate partner violence. Respondents were coded as psychedelic users if they reported one or more instance of using lysergic acid diethylamide and/or psilocybin mushrooms in their lifetime. Results/outcomes: Males reporting any experience using lysergic acid diethylamide and/or psilocybin mushrooms had decreased odds of perpetrating physical violence against their current partner (odds ratio=0.42, p<0.05). Furthermore, our analyses revealed that male psychedelic users reported better emotion regulation when compared to males with no history of psychedelic use. Better emotion regulation mediated the relationship between psychedelic use and lower perpetration of intimate partner violence. This relationship did not extend to females within our sample., Conclusions/interpretation: These findings extend prior research showing a negative relationship between psychedelic use and intimate partner violence, and highlight the potential role of emotion regulation in this association.

The zeitgeist for brief services psychotherapy efficacy is well underway within the individual and family therapy treatment modalities. However, this paradigm shift, to produce clinically significant mental health outcomes in a much shorter time, has evolved to a much lesser degree within the treatment group format. Longer-term treatment group protocols typically do not match treatment-seeking behaviors with high dropout rates for clients. The current authors describe a structured, four-session treatment protocol that integrates the tenets of Externalizing Metaphors Therapy (EMT) with Innovative Moments (IMs) in addressing anxiety for children and youth. EMT is based upon the externalization of problems, transformation of metaphoric imagery, and the shifting of underlying maladaptive emotional schemas. It is suggested that treatment outcomes are enhanced through the integration of three IMs between-session exercises.

Previous research has linked the facial width-to-height ratio (FWHR) to a host of psychological and behavioral characteristics, primarily in men. In two studies, we examined novel links between FWHR and sex drive. In Study 1, a sample of 145 undergraduate students revealed that FWHR positively predicted sex drive. There were no significant FWHR × sex interactions, suggesting that FWHR is linked to sexuality among both men and women. Study 2 replicated and extended these findings in a sample of 314 students collected from a different Canadian city, which again demonstrated links between the FWHR and sex drive (also in both men and women), as well as sociosexuality and intended infidelity (men only). Internal meta-analytic results confirm the link between FWHR and sex drive among both men and women. These results suggest that FWHR may be an important morphological index of human sexuality.

Rapid testosterone fluctuations in response to social stimuli are observed across a wide range of species, and the highly conserved nature of these fluctuations suggests an adaptive function. This paper reviews the current literature on testosterone reactivity, primarily in human males, and illustrates how life-history theory provides an adequate theoretical framework to interpret findings. The review is structured around supporting evidence suggesting that situations implicated in mating effort either directly (e.g., interactions with a mate) or indirectly (e.g., intrasexual competition) are generally associated with a brief elevation of testosterone, while situations implicated in parenting effort (e.g., nurturant interactions with offspring) are generally associated with a decline in testosterone. Further, we discuss how these fluctuations in testosterone have been linked to future behaviors, and how situational, motivational, and physiological variables moderate the interplay between social stimuli, testosterone reactivity, and behavior. Supporting the notion that testosterone can play a causal role in modulating behavior in response to social stimuli, we also summarize recent single administration studies examining the effects of testosterone on physiology, neurobiology, and behavior. A conceptual model provides links between supported findings, and hypothesized pathways requiring future testing., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Although traditional wisdom suggests that baseline levels of testosterone (T) promote aggressive behavior, decades of research have produced findings that have been largely weak and inconsistent. However, more recent experimental work suggests that exogenous administration of T rapidly potentiates amygdala and hypothalamus responses to angry facial expressions. Notably, these brain regions are rich in androgen receptors and play a key role in modulating aggressive behavior in animal models., Methods: The present experiment extends this work by examining whether acutely increasing T potentiates aggressive behavior in men. In a double-blind, placebo-controlled, between-subject design, healthy adult men (n = 121) were administered either T or placebo, and subsequently engaged in a well-validated decision-making game that measures aggressive behavior in response to social provocation. In light of prior correlational research, we also assessed the extent to which T's effects on aggressive behavior would depend on variability in trait dominance and/or trait self-control., Results: Exogenous T on its own did not modulate aggressive behavior. However, T's effects on aggression were strongly influenced by variation in trait dominance and trait self-control. Specifically, T caused an increase in aggressive behavior, but only among men scoring relatively high in trait dominance or low in trait self-control., Conclusions: These findings are the first to demonstrate that T can rapidly (within 60 minutes) potentiate aggressive behavior, but only among men with dominant or impulsive personality styles., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

A contribution to a special issue on Hormones and Human Competition. Since Archer's (2006) influential meta-analysis, there has been a major increase in the number of studies investigating the effect of competition outcome on testosterone reactivity patterns in humans. Despite this increased research output, there remains debate as to whether competition outcome modulates testosterone concentrations. The present paper examines this question using a meta-analytic approach including papers published over the last 35years. Moreover, it provides the first meta-analytic estimate of the effect of competition outcome on testosterone concentrations in women. Results from a meta-analysis involving 60 effect sizes and >2500 participants indicated that winners of a competition demonstrated a larger increase in testosterone concentrations relative to losers (D=0.20)-an effect that was highly heterogeneous. This 'winner-loser' effect was most robust in studies conducted outside the lab (e.g., in sport venues) (D=0.43); for studies conducted in the lab, the effect of competition outcome on testosterone reactivity patterns was relatively weak (D=0.08), and only found in studies of men (D=0.15; in women: D=-0.04). Further, the 'winner-loser' effect was stronger among studies in which pre-competition testosterone was sampled earlier than (D=0.38, after trim and fill correction) rather than within (D=0.09) 10min of the start of the competition. Therefore, these results also provide important insight regarding study design and methodology, and will be a valuable resource for researchers conducting subsequent studies on the 'winner loser' effect., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Correlational research suggests that men show greater attraction to feminine female faces when their testosterone (T) levels are high. Men's preferences for feminine faces also seem to vary as a function of relationship context (short versus long-term). However, the relationship between T and preferences for female facial femininity has yet to be tested experimentally. In the current paper, we report the results of two experiments examining the causal role of T in modulating preferences for facial femininity across both short and long-term mating contexts. Results of Experiment 1 (within-subject design, n=24) showed that participants significantly preferred feminized versus masculinized versions of women's faces. Further, participants showed a stronger preference for feminine faces in the short versus the long-term context after they received T, but not after they received placebo. Post-hoc analyses suggested that this effect was driven by a lower preference for feminine faces in the long-term context when on T relative to placebo, and this effect was found exclusively for men who received placebo on the first day of testing, and T on the second day of testing (i.e., Order x Drug x Mating context interaction). In Experiment 2 (between-subject design, n=93), men demonstrated a significant preference for feminized female faces in the short versus the long-term context after T, but not after placebo administration. Collectively, these findings provide the first causal evidence that T modulates men's preferences for facial femininity as a function of mating context., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Correlational research has linked low mate value (MV)--one's worth as a mating partner to members of the opposite sex--with aggression in men. In 2 experiments, we examined the effects of self-perceived MV on men's reported willingness to aggress directly toward a hypothetical mate poacher (Experiment 1, N = 60) and observable aggression toward a same-sex rival in a laboratory paradigm (Experiment 2, N = 54). In both experiments, the roles of narcissism in moderating the effect of MV condition on subsequent aggression were examined. Results of Experiment 1 indicated that men randomly assigned to the low MV condition were significantly more willing to report aggressive intention than men in the high MV condition. This relationship was moderated by narcissism such that men in the low MV condition who were also high in narcissism were the most likely to aggress. Results of Experiment 2 similarly showed that men in the low MV condition relative to the high MV condition aggressed more toward a same-sex rival when they were high in narcissism. These findings support evolutionary hypotheses surrounding the importance of self-perceived MV in directing aggressive mating efforts, as situated in the framework of threatened egotism.

Men's testosterone is associated with several constructs that are linked to dominance rank, such as risk-taking, mating success, and aggression. However, no study has directly tested the relationship between men's self-perceived dominance and testosterone using an experimental design. We employed a within-subjects, double-blind, placebo-controlled paradigm to assess whether testosterone influences men's self-perceived dominance. Exogenous testosterone or a placebo was administered to healthy adult men and self-perceptions of physical dominance were subsequently assessed by having participants select what they believed to be their true face from an array of images digitally manipulated in masculinity. Men picked a more masculine version of their own face after testosterone versus placebo--an effect that was particularly pronounced among men with relatively low baseline testosterone. These findings indicate that a single administration of testosterone can rapidly modulate men's perceptions of their own physical dominance, which may explain links between testosterone and dominance-related behaviors., (Copyright © 2015 Elsevier Ltd. All rights reserved.)