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Hypertension is the leading cause of stroke, heart failure, and ischemic heart disease. One of the key regulators of blood pressure is the renin-angiotensin aldosterone system (RAAS). Olmesartan medoxomil, an angiotensin receptor blocker (ARB), counteracts some of the primary effects of the RAAS by selectively and irreversibly binding to the type 1 angiotensin II receptor (AT1-R). The pharmacokinetic profi le of this ARB allows for the convenience of one a day dosing. The pharmacodynamic profi le of olmesartan is favorable because it is neither metabolized by, induces, nor inhibits the CYP450 isozyme system. The metabolism of the prodrug to the active form occurs in the gut by the enzyme arylesterase. No further metabolism and a lack of interaction with the CYP450 isozyme system leads to very few drug interactions with olmesartan medoxomil. Numerous studies have been conducted to evaluate the effi cacy, safety, and tolerability of olmesartan medoxomil. Studies have been conducted to compare olmesartan medoxomil to other angiotensin receptor blockers. The effi cacy of olmesartan medoxomil has been compared to other classes of antihypertensive agents. Results of all trials have proven non-inferiority of olmesartan medoxomil to other antihypertensive agents; some studies have shown superior blood pressure control provided by olmesartan medoxomil when starting dosages are evaluated. Overall, olmesartan medoxomil has the potential to facilitate the achievement of blood pressure goals, enhance compliance with a once daily dosing regimen, and is associated with minimal side effects. Olmesartan medoxomil has been proven to be a safe and effective antihypertensive drug when compared to other ARBs and other antihypertensive agents. [ABSTRACT FROM AUTHOR]

BACKGROUND: Blood center labor benchmarking data may be helpful to optimize staffing and to establish productivity targets. Data were gathered and labor productivity was analyzed among blood donor centers of different sizes collecting different product mixes. STUDY DESIGN AND METHODS: Blood collection volumes and blood center labor data were obtained from eight blood centers: six regional centers, one mobile collection operation, and our hospital-affiliated center. A total of 2004 annual whole-blood (WB) collections and apheresis platelet (PLT) collections were captured. Full-time equivalents (FTEs) associated with blood collection operations were captured. With these data total unit (WB + PLT) collection rates per FTE were calculated. To compare value associated with each center's total unit collections, an indexed monetary value was assigned to WB and PLT and the value was calculated. RESULTS: Despite a 12-fold range in the size of operations, there was a strong correlation between total annual products collected and number of FTEs (mean 460 +/- 39 units/FTE). As expected, centers that collected relatively more PLTs had higher value per total unit collected. Surprisingly, however, there was no relationship between proportion of PLTs collected and total units collected per FTE. Centers collecting proportionately more PLTs therefore had higher value per FTE. CONCLUSION: A benchmark scale of labor productivity among blood donor centers of different sizes and product mixes was established. Product mix is not a major determinant of total unit collections per FTE but is an important determinant of value per FTE. Correlating collection targets with benchmark data from this survey may help determine optimal blood center labor allocation strategies. [ABSTRACT FROM AUTHOR]

We investigated whether cement pastes are a possible source of ecotoxicologically potent substances. For this purpose, leaching according to DIN EN 16637-2 was performed on portland cement pastes as well as blast furnace slag cement with and without an air entraining agent (AEA). The AEA, consisting of wood rosin and resin, contained the stabiliser drometrizole and the biocide octylisothiazolinone (OIT), which was confirmed by our non-target screening (NTS). Our ecotoxicological studies (Daphnia magna, Aliivibrio fischeri and Desmodesmus subspicatus) of the pure cement eluates showed no effects at all. In these samples, it was possible to attribute up to 85 % of the dissolved organic carbon (DOC) to acetate, formate and diethylene glycol (DiEG). Eluates from cement pastes with AEA contained up to 70 μg/L octylisothiazolinone (OIT), and no drometrizole was found. Around 90 % of the total OIT release happened within the first 6 h. It was possible to attribute the observed ecotoxicological effects mainly to the OIT concentrations. Additional leaching with elevated sulphate concentrations (800 mg/L) did not influence the release of DOC and OIT or increase the ecotoxicological effects. As a consequence, we advise curing the cement paste for 24 h prior to use, as this largely avoids the release of OIT and the observed ecotoxicological effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Oxytocin (OXT) and its homologs are known to regulate parental care in vertebrates, but it is unknown what role these neuropeptides may play in the evolutionary loss of care. Here, we compared two recently diverged ecotypes of threespine stickleback (Gasterosteus aculeatus) that differ in parental care. Males of the common ecotype provide obligate, uniparental care to their offspring, whereas males of the white ecotype abandon their offspring after fertilization. To test if OXT plays a role in the loss of care, we manipulated OXT in males of both ecotypes via intraperitoneal injection of a vehicle control, OXT single- or double-dose, or an OXT antagonist. We observed the behavioral response to injection at two time points for commons (0 and 4 days post-fertilization (dpf)) and one for whites (0 dpf). Our results suggest that, in commons, OXT promotes the onset of care but not its maintenance. Notably, commons that ultimately terminated their clutches did not respond to OXT at 0 dpf, which may have contributed to their failure to transition to a state of care. Whites responded to OXT manipulation in a different manner than commons, suggesting that the loss of care in whites is not due to a loss of sensitivity to OXT, or insufficient levels of OXT ligand, but rather an evolutionary change to the underlying parental circuit that OXT is acting on. These results provide evidence that ancient hormonal systems like OXT can contribute to losses of care over multiple timescales., (Copyright © 2024. Published by Elsevier Inc.)

Purpose of Review: Members of a technical panel representing Australia, Canada, New Zealand, the UK, and the US collaborated to develop surveys designed to provide military leaders with information to guide decisions early in the COVID-19 pandemic. The goal of this paper is to provide an overview of this collaboration and a review of findings from the resulting body of work., Recent Findings: While surveys pointed to relatively favorable mental health and perceptions of leadership among military personnel early in the pandemic, these observations did not reflect the experiences of personnel deployed in COVID-19 response operations, nor were these observations reflective of later stages of the pandemic. Establishing and leveraging networks that enable the rapid development of employee surveys and sharing of results can serve as a pathway for empowering military leaders in times of crisis. Organizational support and leadership decisions are especially critical for maintaining well-being among personnel during crises., (© 2024. His Majesty the King in Right of Canada as represented by the Minister of National Defence. Parts of this work were authored by US Federal Government authors and are not under copyright protection in the US; foreign copyright protection may apply.)

Eco-evolutionary experiments are typically conducted in semi-unnatural controlled settings, such as mesocosms; yet inferences about how evolution and ecology interact in the real world would surely benefit from experiments in natural uncontrolled settings. Opportunities for such experiments are rare but do arise in the context of restoration ecology-where different "types" of a given species can be introduced into different "replicate" locations. Designing such experiments requires wrestling with consequential questions. (Q1) Which specific "types" of a focal species should be introduced to the restoration location? (Q2) How many sources of each type should be used-and should they be mixed together? (Q3) Which specific source populations should be used? (Q4) Which type(s) or population(s) should be introduced into which restoration sites? We recently grappled with these questions when designing an eco-evolutionary experiment with threespine stickleback ( Gasterosteus aculeatus ) introduced into nine small lakes and ponds on the Kenai Peninsula in Alaska that required restoration. After considering the options at length, we decided to use benthic versus limnetic ecotypes (Q1) to create a mixed group of colonists from four source populations of each ecotype (Q2), where ecotypes were identified based on trophic morphology (Q3), and were then introduced into nine restoration lakes scaled by lake size (Q4). We hope that outlining the alternatives and resulting choices will make the rationales clear for future studies leveraging our experiment, while also proving useful for investigators considering similar experiments in the future., Competing Interests: The authors have no conflict of interest to declare., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch, and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here, we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing. We reveal five distinct clusters of ALS neurons (ALS1-5) and document their laminar distribution in the spinal cord using in situ hybridization. We identify three clusters of neurons located predominantly in laminae I-III of the dorsal horn (ALS1-3) and two clusters with cell bodies located in deeper laminae (ALS4 and ALS5). Our findings reveal the transcriptional logic that underlies ALS neuronal diversity in the adult mouse and uncover the molecular identity of two previously identified classes of projection neurons. We also show that these molecular signatures can be used to target groups of ALS neurons using retrograde viral tracing. Overall, our findings provide a valuable resource for studying somatosensory biology and targeting subclasses of ALS neurons., Competing Interests: Competing interests statement:The authors declare no competing interest.

The masking of specific effects in in vitro assays by cytotoxicity is a commonly known phenomenon. This may result in a partial or complete loss of effect signals. For common in vitro assays, approaches for identifying and quantifying cytotoxic masking are partly available. However, a quantification of cytotoxicity-affected signals is not possible. As an alternative, planar bioassays that combine high-performance thin layer chromatography with in vitro assays, such as the planar yeast estrogen screen (p-YES), might allow for a quantification of cytotoxically affected signals. Affected signals form a typical ring structure with a supressed or completely lacking centre that results in a double peak chromatogram. This study investigates whether these double peaks can be used for fitting a peak function to extrapolate the theoretical, unaffected signals. The precision of the modelling was evaluated for four individual peak functions, using 42 ideal, undistorted peaks from estrogenic model compounds in the p-YES. Modelled ED 50 -values from bisphenol A (BPA) experiments with cytotoxically disturbed signals were 13 times higher than for the apparent data without compensation for cytotoxicity (320 ± 63 ng versus 24 ± 17 ng). This finding has a high relevance for the modelling of mixture effects according to concentration addition that requires unaffected, complete dose-response relationships. Finally, we applied the approach to results of a p-YES assay on leachate samples of an elastomer material used in water engineering. In summary, the fitting approach enables the quantitative evaluation of cytotoxically affected signals in planar in vitro assays and also has applications for other fields of chemical analysis like distorted chromatography signals., (© 2024. The Author(s).)

AbstractThe mechanisms underlying the divergence of reproductive strategies between closely related species are still poorly understood. Additionally, it is unclear which selective factors drive the evolution of reproductive behavioral variation and how these traits coevolve, particularly during early divergence. To address these questions, we quantified behavioral differences in a recently diverged pair of Nova Scotian three-spined stickleback ( Gasterosteus aculeatus ) populations, which vary in parental care, with one population displaying paternal care and the other lacking this. We compared both populations, and a full reciprocal F 1 hybrid cross, across four major reproductive stages: territoriality, nesting, courtship, and parenting. We identified significant divergence in a suite of heritable behaviors. Importantly, F 1 hybrids exhibited a mix of behavioral patterns, some of which suggest sex linkage. This system offers fresh insights into the coevolutionary dynamics of reproductive behaviors during early divergence and offers support for the hypothesis that coevolutionary feedback between sexual selection and parental care can drive rapid evolution of reproductive strategies.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic disrupted U.S. Military operations and potentially compounded the risk for adverse mental health outcomes by layering unique occupational stress on top of general restrictions, fears, and concerns. The objective of the current study was to characterize the prevalence of COVID-19 concerns and information needs, demographic disparities in these outcomes, and the degree to which COVID-19 concerns and information needs were associated with heightened risk for adverse mental health outcomes among U.S. Army soldiers., Materials and Methods: Command-directed anonymous surveys were administered electronically to U.S. soldiers assigned to one of three regional commands in the Northwest United States, Europe, and Asia-Pacific Region. Surveys were administered in May to June 2020 to complete (time 1: n = 21,294) and again in December 2020 to January 2021 (time 2: n = 10,861). Only active duty or active reservists/national guard were eligible to participate. Members from other branches of service were also not eligible., Results: Highly prevalent COVID-19 concerns included the inability to spend time with friends/family, social activities, and changing rules, regulations, and guidance related to COVID-19. Some information needs were endorsed by one quarter or more soldiers at both time points, including stress management/coping, travel, how to protect oneself, and maintaining mission readiness. COVID-19 concerns and information needs were most prevalent among non-White soldiers. Concerns and information needs did not decline overall between the assessments. Finally, COVID-19 concerns were associated with greater risk of multiple adverse mental health outcomes at both time points., Conclusions: COVID-19 concerns and information needs were prevalent and showed little evidence of decrement over the course of the first 6 months of the pandemic. COVID-19 concerns were consistently associated with adverse mental health outcomes. These data highlight two targets and potential demographic subgroups such that local leadership and Army medicine and public health enterprises can be better prepared to monitor and address to maintain force health and readiness in the face of possible future biomedical threats., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Animals in nature are constantly managing multiple demands, and decisions about how to adjust behavior in response to ecologically relevant demands is critical for fitness. Evidence for behavioral correlations across functional contexts (behavioral syndromes) and growing appreciation for shared proximate substrates of behavior prompts novel questions about the existence of distinct neural, molecular, and genetic mechanisms involved in decision-making. Those proximate mechanisms are likely to be an important target of selection, but little is known about how they evolve, their evolutionary history, or where they harbor genetic variation. Herein I provide a conceptual framework for understanding the evolution of mechanisms for decision-making, highlighting insights on decision-making in humans and model organisms, and sketch an emerging synthesis., Competing Interests: Declaration of interests No conflicts of interest are declared., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Parental care is a critical determinant of offspring fitness, and parents adjust their care in response to ecological challenges, including predation risk. The experiences of both mothers and fathers can influence phenotypes of future generations (transgenerational plasticity). If it is adaptive for parents to alter parental care in response to predation risk, then we expect F 1 and F 2 offspring who receive transgenerational cues of predation risk to shift their parental care behaviour if these ancestral cues reliably predict a similarly risky environment as their F 0 parents. Here, we used three-spined sticklebacks ( Gasterosteus aculeatus ) to understand how paternal exposure to predation risk prior to mating alters reproductive traits and parental care behaviour in unexposed F 1 sons and F 2 grandsons. Sons of predator-exposed fathers took more attempts to mate than sons of control fathers. F 1 sons and F 2 grandsons with two (maternal and paternal) predator-exposed grandfathers shifted their paternal care (fanning) behaviour in strikingly similar ways: they fanned less initially, but fanned more near egg hatching. This shift in fanning behaviour matches shifts observed in response to direct exposure to predation risk, suggesting a highly conserved response to pre-fertilization predator exposure that persists from the F 0 to the F 1 and F 2 generations.

Animals frequently make adaptive decisions about what to prioritize when faced with multiple, competing demands simultaneously. However, the proximate mechanisms of decision-making in the face of competing demands are not well understood. We explored this question using brain transcriptomics in a classic model system: threespined sticklebacks, where males face conflict between courtship and territorial defence. We characterized the behaviour and brain gene expression profiles of males confronted by a trade-off between courtship and territorial defence by comparing them to males not confronted by this trade-off. When faced with the trade-off, males behaviourally prioritized defence over courtship, and this decision was reflected in their brain gene expression profiles. A distinct set of genes and biological processes was recruited in the brain when males faced a trade-off and these responses were largely non-overlapping across two brain regions. Combined, these results raise new questions about the interplay between the neural and molecular mechanisms involved in decision-making.

Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express neuropeptide Y (NPY), either permanently or during development, suppress mechanical itch, with no effect on pain. Here, we investigate the role of interneurons that continue to express NPY (NPY-INs) in the adult mouse spinal cord. We find that chemogenetic activation of NPY-INs reduces behaviours associated with acute pain and pruritogen-evoked itch, whereas silencing them causes exaggerated itch responses that depend on cells expressing the gastrin-releasing peptide receptor. As predicted by our previous studies, silencing of another population of inhibitory interneurons (those expressing dynorphin) also increases itch, but to a lesser extent. Importantly, NPY-IN activation also reduces behavioural signs of inflammatory and neuropathic pain. These results demonstrate that NPY-INs gate pain and itch transmission at the spinal level, and therefore represent a potential treatment target for pathological pain and itch., Competing Interests: KB, EP, MG, AD, AC, AB, EJ, AC, MW, DH, GW, JR, AT No competing interests declared, (© 2023, Boyle, Polgar, Gutierrez-Mecinas et al.)

Introduction: American Indian and Alaska Native (AI/AN) individuals in the USA experience higher rates of mental illness and preventable death than the general population. Published research demonstrates that AI/AN veterans experience similar disparities to other minorities compared to non-minority veterans; few studies, however, have assessed mental health outcomes in AI/AN active duty military members. The objective of this study was to determine differences in depression, anxiety, hazardous alcohol consumption, and suicidal ideation among AI/AN soldiers compared to soldiers of other races during the Coronavirus Disease 2019 (COVID-19) pandemic., Materials and Methods: We conducted repeated cross-sectional electronic surveys to assess the mental health of active duty and activated reserve U.S. Army soldiers within three commands in the Northwestern Continental United States , Republic of Korea, and Germany during May-June 2020 (T1) and December 2020-January 2021 (T2). The primary exposure of interest in the present analysis was race and ethnicity, and the primary outcomes were probable depression with functional impairment (subsequently "depression"), probable anxiety with functional impairment (subsequently "anxiety"), hazardous alcohol use, and suicidal ideation. Multivariable logistic regression models were used to determine the association between demographics and COVID-19 concerns on mental health outcomes for each time point., Results: A total of 21,293 participants responded to the survey at T1 (participation rate = 28.0%), and 10,861 participants responded to the survey at T2 (participation rate = 14.7%). In the multivariable model, AI/AN participants had 1.36 higher adjusted odds of suicidal ideation (95% CI: 1.02-1.82) at T1 and 1.50 greater adjusted odds of suicidal ideation at T2 (95% CI: 1.00-2.24), when compared to non-Hispanic White participants. During T1, there was no significant difference detected between AI/AN and non-Hispanic White participants for anxiety (adjusted odds ratio: 1.21; 95% CI: 0.91-1.60) (Table IV). However, AI/AN participants had 1.82 greater adjusted odds of anxiety when compared to non-Hispanic White participants at T2 (adjusted odds ratio: 1.82; 95% CI: 1.29-2.57). There were no significant differences detected between AI/AN participants and non-Hispanic White participants in multivariable models for either depression or hazardous alcohol use at both time points., Conclusions: Although we hypothesized that all adverse mental health outcomes would be higher for AI/AN service members at both time points, there were no significant differences at each of the time points analyzed for most of the outcomes analyzed. However, differences in suicidal ideation were found at both time points. Analyses and proposed interventions should account for diversity and heterogeneity of AI/AN populations., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch., (© 2023. The Author(s).)

A molecular signature found in the brains of monogamous prairie voles begins to decay after prolonged separation from their partner., Competing Interests: AB No competing interests declared, (© 2023, Bell.)

Excitatory interneurons in the superficial dorsal horn (SDH) are heterogeneous, and include a class known as vertical cells, which convey information to lamina I projection neurons. We recently used pro-NPFF antibody to reveal a discrete population of excitatory interneurons that express neuropeptide FF (NPFF). Here, we generated a new mouse line (NPFF Cre ) in which Cre is knocked into the Npff locus, and used Cre-dependent viruses and reporter mice to characterise NPFF cell properties. Both viral and reporter strategies labelled many cells in the SDH, and captured most pro-NPFF-immunoreactive neurons (75-80%). However, the majority of labelled cells lacked pro-NPFF, and we found considerable overlap with a population of neurons that express the gastrin-releasing peptide receptor (GRPR). Morphological reconstruction revealed that most pro-NPFF-containing neurons were vertical cells, but these differed from GRPR neurons (which are also vertical cells) in having a far higher dendritic spine density. Electrophysiological recording showed that NPFF cells also differed from GRPR cells in having a higher frequency of miniature EPSCs, being more electrically excitable and responding to a NPY Y1 receptor agonist. Together, these findings indicate that there are at least two distinct classes of vertical cells, which may have differing roles in somatosensory processing., (© 2023. The Author(s).)

Introduction: The objective of this study is to characterize the associations between demographic, attitudinal, and leadership factors with COVID-19 vaccination rates, vaccination intentions among those not vaccinated, and attitudes about vaccination safety, effectiveness, and importance., Methods: A serial cross-sectional anonymous online survey was administered to soldiers at two large U.S. Army Divisions located in the Southwestern region of the U.S. at two different time points (April-May 2021 [Time 1; T1] N = 24,629; July-August 2021 [Time 2; T2] N = 21,116). Binary logistic regressions were used to assess demographic and attitudinal predictors of vaccination receipt and vaccination intent. Multinomial logistic regressions were used to assess demographic and leadership predictors of endorsement of three vaccination attitudes concerning effectiveness, safety, and importance., Results: Approximately 43% of soldiers reported that they received a COVID-19 vaccine at T1, increasing to 67% at T2. Soldiers who agreed with three separate statements on vaccination effectiveness, safety, or importance were more likely to indicate that they intended to get the vaccination at both time points. Soldiers who reported that their immediate supervisor encouraged soldiers to get a COVID-19 vaccine were more likely to indicate that the vaccination was effective, safe, or important at both time points., Discussion: Negative attitudes about COVID-19 vaccines were prevalent and correlated with less intention to get a vaccination. However, prioritizing leadership engagement around the importance of vaccinations may be a simple but widely effective intervention point to increase future vaccine uptake following the development of novel vaccines to future COVID-19 variants., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Abstract: Neurons in the superficial dorsal horn that express the gastrin-releasing peptide receptor (GRPR) are strongly implicated in spinal itch pathways. However, a recent study reported that many of these correspond to vertical cells, a population of interneurons that are believed to transmit nociceptive information. In this study, we have used a GRPR CreERT2 mouse line to identify and target cells that possess Grpr mRNA. We find that the GRPR cells are highly concentrated in lamina I and the outer part of lamina II, that they are all glutamatergic, and that they account for ∼15% of the excitatory neurons in the superficial dorsal horn. We had previously identified 6 neurochemically distinct excitatory interneuron populations in this region based on neuropeptide expression and the GRPR cells are largely separate from these, although they show some overlap with cells that express substance P. Anatomical analysis revealed that the GRPR neurons are indeed vertical cells, and that their axons target each other, as well as arborising in regions that contain projection neurons: lamina I, the lateral spinal nucleus, and the lateral part of lamina V. Surprisingly, given the proposed role of GRPR cells in itch, we found that most of the cells received monosynaptic input from Trpv1-expressing (nociceptive) afferents, that the majority responded to noxious and pruritic stimuli, and that chemogenetically activating them resulted in pain-related and itch-related behaviours. Together, these findings suggest that the GRPR cells are involved in spinal cord circuits that underlie both pain and itch., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

AbstractFor a species to expand its range, it needs to be good at dispersing and also capable of exploiting resources and adapting to different environments. Therefore, behavioral and cognitive traits could play key roles in facilitating invasion success. Marine threespined sticklebacks ( Gasterosteus aculeatus ) have repeatedly colonized freshwater environments and rapidly adapted to them. Here, by comparing the behavior of hundreds of lab-reared sticklebacks from six different populations, we show that marine sticklebacks are bold, while sticklebacks that have become established in freshwater lakes are flexible. Moreover, boldness and flexibility are negatively correlated with one another at the individual, family, and population levels. These results support the hypothesis that boldness is favored in invaders during the initial dispersal stage, while flexibility is favored in recent immigrants during the establishment stage, and they suggest that the link between boldness and flexibility facilitates success during both the dispersal stage and the establishment stage. This study adds to the growing body of work showing the importance of behavioral correlations in facilitating colonization success in sticklebacks and other organisms.

There is growing evidence that the environment experienced by one generation can influence phenotypes in the next generation via transgenerational plasticity (TGP). One of the best-studied examples of TGP in animals is predator-induced transgenerational plasticity, whereby exposing parents to predation risk triggers changes in offspring phenotypes. Yet, there is a lack of general consensus synthesizing the predator-prey literature with existing theory pertaining to ecology and evolution of TGP. Here, we apply a meta-analysis to the sizable literature on predator-induced TGP (441 effect sizes from 29 species and 49 studies) to explore five hypotheses about the magnitude, form and direction of predator-induced TGP. Hypothesis #1: the strength of predator-induced TGP should vary with the number of predator cues. Hypothesis #2: the strength of predator-induced TGP should vary with reproductive mode. Hypothesis #3: the strength and direction of predator-induced TGP should vary among offspring phenotypic traits because some traits are more plastic than others. Hypothesis #4: the strength of predator-induced TGP should wane over ontogeny. Hypothesis #5: predator-induced TGP should generate adaptive phenotypes that should be more evident when offspring are themselves exposed to risk. We found strong evidence for predator-induced TGP overall, but no evidence that parental predator exposure causes offspring traits to change in a particular direction. Additionally, we found little evidence in support of any of the specific hypotheses. We infer that the failure to find consistent evidence reflects the heterogeneous nature of the phenomena, and the highly diverse experimental designs used to study it. Together, these findings set an agenda for future work in this area., (© 2022. The Author(s).)

Anti-androgens entering the aquatic environment, e.g., by effluents from wastewater treatment plants or agricultural settings are contributing to endocrine disruption in wildlife and humans. Due to the simultaneous presence of agonistic compounds, common in vitro bioassays can underestimate the risk posed by androgen antagonists. On the other hand, cytotoxic effects might lead to false positive assessments of anti-androgenic effects in conventional bioassays. In the present study, a combination of normal phase high-performance thin-layer chromatography (NP-HPTLC) with a yeast-based reporter gene assay is established for the detection of anti-androgenicity as a promising tool to reduce interferences of androgenic and anti-androgenic compounds present in the same sample. To avoid a misinterpretation of anti-androgenicity with cytotoxic effects, cell viability was assessed in parallel on the same plate using a resazurin viability assay adapted to HPTLC plates. The method was characterized by establishing dose-response curves for the model compounds flutamide and bisphenol A. Calculated effective doses at 10% (ED10) were 27.9 ± 1.3 ng zone -1 for flutamide and 20.1 ± 5.1 ng zone -1 for bisphenol A. Successful distinction between anti-androgenicity and cytotoxicity was exemplarily demonstrated with 4-nitroquinoline 1-oxide. As a proof of concept, the detection and quantification of anti-androgenicity in an extract of a landfill leachate is demonstrated. This study shows that the hyphenation of HPTLC with the yeast anti-androgen screen is a matrix-robust, cost-efficient and fast screening tool for the sensitive and simultaneous detection of anti-androgenic and cytotoxic effects in environmental samples. The method offers a wide range of possible applications in environmental monitoring and contributes to the identification of anti-androgenicity drivers in the course of an effect-directed analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Parental care has attracted attention from both proximate and ultimate perspectives. While understanding the adaptive significance of care has been the focus of work in diverse organisms in behavioral ecology, most of what we know about the proximate mechanisms underlying parental care behavior comes from studies in mammals. Although studies on mammals have greatly improved our understanding of care, viewing parental care solely through a mammalian lens can limit our understanding. Here, we draw upon examples from non-mammalian vertebrate systems to show that in many ways mammals are the exception rather than the rule for caregiving: across vertebrates, maternal care is often not the ancestral or the most common mode of care and fathering is not derivative of mothering. Embracing the diversity of parental care can improve our understanding of both the proximate basis and adaptive significance of parental care and the affective processes involved in caregiving., Competing Interests: Conflicts of InterestThe authors declare no competing interests., (© The Society for Affective Science 2022.)

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is "wind-up," in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca 2+ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

There is growing evidence that offspring receive information about their environment vertically, i.e. from their parents (environmental parental effects or transgenerational plasticity). For example, parents exposed to predation risk may produce offspring with heightened antipredator defences. At the same time, organisms can gain information about the environment horizontally, from conspecifics. In this study, we provide some of the first evidence that horizontally acquired social information can be transmitted vertically across generations. Three-spined stickleback ( Gasterosteus aculeatus ) fathers produced larval offspring with altered antipredator behaviour when fathers received visual and olfactory cues from predator-chased neighbours. Although fathers did not personally witness their neighbours being chased (i.e. they never saw the predator), changes in offspring traits were similar to those induced by direct paternal exposure to predation risk. These findings suggest that two different non-genetic pathways (horizontal transfer of social information, vertical transfer via sperm-mediated paternal effects) can combine to affect offspring phenotypes. The implications of simultaneous horizontal and vertical transmission are widely appreciated in the context of disease and culture; our results suggest that they could be equally important for the maintenance of phenotypic variation and could have profound consequences for the rate at which information flows within and across generations.

Resilience can be defined as the ability of an animal to remain productive in the face of diverse environmental challenges. Several factors contribute to an animal's resilience including its ability to resist disease, cope with climatic extremes and respond to stressors. Immune competence, a proxy trait for general disease resistance, is expected to contribute to an animal's resilience. This research aimed to develop a practical method to assess immune competence in Merino sheep which would not restrict the future sale of tested animals, and to estimate genetic parameters associated with the novel trait. We also aimed to explore associations between immune competence and other industry-relevant disease resistance and fitness-related traits and to assess the ability of immune competence phenotypes to predict health outcomes. Here, the ability of Merino wethers (n = 1 339) to mount both an antibody-mediated and cell-mediated immune response was used to define their immune competence phenotype. For that purpose, antigens in a commercial vaccine were administered at the commencement of weaning and their responses were assessed. Univariate sire models were used to estimate variance components and heritabilities for immune competence and its component traits. Bivariate sire models were used to estimate genetic correlations between immune competence and a range of disease resistance and fitness-related traits. The heritability of immune competence and its component traits, antibody-mediated immune response and cell-mediated immune response were estimated at 0.49 ± 0.14, 0.52 ± 0.14 and 0.36 ± 0.11, respectively. Immune competence was favourably genetically correlated with breech flystrike incidence (-0.44 ± 0.39), worm egg count (-0.19 ± 0.23), dag score (-0.26 ± 0.31) and fitness compromise (-0.35 ± 0.24) but not fleece rot (0.17 ± 0.23). Results suggest that selection for immune competence has the potential to improve the resilience of Merino sheep; however, due to the large standard errors associated with correlation estimates reported here, further studies will be required in larger populations to validate associations between immune competence and disease resistance and fitness traits in Australian Merino sheep., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Background: Previous studies have documented the impact of domain-specific leadership behaviors on targeted health outcomes in employees. The goal of the present study was to determine the association between specific leadership behaviors addressing COVID-19 and US soldiers' mental health and adherence to COVID-19 public health guidelines., Methods: An electronic, anonymous survey was administered to US Army soldiers across three major commands (N = 7,829) from December 2020 to January 2021. The primary predictor of interest was soldiers' ratings of their immediate supervisors' behaviors related to COVID-19. The outcomes were soldiers' mental health (i.e., depression and generalized anxiety) and adherence to COVID-19 public health guidelines. Covariates were rank, gender, ratings of immediate supervisors' general leadership, level of COVID-19 concerns, and COVID-19 status (e.g., tested positive, became seriously ill). Logistic regressions were used to model the unique association of COVID-19 leadership behaviors with outcomes after adjusting for covariates., Results: High levels of COVID-19 leadership behaviors were associated with lesser likelihood of soldiers' screening positive for depression (AOR = 0.46; 95% CI [0.39, 0.54]) and anxiety (AOR = 0.54; 95% CI [0.45, 0.64]), and greater likelihood of frequent adherence to preventive health guidelines (AORs = 1.58; 95% CI [1.39, 1.80] to 2.50; 95% CI [2.01, 3.11])., Conclusion: Higher levels of COVID-19 leadership behaviors may support soldiers' mental health and encourage their adherence to COVID-19 public health guidelines. Given the link between these leader behaviors and soldier adaptation to the pandemic over and above general leadership, training for supervisors should focus on targeting specific health-promoting behaviors. Results can inform leader training for the military and other high-risk occupations., (© 2022. The Author(s).)

Projection neurons belonging to the anterolateral system (ALS) underlie the perception of pain, skin temperature and itch. Many ALS cells are located in laminae III-V of the dorsal horn and the adjacent lateral white matter. However, relatively little is known about the excitatory synaptic input to these deep ALS cells, and therefore about their engagement with the neuronal circuitry of the region. We have used a recently developed mouse line, Phox2a::Cre, to investigate a population of deep dorsal horn ALS neurons known as "antenna cells", which are characterised by dense innervation from peptidergic nociceptors, and to compare these with other ALS cells in the deep dorsal horn and lateral white matter. We show that these two classes differ, both in the density of excitatory synapses, and in the source of input at these synapses. Peptidergic nociceptors account for around two-thirds of the excitatory synapses on the antenna cells, but for only a small proportion of the input to the non-antenna cells. Conversely, boutons with high levels of VGLUT2, which are likely to originate mainly from glutamatergic spinal neurons, account for only ∼5% of the excitatory synapses on antenna cells, but for a much larger proportion of the input to the non-antenna cells. VGLUT1 is expressed by myelinated low-threshold mechanoreceptors and corticospinal axons, and these innervate both antenna and non-antenna cells. However, the density of VGLUT1 input to the non-antenna cells is highly variable, consistent with the view that these neurons are functionally heterogeneous.

Women mobilize up to 10% of their bone mass during lactation to provide milk calcium. About 8%-13% of mothers use selective serotonin reuptake inhibitors (SSRI) to treat peripartum depression, but SSRIs independently decrease bone mass. Previously, peripartal use of the SSRI fluoxetine reduced maternal bone mass sustained post-weaning and reduced offspring bone length. To determine whether these effects were fluoxetine-specific or consistent across SSRI compounds, we examined maternal and offspring bone health using the most prescribed SSRI, sertraline. C57BL/6 mice were given 10 mg/kg/day sertraline, from the beginning of pregnancy through the end of lactation. Simultaneously, we treated nulliparous females on the same days as the primiparous groups, resulting in age-matched nulliparous groups. Dams were euthanized at lactation day 10 (peak lactation, n = 7 vehicle; n = 9 sertraline), lactation day 21 (weaning, n = 9 vehicle; n = 9 sertraline), or 3m post-weaning (n = 10 vehicle; n = 10 sertraline) for analysis. Offspring were euthanized at peak lactation or weaning for analysis. We determined that peripartum sertraline treatment decreased maternal circulating calcium concentrations across the treatment period, which was also seen in nulliparous treated females. Sertraline reduced the bone formation marker, procollagen 1 intact N-terminal propeptide, and tended to reduce maternal BV/TV at 3m post-weaning but did not impact maternal or offspring bone health otherwise. Similarly, sertraline did not reduce nulliparous female bone mass. However, sertraline reduced immunofluorescence staining of the tight junction protein, zona occludens in the mammary gland, and altered alveoli morphology, suggesting sertraline may accelerate mammary gland involution. These findings indicate that peripartum sertraline treatment may be a safer SSRI for maternal and offspring bone rather than fluoxetine., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Abstract: Parvalbumin-expressing interneurons (PVINs) in the spinal dorsal horn are found primarily in laminae II inner and III. Inhibitory PVINs play an important role in segregating innocuous tactile input from pain-processing circuits through presynaptic inhibition of myelinated low-threshold mechanoreceptors and postsynaptic inhibition of distinct spinal circuits. By comparison, relatively little is known of the role of excitatory PVINs (ePVINs) in sensory processing. Here, we use neuroanatomical and optogenetic approaches to show that ePVINs comprise a larger proportion of the PVIN population than previously reported and that both ePVIN and inhibitory PVIN populations form synaptic connections among (and between) themselves. We find that these cells contribute to neuronal networks that influence activity within several functionally distinct circuits and that aberrant activity of ePVINs under pathological conditions is well placed to contribute to the development of mechanical hypersensitivity., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Selective serotonin reuptake inhibitors (SSRI) are the most common antidepressant used by pregnant women; however, they have been associated with adverse pregnancy outcomes and perinatal morbidity in pregnant women and animal models. We investigated the effects of two SSRI, fluoxetine and sertraline, on pregnancy and neonatal outcomes in mice. Wild-type mice were treated daily with low and high doses of fluoxetine (2 and 20 mg/kg) and sertraline (10 and 20 mg/kg) from the day of detection of a vaginal plug until the end of lactation (21 days postpartum). Pregnancy rate was decreased only in the high dose of fluoxetine group. Maternal weight gain was reduced in the groups receiving the high dose of each drug. Number of pups born was decreased in the high dose of fluoxetine and low and high doses of sertraline while the number of pups weaned was decreased in all SSRI-treated groups corresponding to increased neonatal mortality in all SSRI-treated groups. In conclusion, there was a dose-dependent effect of SSRI on pregnancy and neonatal outcomes in a non-depressed mouse model. However, the distinct placental transfer of each drug suggests that the effects of SSRI on pup mortality may be mediated by SSRI-induced placental insufficiency rather than a direct toxic effect on neonatal development and mortality.

Background: Less than 5% of eligible adult cancer survivors participate in cancer clinical trials. Survivors identifying as Black, Indigenous, and people of color (BIPOC) are less likely to participate in clinical trials compared to those identifying as non-Hispanic White. Common barriers to BIPOC participation are lack of knowledge, lack of access, and mistrust. These barriers are all factors in the disparities observed in BIPOC cancer-related morbidity and mortality. Clinical trials need adequate BIPOC representation to garner generalizable findings that can reduce or eliminate cancer disparities associated with the social construct of race., Aim: This systematic review examined the use of video education interventions to impact BIPOC survivor participation in clinical trials., Methods: Web of Science, Embase, PubMed, Cochrane, PsycInfo, and CINAHL databases were queried for articles that described or tested video interventions aimed at increasing adult, BIPOC survivor clinical trial participation. Two authors independently screened articles for inclusion, appraised quality, and abstracted relevant data. All authors synthesized the data into themes through discussion and consensus., Results: The search yielded 2,512 articles. Seven selected articles described six distinct interventions. Although the six interventions reduced barriers to participation in clinical trials, their findings varied on Black and Hispanic survivors' readiness to enroll and participate in trials. Four themes emerged: (a) cultural sensitivity is needed in video development and delivery; (b) video content should be aimed to educate and change attitudes about clinical trials; (c) video interventions are feasible and acceptable; and (d) video interventions affect outcomes on intention or actual enrollment., Linking Evidence to Action: Video interventions are well-received by BIPOC survivors and may improve representation in clinical trials. Yet, video interventions are underutilized. More studies are needed to establish best practices for video interventions aimed at diversifying clinical trial participation as widening cancer disparities and rapidly changing cancer care continue to emerge., (© 2021 Sigma Theta Tau International.)

A recently developed Phox2a::Cre mouse line has been shown to capture anterolateral system (ALS) projection neurons. Here, we used this line to test whether Phox2a-positive cells represent a distinct subpopulation among lamina I ALS neurons. We show that virtually all lamina I Phox2a cells can be retrogradely labelled from injections targeted on the lateral parabrachial area (LPb), and that most of those in the cervical cord also belong to the spinothalamic tract. Phox2a cells accounted for ~ 50-60% of the lamina I cells retrogradely labelled from LPb or thalamus. Phox2a was preferentially associated with smaller ALS neurons, and with those showing relatively weak neurokinin 1 receptor expression. The Phox2a cells were also less likely to project to the ipsilateral LPb. Although most Phox2a cells phosphorylated extracellular signal-regulated kinases following noxious heat stimulation, ~ 20% did not, and these were significantly smaller than the activated cells. This suggests that those ALS neurons that respond selectively to skin cooling, which have small cell bodies, may be included among the Phox2a population. Previous studies have defined neurochemical populations among the ALS cells, based on expression of Tac1 or Gpr83. However, we found that the proportions of Phox2a cells that expressed these genes were similar to the proportions reported for all lamina I ALS neurons, suggesting that Phox2a is not differentially expressed among cells belonging to these populations. Finally, we used a mouse line that resulted in membrane labelling of the Phox2a cells and showed that they all possess dendritic spines, although at a relatively low density. However, the distribution of the postsynaptic protein Homer revealed that dendritic spines accounted for a minority of the excitatory synapses on these cells. Our results confirm that Phox2a-positive cells in lamina I are ALS neurons, but show that the Phox2a::Cre line preferentially captures specific types of ALS cells., (© 2021. The Author(s).)

The environment experienced by one generation can influence the phenotypes of future generations. Because parental cues can be conveyed to offspring at multiple points in time, ranging from fertilization to posthatching/parturition, offspring can potentially receive multiple cues from their parents via different mechanisms. We have relatively little information regarding how different mechanisms operate in isolation and in tandem, but it is possible, for example, that offspring phenotypes induced by nongenetic changes to gametes may be amplified by, mitigated by, or depend upon parental care. Here, we manipulated paternal experience with predation risk prior to fertilization in threespine stickleback, Gasterosteus aculeatus , and then examined the potential of paternal care to mitigate and/or amplify sperm-mediated paternal effects. Specifically, we compared (1) offspring of predator-exposed fathers who were reared without paternal care, (2) offspring of predator-exposed fathers who were reared with paternal care, (3) offspring of control (unexposed) fathers who were reared without paternal care and (4) offspring of control fathers who were reared with paternal care. We found that offspring of predator-exposed fathers were less active and had higher cortisol following a simulated predator attack. Although predator-exposed males shifted their paternal care behaviours - reduced fanning early in egg development and increased fanning right before egg hatching compared to control males - this shift in paternal behavior did not appear to affect offspring traits. This suggests that paternal care neither amplifies nor compensates for these phenotypic effects induced by sperm and that nongenetic changes induced by sperm may occur independently of nongenetic changes induced by paternal care. Overall, these results underscore the importance of considering how parents may have multiple nongenetic mechanisms by which they can influence offspring., Competing Interests: We declare that we have no conflicts of interest.

Fuelled by the ongoing genomic revolution, broadscale RNA expression surveys are fast replacing studies targeting one or a few genes to understand the molecular basis of behaviour. Yet, the timescale of RNA-sequencing experiments and the dynamics of neural gene activation are insufficient to drive real-time switches between behavioural states. Moreover, the spatial, functional and transcriptional complexity of the brain (the most commonly targeted tissue in studies of behaviour) further complicates inference. We argue that a Central Dogma-like 'back-to-basics' assumption that gene expression changes cause behaviour leaves some of the most important aspects of gene-behaviour relationships unexplored, including the roles of environmental influences, timing and feedback from behaviour-and the environmental shifts it causes-to neural gene expression. No perfect experimental solutions exist but we advocate that explicit consideration, exploration and discussion of these factors will pave the way toward a richer understanding of the complicated relationships between genes, environments, brain gene expression and behaviour over developmental and evolutionary timescales.

Objective: Within Australia, Aboriginal and Torres Strait Islander (First Nations) populations perceive health and well-being differently to non-Indigenous Australians. Existing health-related quality of life (HR-QoL) measurement tools do not account for these differences. The objective of this study was to develop and validate a culturally specific parent-proxy HR-QoL measurement tool for First Nations children., Design: Scale development was informed by parents/carers of children with a chronic illness and an expert panel. The preliminary 39-item survey was reviewed (n=12) and tested (n=163) with parents/carers of First Nations children aged 0-12 years at baseline with comparative scales: the Kessler Psychological Distress Scale, generic HR-QoL (Paediatric QoL Inventory 4.0, PedsQL 4.0 ) and Spence Children's Anxiety Scale, and repeated (n=46) 4 weeks later. Exploratory Factor Analysis was used for scale reduction. Reliability and validity were assessed by internal consistency, test-retest, and correlations with comparison scales., Results: Items within our First Nations-Child Quality of Life (FirstNations-CQoL) were internally consistent with Cronbach's alpha coefficients of ≥0.7 (quality of life, 0.808; patient experience, 0.880; patient support, 0.768) and overall test-retest reliability was good (r=0.75; 95% CI 0.593 to 0.856). Convergent validity was observed with the PedsQL 4.0 with Pearson's coefficients of r=0.681 (ages 2-4 years); r=0.651 (ages 5-12 years) and with the Kessler Psychological Distress scale (r=-0.513). Divergent validity against the Spence Anxiety Scale was not demonstrated., Conclusions: The FirstNations-CQoL scale was accepted by the participants, reliable and demonstrated convergent validity with comparison measures. This tool requires further evaluation to determine responsiveness, its minimal important difference and clinical utility., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Experiences of parents and/or offspring are often assumed to affect the development of trait values in offspring because they provide information about the external environment. However, it is currently unclear how information from parental and offspring experiences might jointly affect the information-states that provide the foundation for the offspring phenotypes observed in empirical studies of developmental plasticity in response to environmental cues. We analyze Bayesian models designed to mimic fully-factorial experimental studies of trans and within- generational plasticity (TWP), in which parents, offspring, both or neither are exposed to cues from predators, to determine how different durations of cue exposure for parents and offspring, the devaluation of information from parents or the degradation of information from parents would affect offspring estimates of environmental states related to risk of predation at the end of such experiments. We show that the effects of different cue durations, the devaluation of information from parents, and the degradation of information from parents on offspring estimates are all expected to vary as a function of interactions with two other key components of information-based models of TWP: parental priors and the relative cue reliability in the different treatments. Our results suggest empiricists should expect to observe considerable variation in the patterns observed in experimental studies of TWP based on simple principles of information-updating, without needing to invoke additional assumptions about costs, tradeoffs, development constraints, the fitness consequences of different trait values, or other factors., Competing Interests: The authors have declared that no competing interests exist.