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The maintenance of variation within natural populations is key for natural selection to operate. Polymorphism is an intriguing form of variation that involves the persistence of multiple discrete phenotypes called morphs. Polymorphism is often explained by negative frequency dependent selection (NFDS), under which rare morphs have an advantage, such that no one morph takes over. We tested whether mating polymorphism is maintained by NFDS generated by female choice, in the livebearing poeciliid fish, Girardinus metallicus , whose males are either common, plain morphs or rare, black morphs. Females were treated with one morph for several weeks and tested with both, in mate choice and direct competition assays. Contrary to NFDS via female choice, females preferred the morph with which they were treated. This may disrupt the polymorphism given the rarity of black morphs in the wild, unless black morphs have other advantages: we found that black morphs tended to exhibit higher mating activity, and other studies have demonstrated that they are more aggressive. Interestingly, only black morphs display to females prior to copulation; however, there is little evidence for female preference for this morph or the mating display. These results suggest functions for the mating display of black morphs beyond courtship, including aggressive mate guarding, and prompt a discussion of what constitutes courtship behavior. • Variation in the form of polymorphism is maintained if rare morphs have an advantage. • Contrary to this idea, female Girardinus metallicus fish preferred familiar morphs. • However, polymorphism may be maintained by higher mating activity of black morphs. • Only black morphs display, and this may be a form of coercion, as in other studies. • We discuss displays that function in multiple contexts and definitions of courtship. [ABSTRACT FROM AUTHOR]

Introduction: Military studies have investigated acute injuries associated with parachute jumps, but the literature does not address paratroopers' cumulative microtraumatic (CMT) injury risk, nor does it compare injury risks between paratroopers and the rest of the military population. This study determined whether US active duty Army paratroopers experienced greater injury risks than their non-paratrooper soldier counterparts and whether their injuries cost more to treat suggesting greater injury severity., Methods: This retrospective study evaluated electronic medical records (2016-2018) for 31 621 paratroopers and a randomly selected comparison group of 170 715 non-paratrooper soldiers. Analyses included univariate and multivariate regression to quantify odds of injuries associated with risk variables and additional descriptive statistics., Results: Paratroopers had a 57% increase in the odds of experiencing one or more injuries (OR=1.57, 95% CI: 1.52 to 1.62) after controlling for sex, race and age, with a greater proportion of acute injuries (OR=1.38, 95% CI: 1.34 to 1.42), relative to comparison group soldiers. Injury types proportionally higher among paratroopers included head trauma and shoulder injuries. Average injury cost among paratroopers was 13% lower than for non-paratroopers ($2470 vs $2830 per injury). Among both populations, acute injury costs were notably higher than for CMT injuries (paratroopers, $1710/$630; non-paratroopers, $1860/$880 per injury)., Conclusions: Paratroopers were more likely to incur injury, especially an acute injury, than non-paratroopers. However, paratroopers' average injury costs were less. This may be due to higher return-to-duty motivations, fitness levels, and/or facility-specific cost of care. Future studies should investigate causes of injuries found to be proportionally higher among paratroopers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

To prevent SARS-CoV-2 infections and generate long-lasting immunity, vaccines need to generate strong viral-specific B and T cell responses. Previous results from our lab and others have shown that immunizations in the presence of an OX40 agonist antibody lead to higher antibody titers and increased numbers of long-lived antigen-specific CD4 and CD8 T cells. Using a similar strategy, we explored the effect of OX40 co-stimulation in a prime and boost vaccination scheme using an adjuvanted SARS-CoV-2 spike protein vaccine in C57BL/6 mice. Our results show that OX40 engagement during vaccination significantly increases long-lived antibody responses to the spike protein. In addition, after immunization spike protein-specific proliferation was greatly increased for both CD4 and CD8 T cells, with enhanced, spike-specific secretion of IFN-γ and IL-2. Booster (3 rd injection) immunizations combined with an OX40 agonist (7 months post-prime) further increased vaccine-specific antibody and T cell responses. Initial experiments assessing a self-amplifying mRNA (saRNA) vaccine encoding the spike protein antigen show a robust antigen-specific CD8 T cell response. The saRNA spike-specific CD8 T cells express high levels of GrzmB, IFN-γ and TNF-α which was not observed with protein immunization and this response was further increased by the OX40 agonist. Similar to protein immunizations the OX40 agonist also increased vaccine-specific CD4 T cell responses. In summary, this study compares and contrasts the effects and benefits of both protein and saRNA vaccination and the extent to which an OX40 agonist enhances and sustains the immune response against the SARS-CoV-2 spike protein., Competing Interests: AW is founder of AgonOx, which has an ownership interest in OX40 patents. Authors SAbb, SAbr, NJ, AT and AG are/were employed by Precision Nanosystems (PNI). The remaining 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 Duhen, Beymer, Jensen, Abbina, Abraham, Jain, Thomas, Geall, Hu, Fox and Weinberg.)

Lesbian, gay, and bisexual (LGB) individuals are at a particularly high risk for suicidal behavior in the general population of the United States. This study aims to determine if there are differences in the frequency of lifetime suicide ideation and suicide attempts between heterosexual, lesbian/gay, and bisexual service members in the active component of the U.S. Armed Forces. Self-reported data from the 2015 Department of Defense Health-Related Behaviors Survey were used in the analysis. Multivariable logistic regression demonstrated that lesbian/gay and bisexual service members were more likely to report past suicide ideation when compared to heterosexual service members (adjusted odds ratio [AOR] for lesbian/gay: 1.79; 95% CI:1.14-2.82; AOR for bisexual: 2.33; 95% CI: 1.56-3.49). Similar results were observed for past suicide attempt for lesbian/gay (AOR: 2.29; 95% CI: 1.15-4.57) and bisexual SMs (AOR: 2.04; 95% CI: 1.24-3.38). Despite disparities in suicide ideation and attempt by sexual orientation, a majority of service members’ behavioral health questionnaires do not assess sexual orientation. Clinical screenings of suicide risk in military settings should factor in sexual orientation to more comprehensively assess association between sexual orientation and suicidal behavior in this population.

CD4+ Th cells play a key role in orchestrating immune responses, but the identity of the CD4+ Th cells involved in the antitumor immune response remains to be defined. We analyzed the immune cell infiltrates of head and neck squamous cell carcinoma and colorectal cancers and identified a subset of CD4+ Th cells distinct from FOXP3+ Tregs that coexpressed programmed cell death 1 (PD-1) and ICOS. These tumor-infiltrating lymphocyte CD4+ Th cells (CD4+ Th TILs) had a tissue-resident memory phenotype, were present in MHC class II-rich areas, and proliferated in the tumor, suggesting local antigen recognition. The T cell receptor repertoire of the PD-1+ICOS+ CD4+ Th TILs was oligoclonal, with T cell clones expanded in the tumor, but present at low frequencies in the periphery. Finally, these PD-1+ICOS+ CD4+ Th TILs were shown to recognize both tumor-associated antigens and tumor-specific neoantigens. Our findings provide an approach for isolating tumor-reactive CD4+ Th TILs directly ex vivo that will help define their role in the antitumor immune response and potentially improve future adoptive T cell therapy approaches.

Careless responding to surveys has not been sufficiently characterized in military populations. The objective of the current study was to determine the proportion and characteristics of careless responding in a 2019 survey given to a large sample of U.S. Army soldiers at 1 installation (n = 4,892). Two bogus survey items were asked to assess careless responding. Nearly 96% of soldier respondents correctly answered both bogus items and 4.5% incorrectly answered at least 1 bogus question. In the adjusted multiple logistic regression model, race and marital status were associated with incorrect answers to bogus item questions after controlling for all other covariates. Specifically, the odds of Black respondents incorrectly answering the bogus items (adjusted odds ratio [AOR]: 2.53; 95% CI: 1.74-3.68) were more than 2.5 times those of White respondents. The recommendations that stem from the results of surveys can influence policy decisions. A large proportion of careless responses could inadvertently lead to results that are not representative of the population surveyed. Careless responding could be detected through the inclusion of bogus items in military surveys which would allow researchers to analyze how careless responses may impact outcomes of interest.

Introduction: Early childhood caries (ECC), despite being preventable, remains the most prevalent disease of childhood, particularly in children between the ages of 2 and 5 y. The association between the type of health care provider completing initial oral health examinations and subsequent dental caries in children under 6 y of age is unclear., Objective: The objective of the current study is to longitudinally assess the association between age at first oral health examination and provider type at first oral health examination on dental treatment for children under 6 y of age., Methods: Deidentified administrative claims data were used from the IBM Marketscan Multi-State Medicaid Database ( n = 2.41 million Medicaid-enrolled children younger than 6 y in 13 states from 2012 to 2017). A Kaplan-Meier survival analysis was used to examine the association between age at first oral health examination and provider type with first treatment of dental caries at follow-up., Results: The adjusted hazard ratio (HR) of dental caries for children whose first oral health examination at 4 y of age is 5.425 times higher than for children whose first oral health examination was before 1 y of age (95% confidence interval [CI], 5.371-5.479). The adjusted HR of dental caries for children seen by pediatric dentists (HR = 1.215; 95% CI, 1.207-1.223) and physicians (HR = 2.618; 95% CI, 2.601-2.635) was higher than those seen by a general dentist., Conclusions: Findings from this study highlight the importance of children having their first oral health examination no later than 12 mo of age in accordance with existing guidelines and referrals from physicians to prevent the need for invasive treatment., Knowledge of Transfer Statement: Results of this study emphasize the need for a child's first oral health examination to be completed no later than 12 mo of age to prevent dental caries. Reinforcement and referrals by physicians based on this recommendation facilitate early establishment of a dental home in young children.

Mammals adapt to seasons using a neuroendocrine calendar defined by the photoperiodic change in the nighttime melatonin production. Under short photoperiod, melatonin inhibits the pars tuberalis production of TSHβ, which, in turn, acts on tanycytes to regulate the deiodinase 2/3 balance resulting in a finely tuned seasonal control of the intra-hypothalamic thyroid hormone T3. Despite the pivotal role of this T3 signaling for synchronizing reproduction with the seasons, T3 cellular targets remain unknown. One candidate is a population of hypothalamic neurons expressing Rfrp, the gene encoding the RFRP-3 peptide, thought to be integral for modulating rodent's seasonal reproduction. Here we show that nighttime melatonin supplementation in the drinking water of melatonin-deficient C57BL/6J mice mimics photoperiodic variations in the expression of the genes Tshb, Dio2, Dio3, and Rfrp, as observed in melatonin-proficient mammals. Notably, we report that this melatonin regulation of Rfrp expression is no longer observed in mice carrying a global mutation of the T3 receptor, TRα, but is conserved in mice with a selective neuronal mutation of TRα. In line with this observation, we find that TRα is widely expressed in the tanycytes. Altogether, our data demonstrate that the melatonin-driven T3 signal regulates RFRP-3 neurons through non-neuronal, possibly tanycytic, TRα., (© 2020 Federation of American Societies for Experimental Biology.)

MSM/Ms (MSM) is a mouse strain derived from Japanese wild mice, Mus musculus molossinus , that maintains the ability to synthesize melatonin in patterns reflecting the ambient photoperiod. The objective of this study was to characterize the effects of photoperiodic variation on metabolic and reproductive traits, and the related changes in pituitary-hypothalamic gene expression in MSM mice. MSM mice were kept in long (LP) or short photoperiod (SP) for 6 weeks. Our results demonstrate that MSM mice kept in LP, as compared with mice kept in SP, display higher expression of genes encoding thyrotropin (TSH) in the pars tuberalis, thyroid hormone deiodinase 2 (dio2) in the tanycytes and RFamide-related peptide (RFRP3) in the hypothalamus, and lower expression of dio3 in the tanycytes, along with larger body and reproductive organ mass. Additionally, to assess the effects of the gestational photoperiodic environment on the expression of these genes, we kept MSM mice in LP or SP from gestation and studied their offspring. We show that the gestational photoperiod affects the TSH/dio pathway in newborn MSM mice in a similar way to adults. This result indicates a transgenerational effect of photoperiod from the mother to the fetus in utero Overall, these results indicate that photoperiod can influence neuroendocrine regulation in a melatonin-proficient mouse strain, in a manner similar to that documented in other seasonal rodent species. MSM mice may therefore become a useful model for research into the molecular basis of photoperiodic regulation of seasonal biology., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Mus musculus molossinus (MSM) is a wild-derived mouse strain which maintains the ability to synthesize melatonin in patterns reflecting the ambient photoperiod. The objective of this study was to characterize the effects of photoperiodic variation on metabolic and reproductive traits, and the related changes in pituitary-hypothalamic gene expression in MSM mice. MSM mice were kept in long (LP) or short photoperiod (SP) for 6 weeks. Our results demonstrate that MSM mice kept in LP, as compared to mice kept in SP, display higher expression of genes encoding thyrotropin (TSH) in the pars tuberalis, thyroid hormone deiodinase 2 (dio2) in the tanycytes, RFamide-related peptide (RFRP3) in the hypothalamus and lower expression of dio3 in the tanycytes, along with larger body and reproductive organ mass. Additionally, to assess the effects of the gestational photoperiodic environment on the expression of these genes, we kept MSM mice in LP or SP from gestation and studied offspring. We show that the gestational photoperiod affects the TSH/dio pathway in newborn MSM mice in a similar way to adults. This result indicates a transgenerational effect of photoperiod from the mother to the fetus in utero. Overall, these results indicate that photoperiod can influence neuroendocrine regulation in a melatonin-proficient mouse strain, in a manner similar that documented in other seasonal rodent species. MSM mice may therefore become a useful model for research into the molecular basis of photoperiodic regulation of seasonal biology., (© 2020. Published by The Company of Biologists Ltd.)

Background: Tenofovir disoproxil fumarate/emtricitabine preexposure prophylaxis (PrEP) is effective against HIV acquisition when taken as prescribed. Strategies that identify and intervene with those challenged by adherence to daily medication are needed., Setting: PATH-PrEP was an open-label single-arm interventional cohort study conducted at 2 community-based clinical sites in Los Angeles, CA., Methods: We enrolled self-identified men who have sex with men and transgender women ≥18 years of age at an elevated risk of HIV acquisition. Participants received a postexposure prophylaxis (PEP)-based or PrEP-based HIV prevention package for at least 48 weeks. Plasma tenofovir levels from each PrEP visit assessed as below the limit of quantitation (<10 ng/mL) triggered increased adherence support., Results: Three hundred one participants enrolled. Forty-eight-week retention in the PrEP cohort was 75.1%. Biomarker evidence of PrEP adherence consistent with ≥4 doses per week at weeks 4, 12, 24, 36, and 48 was found in 83.1%, 83.4%, 75.7%, 71.6%, and 65.5% of participants, respectively; younger and African American participants were less likely to have protective drug levels. Most of those with suboptimal adherence had adherence improvement after brief intervention. One seroconversion occurred in a participant who discontinued PrEP. Nearly half (46.4%) of participants were diagnosed with at least 1 incident sexually transmitted infection during 48 weeks of study follow-up., Conclusions and Relevance: PrEP was acceptable and well tolerated in a diverse population of men who have sex with men in Los Angeles. A brief intervention triggered from biomarkers of poor adherence was associated with improved adherence. Drug level monitoring has the potential to allow targeting of additional adherence support to those struggling with daily tablet adherence.

Introduction: High viremia combined with HIV-infection status unawareness and increased sexual risk behavior contributes to a disproportionate amount of new HIV infections., Methods: From August 2011 to July 2015, the Los Angeles Lesbian, Gay, Bisexual, and Transgender Center conducted 66,546 HIV tests. We compared factors, including the presence of concomitant sexually transmitted infections, number of recent sex partners and reported condomless anal intercourse between men who have sex with men (MSM) diagnosed with an acute HIV infection and a nonacute HIV infection using multivariable logistic regression., Results: Of 1082 unique MSM who tested HIV-infected for the first time, 165 (15%) had an acute infection and 917 had a nonacute infection. HIV rapid antibody testing was 84.8% sensitive for detecting HIV infection (95% confidence interval (CI): 82.9% to 87.1%). Median HIV viral load among acutely infected MSM was 842,000 copies per milliliter (interquartile range = 98,200-4,897,318). MSM with acute infection had twice the number of sex partners in the prior 30 days (median = 2) and prior 3 months (median = 4) before diagnosis compared with those diagnosed with nonacute infection (P ≤ 0.0001). The odds of acute HIV infection were increased with the numbers of recent sex partners after controlling for age and race/ethnicity (adjusted odds ratio (aOR) >5 partners in past 30 days = 2.74; 95% CI: 1.46 to 5.14; aOR >10 partners in past 3 months = 2.41; 95% CI: 1.36 to 4.25). Non-African American MSM had almost double the odds of being diagnosed with an acute HIV infection compared with African American MSM (aOR = 1.97; 95% CI: 1.10 to 3.52)., Conclusions: MSM with acute HIV infection had nearly twice as many sex partners in the past 30 days and 3 months compared with MSM with newly diagnosed nonacute HIV infection. Those diagnosed with acute HIV infection had decreased odds of being African American MSM.

In female mammals, reproduction shows ovarian and daily rhythms ensuring that the timing of the greatest fertility coincides with maximal activity and arousal. The ovarian cycle, which lasts from a few days to a few weeks, depends on the rhythm of follicle maturation and ovarian hormone production, whereas the daily cycle depends on a network of circadian clocks of which the main one is located in the suprachiasmatic nuclei (SCN). In the last ten years, major progress has been made in the understanding of the neuronal mechanisms governing mammalian reproduction with the finding that two hypothalamic Arg-Phe-amide peptides, kisspeptin (Kp) and RFRP, regulate GnRH neurons. In this review we discuss the pivotal role of Kp and RFRP neurons at the interface between the SCN clock signal and GnRH neurons to properly time gonadotropin-induced ovulation. We also report recent findings indicating that these neurons may be part of the multi-oscillatory circadian system that times female fertility. Finally, we will discuss recent investigations indicating a role, and putative therapeutic use, of these neuropeptides in human reproduction., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Hypothalamic kisspeptin neurons integrate and translate cues from the internal and external environments that regulate gonadotropin-releasing hormone (GnRH) secretion and maintain fertility in mammals. However, the intracellular signaling pathways utilized to translate such information into changes in kisspeptin expression, release, and ultimately activation of the kisspeptin-receptive GnRH network have not yet been identified. PI3K is an important signaling node common to many peripheral factors known to regulate kisspeptin expression and GnRH release. We investigated whether PI3K signaling regulates hypothalamic kisspeptin expression, pubertal development, and adult fertility in mice. We generated mice with a kisspeptin cell-specific deletion of the PI3K catalytic subunits p110α and p110β (kiss-p110α/β-KO). Using in situ hybridization, we examined Kiss1 mRNA expression in gonad-intact, gonadectomized (Gdx), and Gdx + steroid-replaced mice. Kiss1 cell number in the anteroventral periventricular hypothalamus (AVPV) was significantly reduced in intact females but not in males. In contrast, compared with WT and regardless of steroid hormone status, Kiss1 cell number was lower in the arcuate (ARC) of kiss-p110α/β-KO males, but it was unaffected in females. Both intact Kiss-p110α/β-KO males and females had reduced ARC kisspeptin-immunoreactive (IR) fibers compared with WT animals. Adult kiss-p110α/β-KO males had significantly lower circulating luteinizing hormone (LH) levels, whereas pubertal development and fertility were unaffected in males. Kiss-p110α/β-KO females exhibited a reduction in fertility despite normal pubertal development, LH levels, and estrous cyclicity. Our data show that PI3K signaling is important for the regulation of hypothalamic kisspeptin expression and contributes to normal fertility in females.