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Abstract Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, neuro‐acquired HIV (neuroHIV) remains a significant problem and approximately half of people living with HIV will experience HIV‐associated neurocognitive disorders (HAND). Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, neuronal injury and synaptodendritic culling, viral replication, and potentially altering antiretroviral concentrations within the brain. The present study examined the effects of HIV and morphine co‐exposure on the accumulation and spatial distribution of antiretroviral drugs across multiple regions within the brain in an HIV‐1 Tat transgenic mouse model by using infrared‐matrix‐assisted laser desorption electrospray ionization mass spectrometry imaging (IR‐MALDESI MSI). Morphine exposure uniquely decreased antiretroviral concentrations in anterior cerebral (primary motor and somatosensory) cortices, corpus collosum (anterior forceps), caudoputamen, nucleus accumbens, and posterior regions including the hippocampus, corpus callosum (main body), cerebral cortex (somatosensory and auditory cortices), thalamus, and hypothalamus. Interestingly, male mice experienced greater morphine‐associated decreases in antiretroviral concentrations than females. The study also assessed whether changes in antiretroviral concentrations were linked with inflammation in astroglia, assessed through the measurement of astroglial activation using glial fibrillary acidic protein (GFAP) as a marker. Alterations in antiretroviral concentrations co‐registering with areas of astroglial activation exhibited sex‐specific treatment differences. This study highlights the intricate interplay between HIV, opioids, and antiretroviral drugs within the CNS, elucidating distinct regional and sex variations in responsiveness. Our findings emphasize the identification of vulnerabilities within the neural landscape and underscore the necessity of carefully monitoring opioid use to maintain the efficacy of antiretroviral therapies.

Abstract Mate choice is hypothesized to play an important role in maintaining high diversity at major histocompatibility complex (MHC) genes in vertebrates. Many studies have revealed that females across taxa prefer the scent of males with MHC genotypes different to their own. In this study we tested the “opposites‐attract” hypothesis in two species of darter with known differences in female criteria used in mate choice: in the fantail darters (a paternal‐care species), females prefer males with visual traits related to nest guarding and egg tending, while in rainbow darters (not a paternal‐care species) female mate choice criteria are unknown. In dichotomous mate‐choice trials, we presented females of both species with the scents of conspecific males with MHC class IIb genotypes that were either similar or dissimilar to that of the focal female. We evaluated the proportion of time each female spent with each male and calculated the average strength of female preference for both species. Female fantail darters demonstrated a preference for the scent of males with similar (rather than dissimilar) MHC genotypes, but this result was not statistically significant. Rainbow darter females showed no preference for the scent of males with similar or dissimilar MHC genotypes. Our results do not support the “opposites‐attract” hypothesis in darters.

Introduction Stroke is a leading cause of morbidity and mortality, and many factors predict a poor outcome, including age, NIH Stroke Scale (NIHSS), ambulatory status, and ability to swallow1. Mood disorders have previously been associated with an increased risk of cardiovascular disease2. The association between pre‐existing mood disorders and stroke outcome, however, has not been well studied. The objective of the current study was to explore the impact of pre‐existing depression on functional outcomes post‐endovascular treatment. Methods We reviewed the records of 178 patients who received mechanical thrombectomy (MT) at our institution[BH1][BM2] from 2019–2022. We collected data on baseline characteristics and demographics, including functional outcome at 90 days as measured by modified Rankin Scale (mRS), which was categorized as favorable (mRS 0–2) or unfavorable (mRS 3–6). Results Of patients who received MT, 54 (30.3%) had a prior medical history of depression. On univariate analysis, patients with a history of depression had 2.5 times higher odds of an mRS score of 3–6 (cOR = 2.47, 95% CI = 1.11‐5.48). Multivariate analysis included history of smoking, hypertension, obesity, Alberta Stroke Program Early CT Score (ASPECTS)[YC1][KC2], time to recanalization, and discharge NIHSS score, along with history of depression. We found that the odds of having an unfavorable mRS were 5 times higher in those with a history of depression than those with no history (aOR = 5.15, 95% CI = 1.09‐23.31). Additionally, discharge NIHSS was associated with 1.5 times higher odds of unfavorable mRS for each point increase in NIHSS score (aOR = 1.47, 95%CI = 1.25‐1.74). While pre‐existing depression was associated with poorer functional outcomes, it was not associated with mortality, cOR = 1.12, 95%CI = 0.55‐2.27. Conclusions In this study, we found that a prior medical history of depression is associated with unfavorable functional outcomes at 90 days in patients who received MT. Future studies should investigate the association between the severity of depression and stroke outcomes and explore methods to mitigate the impact of depression on stroke outcomes.

Abstract The objective of this study was to determine the effects of dietary fibre level and source on faecal ceftiofur metabolites concentrations after intramuscular administration of therapeutic ceftiofur hydrochloride in finisher pigs. Pens of finisher pigs (n = 36), with an equal number of barrows and gilts, were randomly assigned to 1 of 3 dietary treatment groups: basal diet composed of corn grain and soy bean meal with no supplement and formulated to contain 8.7% neutral detergent fibre (NDF), supplemented with 20% distillers dried grains with solubles (a byproduct of the ethanol production from corn grain) formulated to contain 13.6% NDF, primarily insoluble fibre or supplemented with 14.5% sugar beet pulp formulated to contain 13.6% NDF. Faecal samples were collected 6–8 hr after ceftiofur injection from treated and untreated pen‐mate pigs on days 1 and 3 of the 3‐day treatment regimen. Faecal concentrations of ceftiofur metabolites, including the major metabolite, desfuroylceftiofur, were analysed by reverse‐phase high pressure liquid chromatography with ultraviolet detection. Overall, the faecal concentrations of ceftiofur metabolites did not differ significantly between the dietary treatments. The mean concentrations of metabolites tended to be lower (p = .1) on day 3 compared to day 1 of the 3‐day treatment regimen. Faecal concentrations of metabolites were not affected by the gender of the finisher pigs. The concentrations of ceftiofur metabolites in the faeces are likely reflective of the microbial activity in the hindgut. Our data suggest that the fibre level and source used in the study did not affect the faecal concentrations of ceftiofur metabolites.

Abstract There is growing evidence that prey perceive the risk of predation and alter their behavior in response, resulting in changes in spatial distribution and potential fitness consequences. Previous approaches to mapping predation risk across a landscape quantify predator space use to estimate potential predator‐prey encounters, yet this approach does not account for successful predator attack resulting in prey mortality. An exception is a prey kill site that reflects an encounter resulting in mortality, but obtaining information on kill sites is expensive and requires time to accumulate adequate sample sizes. We illustrate an alternative approach using predator scat locations and their contents to quantify spatial predation risk for elk (Cervus canadensis) from multiple predators in the Rocky Mountains of Alberta, Canada. We surveyed over 1300 km to detect scats of bears (Ursus arctos/U. americanus), cougars (Puma concolor), coyotes (Canis latrans), and wolves (C. lupus). To derive spatial predation risk, we combined predictions of scat‐based resource selection functions (RSFs) weighted by predator abundance with predictions that a predator‐specific scat in a location contained elk. We evaluated the scat‐based predictions of predation risk by correlating them to predictions based on elk kill sites. We also compared scat‐based predation risk on summer ranges of elk following three migratory tactics for consistency with telemetry‐based metrics of predation risk and cause‐specific mortality of elk. We found a strong correlation between the scat‐based approach presented here and predation risk predicted by kill sites and (r = .98, p

Abstract Major Histocompatibility Complex (MHC) genes are one of the most polymorphic gene groups known in vertebrates. MHC genes also exhibit allelic variants that are shared among taxa, referred to as trans‐specific polymorphism (TSP). The role that selection plays in maintaining such high diversity within species, as well as TSP, is an ongoing discussion in biology. In this study, we used deep‐sequencing techniques to characterize MHC class IIb gene diversity in three sympatric species of darters. We found at least 5 copies of the MHC gene in darters, with 126 genetic variants encoding 122 unique amino acid sequences. We identified four supertypes based on the binding properties of proteins encoded by the sequences. Although each species had a unique pool of variants, many variants were shared between species pairs and across all three species. Phylogenetic analysis showed that the variants did not group together monophyletically based on species identity or on supertype. An expanded phylogenetic analysis showed that some darter alleles grouped together with alleles from other percid fishes. Our findings show that TSP occurs in darters, which suggests that balancing selection is acting at the genotype level. Supertypes, however, are most likely evolving convergently, as evidenced by the fact that alleles do not form monophyletic groups based on supertype. Our research demonstrates that selection may be acting differently on MHC genes at the genotype and supertype levels, selecting for the maintenance of high genotypic diversity while driving the convergent evolution of similar MHC phenotypes across different species.

Phosphoinositide 3‐kinase (PI3K) is aberrantly activated in head and neck squamous cell carcinomas (HNSCC) and plays a pivotal role in tumorigenesis by driving Akt signaling, leading to cell survival and proliferation. Phosphorylation of Akt Thr308 by PI3K‐PDK1 and Akt Ser473 by mammalian target of rapamycin complex 2 (mTORC2) activates Akt. Targeted inhibition of PI3K is a major area of preclinical and clinical investigation as it reduces Akt Thr308 phosphorylation, suppressing downstream mTORC1 activity. However, inhibition of mTORC1 releases feedback inhibition of mTORC2, resulting in a resurgence of Akt activation mediated by mTORC2. While the role of PI3K‐activated Akt signaling is well established in HNSCC, the significance of mTORC2‐driven Akt signaling has not been thoroughly examined. Here we explore the expression and function of mTORC2 and its obligate subunit RICTOR in HNSCC primary tumors and cell lines. We find RICTOR to be overexpressed in a subset of HNSCC tumors, including those with PIK3CA or EGFR gene amplifications. Whereas overexpression of RICTOR reduced susceptibility of HNSCC tumor cells to PI3K inhibition, genetic ablation of RICTOR using CRISPR/Cas9 sensitized cells to PI3K inhibition, as well as to EGFR inhibition and cisplatin treatment. Further, mTORC2 disruption led to reduced viability and colony forming abilities of HNSCC cells relative to their parental lines and induced loss of both activating Akt phosphorylation modifications (Thr308 and Ser473). Taken together, our findings establish RICTOR/mTORC2 as a critical oncogenic complex in HNSCC and rationalize the development of an mTORC2‐specific inhibitor for use in HNSCC, either combined with agents already under investigation, or as an independent therapy.

Background The associations of chronic cigarette smoking with blood pressure (BP) remain mixed. It is unclear whether a lack of examination of racial differences contributed to the mixed findings in previous studies. Black smokers metabolize nicotine at a slower rate than White smokers and racial discrimination contributes to nicotine dependence and higher BP among Black smokers. Methods and Results We studied the association between cigarette smoking and longitudinal (30‐year) changes in systolic BP, diastolic BP, and pulse pressure (PP) in 4786 Black and White individuals from the CARDIA (Coronary Artery Risk Development in Young Adults) study using repeated‐measures regression models. Neither systolic BP, nor diastolic BP differed between Black consistent smokers compared with Black never smokers, although Black consistent smokers had higher PP than Black never smokers (β=1.01 mm Hg, P=0.028). White consistent smokers had similar systolic BP, but lower diastolic BP (β=−2.27 mm Hg, P0.05). Conclusions Although the associations of cigarette smoking with alterations in BP are small, the greater PP observed in consistent smokers may contribute in part to the higher cardiovascular disease risk observed in this group because PP is a strong predictor of cardiovascular disease risk after middle age.

Background To determine if accelerometer measured sedentary behavior (SED), light‐intensity physical activity (LPA), and moderate‐to‐vigorous–intensity physical activity (MVPA) in midlife is prospectively associated with cognitive function. Methods and Results Participants were 1970 adults enrolled in the CARDIA (Coronary Artery Risk Development in Young Adults) study who wore an accelerometer in 2005 to 2006 (ages 38–50 years) and had cognitive function assessments completed 5 and/or 10 years later. SED, LPA, and MVPA were measured by an ActiGraph 7164 accelerometer. Cognitive function tests included the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop Test. Compositional isotemporal substitution analysis examined associations of SED, LPA, and MVPA with repeated measures of the cognitive function standardized scores. In men, statistical reallocation of 30 minutes of LPA with 30 minutes of MVPA resulted in an estimated difference of SD 0.07 (95% CI, 0.01–0.14), SD 0.09 (95% CI, 0.02–0.17), and SD −0.11 (95% CI, −0.19 to −0.04) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating better performance. Associations were similar when reallocating time in SED with MVPA, but results were less robust. Reallocation of time in SED with LPA resulted in an estimated difference of SD −0.05 (95% CI, −0.06 to −0.03), SD −0.03 (95% CI, −0.05 to −0.01), and SD 0.05 (95% CI, 0.03– 0.07) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating worse performance. Associations were largely nonsignificant among women. Conclusions Our findings support the idea that for men, higher‐intensity activities (MVPA) may be necessary in midlife to observe beneficial associations with cognition.

Q fever is a zoonotic bacterial infection caused by Coxiella burnetii. Chronic Q fever comprises less than five percent of all Q fever cases and, of those, endocarditis is the most common presentation (up to 78% of cases), followed by vascular involvement. Risk factors for chronic Q fever with vascular involvement include previous vascular surgery, preexisting valvular defects, aneurysms, and vascular prostheses. The most common symptoms of chronic Q fever with vascular involvement are nonspecific, including weight loss, fatigue, and abdominal pain. Criteria for diagnosis of chronic Q fever include clinical evidence of infection and laboratory criteria (antibody detection, detection of Coxiella burnetii DNA, or growth in culture). Treatment of chronic Q fever with vascular involvement includes a prolonged course of doxycycline and hydroxychloroquine (≥18 months) as well as early surgical intervention, which has been shown to improve survival. Mortality is high in untreated chronic Q fever. We report a case of chronic Q fever with vascular involvement in a 77-year-old man with prior infrarenal aortic aneurysm repair, who lived near a livestock farm in the southeastern United States.

Background Isotemporal substitution examines the effect on health outcomes of replacing sedentary time with light‐intensity physical activity or moderate‐to‐vigorous intensity physical activity; however, existing studies are limited by cross‐sectional study designs. Methods and Results Participants were 1922 adults from the CARDIA (Coronary Artery Risk Development in Young Adults) study. Linear regression examined the associations of sedentary, light‐intensity physical activity, and moderate‐to‐vigorous intensity physical activity at year 20 (2005–2006) with waist circumference, blood pressure, glucose, insulin, triglycerides, high‐density lipoprotein cholesterol, and a composite risk score at year 30 (2015–2016). Models then examined change in activity with change in cardiometabolic risk over the same 10‐year period. Replacing 30 min/day of sedentary time with 30 min/day of light‐intensity physical activity at year 20 was associated with a lower composite risk score (−0.01 SD [95% CI, −0.02, −0.00]) at year 30, characterized by lower waist circumference (0.15 cm [95% CI, −0.27, 0.02]), insulin (0.20 μU/mL [95% CI, −0.35, −0.04]), and higher high‐density lipoprotein cholesterol (0.20 mg/dL [95% CI, 0.00, 0.40]; all P

Purpose. To investigate the association of automated visual field (VF) reliability indices (false positive [FP], false negative [FN], and fixation loss [FL]) and sleep quality, VF experience, and age. Methods. Prospective, cross-sectional study. Adult patients (age ≥ 18 years) completing automated VF testing were invited to participate. Baseline participant characteristics were obtained, and all participants were asked to complete the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Nonparametric Spearman correlations and logistical regression models were performed. Results. 63 patients were enrolled. Lower PSQI score was correlated with higher percentage (%) FL in the right eye (p=0.03). Fewer prior VF was significantly correlated with higher %FP in the right eye (p=0.008). Older age was significantly correlated with higher %FN in the left eye (p=0.01). Greater mean deviation (MD) and pattern standard deviation (PSD) were strongly correlated with higher %FN in the right (p=0.02 and 0.002, resp.) and left eyes (p=0.01 and 0.02, resp.). Conclusion. In this prospective, cross-sectional study, worse MD and PSD are strongly correlated with increased FN in both eyes. Increased FN in the left eye associated with older age might be attributable to test fatigue. Worse sleep quality is associated with decreased FL in the right eye.