Analysis of alpha-1-antitrypsin (AAT)-regulated, glucocorticoid receptor-dependent genes in macrophages reveals a novel host defense function of AAT.

Alpha-1-antitrypsin (AAT) plays a homeostatic role in attenuating excessive inflammation and augmenting host defense against microbes. We demonstrated previously that AAT binds to the glucocorticoid receptor (GR) resulting in significant anti-inflammatory and antimycobacterial consequences in macrophages. Our current investigation aims to uncover AAT-regulated genes that rely on GR in macrophages. We incubated control THP-1 cells (THP-1control) and THP-1 cells knocked down for GR (THP-1GR-KD) with AAT, performed bulk RNA sequencing, and analyzed the findings. In THP-1control cells, AAT significantly upregulated 408 genes and downregulated 376 genes. Comparing THP-1control and THP-1GR-KD cells, 125 (30.6%) of the AAT-upregulated genes and 154 (41.0%) of the AAT-downregulated genes were significantly dependent on GR. Among the AAT-upregulated, GR-dependent genes, CSF-2 that encodes for granulocyte-monocyte colony-stimulating factor (GM-CSF), known to be host-protective against nontuberculous mycobacteria, was strongly upregulated by AAT and dependent on GR. We further quantified the mRNA and protein of several AAT-upregulated, GR-dependent genes in macrophages and the mRNA of several AAT-downregulated, GR-dependent genes. We also discussed the function(s) of selected AAT-regulated, GR-dependent gene products largely in the context of mycobacterial infections. In conclusion, AAT regulated several genes that are dependent on GR and play roles in host immunity against mycobacteria.

Acute and Repeated Ashwagandha Supplementation Improves Markers of Cognitive Function and Mood.

BACKGROUND: Ashwagandha has been reported to reduce stress and attenuate cognitive decline associated with inflammation and neurodegeneration in clinical populations. However, the effects as a potential nootropic nutrient in younger populations are unclear. This study examined the effects of liposomal ashwagandha supplementation on cognitive function, mood, and markers of health and safety in healthy young men and women. METHODS: 59 men and women (22.7 ± 7 yrs., 74.9 ± 16 kg, 26.2 ± 5 BMI) fasted for 12 h, donated a fasting blood sample, and were administered the COMPASS cognitive function test battery (Word Recall, Word recognition, Choice Reaction Time Task, Picture Recognition, Digit Vigilance Task, Corsi Block test, Stroop test) and profile of mood states (POMS). In a randomized and double-blind manner, participants were administered 225 mg of a placebo (Gum Arabic) or ashwagandha (Withania somnifera) root and leaf extract coated with a liposomal covering. After 60-min, participants repeated cognitive assessments. Participants continued supplementation (225 mg/d) for 30 days and then returned to the lab to repeat the experiment. Data were analyzed using a general linear model (GLM) univariate analysis with repeated measures and pairwise comparisons of mean changes from baseline with 95% confidence intervals (CI). RESULTS: Ashwagandha supplementation improved acute and/or 30-day measures of Word Recall (correct and recalled attempts), Choice Reaction Time (targets identified), Picture Recognition ("yes" correct responses, correct and overall reaction time), Digit Vigilance (correct reaction time), Stroop Color-Word (congruent words identified, reaction time), and POMS (tension and fatigue) from baseline more consistently with several differences observed between groups. CONCLUSION: Results support contentions that ashwagandha supplementation (225 mg) may improve some measures of memory, attention, vigilance, attention, and executive function while decreasing perceptions of tension and fatigue in younger healthy individuals. Retrospectively registered clinical trial ISRCTN58680760.

A Large Proportion of the Neonatal Iron Pool Is Acquired from the Gestational Diet in a Murine Model.

BACKGROUND: Iron is crucial for growth and development, but excess iron is harmful. Neonatal mice have elevated concentrations of circulating iron, but the source of this iron is unclear. This lack of understanding makes it difficult to optimize early life iron balance. OBJECTIVES: Identify the origins of neonatal tissue-specific iron pools using dietary manipulation and cross-fostering murine models. METHODS: To determine whether tissue-specific neonatal iron was primarily acquired during gestation or after birth, pups born to iron-sufficient or iron-deficient dams were cross-fostered, and tissues were harvested at postnatal days 3-5 to measure iron content. A separate set of female mice were fed a diet enriched with the stable iron isotope 57 (57Fe) for 4 generations to replace naturally abundant liver iron isotope 56 (56Fe) stores with 57Fe. To quantify the proportions of neonatal iron acquired during gestation, pups born to dams with 56Fe or 57Fe stores were cross-fostered, and tissues were harvested at postnatal day 3-5 to determine 56Fe:57Fe ratios by inductively coupled plasma mass spectrometry. Finally, to quantify the proportion of neonatal iron acquired from the maternal diet, female mice with 56Fe or 57Fe stores switched diets upon mating, and pup tissues were harvested on P0 to determine 56Fe:57Fe ratios by inductively coupled plasma mass spectrometry. RESULTS: Perinatal iron deficiency resulted in smaller pups, and gestational iron deficiency resulted in lower neonatal serum and liver iron. Cross-fostering between dams with 56Fe and 57Fe stores demonstrated that ≤70% of neonatal serum, liver, and brain iron were acquired during gestation. Dietary manipulation experiments using dams with 56Fe and 57Fe stores showed that over half of neonatal serum, liver, and brain iron were from the dam's gestational diet rather than preconception iron stores. CONCLUSIONS: This study provides quantitative values for the sources of neonatal iron, which may inform approaches to optimize neonatal iron status.

Paraxanthine provides greater improvement in cognitive function than caffeine after performing a 10-km run.

RATIONALE: Intense exercise promotes fatigue and can impair cognitive function, particularly toward the end of competition when decision-making is often critical for success. For this reason, athletes often ingest caffeinated energy drinks prior to or during exercise to help them maintain focus, reaction time, and cognitive function during competition. However, caffeine habituation and genetic sensitivity to caffeine (CA) limit efficacy. Paraxanthine (PX) is a metabolite of caffeine reported to possess nootropic properties. This study examined whether ingestion of PX with and without CA affects pre- or post-exercise cognitive function. METHODS: 12 trained runners were randomly assigned to consume in a double-blind, randomized, and crossover manner 400 mg of a placebo (PL); 200 mg of PL + 200 mg of CA; 200 mg of PL + 200 mg of PX (ENFINITY®, Ingenious Ingredients); or 200 mg PX + 200 mg of CA (PX+CA) with a 7-14-day washout between treatments. Participants donated fasting blood samples and completed pre-supplementation (PRE) side effects questionnaires, the Berg-Wisconsin Card Sorting Test (BCST), and the Psychomotor Vigilance Task Test (PVTT). Participants then ingested the assigned treatment and rested for 60 minutes, repeated tests (PRE-EX), performed a 10-km run on a treadmill at a competition pace, and then repeated tests (POST-EX). Data were analyzed using General Linear Model (GLM) univariate analyses with repeated measures and percent changes from baseline with 95% confidence intervals. RESULTS: BCST correct responses in the PX treatment increased from PRE-EX to POST-EX (6.8% [1.5, 12.1], p = 0.012). The error rate in the PL (23.5 [-2.8, 49.8] %, p = 0.078) and CA treatment (31.5 [5.2, 57.8] %, p = 0.02) increased from PRE-EX values with POST-EX errors tending to be lower with PX treatment compared to CA (-35.7 [-72.9, 1.4] %, p = 0.059). POST-EX perseverative errors with PAR rules were significantly lower with PX treatment than with CA (-26.9 [-50.5, -3.4] %, p = 0.026). Vigilance analysis revealed a significant interaction effect in Trial #2 mean reaction time values (p = 0.049, ηp2 = 0.134, moderate to large effect) with POST-EX reaction times tending to be faster with PX and CA treatment. POST-EX mean reaction time of all trials with PX treatment was significantly faster than PL (-23.2 [-43.4, -2.4] %, p = 0.029) and PX+CA (-29.6 [-50.3, -8.80] %, p = 0.006) treatments. There was no evidence that PX ingestion adversely affected ratings of side effects associated with stimulant intake or clinical blood markers. CONCLUSIONS: Results provide some evidence that pre-exercise PX ingestion improves prefrontal cortex function, attenuates attentional decline, mitigates cognitive fatigue, and improves reaction time and vigilance. Adding CA to PX did not provide additional benefits. Therefore, PX ingestion may serve as a nootropic alternative to CA.

Effects of Supplementation with Microalgae Extract from Phaeodactylum tricornutum (Mi136) to Support Benefits from a Weight Management Intervention in Overweight Women.

BACKGROUND: Microalgae like Phaeodactylum tricornutum (PT) contain the carotenoid, fucoxanthin, which has been purported to promote fat loss, lower blood lipids, and improve glucose management. This study examined whether dietary supplementation with microalgae extracts from PT containing 4.4 mg/d of fucoxanthin affects changes in body composition or health markers in overweight women during an exercise and diet intervention. MATERIALS AND METHODS: A total of 37 females (28.6 ± 7.9 years, 80.2 ± 14.9 kg, 29.6 ± 3.8 kg/m², 41.4 ± 4.2% fat) fasted for 12 h, donated a fasting blood sample, completed health and mood state inventories, and undertook body composition, health, and exercise assessments. In a counterbalanced, randomized, and double-blind manner, participants ingested a placebo (PL), or microalgae extract of Phaeodactylum tricornutum standardized to 4.4 mg of fucoxanthin (FX) for 12 weeks while participating in a supervised exercise program that included resistance-training and walking (3 days/week) with encouragement to accumulate 10,000 steps/day on remaining days of the week. The diet intervention involved reducing energy intake by about -300 kcal/d (i.e., ≈1400-1600 kcals/d, 55% carbohydrate, 30% fat, 15% protein) to promote a -500 kcal/d energy deficit with exercise. Follow-up testing was performed at 6 and 12 weeks. A general linear model (GLM) with repeated measures statistical analysis was used to analyze group responses and changes from baseline with 95% confidence intervals. RESULTS: Dietary supplementation with microalgae extract from PT containing fucoxanthin for 12 weeks did not promote additional weight loss or fat loss in overweight but otherwise healthy females initiating an exercise and diet intervention designed to promote modest weight loss. However, fucoxanthin supplementation preserved bone mass, increased bone density, and saw greater improvements in walking steps/day, resting heart rate, aerobic capacity, blood lipid profiles, adherence to diet goals, functional activity tolerance, and measures of quality of life. Consequently, there appears to be some benefit to supplementing microalgae extract from PT containing fucoxanthin during a diet and exercise program. Registered clinical trial #NCT04761406.

Adolescent substance use outcomes in response to social consequences of use: the role of empathy.

Evidence suggests empathy deficits have a temporal relationship with substance use severity by late adolescence theorized to decrease use via recognition of social consequences. However, this has yet to be tested empirically along with differences in cognitive and affective empathy. Adolescents admitted to substance use treatment (n= 3,382) were followed through treatment and 12 months after treatment. Variable trajectories were fit using growth curve models; and cross-lagged effects of cognitive and affective empathy on response to social consequences of use were tested along with how response to social consequences affected the mean trajectory of substance use. Results indicate higher cognitive empathy predicted greater response to social consequences of use and response to these consequences at the end of treatment predicted a steeper decrease in substance use. This evidence highlights the importance of cognitive empathy for responding to social consequences of use for motivating less substance use in adolescents.

A Technique for Arthroscopic Fixation of Tibial Eminence Avulsion Fractures: A Physeal-Sparing Construct With All-Suture Anchor Bridge Fixation.

Arthroscopic or open surgical treatment is indicated for displaced tibial spine fractures to obtain anatomic reduction and restore the functionality of the anterior cruciate ligament. Numerous open and arthroscopic techniques for the treatment of tibial spine fractures have been described. The purpose of this technical note is to describe a minimally invasive arthroscopic physeal- and ligament-sparing surgical technique using knotless all-suture anchors to provide stable bridge fixation over displaced tibial spine fractures.

Exploring practices to enhance benefits and reduce risks of chemsex among gay, bisexual, and other men who have sex with men: A meta-ethnography.

BACKGROUND: Chemsex is the intentional combining of specific drugs with sex, primarily by gay, bisexual, and other men who have sex with men (GBMSM), to enhance intimacy, pleasure, and prolong sexual sessions. Practices vary across geographic and social settings. Participants report benefits and risks of chemsex. Studies have previously reviewed chemsex practices and harm reduction interventions separately. This review aims to examine both together by describing and understanding practices that men employ to navigate the perceived benefits and risks of chemsex. METHODS: We conducted a systematic meta-ethnographic review of published qualitative literature, screening titles, abstracts, and full texts on defined inclusion and exclusion criteria. Using reciprocal and refutational translation techniques, we analysed study participants' (first-order) and researchers' (second-order) accounts of benefit-enhancing and risk-reducing chemsex practices. Finally, we employed line-of-argument synthesis techniques to develop our own higher-level interpretations (third-order constructs) of these chemsex practices. RESULTS: Our search yielded 6356 records, from which, we included 23 articles in our review. Most studies were conducted in high-income Western countries. Across studies, participants acted at the individual, interpersonal, and community levels to enhance benefits and reduce risks, which made up our third-order constructs. Eight themes emerged from first- and second-order constructs to describe these practices, which included personal preparation, personal boundaries, biomedical measures, structured use of drugs, leaning on partners, injecting practices, group organising, watching out for others, and teaching and learning. Contextual factors like trust, agency, access, stigma, and setting moderated whether and how participants engaged in these practices, and if practices enhanced benefits or reduced risks. CONCLUSION: Health promotion programmes and research focused on chemsex must account for the benefits and the risks that GBMSM associate with this type of sexualised drug use and target the moderating factors that shape the practices they employ to navigate these benefits and risks.

Accounting for albedo change to identify climate-positive tree cover restoration.

Restoring tree cover changes albedo, which is the fraction of sunlight reflected from the Earth's surface. In most locations, these changes in albedo offset or even negate the carbon removal benefits with the latter leading to global warming. Previous efforts to quantify the global climate mitigation benefit of restoring tree cover have not accounted robustly for albedo given a lack of spatially explicit data. Here we produce maps that show that carbon-only estimates may be up to 81% too high. While dryland and boreal settings have especially severe albedo offsets, it is possible to find places that provide net-positive climate mitigation benefits in all biomes. We further find that on-the-ground projects are concentrated in these more climate-positive locations, but that the majority still face at least a 20% albedo offset. Thus, strategically deploying restoration of tree cover for maximum climate benefit requires accounting for albedo change and we provide the tools to do so.

Physiological Stress Responses to a Live-Fire Training Evolution in Career Structural Firefighters.

OBJECTIVE: This study assessed firefighters' physiological stress response to a live fire training evolution (LFTE). METHODS: Seventy-six ( n = 76) firefighters completed an LFTE. Salivary samples were collected pre-, immediately post, and 30-min post-LFTE and analyzed for α-amylase (AA), cortisol (CORT), and secretory immunoglobulin-A (SIgA). RESULTS: Concentrations of AA, CORT, and SIgA were elevated immediately post LFTE versus pre (P<0.001) and 30-min post (P<0.001). Cohen's d effect size comparing pre and immediately-post means were 0.83, 0.77, and 0.61 for AA, CORT, and SIgA and were 0.54, 0.44, and 0.69 for AA, CORT, and SIgA, comparing immediately-post and 30-min post, respectively. CONCLUSIONS: These data demonstrate the stress response and activation of the hypothalamic-pituitary-adrenal/sympathetic-adreno-medullar axis and immune system immediately after real-world firefighting operations. Future work is needed to understand the impact of elevated stress biomarkers on firefighter performance and disease risk.

Firefighter Health: A Narrative Review of Occupational Threats and Countermeasures.

Structural firefighters are responsible for protecting properties and saving lives during emergency operations. Despite efforts to prepare firefighters for these hazardous occupational demands, the unfortunate reality is that the incidence of health morbidities is increasing within the fire service. Specifically, cardiovascular disease, cancer, and mental health disorders are among the most documented morbidities in firefighters. Pubmed and Google Scholar search engines were used to identify peer-reviewed English language manuscripts that evaluated firefighters' occupational health threats, allostatic factors associated with their occurrence, and evidence-based strategies to mitigate their impact. This narrative review provides fire departments, practitioners, and researchers with evidence-based practices to enhance firefighters' health.

Genomic architecture controls multivariate adaptation to climate change.

As climate change advances, environmental gradients may decouple, generating novel multivariate environments that stress wild populations. A commonly invoked mechanism of evolutionary rescue is adaptive gene flow tracking climate shifts, but gene flow from populations inhabiting similar conditions on one environmental axis could cause maladaptive introgression when populations are adapted to different environmental variables that do not shift together. Genomic architecture can play an important role in determining the effectiveness and relative magnitudes of adaptive gene flow and in situ adaptation. This may have direct consequences for how species respond to climate change but is often overlooked. Here, we simulated microevolutionary responses to environmental change under scenarios defined by variation in the polygenicity, linkage, and genetic redundancy of two independent traits, one of which is adapted to a gradient that shifts under climate change. We used these simulations to examine how genomic architecture influences evolutionary outcomes under climate change. We found that climate-tracking (up-gradient) gene flow, though present in all scenarios, was strongly constrained under scenarios of lower linkage and higher polygenicity and redundancy, suggesting in situ adaptation as the predominant mechanism of evolutionary rescue under these conditions. We also found that high polygenicity caused increased maladaptation and demographic decline, a concerning result given that many climate-adapted traits may be polygenic. Finally, in scenarios with high redundancy, we observed increased adaptive capacity. This finding adds to the growing recognition of the importance of redundancy in mediating in situ adaptive capacity and suggests opportunities for better understanding the climatic vulnerability of real populations.

Associations between forms of aggression and peer victimization: Does prosocial behavior matter?

Relatively little is known regarding factors that may mitigate the strength of the associations between forms of aggressive behavior and peer victimization. The goal of the current study was to investigate prosocial behavior as a moderator of these links over a 2-year period during middle childhood. Participants included 410 third-grade students (53% boys) and their homeroom teachers. Results indicated that prosocial behavior was associated with lower initial levels of victimization, whereas relational aggression was associated with higher initial levels of victimization. Physical aggression predicted more stable patterns of victimization over time, and prosocial behavior moderated the prospective link from relational aggression to peer victimization; specifically, relational aggression predicted decreases in victimization at higher levels of prosocial behavior and more stable patterns over time when levels of prosocial behavior were low. Further, gender differences were observed in the moderating effect of prosocial behavior on the prospective link from physical aggression to peer victimization, such that it served as a risk factor for boys and a protective factor for girls.

Further evidence of renewal in automatically maintained behavior.

Renewal is a relapse phenomenon that refers to the recurrence of a previously reduced behavior following a change in stimulus conditions. Muething et al. (2022) examined the phenomenology of renewal among individuals with automatically maintained challenging behavior treated at an outpatient clinic. We replicated their findings by retrospectively examining renewal across various topographies of automatically maintained behavior treated at an inpatient hospital, and we extended their work by also examining differences across subtypes of automatically maintained self-injurious behavior. The prevalence of renewal was comparable to that observed by Muething et al., supporting the notion that automatically maintained challenging behavior is susceptible to relapse phenomena. Furthermore, renewal was twice as likely to occur for individuals with Subtype 2 versus Subtype 1 self-injurious behavior, providing additional evidence of behavioral differentiation between subtypes. Our findings suggest that even after apparent stability in treatment, practitioners should remain vigilant for the recurrence of automatically maintained behavior during generalization.

Stress response to virtual reality based active shooter training: Impact of caffeine consumption.

Participation in a virtual reality based active shooter training drill (VR-ASD) has been shown to increase biomarkers of stress; however, the impact of caffeine consumption on this response has not been studied. Caffeine ingestion has been shown to have favorable effects on physical and cognitive performance among athletic and tactical occupations alike. This study examined the impact of caffeine ingestion on subjective and physiological markers of stress in response to a mental stress task (MST) which involved participation in a VR-ASD and cognitive challenge consisting of mental arithmetic and a Stroop challenge. Fifty-three subjects were randomly assigned either caffeine (n = 26) or placebo (n = 27) prior to being exposed to the MST. Saliva samples, heart rate (HR), and state-anxiety inventory (SAI) scales, were collected before and after exposure to the MST. Saliva was analyzed for α-amylase (sAA), secretory IgA (SIgA), and cortisol (sCORT) concentrations. The MST resulted in significant increases in sAA, SIgA, HR, and SAI. Immediately post MST, sAA concentrations were significantly higher following the caffeine treatment compared to placebo. These data demonstrate that caffeine consumption results in significantly greater sAA concentrations post MST. This study was pre-registered as a clinical trial ("Impact of supplements on stress markers": NCT05592561).

Adverse outcomes and an immunosuppressed endotype in septic patients with reduced IFN-γ ELISpot.

BACKGROUNDSepsis remains a major clinical challenge for which successful treatment requires greater precision in identifying patients at increased risk of adverse outcomes requiring different therapeutic approaches. Predicting clinical outcomes and immunological endotyping of septic patients generally relies on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision.METHODSAn ex vivo whole-blood enzyme-linked immunosorbent spot (ELISpot) assay for cellular production of interferon γ (IFN-γ) was evaluated in 107 septic and 68 nonseptic patients from 5 academic health centers using blood samples collected on days 1, 4, and 7 following ICU admission.RESULTSCompared with 46 healthy participants, unstimulated and stimulated whole-blood IFN-γ expression was either increased or unchanged, respectively, in septic and nonseptic ICU patients. However, in septic patients who did not survive 180 days, stimulated whole-blood IFN-γ expression was significantly reduced on ICU days 1, 4, and 7 (all P < 0.05), due to both significant reductions in total number of IFN-γ-producing cells and amount of IFN-γ produced per cell (all P < 0.05). Importantly, IFN-γ total expression on days 1 and 4 after admission could discriminate 180-day mortality better than absolute lymphocyte count (ALC), IL-6, and procalcitonin. Septic patients with low IFN-γ expression were older and had lower ALCs and higher soluble PD-L1 and IL-10 concentrations, consistent with an immunosuppressed endotype.CONCLUSIONSA whole-blood IFN-γ ELISpot assay can both identify septic patients at increased risk of late mortality and identify immunosuppressed septic patients.TRIAL REGISTRYN/A.FUNDINGThis prospective, observational, multicenter clinical study was directly supported by National Institute of General Medical Sciences grant R01 GM-139046, including a supplement (R01 GM-139046-03S1) from 2022 to 2024.

Executive function and underlying brain network distinctions for callous-unemotional traits and conduct problems in adolescents.

The complexity of executive function (EF) impairments in youth antisocial phenotypes of callous-unemotional (CU) traits and conduct problems (CP) challenge identifying phenotypic specific EF deficits. We can redress these challenges by (1) accounting for EF measurement error and (2) testing distinct functional brain properties accounting for differences in EF. Thus, we employed a latent modeling approach for EFs (inhibition, shifting, fluency, common EF) and extracted connection density from matching contemporary EF brain models with a sample of 112 adolescents (ages 13-17, 42% female). Path analysis indicated CU traits associated with lower inhibition. Inhibition network density positively associated with inhibition, but this association was strengthened by CU and attenuated by CP. Common EF associated with three-way interactions between density*CP by CU for the inhibition and shifting networks. This suggests those higher in CU require their brain to work harder for lower inhibition, whereas those higher in CP have difficulty engaging inhibitory brain responses. Additionally, those with CP interacting with CU show distinct brain patterns for a more general EF capacity. Importantly, modeling cross-network connection density in contemporary EF models to test EF involvement in core impairments in CU and CP may accelerate our understanding of EF in these phenotypes.

International Society of Sports Nutrition Position Stand: Effects of essential amino acid supplementation on exercise and performance.

Position Statement: The International Society of Sports Nutrition (ISSN) presents this position based on a critical examination of literature surrounding the effects of essential amino acid (EAA) supplementation on skeletal muscle maintenance and performance. This position stand is intended to provide a scientific foundation to athletes, dietitians, trainers, and other practitioners as to the benefits of supplemental EAA in both healthy and resistant (aging/clinical) populations. EAAs are crucial components of protein intake in humans, as the body cannot synthesize them. The daily recommended intake (DRI) for protein was established to prevent deficiencies due to inadequate EAA consumption. The following conclusions represent the official position of the Society: 1. Initial studies on EAAs' effects on skeletal muscle highlight their primary role in stimulating muscle protein synthesis (MPS) and turnover. Protein turnover is critical for replacing degraded or damaged muscle proteins, laying the metabolic foundation for enhanced functional performance. Consequently, research has shifted to examine the effects of EAA supplementation - with and without the benefits of exercise - on skeletal muscle maintenance and performance. 2. Supplementation with free-form EAAs leads to a quick rise in peripheral EAA concentrations, which in turn stimulates MPS. 3. The safe upper limit of EAA intake (amount), without inborn metabolic disease, can easily accommodate additional supplementation. 4. At rest, stimulation of MPS occurs at relatively small dosages (1.5-3.0 g) and seems to plateau at around 15-18 g. 5. The MPS stimulation by EAAs does not require non-essential amino acids. 6. Free-form EAA ingestion stimulates MPS more than an equivalent amount of intact protein. 7. Repeated EAA-induced MPS stimulation throughout the day does not diminish the anabolic effect of meal intake. 8. Although direct comparisons of various formulas have yet to be investigated, aging requires a greater proportion of leucine to overcome the reduced muscle sensitivity known as "anabolic resistance." 9. Without exercise, EAA supplementation can enhance functional outcomes in anabolic-resistant populations. 10. EAA requirements rise in the face of caloric deficits. During caloric deficit, it's essential to meet whole-body EAA requirements to preserve anabolic sensitivity in skeletal muscle.

Cognitive Mechanisms Underlying Prosocial Decision Making in Callous-Unemotional Traits.

Callous-unemotional (CU) traits are characterized by a lack of prosocial emotions, which has been demonstrated with prosocial behavior paradigms. While shaping our understanding of prosocial behavior in youth with CU traits, most of this work relies on outcomes that don't reliably capture cognitive processes during prosocial behavior. Examining prosocial cognitive processes can cue researchers into cognitive mechanisms underlying core impairments of CU traits. Drift diffusion modeling is a valuable tool for elucidating more precise outcomes of latent cognitive processes during forced choice tasks such as drift rate (information accumulation toward a decision boundary) and threshold separation (amount of information considered) as well as metrics outside of the decision-making processing including bias (starting point in decision process) and non-decision time (cognitive processes outside of choice). In a sample of 87 adolescents (12-14, 49% female) we applied diffusion modeling to a prosocial behavior task in which participants either accepted or rejected trials where a real monetary value was given to them and taken away from a charity (self-serving trial) or money was given to a charity and taken from them (donation trial). Results revealed that CU traits associated with information accumulation toward accepting self-serving trials. Exploratory sex differences suggested males trended toward rejecting donation trials and females considered more information during self-serving trials. CU trait associations were independent of conduct problems. Results suggest a unique cognitive profile that are differentiated by sex at higher CU traits when making prosocial decisions involving knowledge accumulation toward self-serving decisions.

Connectome-based predictive modeling of empathy in adolescents with and without the low-prosocial emotion specifier.

Empathy impairments are an important part of a broader affective impairments defining the youth antisocial phenotype callous-unemotional (CU) traits and the DSM-5 low prosocial emotion (LPE) specifier. While functional connectivity underlying empathy and CU traits have been well studied, less is known about what functional connections underly differences in empathy amongst adolescents qualifying for the LPE specifier. Such information can provide mechanistic distinctions for this clinically relevant specifier. The present study uses connectome-based predictive modeling that uses whole-brain resting-state functional connectivity data to predict cognitive and affective empathy for those meeting the LPE specifier (n = 29) and those that do not (n = 57). Additionally, we tested if models of empathy generalized between groups as well as density differences for each model of empathy between groups. Results indicate the LPE group had lower cognitive and affective empathy as well as higher CU traits and conduct problems. Negative and positive models were identified for affective empathy for both groups, but only the negative model for the LPE and positive model for the normative group reliably predicted cognitive empathy. Models predicting empathy did not generalize between groups. Density differences within the default mode, salience, executive control, limbic, and cerebellar networks were found as well as between the executive control, salience, and default mode networks. And, importantly, connections between the executive control and default mode networks characterized empathy differences the LPE group such that more positive connections characterized cognitive differences and less negative connections characterized affective differences. These findings indicate neural differences in empathy for those meeting LPE criteria that may explain decrements in empathy amongst these youth. These findings support theoretical accounts of empathy decrements in the LPE clinical specifier and extend them to identify specific circuits accounting for variation in empathy impairments. The identified negative models help understand what connections inhibit empathy whereas the positive models reveal what brain patterns are being used to support empathy in those with the LPE specifier. LPE differences from the normative group and could be an appropriate biomarker for predicting CU trait severity. Replication and validation using other large datasets are important next steps.