Free-standing membrane incorporating single-atom catalysts for ultrafast electroreduction of low-concentration nitrate.

The release of wastewaters containing relatively low levels of nitrate (NO3-) results in sufficient contamination to induce harmful algal blooms and to elevate drinking water NO3- concentrations to potentially hazardous levels. In particular, the facile triggering of algal blooms by ultra-low concentrations of NO3- necessitates the development of efficient methods for NO3- destruction. However, promising electrochemical methods suffer from weak mass transport under low reactant concentrations, resulting in long treatment times (on the order of hours) for complete NO3- destruction. In this study, we present flow-through electrofiltration via an electrified membrane incorporating nonprecious metal single-atom catalysts for NO3- reduction activity enhancement and selectivity modification, achieving near-complete removal of ultra-low concentration NO3- (10 mg-N L-1) with a residence time of only a few seconds (10 s). By anchoring Cu single atoms supported on N-doped carbon in a carbon nanotube interwoven framework, we fabricate a free-standing carbonaceous membrane featuring high conductivity, permeability, and flexibility. The membrane achieves over 97% NO3- removal with high N2 selectivity of 86% in a single-pass electrofiltration, which is a significant improvement over flow-by operation (30% NO3- removal with 7% N2 selectivity). This high NO3- reduction performance is attributed to the greater adsorption and transport of nitric oxide under high molecular collision frequency coupled with a balanced supply of atomic hydrogen through H2 dissociation during electrofiltration. Overall, our findings provide a paradigm of applying a flow-through electrified membrane incorporating single-atom catalysts to improve the rate and selectivity of NO3- reduction for efficient water purification.

PRC2-independent actions of H3.3K27M in embryonic stem cell differentiation.

The histone H3 variant, H3.3, is localized at specific regions in the genome, especially promoters and active enhancers, and has been shown to play important roles in development. A lysine to methionine substitution in position 27 (H3.3K27M) is a main cause of Diffuse Intrinsic Pontine Glioma (specifically Diffuse Midline Glioma, K27M-mutant), a lethal type of pediatric cancer. H3.3K27M has a dominant-negative effect by inhibiting the Polycomb Repressor Complex 2 (PRC2) activity. Here, we studied the immediate, genome-wide, consequences of the H3.3K27M mutation independent of PRC2 activity. We developed Doxycycline (Dox)-inducible mouse embryonic stem cells (ESCs) carrying a single extra copy of WT-H3.3, H3.3K27M and H3.3K27L, all fused to HA. We performed RNA-Seq and ChIP-Seq at different times following Dox induction in undifferentiated and differentiated ESCs. We find increased binding of H3.3 around transcription start sites in cells expressing both H3.3K27M and H3.3K27L compared with WT, but not in cells treated with PRC2 inhibitors. Differentiated cells carrying either H3.3K27M or H3.3K27L retain expression of ESC-active genes, in expense of expression of genes related to neuronal differentiation. Taken together, our data suggest that a modifiable H3.3K27 is required for proper histone incorporation and cellular maturation, independent of PRC2 activity.

Mapping the duration and severity of preschool-aged children's depressive moods and behaviors.

BACKGROUND: Depressive moods and behaviors are developmentally normative, yet potentially impairing, in preschool-aged children. In addition to frequency, duration of behavior is an important parameter to consider when characterizing risk for worsening mood dysregulation. The goal of this study was to identify the duration and severity of depressive moods and behaviors and associations with impairment in a large community sample of preschool-aged children using an online parent-report daily diary. METHODS: Primary caregivers (N = 900) of 3-5-year-old children reported the daily duration of each instance of seven depressive moods and behaviors for 14 days. We used item response theory analyses to examine duration item characteristics. RESULTS: Moods and behaviors occurred at specific durations to be considered psychometrically severe/rare; for example, instances of sadness had to last an average total of 32 min per day or more, irritability at least 38 min, tantrums at least 30 min, and tearfulness/sensitivity at least 35 min. Longer durations of mood and behavior were associated with daily impairment, as well as older child age and less parental education. CONCLUSIONS: To our knowledge, this is the first study to delineate specific duration ranges for depressive moods and behaviors in preschool-aged children. These data, coupled with information about the frequency of mood-related behaviors, can assist child practitioners in differentiating normative patterns from less normative mood problems to evaluate which children may be at risk. Future work should identify the duration of depressive moods and behaviors in early childhood that predict clinically significant psychopathology over time.

Comparison of Global and Daily Ratings of Associations between Anxiety and Depressive Behaviors and Impairment in Preschool-Aged Children.

Anxiety and depressive difficulties can emerge during early childhood and cause impairment in functioning. Anxiety and depressive behaviors and impairment are typically assessed with global questionnaires that require recall of children's behavior over an extended period which could reduce the accuracy of parent report of children's behavior and functioning. The current study compared parents' report of children's anxiety and depressive behaviors and impairment when evaluated with global measures versus a daily diary measure. Participants (N = 901 parents of 3-5-year-old children) completed global and daily measures of children's behavior and impairment during enrollment to the study. Global measures were completed at baseline and the 14 daily diary measures were completed consecutively for two weeks. Across most measures, daily associations between parent-reported anxiety and depressive behaviors and impairment were stronger compared to associations with global measures. These results suggest that daily measures may better capture links between young children's typical behavior and functioning compared to global measures. In addition, daily assessment might be more effective for measuring mild to moderate yet still impairing behaviors that may be missed on global reports that require longer periods of recall.

Pharmacokinetic and Pharmacodynamic Consequences of Cytochrome P450 3A Inhibition on Mitragynine Metabolism in Rats.

Mitragynine, an opioidergic alkaloid present in Mitragyna speciosa (kratom), is metabolized by cytochrome P450 3A (CYP3A) to 7-hydroxymitragynine, a more potent opioid receptor agonist. The extent to which conversion to 7-hydroxymitragynine mediates the in vivo effects of mitragynine is unclear. The current study examined how CYP3A inhibition (ketoconazole) modifies the pharmacokinetics of mitragynine in rat liver microsomes in vitro. The study further examined how ketoconazole modifies the discriminative stimulus and antinociceptive effects of mitragynine in rats. Ketoconazole [30 mg/kg, oral gavage (o.g.)] increased systemic exposure to mitragynine (13.3 mg/kg, o.g.) by 120% and 7-hydroxymitragynine exposure by 130%. The unexpected increase in exposure to 7-hydroxymitragynine suggested that ketoconazole inhibits metabolism of both mitragynine and 7-hydroxymitragynine, a finding confirmed in rat liver microsomes. In rats discriminating 3.2 mg/kg morphine from vehicle under a fixed-ratio schedule of food delivery, ketoconazole pretreatment increased the potency of both mitragynine (4.7-fold) and 7-hydroxymitragynine (9.7-fold). Ketoconazole did not affect morphine's potency. Ketoconazole increased the antinociceptive potency of 7-hydroxymitragynine by 4.1-fold. Mitragynine (up to 56 mg/kg, i.p.) lacked antinociceptive effects both in the presence and absence of ketoconazole. These results suggest that both mitragynine and 7-hydroxymitragynine are cleared via CYP3A and that 7-hydroxymitragynine is formed as a metabolite of mitragynine by other routes. These results have implications for kratom use in combination with numerous medications and citrus juices that inhibit CYP3A. SIGNIFICANCE STATEMENT: Mitragynine is an abundant kratom alkaloid that exhibits low efficacy at the µ-opioid receptor (MOR). Its metabolite, 7-hydroxymitragynine, is also an MOR agonist but with higher affinity and efficacy than mitragynine. Our results in rats demonstrate that cytochrome P450 3A (CYP3A) inhibition can increase the systematic exposure of both mitragynine and 7-hydroxymitragynine and their potency to produce MOR-mediated behavioral effects. These data highlight potential interactions between kratom and CYP3A inhibitors, which include numerous medications and citrus juices.

Do general and specific factors of preschool psychopathology predict preadolescent outcomes? A transdiagnostic hierarchical approach.

BACKGROUND: Preschool psychiatric symptoms significantly increase the risk for long-term negative outcomes. Transdiagnostic hierarchical approaches that capture general ('p') and specific psychopathology dimensions are promising for understanding risk and predicting outcomes, but their predictive utility in young children is not well established. We delineated a hierarchical structure of preschool psychopathology dimensions and tested their ability to predict psychiatric disorders and functional impairment in preadolescence. METHODS: Data for 1253 preschool children (mean age = 4.17, s.d. = 0.81) were drawn from three longitudinal studies using a similar methodology (one community sample, two psychopathology-enriched samples) and followed up into preadolescence, yielding a large and diverse sample. Exploratory factor models derived a hierarchical structure of general and specific factors using symptoms from the Preschool Age Psychiatric Assessment interview. Longitudinal analyses examined the prospective associations of preschool p and specific factors with preadolescent psychiatric disorders and functional impairment. RESULTS: A hierarchical dimensional structure with a p factor at the top and up to six specific factors (distress, fear, separation anxiety, social anxiety, inattention-hyperactivity, oppositionality) emerged at preschool age. The p factor predicted all preadolescent disorders (ΔR2 = 0.04-0.15) and functional impairment (ΔR2 = 0.01-0.07) to a significantly greater extent than preschool psychiatric diagnoses and functioning. Specific dimensions provided additional predictive power for the majority of preadolescent outcomes (disorders: ΔR2 = 0.06-0.15; functional impairment: ΔR2 = 0.05-0.12). CONCLUSIONS: Both general and specific dimensions of preschool psychopathology are useful for predicting clinical and functional outcomes almost a decade later. These findings highlight the value of transdiagnostic dimensions for predicting prognosis and as potential targets for early intervention and prevention.

Tonic and phasic irritability in 6-year-old children: differential correlates and outcomes.

OBJECTIVE: Irritability is a common and clinically important problem in children and adolescents and a risk factor for later psychopathology and impairment. Irritability can manifest in both tonic (e.g., irritable, touchy mood) and phasic (e.g., temper outburst) forms, and recent studies of adolescents suggest that they predict different outcomes. However, no studies have examined whether tonic and phasic irritability are empirically distinguishable in 6-year-old children and whether they have distinct correlates and outcomes. METHOD: We utilized data from a longitudinal study of an unselected community sample of four hundred fifty-two 6-year-olds followed at 3-year intervals to age 15. We conducted confirmatory factor analysis (CFA) using relevant items from a diagnostic interview and several parent-report inventories. RESULTS: The CFA identified dimensions that were consistent with tonic and phasic irritability. Tonic irritability was independently associated with concurrent parent-reported temperamental negative affectivity and internalizing and externalizing disorders at age 6 and predicted higher rates of internalizing psychopathology, and suicidal ideation, in adolescence. Phasic irritability was independently associated with concurrent parent-reported temperamental negative affectivity, surgency, and low effortful control, maladaptive parenting styles and practices, and externalizing disorders at age 6, and predicted higher rates of externalizing psychopathology in adolescence. CONCLUSIONS: Tonic and phasic irritability in 6-year-old children appear to be distinguishable constructs with different temperament and parenting correlates and psychopathological outcomes. Distinguishing these components has implications for research on the etiology and pathophysiology of irritability and developing effective treatments.

Testing reciprocal associations between child anxiety and parenting across early interventions for inhibited preschoolers.

BACKGROUND: Given the robust evidence base for the efficacy of evidence-based treatments targeting youth anxiety, researchers have advanced beyond efficacy outcome analysis to identify mechanisms of change and treatment directionality. Grounded in developmental transactional models, interventions for young children at risk for anxiety by virtue of behaviorally inhibited temperament often target parenting and child factors implicated in the early emergence and maintenance of anxiety. In particular, overcontrolling parenting moderates risk for anxiety among highly inhibited children, just as child inhibition has been shown to elicit overcontrolling parenting. Although longitudinal research has elucidated the temporal unfolding of factors that interact to place inhibited children at risk for anxiety, reciprocal transactions between these child and parent factors in the context of early interventions remain unknown. METHOD: This study addresses these gaps by examining mechanisms of change and treatment directionality (i.e., parent-to-child vs. child-to-parent influences) within a randomized controlled trial comparing two interventions for inhibited preschoolers (N = 151): the multicomponent Turtle Program ('Turtle') and the parent-only Cool Little Kids program ('CLK'). Reciprocal relations between parent-reported child anxiety, observed parenting, and parent-reported accommodation of child anxiety were examined across four timepoints: pre-, mid-, and post-treatment, and one-year follow-up (NCT02308826). RESULTS: Hypotheses were tested via latent curve models with structured residuals (LCM-SR) and latent change score (LCS) models. LCM-SR results were consistent with the child-to-parent influences found in previous research on cognitive behavioral therapy (CBT) for older anxious youth, but only emerged in Turtle. LCS analyses revealed bidirectional effects of changes in parent accommodation and child anxiety during and after intervention, but only in Turtle. CONCLUSION: Our findings coincide with developmental transactional models, suggesting that the development of child anxiety may result from child-to-parent influences rather than the reverse, and highlight the importance of targeting parent and child factors simultaneously in early interventions for young, inhibited children.

Microalgae Commercialization Using Renewable Lignocellulose Is Economically and Environmentally Viable.

Conventional phototrophic cultivation for microalgae production suffers from low and unstable biomass productivity due to limited and unreliable light transmission outdoors. Alternatively, the use of a renewable lignocellulose-derived carbon source, cellulosic hydrolysate, offers a cost-effective and sustainable pathway to cultivate microalgae heterotrophically with high algal growth rate and terminal density. In this study, we evaluate the feasibility of cellulosic hydrolysate-mediated heterotrophic cultivation (Cel-HC) for microalgae production by performing economic and environmental comparisons with phototrophic cultivation through techno-economic analysis and life cycle assessment. We estimate a minimum selling price (MSP) of 4722 USD/t for producing high-purity microalgae through Cel-HC considering annual biomass productivity of 300 t (dry weight), which is competitive with the conventional phototrophic raceway pond system. Revenues from the lignocellulose-derived co-products, xylose and fulvic acid fertilizer, could further reduce the MSP to 2976 USD/t, highlighting the advantages of simultaneously producing high-value products and biofuels in an integrated biorefinery scheme. Further, Cel-HC exhibits lower environmental impacts, such as cumulative energy demand and greenhouse gas emissions, than phototrophic systems, revealing its potential to reduce the carbon intensity of algae-derived commodities. Our results demonstrate the economic and environmental competitiveness of heterotrophic microalgae production based on renewable bio-feedstock of lignocellulose.

Feeding after spawning and energy balance at spawning are associated with repeat spawning interval in steelhead trout.

Consecutive and skip repeat spawning (1- or ≥2-year spawning interval) life histories commonly occur in seasonally breeding iteroparous fishes. Spawning interval variation is driven by energetic status and impacts fisheries management. In salmonids, energetic status (either absolute level of energy reserves or the rate of change of energy reserves, i.e., energy balance) is thought to determine reproductive trajectory during a critical period ∼1 year prior to initial spawning. However, information on repeat spawners is lacking. To examine the timing and the aspects of energetic status that regulate repeat spawning interval, female steelhead trout (Oncorhynchus mykiss) were fasted for 10 weeks after spawning and then fed ad libitum and compared to ad libitum fed controls. Plasma growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels were measured to assess long-term energy balance. Plasma estradiol levels showed that some fish in both groups initiated a consecutive spawning cycle. In fasted fish, GH was lower at spawning in consecutive versus skip spawners. In consecutive spawners, GH was higher at spawning in fed versus fasted fish. These results suggest that fish with a less negative energy balance at spawning initiated reproductive development in the absence of feeding, but that feeding during the post-spawning period enabled initiation of reproduction in some fish with a more negative energy balance at spawning. Thus, both energy balance at spawning and feeding after spawning regulated reproductive schedules. These results show that the critical period model of salmonid maturation applies to regulation of repeat spawning, and that the reproductive decision window extends into the first 10 weeks after spawning.

The development of depressogenic self-schemas: Associations with children's regional grey matter volume in ventrolateral prefrontal cortex.

Cognitive theories of depression contend that biased cognitive information processing plays a causal role in the development of depression. Extensive research shows that deeper processing of negative and/or shallower processing of positive self-descriptors (i.e., negative and positive self-schemas) predicts current and future depression in adults and children. However, the neural correlates of the development of self-referent encoding are poorly understood. We examined children's self-referential processing using the self-referent encoding task (SRET) collected from 74 children at ages 6, 9, and 12; around age 10, these children also contributed structural magnetic resonance imaging data. From age 6 to age 12, both positive and negative self-referential processing showed mean-level growth, with positive self-schemas increasing relatively faster than negative ones. Further, voxel-based morphometry showed that slower growth in positive self-schemas was associated with lower regional gray matter volume (GMV) in ventrolateral prefrontal cortex (vlPFC). Our results suggest that smaller regional GMV within vlPFC, a critical region for regulatory control in affective processing and emotion development, may have implications for the development of depressogenic self-referential processing in mid-to-late childhood.

Within-person pathways among maternal depressive symptoms and offspring internalizing problems from early childhood through adolescence.

INTRODUCTION: The report examined reciprocal within-person associations among maternal depressive symptoms and offspring depressive, anxiety and irritability symptoms from early childhood to adolescence using a random intercept cross-lagged panel model (RI-CLPM). METHOD: Participants were 609 mother-child dyads participating in the Stony Brook Temperament Study. Child and maternal internalizing symptoms were assessed every 3 years from ages 3 to 15 using maternal report on the Child Behavior Checklist (CBCL) and Diagnostic Inventory for Depression, respectively. RESULTS: At the between-person level, maternal depressive symptoms, and child depressive, anxiety, and irritability symptoms were all positively associated with one another. At the within-person level, greater within-person child anxiety symptoms at age 3 predicted both greater child anxiety and depressive symptoms at age 15 via greater child anxiety from ages 6 to 12, and greater within-person child irritability at age 3 predicted greater maternal depressive symptoms at age 15 via greater child irritability from ages 6 to 12. CONCLUSIONS: Findings reveal novel within-person developmental pathways from early childhood internalizing problems to later internalizing problems in both the child and mother. Intervention and prevention efforts should thus focus on early identification and prevention of childhood internalizing symptoms to reduce negative effects on both child and parent symptoms.

Parsing between- and within-person effects: Longitudinal associations between irritability and internalizing and externalizing problems from early childhood through adolescence.

INTRODUCTION: This report examines between- and within-person associations between youth irritability and concurrent and prospective internalizing and externalizing symptoms from early childhood through adolescence. Distinguishing between- and within-person longitudinal associations may yield distinct, clinically relevant information about pathways to multifinality from childhood irritability. METHODS: Children's irritability and co-occurring symptoms were assessed across five waves between ages 3 and 15 years using the mother-reported Child Behavior Checklist (N = 605, 46% female). Parental history of depressive disorders was assessed with a clinical interview. RESULTS: Results demonstrated that between- and within-person irritability were uniquely associated with concurrent depressive, anxiety, and defiance symptoms, but not ADHD. Prior wave within-person irritability also predicted next wave depressive, anxiety, and defiance symptoms, controlling for prior symptoms; these prospective associations were bidirectional. Child sex and parental depressive disorders moderated associations. DISCUSSIONS: Findings identify pathways from within- and between-person irritability to later internalizing and externalizing psychopathology. Results demonstrate the importance of parsing within- and between-person effects to understand nuanced relations among symptoms over childhood.

Effects of post-spawning ration restriction on reproductive development and the growth hormone/insulin-like growth factor-1 axis in female rainbow trout (Oncorhynchus mykiss).

In iteroparous female salmonids, the growth and reproductive endocrine axes interact during the period after spawning. Energy depletion due to pre-spawn fasting, migration, and ovarian development must be restored, and the next reproductive cycle is initiated in consecutively maturing fish. In the natural environment, food availability is often limited during the post-spawn period. To investigate the growth and reproductive endocrinology of the post-spawn period, we sampled female rainbow trout over the 30 weeks following their first spawning. Fish were fasted for 2 months prior to spawning, then fed a standard or a restricted ration. Analysis was confined to reproductive fish. Plasma estradiol-17ß decreased during the 8 weeks following spawning and then began increasing in both ration groups and was lower in feed-restricted versus standard ration fish from 8 weeks onward. Plasma insulin-like growth factor-1 increased over the same period and then remained constant in both ration groups and was lower in feed-restricted versus standard ration fish from week 8 to week 30. Plasma growth hormone decreased following spawning in standard ration fish and became elevated in feed-restricted versus standard ration fish at 20- and 30-weeks post-spawn. Growth rates, condition factor, and muscle lipid levels were higher in standard ration versus feed-restricted fish within 2-4 weeks after spawning. These results suggest that two phases occurred during the post-spawn period: recovery from spawning and restoration of energy reserves over weeks 0 to 8, followed by adjustment of the growth and reproductive endocrine axes to ration level over weeks 8 to 30.

Is the distinction between tonic and phasic irritability meaningful in 3-year-old children?

Irritability encompasses both normative misbehavior in early childhood and clinically significant problems across development. Recent studies have distinguished between tonic (i.e., persistently angry or grumpy mood) and phasic (i.e., temper tantrums or outbursts) forms of irritability and shown that they have different implications for psychopathology and functioning. However, data on this distinction in young (i.e., preschool aged) children are nonexistent. We utilized data from a longitudinal study of a community sample of 462 3-year-olds followed to age 15. We conducted confirmatory factor analysis (CFA) using items from a diagnostic interview and several parent-report inventories and examined concurrent and prospective associations with clinically relevant variables. The CFA identified dimensions consistent with tonic and phasic irritability. Tonic irritability was independently associated with concurrent parent-reported temperamental negative affectivity and surgency, and depressive and oppositional defiant (ODD) disorders, and predicted higher rates of disruptive behavior disorders (DBD) and suicidal behavior in later childhood and adolescence. Phasic irritability was independently associated with concurrent laboratory observations of child impulsivity, parent-reported temperamental negative affectivity, surgency, and low effortful control, maladaptive parenting, and generalized anxiety disorder (GAD), attention-deficit hyperactivity disorder (ADHD), and ODD, but it did not predict later psychopathology. Tonic and phasic irritability are separable in 3-year-old children, but their correlates and outcomes are not as distinct as in older youth. This may reflect the greater difficulty characterizing normative and pathological irritability in the preschool period.

Offspring irritability: associations with parental psychopathology and personality.

Although there are well-established correlates and outcomes of irritability, there are fewer studies reporting on predictors of the longitudinal course of irritability in youth. The current report examined parent internalizing and externalizing psychopathology and dimensions of personality as predictors of the developmental course of irritability in youth. Offspring irritability was assessed between ages 2 and 10 years using the Irritability Factor from the parent-reported Child Behavior Checklist (N = 570, 53.51% female). Parental psychopathology was assessed with a clinical interview; parents also completed the General Temperament Survey as a measure of personality. Results demonstrated that offspring irritability decreased with age. Offspring irritability was associated with parental depressive and anxiety disorders, higher levels of negative emotionality/neuroticism (NE) and disinhibition, and lower levels of positive emotionality; parental NE and disinhibition remained unique predictors of offspring irritability in a multivariate model. Finally, parental externalizing disorders were associated with more stable trajectories of offspring irritability, whereas offspring of parents without a history of externalizing disorders showed decreasing irritability across time. Findings demonstrate that different aspects of parental personality and psychopathology have differential impacts on levels and course of offspring irritability.

Interactive Effects of µ-Opioid and Adrenergic-α 2 Receptor Agonists in Rats: Pharmacological Investigation of the Primary Kratom Alkaloid Mitragynine and Its Metabolite 7-Hydroxymitragynine.

The primary kratom alkaloid mitragynine is proposed to act through multiple mechanisms, including actions at µ-opioid receptors (MORs) and adrenergic-α 2 receptors (Aα 2Rs), as well as conversion in vivo to a MOR agonist metabolite (i.e., 7-hydroxymitragynine). Aα 2R and MOR agonists can produce antinociceptive synergism. Here, contributions of both receptors to produce mitragynine-related effects were assessed by measuring receptor binding in cell membranes and, in rats, pharmacological behavioral effect antagonism studies. Mitragynine displayed binding affinity at both receptors, whereas 7-hydroxymitragynine only displayed MOR binding affinity. Compounds were tested for their capacity to decrease food-maintained responding and rectal temperature and to produce antinociception in a hotplate test. Prototypical MOR agonists and 7-hydroxymitragynine, but not mitragynine, produced antinociception. MOR agonist and 7-hydroxymitragynine rate-deceasing and antinociceptive effects were antagonized by the opioid antagonist naltrexone but not by the Aα 2R antagonist yohimbine. Hypothermia only resulted from reference Aα 2R agonists. The rate-deceasing and hypothermic effects of reference Aα 2R agonists were antagonized by yohimbine but not naltrexone. Neither naltrexone nor yohimbine antagonized the rate-decreasing effects of mitragynine. Mitragynine and 7-hydroxymitragynine increased the potency of the antinociceptive effects of Aα 2R but not MOR reference agonists. Only mitragynine produced hypothermic effects. Isobolographic analyses for the rate-decreasing effects of the reference Aα 2R and MOR agonists were also conducted. These results suggest mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with Aα 2R and MOR agonists. When combined with Aα 2R agonists, mitragynine could also produce hypothermic synergism. SIGNIFICANCE STATEMENT: Mitragynine is proposed to target the µ-opioid receptor (MOR) and adrenergic-α2 receptor (Aα2R) and to produce behavioral effects through conversion to its MOR agonist metabolite 7-hydroxymitragynine. Isobolographic analyses indicated supra-additivity in some dose ratio combinations. This study suggests mitragynine and 7-hydroxymitragynine may produce antinociceptive synergism with Aα2R and MOR agonists. When combined with Aα2R agonists, mitragynine could also produce hypothermic synergism.

Depression in 3/6-year-old children: clinical and psychosocial outcomes in later childhood and adolescence.

BACKGROUND: In recent years, epidemiological and clinical studies have revealed that depressive disorders can present in early childhood. To clarify the validity and prognostic significance of early childhood-onset depression, we investigated diagnostic and functional outcomes in later childhood and adolescence. METHODS: A community sample (N = 516) was assessed for psychopathology at ages 3 and 6 using the Preschool Age Psychiatric Assessment. When participants were 9, 12, and 15 years old, children and parents completed the Kiddie Schedule for Affective Disorders and Schizophrenia and measures of symptoms and functioning. RESULTS: In models adjusting for covariates, depressed 3/6-year-old children were more likely to experience subsequent episodes of depressive disorders and exhibited significantly higher rates of later anxiety disorder, attention deficit hyperactivity disorder, and suicidality compared to children without depressive disorders at age 3/6. Early childhood depression was also associated with higher levels of mother, but not child, reported depressive symptoms at age 15 compared to children without depressive disorders at age 3/6. Finally, depression at age 3/6 predicted lower levels of global and interpersonal functioning and higher rates of treatment at age 15 compared to children without depressive disorders at age 3/6. CONCLUSIONS: Results support the clinical significance of depression in 3/6-year-old children, although further studies with larger samples are needed.

Early intervention for inhibited young children: a randomized controlled trial comparing the Turtle Program and Cool Little Kids.

BACKGROUND: Children classified as behaviorally inhibited (BI) are at risk for social anxiety. Risk for anxiety is moderated by both parental behavior and social-emotional competence. Grounded in developmental-transactional theory, the Turtle Program involves both parent and child treatment components delivered within the peer context. Our pilot work demonstrated beneficial effects of the Turtle Program ('Turtle') over a waitlist control group. Herein, we report results of a rigorous randomized controlled trial (RCT) comparing Turtle to the best available treatment for young children high in BI, Cool Little Kids (CLK). METHODS: One hundred and fifty-one parents and their 3.5- to 5-year-old children selected on the basis of BI were randomly assigned to Turtle or CLK, delivered in group format over 8 weeks. Effects on child anxiety, life interference, BI, and observed parenting were examined at post-treatment and 1-year follow-up. ClinicalTrials.gov registration: NCT02308826. RESULTS: No significant main effect differences were found between Turtle and CLK on child anxiety; children in both programs evidenced significant improvements in BI, anxiety severity, family accommodation, and child impairment. However, Turtle yielded increased observed warm/engaged parenting and decreased observed negative control, compared with CLK. Parental social anxiety moderated effects; parents with higher anxiety demonstrated diminished improvements in child impairment, and parent accommodation in CLK, but not in Turtle. Children of parents with higher anxiety demonstrated more improvements in child BI in Turtle, but not in CLK. CONCLUSIONS: Turtle and CLK are both effective early interventions for young children with BI. Turtle is more effective in improving parenting behaviors associated with the development and maintenance of child anxiety. Turtle also proved to be more effective than CLK for parents with social anxiety. Results suggest that Turtle should be recommended when parents have social anxiety; however, in the absence of parent anxiety, CLK may offer a more efficient treatment model.

Anaphylaxis among elderly emergency department patients in a large health system in New York.

BACKGROUND: Anaphylaxis in the elderly is poorly understood. OBJECTIVE: To elucidate demographic, clinical, and management characteristics of older adults presenting to emergency departments (EDs) with National Institute of Allergy and Infectious Diseases (NIAID) criteria-confirmed anaphylaxis vs milder, non-anaphylactic acute allergic reactions (AARs). METHODS: A retrospective analysis of ED patients more than or equal to 65 years was conducted, using anaphylaxis International Classification of Diseases, Ninth Revision (ICD-9) codes or ICD-9-based algorithms incorporating the NIAID diagnostic criteria. Descriptive statistics were generated, and the abovementioned characteristics were compared between cohorts. RESULTS: Of 164 eligible visits, 71 (43.3%), 90 (54.9%), and 3 (1.8%) cases were identified by ICD-9 codes, the algorithms, or both, respectively. Only half fulfilled NIAID diagnostic criteria. Compared with the non-anaphylactic AAR group, criteria-confirmed anaphylaxis group had lower drug allergy rates (43.9% vs 61.0%, P = .03) but higher food allergy rates (26.8% vs 12.2%, P = .02). For the criteria-confirmed anaphylaxis group, presenting signs and symptoms in descending frequency were mucocutaneous, respiratory, cardiovascular, and gastrointestinal. Criteria-confirmed anaphylaxis group had higher rates of prior anaphylaxis (13.4% vs 2.4%, P = .009), pre-ED (12.2% vs 0.0%, P = .001) or ED (72.0% vs 4.9%, P < .001) epinephrine administration, and allergy referral (17.1% vs 2.4%, P = .002). Tryptase levels were rarely ordered, occurring once in the criteria-confirmed anaphylaxis group and never in the non-anaphylactic AAR group. Despite low mortality (n = 1), 64.6% of the criteria-confirmed anaphylaxis cohort required hospitalization, with 23.2% admitted to intensive care unit. CONCLUSION: Diagnosis of elderly ED patients with anaphylaxis remains suboptimal. Identifying NIAID criteria-confirmed cases remain challenging, using the existing methods. Management of these patients poorly adheres to current guidelines.