The Impact of Early Childhood Life Adversity on Peripubertal Accelerated Epigenetic Aging and Psychopathology.

OBJECTIVE: To examine longitudinal associations between early life threat and deprivation on epigenetic age acceleration at ages 9 and 15, and examine associations of age acceleration on later internalizing and externalizing symptoms. METHOD: The study examines a large (n= 2,039) and racially diverse (Black/African American = 44%, Latino = 18%, White = 5 %) sample from a national dataset. Epigenetic age acceleration was estimated using the pediatric buccal epigenetic clock. Early life threat and deprivation were measured using composites from the Parent-Child Conflict Tactics Scale and county-level violent and property crime rate data. Internalizing and externalizing symptoms came from parent-reported Child Behavior Checklist. Path analysis models examined associations of threat and deprivation at age 3 on epigenetic age acceleration at ages 9 and 15. Experiences of threat were further broken down into threat experienced in the home and in the community. RESULTS: Home threat experienced at 3 predicted age acceleration at 9 and 15, and community threat experienced at 3 predicted age acceleration at 15, but not 9. Deprivation was not a significant predictor of accelerated aging. Age acceleration at age 9 predicted externalizing, but not internalizing, symptoms at 15. Community threat had a direct effect on externalizing. No association emerged with internalizing. CONCLUSION: Findings revealed that threat, not deprivation, was predictive of age acceleration, demonstrating support for this pattern longitudinally, using an epigenetic clock that is accurate in children. They provide critical nuance to the examination of threat and highlight associated risks and possible intervention points for externalizing symptoms.

The Developmental Unfolding of ADHD Symptoms from Early Childhood Through Adolescence: Early Effects of Exuberant Temperament, Parenting and Executive Functioning.

Temperament, parenting, and executive functioning (EF) are individual and contextual factors that have been identified to play a role in the development of Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms. Specifically, exuberant temperament in toddlerhood has been associated with both adaptive and maladaptive outcomes, including ADHD symptoms. Therefore, it is important to understand factors that predict which exuberant children experience increased ADHD symptoms and the specific mechanisms through which early exuberant temperament impacts later ADHD symptoms. Using a multi-method, prospective longitudinal design, this study examined a moderated mediation model wherein the interactive effects of observed exuberance and parenting at age 3 predicted the development of parent-reported ADHD symptoms from childhood through adolescence (age 5, 7, 9, 12, and 15) via child EF (i.e., inhibitory control) at age 4. Parent-child dyads (n = 291) from a longitudinal study on child temperament were included. A piecewise model of ADHD symptom growth demonstrated stability in ADHD symptoms from age 5-9 and a decrease from age 9-15. Results support a moderated mediation model wherein an increase in ADHD symptoms throughout childhood was predicted from early childhood exuberant temperament by way of EF, but only for children whose parents displayed less directive parenting. Findings suggest identifiable early markers of risk, including temperament, parenting, and EF- pointing to possible targets for early intervention/prevention.

Consensus recommendations for use of maintenance immunosuppression in solid organ transplantation: Endorsed by the American College of Clinical Pharmacy, American Society of Transplantation, and the International Society for Heart and Lung Transplantation.

Advances in maintenance immunosuppression over the past three decades have improved solid organ transplantation outcomes dramatically. Uninterrupted access to immunosuppression is paramount to minimize rejection and maintain allograft and patient survival. There is no standardized approach to maintenance immunosuppression management. Agents used vary based on transplanted organ, center-specific protocol, provider expertise, insurance formularies, ability to cover co-pays, recipient characteristics and tolerability. Published data reflects this heterogeneity. Despite this limitation, maintenance immunosuppression usage cross pollinates between organ groups with standard of care agents often being used off-label, making medication access a challenge for many transplant recipients. A multidisciplinary panel of American transplant clinicians was formed to review published literature on maintenance immunosuppression with the goal to formulate consensus recommendations for their use in specific organ groups. These consensus recommendations are intended to provide transplant clinicians with a summary of literature on maintenance immunosuppression in the modern era and to support transplant team members working to secure medication access for patients.

Consensus recommendations for use of maintenance immunosuppression in solid organ transplantation: Endorsed by the American College of Clinical Pharmacy, American Society of Transplantation, and International Society for Heart and Lung Transplantation: An executive summary.

Advances in maintenance immunosuppression over the past three decades have improved solid organ transplantation outcomes dramatically. Uninterrupted access to immunosuppression is paramount to minimize rejection and maintain allograft and patient survival. Agents used vary based on transplanted organ, center-specific protocol, provider expertise, insurance formularies, ability to cover co-pays, recipient characteristics and tolerability. Published data reflects this heterogeneity. Despite these obstacles, the information about maintenance immunosuppression use cross pollinates between organ groups with standard of care agents often being used off-label, making medication access a challenge for many transplant recipients. A multidisciplinary panel of American transplant clinicians was formed to review published literature on maintenance immunosuppression with the goal to formulate consensus recommendations for their use in specific organ groups. These consensus recommendations are intended to provide transplant clinicians with a summary of literature on maintenance immunosuppression in the modern era, and to support transplant team members working to secure medication access for patients.

Impact of tablet use on young children's inhibitory control and error monitoring.

The purpose of this study was to investigate the cognitive impacts of tablet use on young children's inhibitory control and error monitoring. A total of 70 children (35 boys) aged 3.5 to 5 years completed an age-appropriate go/no-go task and were then randomly assigned to a technology group or a comparison group. In the technology group, children completed a cooking task on a tablet for 15 min. In the comparison group, children completed a similarly structured cooking task with toys for the same length of time. Children then completed the go/no-go task again. Compared with children in the comparison group, children in the technology group demonstrated poorer inhibitory control as evidenced by lower accuracy on no-go trials after the cooking task. However, both groups displayed post-error reaction time slowing. Collectively, these results suggest that brief tablet use can impose selective impairment on young children's cognitive abilities for a short period of time following use.

Neural Activity and Emotion Socialization as Predictors of Later Emotion Regulation Difficulties in Children With and Without Hyperactivity/Impulsivity.

OBJECTIVE: This study examined emotion socialization and neural activity during frustration as predictors of emotion regulation (ER) difficulties, and the interplay of emotion socialization and neural activity, in children with and without hyperactivity/impulsivity (H/I). METHOD: At Time 1, neural activity (P1, N2, P3) during a frustration task, H/I symptoms, and emotion socialization were assessed in 68 children (aged 4-7 years old). At Time 2 (1.5-2 years later), child-report, maternal-report, and observation measures of ER difficulties were assessed. RESULTS: H/I symptoms moderated the relation between predictors and ER difficulties; there were significant relations for children with high, but not low, levels of H/I. Further, as emotion socialization quality increased, relations between event-related potentials and later ER difficulties became weaker. CONCLUSION: The processes underlying ER difficulties differ for children with H/I symptoms. High quality emotion socialization may have a protective effect for children whose neural patterns indicate risk for later ER difficulties.

Impact of L2 automated systems on hazard anticipation and mitigation behavior of young drivers with varying levels of Attention Deficit Hyperactivity Disorder symptomatology.

Level 2 (L2) driving automation systems that maintain latitudinal and longitudinal control of the vehicle decrease mental workload and result in drivers failing to monitor and respond to potential roadway hazards. This issue is potentially important for young drivers with symptoms of Attention Deficit Hyperactivity Disorder (ADHD) since they have known difficulties anticipating and mitigating potential hazards on the road, a skill which requires attention. The objective of this study is to investigate how the use of partially automated (L2) systems and manual systems impacts hazard anticipation and mitigation among young drivers with varying levels of ADHD symptomatology. Sixty-eight drivers, classified into two groups - high and low ADHD symptomatology-navigated twice through three scenarios on a driving simulator, once with an L2 and once with a manual system. The results indicated that: (i) the hazard anticipation skills of drivers with both high and low ADHD symptomatology were depressed in the L2 condition relative to the manual condition; (ii) the hazard mitigations skills of drivers with both high and low ADHD symptomatology were depressed in the L2 condition relative to the manual condition on two measures, but improved on a third measure; and (iii) the hazard anticipation and mitigation skills of drivers with high and low ADHD symptomatology were differentially impacted, both within and across the two levels of automation. Taken together, the results indicate the pernicious and often hard to predict consequences of higher levels of automation for different populations of younger drivers.

Effects of a school readiness intervention on electrophysiological indices of external response monitoring in children in foster care.

This study examined the impact of a school readiness intervention on external response monitoring in children in foster care. Behavioral and event-related potential (ERP) data were collected during a flanker task from children who received the Kids In Transition to School (KITS) Program (n = 26) and children who received services as usual (n = 19) before and after the intervention. While there were no significant group differences on the behavioral data, the ERP data for the two groups of children significantly differed. Specifically, in contrast to the children who received services as usual, the children who received the KITS Program displayed greater amplitude differences between positive and negative performance feedback over time for the N1, which reflects early attention processes, and feedback-related negativity, which reflects evaluation processes. In addition, although the two groups did not differ on amplitude differences between positive and negative performance feedback for these ERP components before the intervention, the children who received the KITS Program displayed greater amplitude differences than the children who received services as usual after the intervention. These results suggest that the KITS Program had an effect on responsivity to external performance feedback, which may be beneficial during the transition into kindergarten.

Behavioral and Neural Markers of Emotion Competence as Predictors of Later Psychopathology in Children With and Without Hyperactive/Impulsive Symptoms.

Objective: We examined behavioral and neural markers of emotion competence in young children as predictors of psychopathology, and as mediators of the relation between hyperactivity/impulsivity (H/I) and psychopathology. Method: At Time 1 (T1), children (n = 49; ages 4-7 years) with and without H/I symptoms completed a frustration task. Frustration, observed emotion, and neural activity (P1, N2, and P3 event-related potentials) were measured. Symptoms of psychopathology were collected 18 months later (Time 2; T2). Results: T1 lability, negative affect, and frustration predicted T2 depression and aggression symptomatology, controlling for T1 symptoms. Children with difficulty allocating neural resources during and after frustration were at risk for depression, aggression, and anxiety symptoms, controlling for earlier symptoms. P3 amplitudes during recovery mediated the relation between H/I and later depression. Conclusion: Markers of emotion competence contribute to psychopathology symptoms, particularly in children at risk for attention-deficit/hyperactivity disorder (ADHD). Emotion competence skills may be useful intervention targets.

A multicenter case series documenting Medicare Part D plan denials of immunosuppressant drug coverage for organ transplant recipients.

Medicare Part D plans make coverage decisions according to FDA-labeled indications and off-label uses endorsed by two CMS-recognized compendia. Patients who rely on Medicare Part D for immunosuppressive drug coverage are at risk for denied coverage when these medications are prescribed off-label. The purpose of this multicenter collaboration was to assemble a case series documenting situations where immunosuppressive therapies prescribed for transplant patients were denied by Medicare Part D prescription drug plans. This case series documents 66 instances in 39 patients where immunosuppressive drug claims were denied coverage due to off-label use not endorsed by the compendia. Patients were recipients of lung (n = 28, 72%), heart (n = 7, 18%), or liver (n = 4, 10%) transplants. Denied claims were for mycophenolate mofetil (n = 22, 33%), azathioprine (n = 18, 27%), sirolimus (n = 15, 23%), mycophenolate sodium (n = 5, 8%), everolimus (n = 5, 8%), and belatacept (n = 1, 1%). Most denials were upheld across all the levels of attempted appeal, including those escalated to a Medicare Administrative Law Judge. This case series demonstrates a critical flaw in the construct of the Medicare Prescription Drug Benefit. The currently referenced compendia are not up to date and do not reflect best practices in organ transplantation.

Effects of Sleep Extension on Inhibitory Control in Children With ADHD: A Pilot Study.

Objective: Children with ADHD often have sleep complaints and cognitive deficits. The aim of this pilot study was to determine whether sleep extension improves inhibitory control, a primary cognitive deficit in ADHD. Method: Children with (n = 11) and without (n = 15) ADHD participated in a within-subject sleep extension intervention that targeted nocturnal sleep duration. Sleep was assessed with actigraphy and polysomnography. Inhibitory control was assessed with a Go/No-Go task. Results: For children without ADHD, there was a significant main effect of time, such that morning inhibitory control was 10% greater than evening inhibitory control. However, inhibitory control did not differ between the baseline and extension conditions in this group. For children with ADHD, although morning inhibitory control did not differ from evening inhibitory control, sleep extension improved inhibitory control by 13% overall. Conclusion: These results suggest that a sleep extension intervention improves inhibitory control in children with ADHD.

Relations between catechol-O-methyltransferase Val158Met genotype and inhibitory control development in childhood.

The Val158Met rs4680 single-nucleotide polymorphism (SNP) at the catechol-O-methyltransferase (COMT) gene, primarily involved in dopamine breakdown within prefrontal cortex, has shown relations with inhibitory control (IC) in both adults and children. However, little is known about how COMT genotype relates to developmental trajectories of IC throughout childhood. Here, our study explored the effects of the COMT genotype (Val/Val, Val/Met, and Met/Met) on IC trajectories between the ages of 5 and 10 years. Children (n = 222) completed a Go/Nogo task at ages 5, 7, and 10; IC was characterized using signal detection theory to examine IC performance (d') and response strategy (RS) (criterion). COMT genotype was not related to initial levels of IC performance and RS at age 5 or change in RS from ages 5 to 10. In contrast, COMT genotype was related to change in IC performance between 5 and 10 years. While Val/Val children did not differ from Val/Met children in development of IC performance, children with the Met/Met genotype exhibited more rapid development of IC performance when compared with Val/Met peers. These results suggest that COMT genotype modulates the development of IC performance in middle childhood.

Development of inhibitory control during childhood and its relations to early temperament and later social anxiety: unique insights provided by latent growth modeling and signal detection theory.

BACKGROUND: Children with the temperament of behavioral inhibition (BI) face increased risk for social anxiety. However, not all children with BI develop anxiety symptoms. Inhibitory control (IC) has been suggested as a moderator of the pathway between BI and social anxiety. This study uses longitudinal data to characterize development of IC and tests the hypothesis that IC moderates associations between early BI and later social anxiety symptoms. METHODS: Children completed a Go/Nogo task at ages 5, 7, and 10 years as part of a longitudinal study of BI (measured at 2-3 years) and social anxiety symptoms (measured at 12 years). To assess IC development, response strategy (criterion) and inhibitory performance (d') were characterized using signal detection theory. Latent growth models were used to characterize the development of IC and examine relations among BI, IC parameters, and social anxiety symptoms. RESULTS: IC response strategy did not change between 5 and 10 years of age, whereas IC performance improved over time. BI scores in toddlerhood predicted neither initial levels (intercept) nor changes (slope) in IC response strategy or IC performance. However, between ages 5 and 10, rate of change in IC performance, but not response strategy, moderated relations between BI and later parent-reported social anxiety symptoms. Specifically, greater age-related improvements in IC performance predicted higher levels of social anxiety in high BI children. CONCLUSIONS: IC development in childhood occurs independent of BI levels. However, rapid increases in IC performance moderate risk for social anxiety symptoms in children with BI. Implications for theory and practice are discussed.

More than a face: Neural markers of motivated attention toward social and non-social reward-related images in children.

Affective images engage motivational systems that shape emotional experience and cognitive processes. However, relatively little work has examined motivated attention toward distinct categories of approach motivation, particularly social motivation, in children. In the current study, event-related potentials (ERPs) were collected while children (n = 43; 22 females; Mage = 8.49 years) completed a picture-viewing task using a novel stimulus set of child relevant images representing social and non-social categories of reward-related images. Results showed that the frontal N400 (fN400) was more prominent for intrapersonal images that showed individuals playing alone or achieving rewards (e.g. medals). For the LPP, males showed the greatest reactivity to non-social object-based reward images. In contrast, females showed a larger LPP response for interpersonal images that showed scenes of social interaction between individuals. Overall, LPP reactivity to intrapersonal images was correlated with greater behavior regulation problems. Collectively, these results highlight unique patterns of neural prioritization to distinct categories of social and non-social reward-related stimuli that may serve as important markers in tracking connections between approach motivation and the development of self-regulation in children.

Everolimus Use for Intolerance or Failure of Baseline Immunosuppression in Adult Heart and Lung Transplantation.

BACKGROUND Everolimus can be utilized after heart or lung transplantation to reduce calcineurin inhibitor associated nephrotoxicity, due to cell cycle inhibitor adverse effects, and as adjunct therapy for rejection, cardiac allograft vasculopathy, and bronchiolitis obliterans syndrome. MATERIAL AND METHODS A single-center, retrospective cohort study was conducted including 51 adult heart transplant patients (n=32) and lung transplant patients (n=19) started on everolimus due to immunosuppressive therapy intolerance or failure, between 2010 and 2017. Everolimus indication, response, efficacy, and tolerability were assessed. RESULTS Everolimus was most commonly initiated due to leukopenia/neutropenia (n=17, 33%) or renal dysfunction (n=13, 25%). Leukopenia/neutropenia resolved in 76% of patients (13 out of 17 patients). Renal function (GFR) increased 7.4 mL/min from baseline to 3 months after everolimus initiation (P=0.011). The most common adverse effects were edema (n=23, 45%) and hyperlipidemia (n=25, 49%). A high discontinuation rate was observed (n=21, 41%), mostly from edema. CONCLUSIONS Everolimus might be beneficial in heart and lung transplant patients with leukopenia or neutropenia and lead to modest, short-term renal function improvement. Patient selection is crucial because adverse effects frequently lead to everolimus discontinuation.

Individualizing immunosuppression in lung transplantation.

Immunosuppression management after lung transplantation continues to evolve, with an increasing number of agents available for use in various combinations allowing for more choice and individualization of immunosuppressive therapy. Therapeutic developments have led to improved outcomes including lower acute rejection rates and improved survival. However, a one size fits all approach for any immunosuppressive strategy may not be best suited to the individual patient and ultimately patient specific factors must be considered when designing the immunosuppressive regimen. Recipient factors including age, race, co-morbidities, immunologic risk, genetic polymorphisms, concomitant and previous pharmacotherapy, and overall immunosuppression burden should be considered. There are several significant drug-drug interactions with select immunosuppressive agents utilized in lung transplant pharmacotherapy that must be considered when choosing and devising a dosing strategy for an individual immunosuppressive agent. Herein, considerations for immunosuppression management in the individual patient will be reviewed.

Positive emotional attention bias in young children with symptoms of ADHD.

Children with attention-deficit/hyperactivity disorder (ADHD) often experience emotional dysregulation. Dysregulation can arise from heightened attention to emotional stimuli. Emotional attention biases are associated with a number of adverse socioemotional outcomes including reward sensitivity and externalizing behaviors. As reward sensitivity and externalizing behaviors are common in children with ADHD, the aim of the current study was to determine whether emotional attention biases are evident in young children with clinically significant ADHD symptoms. To test this, children with (n = 18) and without (n = 15) symptoms of ADHD were tested on a Dot Probe task. Provided recent evidence that emotional attention biases are attenuated by sleep, the task was performed before and after overnight sleep. Children with ADHD symptoms displayed positive, but not negative, attention biases at both time points, whereas typically developing children did not preferentially attend toward or away from positive or negative stimuli. Sleep did not alter attention biases in either group. Collectively, these results indicate that children with ADHD symptoms have stable, positive attention biases.

Sleep Tight, Act Right: Negative Affect, Sleep and Behavior Problems During Early Childhood.

Temperamental negative affect and insufficient sleep have been independently associated with behavior problems during early childhood. However, it is unknown whether these factors interact to contribute to behavioral difficulties in young children. The current study examined the interactions between temperamental negative affect and both sleep onset time and sleep midpoint, assessed by actigraphy, in predicting externalizing and internalizing behaviors in a sample of 117 children (34-69 months of age). Children with high temperamental negative affect and either later sleep onset time or later sleep midpoint were more likely to exhibit externalizing and internalizing behaviors. These results emphasize the association between temperamental negative affect and behavioral difficulties, particularly for children with insufficient sleep.

Improving kindergarten readiness in children with developmental disabilities: Changes in neural correlates of response monitoring.

Among children diagnosed with developmental delays, difficulties in self-regulation are prominent and have been linked to school readiness problems. The current study sought to examine the impact of the Kids in Transition to School (KITS) school readiness intervention program on self-regulation, with a specific focus on response monitoring skills, among children with developmental delays. Children (n = 20 in the KITS group and n = 21 in a services as usual group) were administered a flanker task during which event-related potential data were collected to examine group differences in response monitoring. Findings indicated that children in the KITS group showed significant enhancement of a neural index of response monitoring post-intervention. Specifically, the KITS group showed a significant change in the magnitude of their feedback-related negativity in response to negative performance feedback from baseline to post-intervention, whereas children in the services as usual group did not. There were no significant differences between the groups for the error-related negativity or the error-related positivity on incorrect trials nor were there group differences in behavioral performance on the task at the post-intervention assessment. Overall, these findings provide support for the plasticity of response monitoring skills in young children and support the growing literature demonstrating improved self-regulation outcomes via intervention that enhances children's response monitoring.