Does Anxiety Systematically Bias Estimates of Executive Functioning Deficits in Pediatric Attention-Deficit/Hyperactivity Disorder?

Growing evidence suggests that childhood ADHD is associated with larger impairments in working memory relative to inhibition. However, most studies have not considered the role of co-occurring anxiety on these estimates - a potentially significant confound given prior evidence that anxiety may increase working memory difficulties but decrease inhibition difficulties for these children. The current study extends prior work to examine the extent to which co-occurring anxiety may be systematically affecting recent estimates of the magnitude of working memory/inhibitory control deficits in ADHD. The carefully-phenotyped sample included 197 children with ADHD and 142 children without ADHD between the ages of 8 and 13 years (N = 339; Mage = 10.31, SD = 1.39; 144 female participants). Results demonstrated that ADHD diagnosis predicted small impairments in inhibitory control (d = 0.31) and large impairments in working memory (d = 0.99). However, child trait anxiety assessed dimensionally across multiple informants (child, parent, teacher) did not uniquely predict either executive function, nor did it moderate estimates of ADHD-related working memory/inhibition deficits. When evaluating anxiety categorically and controlling for ADHD, anxiety diagnosis predicted slightly better working memory (d = 0.19) but not inhibitory control for clinically evaluated children generally. Findings from the current study indicate that trait anxiety, measured dimensionally or categorically, does not differentially affect estimates of executive dysfunction in pediatric ADHD. Further, results suggest that trait anxiety is generally not associated with executive dysfunction above and beyond the impact of co-occurring ADHD. Future research is needed to further assess the role of anxiety in ADHD behavioral symptomatology, neurocognitive functioning, and mechanisms underlying these relations.

A preliminary 'shortlist' of individual, family, and social-community assets to promote resilience in pediatric ADHD.

BACKGROUND: Understanding factors that promote resilience in pediatric ADHD is important though highly understudied. AIMS: The current study sought to provide a preliminary 'shortlist' of key individual, family, and social-community assets among children with ADHD. METHODS AND PROCEDURES: The study included well-characterized, clinically-evaluated samples of children with (n=108) and without ADHD (n=98) ages 8-13 years (M=10.31; 41.3% girls; 66.5% White/Non-Hispanic). All subsets regression and dominance analysis identified the subset of predictors that accounted for the most variance in broad-based resilience for children with ADHD and their relative importance. Findings were compared for children with versus without ADHD as preliminary evidence regarding the extent to which identified assets are promotive, protective, or conditionally helpful. OUTCOMES AND RESULTS: Higher levels of peer acceptance, social skills, and academic performance were top predictors of resilience among children with ADHD. Better child working memory, attention, higher levels of hyperactivity, older age, and fewer parent self-reported mental health concerns were also identified as predictors of resilience in ADHD. Both overlapping and unique factors were associated with resilience for children with versus without ADHD. Conclusions and Results: These results, if replicated, provide a strong preliminary basis for strength-based basic/applied research on key assets that promote resilience in ADHD.

The relation between executive functions, error-related brain activity, and ADHD symptoms in clinically evaluated school-aged children.

Two event-related potentials (ERPs) elicited following errors, the error-related negativity (ERN) and error positivity (Pe), have been proposed to reflect cognitive control, though the specific processes remain debated. Few studies have examined the ERN and Pe's relations with individual differences in cognitive control/executive functioning using well-validated tests administered separately from the inhibition tasks used to elicit the ERN/Pe. Additionally, neurocognitive tests of executive functions tend to strongly predict ADHD symptoms, but the extent to which task-based and EEG-based estimates of executive functioning/cognitive control account for the same variance in ADHD symptoms remains unclear. The current study addressed these limitations by examining relations between the ERN/Pe and three core executive functions (working memory, inhibitory control, set shifting) in a clinically-evaluated sample of 53 children ages 8-12 (Mage = 10.36, SD = 1.42; 77.4% White/Non-Hispanic; 16 girls) with and without ADHD. Results demonstrated that neither the ERN nor Pe were related to overall cognitive control/executive functioning, or to working memory or set shifting specifically (all 95%CIs include 0.0). In contrast, a larger Pe was associated with better-developed inhibitory control (ß=-.35, 95%CI excludes 0.0), but did not capture aspects of inhibitory control that are important for predicting ADHD symptoms. Neither the ERN nor Pe predicted ADHD symptoms (95%CIs include 0.0). Results were generally robust to control for age, sex, SES, ADHD symptom cluster, and anxiety, and emphasize the need for caution when interpreting the ERN/Pe as indices of broad-based cognitive control/executive functioning, as well as using the ERN/Pe to examine cognitive processes contributing to ADHD symptomatology.

Linking ADHD and ASD Symptomatology with Social Impairment: The Role of Emotion Dysregulation.

Children with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often experience social impairments. These children also frequently struggle with emotion regulation, and extant literature suggests that emotion dysregulation predicts social impairment in both clinical and neurotypical populations. However, the evidence base linking ADHD/ASD with social impairment comes primarily from samples meeting full diagnostic criteria for ADHD and/or ASD despite evidence that both syndromes reflect extreme ends of natural continuums that are normally distributed across the general population. To our knowledge, the present study is the first to concurrently examine unique and overlapping relations among ADHD/ASD symptoms, emotion regulation, and social difficulties using multi-informant measures (parent, teacher) with a clinically-evaluated sample of 108 children ages 8-13 (40 girls; 66% White/Non-Hispanic) with and without clinically-elevated ASD and ADHD symptoms and other common clinical disorders. Bias-corrected, bootstrapped conditional effects modeling revealed that ADHD-inattentive (ß=-0.23) and ASD-social communication (ß=-0.20) symptoms predicted social impairment directly, whereas ADHD-hyperactive/impulsive (ß=-0.06) and ASD-restricted/repetitive behavior/interests (ß=-0.06) symptoms predicted social impairment only via their shared associations with emotion dysregulation. Sensitivity analyses revealed that most relations were robust to control for item overlap across measures. In contrast, only the ADHD-inattention/social impairment link was robust to control for mono-informant bias, highlighting the importance of multi-informant methods and the potential for different determinants of social functioning across settings. Overall, this study implicates emotion regulation skills and all four ADHD/ASD symptom clusters as potential influences on children's social functioning, albeit with a more nuanced and potentially setting-specific pattern than suggested by prior work.

Characteristics of children ≤36 months of age with DIPG: A report from the international DIPG registry.

BACKGROUND: Children ≤36 months with diffuse intrinsic pontine glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes. METHODS: Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed. RESULTS: Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3-, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (P = .018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation. CONCLUSIONS: Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis.

Volumetric endpoints in diffuse intrinsic pontine glioma: comparison to cross-sectional measures and outcome correlations in the International DIPG/DMG Registry.

BACKGROUND: Cross-sectional tumor measures are traditional clinical trial endpoints; however volumetric measures may better assess tumor growth. We determined the correlation and compared the prognostic impact of cross-sectional and volumetric measures of progressive disease (PD) among patients with DIPG. METHODS: Imaging and clinical data were abstracted from the International DIPG Registry. Tumor volume and cross-sectional product (CP) were measured with mint Lesion™ software using manual contouring. Correlation between CP and volume (segmented and mathematical [ellipsoid] model) thresholds of PD were assessed by linear regression. Landmark analyses determined differences in survival (via log-rank) between patients classified as PD versus non-PD by CP and volumetric measurements at 1, 3, 5, 7, and 9 months postradiotherapy (RT). Hazard ratios (HR) for survival after these time points were calculated by Cox regression. RESULTS: A total of 312 MRIs (46 patients) were analyzed. Comparing change from the previous smallest measure, CP increase of 25% (PD) correlated with a segmented volume increase of 30% (R2 = 0.710), rather than 40% (spherical model extrapolation). CP-determined PD predicted survival at 1 month post-RT (HR = 2.77), but not other time points. Segmented volumetric-determined PD (40% threshold) predicted survival at all imaging timepoints (HRs = 2.57, 2.62, 3.35, 2.71, 16.29), and 30% volumetric PD threshold predicted survival at 1, 3, 5, and 9 month timepoints (HRs = 2.57, 2.62, 4.65, 5.54). Compared to ellipsoid volume, segmented volume demonstrated superior survival associations. CONCLUSIONS: Segmented volumetric assessments of PD correlated better with survival than CP or ellipsoid volume at most time points. Semiautomated tumor volume likely represents a more accurate, prognostically-relevant measure of disease burden in DIPG.

Accuracy of central neuro-imaging review of DIPG compared with histopathology in the International DIPG Registry.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, <50% pontine involvement, focally exophytic morphology, sharply defined margins, and/or marked diffusion restriction throughout. RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). METHODS: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). RESULTS: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. CONCLUSION: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.

Taxonomic shifts in arbuscular mycorrhizal fungal communities with shade and soil nitrogen across conventionally managed and organic coffee agroecosystems.

The composition of arbuscular mycorrhizal fungal (AMF) communities should reflect not only responses to host and soil environments, but also differences in functional roles and costs vs. benefits among arbuscular mycorrhizal fungi. The coffee agroecosystem allows exploration of the effects of both light and soil fertility on AMF communities, because of the variation in shade and soil nutrients farmers generate through field management. We used high-throughput ITS2 sequencing to characterize the AMF communities of coffee roots in 25 fields in Costa Rica that ranged from organic management with high shade and no chemical fertilizers to conventionally managed fields with minimal shade and high N fertilization, and examined relationships between AMF communities and soil and shade parameters with partial correlations, NMDS, PERMANOVA, and partial least squares analysis. Gigasporaceae and Acaulosporaceae dominated coffee AMF communities in terms of relative abundance and richness, respectively. Gigasporaceae richness was greatest in conventionally managed fields, while Glomeraceae richness was greatest in organic fields. While total AMF richness and root colonization did not differ between organic and conventionally managed fields, AMF community composition did; these differences were correlated with soil nitrate and shade. OTUs differing in relative abundance between conventionally managed and organic fields segregated into four groups: Gigasporaceae associated with high light and nitrate availability, Acaulosporaceae with high light and low nitrate availability, Acaulosporaceae and a single relative of Rhizophagus fasciculatus with shade and low nitrate availability, and Claroideoglomus/Glomus with conventionally managed fields but uncorrelated with shade and soil variables. The association of closely related taxa with similar shade and light availabilities is consistent with phylogenetic trait conservatism in AM fungi.

Contrasting Patterns of Functional Diversity in Coffee Root Fungal Communities Associated with Organic and Conventionally Managed Fields.

The structure and function of fungal communities in the coffee rhizosphere are influenced by crop environment. Because coffee can be grown along a management continuum from conventional application of pesticides and fertilizers in full sun to organic management in a shaded understory, we used coffee fields to hold host constant while comparing rhizosphere fungal communities under markedly different environmental conditions with regard to shade and inputs. We characterized the shade and soil environment in 25 fields under conventional, organic, or transitional management in two regions of Costa Rica. We amplified the internal transcribed spacer 2 (ITS2) region of fungal DNA from coffee roots in these fields and characterized the rhizosphere fungal community via high-throughput sequencing. Sequences were assigned to guilds to determine differences in functional diversity and trophic structure among coffee field environments. Organic fields had more shade, a greater richness of shade tree species, and more leaf litter and were less acidic, with lower soil nitrate availability and higher soil copper, calcium, and magnesium availability than conventionally managed fields, although differences between organic and conventionally managed fields in shade and calcium and magnesium availability depended on region. Differences in richness and community composition of rhizosphere fungi between organic and conventionally managed fields were also correlated with shade, soil acidity, and nitrate and copper availability. Trophic structure differed with coffee field management. Saprotrophs, plant pathogens, and mycoparasites were more diverse, and plant pathogens were more abundant, in organic than in conventionally managed fields, while saprotroph-plant pathogens were more abundant in conventionally managed fields. These differences reflected environmental differences and depended on region.IMPORTANCE Rhizosphere fungi play key roles in ecosystems as nutrient cyclers, pathogens, and mutualists, yet little is currently known about which environmental factors and how agricultural management may influence rhizosphere fungal communities and their functional diversity. This field study of the coffee agroecosystem suggests that organic management not only fosters a greater overall diversity of fungi, but it also maintains a greater richness of saprotrophic, plant-pathogenic, and mycoparasitic fungi that has implications for the efficiency of nutrient cycling and regulation of plant pathogen populations in agricultural systems. As well as influencing community composition and richness of rhizosphere fungi, shade management and use of fungicides and synthetic fertilizers altered the trophic structure of the coffee agroecosystem.

Biocompatibility and characterization of a peptide amphiphile hydrogel for applications in peripheral nerve regeneration.

Peripheral nerve injury is a debilitating condition for which new bioengineering solutions are needed. Autografting, the gold standard in treatment, involves sacrifice of a healthy nerve and results in loss of sensation or function at the donor site. One alternative solution to autografting is to use a nerve guide conduit designed to physically guide the nerve as it regenerates across the injury gap. Such conduits are effective for short gap injuries, but fail to surpass autografting in long gap injuries. One strategy to enhance regeneration inside conduits in long gap injuries is to fill the guide conduits with a hydrogel to mimic the native extracellular matrix found in peripheral nerves. In this work, a peptide amphiphile (PA)-based hydrogel was optimized for peripheral nerve repair. Hydrogels consisting of the PA C16GSH were compared with a commercially available collagen gel. Schwann cells, a cell type important in the peripheral nerve regenerative cascade, were able to spread, proliferate, and migrate better on C16GSH gels in vitro when compared with cells seeded on collagen gels. Moreover, C16GSH gels were implanted subcutaneously in a murine model and were found to be biocompatible, degrade over time, and support angiogenesis without causing inflammation or a foreign body immune response. Taken together, these results help optimize and instruct the development of a new synthetic hydrogel as a luminal filler for conduit-mediated peripheral nerve repair.

Chirality-selected phase behaviour in ionic polypeptide complexes.

Polyelectrolyte complexes present new opportunities for self-assembled soft matter. Factors determining whether the phase of the complex is solid or liquid remain unclear. Ionic polypeptides enable examination of the effects of stereochemistry on complex formation. Here we demonstrate that chirality determines the state of polyelectrolyte complexes, formed from mixing dilute solutions of oppositely charged polypeptides, via a combination of electrostatic and hydrogen-bonding interactions. Fluid complexes occur when at least one of the polypeptides in the mixture is racemic, which disrupts backbone hydrogen-bonding networks. Pairs of purely chiral polypeptides, of any sense, form compact, fibrillar solids with a ß-sheet structure. Analogous behaviour occurs in micelles formed from polypeptide block copolymers with polyethylene oxide, where assembly into aggregates with either solid or fluid cores, and eventually into ordered phases at high concentrations, is possible. Chirality is an exploitable tool for manipulating material properties in polyelectrolyte complexation.

Protein Encapsulation via Polypeptide Complex Coacervation.

Proteins have gained increasing success as therapeutic agents; however, challenges exist in effective and efficient delivery. In this work, we present a simple and versatile method for encapsulating proteins via complex coacervation with oppositely charged polypeptides, poly(l-lysine) (PLys) and poly(d/l-glutamic acid) (PGlu). A model protein system, bovine serum albumin (BSA), was incorporated efficiently into coacervate droplets via electrostatic interaction up to a maximum loading of one BSA per PLys/PGlu pair and could be released under conditions of decreasing pH. Additionally, encapsulation within complex coacervates did not alter the secondary structure of the protein. Lastly the complex coacervate system was shown to be biocompatible and interact well with cells in vitro. A simple, modular system for encapsulation such as the one presented here may be useful in a range of drug delivery applications.