From Evidence-Based Guidelines to Clinical Practice: Pediatric Neuropsychology Care in Multidisciplinary Clinics.

OBJECTIVE: High demand for pediatric neuropsychological care has highlighted the time- and resource-intensive nature of traditional comprehensive evaluations. Emerging care models address these constraints by facilitating tiered neuropsychological services provided in various contexts, including multidisciplinary clinics (MDCs). We aim to demonstrate feasibility and acceptability of tiered neuropsychological care in MDCs through examples from a single institution. METHODS: A review of all current MDC practices at a tertiary pediatric care center was conducted to describe clinic workflow, services provided, and triage strategies. Pediatric neuropsychologists (n = 5) and other health care providers (n = 31) completed a survey focused on experience with neuropsychology consultation in MDCs. RESULTS: Neuropsychologists provided care in 11 MDCs, including universal monitoring with consultative interviews and questionnaires, as well as targeted screening. Neuropsychologists (89%) and other health professionals (100%) reported that tiered neuropsychological services improved patient care within MDCs. Other health professionals reported utilizing results from neuropsychology MDC care to inform their clinical approach (48-90%), referrals (58%), and treatment or surveillance decisions (55-71%). CONCLUSION: Tiered neuropsychological care in pediatric MDCs is feasible, and provider experience ratings indicate high acceptability. Practical steps for development of MDCs are provided, including identifying teams, clinic goals and outcomes, operational logistics, and billing.

A Preliminary Study of One Year Safety and Tolerability of Attention-Deficit/Hyperactivity Disorder Medications in Youth with Fontan Palliation or Heart Transplant.

There are no published studies that examine the safety and tolerability of medication to treat attention-deficit/hyperactivity disorder (ADHD) in children with histories of Fontan palliation (Fontan) or heart transplant (HT), despite the high prevalence of ADHD in these populations. To address this gap, we examined the cardiac course, somatic growth, and incidence of side effects for one year after medication initiation amongst children with Fontan or HT and comorbid ADHD. The final sample comprised 24 children with Fontan (12 medication-treated, 12 control) and 20 children with HT (10 medication-treated, 10 control). Demographic, somatic growth (height and weight percentile-for age), and cardiac data (blood pressure, heart rate, results of 24 h Holter monitoring, electrocardiograms) were extracted from electronic medical records. Medication-treated and control subjects were matched by cardiac diagnosis (Fontan or HT), age, and sex. Nonparametric statistical tests were utilized to compare between- and within-group differences prior to, and one year post, medication initiation. There were no differences in somatic growth or cardiac data when comparing medication-treated participants to matched controls, regardless of cardiac diagnosis. Within the medication group, a statistically significant increase in blood pressure was observed, though the group average remained within clinically acceptable limits. While results are preliminary in nature due to our very limited sample size, our findings suggest that ADHD medications can be tolerated with minimal cardiac or somatic growth effects amongst complex cardiac patients. Our preliminary results favor treating ADHD with medication, which has considerable implications for long-term academic/employment outcomes and quality of life for this population. Close collaboration between pediatricians, psychologists, and cardiologists is essential to individualizing and optimizing interventions and outcomes for children with Fontan or HT.

[Formula: see text] The multifaceted role of neuropsychology in pediatric solid organ transplant: preliminary guidelines and strategies for clinical practice.

The incidence of pediatric solid organ transplantation (SOT) has increased in recent decades due to medical and surgical advances as well as improvements in organ procurement. Survival rates for pediatric kidney, liver, and heart transplantation are above 85% but patients continue to experience complex healthcare needs over their lifetime. Long-term developmental and neuropsychological sequelae are becoming increasingly recognized in this population, although preliminary work is limited and deserves further attention. Neuropsychological weaknesses are often present prior to transplantation and may be related to underlying congenital conditions as well as downstream impact of the indicating organ dysfunction on the central nervous system. Neuropsychological difficulties pose risk for functional complications, including disruption to adaptive skill development, social-emotional functioning, quality of life, and transition to adulthood. The impact of cognitive dysfunction on health management activities (e.g., medication adherence, medical decision-making) is also an important consideration given these patients' lifelong medical needs. The primary aim of this paper is to provide preliminary guidelines and clinical strategies for assessment of neuropsychological outcomes across SOT populations for pediatric neuropsychologists and the multidisciplinary medical team, including detailing unique and shared etiologies and risk factors for impairment across organ types, and functional implications. Recommendations for clinical neuropsychological monitoring as well as multidisciplinary collaboration within pediatric SOT teams are also provided.

The proteomic fingerprint in infants with single ventricle heart disease in the interstage period: evidence of chronic inflammation and widespread activation of biological networks.

Introduction: Children with single ventricle heart disease (SVHD) experience significant morbidity across systems and time, with 70% of patients experiencing acute kidney injury, 33% neurodevelopmental impairment, 14% growth failure, and 5.5% of patients suffering necrotizing enterocolitis. Proteomics is a method to identify new biomarkers and mechanisms of injury in complex physiologic states. Methods: Infants with SVHD in the interstage period were compared to similar-age healthy controls. Serum samples were collected, stored at -80°C, and run on a panel of 1,500 proteins in single batch analysis (Somalogic Inc., CO). Partial Least Squares-Discriminant Analysis (PLS-DA) was used to compare the proteomic profile of cases and controls and t-tests to detect differences in individual proteins (FDR <0.05). Protein network analysis with functional enrichment was performed in STRING and Cytoscape. Results: PLS-DA readily discriminated between SVHD cases (n = 33) and controls (n = 24) based on their proteomic pattern alone (Accuracy = 0.96, R2 = 0.97, Q2 = 0.80). 568 proteins differed between groups (FDR <0.05). We identified 25 up-regulated functional clusters and 13 down-regulated. Active biological systems fell into six key groups: angiogenesis and cell proliferation/turnover, immune system activation and inflammation, altered metabolism, neural development, gastrointestinal system, and cardiac physiology and development. Conclusions: We report a clear differentiation in the circulating proteome of patients with SVHD and healthy controls with >500 circulating proteins distinguishing the groups. These proteomic data identify widespread protein dysregulation across multiple biologic systems with promising biological plausibility as drivers of SVHD morbidity.

Collaborative learning of new information in older age: a systematic review.

Ageing is accompanied by a multitude of changes in cognitive abilities, which in turn affect learning. Learning collaboratively may benefit older adults by negating some of these age-related changes. However, studies on collaborative learning in older age differ in their methodology and findings. This systematic review provides an overview of the current research on collaborative learning in older age, exploring what factors influence collaborative learning in this age group. The titles and abstracts of imported 6629 works were screened, as well as four works added manually, which resulted in 29 studies. These studies were conducted across five countries (Canada, United States, United Kingdom, Switzerland and Belgium) between 1993 and 2023. Most studies were quantitative with a non-randomized (n = 16) design. Of the 29 studies, almost all studied collaboration in pairs (n = 28). The results suggest that the benefits of collaborating in older age may depend on the type of learning material, that familiarity between partners does not affect learning, and that age differences appear to decrease or disappear when older adults are provided with adequate time or trials. In addition, this systematic review identifies several gaps in the literature that future research should investigate further. This study was preregistered prior to its commencement on 21 January 2022. The accepted Stage 1 manuscript, unchanged from the point of in-principle acceptance, may be viewed at https://osf.io/tj4w7/. The data and materials of this study can be found at https://osf.io/8xvqf/.

Factors Associated With Attendance for Cardiac Neurodevelopmental Evaluation.

BACKGROUND AND OBJECTIVES: Neurodevelopmental evaluation of toddlers with complex congenital heart disease is recommended but reported frequency is low. Data on barriers to attending neurodevelopmental follow-up are limited. This study aims to estimate the attendance rate for a toddler neurodevelopmental evaluation in a contemporary multicenter cohort and to assess patient and center level factors associated with attending this evaluation. METHODS: This is a retrospective cohort study of children born between September 2017 and September 2018 who underwent cardiopulmonary bypass in their first year of life at a center contributing data to the Cardiac Neurodevelopmental Outcome Collaborative and Pediatric Cardiac Critical Care Consortium clinical registries. The primary outcome was attendance for a neurodevelopmental evaluation between 11 and 30 months of age. Sociodemographic and medical characteristics and center factors specific to neurodevelopmental program design were considered as predictors for attendance. RESULTS: Among 2385 patients eligible from 16 cardiac centers, the attendance rate was 29.0% (692 of 2385), with a range of 7.8% to 54.3% across individual centers. In multivariable logistic regression models, hospital-initiated (versus family-initiated) scheduling for neurodevelopmental evaluation had the largest odds ratio in predicting attendance (odds ratio = 4.24, 95% confidence interval, 2.74-6.55). Other predictors of attendance included antenatal diagnosis, absence of Trisomy 21, higher Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality category, longer postoperative length of stay, private insurance, and residing a shorter distance from the hospital. CONCLUSIONS: Attendance rates reflect some improvement but remain low. Changes to program infrastructure and design and minimizing barriers affecting access to care are essential components for improving neurodevelopmental care and outcomes for children with congenital heart disease.

Implementation of the Cardiac Inpatient Neurodevelopmental Care Optimization (CINCO) programme: an interdisciplinary, generalisable approach to inpatient neurodevelopmental care.

BACKGROUND: Children with CHD are at risk for neurodevelopmental delays, and length of hospitalisation is a predictor of poorer long-term outcomes. Multiple aspects of hospitalisation impact neurodevelopment, including sleep interruptions, limited holding, and reduced developmental stimulation. We aimed to address modifiable factors by creating and implementing an interdisciplinary inpatient neurodevelopmental care programme in our Heart Institute. METHODS: In this quality improvement study, we developed an empirically supported approach to neurodevelopmental care across the continuum of hospitalisation for patients with CHD using three plan-do-study-act cycles. With input from multi-level stakeholders including parents/caregivers, we co-designed interventions that comprised the Cardiac Inpatient Neurodevelopmental Care Optimization (CINCO) programme. These included medical/nursing orders for developmental care practices, developmental kits for patients, bedside developmental plans, caregiver education and support, developmental care rounds, and a specialised volunteer programme. We obtained data from the electronic health record for patients aged 0-2 years admitted for at least 7 days to track implementation. RESULTS: There were 619 admissions in 18 months. Utilisation of CINCO interventions increased over time, particularly for the medical/nursing orders and caregiver handouts. The volunteer programme launch was delayed but grew rapidly and within six months, provided over 500 hours of developmental interaction with patients. CONCLUSIONS: We created and implemented a low-cost programme that systematised and expanded upon existing neurodevelopmental care practices in the cardiac inpatient units. Feasibility was demonstrated through increasing implementation rates over time. Key takeaways include the importance of multi-level stakeholder buy-in and embedding processes in existing clinical workflows.

Telehealth services for cardiac neurodevelopmental care during the COVID-19 pandemic: a site survey from the Cardiac Neurodevelopmental Outcome Collaborative.

OBJECTIVE: COVID-19 has markedly impacted the provision of neurodevelopmental care. In response, the Cardiac Neurodevelopmental Outcome Collaborative established a Task Force to assess the telehealth practices of cardiac neurodevelopmental programmes during COVID-19, including adaptation of services, test protocols and interventions, and perceived obstacles, disparities, successes, and training needs. STUDY DESIGN: A 47-item online survey was sent to 42 Cardiac Neurodevelopmental Outcome Collaborative member sites across North America within a 3-week timeframe (22 July to 11 August 2020) to collect cross-sectional data on practices. RESULTS: Of the 30 participating sites (71.4% response rate), all were providing at least some clinical services at the time of the survey and 24 sites (80%) reported using telehealth. All but one of these sites were offering new telehealth services in response to COVID-19, with the most striking change being the capacity to offer new intervention services for children and their caregivers. Only a third of sites were able to carry out standardised, performance-based, neurodevelopmental testing with children and adolescents using telehealth, and none had completed comparable testing with infants and toddlers. Barriers associated with language, child ability, and access to technology were identified as contributing to disparities in telehealth access. CONCLUSIONS: Telehealth has enabled continuation of at least some cardiac neurodevelopmental services during COVID-19, despite the challenges experienced by providers, children, families, and health systems. The Cardiac Neurodevelopmental Outcome Collaborative provides a unique platform for sharing challenges and successes across sites, as we continue to shape an evidence-based, efficient, and consistent approach to the care of individuals with CHD.

Implications of attention and executive functioning weaknesses in youth with Fontan circulation.

Youth with Fontan circulation (Fontan) are at-risk for impairments in attention and executive functioning (EF) due to a confluence of genetic, prenatal, surgical, and medical risk factors. We sought to describe attention and EF in this population, measured via standardized performance-based tests and caregiver rating scales. We then examined how weaknesses in attention and EF were related to outcomes in other neurobehavioral domains, including adaptive behavior and academic achievement. Our sample included 93 youth with Fontan who were referred for neuropsychological evaluations as part of standard clinical care. The cohort as a whole measured between 0.18 to 0.99 standard deviations below normative means across domains of attention, EF, academic achievement, and intellectual ability. In addition, caregiver-reported concerns for attention, EF, anxiety, and depression were elevated, and approximately 0.35 to 0.85 standard deviations above normative means. Lastly, caregiver-reported adaptive behavior measured 0.93 to 1.24 standard deviations below normative values. Academic outcomes were differentially affected by demographic and attention/EF variables, while depression and caregiver-reported EF predicted adaptive behavior. Findings from this study underscore the importance of routine neuropsychological evaluation as part of comprehensive, multidisciplinary care for individuals with Fontan, with the goal of enhancing neurobehavioral and functional outcomes across the lifespan.

Division of Labor by the HELQ, BLM, and FANCM Helicases during Homologous Recombination Repair in Drosophila melanogaster.

Repair of DNA double-strand breaks by homologous recombination (HR) requires a carefully orchestrated sequence of events involving many proteins. One type of HR, synthesis-dependent strand annealing (SDSA), proceeds via the formation of a displacement loop (D-loop) when RAD51-coated single-stranded DNA invades a homologous template. The 3' end of the single-stranded DNA is extended by DNA synthesis. In SDSA, the D-loop is then disassembled prior to strand annealing. While many helicases can unwind D-loops in vitro, how their action is choreographed in vivo remains to be determined. To clarify the roles of various DNA helicases during SDSA, we used a double-strand gap repair assay to study the outcomes of homologous recombination repair in Drosophila melanogaster lacking the BLM, HELQ, and FANCM helicases. We found that the absence of any of these three helicases impairs gap repair. In addition, flies lacking both BLM and HELQ or HELQ and FANCM had more severe SDSA defects than the corresponding single mutants. In the absence of BLM, a large percentage of repair events were accompanied by flanking deletions. Strikingly, these deletions were mostly abolished in the blm helq and blm fancm double mutants. Our results suggest that the BLM, HELQ, and FANCM helicases play distinct roles during SDSA, with HELQ and FANCM acting early to promote the formation of recombination intermediates that are then processed by BLM to prevent repair by deletion-prone mechanisms.

Integrating Telehealth Into Neurodevelopmental Assessment: A Model From the Cardiac Neurodevelopmental Outcome Collaborative.

OBJECTIVE: In the wake of the COVID-19 pandemic, psychologists were pushed to look beyond traditional in-person models of neurodevelopmental assessment to maintain continuity of care. A wealth of data demonstrates that telehealth is efficacious for pediatric behavioral intervention; however, best practices for incorporating telehealth into neurodevelopmental assessment are yet to be developed. In this topical review, we propose a conceptual model to demonstrate how telehealth can be incorporated into various components of neurodevelopmental assessment. METHODS: Harnessing existing literature and expertise from a multidisciplinary task force comprised of clinicians, researchers, and patient/parent representatives from the subspecialty of cardiac neurodevelopmental care, a conceptual framework for telehealth neurodevelopmental assessment was developed. Considerations for health equity and access to care are discussed, as well as general guidelines for clinical implementation and gaps in existing literature. RESULTS: There are opportunities to integrate telehealth within each stage of neurodevelopmental assessment, from intake to testing, through to follow-up care. Further research is needed to determine whether telehealth mitigates or exacerbates disparities in access to care for vulnerable populations as well as to provide evidence of validity for a wider range of neurodevelopmental measures to be administered via telehealth. CONCLUSIONS: While many practices are returning to traditional, face-to-face neurodevelopmental assessment services, psychologists have a unique opportunity to harness the momentum for telehealth care initiated during the pandemic to optimize the use of clinical resources, broaden service delivery, and increase access to care for pediatric neurodevelopmental assessment.

Neuropsychological Screening in Pediatric Multidisciplinary Clinics: Group Characteristics and Predictive Utility.

OBJECTIVE: To evaluate the feasibility of administering caregiver-report neuropsychological screening measures in pediatric multidisciplinary clinics (MDCs) and investigate predictive utility for cognitive and academic difficulties on follow-up testing. METHOD: The Pediatric Perceived Cognitive Functioning (Peds PCF) and Colorado Learning Difficulties Questionnaire (CLDQ) were administered to caregivers of youth with history of brain tumor (BT), non-central nervous system (CNS) cancer, or Fontan circulation as part of routine neuropsychological consultation in MDCs from 2017 to 2019. We examined cross-sectional differences on screening measures, and relationships between screening and intellectual and academic test performance in a subset who presented for follow-up neuropsychological evaluation. Receiver operating characteristic (ROC) curve analysis was used to identify suggested cut scores on screening measures for predicting who would most benefit from further evaluation. RESULTS: Screening was completed with 192 families. Children with history of non-CNS cancer (n = 29) had fewer parent-reported cognitive and academic concerns compared with either BT (n = 88) or Fontan (n = 75) groups. Peds PCF and CLDQ scores were related to intellectual and academic test performance in the group presenting for neuropsychological evaluation (n = 68). ROC curve analysis identified cut scores across screening measures with maximal sensitivity and specificity for detecting neuropsychological difficulties. CONCLUSIONS: It is feasible to utilize parent rating measures during neuropsychological consultation in pediatric MDCs. The Peds PCF and CLDQ demonstrated sensitivity to intellectual and academic difficulties in children with significant medical histories. Screening may be a helpful tool for pediatric neuropsychologists and other professionals during MDC consultation to inform clinical management.

Age differences in COVID-19 risk-taking, and the relationship with risk attitude and numerical ability.

This study aimed to investigate age differences in risk-taking concerning the coronavirus pandemic, while disentangling the contribution of risk attitude, objective risk and numeracy. We tested (i) whether older and younger adults differed in taking coronavirus-related health risks, (ii) whether there are age differences in coronavirus risk, risk attitude and numerical ability and (iii) whether these age differences in coronavirus risk, attitude and numerical ability are related to coronavirus risk-taking. The study was observational, with measures presented to all participants in random order. A sample of 469 participants reported their coronavirus-related risk-taking behaviour, objective risk, risk attitude towards health and safety risks, numerical ability and risk perception. Our findings show that age was significantly related to coronavirus risk-taking, with younger adults taking more risk, and that this was partially mediated by higher numeracy, but not objective risk or risk attitude. Exploratory analyses suggest that risk perception for self and others partially mediated age differences in coronavirus risk-taking. The findings of this study may better our understanding of why age groups differ in their adoption of protective behaviours during a pandemic and contribute to the debate whether age differences in risk-taking occur due to decline in abilities or changes in risk attitude.

Specific patterns of executive functioning weaknesses among children after heart transplant.

BACKGROUND: Children with a history of heart transplant (HT) are at risk of executive functioning weaknesses secondary to heart disease and associated morbidity. However, specific executive functioning weaknesses have not been identified. METHOD: The present study, anchored in Anderson's (2002) Developmental Model of Executive Functioning, provides a detailed, retrospective analysis of executive functioning in the areas of goal setting, cognitive flexibility, attentional control, and information processing for a clinically referred sample of 53 pediatric HT recipients who underwent neuropsychological evaluations as part of typical clinical care. RESULTS: Broadly, the sample demonstrated mild-to-moderate deficits across cognitive, adaptive behavior, executive functioning, and academic domains, as well as elevated parent-reported concerns for depression and anxiety. Executive functioning weaknesses, while global, persisted after controlling for the effects of depression and anxiety and were most prominent in cognitive flexibility. In addition, poor cognitive flexibility predicted lower adaptive behavior, IQ, and academic outcomes among this population, placing them at considerable risk of extensive impairment in several domains of their lives. CONCLUSIONS: Taken together, children with a history of HT demonstrated broad difficulties across several areas of functioning, with particular concerns for working memory. As such, interventions and accommodations specifically targeting working memory may help provide the most optimal outcomes for this population.

Is Neurodevelopment Related to Exercise Capacity in Single Ventricle Patients Who Have Undergone Fontan Palliation?

Survivors of palliative surgery for single ventricle heart disease (SVHD) are at risk of poor neurodevelopmental outcomes and reduced exercise capacity. In healthy populations, reduced exercise capacity is related to decreased cognition suggesting a possible relationship between exercise capacity and neurodevelopment. Using cardiopulmonary exercise testing (CPET) and neuropsychological testing (NPT) as indicators of exercise capacity and neurodevelopment, respectively, we hypothesized that in SVHD, higher CPET measures are related to better NPT performance. Patients were retrospectively identified. CPET variables included VO2max, anaerobic threshold, peak heart rate, ventilatory efficiency, and respiratory exchange ratio. NPT instruments were divided into domains measuring attention, executive functioning, adaptive functioning, and emotional functioning. Linear regression was used to test for associations between CPET and NPT. 23 subjects with SVHD met inclusion criteria. On both CPET and NPT, the cohort scored worse than healthy, age-matched subjects. Higher VO2max and anaerobic threshold were associated with better parent-rated overall adaptive functioning (p = 0.01 and p = 0.02, respectively). Higher peak heart rate was related to better sustained visual attention (p = 0.01). In SVHD, CPET measures indicating better exercise capacity were positively associated with a subset of scores on NPT. Larger, multisite studies implementing cardiorespiratory fitness intervention and incorporating cognitive outcome measures will be needed to better characterize the relationship between neurodevelopment and functional capacity in this population. Results may assist in providing anticipatory guidance and optimizing post-Fontan developmental trajectories.

Relationships between Physiologic and Neuropsychologic Functioning after Fontan.

OBJECTIVE: To investigate potential relationships between neuropsychologic functioning and cardiac, gastroenterologic/hepatologic, and pulmonary complications in the single ventricle heart disease (SVHD) post-Fontan population. STUDY DESIGN: Following the initiation of a Fontan Multidisciplinary Clinic, patients with SVHD were evaluated systematically according to a clinical care pathway, and data from multiple subspecialty evaluations were collected prospectively from 2016 to 2019. Biomarkers of cardiology, pulmonary, and hepatology/gastroenterology functioning were abstracted, along with neuropsychologic testing results. Bivariate correlations and regression analyses examined cross-sectional relationships between physiologic predictors and neuropsychologic outcomes. RESULTS: The sample included a cohort of 68 youth with SVHD age 3-19 years, after Fontan palliation. Sleep-disordered breathing was related to poorer visual-motor integration skills (r = -0.33; P < .05) and marginally related to poorer executive functioning (r = -0.33; P = .05). Lower arterial blood oxygen content was related to poorer executive functioning (r = .45; P < .05). Greater atrioventricular valve regurgitation was related to lower parent-rated adaptive functioning (ρ = -0.34; P < .01). These results were maintained in regression analyses controlling for history of stroke and/or seizures. CONCLUSIONS: We demonstrated associations between neuropsychologic functioning and potentially modifiable aspects of physiologic functioning in a prospectively evaluated cohort of patients with SVHD with Fontan physiology. Our findings emphasize the importance of multidisciplinary screening and care after a Fontan procedure and suggest avenues for intervention that may improve patient outcomes and quality of life.

Patient and Family Experience in a Multidisciplinary Clinic for Children With Single-Ventricle Heart Disease.

Children with single-ventricle heart disease (SVHD) are at risk for morbidity across multiple organ systems. A single-ventricle multidisciplinary clinic (SVMDC) may address complex health-care needs by providing access to, and coordination among, pediatric subspecialties. However, the patient and family experience of multidisciplinary care for SVHD remains unexplored. We e-mailed a 26-question survey to families after an SVMDC visit, which included evaluation with subspecialists from cardiology, pulmonology, gastroenterology, neuropsychology, and pediatric psychology, as well as social activities during clinic. Responses were anonymized to protect privacy, and data were analyzed quantitatively and qualitatively. Over 3 years, 22% (27/122) of families completed the survey. Overall, families' experiences were positive, with 100% reporting that they would recommend the SVMDC to others. Qualitative themes emerged regarding logistics, multidisciplinary care, key takeaways from clinic, and connection-making with other families. A multidisciplinary clinic demonstrated overall acceptability and perceived benefit to families of children with SVHD. Considerations for mixed experiences regarding financial commitment and connection-making among parents are discussed, as are the benefits of the synergy achieved through multidisciplinary care.

Predictors of neuropsychological functioning and medication adherence in pediatric heart transplant recipients referred for neuropsychological evaluation.

Children who undergo heart transplantation are at risk for long-term neurodevelopmental sequelae secondary to heart disease and its treatment. Detailed neuropsychological profiles in clinical sample status post-pediatric heart transplantation are sparse in the literature, and there is little information regarding predictors of neuropsychological functioning or how it relates to medication adherence in this population. The present study examined these questions in a retrospective analysis of 27 pediatric heart transplantation recipients referred for clinical neuropsychological evaluation. The sample demonstrated mild-to-moderate decrements across domains of neuropsychological functioning. Children with premorbid congenital heart disease performed more poorly in working memory, word reading, and parent-rated conceptual adaptive skills compared to children with premorbid cardiomyopathy. Additionally, a higher number of rejection episodes were related to poorer verbal memory. Children with parent-reported attention problems had better adherence to immunosuppressant medication, which may have represented greater caregiver involvement in medication management. Taken together, clinically referred children with history of heart transplantation showed broad-based difficulties across neuropsychological domains according to formal testing and parent rating scales. This population requires routine neuropsychological monitoring and intervention.

Uncoupling of p97 ATPase activity has a dominant negative effect on protein extraction.

p97 is a highly abundant, homohexameric AAA+ ATPase that performs a variety of essential cellular functions. Characterized as a ubiquitin-selective chaperone, p97 recognizes proteins conjugated to K48-linked polyubiquitin chains and promotes their removal from chromatin and other molecular complexes. Changes in p97 expression or activity are associated with the development of cancer and several related neurodegenerative disorders. Although pathogenic p97 mutations cluster in and around p97's ATPase domains, mutant proteins display normal or elevated ATPase activity. Here, we show that one of the most common p97 mutations (R155C) retains ATPase activity, but is functionally defective. p97-R155C can be recruited to ubiquitinated substrates on chromatin, but is unable to promote substrate removal. As a result, p97-R155C acts as a dominant negative, blocking protein extraction by a similar mechanism to that observed when p97's ATPase activity is inhibited or inactivated. However, unlike ATPase-deficient proteins, p97-R155C consumes excess ATP, which can hinder high-energy processes. Together, our results shed new insight into how pathogenic mutations in p97 alter its cellular function, with implications for understanding the etiology and treatment of p97-associated diseases.

Chromatin Immunoprecipitation (ChIP) of Plasmid-Bound Proteins in Xenopus Egg Extracts.

Xenopus egg extracts provide a cell-free system to analyze various aspects of chromatin biology. Here we describe a modified method of chromatin immunoprecipitation (ChIP) to detect the interaction of proteins with plasmid DNA incubated in extract. The combination of ChIP and Xenopus egg extracts provides a highly versatile and tractable approach to analyze dynamic protein-DNA interactions with great spatial and temporal detail.