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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.

Over the past decade, new research has advanced scientific knowledge of neurodevelopmental trajectories, factors that increase neurodevelopmental risk, and neuroprotective strategies for individuals with congenital heart disease. In addition, best practices for evaluation and management of developmental delays and disorders in this high-risk patient population have been formulated based on literature review and expert consensus. This American Heart Association scientific statement serves as an update to the 2012 statement on the evaluation and management of neurodevelopmental outcomes in children with congenital heart disease. It includes revised risk categories for developmental delay or disorder and an updated list of factors that increase neurodevelopmental risk in individuals with congenital heart disease according to current evidence, including genetic predisposition, fetal and perinatal factors, surgical and perioperative factors, socioeconomic disadvantage, and parental psychological distress. It also includes an updated algorithm for referral, evaluation, and management of individuals at high risk. Risk stratification of individuals with congenital heart disease with the updated categories and risk factors will identify a large and growing population of survivors at high risk for developmental delay or disorder and associated impacts across the life span. Critical next steps must include efforts to prevent and mitigate developmental delays and disorders. The goal of this scientific statement is to inform health care professionals caring for patients with congenital heart disease and other key stakeholders about the current state of knowledge of neurodevelopmental outcomes for individuals with congenital heart disease and best practices for neuroprotection, risk stratification, evaluation, and management.

Children with congenital heart disease (CHD) can face neurodevelopmental, psychological, and behavioural difficulties beginning in infancy and continuing through adulthood. Despite overall improvements in medical care and a growing focus on neurodevelopmental screening and evaluation in recent years, neurodevelopmental disabilities, delays, and deficits remain a concern. The Cardiac Neurodevelopmental Outcome Collaborative was founded in 2016 with the goal of improving neurodevelopmental outcomes for individuals with CHD and pediatric heart disease. This paper describes the establishment of a centralised clinical data registry to standardize data collection across member institutions of the Cardiac Neurodevelopmental Outcome Collaborative. The goal of this registry is to foster collaboration for large, multi-centre research and quality improvement initiatives that will benefit individuals and families with CHD and improve their quality of life. We describe the components of the registry, initial research projects proposed using data from the registry, and lessons learned in the development of the registry.

The World Health Organization has recommended dolutegravir (DTG) as a preferred first-line treatment for treatment naive and experienced people living with human immunodeficiency virus type one (PLWHIV). Based on these recommendations 15 million PLWHIV worldwide are expected to be treated with DTG regimens on or before 2025. This includes pregnant women. Current widespread use of DTG is linked to the drug's high potency, barrier to resistance, and cost-effectiveness. Despite such benefits, potential risks of DTG-linked fetal neurodevelopmental toxicity remain a concern. To this end, novel formulation strategies are urgently needed in order to maximize DTG's therapeutic potentials while limiting adverse events. In regard to potential maternal fetal toxicities, we hypothesized that injectable long-acting nanoformulated DTG (NDTG) could provide improved safety by reducing drug fetal exposures compared to orally administered native drug. To test this notion, we treated pregnant C3H/HeJ mice with daily oral native DTG at a human equivalent dosage (5 mg/kg; n = 6) or vehicle (control; n = 8). These were compared against pregnant mice injected with intramuscular (IM) NDTG formulations given at 45 (n = 3) or 25 (n = 4) mg/kg at one or two doses, respectively. Treatment began at gestation day (GD) 0.5. Magnetic resonance imaging scanning of live dams at GD 17.5 was performed to obtain T 1 maps of the embryo brain to assess T 1 relaxation times of drug-induced oxidative stress. Significantly lower T 1 values were noted in daily oral native DTG-treated mice, whereas comparative T 1 values were noted between control and NDTG-treated mice. This data reflected prevention of DTG-induced oxidative stress when delivered as NDTG. Proteomic profiling of embryo brain tissues harvested at GD 17.5 demonstrated reductions in oxidative stress, mitochondrial impairments, and amelioration of impaired neurogenesis and synaptogenesis in NDTG-treated mice. Pharmacokinetic (PK) tests determined that both daily oral native DTG and parenteral NDTG achieved clinically equivalent therapeutic plasma DTG levels in dams (4,000-6,500 ng/mL). Importantly, NDTG led to five-fold lower DTG concentrations in embryo brain tissues compared to daily oral administration. Altogether, our preliminary work suggests that long-acting drug delivery can limit DTG-linked neurodevelopmental deficits., Competing Interests: HEG and BE are Co-founders of Exavir Therapeutics, Inc., a biotechnology company focused on the development of LA antiretroviral prodrug medicines. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Foster, Sillman, Liu, Summerlin, Kumar, Sajja, Cassidy, Edagwa, Gendelman and Bade.)

Critical congenital heart disease (CHD) presents a lasting threat to quality of life through its adverse impact on neurodevelopmental and psychosocial outcomes. As recognition of this threat has increased, so too has an appreciation for the role of pediatric neuropsychologists in supporting families affected by CHD. But there is more to offer these families than traditional neuropsychological services, which tend to focus on secondary/tertiary forms of prevention. Now that many children with CHD are diagnosed prenatally, it may be possible to begin mitigating CHD-related risks and promoting positive outcomes earlier than ever before. Through primary prevention-oriented fetal neuropsychological consultation, as well as close collaboration with allied specialists, pediatric neuropsychology has an opportunity to re-envision its typical borders and more familiar practice models; to forge early and enduring partnerships with families; and to help promote the best possible neurodevelopmental trajectories, beginning before children are even born. In this conceptual review, we survey and integrate evidence from developmental science, developmental origins of health and disease, maternal-fetal medicine, and cardiac neurodevelopmental literatures, along with current practice norms, arriving ultimately at two central conclusions: 1) there is an important role to fill on multidisciplinary teams for the pediatric neuropsychologist in fetal cardiac care and 2) role expansion (e.g., through valuing broader-based training, flexing more generalist skills) can likely improve neuropsychological outcomes earlier than has been standard for pediatric neuropsychologists. Such a reimagining of our practice may be considered primary prevention neuropsychology . Implications for care in various settings and pragmatic barriers to implementation are discussed.

Autism spectrum disorders are more prevalent in children with congenital heart disease (CHD) than in the general population. Children with CHD without diagnosed autism are also at increased risk for neurodevelopmental and psychiatric impairments. We characterized social and behavioral outcomes in children with CHD and examined neurodevelopmental and psychiatric comorbidities. Children without diagnosed autism who underwent infant open-heart surgery were eligible. Parent-reports assessed social communication, unusual behaviors, self-regulation, anxiety, and executive function (EF). Neuropsychological tests assessing theory of mind (ToM), working memory, and verbal comprehension were administered. Outcomes were compared to normative data. Linear regressions were estimated with parent-reported scores and ToM abilities as outcomes. Predictors were anxiety symptoms, parent-reported EF, and working memory scores. Covariates were age, parental education, ADHD diagnosis, and verbal comprehension. Clinically relevant comorbidities were identified ( N children scoring ≥1 SD below the norm). Fifty-six children (10.8 ± 1.8 years) participated virtually. Compared to norms, children with CHD had impaired ToM, more unusual behaviors ( p = .002), and less self-regulation ( p  = .018), but better social communication ( p  = .014). "Autism-like" traits were positively associated with anxiety symptoms ( ß (95% CI) = 0.28(0.08-0.49), p  = .008) and worse working memory ( ß (95% CI) = -0.36(-0.59-0.13), p  = .003). Twenty-one out of 22 children who displayed clinically relevant social and behavioral scores also showed anxiety symptoms ( n  = 4), impaired EF ( n  = 7), or both ( n  = 10). Children with CHD without diagnosed autism have elevated unusual behaviors, lower self-regulation, and impaired ToM. There is a high risk of co-existing anxiety and impaired EF which may increase disease burden. Targeted therapeutic interventions are needed to reduce long-term psychosocial risks in these children. Abbreviation Attention deficit/hyperactivity disorder (ADHD), Autism Spectrum Rating Scale (ASRS), Behavior Rating Inventory of Executive Functions for school-aged children, 2nd Edition (BRIEF-2), cardiopulmonary bypass (CPB), congenital heart disease (CHD), Empathy/Systematizing Quotient Child Version (ESQ-C), Multidimensional Anxiety Scale for Children, 2nd Edition (MASC-2), Social Responsiveness Scale (School-age form), 2nd Edition (SRS-2), theory of mind (ToM), Theory of Mind Task Battery (ToM-TB), Wechsler Intelligence Scale for Children, 5th edition (WISC-V).

Background and Purpose: Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a neurodegenerative disease of the cerebellum. The disease progression is slow, with up to 25% of people diagnosed needing to use a wheelchair after 15 years from diagnosis. Vestibular symptoms arise from centrally-mediated ocular movement degradation and the reduced vestibular-ocular reflex functioning bilaterally. To date, no report has shown an improvement in VOR gain or gait outcome measures in someone with CANVAS after a course of vestibular physical therapy., Case Description: A 65-year-old male, Patient X, first noticed symptoms in his fourth decade of life and was diagnosed with (CANVAS) in his seventh decade. Patient X reported numbness and tingling in his hands and feet, decreased ability to perform daily activities, and several falls., Intervention: Patient X completed a four-month course of vestibular physical therapy, including vestibular ocular reflex exercises, balance training, gait training, and the VestAid application for eye gaze compliance monitoring. The Vestaid application uses eyes and facial recognition software to record the percentage of time that the patient kept their eyes on the target., Outcomes: After vestibular therapy, Patient X had a clinically meaningful improvement in gait speed: from 1.02 m/s to 1.13 m/s and in the Functional Gait Assessment from 20/30 to 27/30. Patient X's eye gaze compliance improved from a median of 43% (range 25-68%) to a median of 67% (58-83%)., Discussion: This case study demonstrates that vestibular rehabilitation improved eye gaze compliance and functional outcomes in a person living with CANVAS., Competing Interests: Dr. Whitney is a paid consultant for Intelligent Automation, a BlueHalo Company, and is a member of the team who has submitted a patent for VestAid., (© 2023 PLA General Hospital Department of Otolaryngology Head and Neck Surgery. Production and hosting by Elsevier (Singapore) Pte Ltd.)

Introduction: Studies have reported a higher risk of suboptimal neurodevelopment among children who are HIV-exposed uninfected (HEU) compared to children HIV-unexposed uninfected (HUU). Actual academic performance among school-aged children by HIV exposure status has not been studied., Methods: Academic performance in Mathematics, Science, English, Setswana and overall among children enrolled in the Botswana-based FLOURISH study who were attending public primary school and ranging in age from 7.1 to 14.6 years were compared by HIV exposure status using a Cochran-Mantel-Haenszel test. Lower academic performance was defined as a grade of "C" or lower (≤60%). Unadjusted and adjusted logistic regression models were fit to assess for an association between HIV exposure and lower academic performance., Results: Between April 2021 and December 2022, 398 children attending public primary school enrolled in the FLOURSH study, 307 (77%) were HEU. Median age was 9.4 years (IQR 8.9-10.2). Only 17.9% of children HEU were breastfeed versus 100% of children HUU. Among children HEU, 80.3% had foetal exposure to three-drug antiretroviral treatment, 18.7% to zidovudine only and 1.0% had no antiretroviral exposure. Caregivers of children HEU were older compared to caregivers of children HUU (median 42 vs. 36 years) and more likely to have no or primary education only (15.0% vs. 1.1%). In unadjusted analyses, children HEU were more likely to have lower overall academic performance compared to their children HUU (odds ratio [OR]: 1.96 [95% confidence interval (CI): 1.16, 3.30]), and lower performance in Mathematics, Science and English. The association was attenuated after adjustment for maternal education, caregiver income, breastfeeding, low birth weight and child sex (aOR: 1.86 [95% CI: 0.78, 4.43])., Conclusions: In this Botswana-based cohort, primary school academic performance was lower among children HEU compared to children HUU. Biological and socio-demographic factors, including child sex, appear to contribute to this difference. Further research is needed to identify modifiable contributors, develop screening tools to identify the risk of poor academic performance and design interventions to mitigate risk., (© 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Introduction: The VestAid is a tablet-based application that provides feedback about a patient's eye/head movements during exercise after concussion. The goal of this case series was to determine if VestAid could be used to detect eye-gaze accuracy in a participant exposed to directed energy (DE)., Materials and Methods: The VestAid results of a participant with DE were compared to an age- and gender-matched healthy control, a participant post-concussion, and a participant with vestibular neuritis. A tablet with VestAid software was utilized to record eye-gaze accuracy and head speed during VORx1 exercises using eye and facial recognition as participants were exposed to 12 visual scenes., Results: The participant with DE consistently had difficulty with eye-gaze accuracy when the head was rotated towards the right for all trials. The participant with DE had poor eye-gaze accuracy during all phases of the head turn cycle compared to the control participant (mean 47.91%, [SD = 7.32%] for the DE participant versus mean 94.28%, [SD = 5.87%] for the control participant). Post-exercise dizziness and perceived difficulty in the 12 exercises completed by the participant with DE were strongly related (Spearman's rho = 0.7372, P = .0062). The participant with DE had the lowest scores on 10 of the 12 head movement trials., Conclusions: VestAid provided unique information about eye-gaze accuracy that detected eye movement abnormalities in the participants with DE exposure, concussion, and vestibular neuritis. The objective metrics of eye-gaze stability correlate with participants' symptoms and perceived difficulty of the eye/head movements., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

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.

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: To report neurological examination findings at 5 to 12 months of age in infants with congenital heart disease (CHD) and to identify predictors of abnormal neurological examination., Method: This retrospective observational study included infants who required cardiac surgery at less than 3 months of age and underwent a standard neurological examination from a neurologist in the cardiac neurodevelopmental outpatient clinic between age 5 months and 12 months. Predictors for abnormal neurological examination (concerns on structured developmental history, demographic factors, medical history, and newborn neurodevelopmental assessment) were considered for multivariate regression., Results: The sample included 127 infants (mean age 7mo 2wks), who underwent first cardiac surgery at 7 days (4-49 interquartile range [IQR]) of age and were seen for a neurological examination in the cardiac neurodevelopmental clinic. Neurological abnormalities were common; 88% of infants had an abnormal neurological examination in at least one domain assessed. The most common abnormalities were abnormal axial (48%) and extremity (44%) tone, mostly hypotonia. Abnormal neurological examination was associated with concerns on the concurrent structured developmental history, genetic condition, extracardiac anomaly, longer length of stay, more than one cardiac surgery, ongoing early intervention services, and abnormalities on newborn neurodevelopmental assessment., Interpretation: Neurological examination abnormalities are common in infants with CHD after infant heart surgery, supporting the need for early and ongoing therapeutic developmental services and adherence to American Heart Association recommendations for developmental follow-up for children with CHD. What this paper adds Neurological examination abnormalities are common in infants who undergo open-heart surgery. Medical complications in infancy increase risk for neurological abnormalities. Family-reported concerns on structured developmental history may predict abnormal neurological examination at 5 to 12 months of age. Abnormal newborn neurodevelopmental assessment may predict abnormal neurological examination at 5 to 12 months of age., (© 2021 Mac Keith Press.)

Objective: This study examined longitudinal associations between performance on the Rey-Osterrieth Complex Figure-Developmental Scoring System (ROCF-DSS) at 8 years of age and academic outcomes at 16 years of age in 133 children with dextro-transposition of the great arteries (d-TGA)., Method: The ROCF-DSS was administered at the age of 8 and the Wechsler Individual Achievement Test, First and Second Edition (WIAT/WIAT-II) at the ages of 8 and 16, respectively. ROCF-DSS protocols were classified by Organization (Organized/Disorganized) and Style (Part-oriented/Holistic). Two-way univariate (ROCF-DSS Organization × Style) ANCOVAs were computed with 16-year academic outcomes as the dependent variables and socioeconomic status (SES) as the covariate., Results: The Organization × Style interaction was not statistically significant. However, ROCF-DSS Organization at 8 years was significantly associated with Reading, Math, Associative, and Assembled academic skills at 16 years, with better organization predicting better academic performance., Conclusions: Performance on the ROCF-DSS, a complex visual-spatial problem-solving task, in children with d-TGA can forecast academic performance in both reading and mathematics nearly a decade later. These findings may have implications for identifying risk in children with other medical and neurodevelopmental disorders affecting brain development.

In 2018, the Neurodevelopmental and Psychosocial Interventions Working Group of the Cardiac Neurodevelopmental Outcome Collaborative convened through support from an R13 grant from the National Heart, Lung, and Blood Institute to survey the state of neurodevelopmental and psychosocial intervention research in CHD and to propose a slate of critical questions and investigations required to improve outcomes for this growing population of survivors and their families. Prior research, although limited, suggests that individualised developmental care interventions delivered early in life are beneficial for improving a range of outcomes including feeding, motor and cognitive development, and physiological regulation. Interventions to address self-regulatory, cognitive, and social-emotional challenges have shown promise in other medical populations, yet their applicability and effectiveness for use in individuals with CHD have not been examined. To move this field of research forward, we must strive to better understand the impact of neurodevelopmental and psychosocial intervention within the CHD population including adapting existing interventions for individuals with CHD. We must examine the ways in which dedicated cardiac neurodevelopmental follow-up programmes bolster resilience and support children and families through the myriad transitions inherent to the experience of living with CHD. And, we must ensure that interventions are person-/family-centred, inclusive of individuals from diverse cultural backgrounds as well as those with genetic/medical comorbidities, and proactive in their efforts to include individuals who are at highest risk but who may be traditionally less likely to participate in intervention trials.

Case: Phillip is a young man born with hypoplastic left heart syndrome referred to your practice for a range of mental health concerns. He underwent palliation to an extracardiac Fontan in infancy and experienced multiple complications over the next decade including valvular regurgitation and arrhythmias necessitating a pacemaker. Phillip continued to have systolic heart failure with New York Heart Association class II symptoms, managed with 4 medications and anticoagulation.Despite this complex history, Phillip had intact cognitive abilities, achieved typical milestones, and performed well academically in secondary school. His first year of college proved to be more challenging, and Phillip presented to the outpatient psychiatry service with an acute depressive episode. His family history included depression, without known attention-deficit/hyperactivity disorder (ADHD). Treatment, including a selective serotonin reuptake inhibitor, cognitive behavioral therapy, and family support, led to near resolution of his symptoms of depression.In subsequent appointments, Phillip described a long history of inattention and disorganization with onset in childhood. This contributed to the decision to leave college, despite remission of symptoms of depression. Phillip was unable to study for any extended period without "perfect conditions," described as the absence of potential distractions except for background music. Despite attempts to maintain "perfect conditions," Phillip was often off task and "hyperfocusing" on irrelevant topics. Phillip struggled with planning and time management and would misplace items daily. Moreover, although the importance of self-care was well understood, Phillip often forgot to take his cardiac medication or to exercise, and he admitted to inconsistent sleep habits because of losing track of time.Based on a comprehensive psychiatric evaluation including retrospective report from a parent, Phillip was diagnosed with ADHD, coexisting with major depressive disorder, in remission. Significant ADHD symptoms were documented by interview, self-report, and administration of an abbreviated neuropsychological battery.Considering concerns regarding use of stimulants in a patient with congenital heart disease, including death, stroke, and myocardial infarction,1,2 how would you assess the risks-benefits of use of stimulants with Phillip?, References: 1. Wilens TE, Prince JB, Spencer TJ, et al. Stimulants and sudden death: what is a physician to do? Pediatrics. 2006;118:1215-1219.2. Zito JM, Burcu M. Stimulants and pediatric cardiovascular risk. J Child Adolesc Psychopharmacol. 2017;27:538-545., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Compared to the general population, individuals with complex congenital heart disease are at increased risk for deficits in cognitive, neurodevelopmental, psychosocial, and physical functioning, resulting in a diminished health-related quality of life. These deficits have been well described over the past 25 years, but significant gaps remain in our understanding of the best practices to improve neurodevelopmental and psychosocial outcomes and health-related quality of life for individuals with paediatric and congenital heart disease. Innovative clinical, quality improvement, and research opportunities with collaboration across multiple disciplines and institutions were needed to address these gaps. The Cardiac Neurodevelopmental Outcome Collaborative was founded in 2016 with a described mission to determine and implement best practices of neurodevelopmental and psychosocial services for individuals and their families with paediatric and congenital heart disease through clinical, quality improvement, and research initiatives. The vision is to be a multi-centre, multi-national, multi-disciplinary group of healthcare professionals committed to working together and partnering with families to optimise neurodevelopmental outcomes for individuals with paediatric and congenital heart disease through clinical, quality, and research initiatives, intending to maximise quality of life for every individual across the lifespan. This manuscript describes the development and organisation of the Cardiac Neurodevelopmental Outcome Collaborative.

In 2012, the American Heart Association and the American Academy of Paediatrics released a scientific statement with guidelines for the evaluation and management of the neurodevelopmental needs of children with CHD. Decades of outcome research now highlight a range of cognitive, learning, motor, and psychosocial vulnerabilities affecting individuals with CHD across the lifespan. The number of institutions with Cardiac Neurodevelopmental Follow-Up Programmes and services for CHD is growing worldwide. This manuscript provides an expanded set of neurodevelopmental evaluation strategies and considerations for professionals working with school-age children with CHD. Recommendations begin with the referral process and access to the evaluation, the importance of considering medical risk factors (e.g., genetic disorders, neuroimaging), and the initial clinical interview with the family. The neurodevelopmental evaluation should take into account both family and patient factors, including the child/family's primary language, country of origin, and other cultural factors, as well as critical stages in development that place the child at higher risk. Domains of assessment are reviewed with emphasis on target areas in need of evaluation based on current outcome research with CHD. Finally, current recommendations are made for assessment batteries using a brief core battery and an extended comprehensive clinical battery. Consistent use of a recommended assessment battery will increase opportunities for research collaborations, and ultimately help improve the quality of care for families and children with CHD.

Background: We sought to identify predictors of child cytomegalovirus (CMV) infection overall and by maternal HIV status and to assess associations of child CMV status with growth and neurodevelopmental outcomes at 24 months of age in Botswana., Methods: Data and samples were used from the Botswana-based observational Tshipidi study (2010-2014), enrolling pregnant women living with and without HIV and following their infants through 2 years of age. Child plasma samples were tested at 18 months of age for anti-CMV immunoglobulin G (IgG). Associations were assessed between detectable anti-CMV IgG and growth (using the World Health Organization Child Growth Standards) and neurodevelopment (using the Bayley Scales of Infant and Toddler Development III and the Developmental Milestones Checklist) at 24 months of age., Results: Of 317 children, 215 (68%) had detectable anti-CMV IgG at 18 months of age. Comparatively, 83% (n = 178) of HIV-unexposed uninfected (HUU) children had positive CMV serology vs 47% (n = 139) of HIV-exposed uninfected (HEU) children ( P  < .01); 100% of HUU vs 10.5% of HEU children breastfed. Child CMV infection was not associated with weight-for-age, weight-for-length, or length-for-age z-scores at 24 months. In HUU children, CMV infection was associated with smaller head circumference ( P  < .01). No difference was observed by child CMV status in any neurodevelopmental domain at 24 months., Conclusions: We observed high CMV seropositivity in 18-month-old children in Botswana, with higher seropositivity among breastfed (HUU) children. Positive CMV serostatus was not associated with 24-month child growth or neurodevelopmental outcomes, with the exception of smaller head circumference among HUU CMV-positive children., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Most children born with even the most critical forms of CHD are now surviving well into adulthood. However, with increased survival has come increased recognition of the diverse neurobehavioural and psychosocial challenges these children experience. Among these challenges are deficits in executive function skills, including inhibitory control, working memory, and cognitive flexibility. Over the past several years, whereas inhibitory control and working memory deficits have garnered particular attention among clinicians and interventionists, relatively less attention has been paid to cognitive flexibility. This is unfortunate given both the high prevalence of cognitive flexibility deficits observed in children and adolescents with critical CHD, and also the far-reaching relevance of cognitive flexibility in helping individuals achieve optimal quality of life across the lifespan. This paper reviews the construct of cognitive flexibility, including its definition, development, measurement, and neuroanatomical basis, provides a summary of how cognitive flexibility is affected by CHD, and offers evidence-based recommendations to systematically support the development of cognitive flexibility within the context of CHD.

Background: Minimal data exist related to neurodevelopment after in utero exposure to Efavirenz (EFV). We sought to compare neurodevelopmental outcomes in HIV-exposed/uninfected (HEU) children with in utero exposure to EFV-based triple antiretroviral treatment (ART) versus non-EFV-based ART, and to examine whether timing of initial EFV exposure is associated with neurodevelopment deficits., Methods: Women living with HIV who had received EFV-based ART during pregnancy and whose HEU newborn participated in a prior study were reconsented for their HEU toddler to undergo neurodevelopmental testing at 24 months old. We administered the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), Developmental Milestones Checklist (DMC) and Profile of Social Emotional Development (PSED). We compared outcomes to previously-collected data from a cohort of 24-month-old HEU children with in utero exposure to non-EFV-based ART. Adjusted general linear models were used to compare mean outcomes., Results: Our analysis included 493 HEU children (126 EFV-exposed, 367 EFV-unexposed). Adjusted mean scores for the EFV-exposed group were worse than the EFV-unexposed group on BSID-III Receptive Language (adjusted means = 21.5 vs. 22.5, P = 0.05), DMC Locomotor (30.7 vs. 32.0, P < 0.01) and Fine Motor scales (17.8 vs. 19.2, P < 0.01); and PSED (11.7 vs. 9.9, P = 0.02); but better on the DMC Language scale (17.6 vs. 16.5, P = 0.01). Earlier (vs. later) EFV exposure was associated with worse scores on the BSID-III Receptive Language scale (20.7 vs. 22.2, P = 0.02)., Conclusions: HEU children exposed in utero to EFV-based ART may be at higher risk for neurodevelopmental and social-emotional deficits than HEU children exposed to non-EFV-based ART.

Objective: To determine whether visual-spatial processing style is associated with psychopathology in a large sample of adolescents with critical congenital heart disease (CHD). Local (part-oriented) style was hypothesized to increase risk for internalizing (but not externalizing) forms of psychopathology., Method: Participants included 278 adolescents with critical CHD (dextro-transposition of the great arteries = 134, tetralogy of Fallot = 58, single-ventricle cardiac anatomy requiring the Fontan procedure = 86). Visual-spatial processing style was indexed using Copy Style Ratings from the Rey-Osterrieth Complex Figure-Developmental Scoring System. The Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present & Lifetime Version was used to determine presence/absence of diagnosable DSM-IV psychiatric disorder(s). Processing style and psychopathology were assessed concurrently., Results: Thirty-three percent of the sample had a part-oriented processing style. In multivariable binary logistic regression models, part-orientation was associated with more than twice the odds of having an anxiety disorder (lifetime: OR = 2.2, p = .02, 95% CI = 1.1-4.1; current: OR = 2.7, p = .03, 95% CI = 1.1-6.5) but was not associated with an increased risk for ADHD, disruptive behavior, or mood disorders (ps > .05)., Conclusions: Adolescents with critical CHD who approach complex visual-spatial materials in a local, part-oriented fashion are more likely to meet criteria for an anxiety disorder than those who approach complexity more holistically. Part-orientation may make it more difficult for individuals to judge the relative importance of isolated details and engage in more adaptive perspective-taking.

Objectives: To prospectively assess rates and detailed predictors of morbidity and mortality among HIV-exposed uninfected children and HIV-unexposed children in Botswana in a more recent era., Study Design: We enrolled HIV-infected and HIV-uninfected mothers and their children in the prospective observational Tshipidi study at 2 sites (1 city and 1 village) in Botswana from May 2010-July 2012. Live-born children and their mothers were followed for 24 months postpartum. Detailed sociodemographic data, health, and psychosocial characteristics were collected at baseline and prospectively, and health outcomes ascertained. Mothers chose infant feeding method with counselling., Results: A total of 893 live-born HIV-uninfected children (436 HIV-exposed uninfected, 457 HIV-unexposed) were followed. HIV-infected mothers had a median CD4 count of 410 cells/mm 3 , 32% took 3-drug antiretroviral treatment during pregnancy, 67% took only zidovudine, and 1% took <2 weeks of any antiretrovirals antepartum. Twenty four-month vital status was available for 888 (99.4%) children. HIV-exposed uninfected children had a significantly higher risk of death compared with children of HIV-uninfected mothers (5.0% vs 1.8%) (adjusted hazard ratio 3.27, 95% CI 1.44-7.40). High collinearity between maternal HIV status and child feeding method precluded analysis of these factors as independent predictors of mortality. Preterm birth, low birth weight, and congenital anomaly were also associated with mortality (in separate analyses), but maternal socioeconomic factors, depression, substance use, and social support were not significant predictors., Conclusions: The strongest predictors of 24-month mortality among children in Botswana were HIV exposure and formula feeding, although the relative contribution of these factors to child health could not be separated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Congenital heart disease (CHD) affects millions of people worldwide, including over one million children in the United States. Approximately 25% of children born with CHD require intensive surgical intervention within the first year of life. Despite improved rates of survival into adulthood - rates that exceed 90% in the modern era - children and adolescents with CHD remain at risk for neurological injury and a range of neurobehavioral and psychosocial challenges that pose a threat to quality of life across the lifespan. Consequently, as experts in both clinical psychology and brain development, neuropsychologists are becoming increasingly involved in cardiac follow-up and monitoring to promote optimal developmental outcomes. The primary objective of this paper is to provide an evidence-based, clinically-oriented primer on CHD for pediatric neuropsychologists working with this growing population of survivors. Following an introduction to current standard-of-care guidelines for managing children and adolescents with CHD, we present an overview of brain development within the context of CHD, review neuropsychological outcomes, examine factors influencing variability in outcomes, and discuss implications and strategies for clinical assessment.

Among the most significant factors affecting quality of life in individuals with critical congenital heart disease (CCHD) are neurodevelopmental challenges, including deficits in visuospatial processing and academic achievement. Few studies have compared outcomes across CCHD subgroups, despite their significant differences in anatomy/physiology and medical/surgical courses. This study compared visuospatial processing abilities using the Developmental Scoring System for the Rey-Osterrieth Complex Figure (DSS-ROCF) across groups of adolescents with CCHD (d-transposition of the great arteries [TGA, n = 139], Tetralogy of Fallot [TOF, n = 68], single-ventricle cardiac anatomy requiring the Fontan operation [SVF, n = 145]) and a group of healthy controls (CTR, n = 111), and examined the validity of visuospatial processing in predicting concurrent academic outcomes. The CCHD subgroups were found to differ in Organization, ps < .001, Structural Accuracy, ps < .001, and Incidental Elements Accuracy scores, ps ≤ .008; the post hoc analyses show that the SVF group tended to underperform compared to the other CCHD groups. With respect to academic skills, all CCHD groups scored lower than the CTR group, ps ≤ .007; however, the CCHD groups were not different from each other, ps > .23. The regression results showed that the DSS-ROCF Style rating (reflecting integration) accounted for a small yet statistically significant portion of unique variance in "assembled" academic outcomes, over and above the variance already accounted for by DSS-ROCF Organization, p < .01. These findings support the need for comprehensive neuropsychological assessment and monitoring of children and adolescents with CCHD, as well as targeted intervention for organization and integration deficits that may increase their risk for academic underachievement.

Objectives: Although evidence exists of broadly defined memory impairment among adolescents with critical congenital heart disease (CHD), nuanced investigations of declarative memory in this at-risk population have not been conducted. This study had two primary aims: (1) to conduct a fine-grained analysis of a range of relevant learning and memory processes in adolescents with critical biventricular CHD, and (2) to identify risk, odds, and predictors of memory impairment., Methods: Data were combined from two single-center studies of neurodevelopmental outcomes in critical CHD. Two-hundred seven adolescents (M age =15.61±1.0 years) with critical CHD (139 with dextro-transposition of the great arteries and 68 with tetralogy of Fallot without an identified genetic condition), as well as 61 healthy referents (M age =15.27±1.1 years) completed a neuropsychological evaluation which included the Children's Memory Scale., Results: Whereas visual-spatial memory deficits were found in both CHD subgroups, verbal memory abilities were relatively preserved. Adolescents with CHD demonstrated stronger memory for Stories than Word Pairs, t (203)=2.63, p=.009, and for Dot Locations than Faces, t(204)=-2.57, p=.01. CHD subgroup, socioeconomic status, sex, and seizure history were among the most frequent significant predictors of memory impairment. Seizure history, in particular, was associated with a 2 to 3 times greater odds of impaired performance on learning and memory tasks., Conclusions: Adolescents with critical biventricular CHD are at risk for deficits in aspects of declarative memory. Independent risk factors for worse outcome include history of seizures. (JINS, 2017, 23, 627-639).

Objectives: To assess psychiatric disorders and function in adolescents with repaired tetralogy of Fallot (TOF) without and with a genetic diagnosis and to evaluate associations of functioning with medical factors, IQ, and demographics., Study Design: Adolescents with TOF (n = 91) and 87 healthy referents completed a clinician-rated structured psychiatric interview, parent-/self-report measures of psychopathology, and brain magnetic resonance imaging. Twenty-three of the adolescents with TOF had a known genetic diagnosis., Results: The prevalence of anxiety disorders did not differ significantly between adolescents with TOF without genetic diagnosis (n = 68) and referents. Adolescents with TOF and a genetic diagnosis showed an increased lifetime prevalence of anxiety disorder (43%) and lower global psychosocial functioning (median, 70; IQR, 63-75) compared with adolescents with TOF without genetic diagnosis (15% and 83; IQR, 79-87, respectively; P = .04 and <.001, respectively) and referents (6% and 85; IQR, 76-90, respectively; P = .001 and <.001, respectively). Adolescents with TOF without and with a genetic diagnosis had a higher lifetime prevalence of attention deficit-hyperactivity disorder (ADHD) than referents (19% and 39%, respectively, vs 5%; P = .04 and .002, respectively) and worse outcomes on parent-/self-report ratings of anxiety and disruptive behavior compared with referents. Risk factors for anxiety, ADHD, and lower psychosocial functioning for adolescents with TOF without a genetic diagnosis included older age, male sex, and low IQ. Medical variables were not predictive of psychiatric outcomes., Conclusion: Adolescents with TOF, particularly those with a genetic diagnosis, show increased rates of psychiatric disorder and dysfunction. Continued mental health screening and surveillance into young adulthood is warranted for adolescents with TOF., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To establish executive function (EF) structure/organization and test a longitudinal developmental cascade model linking processing speed (PS) and EF skills at 8-years of age to academic achievement outcomes, both at 8- and 16-years, in a large sample of children/adolescents with surgically repaired dextro-transposition of the great arteries (d-TGA)., Method: Data for this study come from the 8- (n = 155) and 16-year (n = 139) time points of the Boston Circulatory Arrest Study and included WISC-III, Trail Making Test, Test of Variables of Attention, and WIAT/WIAT-II tasks., Results: A 2-factor model (Working Memory/Inhibition and Shifting) provided the best fit for the EF data, χ²(3) = 1.581, p = .66, RMSEA = 0, CFI = 1, NNFI = 1.044). Working Memory/Inhibition and Shifting factors were not correlated. In the structural equation model, PS was directly related to both EF factors and Reading at 8 years, and was indirectly related to Math and Reading achievement, both concurrently and longitudinally, via its effects on Working Memory/Inhibition. Shifting at 8 years was significantly associated with Math (but not Reading) at 16 years., Conclusions: The academic difficulties experienced by children and adolescents with d-TGA may be driven, at least in part, by underlying deficits in processing speed and aspects of executive function. Intervention efforts aimed at bolstering these abilities, particularly if implemented early in development, may prove beneficial in improving academic outcomes and, perhaps by extension, in reducing the stress and diminished self-confidence often associated with academic underachievement. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

The objective of this study was to establish latent executive function (EF) and psychosocial adjustment factor structure, to examine associations between EF and psychosocial adjustment, and to explore potential development differences in EF-psychosocial adjustment associations in healthy children and adolescents. Using data from the multisite National Institutes of Health (NIH) magnetic resonance imaging (MRI) Study of Normal Brain Development, the current investigation examined latent associations between theoretically and empirically derived EF factors and emotional and behavioral adjustment measures in a large, nationally representative sample of children and adolescents (7-18 years old; N = 352). Confirmatory factor analysis (CFA) was the primary method of data analysis. CFA results revealed that, in the whole sample, the proposed five-factor model (Working Memory, Shifting, Verbal Fluency, Externalizing, and Internalizing) provided a close fit to the data, χ(2)(66) = 114.48, p < .001; RMSEA = .046; NNFI = .973; CFI = .980. Significant negative associations were demonstrated between Externalizing and both Working Memory and Verbal Fluency (p < .01) factors. A series of increasingly restrictive tests led to the rejection of the hypothesis of invariance, thereby precluding formal statistical examination of age-related differences in latent EF-psychosocial adjustment associations. Findings indicate that childhood EF skills are best conceptualized as a constellation of interconnected yet distinguishable cognitive self-regulatory skills. Individual differences in certain domains of EF track meaningfully and in expected directions with emotional and behavioral adjustment indices. Externalizing behaviors, in particular, are associated with latent Working Memory and Verbal Fluency factors.

Children and adolescents with critical cyanotic congenital heart disease (CHD) are at risk for deficits in aspects of executive function (EF). The primary aim of this investigation was to compare EF outcomes in three groups of children/adolescents with severe CHD and controls (ages 10-19 years). Participants included 463 children/adolescents with CHD [dextro-transposition of the great arteries (TGA), n=139; tetralogy of Fallot (TOF), n=68; and, single-ventricle anatomy requiring Fontan procedure (SVF), n=145] and 111 controls, who underwent laboratory and informant-based evaluation of EF skills. Rates of EF impairment on D-KEFS measures were nearly twice as high for CHD groups (75-81%) than controls (43%). Distinct EF profiles were documented between CHD groups on D-KEFS tasks. Deficits in flexibility/problem-solving and verbally mediated EF skills were documented in all three CHD groups; visuo-spatially mediated EF abilities were impaired in TOF and SVF groups, but preserved in TGA. Parent, teacher, and self-report ratings on the BRIEF highlighted unique patterns of metacognitive and self-regulatory concerns across informants. CHD poses a serious threat to EF development. Greater severity of CHD is associated with worse EF outcomes. With increased understanding of the cognitive and self-regulatory vulnerabilities experienced by children and adolescents with CHD, it may be possible to identify risks early and provide individualized supports to promote optimal neurodevelopment.

This investigation examined the associations between maltreatment and aggression using a gender-informed approach. Peer ratings, peer nominations, and counselor reports of aggression were collected on 211 maltreated and 199 nonmaltreated inner-city youth (M age = 9.9 years) during a summer day camp. Maltreatment was associated with aggressive conduct; however, these effects were qualified by gender, maltreatment subtype, and the form of aggression under investigation. Findings revealed that maltreatment was associated with physical aggression for boys and relational aggression for girls. Physical abuse was associated with physically aggressive behaviors, but sexual abuse predicted relational aggression for girls only. Findings suggest that investigating the interaction between familial risk and gender is important in understanding aggressive behaviors of boys and girls.