Genome Sequencing for Diagnosing Rare Diseases.

BACKGROUND: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined. METHODS: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center. RESULTS: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments. CONCLUSIONS: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).

Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

Purpose: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). Methods: We coupled phenotyping with exome or genome sequencing of 467 pedigrees with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations. Results: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses. Conclusion: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and with new innovative methods can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the GREGoR consortium. Each family's CNV data was analyzed using the seqr platform and candidate CNVs classified using the 2020 ACMG/ClinGen CNV interpretation standards. We developed additional evidence criteria to address situations not covered by the current standards. The addition of CNV calling to exome analysis identified causal CNVs for 173 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb with estimates that 44% would not have been detected by standard chromosomal microarrays. The causal CNVs consisted of 141 deletions, 15 duplications, 4 suspected complex structural variants (SVs), 3 insertions and 10 complex SVs, the latter two groups being identified by orthogonal validation methods. We interpreted 153 CNVs as likely pathogenic/pathogenic and 20 CNVs as high interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

When the implementation of water safety plans fail: rethinking the approach to water safety planning following a serious waterborne outbreak and implications for subsequent water sector reforms.

Water suppliers in New Zealand have been preparing the water safety plans (WSPs) since 2005; large drinking water-associated outbreaks of campylobacteriosis occurred in Darfield in 2012 and in Havelock North in 2016. This paper reviews the WSP that was in place for Havelock North, and analyses why it failed to prevent this outbreak. The risk assessment team completing the WSP underestimated the risks to human health of contamination events, while overestimating the security of the groundwater and bore heads. Historical Escherichia coli transgressions were dismissed as likely despite sampler or testing errors, rather than important warning signals. The outbreak was a consequence of multiple factors including an untreated supply, a local animal faecal source, limitations to the aquifer integrity and bore head protection, and a failure to proactively respond to a flooding event. The overarching issue was a focus on narrow compliance with the Health Act rather than the use of the WSP as a valuable tool to proactively understand and manage public health risks. New Zealand plans to focus on the ability of an organisation to manage risk, with the emphasis on promoting conversations with water suppliers about integrated risk management rather than focusing solely on the preparation of a WSP.

Sleep health behaviors in pediatric patients with newly diagnosed cancer.

OBJECTIVE: Disrupted sleep and fatigue are common symptoms in children with cancer, but little is known about this population's sleep health behaviors and how they may impact nighttime sleep. We aimed to describe the sleep health behaviors of children with newly diagnosed cancer and to determine if they changed over the next 8 weeks. METHODS: Our sample included 169 children with cancer (86 males) who were aged 2-18 years (mean [SD] = 8.14 [4.4] y), with parent proxy report for 140 children (71 male) aged 2-12 years (mean [SD] = 6.67 [3.2] y) and self-report for 78 children (39 male) aged 8-18 years (mean [SD] = 12.0 [2.9] y). Parents and patients completed sleep hygiene questionnaires within 30 days of oncology diagnosis (T1); follow-up questionnaires were collected 8 weeks later (T2). Descriptive analyses characterized the sample by sociodemographic characteristics, cancer diagnosis, treatments received, and prescribed medications. RESULTS: Age-related differences were found in sleep health behaviors, with adolescents reporting better overall sleep health behaviors than younger children at both time points. No differences in sleep health behaviors were found at T1 related to diagnosis, treatment, or medications. Some differences in sleep health behaviors were found at T2 related to gender, diagnosis, treatment, and medications. Sleep health behaviors and sleep problems remained relatively stable over 8 weeks. Fatigue was significantly associated with more pre-bedtime worries, insomnia, and lower rates of daytime sleepiness. CONCLUSIONS: These findings offer novel descriptive characteristics of sleep health behaviors in a pediatric oncology sample and show relatively stable yet somewhat poor sleep health behaviors across 8 weeks. Better understanding of sleep health behaviors as modifiable factors will help inform targeted interventions.

An exploratory study of sleep habits in school-aged survivors of retinoblastoma.

OBJECTIVE/BACKGROUND: Retinoblastoma is an ocular cancer diagnosed in early childhood. Previous research has indicated the impact of cancer treatment on sleep, but little is known about how sleep is impacted among survivors of retinoblastoma. The current study aimed to describe sleep habits of school-age survivors of retinoblastoma, to examine associations between sleep and quality of life, and to examine concordance between parent and child reports of sleep habits. PATIENTS/METHODS: Sixty-nine survivors of retinoblastoma (Mage = 10.89, SD = 1.07, 50.7% female; 56.5% unilateral disease) and their caregivers participated, providing information on both self- and parent-reported sleep habits, quality of life, and demographic data. RESULTS: Greater sleep concerns than national norms were reported by parents (bedtime resistance (t(58) = 2.69, p = .009), greater sleep onset delay (t(66) = 2.46, p = .017), shorter sleep duration (t(57) = 2.12, p = .038), increased daytime sleepiness (t(53) = 6.45, p= <.001)) and children (sleep location (t(61) = 2.39, p = .02), restless legs syndrome (t(62) = -2.21, p = .03), parasomnias (t(64) = 19.19, p=<.001)) . Both children and parents of children who received enucleation endorsed greater sleep concerns across several domains (e.g., electronic use before bed, sleep-disordered breathing). Child- and parent-reported sleep concerns were generally associated with decreased quality of life. Finally, child- and parent-report of sleep habits appeared generally consistent. CONCLUSIONS: Survivors of retinoblastoma experience sleep difficulties. As such, assessment and targeted intervention is important to mitigate any effects on quality of life. Future research should examine sleep habits of survivors of retinoblastoma across cultures and developmental periods.

Working memory and school readiness in preschool children with sickle cell disease compared to demographically matched controls.

Children diagnosed with sickle cell disease (SCD) are at risk of the development of neurobehavioural problems early in life. Specific impairments in executive function skills, including working memory, have been documented in school-aged children with SCD. These executive skills are known to strongly contribute to early academic skills and preparedness for entering kindergarten. This study examined working memory and school readiness in preschool children with SCD compared to a healthy control group matched for race, sex and parent education. A total of 84 patients diagnosed with SCD (61.9% haemoglobin [Hb]SS/HbSß0 -thalassaemia) and 168 controls completed testing. The mean (SD) ages of patients and controls at testing were 4.53 (0.38) and 4.44 (0.65) years respectively. The SCD group performed worse than controls on measures of executive function, working memory and school readiness (p < 0.01; Cohen's D range: 0.32-0.39). Measures of working memory were associated with school readiness after accounting for early adaptive development. Multiple linear regression models among patients diagnosed with SCD revealed that college education of the primary caregiver was positively associated with school readiness (p < 0.001) after controlling for sex, genotype, age and early adaptive development. These results highlight the need to implement school readiness interventions in young children diagnosed with SCD emphasising executive function skills.

Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis.

Background: Causal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort. Methods: GS was performed for 744 individuals with rare disease who were genetically undiagnosed. Analysis included review of single nucleotide, indel, structural, and mitochondrial variants. Results: We successfully solved 218/744 (29.3%) cases using GS, with most solves involving established disease genes (157/218, 72.0%). Of all solved cases, 148 (67.9%) had previously had non-diagnostic ES. We systematically evaluated the 218 causal variants for features requiring GS to identify and 61/218 (28.0%) met these criteria, representing 8.2% of the entire cohort. These included small structural variants (13), copy neutral inversions and complex rearrangements (8), tandem repeat expansions (6), deep intronic variants (15), and coding variants that may be more easily found using GS related to uniformity of coverage (19). Conclusion: We describe the diagnostic yield of GS in a large and diverse cohort, illustrating several types of pathogenic variation eluding ES or other techniques. Our results reveal a higher diagnostic yield of GS, supporting the utility of a genome-first approach, with consideration of GS as a secondary or tertiary test when higher-resolution structural variant analysis is needed or there is a strong clinical suspicion for a condition and prior targeted genetic testing has been negative.

Managing urban riverscapes: An assessment framework to integrate social-ecological values and physical processes.

The services that rivers provide and how they affect the landscape plays a dominate role in urban planning and development. Urban riverscapes, which consist of stream channels, their floodplains, biotic communities, and manmade features, are complex social-ecological and hydrogeomorphic systems. Yet, despite recognition of their place and value, rivers are often degraded in urban settings. Successfully managing urban riverscapes requires improved methods to assess them and to more effectively link stressors to values, and to incorporate these considerations in planning. Assessment of urban riverscapes' physical condition and function-a hydrogeomorphic assessment-is necessary to make these links, and inform more appropriate management strategies for sustainable and valued riverscape systems. The framework and methods used for such an assessment should be appropriate to the urban context, insofar as they are applicable to a range of streams from lightly degraded to highly utilized or constructed. Above all, the framework must prioritize the connection of human communities to riverscapes. In this article, we outline a framework for urban riverscape assessment which considers four facets of urban riverscapes: human values, hydrology, geomorphology, and ecology. The four facets, assessed across multiple nested scales, provide a flexible basis for context-driven hydrogeomorphic assessment, which is vital to informing better planning and management of urban riverscapes. The framework can be integrated with other facets (e.g. geochemical, aquatic ecology) depending on the scope of the assessment. By linking intrinsic, relational, and use-based values to physical conditions, watershed managers can select relevant and measurable indicators that directly inform interventions in the riverscape, catchment, or urban zones to improve riverscape function and urban vitality through planning mechanisms. This assessment framework facilitates dialogue between managers, practitioners, scientists, and the community; enabling technical and non-technical inputs to the development of assessment criteria, and a shared vision to inform targets and goals.

The posterior fossa syndrome questionnaire: using science to inform practice.

INTRODUCTION: Up to 34% of patients with medulloblastoma develop posterior fossa syndrome (PFS) following brain tumor resection and have increased risk of long-term neurocognitive impairments. Lack of agreement in conceptualization and diagnosis of PFS calls for improvements in diagnostic methods. The current study aimed to describe psychometric properties of a new posterior fossa syndrome questionnaire (PFSQ). METHODS: The PFSQ was informed by prior research and developed by a multidisciplinary team with subject matter expertise. Participants (N = 164; 63.4% Male; 78.7% White; Mage at diagnosis = 10.38 years, SD = 5.09, range 3-31 years) included patients with newly diagnosed medulloblastoma enrolled in the SJMB12 clinical trial. Forty-four patients (26.8%) were classified as having PFS based on attending physician's post-surgical yes/no report. A PFSQ was completed by a neurologist within 2 weeks of coming to St. Jude Children's Research Hospital for adjuvant treatment, irrespective of suspicion for PFS. RESULTS: PFSQ items ataxia (100.00%), dysmetria (95.45%), and speech/language changes (79.55%) were most sensitive. However, ataxia (26.50%) and dysmetria (46.61%) demonstrated low specificity. Speech/language changes (81.36%), mutism (95.76%), orofacial apraxia (98.29%) and irritability (96.61%) had high specificity. A principal component analysis found four components: (1) speech/language changes, (2) apraxias (including mutism), (3) motor/oromotor, and (4) emotional lability. CONCLUSIONS: The PFSQ is a dimensional diagnostic approach that can be used to improve diagnostic consistency across clinical and research groups to help accelerate understanding of PFS etiology, identify surgical correlates of risk, predict long-term impairments, and develop targeted interventions. Additional measure validation, including correlation with symptom resolution, is required.

Do Anxiety and Mood Vary among Disparate Sleep Profiles in Youth with Craniopharyngioma? A Latent Profile Analysis.

INTRODUCTION: Craniopharyngioma is a histologically benign brain tumor that arises in the suprasellar region affecting critical neurovascular structures including the hypothalamic-pituitary-adrenal axis and optic pathways. Children with craniopharyngioma often experience excessive daytime sleepiness which may be compounded by anxiety and depression. The current study investigated disparate sleep profiles to better understand psychological adjustment among children diagnosed with craniopharyngioma. Method: Actigraphs recorded nightly sleep data, including measures of sleep onset latency and wake after sleep onset, in a cohort of 80 youth between the ages of 2 and 20 years (median age = 9). Parent reports of behavioral and emotional functioning were included in the analysis. A latent profile analysis examined disparate sleep profiles, and a multinomial logistic regression examined differences of anxiety and depression among the sleep profiles. Results: The latent profile analysis revealed three sleep profiles: "variable sleepers" (48.3%), "consistently poor sleepers" (45.4%), and "night wakers" (6.4%). Consistently poor sleepers had lower rates of anxiety (g = .76; p = .009) and depression (g = .81; p = .003) than variable sleepers and had significantly lower rates of anxiety than night wakers (g = .52; p = .05); all other differences were nonsignificant (ps > .05). Discussion: Youth with craniopharyngioma who have nightly variations in sleep may have worse psychological functioning than those with more consistent, albeit poor, sleep patterns. Patients with craniopharyngioma who report variable sleep should be assessed for anxiety and depression to prevent and intervene on emotional difficulties that may be reciprocally related to sleep.

A Latent Profile Analysis of Sleep, Anxiety, and Mood in Youth with Craniopharyngioma.

Craniopharyngioma is a histologically benign brain tumor that arises in the suprasellar region affecting critical neurovascular structures including the hypothalamic-pituitary-adrenal axis and optic pathways. Children with craniopharyngioma often experience excessive daytime sleepiness (EDS) which may be compounded by anxiety and depression. The current study investigated disparate sleep profiles to better understand psychological adjustment among children diagnosed with craniopharyngioma. METHOD: Actigraphs recorded nightly sleep data, including measures of sleep onset latency (SOL) and wake after sleep onset (WASO), in a cohort of 80 youth between the ages of 2 and 20 years (median age = 9). Parent reports of behavioral and emotional functioning were included in the analysis. A latent profile analysis examined disparate sleep profiles, and a multinomial logistic regression examined differences of anxiety and depression among the sleep profiles. RESULTS: The latent profile analysis revealed three sleep profiles: "healthy sleepers" (68.8%), "night wakers" (21.3%), and "prolonged onset sleepers" (10.0%). Contrary to expectations, sleep profiles were not associated with daytime anxiety (ß = 2.26-4.30, p > .05) or depression (ß = -5.87-4.74, p > .05). CONCLUSIONS: Youth with craniopharyngioma demonstrate poor sleep and EDS. Those with delayed SOL and prolonged WASO are particularly vulnerable to disrupted nighttime sleep, which may significantly compound EDS. Disrupted sleep was not associated with anxiety or depression, which may be related to the overall poor sleep and daytime sleepiness or to timing, as patients were early in their treatment course. Further study should evaluate the factors underlying sleepiness and daytime function in patients with craniopharyngioma.

Nocturnal Enuresis in Sickle Cell: Sociodemographic, Medical, and Quality of Life Factors.

OBJECTIVE: Nocturnal enuresis is more prevalent in youth with sickle cell disease (SCD) compared to the general population. The purpose of this study is to estimate prevalence of nocturnal enuresis using diagnostic criteria and identify associated sociodemographic, medical, and health-related quality of life (HRQOL) factors. METHODS: Youth with SCD (N = 248; ages 6.00-17.99 years) and their caregivers completed semi-structured interviews and questionnaires. HRQOL was measured using the Pediatric Quality of Life (PedsQL) Inventory. Medical information was abstracted from medical record. We generated multivariable logistic regression models to examine associations between factors and current nocturnal enuresis and nocturnal enuresis occurring any time in the past (lifetime). RESULTS: Among participants (mean age, 11.3 ± 3.6 years; 50.8% male), 21.4% reported current nocturnal enuresis and 46% reported lifetime nocturnal enuresis. Male sex [odds ratio (OR), 2.57; p = .001], difficulty arousing from sleep (OR, 3.57; p < .001), higher school functioning HRQOL (OR, 1.02; p = .014), and higher fetal hemoglobin levels (OR, 1.03; p = .048) were associated with lifetime nocturnal enuresis. Younger age (OR, 1.16; p = .005), higher youth-reported fatigue (OR, 1.01; p = .045), difficulty arousing from sleep (OR, 4.92; p < .001), and higher lactate dehydrogenase levels (OR, 1.00; p = .042) were associated with current nocturnal enuresis. CONCLUSIONS: Nocturnal enuresis is prevalent in youth with SCD and is associated with HRQOL, diminished sleep, greater fatigue, and disease severity markers. Routine assessment of sleep behaviors and fatigue are necessary when treating patients with SCD to understand the impact of nocturnal enuresis on HRQOL.

Centrality of the childhood cancer experience and its relation to post-traumatic stress and growth.

OBJECTIVE: Event centrality, the degree to which a traumatic event is perceived as central to one's identity, has been associated with post-traumatic stress (PTS) symptoms and post-traumatic growth (PTG) outcomes in various trauma samples. Trauma frameworks are widely used to understand the psychological impact of pediatric cancer; however, event centrality has not been studied in this population. We investigated event centrality in pediatric cancer survivors and healthy comparisons, and its relation with PTS and PTG outcomes. METHOD: Cancer survivors, age 13-23 (N = 196) and healthy comparisons (N = 131) completed the Centrality of Events Scale and PTS and PTG measures in reference to their most traumatic life event. Cancer survivors who first identified a non-cancer-related event repeated all measures in reference to cancer. RESULTS: Centrality scores were significantly higher when referencing cancer compared to non-cancer events, even in survivors for whom cancer was not rated as most stressful (53.1%). Centrality scores for non-cancer events were not significantly different between survivors and healthy comparisons. Event centrality showed significant positive relations to both PTS and PTG outcomes. CONCLUSION: The pediatric cancer experience is perceived as central to survivors' identity regardless of whether the experience is perceived as highly traumatic. Centrality of cancer is a significant predictor of both positive and negative psychological outcomes in cancer survivors.

Longitudinal Trajectories of Neurocognitive Functioning in Childhood Acute Lymphoblastic Leukemia.

OBJECTIVE: Children with acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits, and examining individual variability is essential to understand these risks. This study evaluated latent longitudinal trajectories and risk factors of neurocognitive outcomes in childhood ALL. METHODS: There were 233 participants with ALL who were enrolled on a phase 3, risk-stratified chemotherapy-only clinical trial (NCT00137111) and who completed protocol-directed neurocognitive assessments [47.6% female, mean (SD) = 6.6 (3.7) years]. Measures of sustained attention, learning/memory, and parent ratings of attention were completed during and after treatment. Longitudinal latent class analyses were used to classify participants into distinct trajectories. Logistic regression was used to identify predictors of class membership. RESULTS: Within the overall group, attention performance was below age expectations across time (Conners Continuous Performance Test detectability/variability, p < 0.01); memory performance and parent ratings were below expectations at later phases (California Verbal Learning Test learning slope, p < 0.05; Conners Parent Rating Scale, Revised attention/learning, p < 0.05). Most participants (80-89%) had stable neurocognitive profiles; smaller groups showed declining (3-6%) or improving (3-11%) trajectories. Older age (p = 0.020), female sex (p = 0.018), and experiencing sepsis (p = 0.047) were associated with greater attention problems over time. Lower baseline IQ was associated with improved memory (p = 0.035) and fewer ratings of attention problems (p = 0.013) over time. CONCLUSIONS: Most patients with ALL have stable neurocognitive profiles. Smaller groups have significant impairments shortly after diagnosis or have worsening performance over time. A tiered assessment approach, which includes consideration of individual and clinical risk factors, may be useful for monitoring neurocognitive functioning during treatment and survivorship.

Neurocognitive functioning in long-term survivors of pediatric hematopoietic cell transplantation.

Survivors of pediatric hematopoietic cell transplantation (HCT) are at risk for impairment in cognitive and academic function. Most research to date has focused on the first years following transplant, and less is known about the long-term effects. We examined global and specific neurocognitive functioning in long-term (>5 years post HCT) survivors in comparison to both normative data and a sample of demographically similar healthy peers. A comprehensive battery of neurocognitive measures was obtained from 83 long-term survivors and 50 healthy comparisons. Analyses were conducted to assess for differences in neurocognitive functions between survivors, normative means, and healthy comparisons, and to examine the impact of medical and demographic variables on neurocognitive performance. Survivors' performance was within the Average range across most measures, although significantly lower than both test norms and healthy comparisons on several measures. Despite generally intact neurocognitive functioning in the survivor group as a whole, survivors who experienced graft-vs.-host disease demonstrated slower processing speed and weaker verbal learning. Use of total body irradiation was not associated with any performance-based measure of neurocognitive functioning. Although subgroups of patients may be at relatively higher risk of neurocognitive impairment, the long-term neurocognitive impact for most survivors is relatively small.

Feasibility and Acceptability of Light Therapy to Reduce Fatigue in Adolescents and Young Adults Receiving Cancer-Directed Therapy.

OBJECTIVE/BACKGROUND: Fatigue is one of the most consistent and distressing symptoms reported by adolescent/young adult (AYA) oncology patients. Bright white light (BWL) is used to treat fatigue in adult oncology but has not been explored in AYA oncology patients. The purpose of the current study was to determine the feasibility and acceptability of BWL for AYA who were receiving cancer-directed therapy. PARTICIPANTS: 51 AYA patients with newly diagnosed solid tumors, including lymphoma. METHODS: Participants were randomized to dim red light (DRL, n = 25) or BWL (n = 26) from devices retrofitted with adherence monitors for 30 minutes upon awakening daily for 8 weeks. Side effects were assessed via modified Systematic Assessment for Treatment-Emergent Effects (SAFTEE). Participants completed the PedsQL Multidimensional Fatigue Scale. RESULTS: Of patients approached, 73% consented and participated. Mean adherence was 57% of days on study with 30.68 average daily minutes of usage. BWL did not cause more extreme treatment-emergent effects over DRL. Patients in the BWL group demonstrated significant improvement on all fatigue outcomes by both self-report and parent proxy report, which was not observed in the DRL group. CONCLUSIONS: This is the first study to evaluate the feasibility and acceptability of light therapy to reduce fatigue in AYA patients receiving cancer-directed therapy. These findings demonstrate the feasibility and acceptability of the intervention and provide preliminary evidence of the potential benefits of BWL, which warrants further study in a confirmatory efficacy trial.ClinicalTrials.gov Identifier Number: NCT02429063.