Prediction of Functional Academic Outcomes by Fine Motor Skills in Individuals With Sickle Cell Disease.

IMPORTANCE: Individuals with sickle cell disease (SCD) are at heightened risk of poor neurocognitive and academic outcomes. The relationship between fine motor skills and academic outcomes is not well understood. OBJECTIVE: To compare the fine motor skills of individuals with SCD with normative expectations, test whether demographic and medical factors are associated with fine motor performance, and determine the impact of fine motor performance on academic performance. DESIGN: Cross-sectional. SETTING: St. Jude Children's Research Hospital. PARTICIPANTS: Individuals with SCD (N = 376; ages 8-24 yr). OUTCOMES AND MEASURES: Fine motor outcomes included visual-motor integration, manual dexterity, and graphomotor speed. Academic outcomes included math fluency and word reading. Demographic and medical variables were obtained via medical records and interviews. RESULTS: Compared with normative expectations, the performance of individuals with SCD on all fine motor measures was lower than expected. Male sex, lower socioeconomic status, and lower oxygen saturation was associated with slower graphomotor speed. Lower socioeconomic status and older age were associated with lower visual-motor integration scores. Performance on all fine motor measures was positively associated with math fluency and word reading. CONCLUSIONS AND RELEVANCE: Individuals with SCD exhibited poorer than expected fine motor skills across multiple motor domains, and these deficits were associated with poorer academic outcomes. Early referral to intervention services for fine motor skills may facilitate improved academic outcomes for individuals with SCD. Plain-Language Summary: This study had three objectives: (1) Compare the fine motor skills of people with sickle cell disease (SCD) with normative expectations, (2) test whether demographic and medical factors are associated with fine motor performance, and (3) determine the impact of fine motor performance on academic performance. We found that SCD is a risk factor for lower than expected fine motor performance across multiple fine motor domains and that these deficits also affect functional academic skills.

Perinatal risk factors and neurocognitive outcomes in children and adolescents with sickle cell disease.

BACKGROUND: The literature on cognitive and academic outcomes for children with sickle cell disease (SCD) who experience perinatal risk factors is limited. We aimed to evaluate if low birthweight (LBW), gestational age, and history of neonatal intensive care unit (NICU) admission were associated with neurocognitive functioning, grade retention, or receipt of early intervention or formal educational support in children with SCD. PROCEDURES: This prospective birth cohort study included 336 participants, ages 8-18, with SCD, who received cognitive testing as part of standard of care and whose caregivers completed behavioral rating scales. Multivariable generalized linear regression models were used to examine associations between perinatal risks and outcome variables, after adjusting for demographic and medical covariates. RESULTS: The prevalence of NICU admission and LBW were 12.03% and 13.50%, respectively. Lower birthweight, earlier gestational age, and NICU admission were associated with worse working memory performance and receipt of early intervention services. Lower birthweight and NICU admission were also associated with slower processing speed. History of NICU admission was associated with caregiver ratings of hyperactivity and emotional dysregulation. The effects of perinatal risk factors on neurocognitive, academic, or educational outcomes were not dependent on SCD genotype. CONCLUSIONS: History of LBW or NICU admission was associated with worse cognitive outcomes and increased use of early intervention services among children with SCD. Early identification of perinatal risk factors will help identify children who will benefit from formal developmental or neuropsychological evaluations to manage the comorbidity of SCD and perinatal risks and facilitate increased intervention.

Association of elevated tricuspid regurgitation velocity with cerebrovascular and kidney disease in children with sickle cell disease.

BACKGROUND: Tricuspid regurgitation velocity (TRV), measured by echocardiography, is a surrogate marker for pulmonary hypertension. Limited pediatric studies have considered the association between TRV and surrogate markers of end-organ disease. METHODS: We conducted a cross-sectional study that evaluated the prevalence of elevated TRV ≥2.5 m/s and its associations with renal and cerebrovascular outcomes in children with sickle cell disease (SCD) 1-21 years of age in two large sickle cell cohorts, the University of Alabama at Birmingham (UAB) sickle cell cohort, and the Sickle Cell Clinical Research and Intervention Program (SCCRIP) cohort at St. Jude Children's Research Hospital. We hypothesized that patients with SCD and elevated TRV would have higher odds of having either persistent albuminuria or cerebrovascular disease. RESULTS: We identified 166 children from the UAB cohort (mean age: 13.49 ± 4.47 years) and 325 children from the SCCRIP cohort (mean age: 13.41 ± 3.99 years) with echocardiograms. The prevalence of an elevated TRV was 21% in both UAB and SCCRIP cohorts. Elevated TRV was significantly associated with cerebrovascular disease (odds ratio [OR] 1.88, 95% confidence interval [CI]: 1.12-3.15; p = .017) and persistent albuminuria (OR 1.81, 95% CI: 1.07-3.06; p = .028) after adjusting for age, sex, treatment, and site. CONCLUSION: This cross-sectional, multicenter study identifies associations between surrogate markers of pulmonary hypertension with kidney disease and cerebrovascular disease. A prospective study should be performed to evaluate the longitudinal outcomes for patients with multiple surrogate markers of end-organ disease.

Intrapulmonary administration of recombinant activated factor VII in pediatric, adolescent, and young adult oncology and hematopoietic cell transplant patients with pulmonary hemorrhage.

Introduction: Diffuse alveolar hemorrhage (DAH) is a devastating disease process with 50-100% mortality in oncology and hematopoietic cell transplant (HCT) recipients. High concentrations of tissue factors have been demonstrated in the alveolar wall in acute respiratory distress syndrome and DAH, along with elevated levels of tissue factor pathway inhibitors. Activated recombinant factor VII (rFVIIa) activates the tissue factor pathway, successfully overcoming the tissue factor pathway inhibitor (TFPI) inhibition of activation of Factor X. Intrapulmonary administration (IP) of rFVIIa in DAH is described in small case series with successful hemostasis and minimal complications. Methods: We completed a single center retrospective descriptive study of treatment with rFVIIa and outcomes in pediatric oncology and HCT patients with pulmonary hemorrhage at a quaternary hematology/oncology hospital between 2011 and 2019. We aimed to assess the safety and survival of patients with pulmonary hemorrhage who received of IP rFVIIa. Results: We identified 31 patients with pulmonary hemorrhage requiring ICU care. Thirteen patients received intrapulmonary rFVIIa, while eighteen patients did not. Overall, 13 of 31 patients (41.9%) survived ICU discharge. ICU survival (n=6) amongst those in the IP rFVIIa group was 46.2% compared to 38.9% (n=7) in those who did not receive IP therapy (p=0.69). Hospital survival was 46.2% in the IP group and 27.8% in the non-IP group (p=0.45). There were no adverse events noted from use of IP FVIIa. Conclusions: Intrapulmonary rFVIIa can be safely administered in pediatric oncology patients with pulmonary hemorrhage and should be considered a viable treatment option for these patients.

The genetic dissection of fetal haemoglobin persistence in sickle cell disease in Nigeria.

The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS/HbSß0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional and haplotype association analyses and included public functional annotation datasets. Association signals were detected for BCL11A (lead SNP rs6706648, ß = -0.39, P = 4.96 × 10-34) and HBS1L-MYB (lead SNP rs61028892, ß = 0.73, P = 1.18 × 10-9), whereas the variant allele for Xmn1-HBG2 was found to be very rare. In addition, we detected three putative new trait-associated regions. Genetically, dissecting the two major loci BCL11A and HBS1L-MYB, we defined trait-increasing haplotypes (P < 0.0001) containing so far unidentified causal variants. At BCL11A, in addition to a haplotype harbouring the putative functional variant rs1427407-'T', we identified a second haplotype, tagged by the rs7565301-'A' allele, where a yet-to-be-discovered causal DNA variant may reside. Similarly, at HBS1L-MYB, one HbF-increasing haplotype contains the likely functional small indel rs66650371, and a second tagged by rs61028892-'C' is likely to harbour a presently unknown functional allele. Together, variants at BCL11A and HBS1L-MYB SNPs explained 24.1% of the trait variance. Our findings provide a path for further investigation of the causes of variable fetal haemoglobin persistence in sickle cell disease.

Catechol-O-methyltransferase gene (COMT) is associated with neurocognitive functioning in patients with sickle cell disease.

PURPOSE: Neurocognitive impairment is a common and debilitating complication of sickle cell disease (SCD) resulting from a combination of biological and environmental factors. The catechol-O-methyltransferase (COMT) gene modulates levels of dopamine availability in the prefrontal cortex. COMT has repeatedly been implicated in the perception of pain stimuli and frequency of pain crises in patients with SCD and is known to be associated with neurocognitive functioning in the general population. The current study aimed to examine the associations of genetic variants in COMT and neurocognitive functioning in patients with SCD. PATIENTS AND METHODS: The Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort was used as a discovery cohort (n = 166). The genotypes for 5 SNPs (rs6269, rs4633, rs4818, rs4680, and rs165599) in COMT were extracted from whole genome sequencing data and analyzed using a dominant model. A polygenic score for COMT (PGSCOMT) integrating these 5 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (CSSCD, n = 156) and the Silent Cerebral Infarction Transfusion (SIT, n = 114) Trial were used as 2 independent replication cohorts. Due to previously reported sex differences, all analyses were conducted separately in males and females. The Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (q-value). RESULTS: In SCCRIP, 1 out of 5 SNPs (rs165599) was associated with IQ at q<0.05 in males but not females, and 2 other SNPs (rs4633 and rs4680) were marginally associated with sustained attention at p<0.05 in males only but did not maintain at q<0.05. PGSCOMT was negatively associated with IQ and sustained attention at p<0.05 in males only. Using 3 cohorts' data, 4 out of 5 SNPs (rs6269, rs4633, rs4680, rs165599) were associated with IQ (minimum q-value = 0.0036) at q<0.05 among male participants but not female participants. The PGSCOMT was negatively associated with IQ performance among males but not females across all cohorts. CONCLUSION: Select COMT SNPs are associated with neurocognitive abilities in males with SCD. By identifying genetic predictors of neurocognitive performance in SCD, it may be possible to risk-stratify patients from a young age to guide implementation of early interventions.

Agreement between youth and caregiver report of pain and functioning in pediatric sickle cell disease: PedsQL sickle cell disease module.

ABSTRACT: Pain is a primary symptom of sickle cell disease (SCD) and is often severe and chronic. To treat SCD-related pain, proper assessment of SCD pain among youth, including the degree of concordance or agreement between youth and caregiver reports of pain, is essential but has not yet been adequately evaluated. In this study, 525 youth with SCD and their parents were evaluated as part of the Sickle Cell Clinical Research and Intervention Program (SCCRIP) to examine pain rating concordance and predictors of concordance. Youth and parents completed the Pediatric Quality of Life Inventory Sickle Cell Disease module (PedsQL-SCD) to measure pain, pain interference, and pain-related constructs. Disease, clinical, and demographic variables were obtained from the SCCRIP database. Intraclass correlations demonstrated moderate-to-poor consistency between youth and caregiver reports of pain and pain interference (ICCs range from 0.17 to 0.54). Analysis of covariance and regression models found that patient age, frequency of hospitalizations and emergency department (ED) visits, economic hardship, and fetal hemoglobin levels were significantly associated with varying pain-rating agreement levels among parent proxy and child self-report pain. Concordance of pain assessments among youth with SCD and their caregivers using the PedsQL-SCD Module was moderate at best, corroborating prior research. Youth factors predicting discordance among pain-related factors included increased ED visits, older age, and female sex. Collectively, these results bolster the use of integrated pain assessments to reduce parent-child discrepancies, thereby improving the adequacy of SCD-related pain assessment and treatment.

Multicomponent Strategy Improves Human Papillomavirus Vaccination Rates Among Adolescents with Sickle Cell Disease.

OBJECTIVE: To evaluate the effectiveness of a vaccine strategy bundle to increase human papillomavirus (HPV) vaccine initiation and completion in a specialty clinic setting. STUDY DESIGN: Our Hematology clinic utilized an implementation framework from October 1, 2018, to December 31, 2019, involving nurses, nursing coordinators, and clinicians in administering the HPV vaccination series to our adolescent sickle cell sample of nearly 500 patients. The bundle included education for staff on the need for HPV vaccine administration, provider incentives, vaccines offered to patients in SCD clinics, and verification of patients' charts of vaccine completion. RESULTS: Following the implementation of the bundle, the cumulative incidence of HPV vaccination initiation and completion improved from 28% to 46% and 7% to 49%, respectively. Both rates remained higher postimplementation as well. HPV vaccination series completion was associated with a decreased distance to the health care facility, lower state deprivation rank, and increased hospitalizations. CONCLUSION: Our clinic's implementation strategy successfully improved vaccine completion rates among adolescents with sickle cell disease (SCD) while continuing to educate staff, patients, and families on the importance of cancer prevention among people living with SCD.

Corrigendum: Academic performance of children with sickle cell disease in the United States: a meta-analysis.

[This corrects the article DOI: 10.3389/fneur.2021.786065.].

Potent and uniform fetal hemoglobin induction via base editing.

Inducing fetal hemoglobin (HbF) in red blood cells can alleviate ß-thalassemia and sickle cell disease. We compared five strategies in CD34+ hematopoietic stem and progenitor cells, using either Cas9 nuclease or adenine base editors. The most potent modification was adenine base editor generation of γ-globin -175A>G. Homozygous -175A>G edited erythroid colonies expressed 81 ± 7% HbF versus 17 ± 11% in unedited controls, whereas HbF levels were lower and more variable for two Cas9 strategies targeting a BCL11A binding motif in the γ-globin promoter or a BCL11A erythroid enhancer. The -175A>G base edit also induced HbF more potently than a Cas9 approach in red blood cells generated after transplantation of CD34+ hematopoietic stem and progenitor cells into mice. Our data suggest a strategy for potent, uniform induction of HbF and provide insights into γ-globin gene regulation. More generally, we demonstrate that diverse indels generated by Cas9 can cause unexpected phenotypic variation that can be circumvented by base editing.

Proinflammatory state promotes red blood cell alloimmunization in pediatric patients with sickle cell disease.

We examined risk factors for red blood cell (RBC) alloimmunization in pediatric patients with sickle cell disease, focusing on the recipients' inflammatory state at the time of transfusion and anti-inflammatory role of hydroxyurea (HU). Among 471 participants, 55 (11.70%) participants were alloimmunized and formed 59 alloantibodies and 17 autoantibodies with an alloimmunization rate of 0.36 alloantibodies per 100 units. Analysis of 27 participants in whom alloantibodies were formed with specificities showed 23.8% (30/126) of units transfused during a proinflammatory event resulting in alloantibody formation compared with 2.8% (27/952) of units transfused at steady state. Therefore, transfusion during proinflammatory events increased the risk for alloimmunization (odds ratio [OR], 4.22; 95% confidence interval [CI], 1.64-10.85; P = .003). Further analysis of all the 471 participants showed that alloimmunization of patients who received episodic transfusion, mostly during proinflammatory events, was not reduced with HU therapy (OR, 6.52; 95% CI, 0.85-49.77; P = .071), HU therapy duration (OR, 1.13; 95% CI, 0.997-1.28; P = .056), or HU dose (OR, 1.06; 95% CI, 0.96-1.16; P = .242). The analysis also identified high transfusion burden (OR, 1.02; 95% CI, 1.003-1.04; P = .020) and hemoglobin S (HbSS) and HbSß0-thalassemia genotypes (OR, 11.22, 95% CI, 1.51-83.38; P = .018) as additional risk factors for alloimmunization. In conclusion, the inflammatory state of transfusion recipients affects the risk of RBC alloimmunization, which is not modified by HU therapy. Judicious use of transfusion during proinflammatory events is critical for preventing alloimmunization.

Genetic regulation of fetal hemoglobin across global populations.

Human genetic variation has enabled the identification of several key regulators of fetal-to-adult hemoglobin switching, including BCL11A, resulting in therapeutic advances. However, despite the progress made, limited further insights have been obtained to provide a fuller accounting of how genetic variation contributes to the global mechanisms of fetal hemoglobin (HbF) gene regulation. Here, we have conducted a multi-ancestry genome-wide association study of 28,279 individuals from several cohorts spanning 5 continents to define the architecture of human genetic variation impacting HbF. We have identified a total of 178 conditionally independent genome-wide significant or suggestive variants across 14 genomic windows. Importantly, these new data enable us to better define the mechanisms by which HbF switching occurs in vivo. We conduct targeted perturbations to define BACH2 as a new genetically-nominated regulator of hemoglobin switching. We define putative causal variants and underlying mechanisms at the well-studied BCL11A and HBS1L-MYB loci, illuminating the complex variant-driven regulation present at these loci. We additionally show how rare large-effect deletions in the HBB locus can interact with polygenic variation to influence HbF levels. Our study paves the way for the next generation of therapies to more effectively induce HbF in sickle cell disease and ß-thalassemia.

Longitudinal effect of disease-modifying therapy on left ventricular diastolic function in children with sickle cell anemia.

Cardiac abnormalities seen in sickle cell anemia (SCA) include diastolic dysfunction, which has been shown to be associated with high morbidity and early mortality. The effect of disease-modifying therapies (DMT) on diastolic dysfunction is poorly understood. We prospectively evaluated the effects of hydroxyurea and monthly erythrocyte transfusions on diastolic function parameters over 2 years. A total of 204 subjects with HbSS or HbSß0-thalassemia (mean age 11 ± 3.7 years), unselected for disease severity, had diastolic function assessed with surveillance echocardiograms twice, 2 years apart. During this 2-year observation period, 112 participants received DMTs (hydroxyurea, n = 72, monthly erythrocyte transfusions, n = 40), 34 initiated hydroxyurea, and 58 did not receive any DMT. The entire cohort showed an increase in left atrial volume index (LAVi) of 3.40 ± 10.86 mL/m2, p = .001 over 2 years. This increase in LAVi was independently associated with anemia, high baseline E/e' or LV dilation. Individuals not exposed to DMT were younger (mean age 8.8 ± 2.9 years), but at baseline their prevalence of abnormal diastolic parameters was similar to that of the DMT-exposed participants who were older (mean age 12 ± 3.8 years). Participants on DMTs saw no improvement in diastolic function over the study period. In fact, participants on hydroxyurea saw a possible worsening in diastolic parameters (14% increase in LAVi and ~5% decrease in septal e') but also a ~9% decrease in fetal hemoglobin (HbF) levels. Further studies are needed to evaluate if exposure to DMT for a longer duration or achieving higher HbF might be beneficial in alleviating diastolic dysfunction.

Attitudes toward COVID-19 vaccine among pediatric patients with sickle cell disease and their caregivers.

OBJECTIVE: To evaluate attitudes toward vaccination and vaccine uptake regarding coronavirus disease 2019 (COVID-19) among pediatric patients with sickle cell disease (SCD) and their caregivers. PROCEDURE: Adolescent patients and caregivers of children with SCD were surveyed during routine clinic visits; we then conducted a logistic regression analysis to understand differences in vaccine status, while qualitative responses were coded thematically. RESULTS: Among respondents, the overall vaccination rate among adolescents and caregivers was 49% and 52%, respectively. Among the unvaccinated, 60% and 68% of adolescents and caregivers, respectively, preferred to remain unvaccinated, most commonly due to lack of perceived personal benefit from vaccination or mistrust in the vaccine. Multivariate logistic regression analysis showed that child's age (odds ratio [OR] = 1.1, 95% confidence interval [CI]: 1.0-1.2, p < .01) and caregiver education (measured by the Economic Hardship Index [EHI] score, OR = 0.76, 95% CI: 0.74-0.78, p < .05) were independent predictors of getting vaccinated. CONCLUSION: Despite the increased risk of severe illness due to COVID-19 in patients with SCD, vaccine hesitancy remains high in this population of families whose children have SCD. Fortunately, the reasons cited for deferring vaccination among those who are unvaccinated were largely due to barriers that may be overcome with quality communication around the utility of the vaccine and information about vaccine safety.

Health literacy correlates with abbreviated full-scale IQ in adolescent and young adults with sickle cell disease.

INTRODUCTION: Sickle cell disease (SCD) is a chronic condition with progressive neurocognitive deficits. Health literacy (HL) is essential during adolescence and young adulthood, as the transition to adult care requires healthcare decisions. HL is known to be low in SCD; however, relation between general cognitive ability and HL has not been investigated. METHODS: This cross-sectional study included adolescent and yound adults (AYAs) with SCD from two institutions. Logistic regression measured the association between HL, measured by the Newest Vital Sign tool, and general cognitive ability, measured with abbreviated full-scale intelligence quotient (FSIQ) on the Wechsler Abbreviated Scale of Intelligence. RESULTS: Our cohort contained 93 participants at two sites: 47 (51%) at Memphis, TN and 46 (49%) at St. Louis, MO, ranging from ages 15-45 years (mean = 21 years) and with a majority (70%) possessing a high school education or greater. Only 40/93 participants (43%) had adequate HL. Lower abbreviated FSIQ (p < .0001) and younger age at assessment (p = .0003) were associated with inadequate HL. For every standard score point increase in abbreviated FSIQ, the odds of having adequate HL compared to limited or possibly limited HL increase by 1.142 (95% confidence interval [CI]: 1.019-1.322) and 1.116 (95% CI: 1.045-1.209), respectively, after adjusting for age, institution, income, and educational attainment. CONCLUSIONS: Understanding and addressing HL is imperative in improving self-management and health outcomes. Among AYA with SCD, low HL was prevalent and influenced by abbreviated FSIQ. Routine screening for neurocognitive deficits and HL should be performed to guide development of interventions to adapt to the HL of AYA with SCD.

Social determinants of neurocognitive and academic performance in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is associated with poor neurocognitive outcomes due to biomedical and psychosocial factors. The aims of this study were to investigate associations between household and neighborhood socioeconomic status (SES) with cognitive and academic outcomes in SCD and to determine if these relationships were modified by sickle genotype, fetal hemoglobin, or age. PROCEDURE: We prospectively recruited patients to complete a battery of neurocognitive and academic measures. Household SES was measured using the Barratt Simplified Measure of Social Status, a composite index of parent education and occupation. The Social Vulnerability Index was used to classify individuals based on social vulnerabilities at the neighborhood level. RESULTS: Overall, 299 patients between the ages of 4 and 18 (mean = 11.4, standard deviation = 4.3) years diagnosed with SCD (57% SS/SB0 -thalassemia) completed testing. Stepwise multivariate models demonstrated that patients with low social vulnerability (i.e., high SES) at the neighborhood level displayed intelligence and math scores that were 4.70 and 7.64 points higher than those living in areas with moderate social vulnerability, respectively (p < .05). Reading performance did not differ based on neighborhood SES; however, the effect of neighborhood SES was dependent on age, such that older participants living in neighborhoods with moderate or high levels of social vulnerability displayed poorer reading scores than those with low social vulnerability (p < .05). CONCLUSIONS: This study identified patients with SCD at higher risk of poor academic performance based on SES. Interventions addressing academic difficulties should be offered to all children with SCD, but should be emergently offered to this subpopulation.

Internalizing Symptoms in Adolescents With Sickle Cell Disease.

OBJECTIVE: Sickle cell disease (SCD) is a genetic blood disorder that may affect patients' mood and behavior. However, measuring the prevalence of internalizing symptoms (anxiety and depression) in patients with SCD has been elusive. We assessed internalizing symptoms in adolescents with SCD to evaluate prevalence and to test whether neurocognitive performance and frequency of pain-related episodes were associated with internalizing concerns. METHODS: One hundred eighty-five patients (57% HbSS/HbSß0-thalassemia, 43% HbSC/HbSß+-thalassemia), ages 12-18 years, received a neuropsychological evaluation as a part of a larger cohort study. Internalizing symptoms were measured using the Behavior Assessment System for Children, Second or Third Edition. Scores on the depression and anxiety scales were compared to normative values using Wilcoxon signed rank test. Spearman correlations examined associations between neurocognitive performances and internalizing symptoms. Robust multivariable regression models measured associations between internalizing symptoms and age, sex, sickle genotype, total hemoglobin, fetal hemoglobin, socioeconomic status, and frequency of pain episodes. RESULTS: Parent- and self-reported ratings of internalizing symptoms were not elevated compared to normative expectations. Overall, 1.8% and 6.3% of the sample displayed clinically elevated symptoms of anxiety and depression based on self-report, respectively. There were no associations between internalizing symptoms and neurocognitive performance (all p > .05). In multivariable analyses, the frequency of pain episodes was positively associated with self-reported anxiety (p = .006) and parent-reported depressive symptoms (p = .017). CONCLUSIONS: Adolescents with SCD do not report elevated internalizing symptoms compared to normative expectations. Further research is needed to examine the trajectory of internalizing symptoms and the bidirectional relationship between pain and psychosocial functioning in SCD.