RESUMEN
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.
Asunto(s)
Anemia de Células Falciformes , Proteínas de Unión al GTP , Estudio de Asociación del Genoma Completo , Haplotipos , Femenino , Humanos , Masculino , Alelos , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/sangre , Predisposición Genética a la Enfermedad , Nigeria , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Represoras/genéticaRESUMEN
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.
Asunto(s)
Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Humanos , Adolescente , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/uso terapéutico , Vacunación , Instituciones de Atención Ambulatoria , Virus del Papiloma HumanoRESUMEN
Myelofibrosis (MF) is a disease associated with high unmet medical needs because allogeneic stem cell transplantation is not an option for most patients, and JAK inhibitors are generally effective for only 2 to 3 years and do not delay disease progression. MF is characterized by dysplastic megakaryocytic hyperplasia and progression to fulminant disease, which is associated with progressively increasing marrow fibrosis. Despite evidence that the inflammatory milieu in MF contributes to disease progression, the specific factors that promote megakaryocyte growth are poorly understood. Here, we analyzed changes in the cytokine profiles of MF mouse models before and after the development of fibrosis, coupled with the analysis of bone marrow populations using single-cell RNA sequencing. We found high interleukin 13 (IL-13) levels in the bone marrow of MF mice. IL-13 promoted the growth of mutant megakaryocytes and induced surface expression of transforming growth factor ß and collagen biosynthesis. Similarly, analysis of samples from patients with MF revealed elevated levels of IL-13 in the plasma and increased IL-13 receptor expression in marrow megakaryocytes. In vivo, IL-13 overexpression promoted disease progression, whereas reducing IL-13/IL-4 signaling reduced several features of the disease, including fibrosis. Finally, we observed an increase in the number of marrow T cells and mast cells, which are known sources of IL-13. Together, our data demonstrate that IL-13 is involved in disease progression in MF and that inhibition of the IL-13/IL-4 signaling pathway might serve as a novel therapeutic target to treat MF.
Asunto(s)
Trastornos Mieloproliferativos , Neoplasias , Mielofibrosis Primaria , Ratones , Animales , Interleucina-13/uso terapéutico , Interleucina-4 , Neoplasias/complicaciones , Trastornos Mieloproliferativos/complicaciones , Mielofibrosis Primaria/genética , Transducción de Señal/genética , Fibrosis , Progresión de la EnfermedadRESUMEN
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.
Asunto(s)
Anemia de Células Falciformes , Trastornos Cerebrovasculares , Insuficiencia de la Válvula Tricúspide , Humanos , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/fisiopatología , Masculino , Femenino , Niño , Adolescente , Insuficiencia de la Válvula Tricúspide/etiología , Insuficiencia de la Válvula Tricúspide/epidemiología , Insuficiencia de la Válvula Tricúspide/fisiopatología , Estudios Transversales , Trastornos Cerebrovasculares/epidemiología , Trastornos Cerebrovasculares/etiología , Preescolar , Adulto Joven , Lactante , Enfermedades Renales/etiología , Enfermedades Renales/epidemiología , Enfermedades Renales/fisiopatología , Ecocardiografía , Adulto , Estudios de Seguimiento , PronósticoRESUMEN
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.
Asunto(s)
Anemia de Células Falciformes , Humanos , Anemia de Células Falciformes/complicaciones , Femenino , Masculino , Niño , Adolescente , Factores de Riesgo , Estudios Prospectivos , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Recién Nacido de Bajo Peso , Embarazo , Edad Gestacional , Estudios de SeguimientoRESUMEN
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.
Asunto(s)
Anemia de Células Falciformes , Destreza Motora , Humanos , Anemia de Células Falciformes/fisiopatología , Masculino , Femenino , Adolescente , Estudios Transversales , Niño , Adulto Joven , Rendimiento Académico , Factores de Edad , Factores SexualesRESUMEN
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.
Asunto(s)
Anemia de Células Falciformes , Disfunción Ventricular Izquierda , Humanos , Niño , Adolescente , Preescolar , Hidroxiurea/uso terapéutico , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Hemoglobina Falciforme , Transfusión de Eritrocitos , Ecocardiografía , Disfunción Ventricular Izquierda/complicacionesRESUMEN
Due to many advantages such as higher statistical power of detecting the association of genetic variants in human disorders and cost saving, extreme phenotype sequencing (EPS) is a rapidly emerging study design in epidemiological and clinical studies investigating how genetic variations associate with complex phenotypes. However, the investigation of the mediation effect of genetic variants on phenotypes is strictly restrictive under the EPS design because existing methods cannot well accommodate the non-random extreme tails sampling process incurred by the EPS design. In this paper, we propose a likelihood approach for testing the mediation effect of genetic variants through continuous and binary mediators on a continuous phenotype under the EPS design (GMEPS). Besides implementing in EPS design, it can also be utilized as a general mediation analysis procedure. Extensive simulations and two real data applications of a genome-wide association study of benign ethnic neutropenia under EPS design and a candidate-gene study of neurocognitive performance in patients with sickle cell disease under random sampling design demonstrate the superiority of GMEPS under the EPS design over widely used mediation analysis procedures, while demonstrating compatible capabilities under the general random sampling framework.
Asunto(s)
Estudio de Asociación del Genoma Completo , Análisis de Mediación , Variación Genética , Humanos , Funciones de Verosimilitud , Modelos Genéticos , FenotipoRESUMEN
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.
Asunto(s)
Anemia de Células Falciformes , Alfabetización en Salud , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Estudios Transversales , Anemia de Células Falciformes/terapia , Anemia de Células Falciformes/complicaciones , Inteligencia , Pruebas de InteligenciaRESUMEN
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.
Asunto(s)
Rendimiento Académico , Anemia de Células Falciformes , Niño , Humanos , Preescolar , Adolescente , Determinantes Sociales de la Salud , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/psicología , Clase SocialRESUMEN
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.
Asunto(s)
Anemia de Células Falciformes , COVID-19 , Vacunas , Adolescente , Humanos , Niño , Vacunas contra la COVID-19 , Cuidadores , COVID-19/epidemiología , COVID-19/prevención & control , Conocimientos, Actitudes y Práctica en Salud , Vacunación , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/terapiaRESUMEN
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.
Asunto(s)
Anemia de Células Falciformes , Dolor , Adolescente , Niño , Humanos , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/psicología , Estudios de Cohortes , Hemoglobina Falciforme , Dolor/psicología , Autoinforme , Ansiedad/psicología , Depresión/psicologíaRESUMEN
We adjusted haematopoietic stem and progenitor cell (HSPC) apheresis collection from patients with sickle cell disease (SCD) by targeting deep buffy coat collection using medium or low collection preference (CP), and by increasing anticoagulant-citrate-dextrose-solution A dosage. In 43 HSPC collections from plerixafor-mobilized adult patients with SCD, we increased the collection efficiency to 35.79% using medium CP and 82.23% using low CP. Deep buffy coat collection increased red blood cell contamination of the HSPC product, the product haematocrit was 4.7% with medium CP and 6.4% with low CP. These adjustments were well-tolerated and allowed efficient HSPC collection from SCD patients.
Asunto(s)
Anemia de Células Falciformes , Eliminación de Componentes Sanguíneos , Compuestos Heterocíclicos , Adulto , Anemia de Células Falciformes/terapia , Bencilaminas , Ciclamas , Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas , Humanos , LeucaféresisRESUMEN
BACKGROUND: Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia. METHODS: We performed a dual-center, phase 1-2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1. RESULTS: Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven. CONCLUSIONS: Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.).
Asunto(s)
Busulfano/administración & dosificación , Terapia Genética , Vectores Genéticos , Subunidad gamma Común de Receptores de Interleucina/genética , Lentivirus , Acondicionamiento Pretrasplante , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/terapia , Antígenos de Diferenciación de Linfocitos T/sangre , Linfocitos B/fisiología , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunoglobulina M/sangre , Lactante , Células Asesinas Naturales , Recuento de Linfocitos , Masculino , Linfocitos T , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/inmunologíaRESUMEN
Hematopoietic stem cell (HSC) transplantation (HSCT) is often exploited to treat hematologic disease. Donor HSCs must survive, proliferate, and differentiate in the damaged environment of the reconstituting niche. Illuminating molecular mechanisms regulating the activity of transplanted HSCs will inform efforts to improve HSCT. Here, we report that G-protein-coupled receptor-associated sorting proteins (GPRASPs) function as negative regulators of HSCT. Silencing of Gprasp1 or Gprasp2 increased the survival, quiescence, migration, niche retention, and hematopoietic repopulating activity of hematopoietic stem and progenitor cells (HSPCs) posttransplant. We further show that GPRASP1 and GPRASP2 promote the degradation of CXCR4, a master regulator of HSC function during transplantation. CXCR4 accumulates in Gprasp-deficient HSPCs, boosting their function posttransplant. Thus, GPRASPs negatively regulate CXCR4 stability in HSCs. Our work reveals GPRASP proteins as negative regulators of HSCT and CXCR4 activity. Disruption of GPRASP/CXCR4 interactions could be exploited in the future to enhance the efficiency of HSCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Animales , Proteínas Portadoras , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Eliminación de Gen , Silenciador del Gen , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Ratones Endogámicos C57BL , Proteolisis , Receptores CXCR4/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
BACKGROUND: Neuropathic pain (NP) has been previously explored in adolescents with sickle cell disease (SCD). This study aims to describe the prevalence of NP in adolescents with SCD at a single institution and to explore associated risk factors. PROCEDURE: We used the painDETECT questionnaire, one of the few pain phenotyping questionnaires validated for adolescents. We also evaluated the relationships between painDETECT scores and frequency of acute care visits and admissions for pain in the previous 12 months, and age, respectively. Patients 12-18 years old were surveyed from June to July 2019. A retrospective approach was used to answer the remaining research questions. RESULTS: Eighty-one and seven surveys were completed in the outpatient and inpatient settings, respectively. PainDETECT scores suggestive of NP were more prevalent in inpatient surveys than in outpatient surveys. The difference between the mean painDETECT scores of each group was significant when using a general linear mixed model. Most inpatients surveyed had ≥3 pain events in the previous 12 months. Further, older age and increased number of pain events in the previous 12 months were independently associated with higher painDETECT scores. CONCLUSIONS: Overall, in our opinion, NP is not being evaluated for and treated sufficiently in pediatric SCD, especially in the setting of inpatient acute vaso-occlusive crisis. Age and number of acute pain events/admissions in the previous 12 months can be used to identify patients likely to be at risk for NP. It is important to continue to identify NP and develop NP-targeting treatment plans.
Asunto(s)
Anemia de Células Falciformes , Neuralgia , Adolescente , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/epidemiología , Niño , Humanos , Neuralgia/diagnóstico , Neuralgia/epidemiología , Neuralgia/etiología , Prevalencia , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
Children with sickle cell disease (SCD) frequently have diminished academic attainment and are particularly vulnerable to reading dysfunction. We explored the effectiveness of a multisensory reading intervention offered during the summer to children with SCD at our institution. Subjects with reading deficits were identified through parent report, clinical findings, or school meetings. Summer reading programs utilizing Phonemic Awareness and Symbol Imagery were provided. The Lindamood-Bell Auditory Conceptualization/Phonemic Awareness Test, Third Edition (LAC-3), and the Symbol Imagery Test were used as pre- and postintervention examinations to measure progress. Fifteen students (median age 9.4 years, range 6-14 years, eight females, all African American) received the Phonemic Awareness intervention, two times a week for 6 weeks. The subjects showed statistically significant gains in standard scores derived from the LAC-3 (mean change 7.9 points, p < .001), with associated improvements in age equivalency (AE) and grade equivalency (GE). Twenty-nine students (median age 9 years, range 6-17 years, 13 females, all African American) participated in the Symbol Imagery reading program, also two times a week for 6 weeks. These students showed significant gains in overall standard scores (mean change 9.8 points, p < .001). Although results should be interpreted with caution due to small sample sizes, we found that summer reading clinics for children with SCD improved phonological processing and symbol imagery skills, potentially leading to substantial gains in reading capability.
Asunto(s)
Anemia de Células Falciformes , Lectura , Anemia de Células Falciformes/terapia , Niño , Femenino , Humanos , Lactante , Masculino , Instituciones AcadémicasRESUMEN
BACKGROUND: Children with sickle cell disease (SCD) experience neurodevelopmental delays; however, there is limited research with preschool-age children. This study examined neurocognitive risk and protective factors in preschoolers with SCD. PROCEDURE: Sixty-two patients with SCD (60% HbSS/HbSß0 -thalassemia; 40% HbSC/HbSß+ -thalassemia) between the ages of 3 and 6 years (mean = 4.77 years) received a neuropsychological evaluation as routine systematic surveillance. Patients were not selected for disease severity, prior central nervous system findings, or existing cognitive concerns. Thirty-four patients (82% HbSS/HbSß0 -thalassemia) were prescribed hydroxyurea (HU) at the time of their neuropsychological evaluation. On average, these patients had been prescribed HU at 2.15 (standard deviation = 1.45) years of age. The average dose was 28.8 mg/kg/day. Besides genotype, there were no group differences in medical or demographic factors based on HU treatment status. RESULTS: Patients with HbSS/HbSß0 -thalassemia scored below normative expectations on measures of intelligence, verbal comprehension, and school readiness (false discovery rate-adjusted p-value [pFDR ] < .05). Age, sickle genotype, and HU treatment exposure were not associated with measured neurocognitive outcomes (pFDR > .05). Greater social vulnerability at the community level was associated with poorer performance on measures of intellectual functioning, verbal comprehension, visuomotor control, and school readiness, as well as parent report of executive dysfunction (pFDR < .05). Greater household socioeconomic status was positively associated with academic readiness. CONCLUSIONS: Preschoolers with severe SCD (HbSS/HbSß0 -thalassemia) perform below age expectations on measures of intelligence and academic readiness. Sociodemographic factors were stronger drivers of neurocognitive performance than disease severity or disease-modifying treatment. Neurodevelopmental interventions targeting the home and broader community environment are needed.
Asunto(s)
Anemia de Células Falciformes , Enfermedad de la Hemoglobina SC , Talasemia , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/epidemiología , Niño , Preescolar , Enfermedad de la Hemoglobina SC/complicaciones , Hemoglobina Falciforme/genética , Humanos , Hidroxiurea/uso terapéutico , Talasemia/complicacionesRESUMEN
BACKGROUND: Transcranial doppler (TCD) ultrasonography can be used to identify stroke risk in children with sickle cell anemia. Previous studies have reported mixed findings on neurocognitive outcomes in children with elevated TCD. This study examined associations between TCD velocity and neurocognitive outcomes in children and adolescents without prior history of stroke. PROCEDURE: Participants were selected from the Sickle Cell Clinical Research Intervention Program cohort. The highest recorded mean maximum TCD velocity was selected for analysis, along with participant's most recent data from serial neurocognitive surveillance. RESULTS: A total of 200 children with sickle cell anemia completed neurocognitive testing (109 males, 91 females; mean age 12.7 years [SD = 3.56]). Most participants were prescribed hydroxyurea (72%) at the time of neurocognitive testing and nearly 16% had a history of chronic transfusions prior to neurocognitive evaluation. Mean age at time of highest TCD value was 6.6 years (SD = 2.5) and 13.5% of screenings were abnormal (≥200 cm/s). Mean interval between TCD and most recent neurocognitive evaluation was 6.1 years (±3.5). There were no significant differences in the interval between TCD and neurocognitive testing across normal, conditional, and abnormal groups. Maximum TCD velocity was not significantly associated with neurocognitive outcomes in multivariate models. CONCLUSIONS: History of elevated TCD in the absence of overt stroke should not be considered a risk factor for poor neurocognitive outcomes in children and adolescents with sickle cell anemia on modern disease-modifying therapy.
Asunto(s)
Anemia de Células Falciformes , Accidente Cerebrovascular , Adolescente , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/diagnóstico por imagen , Anemia de Células Falciformes/tratamiento farmacológico , Velocidad del Flujo Sanguíneo , Transfusión Sanguínea , Niño , Femenino , Humanos , Hidroxiurea/uso terapéutico , Masculino , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/etiología , Ultrasonografía Doppler TranscranealRESUMEN
Nocturnal enuresis is a common symptom in children with sickle cell disease (SCD). Risk factors for development of enuresis are currently unknown. An early manifestation of SCD-associated kidney damage is glomerular hyperfiltration. We test the hypothesis that in a pediatric SCD cohort, individuals with hyperfiltration are more likely to have nocturnal enuresis when compared to children without hyperfiltration. To assess the relationship between nocturnal enuresis and hyperfiltration, we retrospectively evaluated children with SCD enrolled in the Evaluation of Nocturnal Enuresis and Barriers to Treatment among Pediatric Patients with SCD study and prospectively identified children who reported nocturnal enuresis and were enrolled in the longitudinal cohort study Sickle Cell Clinical Research and Intervention Program. Nocturnal enuresis occurred in 46.5% of Pediatric Patients with Sickle Cell Disease participants and was more frequent in participants with HbSS/HbSß 0 thalassemia and in male participants. We did not identify an association between hyperfiltration from 3 to 5 years of age with the later development of enuresis. Severe SCD genotypes and male sex were associated with nocturnal enuresis after age 5 years. We could not identify additional renal or hematologic predictors associated with the diagnosis of nocturnal enuresis. Future studies should incorporate nonrenal risk factors into studies that predict development of enuresis.