Assessing multilevel barriers to hydroxyurea adherence in youth with sickle cell disease using pharmacy-based refill records.

BACKGROUND: Suboptimal medication adherence is common across youth with chronic health conditions and may contribute to health disparities and adverse health outcomes, especially in underserved communities. METHODS: Using pharmacy prescription records and guided by the World Health Organization Multidimensional Adherence Model, we examined patient-, treatment-, and health system-related factors that may affect hydroxyurea adherence in 72 youth with sickle cell disease (SCD), 10-18 years who had participated in the multisite "Hydroxyurea Adherence for Personal Best in SCD" (HABIT) feasibility (6 months) and efficacy (12 months) trials. Pharmacy data were collected from the year prior to study entry through the duration of each trial. We also examined hydroxyurea dose at baseline, prescribing patterns (hydroxyurea formulation and dose prescribed), quantity of hydroxyurea dispensed, and number of daily capsules/tablets prescribed. Data were analyzed using descriptive statistics. RESULTS: On average, youth were prescribed 1095 ± 402 mg hydroxyurea per day, requiring ingestion of 3 or more capsules for 39.4% of youth. Frequently identified potential barriers were complex medication regimens in which dose of hydroxyurea differed by day of week (47.2%); receipt of an inadequate (< 30 days) supply of hydroxyurea from the pharmacy ≥ 3 times during record collection period (29.2%); and prescription of hydroxyurea suspension suggesting problems swallowing capsules (22.2%). In this sample, most youth were exclusively prescribed 500 mg capsules (62.5%), which was associated with complex medication regimens (RR 3.0, 95% CI 1.4-6.7). Potential barriers were common, occurred at all levels and are potentially modifiable with targeted interventions at the treatment- and health system-related levels.

Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment (HABIT) efficacy trial: Community health worker support may increase hydroxyurea adherence of youth with sickle cell disease.

Despite disease-modifying effects of hydroxyurea on sickle cell disease (SCD), poor adherence among affected youth commonly impedes treatment impact. Following our prior feasibility trial, the "Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment (HABIT)" multi-site randomized controlled efficacy trial aimed to increase hydroxyurea adherence for youth with SCD ages 10-18 years. Impaired adherence was identified primarily through flagging hydroxyurea-induced fetal hemoglobin (HbF) levels compared to prior highest treatment-related HbF. Eligible youth were enrolled as dyads with their primary caregivers for the 1-year trial. This novel semi-structured supportive, multidimensional dyad intervention led by community health workers (CHW), was augmented by daily tailored text message reminders, compared to standard care during a 6-month intervention phase, followed by a 6-month sustainability phase. Primary outcomes from the intervention phase were improved Month 6 HbF levels compared to enrollment and proportion of days covered (PDC) for hydroxyurea versus pre-trial year. The secondary outcome was sustainability of changes up to Month 12. The 2020-2021 peak coronavirus disease 2019 (COVID-19) pandemic disrupted enrollment and clinic-based procedures; CHW in-person visits shifted to virtual scheduled interactions. We enrolled 50 dyads, missing target enrollment. Compared to enrollment levels, both HbF level and PDC significantly - but not sustainably - improved within the intervention group (p = .03 and .01, respectively) with parallel increased mean corpuscular volume (MCV) (p = .05), but not within controls. No significant between-group differences were found at Months 6 or 12. These findings suggest that our community-based, multimodal support for youth-caregiver dyads had temporarily improved hydroxyurea usage. Durability of impact should be tested in a trial with longer duration of CHW-led and mobile health support.

Pediatric hematology providers' contraceptive practices for female adolescents and young adults with sickle cell disease: A national survey.

BACKGROUND: Adolescent and young adult (AYA) women with sickle cell disease (SCD) have increased pregnancy-related health risks and are prescribed potentially teratogenic medications, yet limited data are available regarding pediatric SCD provider contraceptive practices. We aimed to assess pediatric hematology providers' beliefs, practices, motivators, and barriers for providing contraceptive care to female AYAs with SCD. METHODS: Guided by the Health Belief Model (HBM), we developed a 25-question, web-based survey to assess practices. Survey links were distributed nationwide to pediatric SCD and/or general hematology providers through their publicly available emails and by request to directors of U.S.-accredited Pediatric Hematology-Oncology fellowship programs for distribution to their SCD providers. Data analysis included descriptive statistics, chi-square analysis, and logistic regression. RESULTS: Of 177 respondents, 160 surveys meeting inclusion criteria were analyzed. Most providers reported counseling (77.5%) and referring female AYA patients for contraception (90.8%), but fewer reported prescribing contraception (41.8%). Proportionally fewer trainees provided counseling compared with established providers (54% vs. 85%, p < .001), with a similar trend for prescribing (p = .05). Prescription practices did not differ significantly by provider beliefs regarding potential teratogenicity of hydroxyurea. Key motivators included patient request and disclosure of sexual activity. Key barriers included inadequate provider training, limited visit time, and perceived patient/parent interest. CONCLUSION: Provider contraceptive practices for female AYAs with SCD varied, especially by provider status. Health beliefs regarding teratogenic potential of hydroxyurea did not correlate with contraceptive practices. Clinical guidelines, provider training, and patient/parent decision-making tools may be tested to assess whether provider contraceptive practices could be improved.

Mental health assessment of youth with sickle cell disease and their primary caregivers during the COVID-19 pandemic.

Youth with sickle cell disease (SCD) and their caregivers are susceptible to stress and depression, perhaps exacerbated by pandemic-associated health and economic concerns. Most of the 50 youth-caregiver dyads enrolled in the multisite trial, Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment (HABIT), took an online survey of self-reported mental health symptoms and food insecurity during the 2020 COVID-19 pandemic. Compared to largely pre-pandemic results, prevalence of mental health symptoms in dyad members appeared to have shifted: fewer youth and more caregivers were affected during the pandemic; many of both groups lacked optimism. Pandemic/post-pandemic screening of youth with SCD for mental health symptoms and food insecurity appears warranted.

Transition Preparation and Satisfaction of Care Among Adolescents and Young Adults With Sickle Cell Disease at the Ghana Institute of Clinical Genetics.

Expanding services in Ghana for people with sickle cell disease is expected to increase childhood survival and need for transition to adult care. Little is known about patient transition experiences in sub-Saharan Africa. We sought to understand those experiences of adolescents and young adults at an adult sickle cell clinic in Accra, Ghana. Individuals 13 to 22 years of age receiving sickle cell care at the Ghana Institute of Clinical Genetics were interviewed to recall their advance preparation and early experiences in adult sickle cell clinic. Mean age of the 100 participants interviewed was 17.9±2.9 years, 65% female. Most had hemoglobin SS (77%) or hemoglobin SC (20%). Twenty-nine participants recalled pretransition preparation; 93% of them (27) had received care at Korle Bu Pediatric Sickle Cell Clinic. Among the remaining 71 who did not recall advance preparation, 54% (34) had received pediatric care at that clinic (P<0.001). More in the group recalling preparation had positive feelings about needing to transition care compared with those not recollecting preparation (55% vs. 32%, P=0.04). Our results suggest that pretransition preparation may ease the peritransition experience. Conduct and evaluation of a program for transitioning into adult sickle cell care in Ghana may facilitate the transfer process.

Food insecurity, housing instability, and dietary quality among children with sickle cell disease: Assessment from a single urban center.

BACKGROUND: Food insecurity and housing instability, both social determinants of health (SDoH), disproportionately affect economically unstable, under-resourced US communities in which children with sickle cell disease (SCD) live. Association between these SDoH markers and dietary quality among children with SCD is unknown. PROCEDURES: We assessed a cross-sectional sample of dyadic parent-child patients and young adult patients up to age 21 from one pediatric SCD center. Food insecurity, housing instability, and dietary quality were measured using validated US instruments and a food frequency questionnaire. Better dietary quality was defined using US dietary guidelines. Multivariate regression assessed for associations among dietary quality and food insecurity with or without (±) housing instability and housing instability alone. RESULTS: Of 100 enrolled participants, 53% were Black and 43% Hispanic; mean age 10.6 ± 5.6 years. Overall, 70% reported less than or equal to one economic instability: 40% housing instability alone and 30% both food insecurity and housing instability. Eighty percent received more than or equal to one federal food assistance benefit. Compared to no economic instability, food insecurity ± housing instability was significantly associated with higher intake of higher dairy and pizza, while housing instability alone was significantly associated with higher dairy intake. Food insecurity ± housing instability was significantly associated with lower intake of whole grains compared to housing instability alone. CONCLUSIONS: Our sample reported high frequencies of both food insecurity and housing instability; having more than or equal to one SDoH was associated with elements of poorer diet quality. Screening families of children with SCD for food insecurity and housing instability may identify those with potential nutrition-related social needs.

Administrative data identify sickle cell disease: A critical review of approaches in U.S. health services research.

To identify people living with sickle cell disease (SCD) and study their healthcare utilization, researchers can either use clinical records linked to administrative data or use billing diagnosis codes in stand-alone administrative databases. Correct identification of individuals clinically managed for SCD using diagnosis codes in claims databases is limited by the accuracy of billing codes in outpatient encounters. In this critical review, we assess the strengths and limitations of claims-based SCD case-finding algorithms in stand-alone administrative databases that contain both inpatient and outpatient records. Validation studies conducted using clinical records and newborn screening for confirmation of SCD case status have found that algorithms that require three or more nonpharmacy claims or one inpatient claim plus two or more outpatient claims with SCD codes show acceptable accuracy (positive predictive value and sensitivity) in children and adolescents. Future studies might seek to assess the accuracy of case-finding algorithms over the lifespan.

Parental Notification Via Text Messaging for Infant Sickle Screening Programs: Exploration of Feasibility and Acceptability in Uganda.

Sickle cell disease (SCD) in Africa has high prevalence, morbidity, and early mortality. Difficulties in reaching parents following infant SCD screening dampen program effectiveness. Text messaging may support initial postscreening parental notification. We explored SCD awareness, and feasibility and acceptability of text messaging about screening follow-up among convenience samples of caretakers with children under 5 years (n=115) at 3 sites: a SCD family conference or 2 general pediatric clinics in urban or rural Uganda. Two thirds of the conference-based participants and 8% at clinic sites had affected children. At the clinics, 64% of caretakers were aware of SCD. In all, 87% claimed current possession of mobile phones; 89% previously had received messages. A sample text on the availability of screening results and need to bring their child to SCD clinic was at least partially understood by 82%. Overall, 52% preferred communication for initial follow-up by telephone over text message. Concerns about texting included phone access, privacy or cost, and readability of messages. Caretakers identified concerns about distance, cost, or preference for another clinic as additional barriers to SCD follow-up. Findings suggest that text messaging to caretakers may be feasible, but less acceptable compared with a telephone call about initial follow-up from newborn SCD screening.

Greater number of perceived barriers to hydroxyurea associated with poorer health-related quality of life in youth with sickle cell disease.

BACKGROUND: Despite medical benefits, hydroxyurea adherence in adolescents is often poor. As part of a baseline assessment of 28 youth (10-18 years) parent dyads who participated in a 6-month feasibility trial to improve hydroxyurea adherence, we measured the relationship between greater barriers to adherence and health-related quality of life (HRQL) from youth and parent perspectives. PROCEDURE: Barriers were measured using the Adolescent and Parent Medication Barriers Scales with nine hydroxyurea items added. Barriers reported by ≥25% of the sample were considered common. Generic and disease-specific HRQL were measured by PedsQL and PedsQL Sickle Cell Disease modules. Data were analyzed using descriptive statistics, Cronbach alpha, Spearman correlation coefficients, and paired t tests. RESULTS: Fifty-six subjects (28 dyads) participated. Youth reported greater barriers compared with parents (5.0 ± 3.9 and 3.5 ± 3.2; P = 0.03), with >80% of respondents reporting ≥1 barriers. Twelve barriers were reported by ≥25% of adolescents, whereas six were reported by ≥25% of parents. Of these, only two were common to both dyad members. Approximately one-third of youth had generic and disease-specific HRQL scores that fell at or below cutoff scores, suggesting being at risk for impaired HRQL. Greater barriers were inversely associated with poorer generic (parent r = -0.43, P = 0.03; youth r = -0.44, P < 0.001) and disease-specific HRQL (parent r = -0.53, P = 0.005; youth r = -0.53, P < 0.001). CONCLUSIONS: Hydroxyurea barriers were frequently reported but differed by dyad members' perspective. Greater barriers were associated with poorer generic and disease-specific HRQL. To reduce barriers to hydroxyurea in youth with sickle cell disease, perspectives of both dyad members should be addressed.

Paediatric immunisation and chemoprophylaxis in a Ugandan sickle cell disease clinic.

AIM: We aimed to assess the receipt of recommended care for young children with sickle cell disease (SCD) in a central SCD clinic in Kampala Uganda, focusing on standard vaccination and antibacterial and antimalarial prophylaxis. METHODS: A cross-sectional assessment of immunisation status and timeliness and prescribed antibacterial and antimalarial prophylaxis was performed in a sample with SCD aged ≤71 months in Mulago Hospital SCD Clinic. Government-issued immunisation cards and clinic-issued visit records for prescribed prophylaxis were reviewed. RESULTS: Vaccinations were documented by immunisation cards in 104 patients, mean age 31.7 months (range 3-70 months). Only 48 (46.2%) received all doses of each of the four recommended vaccine types, including pneumococcal 10-valent conjugate vaccine (pneumococcal conjugate vaccine (PCV)-10), which became available in 2014. Vaccination completion was associated with younger age and, for polio, maternal employment. PCV-10 series was completed in 54.8% of the sample and in 18.2% of those aged 48-71 months. Of children completing all vaccination types, an average 68.8% were immunised on time, defined as <60 days beyond the recommended age. Only 17 (13.5%) children were both fully and timely vaccinated. In an overlapping sample of 147 children, with a mean age of 38.4 months (4-70 months), 81.6% had ≥1 documented prescription for penicillin and/or antimalarial prophylaxis. CONCLUSIONS: Standardised vaccination and antibacterial and antimalarial protective measures for young children at this central SCD clinic were incomplete, especially PCV-10 for age ≥24 months, and often late. Child age, but not general maternal demographics, were associated with vaccination and chemoprophylaxis. Clinic-based oversight may improve timely uptake of these preventative measures.

New Ways to Detect Pediatric Sickle Cell Retinopathy: A Comprehensive Review.

Sickle retinopathy reflects disease-related vascular injury of the eye, which can potentially result in visual loss from vitreous hemorrhage or retinal detachment. Here we review sickle retinopathy among children with sickle cell disease, describe the epidemiology, pediatric risk factors, pathophysiology, ocular findings, and treatment. Newer, more sensitive ophthalmological imaging modalities are available for retinal imaging, including ultra-widefield fluorescein angiography, spectral-domain optical coherence tomography, and optical coherence tomography angiography. Optical coherence tomography angiography provides a noninvasive view of retinal vascular layers that could previously not be imaged and can be quantified for comparative or prospective analyses. Ultra-widefield fluorescein angiography provides a more comprehensive view of the peripheral retina than traditional imaging techniques. Screening for retinopathy by standard fundoscopic imaging modalities detects a prevalence of approximately 10%. In contrast, these more sensitive methods allow for more sensitive examination that includes the retina perimeter where sickle retinopathy is often first detectable. Use of these new imaging modalities may detect a higher prevalence of early sickle pathology among children than has previously been reported. Earlier detection may help in better understanding the pathogenesis of sickle retinopathy and guide future screening and treatment paradigms.

Randomized feasibility trial to improve hydroxyurea adherence in youth ages 10-18 years through community health workers: The HABIT study.

INTRODUCTION: The main therapeutic intervention for sickle cell disease (SCD) is hydroxyurea (HU). The effect of HU is largely through dose-dependent induction of fetal hemoglobin (HbF). Poor HU adherence is common among adolescents. METHODS: Our 6-month, two-site pilot intervention trial, "HABIT," was led by culturally aligned community health workers (CHWs). CHWs performed support primarily through home visits, augmented by tailored text message reminders. Dyads of youth with SCD ages 10-18 years and a parent were enrolled. A customized HbF biomarker, the percentage decrease from each patients' highest historical HU-induced HbF, "Personal best," was used to qualify for enrollment and assess HU adherence. Two primary outcomes were as follows: (1) intervention feasibility and acceptability and (2) HU adherence measured in three ways: monthly percentage improvement toward HbF Personal best, proportion of days covered (PDC) by HU, and self-report. RESULTS: Twenty-eight dyads were enrolled, of which 89% were retained. Feasibility and acceptability were excellent. Controlling for group assignment and month of intervention, the intervention group improved percentage decrease from Personal best by 2.3% per month during months 0-4 (P = 0.30), with similar improvement in adherence demonstrated using pharmacy records. Self-reported adherence did not correlate. Dyads viewed CHWs as supportive for learning about SCD and HU, living with SCD and making progress in coordinated self-management responsibility to support a daily HU habit. Most parents and youth appreciated text message HU reminders. CONCLUSIONS: The HABIT pilot intervention demonstrated feasibility and acceptability with promising effect toward improved medication adherence. Testing in a larger multisite intervention trial is warranted.

Enhanced Long-Term Brain Magnetic Resonance Imaging Evaluation of Children with Sickle Cell Disease after Hematopoietic Cell Transplantation.

Progressive neurovasculopathy in children with sickle cell disease (SCD) results in decreased cognitive function and quality of life (QoL). Hematopoietic cell transplantation (HCT) is believed to halt progression of neurovasculopathy. Quantitative analysis of T2-weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) for white matter hyperintensity (WMH) burden provides a meaningful estimate of small vessel cerebrovascular disease. We asked if quantitative analysis of WMH could complement standardized clinical assessment of MRI/magnetic resonance angiography (MRA) for assessing SCD central nervous system vasculopathy before and after HCT. Retrospective longitudinal clinical examination of scheduled annual MRI/MRA and quantitative analysis of WMH were performed before and 1 to 7 years after HCT at scheduled annual intervals, along with QoL measurements, in children who had engrafted after HCT. Of 18 patients alive and persistently engrafted (median age, 9.1 years), pretransplantation MRI demonstrated that 9 and 5 had sickle-related stroke and/or small infarcts, respectively. Patients were divided into WMH severity tertiles based on pretransplantation WMH volumes. MRI and WMH were assessed 1 to 7 years after HCT. MRI/MRA and WMH volume were stable or slightly better in 17 of 18 patients. By parent- and self-report, post-HCT QoL improved for children in the lowest WMH tertile significantly more than in the other groups. Based on this single-institution retrospective sample, we report that WMH appears to quantitatively support MRI-based findings that HCT stabilizes long-term small and large vessel cerebrovascular changes and is associated with the degree of improved QoL. While confirmation in larger prospective studies and evaluation by neurocognitive testing are needed, these findings suggest that WMH is a useful biomarker of neurovasculopathy after transplantation for SCD.

Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation.

The secretary of the US Department of Health and Human Services in February 2016 recommended that X-linked adrenoleukodystrophy (X-ALD) be added to the recommended uniform screening panel for state newborn screening programs. This decision was informed by data presented on the accuracy of screening from New York, the only state that currently offers X-ALD newborn screening, and published and unpublished data showing health benefits of earlier treatment (hematopoietic stem cell transplantation and adrenal hormone replacement therapy) for the childhood cerebral form of X-ALD. X-ALD newborn screening also identifies individuals with later-onset disease, but poor genotype-phenotype correlation makes predicting health outcomes difficult and might increase the risk of unnecessary treatment. Few data are available regarding the harms of screening and presymptomatic identification. Significant challenges exist for implementing comprehensive X-ALD newborn screening, including incorporation of the test, coordinating follow-up diagnostic and treatment care, and coordination of extended family testing after case identification.Genet Med 19 1, 121-126.

Phenotypic Heterogeneity of Neutropenia and Gastrointestinal Illness Associated with G6PC3 Founder Mutation.

Severe congenital neutropenia type IV (SCN IV) is a syndrome of severe neutropenia, cardiac and urogenital defects, prominent superficial veins, facial dysmorphism, failure to thrive (FTT), and intermittent thrombocytopenia, caused by a glucose-6-phosphatase catalytic subunit 3 (G6PC3) gene mutation. SCN IV has been linked to glycogen storage disease type 1b as both disorders involve disruption of the glucose-6-phosphatase/glucose-6-phosphate transporter complex, leading to arrested neutrophil maturation. Emerging evidence suggests that neutrophil function plays an important role in intestinal integrity, evidenced by inflammatory bowel disease in certain neutropenic patients. Here, we report 3 unrelated Hispanic males from the Dominican Republic with classic features of SCN IV found to share an identical inherited canonical splice-site mutation of the G6PC3 gene (c.218+1G>A). All 3 patients presented with severe FTT and gastrointestinal manifestations. Two of the patients had significant improvement in growth and resolution of gastrointestional symptoms with initiation of granulocyte colony-stimulating factor. We hypothesize that the gene variant described represents a founder mutation in the Dominican Republic, the first to be described in this geographical region. We discuss the potential associations between neutropenia and gastrointestinal disease with FTT and the role of granulocyte colony-stimulating factor in improving neutrophil count and intestinal integrity and growth.

Decreased fetal hemoglobin over time among youth with sickle cell disease on hydroxyurea is associated with higher urgent hospital use.

BACKGROUND: Hydroxyurea (HU) induces dose-dependent increased fetal hemoglobin (HbF) for sickle cell disease (SCD). Large deviation from historical personal best (PBest) HbF, a clinic-based version of maximum dose, may identify a subset with suboptimal HU adherence over time. PROCEDURE: Retrospective clinical data from youth ages 10-18 years prescribed HU at two centers were extracted from medical records at three time points: pre-HU initiation, PBest and a recent assessment. Decrease from PBest HbF of 20% or more at recent assessment despite stable dosing was designated as high deviation from PBest. Acute hospital use was compared between 1-year periods, pre-HU and ±6 months for PBest and recent assessment. Groups were compared using descriptive and bivariate nonparametric statistics. RESULTS: Seventy-five youth, mean HU duration 5.9 years, met eligibility criteria. Mean ages of HU initiation, PBest and recent assessment were 8.0, 10.9 and 13.9 years, respectively. Despite stable dosing, average HbF of 19.5% at PBest overall declined by 31.8% at recent assessment. PBest HbF declined by 11.7 and 40.1% in two groups, the latter comprised 70.7% of the sample, had lower pre-HU and recent HbF and higher dosing. They experienced more urgent hospital use during the year framing recent assessment than during PBest; these findings were supported by sensitivity analysis. CONCLUSIONS: Decline from PBest HbF is a novel approach to assess HU effectiveness, is common among youth and may represent suboptimal adherence. Larger prospective studies using additional adherence measures are needed to confirm our approach of tracking HbF deviation over time and to define an appropriate cutoff.

Evaluating Harms in the Assessment of Net Benefit: A Framework for Newborn Screening Condition Review.

BACKGROUND: The Department of Health and Human Services (HHS) Advisory Committee on Heritable Disorders in Newborns and Children ("Advisory Committee") makes recommendations to the HHS Secretary regarding addition of new conditions to the national Recommended Uniform Screening Panel for newborns. The Advisory Committee's decision-making process includes assessing the net benefit of screening for nominated conditions, informed by systematic evidence reviews generated by an independent Condition Review Workgroup. The evidence base regarding harms associated with screening for specific conditions is often more limited than that for benefits. PROCEDURES: The process for defining potential harms from newborn screening reviewed the frameworks from other public health evidence-based review processes, adapted to newborn screening by experts in systematic review, newborn screening programs and bioethics, with input from and approval by the Advisory Committee. MAIN FINDINGS: To support the Advisory Committee's review of nominated conditions, the Workgroup has developed a standardized approach to evaluation of harms and relevant gaps in the evidence. Types of harms include the physical burden to infants; psychosocial and logistic burdens to families from screening or diagnostic evaluation; increased risk of medical treatment for infants diagnosed earlier than children with clinical presentation; delayed diagnosis from false negative results; psychosocial harm from false positive results; uncertainty of clinical diagnosis, age of onset or clinical spectrum; and disparities in access to diagnosis or therapy. CONCLUSIONS: Estimating the numbers of children at risk, the magnitude, timing and likelihood of harms will be integrated into Workgroup reports to the Advisory Committee.

Variation in Gamma-Globin Expression before and after Induction with Hydroxyurea Associated with BCL11A, KLF1 and TAL1.

The molecular mechanisms governing γ-globin expression in a subset of fetal hemoglobin (α2γ2: HbF) expressing red blood cells (F-cells) and the mechanisms underlying the variability of response to hydroxyurea induced γ-globin expression in the treatment of sickle cell disease are not completely understood. Here we analyzed intra-person clonal populations of basophilic erythroblasts (baso-Es) derived from bone marrow common myeloid progenitors in serum free cultures and report the level of fetal hemoglobin production in F-cells negatively correlates with expression of BCL11A, KLF1 and TAL1. We then examined the effects of hydroxyurea on these three transcription factors and conclude that a successful induction of γ-globin includes a reduction in BCL11A, KLF1 and TAL1 expression. These data suggests that expression changes in this transcription factor network modulate γ-globin expression in F-cells during steady state erythropoiesis and after induction with hydroxyurea.

Sickle cell in Latin America and the United States [corrected].

Latin Americans are an underappreciated population affected by sickle cell disease (SCD). Sickle trait and SCD exist throughout Latin America and U.S. Latino communities. We describe the epidemiology and genetic heterogeneity of SCD among Latin Americans, and fetal hemoglobin expression. National population-based newborn screening for SCD is limited to Brazil, Costa Rica, and the U.S. Available and extrapolated data suggest that over 6,000 annual births and 100,000-150,000 Latin Americans are affected by SCD. This comprehensive review highlights the substantial numbers and population distribution of SCD and sickle trait in Latin America, and where national newborn screening programs for SCD exist.