Search

Abstract: In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier-based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate-severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Most adults with sickle cell disease will experience a silent cerebral infarction (SCI) or overt stroke. Identifying patient subgroups with increased stroke incidence is important for future clinical trials focused on stroke prevention. Our 3-center prospective cohort study tested the primary hypothesis that adults with sickle cell disease and SCIs have a greater incidence of new stroke or SCI compared with those without SCI. A secondary aim focused on identifying additional risk factors for progressive infarcts, particularly traditional risk factors for stroke in adults., Methods and Results: This observational study included adults with sickle cell disease and no history of stroke. Magnetic resonance imaging scans of the brain completed at baseline and >1 year later were reviewed by 3 radiologists for baseline SCIs and new or progressive infarcts on follow-up magnetic resonance imaging. Stroke risk factors were abstracted from the medical chart. Time-to-event analysis was utilized for progressive infarcts. Median age was 24.1 years; 45.3% of 95 participants had SCIs on baseline magnetic resonance imaging. Progressive infarcts were present in 17 participants (17.9%), and the median follow-up was 2.1 years. Incidence of new infarcts was 11.95 per 100 patient-years (6.17-20.88) versus 3.74 per 100 patient-years (1.21-8.73) in those with versus without prior SCI. Multivariable Cox regression showed that baseline SCI predicts progressive infarcts (hazard ratio, 3.46 [95% CI, 1.05-11.39]; P =0.041); baseline hypertension was also associated with progressive infarcts (hazard ratio, 3.23 [95% CI, 1.16-9.51]; P =0.025)., Conclusions: Selecting individuals with SCIs and hypertension for stroke prevention trials in sickle cell disease may enrich the study population with those at highest risk for infarct recurrence.

Sickle cell disease (SCD)-related organ complications are a major cause of morbidity and mortality in patients with SCD. We sought to assess whether hematopoietic stem cell transplantation (HSCT) stabilizes, attenuates, or exacerbates organ decline. We performed a systematic review and meta-analysis of trials investigating organ function before and after HSCT in patients with SCD. We searched MEDLINE/PubMed and EMBASE up to September 21, 2023. Continuous data were expressed as standardized mean difference (SMD) and pooled in a weighted inverse-variance random-effects model; binomial data were expressed as risk ratio (RR) using the Mantel-Haenszel random-effects meta-analyses. Of 823 screened studies, 34 were included in this review. Of these, 17 (774 patients, 23.6% adults, 86.3% HLA-identical sibling donor, 56.7% myeloablative conditioning regimen) were included in the meta-analyses. Pulmonary function remained stable. Mean tricuspid regurgitant jet velocity decreased but did not reach statistical significance. In children, estimated glomerular filtration rate decreased (SMD -0.80, p = .01), and the presence of proteinuria increased (RR 2.00, p = <.01), while splenic uptake and phagocytic function improved (RR 0.31, p = <.01; RR 0.23, p = <.01). Cerebral blood flow improved (SMD -1.39, p = <.01), and a low incidence of stroke after transplantation in high-risk patients was found. Retinopathy and avascular osteonecrosis were investigated in only one study, showing no significant changes. While HSCT can improve some SCD-related organ dysfunctions, transplantation-related toxicity may have an adverse effect on others. Future research should focus on identifying individuals with SCD who might benefit most from HSCT and which forms of organ damage are more likely to exacerbate post-transplantation., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background and Objectives: Previously we demonstrated that 90% of infarcts in children with sickle cell anemia occur in the border zone regions of cerebral blood flow (CBF). We tested the hypothesis that adults with sickle cell disease (SCD) have silent cerebral infarcts (SCIs) in the border zone regions, with a secondary hypothesis that older age and traditional stroke risk factors would be associated with infarct occurrence in regions outside the border zones., Methods: Adults with SCD 18-50 years of age were enrolled in a cross-sectional study at 2 centers and completed a 3T brain MRI. Participants with a history of overt stroke were excluded. Infarct masks were manually delineated on T2-fluid-attenuated inversion-recovery MRI and registered to the Montreal Neurological Institute 152 brain atlas to generate an infarct heatmap. Border zone regions between anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA) were quantified using the Digital 3D Brain MRI Arterial Territories Atlas, and logistic regression was applied to identify relationships between infarct distribution, demographics, and stroke risk factors., Results: Of 113 participants with SCD (median age 26.1 years, interquartile range [IQR] 21.6-31.4 years, 51% male), 56 (49.6%) had SCIs. Participants had a median of 5.5 infarcts (IQR 3.2-13.8). Analysis of infarct distribution showed that 350 of 644 infarcts (54.3%) were in 4 border zones of CBF and 294 (45.6%) were in non-border zone territories. More than 90% of infarcts were in 3 regions: the non-border zone ACA and MCA territories and the ACA-MCA border zone. Logistic regression showed that older participants have an increased chance of infarcts in the MCA territory (odds ratio [OR] 1.08; 95% CI 1.03-1.13; p = 0.001) and a decreased chance of infarcts in the ACA-MCA border zone (OR 0.94; 95% CI 0.90-0.97; p < 0.001). The presence of at least 1 stroke risk factor did not predict SCI location in any model., Discussion: When compared with children with SCD, in adults with SCD, older age is associated with expanded zones of tissue infarction that stretch beyond the traditional border zones of CBF, with more than 45% of infarcts in non-border zone regions.

Case Study: On May 9th, 2023, a U.S. Border Patrol detained a family of five near Brownsville, TX. During processing, one of the family members, an eight-year-old girl, ADRA, was noted to have sickle cell anemia and a heart disease condition. Five days after they arrived at the Donna Facility, on May 14th, ADRA displayed symptoms, including abdominal pain and fever, and tested positive for Influenza A. She was administered medication and transferred to a designated isolation unit at the Harlingen Border Patrol Station. Despite her deteriorating condition and her mother's urgent requests for medical intervention, there were no documented consultations with an on-call physician or considerations for her transfer to a local hospital. On May 17th, ADRA's health critically declined, marked by multiple visits to the medical unit for vomiting and abdominal pain. An ambulance was dispatched only after ADRA experienced a seizure and became unresponsive, Fig. 1. Her subsequent death was deemed a "preventable tragedy" attributed to systemic failures in the Border Patrol's medical care and decision-making processes in a juvenile care monitor's report. 1 IMPACT: This article adds to the existing literature by: Summarizing the gap in age-specific guidelines for six chronic diseases that occur in children and adolescents held in custody. Identifying the lack of adequate intervention strategies for acute management of chronic diseases for youth held in custody and strategies for improving health equity., (© 2023. The Author(s).)

Abstract: Preliminary evidence from a series of 4 adults with sickle cell disease (SCD) suggests that hematopoietic stem cell transplant (HSCT) improves cerebral hemodynamics. HSCT largely normalizes cerebral hemodynamics in children with SCD. We tested the hypothesis in adults with SCD that cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) measured using magnetic resonance imaging, normalized to healthy values, comparing measurements from ∼1 month before to 12 to 24 months after HSCT (n = 11; age, 33.3 ± 8.9 years; 389 ± 150 days after HSCT) with age-, race- and sex-matched values from healthy adults without sickle trait (n = 28; age, 30.2 ± 5.6 years). Before transplant, 7 patients had neurological indications for transplant (eg, overt stroke) and 4 had nonneurological reasons for haploidentical bone marrow transplant (haplo-BMT). All received haplo-BMT from first-degree relatives (parent, sibling, or child donor) with reduced-intensity preparation and maintained engraftment. Before transplant, CBF was elevated (CBF, 69.11 ± 24.7 mL/100 g/min) compared with that of controls (P = .004). Mean CBF declined significantly after haplo-BMT (posttransplant CBF, 48.2 ± 13.9 mL/100 g/min; P = .003). OEF was not different from that of controls at baseline and did not change significantly after haplo-BMT (pretransplant, 43.1 ± 6.7%; posttransplant, 39.6 ± 7.0%; P = .34). After transplant, CBF and OEF were not significantly different from controls (CBF, 48.2 ± 13.4 mL/100 g/min; P = .78; and OEF, 39.6 ± 7.0%; P > .99). CMRO2 did not change significantly after haplo-BMT (pretransplant, 3.18 ± 0.87 mL O2/100 g/min; posttransplant, 2.95 ± 0.83; P = .56). Major complications of haplo-BMT included 1 infection-related death and 1 severe chronic graft-versus-host disease. Haplo-BMT in adults with SCD reduces CBF to that of control values and maintains OEF and CMRO2 on average at levels observed in healthy adult controls. The trial was registered at www.clinicaltrials.gov as #NCT01850108., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The ideal curative therapy for sickle cell disease (SCD) must be applicable across all ages and include individuals with strokes and preexisting heart, lung, and kidney disease. Myeloablative, matched sibling donor hematopoietic stem cell transplant (HCT) for children with SCD has shown excellent outcomes over the past 3 decades but has been restricted due to the limited availability of a human leukocyte antigen-matched sibling donor (10%-15%) and increased treatment-related death in adults with myeloablative conditioning. To overcome these 2 significant barriers to curative therapy in SCD, related haploidentical HCT has become an active area of research. The use of related haploidentical donors (first- and second-degree relatives) increases the donor pool to at least 90% of those eligible across the life span. Importantly, most adults, even with strokes or significant comorbidities, can tolerate the nonmyeloablative conditioning regimen without treatment-related death. Since 2013, at least 3 related haploidentical HCT strategies have emerged as potential curative therapies for SCD: (1) a nonmyeloablative, T-cell replete, bone marrow transplant with thiotepa and posttransplant cyclophosphamide with a goal of complete donor chimerism; (2) a nonmyeloablative, in vivo T-cell depletion, using peripheral blood stem cells (PBSCs) with a goal of stable mixed donor-recipient chimerism; and (3) a myeloablative, ex vivo T-cell depletion using PBSCs and advanced-technology graft manipulation, with a goal of complete donor chimerism. We review the similarities, differences, outcomes, and gaps in knowledge with these 3 haploidentical HCT approaches for SCD., (Copyright © 2023 by The American Society of Hematology.)

Previously, we demonstrated that older children with sickle cell anemia (SCA) living in Nigeria are at increased risk of death if they are underweight (weight-for-age z score < -1). We now conducted a cross-sectional study in low- and high-income settings to determine the risk factors for being underweight a in children aged 5 to 12 years with SCA. The children from low- and high-income settings were eligible participants for the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria (SPRING; N = 928) and the Silent Cerebral Infarct (SIT, North America/Europe; N = 1093) trials, respectively. The median age in the SPRING and SIT cohorts was 8.1 and 8.5 years, respectively (P < .001). A total of 87.9% (n = 816) of participants in the SPRING trial (low-income) met the study criteria for being underweight (weight-for-age z score < -1), and 22.7% (n = 211) for severely underweight (weight-for-age z score < -3), significantly higher than the SIT (high-income) cohort at 25.7% underweight (n = 281) and 0.7% severely underweight (n = 8; P < .001 for both comparisons). In the combined cohort, older age (odds ratio [OR], 1.24; P < .001) and lower hemoglobin level (OR, 0.67; P < .001) were associated with being underweight. Age and hemoglobin level remained statistically significant in separate models for the SPRING and SIT cohorts. Older age and lower hemoglobin levels in children aged 5 to 12 years with SCA are associated with being underweight in low- and high-income settings., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Children with sickle cell anemia (SCA) living in Nigeria are at an increased risk of malnutrition, which contributes to increased morbidity and mortality. However, evidence-based guidelines for managing malnutrition in children with SCA are lacking. To address this gap, we conducted a multicenter, randomized controlled feasibility trial to assess the feasibility and safety of treating children with SCA aged from 5 to 12 years and having uncomplicated severe acute malnutrition (body mass index z score of <-3.0). Children with SCA and uncomplicated severe acute malnutrition were randomly allocated to receive supplemental ready-to-use therapeutic food (RUTF) with or without moderate-dose hydroxyurea therapy (20 mg/kg per day). Over a 6-month enrollment period, 3190 children aged from 5 to 12 years with SCA were evaluated for eligibility, and 110 of 111 children who were eligible were enrolled. During the 12-week trial, no participants withdrew or missed visits. One participant died of unrelated causes. Adherence was high for hydroxyurea (94%, based on pill counts) and RUTF (100%, based on the number of empty sachets returned). No refeeding syndrome event or hydroxyurea-related myelosuppression occurred. At the end of the trial, the mean change in body mass index z score was 0.49 (standard deviation = 0.53), and 39% of participants improved their body mass index z score to ≥-3.0. Our findings demonstrate the feasibility, safety, and potential of outpatient treatment for uncomplicated severe acute malnutrition in children with SCA aged from 5 to 12 years in a low-resource setting. However, RUTF sharing with household and community members potentially confounded the response to malnutrition treatment. This trial was registered at clinicaltrials.gov as #NCT03634488., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The Food and Drug Administration requires contemporaneous controls to compare clinical outcomes for participants receiving experimental gene therapy or gene editing clinical trials. However, developing a contemporaneous cohort of rare diseases requires multiple person-hours. In a single referral center for sickle cell disease, we tested the hypothesis that we could create an automated contemporaneous cohort of children and adults with sickle cell anemia (SCA) to predict mortality. Data were obtained between 1 January 2004 and 30 April 2021. We identified 419 individuals with SCA with consistent medical care defined as followed continuously for >0.5 years with no visit gaps >3.0 years. The median age was 10.2 years (IQR, 1-24 years), with a median follow-up of 7.4 years (IQR, 3.6-13.5 years) and 47 deaths. A total of 98% (274 of 277) of the children remained alive at 18 years of age, and 34.3% (94 of 274) of those children were followed into adulthood. For adults, the median age of survival was 49.3 years. Treatment groups were mutually exclusive and in a hierarchical order: hematopoietic stem cell transplant (n = 22)>regular blood transfusion for at least 2 years (n = 56)>hydroxyurea for at least 1 year (n = 243)>no disease-modifying therapy (n = 98). Compared to those receiving no disease-modifying treatment, those treated with hydroxyurea therapy had a significantly lower hazard of mortality (hazard ratio = 0.38; P = 0.016), but no statistical difference for those receiving regular blood transfusions compared to no disease-modifying therapy (hazard ratio = 0.71; P = 0.440). An automated contemporaneous SCA cohort can be generated to estimate mortality in children and adults with SCA., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In high-income countries, premarital genetic counseling for Sickle Cell Disease (SCD) is a standard practice. However, in Nigeria, there is no formal premarital genetic counseling program available for SCD. We conducted a series of focus group discussions with health care professionals, patients with SCD, and parents of the patients with or without SCD to gain an understanding of their attitudes and beliefs towards SCD/Sickle Cell Trait and premarital genetic counseling for SCD. Data were analyzed using Charmaz's constructivist grounded theory approach. Two themes were highlighted in the analysis as follows: (1) the difference between the perception of premarital sickle cell screening among individuals with SCD versus the general population, and (2) the personal beliefs and physical challenges that could lead to the avoidance of premarital screening within the general community. Lack of disease-related knowledge, testing facilities, transportation, and stigma associated with the disease were the most commonly perceived barriers to premarital testing. Also, a willingness to receive premarital testing for SCD exists within our community to reduce the spread of the disease and advocate for improved health-related quality of life of patients with SCD. The content and structure of a premarital genetic counseling program in Kano, Northern Nigeria, needs to be developed., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Silent cerebral infarcts (SCI) in sickle cell anemia (SCA) are associated with future strokes and cognitive impairment, warranting early diagnosis and treatment. Detection of SCI, however, is limited by their small size, especially when neuroradiologists are unavailable. We hypothesized that deep learning may permit automated SCI detection in children and young adults with SCA as a tool to identify the presence and extent of SCI in clinical and research settings., Methods: We utilized UNet-a deep learning model-for fully automated SCI segmentation. We trained and optimized UNet using brain magnetic resonance imaging from the SIT trial (Silent Infarct Transfusion). Neuroradiologists provided the ground truth for SCI diagnosis, while a vascular neurologist manually delineated SCI on fluid-attenuated inversion recovery and provided the ground truth for SCI segmentation. UNet was optimized for the highest spatial overlap between automatic and manual delineation (dice similarity coefficient). The optimized UNet was externally validated using an independent single-center prospective cohort of SCA participants. Model performance was evaluated through sensitivity and accuracy (%correct cases) for SCI diagnosis, dice similarity coefficient, intraclass correlation coefficient (metric of volumetric agreement), and Spearman correlation., Results: The SIT trial (n=926; 31% with SCI; median age, 8.9 years) and external validation (n=80; 50% with SCI; age, 11.5 years) cohorts had small median lesion volumes of 0.40 and 0.25 mL, respectively. Compared with the neuroradiology diagnosis, UNet predicted SCI presence with 100% sensitivity and 74% accuracy. In magnetic resonance imaging with SCI, UNet reached a moderate spatial agreement (dice similarity coefficient, 0.48) and high volumetric agreement (intraclass correlation coefficient, 0.76; ρ=0.72; P <0.001) between automatic and manual segmentations., Conclusions: UNet, trained using a large pediatric SCA magnetic resonance imaging data set, sensitively detected small SCI in children and young adults with SCA. While additional training is needed, UNet may be integrated into the clinical workflow as a screening tool, aiding in SCI diagnosis., Competing Interests: Disclosures Dr Fields reports salary support in Global Blood Therapeutics, Inc, Monteore Medical Center, and Proclara Biosciences and from Washington University in St. Louis. H. An reports compensation from Pfizer, Inc, for consultant services and grants from the National Institutes of Health. Dr Binkley reports consultant services from CNS Consultants LLC and OpenCell Technologies. Dr Lee reports consultant services from Biogen. Dr McKinstry reports consultant services from NOUS Imaging, Inc, Philips, and Siemens. Dr Jordan reports compensation for expert witness and salary support from the National Institutes of Health and Vanderbilt University. Dr DeBaun reports consultant services from Forma Therapeutics, Global Blood Therapeutics, Graphite Bio, Novartis, and salary support Vanderbilt University. The other authors report no conflicts.

Competing Interests: Declaration of interests MRA has received grants or contracts with Novartis, Pfizer, Global Blood Therapeutics, and Forma Therapeutics; and participated in Data Safety Monitoring Boards or Advisory Boards for Vertex, GBT, Forma, Novartis, and Aggios. BA has participated in Data Safety Monitoring Boards or Advisory Boards for Agios, Aruvant, bluebird bio, CRISPR, Accordant (CVS), Emmaus, Forma Therapeutics, Fulcrum, Global Blood Therapeutics, Hemanext, Novartis, NovoNordisk, and Vertex. RF has received grants from the European Horizon 2020 and Horizon Europe schemes and a contract with Global Blood Therapeutics; received consulting fees from Novartis and Global Blood Therapeutics; received honoraria for a Physicians’ Education Resource and from Global Blood Therapeutics; participated in Data Safety Monitoring Boards or Advisory Boards for Vertex, Addmedica and Novonordisk; and a leadership or fiduciary role as a member of the Steering Committee and Coordinator of the Red Cell Disorder Working Group of the Italian Association of Pediatric Hematology Oncology. NC has received a research grant for Novartis Precision Medicine. MdM has received honoraria for presentations by Addmedica and Novartis and support from Addmedica for attending a conference; and participated in a Data Safety Monitoring Board or Advisory Board for Addmedica, Vertex, and Novartis. JE has received grants from the European Horizon 2020 scheme and participated in the Data Safety Monitoring Board or Advisory Board of the Fondation Pierre Fabre. EE has received consulting fees from bluebird bio. ALG has an honorary advisory role on the Australian Sickle Cell Advisory Board. IMI has received a grant from the American Society of Hematology; consulting fees from Agios Pharmaceuticals; and honoraria from the American Society of Hematology. LCJ received royalties for a book chapter. AAK has received support from the Health resources and Services Administration. MLP has received consulting fees from the American College of Medical Genetics and Genomics; and participated in a Data Safety Monitoring Board or Advisory Board for the American College of Medical Genetics and Genomics and the American Academy of Pediatrics. ON has received travel support from the American Society of Hematology to attend a conference. DCR has received consulting fees from Vertex, Forma, Agios, and Vifor; received honoraria from Vertex; and participated in a Data Safety Monitoring Board or Advisory Board for TauRx and Mitsubishi. AS has received a scholar award from the American Society of Hematology, an advancing cures research award from the Doris Duke Charitable Foundation, and a Working group award from the Center for ELSI Resources and Analysis; consulting fees from Spotlight Therapeutics, Medexus, Vertex, Editas Medicine, and Sangamo Therapeutics; has received honoraria from Vindico Medical Education; and has a leadership or fiduciary role in the American Society for Transplantation and Cellular Therapy Content Committee, the Scientific Executive Committee, Sickle Cell Transplant Advocacy & Research Alliance, and the Pediatric Transplantation and Cellular Therapy Consortium Supportive Care Committee; and has financial interests with CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis Pharmaceuticals, Magenta Therapeutics, and Beam Therapeutics. AAT has received consulting fees from GlaxoSmithKline and Global Blood Therapeutics; and honoraria from Novartis. REW has received consulting fees from Nova Laboratories; participated in a Data Safety Monitoring Board for Novartis and Editas; and received donations and support for clinical trials from Bristol Myers Squib, Addmedica, and Hemex Health. DJW has received a grant or contract from the US National Institutes for Health; received payment for expert testimony from Fredslough Law Firm; participated in a Data Safety Monitoring Board or Advisory board for Northwestern University; and is the founder and chairman of eNursing.

Sickle cell hemoglobin SC (HbSC) disease is the second most frequent sickle cell disease (SCD) genotype after sickle cell anemia (HbSS). Globally, ∼55 000 newborns with HbSC are delivered annually, with the highest HbC gene frequency in West Africa. In Ghana, 40% of adults visiting the Ghana Institute of Clinical Genetics SCD clinic have HbSC. Unlike HbSS, hydroxyurea use is not routinely recommended for individuals with HbSC because of the perceived high-risk to benefit ratio. To test the hypothesis that at least 5% of adults with HbSC will meet the American Society of Hematology criteria for severe disease, we conducted a retrospective descriptive cohort study of all individuals with HbSC (≥18 years) who visited the clinic in 2019. Adults with HbSC aged from 18 to 45 years were selected. We identified a comparison group of 639 individuals with HbSS and matched the frequency based on the age and sex of individuals with HbSC. Severe disease was defined as a history of ≥3 SCD-associated moderate or severe pain episodes per year, history of acute chest syndrome, and severe symptomatic chronic anemia that interferes with daily activities or quality of life. The study end points were the proportion of individuals with SCD who met the definition of severe disease and were eligible for hydroxyurea. In total, 64 of 639 (10.0%) individuals with HbSC met the eligibility criteria for hydroxyurea therapy compared with 154 of 639 (24.1%) individuals with HbSS. Less than 1% and 3% of individuals with severe HbSC and HbSS, respectively, were routinely prescribed with hydroxyurea in this tertiary care medical center., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Undernutrition is a risk factor for under-5 mortality and is also postulated to be a risk factor for mortality in older children and adults with sickle cell anemia (SCA). We tested the hypothesis that underweight is associated with mortality in children aged 5 to 12 years with SCA. We performed a secondary analysis of participants in the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria trial, a double-blind, parallel-group randomized controlled trial for low-dose or moderate-dose hydroxyurea in children with abnormal transcranial Doppler velocities and a comparison group of participants with nonelevated transcranial Doppler velocities in northern Nigeria. Nutritional status was classified as underweight (weight-for-age z score), stunting (height-for-age z score), and wasting (body mass index z score) using the World Health Organization growth reference. The mean weight-for-age z score was lower in children who died during the study than in those who survived. Otherwise, the baseline characteristics of children who died during the study were not significantly different from those of the children who survived. A pooled analysis of participants demonstrated that a lower weight-for-age z score was associated with an increased hazard of death. Underweight participants (weight-for-age z score <-1) had a greater probability of death during follow-up than those who were not underweight. Underweight status in school-aged children with SCA is a previously unrecognized risk factor for early mortality in Nigeria and can be easily applied to screen children at risk for death. This trial was registered at www.clinicaltrials.gov as #NCT02560935., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

We tested the hypothesis that fixed oral moderate-dose hydroxyurea (20 mg/kg per day) for initial treatment of secondary stroke prevention results in an 80% relative risk reduction of stroke or death when compared with fixed oral low-dose hydroxyurea (10 mg/kg per day) in a phase 3 double-blind, parallel-group, randomized controlled trial in children with sickle cell anemia (SCA) living in Nigeria. A total of 101 participants were randomly allocated to low-dose (n = 49) and moderate-dose (n = 52) hydroxyurea treatment groups. The median participant follow-up was 1.6 years (interquartile range, 1.0-2.3), with a planned minimum follow-up of 3.0 years. A total of 6 recurrent strokes and 2 deaths vs 5 recurrent strokes and 3 deaths occurred in the low- and moderate-dose groups, respectively. The incidence rate ratio (IRR) of the primary outcome measure of stroke or death in the low- and moderate-dose hydroxyurea treatment groups was 0.98 (95% confidence interval [CI], 0.32-3.00; P = .97). The trial was stopped early owing to no clinical difference in the incidence rates of the primary outcome measure. The incidence rates of recurrent strokes were 7.1 and 6.0 per 100 person-years in the low- and moderate-dose groups, respectively, (IRR, 1.18; 95% CI, 0.30-4.88; P = .74). As a measure of adherence to the oral hydroxyurea therapy, the median percent of returned pills was 3.0% and 2.6% in the low- and moderate-dose groups, respectively. No participant had hydroxyurea therapy stopped for myelosuppression. For children with SCA in low-income settings without access to regular blood transfusion therapy, initial low-dose hydroxyurea is a minimum known efficacious dose for secondary stroke prevention., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Ischemic priapism is a common but underrecognized morbidity affecting about 33% of adult men with sickle cell disease (SCD). The onset of priapism occurs in the prepubertal period and tends to be recurrent with increasing age. Significantly, priapism is associated with an unrecognized high burden of mental duress and sexual dysfunctions. The diagnosis of priapism is clinical. Many episodes of priapism will resolve spontaneously, but when an episode lasts longer than 4 hours, the episode is considered a urologic emergency requiring quick intervention with either corporal aspiration or shunt surgery. Only 3 randomized clinical trials (stilbesterol, ephedrine or etilefrine, and sildenafil) have been conducted for secondary priapism prevention in SCD. All 3 trials were limited with small sample sizes, selection biases, and inconclusive results after completion. The current molecular understanding of the pathobiology of priapism suggests a relative nitric oxide (NO) deficiency secondary to chronic hemolysis in SCD and associated phosphodiesterase type 5 dysregulation. We posit an increase in NO levels will restore the normal homeostatic relationship between voluntary erection and detumescence. Currently, 2 randomized phase 2 trials (1 double-blind, placebo-controlled trial and 1 open-label, single-arm intervention) are being conducted for secondary priapism prevention in men at high risk for recurrent priapism (NCT03938454 and NCT05142254). We review the epidemiology and pathobiology of priapism, along with mechanistic therapeutic approaches for secondary prevention of priapism in SCD., (Copyright © 2022 by The American Society of Hematology.)

Pregnancy in women with sickle cell disease (SCD) is a life-threatening condition. In both high- and low-income countries, there is an 11-fold increased risk of maternal death and a 4-fold increased risk of perinatal death. We highlight the epidemiology of SCD-specific and obstetric complications commonly seen during pregnancy in SCD and propose definitions for acute pain and acute chest syndrome (ACS) episodes during pregnancy. We conducted a systematic review of the recent obstetric and hematology literature using full research articles published within the last 5 years that reported outcomes in pregnant women with SCD. The prevalence of acute pain episodes during pregnancy ranged between 4% and 75%. The prevalence of ACS episodes during pregnancy ranged between 4% and 13%. The estimated prevalence of pulmonary thromboembolism in women with SCD during pregnancy is approximately 0.5 to 1%. ACS is the most common cause of death and is often preceded by acute pain episodes. The most crucial time to develop these complications in pregnancy is during the third trimester and postpartum period. In a pooled analysis from studies in low- and middle-income settings, maternal death in women with SCD is approximately 2393 and 4300 deaths per 100 000 live births with and without multidisciplinary care, respectively. In comparison, in the US and northern Europe, the general maternal mortality rate is approximately 23.8 and 8 deaths per 100 000 live births, respectively. A multidisciplinary SCD obstetrics care approach reduces maternal and perinatal morbidity and mortality in low- and middle-income countries., (Copyright © 2022 by The American Society of Hematology.)

We conducted one of the first prospective studies to test the hypothesis that the clinical history of priapism underestimates priapism incidence compared with a priapism pain diary. Eligibility criteria were men with sickle cell anemia (SCA) between 18 and 40 years of age who have had at least 3 episodes of priapism in the past 12 months. Seventy-one men with SCA completed the diary for at least 3 months. The first 3 months of the priapism diary were included in the analysis. A total of 298 priapism episodes were recorded, and 80% (57 of 71) of the participants had at least 1 priapism event. Priapism severity was reported in the range of moderate to the worst imaginable pain in 81.5% (263 of 298), and a total 57 participants (80%) had a median pain rating of 6 (interquartile range: 5-8) on a scale from 1 to 10. The monthly incidence rate of priapism per participant based on history versus self-report pain diary was 2.0 (95% confidence interval, 1.9-2.1) and 1.4 (95% confidence interval, 1.2-1.6), respectively (P < .001). For participants that had a prior priapism episode, 80% had another episode during the 3-month interval follow-up. The median time to that second episode was 27.5 days. Major priapism occurred in 9.9% of episodes and was associated with the sum of all prospective priapism events. Men with SCA and at least 3 priapism episodes in the past 12 months are at significant risk for recurrent priapism in the following 3 months., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: Evidence-based practice for stroke prevention in high-income countries involves screening for abnormal transcranial Doppler (TCD) velocity and initiating regular blood transfusions for at least 1 year, followed by treatment with hydroxyurea. This practice has not been transferred to low-resource settings like Nigeria, the country with the highest global population density of SCD. Following a multi-center randomized controlled trial among children with SCA in northern Nigeria, screening for stroke and initiation of hydroxyurea was established as standard of care at the clinical trial sites and other locations. We aim to describe the critical steps we took in translating research into practice for stroke prevention in SCA in Nigeria. Guided by the PRISM framework, we describe how we translated results from a randomized controlled trial for primary prevention of stroke in children with sickle cell anemia into usual care for children with SCA in Kaduna, Nigeria., Results: Findings from this study demonstrate the importance of organizational support and stakeholder involvement from the onset of a clinical trial. Having the dual objective of conducting an efficacy trial while simultaneously focusing on strategies for future implementation can significantly decrease the lag time between discovery and routine practice., (© 2021. The Author(s).)

In the United States, primary stroke prevention in children with sickle cell anemia (SCA) is the standard of care and includes annual transcranial Doppler ultrasound to detect elevated velocities. For children with velocities ≥200 cm/sec, initial monthly blood transfusion therapy for at least a year, followed by the option of hydroxyurea therapy, results in a significant decline in the stroke rate. In Africa, no prior strategy exists for primary stroke prevention because regular blood transfusion therapy is not feasible. We completed a randomized controlled trial for primary stroke prevention using initial low- and moderate-dose hydroxyurea as an alternative to blood transfusion therapy. The trial results demonstrated equal primary stroke prevention efficacy with both doses. After the trial, we provided a state-supported stroke screening service and treatment for over 20,000 children in Kano, Nigeria. We will review the strategies implemented to conduct clinical research and provide humanitarian assistance to children with SCA in Nigeria., (© 2022 The American Clinical and Climatological Association.)

Despite priapism being one of the most frequent complications of sickle cell anemia (SCA) in male individuals, little has been reported about the impact of priapism in this population. The authors used a sequential independent mixed-methods design, which used both international multicenter focus group discussions (n=35) and a quantitative patient-reported outcome measure (n=131) to determine the impact of priapism on men with SCA in Nigeria and the United States. The authors analyzed data from focus groups using an iterative inductive-deductive approach. Comparison of the Priapism Impact Profile data was done using the Kruskal-Wallis H test. Our result showed that priapism, across cultures, is associated with shame and embarrassment. These emotions interfere with timely clinical and family communication about priapism symptoms and complications. Participants were dissatisfied with the quality of care at emergency facilities. The quality of life and physical wellness of men with SCA-related priapism were significantly different for the 3 groups: (1) priapism condition getting better, (2) priapism condition getting worse, and (3) priapism condition remain the same (P=0.002 and P=0.019, respectively). Psychological, sexual, and physical wellbeing are all adversely affected by priapism. Evidence-based methods are necessary for adequate medical, educational, and psychological treatment for recurrent priapism., Competing Interests: M.R.D. and his institution are the sponsors of 2 externally funded research investigator-initiated projects. Global Blood Therapeutics (GBT) will provide funding for the cost of the clinical studies. GBT will not be a cosponsor of either study. M.R.D. is not receiving any compensation for the conduct of these 2 investigator-initiated observational studies. Also, M.R.D. is a member of the GBT advisory board for a proposed randomized controlled trial for which he receives compensation. M.R.D. is the Chair of the steering committee for an industry-supported phase II trial (SPARTAN) to prevent priapism in men. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. In Africa, where regular blood transfusion is not feasible for most children, we tested the hypothesis that initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities., Methods: SPRING is a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5-12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, we used a permuted block allocation scheme with block sizes of four, stratified by sex and site. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 1:1 ratio to low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea taken once daily with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. The secondary outcome was all-cause hospitalisation. We used the intention-to-treat population for data analysis. The trial was stopped early for futility after a planned minimum follow-up of 3·0 years to follow-up for participants. This trial was registered with ClinicalTrials.gov, number NCT02560935., Findings: Between Aug 2, 2016, and June 14, 2018, 220 participants (median age 7·2 years [IQR 5·5-8·9]; 114 [52%] female) were randomly allocated and followed for a median of 2·4 years (IQR 2·0-2·8). All participants were Nigerian and were from the following ethnic groups: 179 (82%) people were Hausa, 25 (11%) were Fulani, and 16 (7%) identified as another ethnicity. In the low-dose hydroxyurea group, three (3%) of 109 participants had strokes, with an incidence rate of 1·19 per 100 person-years and in the moderate-dose hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1·92 per 100 person-years (incidence rate ratio 0·62 [95% CI 0·10-3·20], p=0·77). The incidence rate ratio of hospitalisation for any reason was 1·71 (95% CI 1·15-2·57, p=0·0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27·43 vs 16·08). No participant had hydroxyurea treatment stopped for myelosuppression., Interpretation: Compared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke., Funding: National Institute of Neurological Disorders and Stroke., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We used the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to evaluate a Stroke Prevention Team's readiness to prevent strokes in children with sickle cell anemia living in northern Nigeria. The NIH sponsored Stroke Prevention Trial in Nigeria included a goal of a sustainable stroke prevention program. The program's 1-year reach for transcranial Doppler screening was 14.7% (4710/32,000) of which 6.0% (281/4710) had abnormal velocities (≥200 cm/s). All participants with abnormal transcranial Doppler velocities were started on hydroxyurea (effectiveness). The leaders of all 5 hospitals agreed to adopt the program. After 1 year, program-implementation and maintenance rates were 100%, demonstrating the program's feasibility and short-term sustainability., Competing Interests: M.R.D.: had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. M.R.D.: designed the study. S.U.A. and M.A.T.: provided the TCD training. A.H.D., H.B.-M., H.I., A.T., A.A.S., B.W.J., S.G., Y.K., L.H., S.A., M.A.Z., and N.I.: administered the TCD screening. E.T. and L.J.: verified the neurological examinations. A.I.G., F.M.U., M.A.T., A.I.G., S.U.A., B.C.G., J.G., and D.L.G.: collected the data. D.L.G. and M.R.: performed the analyses. M.R.D., S.A., D.L.G., A.A.B., M.R.D.: interpreted the results. D.L.G., A.A.B., L.C.J., E.T., M.H.A., and M.R.D.: wrote the manuscript. Before submission, all authors reviewed the manuscript.The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Nigeria has the highest proportion of children with sickle cell anemia (SCA) globally; an estimated 150,000 infants with SCA are born annually. Primary stroke prevention in children with SCA must include Nigeria. We describe capacity-building strategies in conjunction with two National Institutes of Health-funded primary stroke prevention trials (a feasibility trial and phase III randomized controlled trial) with initial hydroxyurea treatment for children with SCA and abnormal transcranial Doppler (TCD) velocities in Nigeria. We anticipated challenges to conducting clinical trials in a low-resource setting with a local team that had not previously been involved in clinical research and sought a sustainable strategy for primary stroke prevention., Methods: This is a descriptive, prospective study of challenges, solutions, and research teams in two trials that enrolled a total of 679 children with SCA., Results: As part of the capacity-building component of the trials, over eight years, 23 research personnel (physicians, nurses, research coordinators, a statistician, and a pharmacist) completed a one-month research governance and ethics training program at Vanderbilt University Medical Center, USA. A lead research coordinator for each site completed the Society of Clinical Research Professionals certification. TCD machines were donated; radiologists and nonradiologists were trained and certified to perform TCD. A scalable E-prescription was implemented to track hydroxyurea treatment. We worked with regional government officials to support ongoing TCD-based screening and funding for hydroxyurea for children with SCA at a high risk of stroke., Conclusions: Our trials and capacity building demonstrate a sustainable strategy to initiate and maintain pediatric SCA primary stroke prevention programs in Africa., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Recently, encouraging data provided long-awaited hope for gene therapy as a cure for sickle cell disease (SCD). Nevertheless, the transient suspension of the bluebird bio gene therapy trial (clinicaltrials.gov: NCT02140554) after participants developed acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) raised concerns. Potential possibilities for these cases include busulfan, insertional mutagenesis, both, or neither. Busulfan was considered the cause in the first reported case because the transgene was not present in the AML/MDS. However, busulfan is unlikely to have contributed to the most recent case. The transgene was present in the patient's malignant cells, indicating they were infused after busulfan treatment. Several lines of evidence suggest an alternative explanation for events in the bluebird bio trial, including that SCD population studies show an increased relative, but a low absolute, risk of AML/MDS. We propose a new hypothesis: after gene therapy for SCD, the stress of switching from homeostatic to regenerative hematopoiesis by transplanted cells drives clonal expansion and leukemogenic transformation of preexisting premalignant clones, eventually resulting in AML/MDS. Evidence validating our hypothesis will support prescreening individuals with SCD for preleukemic progenitors before gene therapy. While presumed viable, safe strategy has been implemented to resume gene therapy in adults with severe SCD, reasonable alternative curative therapy should be considered for children and adults with severe SCD. Currently, open multicenter clinical trials are incorporating nonmyeloablative conditioning, related haploidentical donors, and posttransplantation cyclophosphamide. Preliminary results from these trials appear promising, and National Institutes of Health-sponsored trials are ongoing in individuals with SCD using this platform., (© 2021 by The American Society of Hematology.)

Objective: The primary objective of this study was to test perceived controllability of stressors as a moderator of the association between coping and depressive symptoms in children and adolescents with sickle cell anemia (SCA)., Method: Twenty-eight children and adolescents (Mage = 11.71, SD = 4.31; 60.7% female) with SCA were enrolled. Caregivers provided reports of child and adolescent coping using the Response to Stress Questionnaire (RSQ), perceived control of stressors using the RSQ, and depressive symptoms using the Child Behavior Checklist. Children and adolescents also completed Wechsler assessments of working memory and verbal comprehension., Results: Secondary control coping (i.e., cognitive reappraisal, positive thinking, acceptance, and distraction) was a significant predictor of depressive symptoms such that greater use of secondary control coping was related to fewer reported depressive symptoms when accounting for perceived control of stress and neurocognitive variables. Furthermore, perceived control of peer-related stress was a significant moderator of the association between secondary control coping and depressive symptoms such that there was a significant negative association of secondary control coping with depressive symptoms only for low perceived control., Conclusion: Secondary control coping may be particularly helpful for reducing depressive symptoms when adolescents' peer-related stressors are perceived as uncontrollable. Interventions to reduce internalizing problems in this population should consider teaching children and adolescents secondary control coping skills in addition to skills in identifying uncontrollable sources of stress., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Sickle cell disease is associated with progressive and increased neurological morbidity throughout the lifespan. In people with sickle cell anaemia (the most common and severe type of sickle cell disease), silent cerebral infarcts are found in more than a third of adolescents by age 18 years and roughly half of young adults by age 30 years, many of whom have cognitive impairment despite having few or no conventional stroke risk factors. Common anatomical neuroimaging in individuals with sickle disease can assess structural brain injury, such as stroke and silent cerebral infarcts; however, emerging advanced neuroimaging methods can provide novel insights into the pathophysiology of sickle cell disease, including insights into the cerebral haemodynamic and metabolic contributors of neurological injury. Advanced neuroimaging methods, particularly methods that report on aberrant cerebral blood flow and oxygen delivery, have potential for triaging patients for appropriate disease-modifying or curative therapies before they have irreversible neurological injury, and for confirming the benefit of new therapies on brain health in clinical trials., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Purpose: Individuals with sickle cell anemia experience cognitive deficits, even in the absence of cerebral infarcts or strokes. This study tested the hypothesis that elevated cerebral blood flow and oxygen extraction fraction are associated with lower executive function in individuals with sickle cell anemia., Methods: Three-Tesla brain magnetic resonance imaging was performed, including anatomic, gray matter cerebral blood flow, and global oxygen extraction fraction imaging. Executive function was measured using the working memory index from an age-appropriate Wechsler battery and tasks from the National Institutes of Health Toolbox Cognition Battery. Bivariate and multivariate models were examined (significance: P <0.05)., Results: Fifty-four participants (age range=6-31 years) with sickle cell anemia were enrolled. Hematocrit was positively related to fluid cognition, cerebral blood flow was inversely related to working memory and inhibitory control, and oxygen extraction fraction was inversely related to processing speed. Associations remained significant in multivariate analyses controlling for age, income, and infarcts., Conclusions: Elevated cerebral blood flow and oxygen extraction fraction, markers of hemodynamic impairment, are associated with deficits in executive function in individuals with sickle cell anemia.

Strokes in children with sickle cell anemia (SCA) are associated with significant morbidity and premature death. Primary stroke prevention in children with SCA involves screening for abnormal transcranial Doppler (TCD) velocity coupled with regular blood transfusion therapy for children with abnormal velocities, for at least one year. However, in Africa, where the majority of children with SCA live, regular blood transfusions are not feasible due to inadequate supply of safe blood, cost, and the reluctance of caregivers to accept transfusion therapy for their children. We describe the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria Trial [ S troke Pr evention i n N i g eria (SPRING) trial, NCT02560935], a three-center double-blinded randomized controlled Phase III clinical trial to 1) determine the efficacy of moderate fixed-dose (20 mg/kg/day) versus low fixed-dose (10 mg/kg/day) hydroxyurea therapy for primary stroke prevention; 2) determine the efficacy of moderate fixed-dose hydroxyurea for decreasing the incidence of all cause-hospitalization (pain, acute chest syndrome, infection, other) compared to low fixed-dose hydroxyurea. We will test the primary hypothesis that there will be a 66% relative risk reduction of strokes in children with SCA and abnormal TCD measurements, randomly allocated, for a minimum of three years to receive moderate fixed-dose versus low fixed-dose hydroxyurea (total n = 220). The results of this trial will advance the care of children with SCA in sub-Saharan Africa, while improving research capacity for future studies to prevent strokes in children with SCA.

Background: Prevalence and contribution of intracranial and extracranial arterial stenosis to stroke risk were assessed prospectively in children and young adults with sickle cell disease., Methods: In this cross-sectional study, children and young adults (mean = 19.4 years) with sickle cell disease underwent neurological examination, brain MRI, and magnetic resonance angiography of the head and neck. Two neuroradiologists independently recorded infarcts and arterial stenosis. Clinical features and stroke outcomes were compared between participants with and without stenosis and between children and young adults. Logistic regression analysis assessed the association of variables of interest with overt stroke and silent cerebral infarct., Results: Of 167 participants (79 children and 88 young adults), 20 (12.0%) had intracranial stenosis, all in the anterior circulation, and nine had concurrent extracranial stenosis. No participants had isolated extracranial stenosis. Participants with intracranial stenosis were more likely than those without stenosis to have an overt stroke (70% vs 5%, P < 0.001) or silent cerebral infarct (95% vs 35%, P < 0.001). Logistic regression analysis indicated that intracranial stenosis was strongly associated with overt stroke when compared with participants with silent cerebral infarct alone and strongly associated with silent cerebral infarct when compared with participants with normal brain MRI; male sex and age were also significant predictors of silent cerebral infarct., Conclusions: Intracranial stenosis was strongly associated with both overt stroke and silent cerebral infarct; prevalence of intracranial stenosis was similar to prior estimates in sickle cell disease. Extracranial stenosis without concurrent intracranial stenosis did not occur and thus could not be evaluated as an independent risk factor for stroke., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The basic model of SCD physiology states that vaso-occlusion occurs when hemoglobin S-containing red blood cells (RBC) undergo sickling before they escape the capillary into a larger vessel. We have shown that mental stress, pain and cold, and events reported by patients to trigger SCD vaso-occlusive crisis (VOC), cause rapid and significant decrease in blood flow, reducing the likelihood that RBC could transit the microvasculature before sickling occurs. However, the critical link between decrease in microvascular blood flow and the incidence of future sickle VOC has never been established experimentally in humans. Using data from centrally adjudicated, overnight polysomnograms (PSG), previously collected in a prospective multi-center cohort sleep study, we analyzed the beat-to-beat amplitudes of vasoconstriction reported by the fingertip photoplethysmogram in 212 children and adolescents with SCD and developed an algorithm that detects vasoconstriction events and quantifies the magnitude (M vasoc ), duration, and frequency of vasoconstriction that reflect the individual's inherent peripheral vasoreactivity. The propensity to vasoconstrict, quantified by median M vasoc , predicted the incidence rate of post-PSG severe acute vaso-occlusive pain events (P = .006) after accounting for age and hemoglobin. Indices of sleep-disordered breathing contributed to median M vasoc but did not predict future pain rate. Median M vasoc was not associated with vaso-occlusive pain events that occurred prior to each PSG. These results show that SCD individuals with high inherent propensity to vasoconstrict have more frequent severe acute pain events. Our empirical findings are consistent with the fundamental SCD hypothesis that decreased microvascular flow promotes microvascular occlusion., (© 2020 Wiley Periodicals LLC.)

Background: Optimal strategies for regular blood transfusion therapy are not well defined in sickle cell disease (SCD). This analysis tested the hypothesis that in the first of year of regular transfusions, when chelation therapy use is minimal, automated exchange transfusion would be the superior method for attenuating the rise in ferritin levels compared to simple and manual exchange transfusions., Study Design and Methods: The Silent Cerebral Infarct Multi-Center Clinical Trial randomly allocated children with SCD and silent cerebral infarcts to receive standard care or regular transfusions with a target pre-transfusion HbS concentration ≤ 30% and minimum hemoglobin level > 9.0 g/dL. Participants with at least nine transfusions and sufficient ferritin testing in the first year of the trial were included in a planned secondary analysis. Ferritin levels by the end of the first study year were compared between participants receiving automatic exchange transfusion, manual exchange transfusion, and simple transfusion., Results: A total of 83 participants were analyzed. During the first year of the study, 75.9% of the participants had >80% of transfusions via one transfusion method. At baseline no significant differences in ferritin levels were observed in the three transfusion groups (p = 0.1). After 1 year of transfusions the median (interquartile range) ferritin levels in the simple transfusion (n = 40), manual exchange transfusion (n = 34) and automatic exchange transfusion (n = 9) groups were 1800 ng/mL (1426-2204 ng/mL), 1530 ng/mL (1205-1805 ng/mL), and 355 ng/mL (179-579 ng/mL), respectively (p < 0.001)., Conclusion: Automated exchange transfusion, when compared to other transfusion methods, is the optimal transfusion strategy for attenuating increase in ferritin levels in children with SCD., (© 2020 AABB.)

Severe anaemia, defined as haemoglobin level < 6·0 g/dl, is an independent risk factor for death in individuals with sickle cell disease living in resource-limited settings. We conducted a cross-sectional study of 941 children with sickle cell anaemia, who had been defined as phenotype HbSS or HbSβ 0 thalassaemia, aged five to 12 years, and were screened for enrollment into a large primary stroke prevention trial in Nigeria (SPRING; NCT02560935). The main aim of the study was to determine the prevalence and risk factors for severe anaemia. We found severe anaemia to be present in 3·9% (37 of 941) of the SPRING study participants. Severe anaemia was significantly associated with the lower educational level of the head of the household (P = 0·003), as a proxy for poverty, and a greater number of children per room in the household (P = 0·004). Body mass index was not associated with severe anaemia. The etiology of severe anaemia in children living with sickle cell anaemia in Nigeria is likely to be multifactorial with an interplay between an individual's disease severity and other socio-economic factors related to poverty., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Recurrent ischemic priapism is a common complication of sickle cell disease (SCD). We assessed the burden, characteristics, and types of priapism, including sexual dysfunction, in a cohort of men with and those without SCD, to test the hypothesis that sexual dysfunction is more prevalent in men with SCD. In Kano, Nigeria, we conducted a comparative cross-sectional survey that included 500 and 250 men 18 to 40 years of age, with and without SCD, respectively. The survey used the Priapism Questionnaire and the International Index of Erectile Function for sexual function assessment. All eligible participants approached for the study gave informed consent and were enrolled. Stuttering and major priapism were defined based on the average duration of priapism experiences that lasted ≤4 and >4 hours, respectively. The prevalence of priapism was significantly higher in men with SCD than in those without it (32.6% vs 2%; P < .001). Stuttering priapism accounted for 73.6% of the priapism episodes in men with SCD. Nearly 50% of the participants with SCD-related priapism had never sought medical attention for this complication. The majority of the men with SCD-related priapism used exercise as a coping mechanism. Priapism affected the self-image of the men with SCD, causing sadness, embarrassment, and fear. The percentage of the men with SCD who had erectile dysfunction was more than twofold higher than that of those without SCD who had erectile dysfunction (P = .01). The men with SCD had a higher prevalence of priapism and sexual dysfunction than the men without SCD., (© 2020 by The American Society of Hematology.)

Cysteinyl leukotrienes (CysLTs) are lipid mediators of inflammation. In patients with sickle cell disease (SCD), levels of CysLTs are increased compared with controls and associated with a higher rate of hospitalization for pain. We tested the hypothesis that administration of the CysLT receptor antagonist montelukast would improve SCD-related comorbidities, including pain, in adolescents and adults with SCD. In a phase 2 randomized trial, we administered montelukast or placebo for 8 weeks. The primary outcome measure was a >30% reduction in soluble vascular cell adhesion molecule 1 (sVCAM), a marker of vascular injury. Secondary outcome measures were reduction in daily pain, improvement in pulmonary function, and improvement in microvascular blood flow, as measured by laser Doppler velocimetry. Forty-two participants with SCD were randomized to receive montelukast or placebo for 8 weeks. We found no difference between the montelukast and placebo groups with regard to the levels of sVCAM, reported pain, pulmonary function, or microvascular blood flow. Although montelukast is an effective treatment for asthma, we did not find benefit for SCD-related outcomes. This clinical trial was registered at www.clinicaltrials.gov as #NCT01960413., (© 2020 by The American Society of Hematology.)

Objective: To provide a comprehensive quantitative review of biological, environmental, and behavioral correlates across domains of cognitive function in sickle cell disease (SCD)., Methods: Forty-seven studies were identified in PubMed, MedLine, and PsycINFO involving 2573 participants with SCD., Results: Meta-analytic findings across all identified samples indicate that hemoglobin and hematocrit were positively correlated with Full Scale IQ [FSIQ; r = .15, 95% confidence interval (CI) = .10 to .21], language and verbal reasoning (r = .18, 95% CI = .11 to .24), and executive function (r = .10, 95% CI = .01 to .19) with small effects and significant heterogeneity. Transcranial Doppler velocity was negatively associated with visual spatial and perceptual reasoning (r = -.18, 95% CI = -.31 to -.05). Socioeconomic status was positively associated with FSIQ (r = .23, 95% CI = .17 to .28), language and verbal reasoning (r = .28, 95% CI = .09 to .45), visual spatial and perceptual reasoning (r = .26, 95% CI = .09 to .41), and executive function (r = .18, 95% CI = .07 to .28) with small to medium effects. Finally, total behavioral problems were negatively associated with FSIQ (r = -.12, 95% CI = -.21 to -.02) such that participants with lower FSIQ exhibited greater behavioral and emotional problems., Conclusions: Findings provide evidence for biological, environmental, and psychosocial corelates across multiple domains of cognitive function in SCD. More research on more specific cognitive domains and psychosocial correlates is needed in addition to assessments of interactional models among risk factors., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)