Recent studies have reached opposing conclusions about whether clonal hematopoiesis (CH) is increased or decreased in patients with sickle cell disease (SCD). Given that CH is typically age-related, its presence in children with SCD could offer unique insights into early-life mutagenesis and disease-related stressors. We tested the primary and secondary hypotheses, that children with SCD would have a higher prevalence of CH when compared to age, sex, and race matched children without SCD; and children with hydroxyurea would have a higher CH prevalence than children not treated with hydroxyurea. To address this, we conducted a cross-sectional study in two independent cohorts of children, ages 0-18 years, with SCD (n=1,025 and n=1,293, respectively) and a 2,957-person matched comparison group. Using a highly sensitive, error-corrected sequencing assay capable of detecting CH at a variant allele frequency ≥ 0.5%, we found that children with SCD have a significantly higher prevalence of CH in relation to the comparison group (odds ratio (OR)=4.2, p=7.4x10-13). Additionally, CH was not associated with exposure to hydroxyurea therapy (OR=0.76, p=0.44).

ABSTRACT:We conducted a pooled analysis to evaluate the effectiveness of hydroxyurea (HU), chronic blood transfusion (CBT), myeloablative allogeneic hematopoietic stem cell transplant (HCT) with a matched related donor, and revascularization surgery (RVS) in children with sickle cell anemia (SCA). We compared the interventions with no therapy for primary and secondary stroke prevention. The Medline and EMBASE databases were searched for articles that included ≥6 patients published before January 2025. Four reviewers reviewed all studies to arrive at a consensus assessment. The stroke rates (per 100 person-year) for primary stroke prevention in children with transcranial Doppler measurement ≥200 cm/s were as follows: no therapy, 10.7; after initial HU, 1.0; and after initial CBT, 1.0. The stroke recurrence rates for secondary stroke prevention per 100 person-years were 19.6 after no therapy, 3.5 after initial HU, 2.7 after initial CBT, 1.0 after HCT, and 3.3 after RVS. Neither the HCT nor the RVS study adjusted for the time-dependent stroke recurrence rate, resulting in an overestimation of their therapeutic benefit compared to the stroke recurrence rates before the intervention. In low- and middle-income countries (LMICs), where ∼99% of all children with SCA are born, the stroke recurrence rate in untreated children in the first year was 36.4 to 51.4 strokes per 100 person-years, in 2 studies; in the only randomized controlled trial for secondary stroke prevention with initial HU (SPRING trial n = 101), 38% (5 of 13) of the deaths occurred within the first year. For children in LMICs where local HU costs <$0.20 per day, HU is a practical, inexpensive option for primary and secondary stroke prevention.

Introduction Malnutrition in children with sickle cell anemia (SCA) is associated with higher rates of hospitalizations and early mortality, particularly in low-income settings such as northern Nigeria. However, there are no established guidelines for the optimal management of malnutrition in children with SCA, and key parameters such as caloric targets and treatment duration have yet to be defined. Our feasibility trial demonstrated that nutritional supplementation with ready-to-use therapeutic food (RUTF), with or without moderate fixed-dose hydroxyurea (20 mg/kg/day), is safe and supports weight gain in children with SCA and severe malnutrition (body mass index [BMI] z-score < −3.0) (Abdullahi et al., Blood Advances, 2023). However, 61% (n = 66 of 108) of children remained severely malnourished after the initial 12-week intervention. We therefore conducted a 12-week, single-arm extension to assess whether increasing caloric intake and treatment duration would improve recovery and to identify predictors of nutritional response. Methods We conducted a 12-week, single-arm extension of a multicenter randomized controlled feasibility trial (NCT03634488) evaluating nutritional management in children aged 5–12 years with SCA in northern Nigeria. Children who remained severely malnourished (BMI z-score < −3.0) after the initial 12-week intervention were enrolled in the extension phase. Unlike the parent trial, which provided RUTF as a supplement, the extension phase provided RUTF as a complete nutritional replacement at 2,000–2,500 kcal/day. All participants received moderate fixed-dose hydroxyurea. Follow-up visits occurred at weeks 4, 8, and 12 of the extension (corresponding to weeks 16, 20, and 24 since initial enrollment). The primary outcome was nutritional recovery, defined as BMI z-score ≥ −3.0. Results Participant Characteristics: Of 108 children with SCA and severe malnutrition who completed the initial 12-week intervention, 66 (61%) remained severely malnourished (BMI z-score < −3.0) and were enrolled in the 12-week extension phase. Change in Nutritional Status from 12 to 24 Weeks: Among the 66 children enrolled in the extension, 11 (17%) achieved a BMI z-score of > -3.0 at week 24. The mean change in BMI z-score during the 12-week extension was 0.13 (SD 0.47). In a linear regression model, female sex was associated with a greater improvement in BMI z-score from weeks 12 to 24 (β = 0.262, p = 0.032). No significant associations were observed for age, hemoglobin concentration, treatment group, or the 12-week BMI z-score. Among the extension cohort, in a penalized logistic regression model, a higher 12-week BMI z-score remained associated with recovery at 24 weeks (OR = 14.44, p = 0.039). Predictors of Treatment Success: Children who recovered by 12 weeks had greater early weight gain at 4 weeks from enrollment than those recovering by 24 weeks, with the smallest early gains seen in children who never recovered (p < 0.001). Logistic regression analysis, including all 108 participants (combining the initial and extension phases), revealed that younger age (OR = 1.39, p = 0.006) and early change in BMI z-score during the first 4 weeks were associated with treatment success (OR = 12.38, p < 0.01). Conclusions Baseline BMI z-score and early weight gain during nutritional intervention are important indicators of treatment response. A 4-week progress assessment may help identify children who may benefit from closer clinical evaluation and address socioeconomic barriers. While early weight gain predicts recovery, our findings and prior work in younger children without SCA suggest that early non-response is not a definitive indicator of treatment failure (Cazes et al., PLOS Glob Public Health, 2025). However, even with extended high-calorie RUTF, only a small proportion (17%) of children recovered, suggesting that delaying treatment intensification until 12 weeks may be too late for many. Because both clinical and socioeconomic factors influence malnutrition in children with SCA, optimizing outcomes will require tailored interventions. Our ongoing and future work focuses on integrating nutritional education and vocational training into malnutrition prevention and treatment programs for children with SCA.

Moyamoya is a non-atherosclerotic intracranial steno-occlusive condition that places patients at high risk for ischaemic stroke. Randomized trials of surgical revascularization demonstrating efficacy in ischaemic moyamoya have not been performed, and as such, biomarkers of parenchymal haemodynamic impairment are needed to assist with triage and evaluate post-surgical response. In this prospective study, we test the hypothesis that parenchymal cerebrovascular reactivity (CVR) metrics in response to a fixed-inspired 5% carbon dioxide challenge correlate with recent focal ischaemic symptoms. Hypercapnic reactivity blood oxygenation level-dependent MRI (echo time = 35 ms; spatial resolution = 3.5 x 3.5 x 3.5 mm) and catheter angiography assessments of cortical reserve capacity and vascular patency, respectively, in moyamoya disease and syndromic participants (n = 73) were performed in sequence. Cerebrovascular reactivity uncorrected for response time (CVRRAW) was quantified, and time regression analyses were applied to quantify maximum cerebrovascular reactivity (CVRMAX) and cerebrovascular reactivity response time (CVRDELAY). Symptomatology was categorized by a stroke neurologist by hemisphere: symptomatic (lateralizing ischaemic symptoms < 6 months) or asymptomatic (no ischaemic symptom history). Values are presented as median [interquartile range]; logistic regression assessed the association of cerebrovascular reactivity metrics with symptoms, controlling for age and sex. A total of 109 hemispheres, including 39 symptomatic and 70 asymptomatic hemispheres, met inclusion criteria. Symptomatic hemispheres displayed reduced CVRRAW (P < 0.01) (symptomatic = 0.45 [0.28-0.70] z-statistic/Delta EtCO2 versus asymptomatic = 0.67 [0.44-0.98] z-statistic/Delta EtCO2), lengthened CVRDELAY (P < 0.001) (symptomatic = 47.6 [37.7-57.0] seconds versus asymptomatic = 37.7 [30.4-46.4] seconds), and reduced CVRMAX (P = 0.037) (symptomatic = 1.31 [0.99-1.94] z-statistic/Delta EtCO(2 )versus asymptomatic = 1.64 [1.29-2.12] z-statistic/Delta EtCO2). CVRDELAY (P < 0.001) was found to be significantly related to age in asymptomatic hemispheres (0.33-unit increase/year). Of assessed measures, the receiver operating characteristic curves suggest that CVR(DELAY )is associated most closely with recent ischaemic symptoms (P < 0.001). Findings support that cerebrovascular reactivity metrics are uniquely altered in hemispheres with recent ischaemic symptoms, further motivating their utilization as biomarkers of ischaemic symptomatology and potential treatment efficacy in moyamoya disease and syndrome.

Introduction Children with sickle cell anaemia (SCA) in Sub-Saharan Africa face a higher risk of malnutrition, increasing morbidity and mortality rates. We conducted a randomised controlled feasibility trial to treat children aged 5–12 years with SCA and severe acute malnutrition (body mass index Z-score <−3.0) in Kano, Nigeria (n=108). Despite high rates of ready-to-use therapeutic food (RUTF) consumption, as measured by returned RUTF sachets, suboptimal weight gain was observed, possibly due to widespread sharing of RUTF. In this ancillary study, we aimed to identify factors influencing adherence to the RUTF.Methods We conducted seven focus group discussions with 55 caregivers of trial participants in the two sites participating in the trial in Kano, Nigeria. We analysed transcripts using a hierarchical coding system and an iterative inductive-deductive approach informed by Social Cognitive Theory and the biopsychosocial model.Results An interplay between person-level and contextual factors influenced adherence to RUTF. Caregivers’ beliefs about nutrition and malnutrition changed when they saw positive changes in their child’s health, increasing their motivation to adhere to RUTF. The male head of household and cultural beliefs increased adherence to RUTF for some mothers and were a barrier to adherence for others. Barriers to adherence included financial hardship, along with cultural norms and religious practices related to communal eating and sharing food. Caregivers employed strategies to promote adherence, including modifying food preparation and food storage practices and controlling meal timing and meal participants. Some households maintained or provided more food, while others reduced it and reallocated their savings.Conclusion For older children with SCA and severe acute malnutrition living in Nigeria, social-cultural context, family dynamics and strategic modifications influence RUTF adherence. Insights from this study may guide the development of tailored strategies, family education and empowerment initiatives to enhance adherence to malnutrition interventions for children with SCA.Trial registration number SAMS trial (NCT03634488).

BACKGROUND:In this planned ancillary analysis of our completed clinical trial, we hypothesized that among older children with sickle cell anemia (SCA) and severe acute malnutrition, those with higher levels of food insecurity would have lower end-of-trial body mass index (BMI) z-scores compared to their peers with SCA and lower levels of food insecurity. PROCEDURE:Data from 108 children who completed the feasibility trial for managing severe acute malnutrition in older children with SCA in Nigeria were analyzed. Children aged 5-12 years old with severe acute malnutrition (BMI z-score of <-3.0) were randomly allocated to receive either supplemental ready-to-use therapeutic food (RUTF) alone or RUTF with moderate-dose hydroxyurea (20 mg/kg/day). Caregivers completed the United States Household Food Security Survey Module to measure food security. We focused on the childhood section for its accuracy in assessing food security in older children. Higher scores (0-8) indicate greater food insecurity. We constructed multivariable linear regression models to estimate the association between childhood food insecurity and BMI z-scores at baseline and endpoint. RESULTS:Most participants were food insecure, with 55% (n = 59) and 34% (n = 37) having low and very low food security, respectively. Higher scores on the continuous food security measure, indicating lower food security, were associated with lower BMI z-scores at both study entry (β = -0.05, p = 0.047) and after malnutrition treatment (β = -0.07, p = 0.016). CONCLUSIONS:Among severely malnourished children with SCA, lower childhood food security scores are associated with an adverse treatment response, reflected by a lower BMI z-score at the trial's end. URL AND TRIAL IDENTIFICATION NUMBER:NCT03634488, https://clinicaltrials.gov/study/NCT03634488.

Best treatment approaches for malnutrition in children with sickle cell anemia (SCA) remain underexplored. We hypothesized that (1) children with SCA (CwSCA) enrolled in a malnutrition trial alongside their non-SCA siblings would experience greater nutritional improvements than those without an enrolled sibling and (2) enrolled malnourished siblings without SCA would have higher baseline nutritional status and greater improvements in nutritional status than CwSCA. We tested these hypotheses as part of a randomized controlled feasibility trial at 2 medical centers in northern Nigeria, a low-resource setting with a significant burden of malnutrition and SCA. Participants included 108 CwSCA (5-12 years) with severe malnutrition (body mass index (BMI) z-score <-3.0), 21 of whom had an enrolled sibling (Sibling) with severe malnutrition but without SCA (5-12 years, n = 22). All participants received daily ready-to-use therapeutic food (RUTF) for 12 weeks. CwSCA with a Sibling had a higher mean BMI z-score change than CwSCA without a Sibling (0.8 vs 0.4, P = .003). The mean baseline BMI z-scores for the CwSCA (-3.7) were comparable to those of their Siblings (-3.6; P = .47). Improvement in BMI z-score was similar between CwSCA and their malnourished siblings without SCA. In conclusion, our findings suggest that including malnourished siblings in nutritional interventions enhances outcomes for CwSCA. We postulate that the additional calories delivered by co-treating siblings reduce intrahousehold competition for RUTF, thereby allowing CwSCA to consume a greater share of the therapeutic food. This trial was registered at clinicaltrials.gov (NCT03634488).

Stroke in children with sickle cell disease (SCD) is associated with significant morbidity and mortality. Transcranial Doppler (TCD) velocities, specifically time-averaged maximum mean velocity (TAMMV), are critical for stroke risk stratification. Variability in TCD velocity measurements across different machines and ultrasonographers complicates clinical decision-making. Using a phantom Doppler flow machine generating a fixed flow, we evaluated four non-imaging and one imaging TCD machine against a reference TAMMV of 191 cm/s. All machines demonstrated high precision but varied accuracy, with mean velocities ranging from 169 to 189 cm/s. All non-imaging machines underestimated the TAMMV (p < 0.001). The imaging TCD machine also underestimated the velocity, even after a standard adjustment of adding 15 cm/s to the velocity (p < 0.001). Based on the results of the local non-imaging TCD machines accuracy, the northern Nigerian pediatricians agreed on the following threshold for primary stroke prevention for all non-imaging TCD machines: two independent ultrasonographers' velocities for any velocity ≥ 180 cm/sec and < 220 cm/sec or one TCD velocity > 200 cm/sec.

BACKGROUND:To identify predictors of drug-resistant epilepsy (DRE) in children with a history of perinatal ischemic stroke (PIS). METHODS:This single-center retrospective observational study analyzed children with PIS using international classification of diseases, ninth revision (ICD-9) codes, institutional databases, medical records, and neuroimaging from 2012 to 2023. DRE was defined as seizures unresponsive to ≥2 antiseizure medications. The Pediatric Stroke Outcome Measure (PSOM) was retrospectively scored. RESULTS:Of 96 children with PIS, 56% developed epilepsy and 20 (21%) had DRE. Median age at the last visit was 7.9 years (interquartile range, 3.1-11.7 years.) Among those with DRE, 70% had presumed perinatal stroke and 30% had symptomatic neonatal stroke. PSOM scores differed by epilepsy status: median PSOM was 2.5 for DRE, 1.8 for non-DRE epilepsy and 1.0 for children without epilepsy; paired comparisons for neurological outcome found a difference between those with DRE compared to those without epilepsy (P < 0.001). Hippocampal volume reduction was the only predictor of DRE (odds ratio 6.45, 95% confidence interval 1.80-23.16, P = 0.004) in a multivariable model including sex, neonatal seizures, and total PSOM. Children with DRE tried a median of four antiseizure medications after the newborn period, and 13 (65%) underwent epilepsy surgery. Favorable outcomes (seizure-free or >90% reduction) were seen in 62% postsurgery, including three focal resections, four functional hemispherectomies, and one posterior quadrant disconnection. CONCLUSIONS:Hippocampal volume reduction is a strong predictor of DRE following PIS. Epilepsy and DRE were more common in older children. Hemispherectomy and focal resections were associated with favorable seizure outcomes.

Introduction Malnutrition is a significant cause of morbidity and mortality for children living in low- and middle-income countries (LMICs). For older children (5-12 years old) with sickle cell anemia (SCA), malnutrition (weight for age Z-score <-1.0) is associated with premature death (Klein et al., Blood Advances, 2023). Despite the high prevalence of malnutrition in children with SCA living in LMICs, no studies have assessed nutrition education and vocational training for caregivers of children with SCA and malnutrition. In non-SCA populations, vocational training has been shown to improve income and employment, while nutrition education enhances caregiver knowledge and feeding practices. We tested the feasibility of a novel program providing both nutrition education and vocational training to caregivers of older children with SCA and severe malnutrition. Methods We conducted an ancillary feasibility cohort study nested within our trial for the management of severe acute malnutrition in children aged 5-12 years old with SCA (SAMS trial, NCT03634488) in Kano, Nigeria. Caregivers of children enrolled in the SAMS trial were invited to participate in nutrition education and vocational training. The primary outcomes for this feasibility study were recruitment, attendance, and retention to the nutrition education and vocational training sessions for caregivers of children participating in the SAMS trial. Caregivers attended three full-day nutrition education sessions. Each caregiver was accompanied by a designated partner of their choosing who played an influential role in the child's dietary intake. Sessions, led by a dietician, included: (1) introduction to nutrition needs in children with SCA, preparation and preservation of local nutrient-rich foods, and feeding practices; (2) demonstration of a high-protein, high-calorie formula consisting of millet, soybeans, and peanuts; and (3) caregiver-led practical preparation. Caregivers also attended three separate vocational sessions led by a local trainer and two assistants. During these sessions, caregivers learned income-generating skills of their choice and received training on household budgeting. Pre-intervention questionnaires assessed caregivers' baseline nutrition knowledge, feeding practices, household income, and food purchasing habits. Post-intervention questionnaires, completed at the final visit and four-week follow-up, evaluated the implementation of nutrition education and perceptions and impact of vocational training. Results The enrollment and retention rates were both 100% (n = 27). Attendance was 100% among caregivers (n = 27) and 98.8% among designated partners (n = 27), with one designated partner missing the third nutrition visit. Most caregivers were mothers, participating in 79 of 81 nutrition visits and 80 of 81 vocational training sessions. In three sessions, a foster parent or a relative substituted for the mother. At baseline, 54% of caregivers (13 of 24) were not employed. The most frequently selected designated partner was the child's sister (n = 12 of 27, 44%), followed by the child's aunt/uncle (n = 7 of 27, 25%). Following the intervention, 100% of caregivers (n = 27 of 27) reported incorporating new foods into their child's diet, and 82% (n = 22 of 27) reported implementing the nutrition education daily over the past seven days. Among those with available data, 95% (n = 20 of 21) indicated that vocational training positively influenced their household income. Of these, 80% (n = 16 of 20) reported using income from vocational activities to purchase food, and 45% (n = 9 of 20) reported generating additional income because of implementing skills learned during vocational training. Conclusion Incorporating a combined nutrition education and vocational training program for caregivers of children with SCA is feasible based on the high recruitment, attendance, and retention rates. Caregivers showed meaningful improvements in knowledge, nutrition-related behaviors, and financial capacity, which can translate into better dietary care for children with SCA. This training was completed locally and could be repeated with local funding or even by an SCA community-based organization, and may serve as a model for future research on malnutrition in understudied populations. Larger studies with longer follow-up are warranted to assess its impact on health outcomes.

ABSTRACT:Pregnant women with sickle cell disease (SCD) are at higher risk of SCD-related morbidity and mortality than after pregnancy. Existing data from health care use suggest increased acute vaso-occlusive pain events during pregnancy, particularly in the third trimester and puerperium (6 weeks after childbirth). Many acute vaso-occlusive pain events are managed at home and may not capture the full scope of pregnancy-related morbidity. To date, to our knowledge, no studies have examined daily self-reported acute vaso-occlusive pain events during pregnancy and after pregnancy to assess their occurrence at home. Based on self-report using an electronic diary (eDiary) mobile application, we tested the primary hypothesis that self-reported acute SCD pain events during pregnancy (third trimester to puerperium) are greater than after pregnancy (beginning of 6, to end of 9 months, after childbirth).In a tertiary care hospital in Ghana, we approached 42 pregnant women with SCD at ≤16 weeks gestation to participate in the prospective study; 40 of 42 (95.2%) pregnant women with SCD agreed to participate; only 33 participants completed 71.5% of expected eDiary mobile application entries during and after pregnancy. The eDiary data revealed a 1.85-fold higher self-reported acute SCD pain incidence rate during pregnancy than after pregnancy (0.74 vs 0.40 events per person-month; P < .001). Based on the eDiary mobile application, we demonstrated a higher rate of self-reported acute SCD pain during pregnancy than after pregnancy. Preconception counseling for women with SCD should address the expected increase above their baseline in acute vaso-occlusive pain events, particularly in the third trimester and puerperium.

OBJECTIVE Both direct and indirect surgical revascularization techniques are commonly applied for the treatment of moyamoya disease and syndrome; however, responses can be heterogeneous and efficacy in the context of ischemic disease is not yet formally known from randomized clinical trials. Here, a prospective, longitudinal interventional study was performed to test the hypothesis that presenting 1) parenchymal cerebrovascular reactivity (CVR) and 2) CVR response times portend hemodynamic improvements after direct and indirect revascularization. METHODS Catheter angiography and hypercapnic blood oxygenation–weighted 3-T MRI (spatial resolution 3.5 × 3.5 × 3.5 mm, repetition time 2000 msec) were acquired before and 11.0 ± 7.9 months and 12.6 ± 6.9 months after surgery, respectively. In response to a 5% fixed-inspired CO2 respiratory challenge, time regression analyses were utilized to quantify maximal cerebrovascular reactivity (CVRmax) and time to reach maximal cerebrovascular reactivity (CVRdelay) to test the overarching hypothesis that presurgical measures predicted postsurgical CVRmax increases and CVRdelay reductions. Age, sex, surgical type, and preoperative impairment were considered as relevant explanatory variables in the regression analysis (significance criterion p < 0.05). RESULTS A total of 47 operative hemispheres (32 indirect-only and 15 direct or combined direct-indirect revascularization) from 30 adult patients (median [range] age 43 [20–59] years) were evaluated. Direct/combined versus indirect revascularized brain hemispheres were matched for age (44.1 ± 11.1 vs 44.7 ± 13.8 years, p = 0.864), prior infarct (92.9% vs 92.6%, p = 0.976), and Suzuki stage within 1 stage on the 6-point staging scale (4.1 ± 0.7 vs 3.4 ± 0.6). Across all hemispheres and surgical procedures, CVRmax increased (p = 0.022) and CVRdelay decreased (p = 0.009) after surgery; however, responses varied considerably across hemispheres and surgical procedures. On multiple regression analysis, extent of preoperative impairment, quantified as preoperative CVRmax and moderated by the type of surgery performed, was an indicator of intervention-induced outcome in hemodynamics (p = 0.015). No effect of preoperative CVRdelay or age was found for outcomes. CONCLUSIONS The findings confirm heterogeneous CVR responses approximately 1 year after revascularization across patients, albeit moderated by type of revascularization. Of the variables considered, lower presurgical CVR provided the most significant indicator of the likelihood of postsurgical hemodynamic improvement.

Sickle cell anemia (SCA) leads to reduced physical functioning and cardiopulmonary fitness. Prior studies suggest that airway hyperresponsiveness to bronchoprovocation testing is common in SCA, but the prevalence of exercise-induced bronchospasm (EIB) is understudied. We hypothesized that EIB is more common in children with SCA than in controls. Non-asthmatic subjects 10-21 years old with SCA and race-matched controls underwent (1) maximal Cardiopulmonary Exercise Testing (CPET) by cycle ergometry and (2) a Controlled Intensity Interval Test (CIIT) consisting of eight bouts of constant workload cycling, randomized to 50% (moderate) or 70% (vigorous) of peak workload. Spirometry was performed pre/post CPET and CIIT. Multivariable logistic regression models tested associations between SCA status and EIB in response to CPET and CIIT. Compared to controls, subjects with SCA demonstrated lower hemoglobin, reduced baseline spirometry values, and decreased CPET maximal workload. Baseline lower airway obstruction and completion rates for CPET and CIIT were similar between groups. No adverse events occurred. The percentage of participants who met criteria for EIB did not differ between subjects and controls after CPET (21% vs. 26%, p = 0.537) or CIIT (32% vs. 17%, p = 0.126). In adjusted models, SCA status was not associated with EIB after CPET or CIIT. EIB was not more common in subjects with SCA versus controls after maximal CPET or submaximal exercise challenge of longer duration. Further research is needed to inform the development of exercise guidelines and to better understand the effects of exercise on airway dynamics in SCA. Trial Registration: ClinicalTrials.gov identifier: NCT03653676.

IntroductionNigeria has the highest proportion of children with sickle cell anemia (SCA) globally; without transcranial Doppler screening and ongoing treatment (regular blood transfusions or hydroxyurea therapy), 10% will have a stroke in childhood. In low-resource settings, training to recognize and prevent strokes in children with SCA is vital. A sustainable Sickle Cell Disease Stroke Prevention Teams program was established, as part of clinical trials, to address the need for stroke care in northern Nigeria. We describe our health professional stroke training curriculum and specific application to detect strokes in clinical trials in low-resource settings.MethodsChildren aged 5–12 and 2–16 years with SCA in northern Nigeria were enrolled in the SPRING and SPRINT primary and secondary stroke prevention trials, respectively. The primary outcome measure in both trials was a clinical stroke based on the World Health Organization definition. Non-neurologist physicians were trained in-person and via video lectures regarding stroke recognition, performing neurological examinations using the adapted Pediatric NIH Stroke Scale, and acute stroke care. Central stroke adjudicators, two pediatric neurologists, reviewed the case report forms and recorded videos of the neurological examinations.ResultsSix physicians completed the curriculum at three sites and were certified to detect strokes. Of 20 children with suspected stroke, 8 and 11 children had acute initial or acute recurrent strokes confirmed in the SPRING (N = 220) and SPRINT (N = 101) trials, respectively. The concordance rate between local stroke diagnoses and the central stroke adjudication process was 95% (19 of 20). One child presented with non-specific symptoms and hypertonia and was mislabeled locally as an acute stroke.DiscussionA curriculum to train healthcare providers in pediatric acute stroke recognition and care in a low-resource setting is feasible and sustainable. We successfully identified strategies for task shifting from a single pediatric neurologist in the region to multiple non-neurologist physicians.

BACKGROUND AND OBJECTIVES:Understanding age-related changes in cerebral blood flow (CBF, rate of blood delivery to brain tissue) in sickle cell anemia (SCA) is a prerequisite to incorporating CBF as a marker of brain health. CBF decreases from school-age through adulthood in nonanemic people. In SCA, CBF is generally increased to compensate for anemia, but knowledge of age-related norms is limited. We hypothesized that age-related CBF trajectories differ for SCA vs nonanemic healthy persons: CBF increases from childhood to early adulthood in SCA to compensate for reduced blood oxygen content and then plateaus because of reduced vasodilatory capacity with older age. METHODS:Children and adults with SCA and race-matched controls (hemoglobin [Hb] AA) aged 6-45 years were enrolled in an observational cross-sectional study from 2014 to 2023 at an academic and community health center. History of overt stroke or arterial stenosis >50% were exclusions. Brain MRIs were performed at 3T with arterial-spin-labeling measurements of gray matter CBF. Regression analyses assessed how age, imaging markers of ischemia, Hb, and arterial oxygen saturation (SpO2) related to CBF. RESULTS:In 192 Black participants with SCA (N = 126; mean age = 18.7 ± 9.0 years, 52.4% female) or without SCA (N = 66; mean age = 22.4 ± 9.7 years, 54.5% female), total Hb was lower in SCA (mean Hb = 8.9 ± 1.3 g/dL) vs control (mean Hb = 13.4 ± 1.5 g/dL) participants (p < 0.001) and did not differ with age in the SCA group. SpO2 was reduced in SCA (median SpO2 = 96%; interquartile range [IQR] = 94-97.4%) vs controls (median SpO2 = 98%, IQR = 97-99%, p < 0.001). In SCA participants, SpO2 was lower in adults (median SpO2 = 95%, IQR = 94%-97%, p = 0.001) compared with children (SpO2 = 96.5%, IQR = 95%-98.2%). Regression analyses, including an interaction between age and group (SCA vs control), showed that CBF increases in SCA by 5.03 mL/100 g/min per decade (95% CI 1.70-8.37) and plateaus at approximately age 30-35 years. In controls, CBF decreased by -5.20 mL/100 g/min per decade (95% CI -8.96 to -1.94). DISCUSSION:The divergent age dependency of CBF between SCA and non-anemic persons may be explained by a gradient of increasing CBF with age required to compensate for reductions in blood oxygen content in SCA, with possible exhaustion of cerebral vasodilatory abilities in the fourth decade of life. Longitudinal studies are needed.

ABSTRACT:Recurrent ischemic priapism is a common complication of sickle cell anemia (SCA) and is associated with devastating physical and psychosocial consequences. All previous trials for priapism prevention have failed to demonstrate clear efficacy. We conducted a randomized, controlled, double-blind phase 2 feasibility trial comparing fixed moderate-dose hydroxyurea plus placebo (usual-care arm) with fixed moderate-dose hydroxyurea plus tadalafil (experimental arm) in 64 males (aged 18-40 years) with at least 3 episodes of SCA-related priapism in the past 12 months. Priapism data were obtained via daily text messages to the participants. The trial's primary outcome measures were 100% recruitment, 98.4% retention, and 93.5% adherence rates. Over a median of 10 months (interquartile range, 3-12), 2.5 and 3.02 priapism events per participant-month were recorded in the usual-care and the experimental arms, with an incidence rate ratio of 0.8 (95% confidence interval [CI], 0.3-1.9; P = .654). The rates of serious adverse events (P = .999) and hospitalization (P = .289) were similar in the 2 arms. Sperm concentration, motility, and normal morphology significantly decreased on hydroxyurea therapy but recovered to prehydroxyurea levels 3 months after therapy cessation. Post hoc, single-arm, pre-post analysis showed a 58.3% priapism incidence rate reduction in the usual-care arm (5.9-2.5 events per month; difference, 3.4; 95% CI, 1.1-5.8; P = .005) and a 66.3% priapism reduction in the experimental arm (8.9-3.02 events per month; difference, 5.9; 95% CI, 3.4-8.5; P < .001) compared with the prerandomization rates. A randomized controlled trial for priapism prevention is feasible in men with SCA. This trial was registered at www.clinicaltrials.gov as #NCT05142254.