Nancy S. Green’s research while affiliated with Translational Genomics Research Institute and other places

Introduction Academic proficiency is crucial for advancing learning goals, school advancement, and future economic security. Children with sickle cell anemia (SCA) in sub‐Saharan Africa (SSA) may be at risk of disease‐associated learning difficulties. Limited data exist on this topic among school‐age children in the region. We aimed to assess academic proficiency in a sample of children with SCA in Uganda compared with unaffected controls. Methods This cross‐sectional study was conducted in Kampala, Uganda. Participants were school‐going children with SCA, aged 6–12 years, attending Mulago Hospital SCA Clinic, and age‐matched sibling controls without SCA. Academic proficiency was assessed by the Wide Range Achievement Test, Fourth Edition (WRAT4) using outcome measures of spelling, mathematical computation, word reading, and sentence comprehension by age‐normalized z‐scores. Results Among 68 children with SCA and 69 controls tested; the mean age for each group was 9.4±2.0 years; 38 (55.9%) with SCA and 32 (46.4%) controls were male. Mean hemoglobin was 7.9 ± 0.9 g/dL for the SCA group versus 12.8 ± 1.0 g/dL for controls ( p < 0.001). Compared with the control sample, children with SCA scored significantly lower in mathematical computation (median [interquartile range]: −0.47 [−1.11 to 0.08] versus −0.02 [−0.46 to 0.61], p = 0.0012). Spelling but not mathematic proficiency decreased with age in the SCA group. No significant differences by group were found in spelling, word reading, or sentence comprehension. Discussion School‐aged children with SCA are at risk of poor academic proficiency, especially in mathematical computation. Our findings suggest that children with SCA in Uganda need educational evaluation and may benefit from support for learning.

Children with sickle cell anemia (SCA) frequently develop progressive neurocognitive impairment. We aimed to determine effects of hydroxyurea therapy on neurocognitive function in Ugandan children with SCA by comparing levels at enrollment to a planned 18-month interim assessment. Ugandan children (N=264) ages 3-9 years were enrolled from a SCA clinic and treated in a 30-month single-arm open-label trial with escalation to maximum tolerated dose (MTD). Primary outcome was the effects of hydroxyurea on cognition, attention and executive function, along with transcranial doppler ultrasound (TCD) blood flow velocity. Sibling controls (N=110) without SCA underwent neurocognitive testing in parallel to establish age-normalized z-scores for comparison. Participant enrollment mean age was 5.6±1.2 years, with comparable socio-economic status (SES) and caregiver education versus controls. At enrollment, SCA participants had lower mean cognitive z-scores than controls; 8.7% had cognitive impairment versus 1.6% controls. Month 18 mean dose 25.4mg/kg, with participants significantly improved z-scores versus baseline in all three domains: cognition: -0.54±1.10 vs. -0.07±1.16, p<0.001; attention: -0.07±1.01 vs. 0.27±0.84, p<0.001; and executive function: -0.06±0.62 vs. 0.08 ±0.72, p=0.010. No measure differed from controls. Proportion with SCA and cognitive impairment declined to 4.0%, with decreased mean TCD velocity. Higher neurocognitive treatment z-scores were primarily associated with higher baseline, also with better SES, hydroxyurea-induced TCD and hematological effects. Despite improvement, unadjusted cognitive scores remained negatively associated with age. Hydroxyurea therapy improved SCA neurocognitive function in sub-Saharan children, potentially aided by practice effects. Early treatment is needed for optimal effect. Our ongoing trial will assess impact from longer-term therapy. This trial was registered at www.clinicaltrials.gov as NCT04750707.

Objectives To develop and disseminate a technical framework for administering the Research Participant Perception Survey (RPPS) and aggregating data across institutions using REDCap. Materials and Methods Six RPPS Steering Committee (RSC) member institutions met bi-weekly to achieve consensus on survey sampling techniques, data standards, participant and study descriptor variables, and dashboard design. Results RSC members implemented the infrastructure to send the RPPS to participants and shared data to the Empowering the Participant Voice Consortium Database. Two pilot sites used the tools generated by the RSC to implement the RPPS. Discussion The RSC created a REDCap project setup file, an external module visual analytics dashboard, an English/Spanish language file, and an implementation guide. Conclusion The technical setup materials created by the RSC were effective in aiding new sites in implementing the RPPS and could help future sites adopt the RPPS to better understand participant experiences to improve research recruitment and retention.

Introduction Transcranial doppler ultrasound (TCD) screening for primary stroke prevention in children with sickle cell anemia (SCA) was established in higher-resource regions, targeting interventions for highest velocity (abnormal category). We sought to identify additional stroke risk factors in Uganda. Methods We conducted a 30-month open-label single-arm Ugandan hydroxyurea trial, dose-escalated to maximum tolerated dose, aimed to test brain protection for children aged 3-9 years with SCA. Study procedures included history, clinical stroke examination and prospective TCD and laboratory assessments. Results Overall, 264 children received study HU, mean age 5.6 SD1.7, hemoglobin 7.8 SD1.2g/dL, fetal hemoglobin (HbF) 11.9 SD8.1%, enrolment TCD maximum velocity 148.4 SD29.3cm/second; 15 (5.7%) had abnormal TCD. Mean TAMV at trial completion was 131.9 SDSD25.7 cm/sec. Four participants without abnormal enrolment TCD developed acute stroke within the initial 16 months (incidence 0.62 per 100 person years); Two had enrolment HbF 3.1%, 2 had low oxygen saturation (90%), 1 had recurring severe anemia necessitating multiple transfusions. Apparent stroke precipitants were severe malaria, acute chest syndrome, recent pain crisis or uncertain cause. At trial completion, 8 additional participants had a higher risk TCD category than at enrolment. Conclusion Effectiveness of TCD screening for stroke prevention may vary by region, as no participant with incident stroke was at highest risk. Antecedent and/or ongoing SCA-related risks of anemia, low HbF, hypoxemia, infections and/or disease complications likely contributed to stroke despite trial HU. Results suggest that TCD alone may not fully identify highest stroke risk in the region, and need for primary stroke prevention from early and continuous hydroxyurea therapy.

Background Research participants” feedback about their participation experiences offers critical insights for improving programs. A shared Empowering the Participant Voice (EPV) infrastructure enabled a multiorganization collaborative to collect, analyze, and act on participants’ feedback using validated participant-centered measures. Methods A consortium of academic research organizations with Clinical and Translational Science Awards (CTSA) programs administered the Research Participant Perception Survey (RPPS) to active or recent research participants. Local response data also aggregated into a Consortium database, facilitating analysis of feedback overall and for subgroups. Results From February 2022 to June 2024, participating organizations sent surveys to 28,096 participants and received 5045 responses (18%). Respondents were 60% female, 80% White, 13% Black, 2% Asian, and 6% Latino/x. Most respondents (85–95%) felt respected and listened to by study staff; 68% gave their overall experience the top rating. Only 60% felt fully prepared by the consent process. Consent, feeling valued, language assistance, age, study demands, and other factors were significantly associated with overall experience ratings. 63% of participants said that receiving a summary of the study results would be very important to joining a future study. Intersite scores differed significantly for some measures; initiatives piloted in response to local findings raised experience scores. Conclusion RPPS results from 5045 participants from seven CTSAs provide a valuable evidence base for evaluating participants’ research experiences and using participant feedback to improve research programs. Analyses revealed opportunities for improving research practices. Sites piloting local change initiatives based on RPPS findings demonstrated measurable positive impact.

Introduction: Children with sickle cell anemia (SCA) are at risk of neurocognitive impairment. The primary outcome of our open label hydroxyurea (HU) trial for children with SCA in Uganda, “BRAIN SAFE II,” was neurocognitive function at month 30 trial completion compared to enrolment. We previously reported significantly improved function at the month 18 interim assessment.1 Here we present neurocognitive results at trial completion. Methods: A random sample of 265 children ages 3-9 years with confirmed SCA were enrolled from the Mulago Hospital Sickle Cell Clinic in Kampala if: a) HU use was <6 months; and b) without evidence of prior stroke by stroke-focused neurologic exam. HU dose was escalated to maximum tolerated dose (MTD). Three key neurocognitive domains were assessed at trial months 0, 18 and 30: cognition, attention and executive function. Transcranial Doppler ultrasound (TCD) was performed in parallel by trained study medical staff. Participants' age-aligned siblings (N=110), all confirmed as being without SCA, underwent neurocognitive testing to establish age-normalized Z-scores for the SCA sample. Results: At enrolment, mean age of SCA participants was 5.6±1.7 years and fetal Hb (HbF) was 11.9±8.1%. Mean hemoglobin (Hb) was 7.8±1.2 vs. 12.5±1.1g/dL (p<.001) in the SCA and control groups, respectively. At enrolment the SCA sample scored significantly lower than controls in the 3 neurocognitive domains. At the month 18 interim assessment, re-testing of the 254 active SCA participants had demonstrated significantly improved mean Z-scores in all 3 tested areas. At month 30, the 252 active participants were mean age 8.1±1.7 years. Mean HU dose was 25.9±2.7mg/kg, Hb 8.8±1.5g/dL and HbF 21.6±10.9%. Neurocognitive Z-scores were significantly higher in cognition and attention compared to both enrolment and month 18 (p<.001). In contrast, executive function at month 30 was no longer significantly improved vs. enrolment. Anemia, HbF, blood oxygen saturation each significantly improved at months 18 and 30 vs. enrolment. As reported at month 18,1 improved scores were associated with younger age and higher Hb, as well as lower TCD velocity vs. enrolment. Conclusions: These findings confirm our prior month-18 interim findings that HU therapy at MTD improved neurocognitive function in Ugandan children with SCA. Additional findings at trial completion were: 1) Cognition and attention further improved at month 30 vs. month 18; 2) Better function found at month 18 was not sustained at month 30; and 3) Predictors of good response included higher HbF and lower TCD velocity vs. enrolment. Additional analyses now underway will more precisely identify key clinical and demographic variables for predicting the neurocognitive impact of HU. Our results demonstrate that neurocognitive impairment in children with SCA is reversible with HU therapy and that most improvements seen at month 18 were sustained at month 30. Our findings suggest that early, continuous HU therapy may have long-term benefits on preserving brain function in children with SCA. References: 1S. Kasule Naggayi, et al., Blood 142 (2023) 275-276

Introduction: Sickle cell disease (SCD) is a significant contributor to childhood morbidity and mortality in Uganda and sub-Saharan Africa. However, with improvements in clinical care, many children have reached adulthood. However, there is a paucity of data on their experiences despite the importance of patient-reported perspectives to inform interventions for improving their quality of life. We explored the lived experiences and coping strategies of adults living with SCD in Kampala, Uganda. Methods: We conducted a qualitative study at the oldest and largest sickle cell clinic in Uganda located at Mulago National Referral Hospital in Kampala between March and July 2022. Data were collected through in-depth interviews with 15 adults aged 25 to 40 years living with SCD attending the clinic, as well as five key informant interviews with healthcare workers at the sickle cell clinic, the Ministry of Health and a non-government organization providing support to people living with SCD. All interviews were audio recorded, transcribed verbatim and analyzed using a content thematic approach. Results: The adults living with SCD described facing significant physical, social and emotional challenges such as stigma and discrimination at family, community and institutional levels in the context characterized by inadequate support. Furthermore, adults with SCD encountered difficulties in attaining education, securing employment and accessing health care services, each of which they perceive as having negatively affected their quality of life. The major coping strategies adopted were drawing on religious beliefs, striving to attain adherence to medical treatment and seeking support from their networks, especially their families. Conclusions: The voices of adults living with SCD in this study depict the intersecting social, economic and psychological challenges and vulnerabilities that negatively affect the quality of life of affected adults. Stigma, challenges from health care, educational and vocational systems, as well as a general lack of formal support, dominate the everyday experiences of adults living with SCD in Uganda. Affected adults draw on religion, adherence to medical treatment and support, especially from their families, as major coping strategies. There is a need to strengthen support from health care, social, religious and vocational support for patients with SCD beyond childhood. Addressing this gap in support will require more investment from public and private sectors with local, national and global resources to optimize the health and well-being of young adults living with SCD.

Introduction Transcranial Doppler Ultrasound (TCD) screening for children with sickle cell anemia (SCA) was established in high-income regions for primary stroke prevention through targeted intervention for time-averaged mean velocity (TAMV) in the highest “abnormal” range. Additional stroke risk factors include severe anemia, low HbF, infections, acute SCA complications, e.g. acute chest syndrome (ACS), pain crisis. In low- and middle-income countries (LMICs), children may have additional risks, e.g. higher infectious burden (e.g. malaria) and malnutrition. Of 4 children who developed acute stroke in our hydroxyurea (HU) treatment trial in Uganda, none had abnormal TCD. We sought to identify stroke risk factors for children with SCA in LMICs beyond high TAMV. Methods Our single arm, open-label, 30-month hydroxyurea (HU) trial, “BRAIN SAFE-II,” aimed to reduce stroke and improve cognitive function. Acute stroke or death were early trial endpoints. Children aged 3-9 years attended Mulago Hospital SCA clinic and confirmed SCA by hemoglobin (Hb) electrophoresis were eligible if prior HU use <6 months and no evidence of prior stroke by pediatric stroke exam (PedNIHSS). Study procedures included enrolment TCD per the STOP trial, categorized by maximum TAMV.1 Study staff underwent TCD training and supervision, and followed standard quality assurance measures. HU was escalated from 20±2.5mg/kg to maximum tolerated dose (MTD). Results In all, 264 children enrolled and started HU, mean age 5.6±1.7 years and mean Hb 7.8±1.2g/dL. A total of 252 completed the trial, as 4 had acute stroke (incidence 0.62 per 100 person years), 4 others died without evidence of stroke and 4 withdrew/ lost to follow-up. Acute stroke occurred at mean 9.3 trial months, prior to month 18 scheduled repeat TCD and HbF. These 4 were aged 3-8 years, 3 were male, mean HU dose 24.4± 4.6mg/kg. Their mean study Hb preceding the stroke was 8.5±1.0g/dL vs. 8.8 ±1.4 g/dL (P=0.23) for the entire sample at comparable study time. Mean HbF at enrolment was 4.6±1.02% vs. 12.0±8.13% (P=0.035) for the entire sample. None were malnourished per global criteria; 3 had history of headaches. Each apparent stroke precipitant was malarial infection, ACS, recent pain crisis; one was of uncertain cause. Their enrolment TCDs were: 2 normal, 1 conditional, 1 inadequate. For the entire sample, mean enrolment TAMV was 147.7cm/sec: 15.9%; conditional, 5.7% abnormal, 5.3% inadequate. At month 18, mean HU dose for 254 active participants was 25.4 ±3.04mg/kg and mean TAMV 130.7cm/sec. At month 30, mean HU dose was 25.9 ±2.7mg/kg and TMAV was 131.2cm/sec. Discussion In high-income countries, TCD screening is essential for primary stroke prevention in children with SCA.1 HU reliably reduces TAMV in high-income and LMICs, raises HbF and reduces incidence of pain crises, ACS and clinical malaria. Of the 4 Ugandan participants with acute stroke despite HU therapy, TCD did not identify them as at high stroke risk. Low baseline HbF, malarial infection and episodes of ACS and pain and likely contributed to stroke risk. Children in LMICs with normal or conditional TCD and/or with acute infections or SCA complications may have elevated risk due to low HbF or other factors, potentially necessitating broader considerations for stroke prevention. A similar question was recently raised by a non-HU TCD observational study in southern Africa.2 References: 1Adams RJ, et al., Controlled Clinical Trials, 1998; 2O'Brian NF, et al, EJHaem, 2023.