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

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

Hydroxyurea Therapy for Neurological and Cognitive Protection in Pediatric Sickle Cell Anemia in Uganda (BRAIN SAFE II): Protocol for a single-arm open label trial.

Background: Children with sickle cell anemia (SCA) in Sub-Saharan Africa are at high risk of sickle cerebrovascular injury (SCVI). Hydroxyurea, a commonly used disease-modifying therapy, may prevent or decrease SCVI for reduced incident stroke, stroke risk and potentially cognitive dysfunction. We aim to test the impact of daily hydroxyurea therapy on these outcomes in Ugandan children with SCA. We hypothesize that hydroxyurea therapy over 36 months will prevent, stabilize or improve these complications of SCA. Methods: The BRAIN SAFE II study is an open-label, single-arm trial of daily hydroxyurea for 270 children with SCA (HbSS) in Uganda, ages 3-9 years. Following baseline assessments, participants began hydroxyurea therapy and clinically followed per local guidelines. Standard hydroxyurea dose is escalated to maximum tolerated dose (MTD). SCVI is assessed by cerebral arterial velocity using Doppler ultrasound, with cognitive function determined by formal neurocognitive testing (primary outcomes). Structural SCVI is assessed by magnetic resonance imaging (MRI) and angiography (MRA) in a sub-sample of 90 participants ages ≥5 years, along with biomarkers of anemia, inflammation and malnutrition (secondary outcomes). At trial midpoint (18 months) and completion (36 months), primary outcomes will be compared to participants' baseline to determine hydroxyurea impact and relationships to secondary outcomes. Conclusion: This open-label, single-arm trial will examine the impact of hydroxyurea on preventing or ameliorating SCA SCVI in children, assessed by reducing incident stroke, stroke risk and neurocognitive dysfunction. Trial results will provide important insight into the role of hydroxyurea therapy on critical manifestations of SCVI in children with SCA.

Neurocognitive Impairment in Ugandan Children with Sickle Cell Anemia Compared to Sibling Controls: A cross-sectional study.

Introduction: Neurocognitive function in Ugandan children aged 1-12 years with sickle cell anemia (SCA) were compared to their non-SCA siblings to identify risk factors for disease-associated impairment. Methods: This cross-sectional neurocognitive function study of children with SCA (N=242) and non-SCA siblings (N=127) used age- and linguistically-appropriate standardized tests of cognition, executive function and attention for children ages 1-4 and 5-12 years. Test scores were converted to locally derived age-normalized z-scores. The SCA group underwent standardized stroke examination for prior stroke and transcranial doppler ultrasound (TCD) to determine stroke risk by arterial flow velocity. Results: The SCA group was younger than siblings (mean ages 5.46±3.0 versus 7.11±3.51 years, respectively; p <.001), with lower hemoglobin concentration (7.32±1.02 vs. 12.06±1.42, p <.001). Overall cognitive SCA z-scores were lower: -0.73 ±0.98 vs. siblings -0.25 ±1.12 (p<.001), with comparable findings for executive function of -1.09±0.94 versus -0.84±1.26 (p=0.045), respectively. Attention z-scores for ages 5-12 for the SCA group and controls were similar: -0.37±1.4 vs. -0.11±0.17 (p=.09). Overall differences by SCA status were largely driven by the older age group, as z-scores in the younger sub-sample did not differ from controls. Analyses revealed the strongest predictors of poor neurocognitive outcomes among the SCA sample to be the disease, age and prior stroke (each p<.001). Impact from anemia and SCA were indistinguishable. Discussion: Neurocognitive testing in children with SCA compared to non-SCA siblings revealed poorer SCA-associated functioning in children older than age 4. Results indicate need for trials assessing impact from disease modification for children with SCA.

Mental and Emotional Health of Caregivers of Youth with Sickle Cell Disease: A Systematic Review.

People of African descent and those identifying as Black and/or Latino experience a disproportionate burden of sickle cell disease (SCD), a chronic, serious blood condition. Caregivers of children with chronic medical conditions report worse mental health than others. Disease-associated stressors can affect caregivers of children with SCD. We conducted a systematic review to summarize the prevalence of mental health symptoms in caregivers of children with SCD and to see if symptoms were associated with the child's SCD. This review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We searched PubMed, PsycINFO, and Embase, identifying 1,322 records of which 40 met criteria for inclusion in this review. Findings suggest caregivers experience mental health problems, and poorer mental health was associated with worse child SCD-related outcomes and treatment adherence. Efforts should be made to routinely screen SCD caregiver mental health and to refer accordingly.

Neurofilament light chain: A potential biomarker for cerebrovascular disease in children with sickle cell anaemia.

Cerebrovascular injury frequently occurs in children with sickle cell anaemia (SCA). Limited access to magnetic resonance imaging and angiography (MRI-MRA) in sub-Saharan Africa impedes detection of clinically unapparent cerebrovascular injury. Blood-based brain biomarkers of cerebral infarcts have been identified in non-SCA adults. Using plasma samples from a well-characterized cross-sectional sample of Ugandan children with SCA, we explored relationships between biomarker levels and MRI-detected cerebral infarcts and transcranial Doppler (TCD) arterial velocity. Testing was performed using a 4-plex panel of brain injury biomarkers, including neurofilament light chain (NfL), a central nervous system neuron-specific protein. Mean biomarker levels from the SCA group (n = 81) were similar to those from non-SCA sibling controls (n = 54). Within the SCA group, NfL levels were significantly higher in those with MRI-detected infarcts compared to no infarcts, and higher with elevated TCD velocity versus normal velocity. Elevated NfL remained strongly associated with MRI-detected infarcts after adjusting for sex and age. All non-SCA controls and SCA participants lacking MRI-detected infarcts had low NfL levels. These data suggest potential utility of plasma-based NfL levels to identify children with SCA cerebrovascular injury. Replication and prospective studies are needed to confirm these novel findings and the clinical utility of NfL versus MRI imaging.

Changes in Hydroxyurea Use Among Youths Enrolled in Medicaid With Sickle Cell Anemia After 2014 Revision of Clinical Guidelines.

Importance: Youths with sickle cell anemia (SCA) are at risk of pain crises, stroke, and early death. Complications can be reduced by the oral disease-modifying medication hydroxyurea, and in 2014, the National Heart, Lung, and Blood Institute published revised guidelines that hydroxyurea should be offered to youths aged 9 months and older with SCA regardless of disease severity. Objective: To describe changes in hydroxyurea use among youths with SCA before and after release of the National Heart, Lung, and Blood Institute guidelines. Design, Setting, and Participants: This cross-sectional study was conducted using administrative data from 2010 to 2018 from Michigan and New York State (NYS) Medicaid programs. The study population included youths aged 1 to 17 years with SCA enrolled in the Michigan or NYS Medicaid programs for at least 1 year (Michigan: 2010-2018; NYS: 2012-2018). Youths with SCA were identified using validated claims-based definitions. Data were analyzed from June to October 2020. Main Outcomes and Measures: The main outcome was hydroxyurea use characterized as mean annual counts of days' supply of filled hydroxyurea prescriptions. Rates of hydroxyurea use over time were assessed using regression models (Michigan: zero-inflated negative binomial; NYS: negative binomial). Models included indicators for periods before and after guideline release. Results: A total of 4302 youths with SCA (2236 males [52.0%]; 2676 born 2005-2017 [62.2%]; 150 Hispanic [3.5%], 2929 non-Hispanic Black [68.0%], and 389 non-Hispanic White [9.0%]) contributed 12 565 person-years. The mean (SD) annual days' supply of hydroxyurea was 47.2 (93.6) days per youth in Michigan and 97.4 (137.0) days per youth in NYS. In Michigan, there was an increase in the odds of having nonzero days' supply after the guidelines were released (odds ratio, 1.52; 95% CI, 1.07-2.14). In NYS, no change was seen in the mean days' supply of filled hydroxyurea. Conclusions and Relevance: These findings suggest that hydroxyurea was substantially underused among youths with SCA, despite establishment as the primary disease-modifying therapy for SCA, and that there was incomplete clinician or patient uptake of newly released guidelines. Results suggest that expanding use of hydroxyurea may require a multifaceted approach that includes addressing multiple system- and patient-level barriers.

The Consortium on Newborn Screening in Africa for sickle cell disease: study rationale and methodology.

Sickle cell disease (SCD) is a common condition within sub-Saharan Africa and associated with high under-5 mortality (U5M). The American Society of Hematology instituted the Consortium on Newborn Screening in Africa (CONSA) for SCD, a 7-country network of sites to implement standardized newborn hemoglobinopathy screening and early intervention for children with SCD in sub-Saharan Africa. CONSA's overall hypothesis is that early infant SCD screening and entry into standardized, continuous care will reduce U5M compared with historical estimates in the region. Primary trial objectives are to determine the population-based birth incidence of SCD and effectiveness of early standardized care for preventing early mortality consortium-wide at each country's site(s). Secondary objectives are to establish universal screening and early interventions for SCD within clinical networks of CONSA partners and assess trial implementation. Outcomes will be evaluated from data collected using a shared patient registry. Standardized trial procedures will be implemented among designated birth populations in 7 African countries whose programs met eligibility criteria. Treatment protocol includes administering antibacterial and antimalarial prophylaxis and standard childhood vaccinations against infections commonly affecting children with SCD. Infants with a positive screen and confirmation of SCD within the catchment areas defined by each consortium partner will be enrolled in the clinical intervention protocol and followed regularly until age of 5 years. Effectiveness of these early interventions, along with culturally appropriate family education and counseling, will be evaluated by comparing U5M in the enrolled cohort to estimated preprogram data. Here, we describe the methodology planned for this trial.

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

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

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

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

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

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

Brain Magnetic Resonance Imaging and Angiography in Children with Sickle Cell Anaemia in Uganda in a Cross-Sectional Sample.

OBJECTIVE: Children with sickle cell anaemia (SCA) are highly susceptible to cerebrovascular injury. We performed brain magnetic resonance imaging and angiography (MRI-MRA) in Ugandan children with SCA to identify structural cerebrovascular abnormalities and examine their relationship to standardized clinical assessments. METHODS: A sub-sample (n=81) was selected from a cross-sectional study of children attending SCA clinic, including 52 (64.2%) with and 29 (35.8%) without clinically detected abnormalities. Clinical evaluation included assessment for prior stroke, cognitive testing and cerebral arterial transcranial doppler (TCD) flow velocity. MRI-MRA scans were interpreted by at least two neuroradiologists. RESULTS: Mean age was 6.5±2.7 years, with 39 (48.1%) female. Mean haemoglobin was 7.3±0.9 g/dl. Overall, 13 (16.0%) were malnourished. Infarcts and/or stenoses were detected in 55 (67.9%) participants, with stenoses primarily in the anterior circulation. Infarcts were seen in those with normal 17/29 (58.6%) or abnormal 34/52 (65.4%) clinical testing (p=0.181). Neither abnormal MRI nor MRA was associated with age, sex, haemoglobin, or malnutrition. Abnormal MRA was highly associated with infarcts (p<0.0001). Participants with abnormal imaging had two-fold higher proportion of stroke on exam and/or impaired cognition. Stroke on exam was strongly associated with an imaging abnormality after adjusting for age, sex, malnutrition, and haemoglobin (OR 11.8, 95%CI 1.87-74.2). CONCLUSION: Over half of these SCA children had cerebrovascular infarcts and/or arterial stenoses. Cerebrovascular disease was frequently undetectable by clinical assessments. While rarely available in under-resourced settings, MRI-MRA brain imaging is an important tool for defining SCA cerebrovascular disease and for assessing impact of clinical intervention trials.

Managing Human Subjects Research During a Global Pandemic at an Academic Center: Lessons Learned From COVID-19.

By March 2020, New York City became the early epicenter of the COVID-19 pandemic in the United States. Consequently, Columbia University, with its large portfolio of human subjects research, had to address the challenges of protecting thousands of research participants and research staff from potential exposure to COVID-19 while facilitating essential biomedical research, especially pandemic-related studies. The authors describe, from the perspective of Columbia's research administration leadership, how the University and its primary teaching hospital ramped down-and later ramped up-human subjects research and reflect on lessons learned. As the pandemic unfolded, only studies offering the prospect of direct benefit to subjects were permitted to continue with in-person contact. New in-person participant enrollment ceased, except for COVID-19 prevention or treatment studies. Centralized, frequently updated communication about policies and procedures was disseminated to the Columbia research community. Procedural efficiencies were rapidly developed and implemented for review and oversight of human subjects research and contractual agreements for clinical trials. More frequent institutional review board meetings and 24-hour support markedly reduced turnaround time for COVID-19 studies, without delaying approvals of non-COVID-19 research. Research administration worked closely with relevant principal federal agencies, whose regulatory flexibility facilitated the efficient implementation of COVID-19-related research. Overall, the ramp-down and ramp-up of the majority of human subjects research, with specified priorities and accelerated processes, worked well. Adjustments were made to handle the increase in administrative tasks, the need to respond rapidly to added oversight responsibilities, and the management of the many new COVID-19-related research protocols. Timely, centralized communication, support for staff needs, prioritization, and collaboration were critical to successful research oversight at a large-scale academic setting in the midst of a pandemic. These perspectives may be useful to academic research centers addressing the current and future pandemics.

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

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

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

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

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

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

Quality of Life of Latino and Non-Latino Youth With Sickle Cell Disease as Reported by Parents and Youth.

INTRODUCTION: Approximately 10% to 15% of people affected by sickle cell disease (SCD) in the United States are Latino, many of whom are primary Spanish speakers. A key tool for self-reported outcome measures, the Pediatric QOL Inventory (PedsQL) SCD module, was not available in Spanish. Here, we assess the linguistic validity of a Spanish translation and compare perception of disease-specific and generic quality of life (QOL) in a sample of Latino and non-Latino children with SCD and their parents. METHOD: Following forward and backward translation, Spanish-speaking child-parent dyads linguistically validated the translated instruments. Disease-specific and generic QOL perception of 28 child-parent dyads who participated in a clinical feasibility trial, HABIT (Hydroxyurea Adherence for Personal Best in Sickle Cell Disease), were compared by ethnicity. Data were analyzed by descriptive statistics, Mann-Whitney U test, absolute score differences, and minimal clinically important differences (MCID). RESULTS: The translated questionnaire required no further language changes. QOL scores were higher for Latino children and parents compared with non-Latinos, with score differences exceeding MCIDs for total scores and the majority of subscale scores. CONCLUSION: Spanish language PedsQL SCD instruments allow measurement of QOL in Spanish-speaking Latino children with SCD and their parents. Score differences for Latinos mostly exceeded MCIDs, suggesting that these differences are clinically meaningful. Confirmation of these findings is warranted.

End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.

To address the global burden of sickle cell disease and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to patient-reported outcome, pain (non-patient-reported outcomes), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the end-organ considerations, measurement of cure, and low-resource settings panels as well as relevant findings and recommendations from the biomarkers panel.

HABIT efficacy and sustainability trial, a multi-center randomized controlled trial to improve hydroxyurea adherence in youth with sickle cell disease: a study protocol.

BACKGROUND: Hydroxyurea (HU) is recommended as standard practice for youth with sickle cell disease (SCD). Yet, despite its efficacy, HU adherence in adolescents and young adults is often poor. Poor medication adherence increases disease burden, healthcare cost and widens health disparities. Adolescence is a critical time to improve adherence through improved chronic disease self-management. This study aims to test the efficacy of an intervention delivered to youth/parent dyads by community health workers (CHWs), augmented by tailored text messages on HU adherence (primary outcome). Secondary outcomes are intervention sustainability, youth health-related quality of life, self-management responsibility concordance, acute hospital use and self-reported disease symptoms. METHODS: Hydroxyurea Adherence for Personal Best in Sickle Cell Disease, "HABIT," is a 12 month multi-center randomized controlled trial. One hundred four youth, 10 to 18 years of age prescribed HU who meet eligibility criteria, enrolled with their parent as dyads, will be randomized 1:1 to either the HABIT intervention or to usual clinical care plus education handouts. All subjects will complete clinic visits at months 0, 2, 4, 6 (efficacy component), 9 and 12 (sustainability component) for assessment of HbF biomarker, other hematologic parameters, and to complete questionnaires. In addition, dyads assigned to the HABIT intervention will work with CHWs to identify a daily habit (e.g., brushing teeth) on which to build a HU adherence habit. Tailored daily text message reminders to support the habit will be developed by the dyad in collaboration with the CHWs and sent to parent and youth. At the 6 month visit, the intervention will end and the sustainability portion of the trial will begin. All data analyses will be based on intention to treat with all randomized subjects included in the analyses. DISCUSSION: Prior retrospective studies demonstrate that a majority of adolescents are poorly adherent to HU. If efficacious, the HABIT intervention has the potential to improve the lives of youth with SCD. TRIAL REGISTRATION: Clinicaltrials.gov NCT03462511 . Registered March 6, 2018, last updated July 26, 2019.

Burden of neurological and neurocognitive impairment in pediatric sickle cell anemia in Uganda (BRAIN SAFE): a cross-sectional study.

BACKGROUND: Children with sickle cell anemia (SCA) are highly susceptible to stroke and other manifestations of pediatric cerebral vasculopathy. Detailed evaluations in sub-Saharan Africa are limited. METHODS: We aimed to establish the frequency and types of pediatric brain injury in a cross-sectional study at a large SCA clinic in Kampala, Uganda in a randomly selected sample of 265 patients with HbSS ages 1-12 years. Brain injury was defined as one or more abnormality on standardized testing: neurocognitive impairment using an age-appropriate test battery, prior stroke by examination or transcranial Doppler (TCD) velocities associated with stroke risk in children with SCA (cerebral arterial time averaged mean maximum velocity ≥ 170 cm/second). RESULTS: Mean age was 5.5 ± 2.9 years; 52.3% were male. Mean hemoglobin was 7.3 ± 1.01 g/dl; 76.4% had hemoglobin < 8.0 g/dl. Using established international standards, 14.7% were malnourished, and was more common in children ages 5-12. Overall, 57 (21.5%) subjects had one to three abnormal primary testing. Neurocognitive dysfunction was found in 27, while prior stroke was detected in 15 (5.7%). The most frequent abnormality was elevated TCD velocity 43 (18.1%), of which five (2.1%) were in the highest velocity range of abnormal. Only impaired neurocognitive dysfunction increased with age (OR 1.44, 95%CI 1.23-1.68), p < 0.001). In univariate models, malnutrition defined as wasting (weight-for-height ≤ -2SD), but not sex or hemoglobin, was modestly related to elevated TCD (OR 1.37, 95%CI 1.01-1.86, p = 0.04). In adjusted models, neurocognitive dysfunction was strongly related to prior stroke (OR 6.88, 95%CI 1.95-24.3, p = .003) and to abnormal TCD (OR 4.37, 95%CI 1.30, p = 0.02). In a subset of 81 subjects who were enriched for other abnormal results, magnetic resonance imaging and angiography (MRI/MRA) detected infarcts and/or arterial stenosis in 52%. Thirteen subjects (25%) with abnormal imaging had no other abnormalities detected. CONCLUSIONS: The high frequency of neurocognitive impairment or other abnormal results describes a large burden of pediatric SCA brain disease in Uganda. Evaluation by any single modality would have underestimated the impact of SCA. Testing the impact of hydroxyurea or other available disease-modifying interventions for reducing or preventing SCA brain effects is warranted.