Hydroxyurea for secondary stroke prevention in children with sickle cell anemia in Nigeria: a randomized controlled trial.

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.

Transcranial doppler velocity in iron-deficient Nigerian children with sickle cell anemia.

Oral iron supplementation in iron deficient children with sickle cell anemia and normal transcranial Doppler ultrasound (TCD) velocities does not reduce arterial flow in the middle cerebral artery.

Establishing Sickle Cell Disease Stroke Prevention Teams in Africa is Feasible: Program Evaluation Using the RE-AIM Framework.

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.

Primary prevention of stroke in children with sickle cell anemia in sub-Saharan Africa: rationale and design of phase III randomized clinical trial.

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 [StrokePreventioninNigeria (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.

Low educational level of head of household, as a proxy for poverty, is associated with severe anaemia among children with sickle cell disease living in a low-resource setting: evidence from the SPRING trial.

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 HbSß0 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.

Maternal Instruction About Jaundice and the Incidence of Acute Bilirubin Encephalopathy in Nigeria.

OBJECTIVE: To evaluate whether teaching mothers about neonatal jaundice will decrease the incidence of acute bilirubin encephalopathy among infants admitted for jaundice. STUDY DESIGN: This was a multicenter, before-after and cross-sectional study. Baseline incidences of encephalopathy were obtained at 4 collaborating medical centers between January 2014 and May 2015 (Phase 1). Structured jaundice instruction was then offered (May to November 2015; Phase 2) in antenatal clinics and postpartum. Descriptive statistics and logistic regression models compared 3 groups: 843 Phase 1 controls, 338 Phase 2 infants whose mothers received both antenatal and postnatal instruction (group A), and 215 Phase 2 infants whose mothers received no instruction (group B) either because the program was not offered to them or by choice. RESULTS: Acute bilirubin encephalopathy occurred in 147 of 843 (17%) Phase 1 and 85 of 659 (13%) Phase 2 admissions, which included 63 of 215 (29%) group B and 5 of 338 (1.5%) group A infants. OR for having acute bilirubin encephalopathy, comparing group A and group B infants adjusted for confounding risk factors, was 0.12 (95% CI 0.03-0.60). Delayed care-seeking (defined as an admission total bilirubin ≥18 mg/dL at age ≥48 hours) was the strongest single predictor of acute bilirubin encephalopathy (OR 11.4; 6.6-19.5). Instruction decreased delay from 49% to 17%. Other major risk factors were home births (OR 2.67; 1.69-4.22) and hemolytic disease (hematocrit ≤35% plus bilirubin ≥20 mg/dL) (OR 3.03; 1.77-5.18). The greater rate of acute bilirubin encephalopathy with home vs hospital birth disappeared if mothers received jaundice instruction. CONCLUSIONS: Providing information about jaundice to mothers was associated with a reduction in the incidence of bilirubin encephalopathy per hospital admission.

Follow-up of Children with Kernicterus in Kano, Nigeria.

INTRODUCTION: Acute bilirubin encephalopathy (ABE) is associated with long-term sequelae (kernicterus). It continues to be a significant issue in our region of Nigeria, accounting for much morbidity and mortality. Herein we report the outcome of neonates with ABE seen at our centre. METHODOLOGY: We established a surveillance of children who had ABE and returned to follow-up from prospective cases of ABE (2012-2014). ABE was diagnosed based on a bilirubin-induced neurologic dysfunction score of ≥ 1. Kernicterus was subsequently established based on a history of developmental delays, hearing impairments and abnormal physical and neurologic examinations at follow-up age ≥3 months. RESULT: Five hundred fifty-one neonates had hyperbilirubinaemia of whom 104 (18.8%) had ABE. Mean transcutaneous bilirubin using the Ingram icterometer was 18.3 mg/dl ± SD 1.9 [(12.5-19.1), total serum bilirubin of 18.1 ± 10.9] (range: 10.3-64 mg/dl). Sixty-five infants returned for follow-up (41 males and 24 females); mean age 9 months (22 days to 17 months). Most (58 of 65; 89.2%) had abnormal neurological findings and 15 (25.9%) had probable kernicterus. CONCLUSION: There is a critical need for a National Kernicterus Registry to document all cases of kernicterus and formulate an effective treatment and prevention policy.

Feasibility trial for primary stroke prevention in children with sickle cell anemia in Nigeria (SPIN trial).

The vast majority of children with sickle cell anemia (SCA) live in Africa, where evidence-based guidelines for primary stroke prevention are lacking. In Kano, Nigeria, we conducted a feasibility trial to determine the acceptability of hydroxyurea therapy for primary stroke prevention in children with abnormal transcranial Doppler (TCD) measurements. Children with SCA and abnormal non-imaging TCD measurements (≥200 cm/s) received moderate fixed-dose hydroxyurea therapy (∼20 mg/kg/day). A comparison group of children with TCD measurements <200 cm/s was followed prospectively. Approximately 88% (330 of 375) of families agreed to be screened, while 87% (29 of 33) of those with abnormal TCD measurements, enrolled in the trial. No participant elected to withdraw from the trial. The average mean corpuscular volume increased from 85.7 fl at baseline to 95.5 fl at 24 months (not all of the children who crossed over had a 24 month visit), demonstrating adherence to hydroxyurea. The comparison group consisted of initially 210 children, of which four developed abnormal TCD measurements, and were started on hydroxyurea. None of the monthly research visits were missed (n = total 603 visits). Two and 10 deaths occurred in the treatment and comparison groups, with mortality rates of 2.69 and 1.81 per 100 patient-years, respectively (P = .67). Our results provide strong evidence, for high family recruitment, retention, and adherence rates, to undertake the first randomized controlled trial with hydroxyurea therapy for primary stroke prevention in children with SCA living in Africa.

Primary stroke prevention in Nigerian children with sickle cell disease (SPIN): challenges of conducting a feasibility trial.

BACKGROUND: The majority of children with sickle cell disease (SCD), approximately 75%, are born in sub-Saharan Africa. For children with elevated transcranial Doppler (TCD) velocity, regular blood transfusion therapy for primary stroke prevention is standard care in high income countries, but is not feasible in sub-Saharan Africa. PROCEDURE: In the first U.S. National Institute of Health (NIH) sponsored SCD clinical trial in sub-Saharan Africa, we describe the protocol and challenges unique to starting a clinical trial in this region. We are conducting a single arm pilot trial of hydroxyurea therapy in children with TCD velocity ≥200 cm/sec in the middle cerebral arteries. Eligible children will be placed on hydroxyurea (n = 40) and followed for 3 years at Aminu Kano Teaching Hospital, Nigeria. Adherence will be measured via the Morisky Scale and adverse events will be determined based on hospitalization. RESULTS: Originally, a randomized placebo trial was planned; however, placebo was not approved by the local Ethics Committee. Hence a single arm trial of hydroxyurea will be conducted and five controls per patient with normal TCD measurements will be followed to compare the rate of adverse events to those with abnormal TCD measurements taking hydroxyurea. Using non-NIH funding, over 9 months, multiple face-to-face investigator meetings were conducted to facilitate training. CONCLUSION: A hydroxyurea trial (NCT01801423) for children with SCD is feasible in sub-Saharan Africa; however, extensive training and resources are needed to build a global patient oriented multi-disciplinary research team with a common purpose.

Impact of maternal depression on malnutrition treatment outcomes in older children with sickle cell anemia.

BACKGROUND: Malnutrition and sickle cell anemia (SCA) result in high childhood mortality rates. Although maternal depression is an established risk factor for malnutrition in younger children, little is known about its impact on treatment response in children with malnutrition. We aimed to determine the relationship, if any, between maternal depression scores and malnutrition treatment outcomes in older children with SCA. METHODS: We conducted a planned ancillary study to our randomized controlled feasibility trial for managing severe acute malnutrition in children aged 5-12 with SCA in northern Nigeria (NCT03634488). Mothers of participants completed a depression screen using the Patient Health Questionnaire (PHQ-9).We used a multivariable linear regression model to describe the relationship between the baseline maternal PHQ-9 score and the trial participant's final body mass index (BMI) z-score. RESULTS: Out of 108 mother-child dyads, 101 with maternal baseline PHQ-9 scores were eligible for inclusion in this analysis. At baseline, 25.7% of mothers (26 of 101) screened positive for at least mild depression (PHQ-9 score of 5 or above). The baseline maternal PHQ-9 score was negatively associated with the child's BMI z-score after 12 weeks of malnutrition treatment (ß=-0.045, p = 0.041). CONCLUSIONS: Maternal depressive symptoms has an impact on malnutrition treatment outcomes. Treatment of malnutrition in older children with sickle cell anemia should include screening for maternal depression and, if indicated, appropriate maternal referral for depression evaluation and treatment. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov (#NCT03634488) on January 30, 2018, https://clinicaltrials.gov/study/NCT03634488 .

Tuberculin screening of some selected Fulani lactating cows in North-Central Nigeria.

The prevalence of mycobacterial infection among lactating Fulani cows was investigated in the Federal Capital Territory, Abuja and Kaduna State of Nigeria. Tuberculin testing using single comparative intradermal tuberculin test showed a 14.6 % positive, 4 % doubtful, and 81.4 % negative reactors. Mycobacterial infection was found to be present in the nomadic (constantly moving) and seminomadic (limited movement) management systems studied but management showed no significant effect on the prevalence of the disease. However, the prevalence was significantly higher in older age groups than the younger ones (P < 0.05).

Burkitt's Lymphoma of the Breast in an HIV-Positive Patient: A Rare Presentation.

Introduction: Breast cancer is the most common female cancer worldwide, affecting 13.5-30 per 100,000 women in sub-Saharan Africa. The most common histopathologic variants of breast cancer are those that originate from the glandular epithelium of the breast. Primary breast lymphomas are uncommon, and they represent only 0.04%-0.5% of all breast cancers. Burkitt lymphoma is the least of this rare group. The report intends to present Burkitt's lymphoma, a rare histopathological diagnosis of primary breast tumour in an HIV+ patient. Description of a case of bilateral breast disease and the histopathologic diagnosis. Our case was a 28-year-old HIV+ woman who presented with multiple bilateral breast lumps for 2 months duration, associated with bilateral axillary lumps, weight loss, night sweat, and malaise. Lumps range from 2 to 8 cm in size with multiple axillary lymph nodes. Core tissue biopsy showed a monotonous population of intermediate-sized lymphoid cells with round nuclei, clumped chromatin, and several nucleoli interspersed by numerous tangible body macrophages, presenting a starry-sky appearance. Diagnosis of bilateral primary breast Burkitt's lymphoma was performed, and the patient was referred to oncology. She was placed on antiretroviral therapy and chemotherapy (cyclophosphamide, hydroxydaunorubicin, vincristine sulphate, and prednisone) and clinically responded to therapy. Conclusions: Breast lumpiness in immunocompromised patients calls for the suspicion of lymphoma.

Underweight children older than 5 years with sickle cell anemia are at risk for early mortality in a low-resource setting.

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.

Risk factors in underweight older children with sickle cell anemia: a comparison of low- to high-income countries.

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.

Feasibility trial for the management of severe acute malnutrition in older children with sickle cell anemia in Nigeria.

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.

Comparative study and dyeing performance of as-synthesized azo heterocyclic monomeric, polymeric, and commercial disperse dyes.

In this study poly (4-nitrophenylazo-3-aminopyridine - formaldehyde) (PNAAP-F) and poly (4-nitroarylazo-3-chloro-6-hydroxypyridine - formaldehyde) (NAACHP-F) were synthesized via diazotization, coupling and polycondensation reactions. The structural properties of the as-synthesized dyes were acquired using Fourier-transform infrared spectroscopy (FTIR) and UV-visible absorption maxima and their color, yield, melting point, solubility, and viscosity were determined via standard methods. UV-visible and FTIR results show successful formation of the polymeric dyes due to shift of wavelength of maximum absorption (λmax) (440-490 nm, 480-540 nm) and new absorption peak at around (2780-2995 cm-1) for methylene bridge respectively. The dyes were found to be of good yield (monomeric: 73.3%-87.2 %, polymeric: 53.8%-76.6 %), low melting point (monomeric: 112.6-121.2, and 136.0-137.0 °C, while polymeric: 134.0-144.5, and 149.4-154.7 °C), soluble in some solvents. The dyeing activity was carried out and assessed on nylon and polyester fabrics using the standard methods. The dyeing process was carried out via high temperature and carrier dyeing methods. The dyeing properties of the synthesized dyes were compared with those of commercial disperse dyes (terasil brilliant violet and terasil scarlet, brown). The dyeings of nylon and polyester had a very attractive hue and the color ranges from yellow and deep yellow shades with very good to excellent fastness to light, washing, hot pressing, and rubbing.

Adsorption Behavior of Methylene Blue Cationic Dye in Aqueous Solution Using Polypyrrole-Polyethylenimine Nano-Adsorbent.

In this work, a polypyrrole-polyethyleneimine (PPy-PEI) nano-adsorbent was successfully synthesized for the removal of methylene blue (MB) from an aqueous solution. Synthetic dyes are among the most prevalent environmental contaminants. A new conducting polymer-based adsorbent called (PPy-PEI) was successfully produced using ammonium persulfate as an oxidant. The PEI hyper-branched polymer with terminal amino groups was added to the PPy adsorbent to provide more effective chelating sites for dyes. An efficient dye removal from an aqueous solution was demonstrated using a batch equilibrium technique that included a polyethyleneimine nano-adsorbent (PPy-PEI). The best adsorption parameters were measured at a 0.35 g dosage of adsorbent at a pH of 6.2 and a contact period of 40 min at room temperature. The produced PPy-PEI nano-adsorbent has an average particle size of 25-60 nm and a BET surface area of 17 m2/g. The results revealed that PPy-PEI nano-composite was synthesized, and adsorption was accomplished in the minimum amount of time. The maximum monolayer power, qmax, for MB was calculated using the isothermal adsorption data, which matched the Langmuir isotherm model, and the kinetic adsorption data, which more closely fitted the Langmuir pseudo-second-order kinetic model. The Langmuir model was used to calculate the maximum monolayer capacity, or qmax, for MB, which was found to be 183.3 mg g-1. The as-prepared PPy-PEI nano-adsorbent totally removes the cationic dyes from the aqueous solution.