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Introduction: Stroke is a severe complication of sickle cell anemia (SCA), with devastating sequelae. Transcranial Doppler (TCD) ultrasonography predicts stroke risk, but implementing TCD screening with suitable treatment for primary stroke prevention in low-resource environments remains challenging. SPHERE (NCT03948867) is a prospective phase 2 open-label hydroxyurea trial for SCA in Tanzania. Methods: After formal training and certification, local personnel screened children 2–16 years old; those with conditional (170–199 cm/s) or abnormal (≥200 cm/s) time-averaged mean velocities (TAMVs) received hydroxyurea at 20 mg/kg/day with dose escalation to maximum tolerated dose (MTD). The primary study endpoint is change in TAMV after 12 months of hydroxyurea; secondary endpoints include SCA-related clinical events, splenic volume and function, renal function, infections, hydroxyurea pharmacokinetics, and genetic modifiers. Results: Between April 2019 and April 2020, 202 children (average 6.8 ± 3.5 years, 53% female) enrolled and underwent TCD screening; 196 were deemed eligible by DNA testing. Most had numerous previous hospitalizations and transfusions, with low baseline hemoglobin (7.7 ± 1.1 g/dL) and %HbF (9.3 ± 5.4%). Palpable splenomegaly was present at enrollment in 49 (25%); average sonographic splenic volume was 103 mL (range 8–1,045 mL). TCD screening identified 22% conditional and 2% abnormal velocities, with hydroxyurea treatment initiated in 96% (45/47) eligible children. Conclusion: SPHERE has built local capacity with high-quality research infrastructure and TCD screening for SCA in Tanzania. Fully enrolled participants have a high prevalence of elevated baseline TCD velocities and splenomegaly. SPHERE will prospectively determine the benefits of hydroxyurea at MTD for primary stroke prevention, anticipating expanded access to hydroxyurea treatment across Tanzania.

Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) provides hydroxyurea at maximum tolerated dose (MTD) for children with sickle cell anemia (SCA) in sub-Saharan Africa. Beyond reducing SCA-related clinical events, documented treatment benefits include ∼50% reduction in malaria incidence. To identify associations and propose mechanisms by which hydroxyurea could be associated with lower malaria rates, infections were recorded across all clinical sites (Angola, Democratic Republic of Congo, Kenya, and Uganda). Hazard ratios (HR) with 95% confidence intervals (CIs) for baseline demographics, and time-varying laboratory and clinical parameters were estimated in a modified Cox gap-time model for repeated events. Over 3387 patient-years of hydroxyurea treatment, 717 clinical malaria episodes occurred in 336 of 606 study participants; over half were confirmed by blood smear and/or rapid diagnostic testing with 97.8% Plasmodium falciparum. In univariate analysis limited to 4 confirmed infections per child, malaria risk was significantly associated with absolute neutrophil count (ANC), splenomegaly, hemoglobin, and achieving MTD; age, malaria season, MTD dose, fetal hemoglobin, α-thalassemia, and glucose-6-phosphate dehydrogenase deficiency had no effect. In multivariable regression of confirmed infections, ANC was significant (HR, 1.37 per doubled value; 95% CI, 1.10-1.70; P = .0052), and ANC values

In this study, we present data from a neurosurgical training program in Tanzania for the treatment of pediatric hydrocephalus. The objectives of the study were to identify the demographics and clinical characteristics of pediatric patients with hydrocephalus who were admitted to Bugando Medical Centre in Mwanza, Tanzania, as well as to describe their surgical treatment and early clinical outcomes.This cross-sectional study included 38 pediatric patients. Physical examinations were conducted pre- and postoperatively, and their mothers completed a questionnaire providing demographic and clinical characteristics.There was a slight preponderance of male sex (21/38; 55.3%) with median age at the time of admission of 98.5 days. The majority of patients were surgically treated (33/38; 86.8%). Among those surgically treated, most received a ventriculoperitoneal shunt (23/33; 69.7%), whereas 7 were treated with an endoscopic third ventriculostomy (7/33; 21.2%). At the time of admission, the majority of patients (86%) had head circumferences that met criteria for macrocephaly. The median time between admission and surgery was 23 days (2-49 days). Overall, 5 patients (13.2%) died, including 2 who did not receive surgical intervention.We found that in our population, pediatric patients with hydrocephalus often present late for treatment with additional significant delays prior to receiving any surgical intervention. Five patients died, of whom 2 had not undergone surgery. Our study reinforces that targeted investments in clinical services are needed to enable access to care, improve surgical capacity, and alleviate the burden of neurosurgical disease from pediatric hydrocephalus in sub-Saharan Africa.

Hydroxyurea (hydroxycarbamide) is an effective treatment for sickle cell anaemia (SCA), but clinical responses depend primarily upon the degree of fetal haemoglobin (HbF) induction and the heterogeneity of HbF expression across erythrocytes. The number and characteristics of HbF-containing cells (F-cells) are not assessed by traditional HbF measurements. Conventional hydroxyurea dosing (e.g. fixed doses or low starting doses with stepwise escalation) produces a moderate heterocellular HbF induction, but haemolysis and clinical complications continue. Robust, pancellular HbF induction is needed to minimise or fully inhibit polymerisation of sickle haemoglobin. We treated children with hydroxyurea using an individualised, pharmacokinetics-guided regimen starting at predicted maximum tolerated dose (MTD). We observed sustained HbF induction (mean >30%) for up to 6 years, which was not dependent on genetic determinants of HbF expression. Nearly 70% of patients had ≥80% F-cells (near-pancellular), and almost half had ≥90% F-cells (pancellular). The mean HbF/F-cell content was ~12 pg. Earlier age of initiation and better medication adherence were associated with high F-cell responses. In summary, early initiation of hydroxyurea using pharmacokinetics-guided starting doses at predicted MTD can achieve sustained near-pancellular or pancellular HbF expression and should be considered an achievable goal for children with SCA treated with hydroxyurea at optimal doses. Clinical trial registration number: NCT02286154 (clinicaltrials.gov).

We conducted a pilot study to determine the effectiveness of a linkage to care intervention with social workers to improve 12-month post-hospital mortality for children in Tanzania with sickle cell disease. Comparison was done with a historical cohort. Mortality was 6.7% in the interventional cohort compared with 19.2% (adjusted Hazard Ratio, 0.26; 95% CI, 0.08-0.83).

Background: Anemia causes significant morbidity and mortality in low-resource settings and is a common problem in sickle cell disease (SCD). Timely, accurate diagnosis of anemia enables appropriate triage and treatment. In the Bedside Expedited Testing for Anemia and Sickle Cell Disease (BETA) study, we aimed to evaluate the accuracy of two simple point-of-care diagnostic devices in the hands of the intended end-users: one for anemia and one for SCD. Here we present the results of the Anemocheck-LRS assay, a simple, inexpensive, color-based test that quickly quantifies hemoglobin concentration to diagnose anemia. Methods: BETA was performed at …

BACKGROUND/OBJECTIVES: Sickle cell disease (SCD) is an important, hidden cause of childhood mortality worldwide. It is most prevalent in sub-Saharan Africa where national newborn screening programs remain unavailable and most children in rural areas are never diagnosed. We conducted a study at a rural district hospital in northern Tanzania to determine the birth prevalence and community awareness of SCD and to determine the feasibility of using point-of-care testing to enroll newborns in a new SCD clinic for ongoing treatment. DESIGN/METHODS: We screened infants at Shirati KMT hospital for SCD using HemoTypeSC, an inexpensive point-of-care test. Infants who screened positive were enrolled in the SCD clinic and instructed to return at 6–12 weeks for confirmatory testing, counseling, and preventive care. RESULTS: A total of 999 newborns were screened from February to September 2019. Among these, 31.6% (315/999) had sickle cell trait and 3.9% (39/999) had SCD. No hemoglobin C was detected. Very few parents knew their own sickle cell status (0.3%). At 5 months after completion, 12 infants from the screening study and 30 additional children had been seen at the SCD clinic for ongoing counseling and care. CONCLUSIONS: Birth prevalence of SCD in rural Tanzania is extremely high and community awareness is low. Newborn point-of-care testing enhances case finding and enables early enrollment in preventive care for SCD, even in rural sub-Saharan Africa with minimal laboratory capacity. SCD-specific clinical services implemented at the district hospital level could expand access to many children and significantly reduce early SCD morbidity and mortality.

Introduction: Sickle cell anemia (SCA) is highly prevalent in sub-Saharan Africa with >300,000 annual births, and substantial morbidity and mortality due to limited resources. The burden of stroke in this population is of particular concern, given the devastating clinical and neurocognitive sequelae of these events. Hydroxyurea, a potent disease modifying therapy for SCA, is safe and feasible for low-resource and malarial endemic countries within sub-Saharan Africa and when used at maximum tolerated dose (MTD), decreases the incidence of acute painful vaso-occlusive events, infections, malaria, transfusions, hospitalizations, and death. Whether hydroxyurea can prevent primary stroke in SCA within Africa has not yet been determined, due in part to lack of stroke screening programs using transcranial Doppler (TCD) ultrasonography. If effective, hydroxyurea would have even more therapeutic benefits for children with SCA, particularly in settings where blood is not available, affordable, or safe. We designed the Stroke Prevention with Hydroxyurea Enabled through Research and Education (SPHERE) trial to determine the stroke risk among Tanzanian children using TCD screening and to investigate the effects of hydroxyurea to reduce that risk. Methods: The SPHERE trial (NCT03948867) is a single center prospective phase 2 open-label screening and treatment pilot study at Bugando Medical Centre, a teaching and referral hospital in Mwanza, Tanzania. Children 2-16 years old with SCA consented to TCD screening by locally trained and certified examiners; recent febrile illness, red cell transfusion, or hospitalization were temporary exclusions. Study participants with maximum Time-Averaged Mean Velocity (TAMV) on TCD exam categorized as conditional (170-199 cm/sec) or abnormal (≥200 cm/sec) are offered hydroxyurea with escalation to MTD, while those with normal TCD screening exams will be rescreened annually. Hydroxyurea is initiated at ~20 mg/kg/day using 500 mg capsules and a weekly dosing calculator, then escalated every 8 weeks by 5 mg/kg/day up to 35 mg/kg/day. Children on hydroxyurea are seen monthly during dose escalation and every 3 months after reaching MTD. The primary endpoint is change in TCD velocity after 12 months of hydroxyurea therapy. Secondary endpoints include changes in splenic volume and filtrative function; change in renal function; incidence of infection, especially malaria; hydroxyurea pharmacokinetics; and genetic modifiers of disease including pharmacogenomics. Results: From April 2019 to April 2020, a total of 202 children underwent TCD screening, exceeding the projected enrollment pace and goal (Figure). The average age (mean ± SD) at enrollment was 6.8 ± 3.5 years, and 53% were female. A majority had previous dactylitis (75%), painful vaso-occlusive episode (93%), blood transfusion (68%), and malaria (89%). Recurrent hospitalization was common with 30% having >5 previous hospitalizations. Only 4% had previously used hydroxyurea. Baseline labs included hemoglobin = 7.8 ± 1.3 g/dL, HbF = 9.3 ± 5.4 %, and ANC = 5.5 ± 2.4 x 109/L. Baseline assessment revealed a palpable spleen in 46 children (23%), and most of these (29) were ≥5 cm below the costal margin. Abdominal ultrasonography documented splenic tissue in 91% of children with an average volume of 101 ± 123 mL (range 8-1045). TCD examinations were performed in all children at enrollment with average TAMV of 148 ± 27 cm/sec [median 144, IQR 130-169 cm/sec] with 76% normal, 21% conditional, 2% abnormal, and 1% inadequate exams. Of 47 children eligible for hydroxyurea for elevated TCD velocities, 45 successfully initiated treatment, while 1 lived too far away for regular visits, and 1 had low blood counts from acute splenic sequestration and died before initiating study treatment. Conclusion: Children with SCA in Tanzania have a high risk for primary stroke. Identification of elevated TCD velocities through screening by local trained certified examiners, coupled with initiation of hydroxyurea treatment with dose escalation to MTD, offers a feasible and affordable means by which to lower TCD velocities and reduce primary stroke risk. Now fully enrolled, SPHERE has built local clinical capacity, research infrastructure and high-quality TCD screening, and will prospectively determine the benefits of hydroxyurea for stroke prevention, as a prelude for expanding hydroxyurea access for children with SCA in Tanzania. Figure Disclosures No relevant conflicts of interest to declare.

I NTRODUCTION: The hallmark of sickle cell disease (SCD) is hemoglobin S (HbS) polymerization upon deoxygenation, resulting in red blood cell (RBC) sickling, oxidative damage, membrane damage, hemolysis, cell adhesion, and vaso-occlusion. Exacerbating the pathogenesis of SCD, the HbS RBC has [1] increased (↑) 2,3-DPG with decreased (↓) O2 affinity (↑ P50) and [2] ↓ RBC ATP. FT-4202, a small molecule allosteric activator of erythrocyte pyruvate kinase (PKR), increases PKR activity resulting in ↓ 2,3-DPG levels and ↑ ATP levels in RBCs. In healthy volunteer (HV) studies (Kalfa et al. Blood 2019), FT-4202 was well tolerated, demonstrating physiologic responses (↓ 2,3-DPG and ↑ ATP) with biologic effects including ↑ O2 affinity, ↓ reticulocytes (P METHODS: In the SD and 14-day MD cohorts, pts with SCD were randomized 3:1 to FT-4202 or placebo. Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, ECGs and laboratory parameters. PK/PD blood sampling was performed for up to 72h after the last dose and at the end-of-study visit; PD parameters included 2,3-DPG, ATP, P50, RBC deformability with controlled deoxygenation and reoxygenation (Lorrca® oxygenscan) and varying osmolality (Lorrca® osmoscan). To maintain study blind, pt identifiers were removed when needed. RESULTS: As of 17-July-2020, the SD (700 mg FT-4202) cohort is complete and the 1st MD cohort (MD-1, 300 mg once daily) is enrolling. Unblinded data from the SD and blinded data from the MD-1, 3 pt safety lead-in (randomized 2:1) are summarized. No serious adverse events (SAEs) or TEAEs leading to pt withdrawal were reported. In the SD cohort, 7 pts (2 males, 5 females, all HbSS) received 700 mg FT-4202 (n=5) or placebo (n=2). Six transient Grade 1 TEAEs occurred in 4 of 7 (57%) pts, including 3 TEAEs (arthralgia, headache, palpitations) in 2 of 5 (40%) pts receiving FT-4202 and 3 TEAEs (back pain, myalgia, pruritis) in 2 of 2 (100%) pts receiving placebo. RBC ATP concentrations increased by 30% and RBC 2,3-DPG concentrations decreased by 26% 24h after FT-4202. Increased O2 affinity (↓P50) with a decreased point of sickling (PoS) and improved HbS RBC deformability were observed in all FT-4202-treated pts. Improved HbS RBC membrane function was also demonstrated with a shift of the osmoscan results towards normal. Improved hematologic parameters, including ~0.9 g/dL Hb increase compared with placebo, were also observed 24h after a single dose of FT-4202. In 3 pts with SCD (3 females, all HbSS) who thus far completed MD-1, 14 days of 300 mg FT-4202 or placebo daily was well tolerated, with 1 pt reporting transient, unrelated Grade 2 TEAEs of nausea/vomiting at the end of the 14-day dosing period. Laboratory changes relative to pretreatment for each pt are shown in Table 1. In 2 of 3 SCD MD-1 pts treated with FT-4202/placebo (currently blinded), Hb increased by > 1 g/dL, % reticulocytes decreased, and markers of hemolysis were improved after 14 days of treatment (compared to pre-treatment levels). Hematologic parameters returned to pre-treatment levels 4 to 7 days post-treatment (data not shown) without clinical AEs. Functional studies in the 2 pts with increased Hb showed improved RBC deformability (↓ PoS) and improved RBC membrane function while on study treatment relative to pre-treatment and/or post-treatment. CONCLUSION: FT-4202 has a favorable safety profile in pts with SCD receiving a single dose or up to 14 days of dosing. A single dose of FT-4202 led to decreased 2,3-DPG and increased ATP, resulting in increased O2 affinity, decreased PoS, improved RBC deformability, and improved RBC membrane function. Initial blinded results of daily dosing with 300 mg FT-4202/placebo over 14 days show improvement in both hematologic and hemolytic parameters in 2 of 3 pts with SCD, along with improved RBC functional studies, suggesting the pharmacodynamic consequences of PKR activation may be of clinical benefit in SCD. Multiple-dose cohorts are ongoing to further evaluate the safety, PK/PD, and biological activity of FT-4202 following daily administration in pts with SCD; updated data will be presented. Disclosures Brown: Imara, Inc.: Consultancy, Research Funding; Forma Therapeutics, Inc,: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis, Inc.: Consultancy, Research Funding. Kalfa:Agios Pharmaceuticals, Inc: Consultancy, Research Funding; Forma Therapeutics, Inc: Research Funding. Kuypers:Forma Therapeutics, Inc.: Research Funding. Saraf:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Boards, Speakers Bureau; Novartis, Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer, Global Blood Therapeutics, Novartis: Research Funding. Estepp:Global Blood Therapeutics, Forma Therapeutics, Pfizer, Eli Lilly and Co: Research Funding; Daiichi Sankyo, Esperion, Global Blood Therapeutics: Consultancy; ASH, NHLBI: Research Funding. Malik:Aruvant Sciences, CSL Behring: Patents & Royalties; Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy. Ribadeneira:Forma Therapeutics, Inc.: Current Employment. Forsyth:Forma Therapeutics, Inc.: Current Employment. Schroeder:Forma Therapeutics, Inc.: Current Employment. Wu:Forma Therapeutics, Inc.: Current Employment. Kelly:Forma Therapeutics, Inc.: Current Employment. Telen:Forma Therapeutics: Research Funding; GlycoMimetics Inc.: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

To determine the regional- and district-level newborn prevalence of sickle cell trait and disease, and the prevalence of haemoglobin variants and genetic modifiers of sickle cell disease, in the nine regions of north-western United Republic of Tanzania.We repurposed dried blood spot samples from children (aged 0-24 months) born to mothers living with human immunodeficiency virus (HIV), collected as part of the HIV Early Infant Diagnosis programme, for sickle cell diagnosis. We performed isoelectric focusing to determine whether samples had normal haemoglobin, sickle cell trait, sickle cell disease or a rare haemoglobin variant. We shipped samples diagnosed as disease or variant to Cincinnati Children's Hospital in the United States of America for deoxyribonucleic-acid-based analyses to determine the prevalence of α-thalassaemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency or fetal haemoglobin genetic modifiers.We analysed a total of 17 200 specimens during February 2017-May 2018. We observed a prevalence of sickle cell trait and disease of 20.3% (3492/17 200) and 1.2% (210/17 200), respectively. District-level trait varied from 8.6% (5/58) to 28.1% (77/274). Among confirmed sickle cell disease specimens, we noted 42.7% (61/143) had 1-gene deletion and 14.7% (21/143) had 2-gene deletion α-thalassaemia trait. We documented G6PD AOur calculated prevalence is twice as high as previously reported and reinforces the need for enhanced sickle cell diagnostic services. Our district-level data will inform public health policy, allowing screening and disease-modifying hydroxyurea therapy to be focused on high-prevalence areas, until universal newborn screening is available.Déterminer la prévalence de la drépanocytose et du trait drépanocytaire chez les nouveau-nés, ainsi que la prévalence de variants d'hémoglobine et de modificateurs génétiques de la drépanocytose dans les neuf régions du nord-ouest de la République-Unie de Tanzanie.Nous avons réutilisé des échantillons de gouttes de sang séché provenant d'enfants (âgés de 0 à 24 mois) nés de mères atteintes du virus de l'immunodéficience humaine (VIH), prélevés dans le cadre du programme de diagnostic précoce de l'infection à VIH chez le nourrisson pour détecter une éventuelle drépanocytose. Nous avons procédé à une focalisation isoélectrique pour savoir si les échantillons présentaient une hémoglobine normale, un trait drépanocytaire, une drépanocytose ou un variant d'hémoglobine rare. Ensuite, nous avons envoyé les échantillons identifiés comme porteurs de la maladie ou d'un variant à l'hôpital pour enfants de Cincinnati, aux États-Unis, afin d'analyser l'acide désoxyribonucléique et de mesurer la prévalence d'une α-thalassémie, d'un déficit en glucose-6-phosphate déshydrogénase (G6PD) ou de modificateurs génétiques de l'hémoglobine fœtale.Nous avons étudié 17 200 spécimens au total entre février 2017 et mai 2018. Nous avons observé une prévalence de 20,3% (3492/17 200) pour la drépanocytose, et de 1,2% (210/17 200) pour le trait drépanocytaire. D'un district à l'autre, la présence du trait variait de 8,6% (5/58) à 28,1% (77/274). Nous avons constaté que 42,7% (61/143) des spécimens chez qui une drépanocytose avait été confirmée étaient privés d'un gène, et 14,7% (21/143) de deux gènes du trait α-thalassémique. Enfin, nous avons répertorié un déficit en G6PD ALa prévalence que nous avons calculée est deux fois supérieure aux chiffres mentionnés précédemment, et souligne la nécessité d'instaurer de meilleurs services de diagnostic de la drépanocytose. Nos données réparties par district fourniront des informations en matière de politique de santé publique, afin que le dépistage et le traitement modificateur de la maladie, à base d'hydroxyurée, se concentrent sur les zones de forte prévalence jusqu'à ce qu'un dépistage universel des nouveau-nés soit disponible.Determinar la prevalencia de la enfermedad y del rasgo de las células falciformes en los recién nacidos a nivel regional y de distrito, y la prevalencia de las variantes de hemoglobina y de los modificadores genéticos de la drepanocitosis en las nueve regiones del noroeste de la República Unida de Tanzania.Se reutilizaron las muestras de las manchas de sangre seca de los niños (de 0 a 24 meses de edad) nacidos de madres que padecían el virus de la inmunodeficiencia humana (VIH); estas muestras se obtuvieron a través del programa de Diagnóstico precoz del VIH en niños para diagnosticar las células falciformes. Se aplicó la técnica del enfoque isoeléctrico para determinar si las muestras tenían hemoglobina, rasgos de células falciformes, drepanocitosis normales o una variante de hemoglobina poco frecuente. Se enviaron muestras diagnosticadas como enfermedad o variante al Hospital Infantil de Cincinnati (Cincinnati Children's Hospital) en los Estados Unidos de América para analizarlas a base de ácido desoxirribonucleico y así determinar la prevalencia de talasemia α, de deficiencia de glucosa-6-fosfato deshidrogenasa (G6PD, por sus siglas en inglés) o de modificadores genéticos de hemoglobina fetal.Se analizaron un total de 17 200 muestras entre febrero de 2017 y mayo de 2018. Se observó una prevalencia del rasgo de las células falciformes y de la drepanocitosis del 20,3 % (3492/17 200) y del 1,2 % (210/17 200), respectivamente. El rasgo a nivel de distrito varió del 8,6 % (5/58) al 28,1 % (77/274). Se observó que en las muestras de drepanocitosis confirmadas, el 42,7 % (61/143) presentaba la eliminación de un gen y el 14,7 % (21/143) la eliminación de dos genes en el rasgo de talasemia α. Se registró una deficiencia de G6PD A- en el 19,2 % (14/73) de los varones.La prevalencia que se calcula aquí es el doble de la que se notificó anteriormente y refuerza la necesidad de mejorar los servicios para el diagnóstico de la drepanocitosis. Estos datos a nivel de distrito contribuirán a la política de salud pública, ya que permitirán que los cribados y la terapia con hidroxicarbamida que modifica la enfermedad se centren en las zonas de alta prevalencia, hasta que se disponga de un cribado universal de los recién nacidos.الغرض تحديد معدل انتشار سمات ومرض الخلايا المنجلية لدى حديثي الولادة على مستوى الأقاليم والمناطق، وانتشار متغيرات الهيموجلوبين والمعدلات الجينية لمرض فقر الدم المنجلي، في المناطق التسع الواقعة شمال غرب جمهورية تنزانيا المتحدة. الطريقة قمنا بإعادة استخدام عينات بقع الدم المجففة من الأطفال (من حديثي الولادة إلى 24 شهرًا) المولودين لأمهات مصابات بفيروس نقص المناعة البشرية (HIV)، والتي تم جمعها كجزء من برنامج التشخيص المبكر لفيروس نقص المناعة البشرية للرضع، لتشخيص مرض الخلايا المنجلية. أجرينا تركيزًا متساوي الجهد الكهربائي لتحديد ما إذا كانت العينات تحتوي على هيموجلوبين طبيعي، أو سمة للخلايا المنجلية، أو مرض الخلايا المنجلية، أو أحد المتغيرات النادرة للهيموجلوبين. كما قمنا بشحن عينات تم تشخيصها على أنها مصابة بالمرض أو أحد المتغيرات، إلى مستشفى سينسيناتي للأطفال في الولايات المتحدة الأمريكية، لإجراء تحليلات باستخدام حمض الديوكسي ريبونيوكليك لتحديد مدى انتشار كل من ثلاسيميا ألفا، أو النقص في نازع هيدروجين الجلوكوز 6 فوسفات (G6PD)، أو المعدلات الوراثية للهيموجلوبين الجنيني. النتائج قمنا بتحليل إجمالي 17200 عينة خلال الفترة من فبراير/شباط 2017 إلى مايو/أيار 2018. ولاحظنا انتشار سمة ومرض الخلايا المنجلية بنسبة 20.3% (3492/17200)، و1.2% (210/17200)، على الترتيب. تنوعت السمات على مستوى المناطق من 8.6% (5/58) إلى 28.1% (77/274). ولاحظنا من بين عينات مرض الخلايا المنجلية المؤكد، أن 42.7% (61/143) قد عانت من حذف جين واحد، و14.7% (21/143) عانت من حذف جينين من سمة ألفا ثلاسيميا. وكما بتوثيق النقص في G6PD A في 19.2% (14/73) من الذكور. الاستنتاج إن معدل الانتشار الذي قمنا باحتسابه هو ضعف ما تم الإبلاغ عنه سابقًا، ويعزز الحاجة إلى خدمات محسنة لتشخيص مرض الخلايا المنجلية. ستؤدي البيانات على مستوى المقاطعات لدينا إلى توجيه سياسة الصحة العامة، مما يسمح لكل من الفحص والمعالجة باستخدام هيدروكسي اليوريا المعدل للأمراض، بالتركيز على المناطق ذات الانتشار المرتفع، حتى يتوفر فحص شامل لحديثي الولادة.确定坦桑尼亚联合共和国西北九个地区，新生儿镰状细胞性状和镰状细胞疾病的患病率，以及血红蛋白变体和镰状细胞疾病遗传修饰因子的患病率。.作为 HIV 早期婴儿诊断计划的一部分，我们将携带人类免疫缺陷病毒 (HIV) 的母亲所生婴儿（0-24 个月）的干血斑样本重新用于诊断镰状细胞。我们对其实施等电聚焦，以确定样本的血红蛋白是否正常、是否具有镰状细胞性状、镰状细胞疾病或罕见的血红蛋白变体。我们将诊断出患有疾病或变异的样本运送到美国辛辛那提儿童医院，进行脱氧核糖核酸分析，以确定α地中海贫血、6-磷酸葡萄糖脱氢酶 (G6PD) 缺失症或胎儿血红蛋白遗传修饰因子的患病率。.我们在 2017 年 2 月至 2018 年 5 月期间共分析了 17200 个样本。我们观察到镰状细胞性状和镰状细胞疾病的患病率分别为 20.3％ (3492/17 200) 和 1.2％ (210/17 200)。区级镰状细胞性状患病率则从 8.6% (5/58) 到 28.1% (77/274) 不等。在确诊的镰状细胞疾病样本中，我们发现 42.7% (61/143) 具有 1 基因缺失型 α 地中海贫血性状，14.7% (21/143) 具有 2 基因缺失型 α 地中海贫血性状。我们注意到 19.2% (14/73) 的男婴患有 G6PD A–缺乏症。.我们计算得出的患病率是先前报道的两倍，这凸显了加强镰状细胞诊断服务的必要性。我们的区级数据将为公共卫生政策提供信息，从而确保在新生儿普查之前，对高发地区集中展开筛查和疾病修饰羟基脲疗法。.Определить на национальном уровне и на уровне районов распространенность среди новорожденных носительства признака серповидно-клеточной анемии и самого этого заболевания, а также распространенность вариантов гемоглобина и генетических модификаторов серповидно-клеточной анемии в девяти регионах на северо-западе Объединенной Республики Танзания.Для диагностики серповидно-клеточной анемии авторы использовали взятые методом высушивания пятна образцы крови детей в возрасте от 0 до 24 месяцев, чьи матери живут с вирусом иммунодефицита человека (ВИЧ); эти образцы были собраны в рамках программы ранней диагностики ВИЧ у детей. Для определения наличия в образцах нормального гемоглобина, носительства признака серповидно-клеточной анемии, собственно серповидно-клеточной анемии или редкого варианта гемоглобина использовался метод изоэлектрической фокусировки. Образцы, которые были диагностированы как соответствующие проявлениям заболевания или как содержащие вариантный гемоглобин, были направлены в Детскую больницу Цинциннати, США, для проведения ДНК-анализа с целью определения распространенности в них α-талассемии, дефицита глюкозо-6-фосфат-дегидрогеназы (Г6ФД) или наличия генетических модификаторов фетального гемоглобина.Авторы проанализировали 17 200 образцов в период с февраля 2017 г. по май 2018 г. Носительство признака серповидно-клеточной анемии было обнаружено в 20,3% случаев (3492 из 17 200 образцов), а серповидно-клеточная анемия — в 1,2% (210 из 17 200 образцов). Наличие признака в разных районах варьировалось от 8,6% (5 из 58 образцов) до 28,1% (77 из 274 образцов). Среди образцов с подтвержденным диагнозом серповидно-клеточной анемии в 42,7% случаев (61 из 143) наблюдался признак α-талассемии с делецией 1 гена и в 14,7% (21 из 143) — с делецией 2 генов. Дефицит Г6ФД был зафиксирован у 19,2% (14 из 73) мальчиков.Рассчитанная авторами распространенность заболевания вдвое превышает опубликованные ранее значения и еще раз указывает на необходимость укрепления и расширения услуг по диагностике СКА. Полученные данные по районам станут основой для выработки политики в области общественного здравоохранения, которая бы позволяла сосредоточить скрининговое обследование и лечение гидроксимочевиной (изменяющее течение заболевания) в областях с высоким распространением заболевания до тех пор, пока не станет возможным всеобщее скрининговое обследование новорожденных.

BackgroundAfrica has the highest rates of child mortality. Little is known about outcomes after hospitalization for children with very severe anemia.ObjectiveTo determine one year mortality and predictors of mortality in Tanzanian children hospitalized with very severe anemia.MethodsWe conducted a prospective cohort study enrolling children 2-12 years hospitalized from August 2014 to November 2014 at two public hospitals in northwestern Tanzania. Children were screened for anemia and followed until 12 months after discharge. The primary outcome measured was mortality. Predictors of mortality were determined using Cox regression analysis.ResultsOf the 505 children, 90 (17.8%) had very severe anemia and 415 (82.1%) did not. Mortality was higher for children with very severe anemia compared to children without over a one year period from admission, 27/90 (30.0%) vs. 59/415 (14.2%) respectively (Hazard Ratio (HR) 2.42, 95% Cl 1.53–3.83). In-hospital mortality was 11/90 (12.2%) and post-hospital mortality was 16/79 (20.2%) for children with very severe anemia. The strongest predictors of mortality were age (HR 1.01, 95% Cl 1.00–1.03) and decreased urine output (HR 4.30, 95% Cl 1.04 – 17.7).ConclusionsChildren up to 12 years of age with very severe anemia have nearly a 30% chance of mortality following admission over a one year period, with over 50% of mortality occurring after discharge. Post-hospital interventions are urgently needed to reduce mortality in children with very severe anemia, and should include older children.

Malaria remains common in sub-Saharan Africa, but it is frequently over-diagnosed and over-treated in hospitalized children. HIV is prevalent in many malaria endemic areas and may delay parasite clearance and increase mortality among children with malaria. This prospective cohort study enrolled children with suspected malaria between 3 months and 12 years of age hospitalized at two referral hospitals in Tanzania. Both a thick blood smear (BS) and a malaria rapid diagnostic test (mRDT) were performed. If discordant results were obtained, PCR was performed for Plasmodium falciparum. Malaria was confirmed if two out of three tests were positive. Malaria parasite densities were determined for two consecutive days after diagnosis and treatment of malaria. All participants were tested for HIV. Among 1492 hospitalized children, 400 (26.8%) were enrolled with suspected malaria infection. There were 196/400 (49.0%) males, and the median age was 18 [9-36] months. BS was positive in 95/400 (23.8%), and mRDT was positive in 70/400 (17.5%), with moderate agreement (Kappa=0.598). Concordant results excluded malaria in 291/400 (72.8%) and confirmed malaria in 56/400 (14.0%). PCR performed on 53 discordant results confirmed malaria in 1/39 of the BS-positive/mRDT-negative cases, and 6/14 of the BS-negative/mRDT-positive cases. The prevalence of confirmed malaria was 63/400 (15.8%). In multivariable logistic regression, malaria was associated with HIV (OR 3.45 [1.65-7.20], p=0.001). Current breastfeeding (OR 0.25 [0.11-0.56], p=0.001) and higher hemoglobin (OR 0.70 [0.60-0.81], p

Tanzania has the third highest number of infants in the world born annually with sickle cell disease (SCD). Tanzania lacks a national newborn screening program, and a large majority of the clinical care, resources, and research for SCD are located in the coastal city of Dar es Salaam. Previous

e19086 Background: TNBC is a heterogeneous sub-type of breast cancer characterized by younger age of onset, more aggressive course, and higher incidence among African Americans who also experience disparities in access to health care including health insurance coverage and cancer screening. Methods: We performed a retrospective analysis of the NCDB to study the impact of race and insurance status on the stage at diagnosis and overall survival of people with TNBC. Chi-square tests analysis was used for univariate analysis. Cox models were used to test for survival differences between race and insurance status adjusted for other covariates such as age at diagnosis, gender. Results: Among 1,148,016 people with TNBC registered in the NCDB from 2010 to 2016, 87.7% were identified as white and 12.3% were identified as black. The majority (99%) were female. Mean age at diagnosis was 62.0 years for females and 65.9 years for males. Among white patients, 1.8% were uninsured while 3.6% of black patients were uninsured. Advanced stage at diagnosis was less common among white people (9.4%, Stage 3; 4.9%, Stage 4) than black people (13.3%, Stage 3; 7.6%, Stage 4). Uninsured patients had more advanced disease at time of diagnosis (16.2%, Stage 3; 14.1%, Stage 4) than insured patients (9.8%, Stage 3; 5.0%, Stage 4). Overall survival after adjustment for age at diagnosis, gender and insurance status was greater for white patients compared to black patients (harm ratio 0.60). Overall survival after adjustment for age at diagnosis, gender and race was lower for uninsured patients than insured patients (harm ratio 2.25). Conclusions: Racial disparities significantly affect TNBC patients, with black women having lower insurance coverage and worse overall survival. [Table: see text]

Background Worldwide Helicobacter pylori (H.pylori) treatment is of great challenge due to increased antibiotic resistance. The burden of H. pylori antibiotic resistance in Africa is high with unclear information regarding the real magnitude. This systematic review and meta-analysis was conducted to investigate the magnitude of H.pylori antibiotic resistance in Africa to gain insight of the extent of the problem among H.pylori naïve treatment patients. Method The search was performed in the academic databases, Embase, PubMed, Web of Science and Africa Wide Information. ProQuest Dissertation and Theses, Scopus, Ethos, Africa Index Medicus (WHO), BioMed Central Proceedings, BASE, British Library, Open grey, Library of Congress and the New York Academy of Grey Literature Report were additionally searched for grey literature. Published articles from Africa on H.pylori antibiotic resistance between 1986 and June 2017 were systematically reviewed to estimate the H. pylori extent of resistance to macrolides, quinolones, amoxicillin, tetracycline and metronidazole. Results In 26 articles a total of 2085 isolates were tested for metronidazole, 1530 for amoxicillin, 1277 for tetracycline, 1752 for clarithromycin and 823 for quinolones.The overall pooled proportion of H.pylori resistance to quinolones, clarithromycin, tetracycline, metronidazole and amoxicillin were: (17.4%, 95%CI 12.8 - 21.9), (29.2%, 95%CI:26.7-31.8), (48.7%, 95%CI: 44.5-52.9), (75.8%, 95% CI: 74.1-.77.4) and (72.6%, 95% CI: 68.6-76.6), respectively. The commonest mutation detected were A2143G (49/97) for clarithromycin, RdxA (41/56) for metronidazole and D87I (16/40) for quinolones. Conclusion Prevalence of metronidazole, clarithromycin, and amoxicillin resistance is high in developing world including Africa. This could impair the first line triple therapy of the H.pylori infection. There is a need of conducting surveillance of H.pylori susceptibility pattern in Africa for dual and triple resistance which can be used for the empirical treatment. Electronic supplementary material The online version of this article (10.1186/s12879-018-3099-4) contains supplementary material, which is available to authorized users.

The vast majority of the world's population of children and adults with sickle cell disease (SCD) are born in low-resource settings, particularly in sub-Saharan Africa, the Caribbean, the Middle East, and India. As a result numerous well-established, cost-effective, and evidence-based strategies for managing SCD such as newborn screening, early education, vaccinations, screening for stroke prevention, and treatments with safe transfusions and hydroxyurea are often unavailable, leading to substantial morbidity and increased mortality. Collaborations between high-income countries and these low-resource settings (North-South partnerships) have been advocated, with the goal of improving clinical care. Based on directives promulgated by the World Health Organization, we have developed a strategy of developing prospective research programs that focus on training, capacity building, and local data collection. This strategy involves consideration of important guiding principles, full partnerships, proper planning, and financial issues before program launch, after which rigorous program management is required for full effect and long-term sustainability. Ultimately these collaborative research programs should help create national guidelines and lead to improved clinical care for all children and adults with SCD.

Tanzania has the third highest birth rate of sickle cell anaemia (SCA) in Africa, but few studies describe severity of complications or available treatments, especially in Northwest Tanzania around Lake Victoria where the sickle gene is most prevalent. This is a report of the spectrum of clinical disease and range of interventions available at Bugando Medical Centre (Bugando) in Northwest Tanzania in Africa.A cross-sectional study was carried out in Bugando between 1 August 2012 and 30 September 2012. Children (15 years old) with SCA attending Bugando were sequentially enrolled. A trained research assistant completed a Swahili questionnaire with the parent or guardian of each participant concerning demographic information, clinical features of disease, and treatments received.Among the 124 participants enrolled, the median age was 6 years (interquartile range [IQR] 4-8.5), and only 13 (10.5%) were3 years old. Almost all participants (97.6%) had a prior history of a vaso-occlusive episode, 83 (66.9%) had prior acute chest syndrome, and 21 (16.9%) had prior stroke. In the preceding 12 months, 120 (96.8%) had been hospitalized, and a vaso-occlusive episode was the most common reason for hospitalization (35.5%). Prescriptions for folic acid (92.7%) and malaria prophylaxis (84.7%) were common, but only one had received a pneumococcal vaccine, and none had received hydroxyurea or prophylactic penicillin.Children with SCA receiving care in Tanzania are diagnosed late, hospitalized frequently, and have severe complications. Opportunities exist to improve care through wider access to screening and diagnosis as well as better coordination of comprehensive care.

Background Sub-Saharan Africa has the highest rates of child mortality worldwide. Little is known about post-hospital outcomes after an index hospitalization for older children. We determined 12-month post-hospital mortality rate and identified factors associated with higher mortality. Methods In this prospective cohort study, we enrolled children 2–12 years of age admitted to the pediatric wards of two public hospitals in northwestern Tanzania. Participants or proxies were contacted at 3, 6 and 12 months post-hospitalization. The primary outcome measured was mortality. Factors associated with mortality were determined using Cox regression analysis. Results A total of 506 participants were enrolled. In-hospital mortality rate was 7.7% (39/506). Of the 467 participants discharged, the post-hospital mortality rate was 10.1% (47/467). Sickle cell disease (Hazard Ratio (HR) 3.32, 95% CI 1.44–7.68), severe malnutrition (HR 3.19, 95% CI 1.18–8.57), neurologic diseases (HR 3.51, 95% CI 1.35–9.11), heart disease (HR 7.11, 95% CI, 2.89–17.51), cancer (HR 11.79, 95% CI 4.95–28.03), and septic shock (HR 4.64, 95% CI 1.42–15.08) had higher association with mortality compared to other diagnoses. The risk factors significantly associated with mortality included older age (HR 1.01, 95% CI 1.00–1.08), lower hemoglobin level (HR 0.83, 95% CI 0.76–0.90), lower Glasgow Coma Scale (HR 0.66, 95% CI 0.59–0.74), history of decreased urine output (HR 2.87, 95% CI 1.49–5.53), higher respiratory rate (HR 1.02, 95% CI 1.00–1.03), estimated glomerular filtration rate less than 60 ml/min/1.73m2 (binary) (HR 1.84, 95% CI 1.10–3.10), and lower oxygen saturation (HR 0.96, 95% CI 0.92–0.99). Conclusions Post-hospital mortality is disturbingly high among children 2–12 years of age in Tanzania. Post-hospital interventions are urgently needed especially for older children with chronic illnesses.

Parvovirus B19 (B19) can cause transient aplastic crisis and lead to acute severe anemia. This study investigated the relationship between B19 and anemia among children

Both anemia and sickle cell disease (SCD) are highly prevalent across sub-Saharan Africa, and limited resources exist to diagnose these conditions quickly and accurately. The development of simple, inexpensive, and accurate point-of-care (POC) assays represents an important advance for global hematology, one that could facilitate timely and life-saving medical interventions. In this prospective study, Robust Assays for Point-of-care Identification of Disease (RAPID), we simultaneously evaluated a POC immunoassay (Sickle SCAN™) to diagnose SCD and a first-generation POC color-based assay to detect anemia. Performed at Bugando Medical Center in Mwanza, Tanzania, RAPID tested 752 participants (age 1 day to 20 years) in four busy clinical locations. With minimally trained medical staff, the SCD POC assay diagnosed SCD with 98.1% sensitivity and 91.1% specificity. The hemoglobin POC assay had 83.2% sensitivity and 74.5% specificity for detection of severe anemia (Hb ≤ 7 g/dL). Interobserver agreement was excellent for both POC assays (r = 0.95–0.96). Results for the hemoglobin POC assay have informed the second-generation assay design to be more suitable for low-resource settings. RAPID provides practical feasibility data regarding two novel POC assays for the diagnosis of anemia and SCD in real-world field evaluations and documents the utility and potential impact of these POC assays for sub-Saharan Africa.

Introduction Little is known about hepatotoxicity in patients with schistosome and HIV co-infections. Several studies have reported increased liver enzymes and bilirubin levels associated with schistosome infection. We investigated whether HIV-infected adults on antiretroviral therapy who had S. mansoni co-infection had a higher prevalence of hepatotoxicity than those without. Methodology/Principal findings We determined the presence and grade of hepatotoxicity among 305 HIV-infected outpatients who had been on medium-term (3–6 months) and long-term (>36 months) antiretroviral therapy in a region of northwest Tanzania where S. mansoni is hyperendemic. We used the AIDS Clinical Trial Group definition to define mild to moderate hepatotoxicity as alanine aminotransferase, alanine aminotransferase, and/or bilirubin elevations of grade 1 or 2, and severe hepatotoxicity as any elevation of grade 3 or 4. We determined schistosome infection status using the serum circulating cathodic antigen rapid test and used logistic regression to determine factors associated with hepatotoxicity. The prevalence of mild-moderate and severe hepatotoxicity was 29.6% (45/152) and 2.0% (3/152) in patients on medium-term antiretroviral therapy and 19.6% (30/153) and 3.3% (5/153) in the patients on long-term antiretroviral therapy. S. mansoni infection was significantly associated with hepatotoxicity on univariable analysis and after controlling for other factors associated with hepatotoxicity including hepatitis B or C and anti-tuberculosis medication use (adjusted odds ratio = 3.0 [1.6–5.8], p = 0.001). Conclusions/Significance Our work demonstrates a strong association between S. mansoni infection and hepatotoxicity among HIV-infected patients on antiretroviral therapy. Our study highlights the importance of schistosome screening and treatment for patients starting antiretroviral therapy in schistosome-endemic settings. Additional studies to determine the effects of schistosome-HIV co-infections are warranted., Author summary Schistosoma sp. are parasitic worms that infect at least 218 million people worldwide. Over 90% of these individuals live in Africa, where HIV infection is also endemic. Schistosome worms lay eggs that damage the gastrointestinal and genitourinary tracts, causing extensive morbidity and mortality. Patients who have HIV and Schistosoma mansoni co-infections are at risk for damage to the liver due to both the effects of the schistosome parasite and the side-effects of antiretroviral therapy. However, little is known about the additional liver effects of schistosome infection in patients already taking antiretroviral therapy. Therefore, we conducted a study in northwest Tanzania, where our prior work has shown that approximately one-third of HIV-infected patients also have schistosome infections, to investigate the effect of co-infection with Schistosoma mansoni on liver damage in patients taking antiretroviral therapy. We studied 305 HIV-infected outpatients on medium and long-term antiretroviral therapy and determined both liver damage and S.mansoni infection in those patients. We found that among patients on antiretroviral therapy, those with HIV-schistosome co-infection were 3 times more likely to have liver damage than those with HIV infection alone. Our work shows the importance of screening and treating for Schistosoma mansoni to decrease the risk of liver damage in patients infected with HIV.

Background Worldwide, hemoglobinopathies affect millions of children. Identification of hemoglobin disorders in most sub-Saharan African countries is delayed until clinical signs of the disease are present. Limited studies have been conducted to understand their prevalence and clinical presentation among newborns in resource-limited settings. Methodology This was a prospective cohort study. Newborns (aged 0–7 days) at two hospitals in Northwestern Tanzania were enrolled and followed prospectively for 6 months. Clinical and laboratory information were collected at baseline. Participants were screened for hemoglobinopathies using high-performance liquid chromatography. Clinical and laboratory follow-up was performed at 3 and 6 months for those with hemoglobinopathies as well as a comparison group of participants without hemoglobinopathies. Results A total of 919 newborns were enrolled. Among these, 1.4% (13/919) had sickle cell anemia or Hb S/β0-thalassemia (Hb FS), and 19.7% (181/919) had sickle cell trait or Hb S/β+ thalassemia (Hb FAS). Furthermore, 0.2% (two of 919) had β+-thalassemia. Red cell indices compared between Hb FS, Hb FAS, and Hb FA were similar at baseline, but hemoglobin was lower and red cell distribution width was higher in children with Hb FS at 3- and 6-month follow-up. Febrile episodes were more common for children with Hb FS at 3- and 6-month follow-up. Conclusion The prevalence of sickle cell disease among neonates born in Northwestern Tanzania is one of the highest in the world. Newborn screening is needed early in life to identify neonates with hemoglobinopathies so that clinical management may commence and morbidity and mortality related to hemoglobinopathies be reduced.

Background Severe traumatic brain injury (TBI) is a major cause of death and disability worldwide. Prospective TBI data from sub-Saharan Africa are sparse. This study examines epidemiology and explores management of patients with severe TBI and adherence to Brain Trauma Foundation Guidelines at a tertiary care referral hospital in Tanzania. Methods Patients with severe TBI hospitalized at Bugando Medical Centre were recorded in a prospective registry including epidemiologic, clinical, treatment, and outcome data. Results Between September 2013 and October 2015, 371 patients with TBI were admitted; 33% (115/371) had severe TBI. Mean age was 32.0 years ± 20.1, and most patients were male (80.0%). Vehicular injuries were the most common cause of injury (65.2%). Approximately half of the patients (47.8%) were hospitalized on the day of injury. Computed tomography of the brain was performed in 49.6% of patients, and 58.3% were admitted to the intensive care unit. Continuous arterial blood pressure monitoring and intracranial pressure monitoring were not performed in any patient. Of patients with severe TBI, 38.3% received hyperosmolar therapy, and 35.7% underwent craniotomy. The 2-week mortality was 34.8%. Conclusions Mortality of patients with severe TBI at Bugando Medical Centre, Tanzania, is approximately twice that in high-income countries. Intensive care unit care, computed tomography imaging, and continuous arterial blood pressure and intracranial pressure monitoring are underused or unavailable in the tertiary referral hospital setting. Improving outcomes after severe TBI will require concerted investment in prehospital care and improvement in availability of intensive care unit resources, computed tomography, and expertise in multidisciplinary care.

The global burden of kidney disease is increasing, and several etiologies first begin in childhood. Risk factors for pediatric kidney disease are common in Africa, but data regarding its prevalence are lacking. We completed a systematic review of community-based studies describing the prevalence of proteinuria, hematuria, abnormal imaging, or kidney dysfunction among children in sub-Saharan Africa. Medline and Embase were searched. Five hundred twenty-three references were reviewed. Thirty-two references from 9 countries in sub-Saharan Africa were included in the qualitative synthesis. The degree of kidney damage and abnormal imaging varied widely: proteinuria 32.5% (2.2%-56.0%); hematuria 31.1% (0.6%-67.0%); hydronephrosis 11.3% (0.0%-38.0%), hydroureter 7.5% (0.0%-26.4%), major kidney abnormalities 0.1% (0.0%-0.8%). Serum creatinine was reported in four studies with insufficient detail to identify the prevalence renal dysfunction. A majority of the studies were performed in Schistosoma haematobium endemic areas. A lower prevalence of kidney disease was observed in the few studies from non-endemic areas. Published data on pediatric kidney disease in sub-Saharan Africa is highly variable and dependent on S. haematobium prevalence. More community-based studies are needed to describe the burden of pediatric kidney disease, particularly in regions where S. haematobium infection is non-endemic.

Introduction. Based on sparse historical data, Tanzania ranks fourth globally for the estimated number of annual births with sickle cell disease. Northwest Tanzania is projected to have an especially high burden of sickle cell disease, but no contemporary surveillance data exist to verify this projection. We designed a large prospective study to determine the prevalence of both sickle cell trait and sickle cell disease in northwest Tanzania. Additional objectives included an analysis of two known genetic modifiers of sickle cell disease [alpha thalassemia trait and glucose-6-phosphate dehydrogenase (G6PD) deficiency], as well as genetic variants affecting fetal hemoglobin (HbF) expression and characterization of hemoglobin variants. Methods. The Tanzania Sickle Surveillance Study (TS3) is a prospective cross-sectional study to determine the prevalence of sickle cell trait and disease in an area projected to be at high risk. Dried blood spots (DBS) from all children born to HIV-infected mothers in the 9 regions across northwest Tanzania were collected by the HIV Early Infant Diagnosis (EID) program and transported to a central laboratory at Bugando Medical Centre, a teaching and consultancy hospital in Mwanza. DBS were tested by isoelectric focusing and scored as normal, trait, disease, or variant. Samples scored as disease or variant were retested for confirmation, and then frozen for subsequent genetic analysis. In the US, genomic DNA was extracted from each DBS, and sickle cell disease status was confirmed by PCR and TaqMan genotyping. All confirmed samples were then analyzed for alpha thalassemia trait (rightward -3.7 gene deletion) using quantitative real time PCR, and for G6PD deficiency using three real time PCR probes to distinguish A and B G6PD isoforms, to identify the G6PD A- variant, and to confirm the sex, respectively. Single nucleotide polymorphisms within 3 quantitative trait loci [BCL11A, the HBS1L-MYB intergenic polymorphism (HMIP) region, and the gamma-globin promoter XmnI site] that modify baseline HbF were analyzed using TaqMan genotyping. DBS with hemoglobin variants were investigated for the presence of common variants found in East Africa. Results. Between February 2017 and May 2018, a total of 232 IEF gels were completed by local staff in Tanzania. Among EID samples from children Conclusion. The prevalence of sickle cell trait and disease among infants in northwest Tanzania is very high, exceeding 20% trait and 1.2% disease. Regional prevalence data paired with region-specific crude birth rates predict 10,055 births annually in the northwest regions, more than doubling previous estimates. Concomitant alpha thalassemia trait and G6PD deficiency are frequently co-inherited and may affect the phenotype, as well as common genetic modifiers of HbF expression. Our detailed genetic analysis of a geographically representative surveillance cohort provides a foundation for future targeted screening and the introduction of hydroxyurea for treatment of sickle cell disease in northwest Tanzania. Disclosures Ware: Bristol Myers Squibb: Other: Research Drug Donation; Addmedica: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB.

Aims Diabetes increases the risk of tuberculosis and the prevalence of diabetes is rising in tuberculosis-endemic regions such as sub-Saharan Africa. Resource-appropriate strategies for tuberculosis case finding among African adults with diabetes are needed. The aims of this study were to determine prevalence of tuberculosis and evaluate one screening strategy among adult Tanzanians with diabetes. Methods In this prospective cohort study, we evaluated a ‘cough-triggered’ strategy for tuberculosis case finding among adults with diabetes at our zonal hospital in Tanzania. All adults with diabetes and cough underwent further tuberculosis symptom assessment, and those with productive cough had sputum collected for microscopy and Mycobacterium tuberculosis culture. Results Between September 2011 and March 2012, 700 adults with diabetes attended our hospital. A total of 693 were enrolled, 121/693 (17.5%) had cough and 32/693 (4.6%) had at least two of the classic symptoms of tuberculosis. Of note, 87/121 (71.9%) of patients with cough could not produce sputum spontaneously. Nine patients were diagnosed with tuberculosis for a prevalence of 1299/100 000 (1.3%), sevenfold greater than the national average. Conclusions Tuberculosis is common among Tanzanian adults with diabetes, but tuberculosis case finding is challenging because of the high prevalence of non-productive cough. This low-cost, ‘cough-triggered’ tuberculosis case-finding strategy may serve as a reasonable first step for improving tuberculosis screening among adults with diabetes in sub-Saharan Africa.

Hypertension is believed to be an increasingly common driver of the epidemic of noncommunicable diseases (NCDs) in sub-Saharan Africa, but prospective data are scarce. The objective of this prospective study was to determine the contribution of hypertension to deaths, admissions, and hospital days at a Tanzanian zonal hospital.Between 2009 and 2011, diagnoses were recorded for all medical admissions together with age, sex, length of hospitalization and in-hospital mortality.Among 11045 consecutive admissions, NCDs accounted for nearly half of all deaths, admissions, and hospital days. Among NCDs, hypertension-related diseases were the most common and accounted for 314 (33.9%) of the total NCD deaths, 1611 (29.9%) of the NCD admissions, and 12837 (27.8%) NCD hospital days. Stroke (167 deaths) was the leading cause of hypertension-related death. Hypertension was the leading cause of death in patients over the age of 50 years and 57% of hypertension-related deaths occurred in patients less than 65 years old.NCDs account for half of all deaths, admissions and hospital days at our Tanzanian hospital and hypertension-related diseases were the most common NCD. Hypertension accounted for 34% of NCD deaths and 15% of all deaths. Hypertension was the second most common cause of death overall and the leading cause of death in patients more than 50 years old. More than half of hypertension-related deaths occurred before retirement age. These findings have important implications for public health and medical education in sub-Saharan Africa, wherein hypertension and related diseases have not traditionally been given a high priority.

Background. Hypertension is increasingly common in sub-Saharan Africa where traditional medicine use is also common. We conducted a hospital-based, mixed-methods study to determine prevalence, pattern, and correlates of herbal and alternative medicine use in Tanzanian adults hospitalized with hypertension. Methods. A standardized questionnaire was administered. In-depth interviews were performed on a subset of participants. Factors associated with herbal medicine use were determined by logistic regression. The association between traditional medicine uses and allopathic medication adherence was determined using ordinal logistic regression. Qualitative data were analyzed according to grounded theory. Results. Of 213 adults enrolled, 52 (24.4%) reported using herbs during the previous month and 47 (22.1%) reported concurrent use of herbs and allopathic medicines. Lower educational level, nonprofessional employment, and lack of health insurance were significantly associated with herbal medicine use. Alternative medicines use was not associated with lower medication adherence. Qualitative interviews identified several important themes including reasons for herbal medicine use. Conclusion. The use of traditional medicines is very common among patients with hypertension. Adults from low socioeconomic status, those with misunderstandings about hypertension, and those without health insurance were more likely to take herbs. Open, nonjudgmental communication between healthcare workers and patients regarding use of traditional medicines must be encouraged in Africa.

Background The number of adults with diabetes mellitus is increasing worldwide, particularly in Asia and Africa. In sub-Saharan Africa, renal complications of diabetes may go unrecognized due to limited diagnostic resources. The prevalence of chronic kidney disease (CKD) among adult diabetics in sub-Saharan Africa has not been well described. Methods This study was conducted at the diabetes mellitus clinic of Bugando Medical Centre in Mwanza, Tanzania. A total 369 consecutive adult diabetic patients were enrolled and interviewed. Each patient provided a urine sample for microalbuminuria and proteinuria and a blood sample for serum creatinine level. Estimated glomerular filtration rate (eGFR) was calculated using the Cockroft-Gault equation. CKD was staged according to the Kidney Disease Improving Global Outcomes system. Results A total of 309 (83.7%) study participants had CKD; 295 (80.0%) had significant albuminuria and 91 (24.7%) had eGFR

Tanzania ranks third in Africa for the estimated number of annual births with sickle cell disease, but these estimates are based on sparse data from small studies reported over the past 50 years. A recently completed surveillance study from Uganda documented substantial variation in the prevalence of sickle cell trait and disease across the country. Tanzania lacks a national newborn screening program, and no contemporary multi-regional screening of infants has been undertaken. We designed and conducted a prospective study to determine the prevalence of sickle cell trait and disease by region and district in northwest Tanzania, where the prevalence of sickle cell is thought to be highest. The study used existing public health infrastructure while building local capacity for accurate diagnosis of sickle cell disease. Secondary objectives included characterization of hemoglobin variants and exploration of associations between sickle cell trait, sickle cell disease, malaria, and HIV. The Tanzania Sickle Surveillance Study (TS3) is a prospective cross-sectional study of HIV-exposed infants born in 9 regions across the Lake Zone of northwest Tanzania. In Tanzania, the HIV early infant diagnosis (EID) program collects dried blood spots (DBS) from all children born to HIV-infected mothers. DBS are transported to a central laboratory for prompt detection of HIV vertical transmission. In northwest Tanzania, the DBS are transported to Bugando Medical Centre, a teaching and consultancy hospital in Mwanza, where they are tested for HIV and then stored on-site, and thus available for further testing. Isoelectric focusing (IEF) equipment was donated to Bugando Medical Centre along with reagents and supplies. Two laboratory staff were trained by a board certified hematologist, and then attended a two day seminar by the IEF manufacturer. One pediatrician completed a 2-month observership at Cincinnati Children's Hospital. All DBS samples were tested by IEF using appropriate controls. Completed gels were scored independently by two Tanzanian staff members as normal, disease, trait, variant, or uninterpretable. DBS samples scored as disease or variant were repeated for confirmation and preserved for later genotyping. Regular Skype calls were convened with US-based collaborators to improve quality and interpretation. HIV test results were obtained from the local EID program. Between February 2017 and May 2018, 232 IEF gels were completed by the local staff. After children >24 months of age were excluded to obtain a more accurate newborn prevalence, the median age of children tested was 52 days (IQR 41-93 days), and a total of 17,278 unique DBS samples were scored. The quality of laboratory testing was extremely high with only 20 samples scored as uninterpretable and 54 with missing results, and the primary analysis was performed on the 17,204 remaining samples. The overall prevalence of sickle cell trait and disease in the entire cohort was 20.3% and 1.2%, respectively, with a 0.1% prevalence of hemoglobin variants. This corresponds to an allelic frequency of 0.114 for the sickle gene mutation and demonstrates perfect Hardy-Weinberg equilibrium. No HbC or other common beta-globin variants were identified. Geospatial mapping revealed some variation across regions, with sickle trait ranging from 16.6% to 22.5% and disease ranging from 0.5% to 1.5%. Analysis of individual districts with >100 samples revealed wider geographic variability, with sickle trait ranging from 15.2% to 27.8% and disease ranging from 0.0% to 4.3%. Co-morbidity between HIV and sickle cell disease was analyzed to compare it with the effect on mortality previously observed in Uganda. The prevalence of sickle cell disease was the same among HIV-infected and HIV-negative children (1.2%), suggesting no difference in mortality. The prevalence of sickle cell trait and disease among infants born in northwest Tanzania is very high, exceeding 20% trait and 1.2% disease. All regions in the Lake Zone are affected possibly due to lack of immigration to the area and similar environmental exposures. Targeted newborn screening can be started in high prevalence districts, using existing public health infrastructure with minimal start-up cost and training. Future work will evaluate the correlation between historical malaria prevalence and sickle cell prevalence, and identify hemoglobin variants. Disclosures Ware: Addmedica: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Agios: Other: advisory board; Global Blood Therapeutics: Other: advisory board; Biomedomics: Research Funding; Nova Laboratories: Consultancy.

Severe anemia is common in limited-resource settings (LRS) of sub-Saharan Africa, affecting up to 30% of hospitalized patients and associated with high mortality rates. The World Health Organization (WHO) recommends blood transfusion for patients with hemoglobin (Hb) concentration Lack of timely transfusions for children with severe anemia has been associated with significant increase in mortality in several studies within Africa. However, accurate diagnosis of anemia is often difficult or impossible in LRS due to lack of equipment, inadequate replenishment of reagents, poor maintenance or calibration of existing equipment, inadequately trained laboratory personnel, or unreliable and inconsistent access to electricity. A recent publication (Opoka RO et al. BMC Health Serv Res2018) examining transfusion practices in Uganda demonstrated that over half of blood transfusions were administered inappropriately, either without a Hb measurement or with Hb values for which transfusion would not be recommended. The WHO Haemoglobin Colour Scale (HCS), a simple, rapid, point-of-care (POC) test requiring a single drop of blood on filter paper, was developed in an effort to improve the accurate diagnosis of anemia in settings where more definitive laboratory testing is not available. There have been many published reports of the HCS with heterogeneous results, including a recent meta-analysis demonstrating significant variation in sensitivity for the detection of anemia and severe anemia, defined as Hb ≤11 g/dL and Hb ≤7 g/dL respectively (36-76%, Marn H. Lancet Glob Health 2016). The lower limit of the HCS is 4 g/dL, and there is very limited data on its accuracy to diagnose severe anemia requiring transfusion (Hb ≤5 g/dL). The AnemoCheckTMis a rapid, inexpensive, color-based POC test initially designed to diagnose anemia in higher-resource settings, and subsequently modified for use in limited-resource settings (Tyburski et al. J Clin Invest 2014). Based on mixed results both in controlled settings within the US and in the field in Tanzania, AnemoCheck was adapted to focus on its ability to detect severe anemia warranting transfusion. The newly modified AnemoCheck-LRS test allows identification of Hb ranging from 2-8 g/dL, with sharp color changes especially differentiable at the clinically relevant 5 g/dL threshold (Figure 1) to allow accurate diagnosis of clinically meaningful severe anemia in settings where this is common. We prepared and tested 200 samples of varying Hb concentration, each of which was evaluated independently by three separate readers, for a total of 1200 evaluations. By standard CBC measurement, the 200 samples had a mean (±SD) Hbof 5.2±1.9 g/dL (range 1.7 to 10.1 g/dL). Of the 570 samples with Hb ≤8 g/dL (upper limit of AnemoCheck), the absolute difference between AnemoCheck and the gold standard CBC Hb was 0.5±0.4 g/dL (actual difference 0.2±0.7 g/dL). The WHO HCS was inaccurate, with Hb readings consistently higher than the CBC Hb, and an absolute and actual difference of 4.9±1.3 g/dL for samples within the detection range of the HCS (4-14 g/dL, n=405). Table 1 summarizes the ability of both tests to diagnose severe anemia (Hb ≤5 g/dL), demonstrating the accuracy of AnemoCheck-LRS. Furthermore, given that most readings that missed the diagnosis of anemia were within 1 g/dL of actual Hb, if 6 g/dL was used as the screening threshold to identify patients who need a more definitive diagnosis, the sensitivity of AnemoCheck increased to 99%. This study demonstrates that the new AnemoCheck-LRS assay is an accurate POC test to diagnosis very severe anemia in a controlled laboratory setting. The widely cited WHO HCS performed poorly, with a stark inability to diagnose very severe anemia in most cases. This study provides important preliminary data to support follow-up field studies that will use AnemoCheck-LRS to diagnose severe anemia, with the goal of the assay serving as a primary screening test for rapid and accurate diagnosis in settings where laboratory capacity and resources are limited. Disclosures Tyburski: Sanguina, LLC: Employment, Equity Ownership. Ware:Bristol Myers Squibb: Research Funding; Nova Laboratories: Consultancy; Biomedomics: Research Funding; Global Blood Therapeutics: Other: advisory board; Addmedica: Research Funding; Agios: Other: advisory board; Novartis: Membership on an entity's Board of Directors or advisory committees.

OBJECTIVE: To compare short-term and long-term cardiovascular disease (CVD) risk scores and prevalence of metabolic syndrome in HIV-infected adults receiving and not receiving antiretroviral therapy (ART) to HIV-negative controls. METHODS: A cross-sectional study including 151 HIV-infected, ART-naive, 150 HIV-infected on ART and 153 HIV-negative adults. Traditional cardiovascular risk factors were determined by standard investigations. The primary outcome was American College of Cardiology/American Heart Association Atherosclerotic CVD (ASCVD) Risk Estimator lifetime CVD risk score. Secondary outcomes were ASCVD 10-year risk, Framingham risk scores, statin indication and metabolic syndrome. RESULTS: Compared with HIV-negative controls, more HIV-infected adults on ART were classified as high lifetime CVD risk (34.7% vs 17.0%, p CONCLUSIONS: HIV-infected ART-treated individuals have high lifetime cardiovascular risk, and this risk seems to develop rapidly in the first 3-4 years of ART as does the development of clusters of metabolic syndrome criteria. These data identify a new subgroup of low short-term/high-lifetime risk HIV-infected individuals on ART who do not currently meet criteria for CVD risk factor modification but require further study.

Jennifer Downs and colleagues describe a low-tech performance improvement project to improve newborn HIV testing turnaround times.

Hypertension control rates are low in sub-Saharan Africa. Population-specific determinants of blood pressure (BP) control have not been adequately described. The authors measured BP and conducted interviews to determine factors associated with BP control among adults attending a hypertension clinic in Tanzania. Three hundred adults were enrolled. BP was controlled in 47.7% of patients at the study visit but only 28.3% over three consecutive visits. Demographic and socioeconomic factors were not associated with control. Obesity and higher medication cost were associated with decreased control. Their effect was mediated through adherence. Good knowledge of (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.0-6.1; P=.047), attitudes towards (OR, 2.7; 95% CI, 1.0-7.1; P=.04), and practices concerning (OR, 5.4; 95% CI, 2.3-13.0; P

IntroductionMillions of HIV-infected Africans are living longer due to long-term antiretroviral therapy (ART), yet little is known about glucose metabolism disorders in this group. We aimed to compare the prevalence of glucose metabolism disorders among HIV-infected adults on long-term ART to ART-naïve adults and HIV-negative controls, hypothesizing that the odds of glucose metabolism disorders would be 2-fold greater even after adjusting for possible confounders.MethodsIn this cross-sectional study conducted between October 2012 and April 2013, consecutive adults (>18 years) attending an HIV clinic in Tanzania were enrolled in 3 groups: 153 HIV-negative controls, 151 HIV-infected, ART-naïve, and 150 HIV-infected on ART for ≥ 2 years. The primary outcome was the prevalence of glucose metabolism disorders as determined by oral glucose tolerance testing. We compared glucose metabolism disorder prevalence between each HIV group vs. the control group by Fisher's exact test and used multivariable logistic regression to determine factors associated with glucose metabolism disorders.ResultsHIV-infected adults on ART had a higher prevalence of glucose metabolism disorders (49/150 (32.7%) vs.11/153 (7.2%), pConclusionsHIV-infected adults on long-term ART had 5-fold greater odds of glucose metabolism disorders than HIV-negative controls but were rarely aware of their diagnosis. Intensive glucose metabolism disorder screening and education are needed in HIV clinics in sub-Saharan Africa. Further research should determine how glucose metabolism disorders might be related to immune reconstitution.

11514 Background: Contemporary chemotherapy-based regimens provide cures for most pediatric & AYA cancers. However, for patients with relapsed/refractory malignancies, outcomes are poor & imply a distinct and aggressive biology. Identifying common themes in the molecular architecture & oncogenic mechanisms in these patients is a critical priority for drug development. We hypothesized that the molecular signature of cancers in these patients would be independent of histology. We also assessed the response to molecular alteration (MA)-targeted therapies. Methods: IRB-approved analysis of MAs in 306 relapsed/refractory pediatric & AYA malignancies (116 hematologic malignancies, 68 sarcomas, 46 neuroblastomas, 36 CNS, 14 liver, 9 renal, 17 other) was performed. DNA was analyzed for MAs (Foundation Medicine, Cambridge, MA; Univ of Washington, Seattle, WA); additional MAs were identified by cytogenetic & fluorescent in situ hybridization analyses. Results: Median age was 8 years (range birth - 44 yrs). MAs were identified in 90.1% of patients & included a median of 2 mutations (range 0-18) in 133 cancer-related genes. In contrast to genomic analyses of de novo malignancies in children, a high frequency of TP53 MAs was identified (20.4% of patients) and was associated with inferior survival. MAs were identified in targetable pathways including cell cycle regulation (32.6%), DNA repair (7.2%), epigenetic (28.6%), RAS/RAF/MEK (24%), tyrosine kinase (TK; 18.4%), PI3K/AKT/mTOR (11.8%), and NOTCH/WNT (8.9%). A higher number of MAs was associated with inferior survival. Patients with alterations in epigenetic & TK pathways also had inferior outcomes. MAs were frequently independent of histology & the spectrum of mutations was similar to adult cancers. Exceptional responses were observed with MA-based assignment of therapies (epigenetic, NTRK, RAS/RAF/MEK & ALK). Conclusions: Relapsed/refractory pediatric & AYA cancers have frequent MAs independent of histology. The spectrum of MAs is distinct from de novo disease & potentially reflects tumor evolution & resistance mechanisms. These findings support MA-guided approaches to new drug development paired with adult trials.

Hypertension is increasingly common in sub-Saharan Africa, and rates of hypertension control are low. Use of traditional herbal medicines (THM) is common among adults in sub-Saharan Africa and may affect hypertension therapy. We searched Ovid MEDLINE, Ovid EMBASE, and Web of Knowledge in June 2013 to find studies about THM use among hypertensive patients living in sub-Saharan Africa. Two independent reviewers evaluated titles and abstracts. Qualifying references were reviewed in full text. Data were extracted using a standardized questionnaire. Four hundred and eighty-one references were retrieved, and four articles from two countries met criteria for inclusion. The prevalence of THM use was 25–65 % (average 38.6 %). THM was the most common type of complementary and alternative medicines used by patients (86.7–96.6 %). Among THM users, 47.5 % concomitantly used both allopathic medicine and THM. Increased age (p

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a common cause of hospital admissions worldwide. Aetiologies vary by sociodemographics and geography. Retrospective studies of endoscopies in much of Africa have documented oesophageal varices as a leading cause of UGIB. Prospective studies describing outcomes and associations with clinical factors are lacking. METHODS: We conducted a prospective cohort study at a referral hospital in Mwanza, Tanzania where schistosomiasis is endemic. Adults admitted with haematemesis underwent laboratory workup, schistosomiasis antigen testing and elective endoscopy, and were followed for two months for death or re-bleeding. We assessed predictors of endoscopic findings using logistic regression models, and determined prediction rules that maximised sensitivity and positive predictive value (PPV). RESULTS: Of 124 enrolled patients, 13 died within two months (10%); active schistosomiasis prevalence was 48%. 64/91(70%) patients had oesophageal varices. We found strong associations between varices and numerous demographic or clinical findings, permitting construction of simple, high-fidelity prediction rules for oesophageal varices applicable even in rural settings. Portal vein diameter ≥ 13 mm or water sourced from the lake yielded sensitivity, specificity, PPV and NPV >90% for oesophageal varices; presence of splenomegaly or water sourced from the lake maintained sensitivity and PPV >90%. CONCLUSIONS: Our results guide identification of patients, via ultrasound and clinical examination, likely to have varices for whom referral for endoscopy may be life-saving. Furthermore, they support empiric anti-schistosome treatment for patients with UGIB in schistosome-endemic regions. These interventions have potential to reduce UGIB-related morbidity and mortality in Africa.