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Although it has been recognized for only two decades, parvovirus B19 is now known to be a ubiquitous, potentially lethal pathogen. Its clinical manifestations range from fifth disease to prolonged anemia and fetal death. [ABSTRACT FROM AUTHOR]

HbSC disease is a common form of sickle cell disease with significant morbidity and early mortality. Whether hydroxyurea is beneficial for HbSC disease is unknown. Prospective Identification of Variables as Outcomes for Treatment (PIVOT, Trial ID PACTR202108893981080) is a double-blind, randomised, placebo-controlled phase II trial of hydroxyurea for people with HbSC, age 5-50 years, in Ghana. After screening, participants were randomised to placebo (standard of care) or hydroxyurea. The primary outcome is the cumulative incidence of haematological toxicities during 12 months of blinded treatment; secondary outcomes include multiple laboratory and clinical assessments. Between April 2022 and June 2023, 112 children and 102 adults were randomised, including 44% females and average age 21.6 ± 14.5 years. Participants had substantial morbidity including previous hospitalisations (93%), vaso-occlusive events (86%), malaria (79%), often received transfusions (20%), with baseline haemoglobin 11.0 ± 1.2 g/dL and foetal haemoglobin 1.8% ± 1.5%. The spleen was palpable in six children and one adult, and ultrasonographic volumes were collected. Proliferative sickle retinopathy was common (30% children, 75% adults), but proteinuria was less common (3% children, 8% adults). Whole blood viscosity, ektacytometry, point-of-sickling, transcranial Doppler, near-infrared spectrometry (NIRS), 6-minute walk, and quality of life were also measured. Now fully enrolled, PIVOT will document the safety and potential benefits of hydroxyurea on clinical and laboratory outcomes in HbSC disease., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

PET/CT devices with an axial field-of-view (FOV) of 1 m allow simultaneous imaging from the head to the upper thighs, the typical axial extent of many "whole-body" oncological studies acquired by moving a patient sequentially through a conventional FOV device, or rapid total-body imaging using the same approach. Increasing the FOV to around 2 m provides true simultaneous total-body imaging. Either approach dramatically increases the sensitivity for detection of annihilation events arising within the body. For the purposes of this review, both configurations are considered to represent "total-body" PET/CT devices because they share both advantages and disadvantages. These pros and cons are discussed in the context of both clinical and research applications from a patient and institutional perspective., Competing Interests: Declaration of competing interest RJH is the founder and major shareholder of PreMIT Pty Ltd and Precision Molecular Imaging and Theranostics Pty Ltd, which are involved in developing novel theranostic agents and have a collaborative research agreement with Siemens Healthineers. He is also an advisor to GE Medical Systems and a shareholder and Scientific Advisor to Telix Pharmaceuticals. REW is a director and shareholder in Cyclotek Australia Pty Ltd, which is a commercial supplier of PET radiopharmaceuticals in Australia. He is also a shareholder in PreMIT Pty Ltd and Precision Molecular Imaging and Theranostics Pty Ltd. JC has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The mechanisms of action of l-glutamine for the treatment of sickle cell disease (SCD) are not well understood and there are no validated clinical biomarkers to assess response. We conducted a three-week, dose-ascending trial of glutamine and measured the pharmacokinetic (PK) exposure parameters, peak concentration (C max ) and area under the curve (AUC). We used a panel of biomarkers to investigate the pharmacodynamics (PD) of glutamine and studied PK-PD relationships. There was no plasma accumulation of glutamine, glutamate, arginine or other amino acids over time, but modestly improved arginine bioavailability was observed. In standard analysis by dose levels over time, there were no measurable effects on blood counts, viscosity, ektacytometry or reactive oxygen species (ROS). In PK-PD analysis, however, higher glutamine exposure (C max or AUC) was associated with increased whole blood viscosity and cellular dehydration, yet also with higher haemoglobin concentration, increased haematocrit-to-viscosity ratio, decreased reticulocyte ROS, improved RBC deformability and decreased point of sickling. This novel PK-PD analysis identified biomarkers reflecting the positive and negative effects of glutamine, helping to elucidate its mechanisms of action in SCD. PK-optimized dosing to achieve glutamine exposure (AUC or C max ) that is associated with salutary biological effects should be studied to support its therapeutic use., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Hydroxyurea treatment for children with sickle cell anemia (SCA) is effective and life-saving. Stepwise escalation to maximum tolerated dose (MTD) provides optimal benefits, but is logistically challenging and time-consuming, especially in low-income countries where most people with SCA live. Model-informed precision dosing (MIPD) of hydroxyurea expedites MTD determination and improves outcomes compared with trial-and-error dose adjustments. HdxSim, a user-friendly, online, clinical decision support tool was developed to facilitate hydroxyurea MIPD and evaluated using real-world pharmacokinetic (PK) data. First-dose hydroxyurea PK profiles were analyzed from two clinical trial datasets (Hydroxyurea Study of Long-Term Effects (HUSTLE), NCT00305175 and Therapeutic Response Evaluation and Adherence Trial (TREAT), NCT02286154). Areas under the concentration-time curve (AUC) estimated by HdxSim were compared with those determined using traditional trapezoidal methodology and PK software (MWPharm-DOS). The doses predicted by HdxSim and MWPharm-DOS were compared with the observed clinical MTD. For HUSTLE participants, HdxSim accurately estimated hydroxyurea AUC compared with the trapezoidal method, with < 20% variance. The average (mean ± SD) AUC for TREAT participants estimated with HdxSim (68.6 ± 18.0 mg*hour/L) was lower than MWPharm-DOS (78.6 ± 20.7 mg*hour/L, P = 0.012), but the average recommended doses were not different (425 vs. 423 mg/day, P = 0.97). Moreover, HdxSim was non-inferior to MWPharm-DOS at predicting clinical MTD (absolute difference 3.9 ± 5.8 vs. 4.9 ± 8.2 mg/kg/day, P = 0.19). HdxSim accurately estimates hydroxyurea exposure and is noninferior to traditional PK approaches at predicting the clinical hydroxyurea MTD. Hydroxyurea dosing based on target exposure leads to improved outcomes in children with SCA, and has the potential to make PK-guided hydroxyurea dosing more accessible to this neglected population globally., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Background: Recently, there has been an unexplained increase in the incidence of blackwater fever (BWF) in Eastern Uganda. In this study, we evaluate the association between immune complexes, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and the occurrence and recurrence of BWF in children with severe malaria (SM)., Methods: Between 2014 and 2017, children aged six months to <4 years hospitalized with SM and community children (CC) were recruited at two hospitals in Central and Eastern Uganda. We measured serum circulating immune complexes (cIC) and their relationship to SM complications and post-discharge outcomes and evaluated effect mediation through G6PD deficiency., Results: 557 children with SM and 101 CC were enrolled. The mean age of children was 2.1 years. Children with SM had higher cIC levels than CC, p<0.001. After controlling for age, sex, and site, cIC were associated with severe anemia, jaundice, and BWF (adjusted odds ratio, 95% confidence interval: 7.33 (3.45, 15.58), p<0.0001; 4.31 (1.68, 11.08), p=0.002; and 5.21 (2.06, 13.18), p<0.0001), respectively. cIC predicted readmissions for SM, severe anemia, and BWF (adjusted incidence rate ratios (95% confidence interval): 2.11 (1.33, 3.34), p=0.001; 8.62 (2.80, 26.59), p<0.0001; and 7.66 (2.62, 22.45), p<0.0001), respectively. The relationship was most evident in males where the frequency of the G6PD African allele (A-) was 16.8%. G6PD deficiency was associated with increases in cIC in males (p=0.01) and mediation analysis suggested G6PD deficiency contributes to recurrent severe anemia and BWF via increased cIC., Conclusions: Immune complexes are associated with hemolytic complications and predict recurrences in SM survivors., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: People with sickle cell anemia (SCA) may require frequent blood transfusions to treat acute and chronic complications. Hydroxyurea is a life-saving treatment for SCA that could also decrease the need for blood transfusions. Inadequate medication access and challenges in dose optimization limit the widespread use of hydroxyurea in Africa. If feasible, pharmacokinetic (PK) dosing might improve dose determination to minimize toxicities and maximize clinical benefits. The Alternative Dosing And Prevention of Transfusions (ADAPT, NCT05662098) trial will analyze the impact of hydroxyurea on transfusion rate and serve as a pilot study to evaluate the feasibility of PK-guided hydroxyurea dosing in Uganda., Methods: Herein we describe the rationale and design of ADAPT, a prospective cohort study of ∼100 children with SCA in Jinja, Uganda. The primary hypothesis is that hydroxyurea will decrease blood transfusion use by ≥ 50%, comparing the transfusion incidence rate ratio between a 3-month pretreatment and a 12-month treatment period. A key secondary hypothesis is that our PK-dosing approach will generate a suitable hydroxyurea dose for ≥80% of participants. Every ADAPT participant will undergo hydroxyurea PK testing, and if a dose is generated within 15-35 mg/kg/day, participants will start on their individualized dose. If not, they will start on a default dose of 20 mg/kg/day. Hydroxyurea dose optimization will occur with periodic dose adjustments., Conclusion: Overall, demonstrating the reduction in blood transfusion utilization with hydroxyurea treatment would provide leverage to increase hydroxyurea access, and PK-guided hydroxyurea dosing should optimize the safe and effective treatment of SCA across sub-Saharan Africa., (© 2024 S. Karger AG, Basel.)

Background: Realizing Effectiveness Across Continents with Hydroxyurea (REACH) is an open-label non-randomised trial of hydroxyurea (hydroxycarbamide) in children with sickle cell anaemia in sub-Saharan Africa. The short-term results of REACH on safety, feasibility, and effectiveness of hydroxyurea were published previously. In this paper we report results from extended hydroxyurea treatment in the REACH cohort up to 8 years., Methods: In this open-label, non-randomised, phase 1/2 trial, participants were recruited from four clinical sites in Kilifi, Kenya; Mbale, Uganda; Luanda, Angola; and Kinshasa, Democratic Republic of Congo. Eligible children were 1-10 years old with documented haemoglobin SS or haemoglobin Sβ zero thalassaemia, weighing at least 10 kg. Participants received fixed-dose hydroxyurea of 17.5 (±2.5) mg/kg per day for 6 months (fixed-dose phase), followed by 6 months of dose escalation (2·5-5·0 mg/kg increments every 8 weeks) as tolerated, up to 20-35 mg/kg per day (maximum tolerated dose; MTD), defined as mild myelosuppression. After the MTD was reached, hydroxyurea dosing was optimised for each participant on the basis of changes in bodyweight and laboratory values over time (MTD with optimisation phase). After completion of the first 12 months, children with an acceptable toxicity profile and favourable responses were given the opportunity to continue hydroxyurea until the age of 18 years. The safety and feasibility results after 3 years has been reported previously. Here, haematological responses, clinical events, and toxicity rates were compared across the dosing phases (fixed-dose hydroxyurea vs MTD with optimisation phase) as protocol-specified outcomes. REACH is registered on ClinicalTrials.gov (NCT01966731) and is ongoing., Findings: We enrolled 635 children between July 4, 2014, and Nov 11, 2016. 606 children were given hydroxyurea and 522 (86%; 266 [51%] boys and 256 [49%] girls) received treatment for a median of 93 months (IQR 84-97) with 4340 patient-years of treatment. The current (Oct 5, 2023) mean dose is 28·2 (SD 5·2) mg/kg per day with an increased mean haemoglobin concentration (7·3 [SD 1·1] g/dL at baseline to 8·5 [1·5] g/dL) and mean fetal haemoglobin level (10·9% [SD 6·8] to 23·3% [9·5]) and decreased absolute neutrophil count (6·8 [3·0] × 10 9 cells per L to 3·6 [2·2] × 10 9 cells per L). Incidence rate ratios (IRR) comparing MTD with fixed-dose hydroxyurea indicate decreased vaso-occlusive episodes (0·60; 95% CI 0·52-0·70; p<0·0001), acute chest syndrome events (0·21; 0·13-0·33; p<0·0001), recurrent stroke events (0·27; 0·07-1·06; p=0·061), malaria infections (0·58; 0·46-0·72; p<0·0001), non-malarial infections (0·52; 0·46-0·58; p<0·0001), serious adverse events (0·42; 0·27-0·67; p<0·0001), and death (0·70; 0·25-1·97; p=0·50). Dose-limiting toxicity rates were similar between the fixed-dose (24·1 per 100 patient-years) and MTD phases (23·2 per 100 patient-years; 0·97; 0·70-1·35; p=0·86). Grade 3 and 4 adverse events were infrequent (18·5 per 100 patient-years) and included malaria infection, non-malarial infections, vaso-occlusive pain, and acute chest syndrome. Serious adverse events were uncommon (3·6 per 100 patient-years) and included malaria infections, parvovirus-associated anaemia, sepsis, and stroke, with no treatment-related deaths., Interpretation: Hydroxyurea dose escalation to MTD with dose optimisation significantly improved clinical responses and treatment outcomes, without increasing toxicities in children with sickle cell anaemia in sub-Saharan Africa., Funding: US National Heart, Lung, and Blood Institute and Cincinnati Children's Research Foundation., Competing Interests: Declaration of interests REW receives hydroxyurea donations from Bristol Myers Squibb and Addmedica; research donations from Hemex Health; and serves as Medical Advisor to Nova Laboratories. BA served on the Medical Advisory Board for Global Blood Therapeutics, Pfizer, Agios, and Bluebird Bio and receives research support from Pfizer and Bluebird Bio. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: Sickle cell disease (SCD) is a hereditary red cell disorder with a large disease burden at a global level. In the United States and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the United States and Europe over the last 2 decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 ODs for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021), development of 34 of 57 ODs was completed. Four ODs were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared with products targeting disease consequences. Large companies showed a fourfold higher success rate compared with small-medium enterprises. Failures in clinical development were mainly seen in phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study end point, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical end points., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: After starting hydroxyurea treatment, Ugandan children with sickle cell anemia had 60% fewer severe or invasive infections, including malaria, bacteremia, respiratory tract infections, and gastroenteritis, than before starting hydroxyurea treatment (incidence rate ratio, 0.40 [95% confidence interval, 0.29-0.54]; P < .001)., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Children with sickle cell anemia (SCA) in Africa frequently require transfusions for SCA complications. Despite limited blood supplies, strategies to reduce their transfusion needs have not been widely evaluated or implemented. We analyzed transfusion utilization in children with SCA before and during hydroxyurea treatment. REACH (Realizing Effectiveness Across Continents with Hydroxyurea, NCT01966731) is a longitudinal Phase I/II trial of hydroxyurea in children with SCA from Angola, Democratic Republic of Congo, Kenya, and Uganda. After enrollment, children had a two-month pre-treatment screening period followed by 6 months of fixed-dose hydroxyurea (15-20 mg/kg/day), 18 months of dose escalation, and then stable dosing at maximum tolerated dose (MTD). Characteristics associated with transfusions were analyzed with univariate and multivariable models. Transfusion incidence rate ratios (IRR) across treatment periods were calculated. Among 635 enrolled children with 4124 person-years of observation, 258 participants (40.4%) received 545 transfusions. The transfusion rate per 100 person-years was 43.2 before hydroxyurea, 21.7 on fixed-dose, 14.5 during dose escalation, and 10.8 on MTD. During MTD, transfusion incidence was reduced by 75% compared to pre-treatment (IRR 0.25, 95% confidence interval [CI] 0.18-0.35, p < .0001), and by 50% compared to fixed dose (IRR 0.50, 95% CI 0.39-0.63, p < .0001). Hydroxyurea at MTD decreases transfusion utilization in African children with SCA. If widely implemented, universal testing and hydroxyurea treatment at MTD could potentially prevent 21% of all pediatric transfusions administered in sub-Saharan Africa. Increasing hydroxyurea access for SCA should decrease the transfusion burden and increase the overall blood supply., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background and Objective: L-Glutamine is a treatment for children and adults with sickle cell disease. A comprehensive evaluation of the pharmacokinetics of L-glutamine in sickle cell disease has not been conducted. We aimed to assess the effects of long-term dosing, multiple dose levels, and food intake on L-glutamine exposure in patients with sickle cell disease compared to normal participants., Methods: We conducted an open-label dose-ascending trial of L-glutamine in pediatric and adult participants with sickle cell disease (N = 8) and adult healthy volunteers (N = 4), providing a total of 400 plasma L-glutamine concentrations. Each participant received three ascending oral doses (0.1 and 0.3 g/kg twice daily and 0.6 g/kg once daily) over 3 weeks. Plasma L-glutamine concentrations were quantified using ion exchange chromatography. Both a non-compartmental pharmacokinetic analysis and a population pharmacokinetic analysis were performed., Results: L-glutamine had rapid absorption and elimination, and there was no significant change in the baseline (pre-dose) L-glutamine concentration throughout the study, indicating no drug accumulation. Pharmacokinetics was best described by a one-compartment model with first-order kinetics. The dose-normalized peak concentration decreased with dose escalation, indicating the capacity-limited non-linear pharmacokinetics of oral L-glutamine. A covariate analysis showed that baseline L-glutamine concentrations correlated negatively with glutamine clearance, whereas dose positively correlated with volume of distribution. Food intake did not significantly affect glutamine clearance, indicating that L-glutamine can be taken with or without food., Conclusions: We report the first pharmacokinetic study of multiple-dose, long-term oral L-glutamine therapy and the first population pharmacokinetic analysis of L-glutamine for sickle cell disease. These findings may permit optimized dosing of L-glutamine for patients with sickle cell disease to maximize treatment benefits., Clinical Trial Registration: This trial is registered at ClinicalTrials.gov (NCT04684381)., (© 2024. The Author(s).)

Accurate laboratory screening for sickle cell disease and other haemoglobin disorders is expanding worldwide. Two new reports describe different methods and strategies for screening in Mali and Denmark, respectively, and their encouraging results suggest that countries should tailor their screening programmes according to local needs, resources and opportunities. Commentary on: Guindo et al. Potential for a large-scale newborn screening strategy for sickle cell disease in Mali: a comparative diagnostic performance study of two rapid diagnostic tests (SickleScan® and HemotypeSC®) on cord blood. Br J Haematol 2024;204:337-345 and Gravholt et al. The Danish national haemoglobinopathy screening programme: report from 16 years of screening in a low-prevalence, non-endemic region. Br J Haematol 2024;204:329-336., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Background and Objective: The disease burden of sickle cell anemia (SCA) in sub-Saharan African (SSA) countries is substantial, with many children dying without an established diagnosis or proper treatment. The global burden of SCA is increasing each year, making therapeutic intervention a high priority. Hydroxyurea is the only disease-modifying therapy with proven feasibility and efficacy suitable for SSA; however, no one has quantified the health economic implications of its use. Therefore, from the perspective of the health care provider, we estimated the incremental cost-effectiveness of hydroxyurea as a fixed-dose regimen or maximum tolerated dose (MTD) regimen, versus SCA care without hydroxyurea., Methods: We estimated the cost of providing outpatient treatment at a pediatric sickle cell clinic in Kampala, Uganda. These estimates were used in a discrete-event simulation model to project mean costs (2021 US$), disability-adjusted life years (DALYs), and consumption of blood products per patient (450 mL units), for patients between 9 months and 18 years of age. We calculated cost-effectiveness as the ratio of incremental costs over incremental DALYs averted, discounted at 3% annually. To test the robustness of our findings, and the impact of uncertainty, we conducted probabilistic and one-way sensitivity analyses, scenario analysis, and price threshold analyses., Results: Hydroxyurea treatment averted an expected 1.37 DALYs and saved US$ 191 per patient if administered at the MTD, compared with SCA care without hydroxyurea. In comparison, hydroxyurea at a fixed dose averted 0.80 DALYs per patient at an incremental cost of US$ 2. The MTD strategy saved 11.2 (95% CI 11.1-11.4) units of blood per patient, compared with 9.1 (95% CI 9.0-9.2) units of blood per patient at the fixed-dose alternative., Conclusions: Hydroxyurea at MTD is likely to improve quality of life and reduce the consumption of blood products for children with SCA living in Uganda. Compared with a fixed dose regimen, treatment dosing at MTD is likely to be a cost-effective treatment for SCA, using realistic ranges of hydroxyurea costs that are relevant across SSA. Compared with no use of the drug, hydroxyurea could lead to substantial net savings per patient, while reducing the disease morbidity and mortality and increasing quality of life., (© 2023. The Author(s).)

Effective treatments for genetic disorders that coevolved with pathogens require simultaneous betterment of both conditions. Hydroxyurea (HU) offers safe and efficacious treatment for sickle cell anemia (SCA) by reducing clinical complications, transfusions, and death rates. Despite concerns that the HU treatment for SCA would increase infection risk by the human malaria Plasmodium falciparum, (the genetic driver of the sickle mutation), HU instead reduced clinical malaria. We used physiologically relevant drug exposures that mimic in vivo pharmacokinetics in humans. Under these conditions, we showed that HU and other ribonucleotide reductase (RNR) inhibitors have significant, intrinsic killing activity in vitro against schizont stages of P falciparum in both normal and sickle red blood cells. Long-term in vitro selection with HU increased the expression of Pfrnr genes but showed a low risk of eliciting stably resistant parasites or compromising the potency of current antimalarial drugs. Additive activity devoid of antagonism by HU was observed with a wide spectrum of commonly used antimalarial treatments. These data endorse broad, safe, and long-term use of HU for SCA in malaria-endemic countries and provide a novel biological model for the treatment of a genetic disorder with simultaneous, adjunct therapy of a life-threatening infection needed in a global health setting., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Haemoglobin SC (HbSC) is a common form of sickle cell disease (SCD), especially among individuals of West African ancestry. Persons with HbSC disease suffer from the same clinical complications and reduced quality of life that affect those with sickle cell anaemia (HbSS/Sβ 0 ). Retrospective anecdotal data suggest short-term safety and benefits of hydroxyurea for treating HbSC, yet rigorous prospective data are lacking regarding optimal dosing, clinical and laboratory effects, long-term safety and benefits, and appropriate endpoints to monitor. Prospective Investigation of Variables as Outcomes for Treatment (PIVOT) was designed with three aims: (1) to measure the toxicities of hydroxyurea treatment on laboratory parameters, (2) to assess the effects of hydroxyurea treatment on sickle-related clinical and laboratory parameters, and (3) to identify study endpoints suitable for a future definitive phase III trial of hydroxyurea treatment of HbSC disease., Methods: PIVOT is a randomised, placebo-controlled, double blind clinical trial of hydroxyurea. Approximately 120 children and 120 adults ages 5-50 years with HbSC disease will be enrolled, screened for 2 months, and then randomised 1:1 to once-daily oral hydroxyurea or placebo. Study treatment will be prescribed initially at 20 ± 5 mg/kg/day with an opportunity to escalate the dose twice over the first 6 months. After 12 months of blinded study treatment, all participants will be offered open-label hydroxyurea for up to 4 years. Safety outcomes include treatment-related cytopenias, whole blood viscosity, and adverse events. Efficacy outcomes include a variety of laboratory and clinical parameters over the first 12 months of randomised treatment, including changes in haemoglobin and fetal haemoglobin, intracranial arterial velocities measured by transcranial Doppler ultrasound, cerebral oxygenation using near infrared spectrometry, spleen volume and kidney size by ultrasound, proteinuria, and retinal imaging. Exploratory outcomes include functional erythrocyte analyses with ektacytometry for red blood cell deformability and point-of-sickling, patient-reported outcomes using the PROMIS questionnaire, and 6-min walk test., Discussion: For children and adults with HbSC disease, PIVOT will determine the safety of hydroxyurea and identify measurable changes in laboratory and clinical parameters, suitable for future prospective testing in a definitive multi-centre phase III clinical trial., Trial Registration: PACTR, PACTR202108893981080. Registered 24 August 2021, https://pactr.samrc.ac.za., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Pregnant and lactating women were not included in the initial large vaccine clinical trials for SARS-CoV-2 (COVID) infection. Delineating the antibody titers in serum and breast milk of lactating women is important to determine the safety and benefits of vaccination in this special population. Objective: To investigate COVID vaccinations in breastfeeding dyads and effects on lactation, the Antibody Detection of Vaccine-Induced Secretory Effects trial (ADVISE) prospectively evaluated anti-COVID antibodies in serum and breast milk after initial paired and booster vaccines. Methods: This is a prospective longitudinal surveillance cohort study of lactating women. Eligibility criteria included ≥18 years of age, currently lactating, and at enrollment either received COVID vaccination within the past 60 days or planning vaccination within 60 days. Results: Among 63 lactating mothers, COVID vaccination led to breast milk secretory IgA (sIgA) and IgG antibodies with consistent viral neutralizing activity. Milk sIgA titers increased further after second vaccination and were prolonged after a third booster dose, including women with extended breastfeeding beyond 12 months. Milk IgG antibody titers were higher and more sustained than sIgA. Antibody titers were not associated with individual dyad characteristics or vaccine manufacturer. Vaccine-induced antibodies from milk were not detected in infant circulation. Conclusions and Relevance: Maternal COVID vaccination during lactation is well tolerated and generates sustained and boosted antibody responses in breast milk. COVID-specific sIgA and IgG antibodies with neutralizing activity are found in breast milk, including boosted mothers who continue breastfeeding beyond 12 months. These data support universal COVID vaccinations for all lactating mothers, including booster immunizations during extended breastfeeding (NCT04895475).

Competing Interests: Declaration of interests MRA has received grants or contracts with Novartis, Pfizer, Global Blood Therapeutics, and Forma Therapeutics; and participated in Data Safety Monitoring Boards or Advisory Boards for Vertex, GBT, Forma, Novartis, and Aggios. BA has participated in Data Safety Monitoring Boards or Advisory Boards for Agios, Aruvant, bluebird bio, CRISPR, Accordant (CVS), Emmaus, Forma Therapeutics, Fulcrum, Global Blood Therapeutics, Hemanext, Novartis, NovoNordisk, and Vertex. RF has received grants from the European Horizon 2020 and Horizon Europe schemes and a contract with Global Blood Therapeutics; received consulting fees from Novartis and Global Blood Therapeutics; received honoraria for a Physicians’ Education Resource and from Global Blood Therapeutics; participated in Data Safety Monitoring Boards or Advisory Boards for Vertex, Addmedica and Novonordisk; and a leadership or fiduciary role as a member of the Steering Committee and Coordinator of the Red Cell Disorder Working Group of the Italian Association of Pediatric Hematology Oncology. NC has received a research grant for Novartis Precision Medicine. MdM has received honoraria for presentations by Addmedica and Novartis and support from Addmedica for attending a conference; and participated in a Data Safety Monitoring Board or Advisory Board for Addmedica, Vertex, and Novartis. JE has received grants from the European Horizon 2020 scheme and participated in the Data Safety Monitoring Board or Advisory Board of the Fondation Pierre Fabre. EE has received consulting fees from bluebird bio. ALG has an honorary advisory role on the Australian Sickle Cell Advisory Board. IMI has received a grant from the American Society of Hematology; consulting fees from Agios Pharmaceuticals; and honoraria from the American Society of Hematology. LCJ received royalties for a book chapter. AAK has received support from the Health resources and Services Administration. MLP has received consulting fees from the American College of Medical Genetics and Genomics; and participated in a Data Safety Monitoring Board or Advisory Board for the American College of Medical Genetics and Genomics and the American Academy of Pediatrics. ON has received travel support from the American Society of Hematology to attend a conference. DCR has received consulting fees from Vertex, Forma, Agios, and Vifor; received honoraria from Vertex; and participated in a Data Safety Monitoring Board or Advisory Board for TauRx and Mitsubishi. AS has received a scholar award from the American Society of Hematology, an advancing cures research award from the Doris Duke Charitable Foundation, and a Working group award from the Center for ELSI Resources and Analysis; consulting fees from Spotlight Therapeutics, Medexus, Vertex, Editas Medicine, and Sangamo Therapeutics; has received honoraria from Vindico Medical Education; and has a leadership or fiduciary role in the American Society for Transplantation and Cellular Therapy Content Committee, the Scientific Executive Committee, Sickle Cell Transplant Advocacy & Research Alliance, and the Pediatric Transplantation and Cellular Therapy Consortium Supportive Care Committee; and has financial interests with CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis Pharmaceuticals, Magenta Therapeutics, and Beam Therapeutics. AAT has received consulting fees from GlaxoSmithKline and Global Blood Therapeutics; and honoraria from Novartis. REW has received consulting fees from Nova Laboratories; participated in a Data Safety Monitoring Board for Novartis and Editas; and received donations and support for clinical trials from Bristol Myers Squib, Addmedica, and Hemex Health. DJW has received a grant or contract from the US National Institutes for Health; received payment for expert testimony from Fredslough Law Firm; participated in a Data Safety Monitoring Board or Advisory board for Northwestern University; and is the founder and chairman of eNursing.

Data from small clinical trials in the United States and India suggest zinc supplementation reduces infection in adolescents and adults with sickle cell anemia (SCA), but no studies of zinc supplementation for infection prevention have been conducted in children with SCA living in Africa. We conducted a randomized double-blind placebo-controlled trial to assess zinc supplementation for prevention of severe or invasive infections in Ugandan children 1.00-4.99 years with SCA. Of 252 enrolled participants, 124 were assigned zinc (10 mg) and 126 assigned placebo once daily for 12 months. The primary outcome was incidence of protocol-defined severe or invasive infections. Infection incidence did not differ between treatment arms (282 vs. 270 severe or invasive infections per 100 person-years, respectively, incidence rate ratio of 1.04 [95% confidence interval (CI), 0.81, 1.32, p=0.78]), adjusting for hydroxyurea treatment. There was also no difference between treatment arms in incidence of serious adverse events or SCA-related events. Children receiving zinc had increased serum levels after 12-months, but at study exit, 41% remained zinc deficient (<65 μg/dL). In post-hoc analysis, occurrence of stroke or death was lower in the zinc treatment arm (adjusted hazard ratio (95% CI), 0.22 (0.05, 1.00); p=0.05). Daily 10 mg zinc supplementation for 12 months did not prevent severe or invasive infections in Ugandan children with SCA, but many supplemented children remained zinc deficient. Optimal zinc dosing and the role of zinc in preventing stroke or death in SCA warrant further investigation. This trial was registered at clinicaltrials.gov as #NCT03528434., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The mechanism for anaphylaxis following mRNA COVID-19 vaccination has been widely debated; understanding this serious adverse event is important for future vaccines of similar design. A mechanism proposed is type I hypersensitivity (i.e., IgE-mediated mast cell degranulation) to polyethylene glycol (PEG). Using an assay that, uniquely, had been previously assessed in patients with anaphylaxis to PEG, our objective was to compare anti-PEG IgE in serum from mRNA COVID-19 vaccine anaphylaxis case-patients and persons vaccinated without allergic reactions. Secondarily, we compared anti-PEG IgG and IgM to assess alternative mechanisms., Methods: Selected anaphylaxis case-patients reported to U.S. Vaccine Adverse Event Reporting System December 14, 2020-March 25, 2021 were invited to provide a serum sample. mRNA COVID-19 vaccine study participants with residual serum and no allergic reaction post-vaccination ("controls") were frequency matched to cases 3:1 on vaccine and dose number, sex and 10-year age category. Anti-PEG IgE was measured using a dual cytometric bead assay (DCBA). Anti-PEG IgG and IgM were measured using two different assays: DCBA and a PEGylated-polystyrene bead assay. Laboratorians were blinded to case/control status., Results: All 20 case-patients were women; 17 had anaphylaxis after dose 1, 3 after dose 2. Thirteen (65 %) were hospitalized and 7 (35 %) were intubated. Time from vaccination to serum collection was longer for case-patients vs controls (post-dose 1: median 105 vs 21 days). Among Moderna recipients, anti-PEG IgE was detected in 1 of 10 (10 %) case-patients vs 8 of 30 (27 %) controls (p = 0.40); among Pfizer-BioNTech recipients, it was detected in 0 of 10 case-patients (0 %) vs 1 of 30 (3 %) controls (p >n 0.99). Anti-PEG IgE quantitative signals followed this same pattern. Neither anti-PEG IgG nor IgM was associated with case status with both assay formats., Conclusion: Our results support that anti-PEG IgE is not a predominant mechanism for anaphylaxis post-mRNA COVID-19 vaccination., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mary A Staat reports a relationship with Pfizer that includes: funding grants. Mary A Staat reports a relationship with Merck & Co Inc that includes: funding grants. Mary A Staat reports a relationship with UpToDate that includes: consulting or advisory. Donna S. Hummell reports a relationship with Merck & Co Inc that includes: consulting or advisory. Kathryn M. Edwards reports a relationship with Bionet that includes: consulting or advisory. Kathryn M. Edwards reports a relationship with IBM that includes: consulting or advisory. Kathryn M. Edwards reports a relationship with Member Data that includes: consulting or advisory. Kathryn M. Edwards reports a relationship with Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, Roache, Novavax, Brighton Collaboration that includes: consulting or advisory. UpToDate fees for Mary A. Stadt were classified as royalties that are unrelated to this work. Consultative work by Kathryn M. Edwards for X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, Roche, Novavax, Brighton Collaboration was serving on Safety and Monitoring Boards. Consultative work by Donna S. Hummel for Merck was for eDMC monitoring for clinical trial., (Published by Elsevier Ltd.)

Introduction: Hydroxyurea is effective disease-modifying treatment for sickle cell anemia (SCA). Escalation to maximum tolerated dose (MTD) achieves superior benefits without additional toxicities, but requires dose adjustments with serial monitoring. Pharmacokinetic (PK)-guided dosing can predict a personalized optimal dose, which approximates MTD and requires fewer clinical visits, laboratory assessments, and dose adjustments. However, PK-guided dosing requires complex analytical techniques unavailable in low-resource settings. Simplified hydroxyurea PK analysis could optimize dosing and increase access to treatment. Methods: Concentrated stock solutions of reagents for chemical detection of serum hydroxyurea using HPLC were prepared and stored at -80C. On the day of analysis, hydroxyurea was serially diluted in human serum, then spiked with N-methylurea as an internal standard and analyzed using two commercial HPLC machines: 1) standard benchtop Agilent with 449 nm detector and 5 micron C18 column; and 2) portable PolyLC with 415 nm detector and 3.5 micron C18 column. After validation in the United States, the portable HPLC and chemicals were transported to Tanzania. Results: A calibration curve using hydroxyurea 2-fold dilutions ranging from 0 to 1000 µM was plotted against the hydroxyurea:N-methylurea ratio. In the United States, both HPLC systems yielded calibration curves with R 2 > 0.99. Hydroxyurea prepared at known concentrations confirmed accuracy and precision within 10%-20% of the actual values. Both HPLC systems measured hydroxyurea with <10% variance from the prepared concentrations, and paired analysis of samples on both machines documented <15% variance. Serial measurements of 300 and 100 μM concentrations using the PolyLC system were precise with 2.5% coefficient of variance. After transport to Tanzania with setup and training, the modified PolyLC HPLC system produced similar calibration curves with R 2 > 0.99. Conclusion: Increasing access to hydroxyurea for people with SCA requires an approach that eases financial and logistical barriers while optimizing safety and benefits, especially in low-resource settings. We successfully modified a portable HPLC instrument to quantify hydroxyurea, validated its precision and accuracy, and confirmed capacity building and knowledge transfer to Tanzania. HPLC measurement of serum hydroxyurea is now feasible in low-resource settings using available laboratory infrastructure. PK-guided dosing of hydroxyurea will be tested prospectively to achieve optimal treatment responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Smart, Charles, McElhinney, Dong, Power-Hays, Howard, Vinks, Ambrose and Ware.)

Sickle cell anemia (SCA) is a life-threatening genetic condition contributing to high-risk pregnancies affecting both the mother and fetus. With improved management of children with SCA, this life-threatening hematological disorder has evolved into a chronic disease of adults, and consequently parenthood has now become a possible and important life goal for many patients. Providing continuous management with healthy red blood cell function and avoiding SCA-associated complications, such as pain crises, acute chest syndrome, and stroke, are crucial for a healthy pregnancy. Despite its excellent safety profile in non-pregnant adults and children, and based on theoretical concerns derived from data using animal models and supraphysiological dosing, hydroxyurea is currently contraindicated for pregnant and lactating women with SCA. Clinical experience of hydroxyurea use during pregnancy is increasingly reported, however, and has shown inconsistent results of fetal or infant adverse effects. How the hydroxyurea exposure level may correlate with pregnancy outcomes is still unclear. Accordingly, efforts should be made to systemically evaluate exposure and safety of hydroxyurea treatment during pregnancy and lactation. Novel approaches such as physiologically based pharmacokinetic (PBPK) modeling, coupled with the ex vivo human placental cotyledon perfusion assay, provide opportunities to understand hydroxyurea exposure not only in pregnant women but also in the developing fetus. Combined with animal data, research using these approaches might be able to define safe and effective hydroxyurea dosing regimens for pregnant and lactating women with SCA, when the benefits of continuing hydroxyurea treatment likely outweigh the risks of non-treatment, by avoiding substantial morbidity and even mortality for both mothers and infants., (© 2023 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Ischaemic stroke is a common complication of sickle cell disease (SCD) and without intervention can affect 11% of children with SCD before the age of 20. Within the Trans-Omics for Precision Medicine (TOPMed), a genome-wide association study (GWAS) of ischaemic stroke was performed on 1333 individuals with SCD from Brazil (178 cases, 1155 controls). Via a novel Cox proportional-hazards analysis, we searched for variants associated with ischaemic stroke occurring at younger ages. Variants at genome-wide significance (p < 5 × 10 -8 ) include two near genes previously linked to non-SCD early-onset stroke (<65 years): ADAMTS2 (rs147625068, p = 3.70 × 10 -9 ) and CDK18 (rs12144136, p = 2.38 × 10 -9 ). Meta-analysis, which included the independent SCD cohorts Walk-PHaSST and PUSH, exhibited consistent association for variants rs1209987 near gene TBC1D32 (p = 3.36 × 10 -10 ), rs188599171 near CUX1 (p = 5.89 × 10 -11 ), rs77900855 near BTG1 (p = 4.66 × 10 -8 ), and rs141674494 near VPS13C (1.68 × 10 -9 ). Findings from this study support a multivariant model of early ischaemic stroke risk and possibly a shared genetic architecture between SCD individuals and non-SCD individuals younger than 65 years., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Transcranial Doppler screening with chronic transfusions reduces stroke risk in children with sickle cell anaemia but is not feasible in low-resource settings. Hydroxyurea is an alternative treatment to decrease stroke risk. We aimed to estimate stroke risk in children with sickle cell anaemia in Tanzania and to determine the efficacy of hydroxyurea to decrease and prevent stroke., Methods: We did an open-label, phase 2 trial (SPHERE) at Bugando Medical Centre, Mwanza, Tanzania. Children aged 2-16 years with a diagnosis of sickle cell anaemia confirmed by haemoglobin electrophoresis were eligible for enrolment. Participants had transcranial Doppler ultrasound screening by a local examiner. Participants with elevated Doppler velocities, either conditional (170-199 cm/s) or abnormal (≥200 cm/s), received oral hydroxyurea starting at 20 mg/kg once daily and escalated every 8 weeks by 5 mg/kg per day to the maximum tolerated dose. Participants with normal Doppler velocities (<170 cm/s) received usual care from the sickle cell anaemia clinic and were rescreened after 12 months to determine whether they qualified for treatment on trial. The primary endpoint was change in transcranial Doppler velocity from the baseline visit to after 12 months of hydroxyurea treatment, analysed in all patients who had paired baseline and follow-up measurements collected after 12 months of treatment. Safety was analysed in the per-protocol population (all participants who received study treatment). This study is registered with ClinicalTrials.gov, NCT03948867., Findings: Between April 24, 2019, and April 9, 2020, 202 children were enrolled and had transcranial Doppler screening. Sickle cell anaemia was confirmed by DNA-based testing in 196 participants (mean age 6·8 years [SD 3·5], 103 [53%] were female, and 93 [47%] were male). At the baseline screening, 47 (24%) of 196 participants had elevated transcranial Doppler velocities (43 [22%] conditional, four [2%] abnormal); 45 initiated hydroxyurea at a mean dose of 20·2 mg/kg per day (SD 1·4) with escalation to a mean dose of 27·4 mg/kg per day (5·1) after 12 months. Treatment response was analysed after 12 months (± 1 month; median 11 months, IQR 11-12) and 24 months (±3 months; median 22 months, 22-22). Transcranial Doppler velocities decreased to a mean of 149 cm/s (SD 27) compared with 182 cm/s (12) at baseline, which was significantly lower than baseline (p<0·0001), with an average decline of 35 cm/s (SD 23) after 12 months of treatment in 42 participants with paired results available at baseline and 12 months. No clinical strokes occurred, and 35 (83%) of 42 participants reverted to normal transcranial Doppler velocities. Clinical adverse events were mild, and dose-limiting toxicities were uncommon. The most common grade 3 adverse events were malaria (12 [29%] episodes in 45 patients) and sepsis (13 [32%] episodes). There were three serious adverse events, none of which were treatment-related, and no treatment-related deaths occurred., Interpretation: Children with sickle cell anaemia in Tanzania have a high baseline stroke risk. Hydroxyurea at the maximum tolerated dose significantly lowers transcranial Doppler velocities and reduces primary stroke risk. Transcranial Doppler screening plus hydroxyurea at the maximum tolerated dose is an effective stroke prevention strategy, supporting wider hydroxyurea access for patients with sickle cell anaemia across sub-Saharan Africa., Funding: American Society of Hematology, National Institutes of Health, Cincinnati Children's Research Foundation., Competing Interests: Declaration of interests EEA reports research funding from the American Society of Hematology to support this work. SES is a consultant for the American Society of Hematology Research Collaboration. REW is a board member for the Foundation of Women and Girls with Blood Disorders (unpaid); receives hydroxyurea donations from Bristol Myers Squibb and Addmedica; and chairs Data and Safety Monitoring Boards for Novartis and Editas. LRS reports grant funding from the American Society of Hematology and the National Institutes of Health National Heart Lung and Blood Institute. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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 <3.0 × 109/L were associated with lower malaria incidence. Compared with nonpalpable spleen, 1- to 4-cm splenomegaly also was associated with higher malaria risk (HR, 2.01; 95% CI, 1.41-2.85; P = .0001). Hydroxyurea at MTD is associated with lower malaria incidence in SCA through incompletely defined mechanisms, but treatment-associated mild myelosuppression with ANC <3.0 × 109/L is salutary. Splenomegaly is an unexplained risk factor for malaria infections among children with SCA in Africa., (© 2023 by The American Society of Hematology.)

Hydroxyurea is approved for treating children and adults with sickle cell anemia (SCA). Despite its proven efficacy, concerns remain about its mutagenic and carcinogenic potential that hamper its widespread use. Cell culture- and animal-based investigations indicate that hydroxyurea's genotoxic effects are due to indirect clastogenicity in select cell types when high dose and time thresholds are exceeded (reviewed by Ware & Dertinger, 2021). The current study extends these preclinical observations to pediatric patients receiving hydroxyurea for treatment of SCA. First, proof-of-principle experiments with testicular cancer patients exposed to a cisplatin-based regimen validated the ability of flow cytometric blood-based micronucleated reticulocyte (MN-RET) and PIG-A mutant reticulocyte (MUT RET) assays to detect clastogenicity and gene mutations, respectively. Second, these biomarkers were measured in a cross-sectional study with 26 SCA patients receiving hydroxyurea and 13 SCA patients without exposure. Finally, a prospective study was conducted with 10 SCA patients using pretreatment blood samples and after 6 or 12 months of therapy. Cancer patients exposed to cisplatin exhibited increased MN-RET within days of exposure, while the MUT RET endpoint required more time to reach maximal levels. In SCA patients, hydroxyurea induced MN-RET in both the cross-sectional and prospective studies. However, no evidence of PIG-A gene mutation was found in hydroxyurea-treated children, despite the fact that the two assays use the same rapidly-dividing, highly-exposed cell type. Collectively, these results reinforce the complementary nature of MN-RET and MUT RET biomarkers, and indicate that hydroxyurea can be clastogenic but was not mutagenic in young patients with SCA., (© 2023 Environmental Mutagen Society.)

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., (© 2022 S. Karger AG, Basel.)

Sickle cell disease (SCD) is a common condition within sub-Saharan Africa and associated with high under-5 mortality (U5M). The American Society of Hematology instituted the Consortium on Newborn Screening in Africa (CONSA) for SCD, a 7-country network of sites to implement standardized newborn hemoglobinopathy screening and early intervention for children with SCD in sub-Saharan Africa. CONSA's overall hypothesis is that early infant SCD screening and entry into standardized, continuous care will reduce U5M compared with historical estimates in the region. Primary trial objectives are to determine the population-based birth incidence of SCD and effectiveness of early standardized care for preventing early mortality consortium-wide at each country's site(s). Secondary objectives are to establish universal screening and early interventions for SCD within clinical networks of CONSA partners and assess trial implementation. Outcomes will be evaluated from data collected using a shared patient registry. Standardized trial procedures will be implemented among designated birth populations in 7 African countries whose programs met eligibility criteria. Treatment protocol includes administering antibacterial and antimalarial prophylaxis and standard childhood vaccinations against infections commonly affecting children with SCD. Infants with a positive screen and confirmation of SCD within the catchment areas defined by each consortium partner will be enrolled in the clinical intervention protocol and followed regularly until age of 5 years. Effectiveness of these early interventions, along with culturally appropriate family education and counseling, will be evaluated by comparing U5M in the enrolled cohort to estimated preprogram data. Here, we describe the methodology planned for this trial., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Emerging resistance to artemisinin drugs threatens the elimination of malaria. Resistance is widespread in South East Asia (SEA) and Myanmar. Neighboring Bangladesh, where 90% of infections occur in the Chittagong Hill Tracts (CHTs), lacks recent assessment. We undertook a prospective study in the sole district-level hospital in Bandarban, a CHT district with low population densities but 60% of reported malaria cases. Thirty patients presented with malaria in 2018. An increase to 68 patients in 2019 correlated with the district-level rise in malaria, rainfall, humidity, and temperature. Twenty-four patients (7 in 2018 and 17 in 2019) with uncomplicated Plasmodium falciparum monoinfection were assessed for clearing parasites after starting artemisinin combination therapy (ACT). The median (range) time to clear half of the initial parasites was 5.6 (1.5 to 9.6) h, with 20% of patients showing a median of 8 h. There was no correlation between parasite clearance and initial parasitemia, blood cell counts, or mutations of P. falciparum gene Pfkelch13 (the molecular marker of artemisinin resistance [AR]). The in vitro ring-stage survival assay (RSA) revealed one (of four) culture-adapted strains with a quantifiable resistance of 2.01% ± 0.1% (mean ± standard error of the mean [SEM]). Regression analyses of in vivo and in vitro measurements of the four CHT strains and WHO-validated K13 resistance mutations yielded good correlation ( R 2 = 0.7; ρ = 0.9, P  < 0.005), strengthening evaluation of emerging AR with small sample sizes, a challenge in many low/moderate-prevalence sites. There is an urgent need to deploy multiple, complementary approaches to understand the evolutionary dynamics of the emergence of P. falciparum resistant to artemisinin derivatives in countries where malaria is endemic. IMPORTANCE Malaria elimination is a Millennium Development Goal. Artemisinins, fast-acting antimalarial drugs, have played a key role in malaria elimination. Emergence of artemisinin resistance threatens the global elimination of malaria. Over the last decade, advanced clinical and laboratory methods have documented its spread throughout South East Asia and Myanmar. Neighboring Bangladesh lies in the historical path of dissemination of antimalarial resistance to the rest of the world, yet it has not been evaluated by combinations of leading methods, particularly in the highland Chittagong Hill Tracts adjacent to Myanmar which contain >90% of malaria in Bangladesh. We show the first establishment of capacity to assess clinical artemisinin resistance directly in patients in the hilltops and laboratory adaptation of Bangladeshi parasite strains from a remote, sparsely populated malaria frontier that is responsive to climate. Our study also provides a generalized model for comprehensive monitoring of drug resistance for countries where malaria is endemic.