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BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: By leveraging data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) and the Atopic Dermatitis Research Network (ADRN), we aim to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum (N=21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. For details, please see the Methods section in this article’s Online Repository at www.jacionline.org. RESULTS: We identified six loci at genome-wide significance (P

EXpanding Treatment for Existing Neurological Disease (EXTEND) investigated whether hydroxycarbamide lowers transcranial Doppler (TCD) velocities in Jamaican children with sickle cell anaemia (SCA) and elevated TCD velocity with or without previous stroke. Forty-three children (age 2-17 years) with baseline maximum time-averaged mean velocity (TAMV) ≥ 170 cm/s were stratified into three risk categories based on treatment status and stroke history: Group 1 (no history of stroke, on hydroxycarbamide, n = 12); and Groups 2 (no stroke, no hydroxycarbamide, n = 21) and 3 (previous stroke, no hydroxycarbamide, n = 10). Open-label hydroxycarbamide at 20 mg/kg/day was commenced, with escalation to maximum tolerated dose (MTD) based on mild marrow suppression (average dose 25·4 ± 4·5 mg/kg/day). TCD was performed every six months with brain magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) at baseline and after 18-months of hydroxycarbamide. The maximum TAMV decreased significantly compared to baseline (24 ± 30 cm/s, P < 0·0001), with similar declines in all groups. Clinical stroke occurred in five children, one in Group 1, none in Group 2, and four in Group 3, P = 0·0032, comparing group incidence rates. Brain MRI/MRA was stable in children without clinical stroke. EXTEND documents the feasibility and benefits of hydroxycarbamide at MTD to lower TCD velocities and reduce stroke risk in children with SCA and no history of primary stroke in low-resource settings without transfusion management.

Purpose: In an effort to transition toward universal health coverage (UHC), Jamaica abolished user fees at all public health facilities in 2008. We aimed to determine the extent of out-of-pocket payments (OPPs) and the other cost barriers to UHC among patients with sickle cell disease (SCD). Methods: Patients presenting to the Sickle Cell Unit in Kingston, Jamaica, for routine care between October 2019 and August 2020 were consecutively recruited and interviewed about their latest hospitalization within the previous 4 weeks. Parents or guardians completed the questionnaire on behalf of pediatric patients. The questionnaire included the Patient Satisfaction Questionnaire Short Form (PSQ)-18 and the health module of the Jamaica Survey of Living Conditions. Results: There were 103 patients with ages ranging from 7 months to 56 years (51.5% female, 60.2% public hospitalizations, and 54.4% pediatric). The modal income (J$6200–$11,999 per week) was similar to the minimum wage and 48.5% lived in overcrowded households. Government drug-subsidy cards were owned by 39.8%. OPPs were made by 19.4% of persons for items and tests that were unavailable at public facilities. There were no costs reported by 69.6%, who visited public pharmacies. Similarly, the cost of admission to public hospitals was free for 95.4% of subjects. Using public transportation, private hospitalization, and having more disease complications were predictive of a perception that health care is unaffordable. Conclusion: Most SCD subjects reported no expense with public hospitalizations; however, approximately one in five reported OPPs. Efforts are needed to increase the availability of subsidized items, and the use of drug-subsidy cards, to improve UHC.

Background: Pulmonary complications of sickle cell disease (SCD) are diverse and encompass acute and chronic disease. The understanding of the natural history of pulmonary complications of SCD is limited, no specific therapies exist, and these complications are a primary cause of morbidity and mortality. Methods: We gathered a multidisciplinary group of pediatric and adult hematologists, pulmonologists, and emergency medicine physicians with expertise in SCD-related lung disease along with an SCD patient advocate for an American Thoracic Society–sponsored workshop to review the literature and identify key unanswered clinical and research questions. Participants were divided into four subcommittees on the basis of expertise: 1) acute chest syndrome, 2) lower airways disease and pulmonary function, 3) sleep-disordered breathing and hypoxia, and 4) pulmonary vascular complications of SCD. Before the workshop, a comprehensive literature review of each subtopic was conducted. Clinically important questions were developed after literature review and were finalized by group discussion and consensus. Results: Current knowledge is based on small, predominantly observational studies, few multicenter longitudinal studies, and even fewer high-quality interventional trials specifically targeting the pulmonary complications of SCD. Each subcommittee identified the three or four most important unanswered questions in their topic area for researchers to direct the next steps of clinical investigation. Conclusions: Important and clinically relevant questions regarding sickle cell lung disease remain unanswered. High-quality, multicenter, longitudinal studies and randomized clinical trials designed and implemented by teams of multidisciplinary clinician-investigators are needed to improve the care of individuals with SCD.

BackgroundThe greatest disease burden of sickle cell disease occurs early in life. Understanding factors that reduce disease related events in this period is therefore important. Hence, we assessed the impact of early care at a specialist center on the incidence of acute events during the first five years.MethodsThis was a retrospective cohort study among Jamaican children with sickle cell disease. Medical records of patients born January, 2004 to December, 2009, who were registered at the Sickle Cell Unit, a specialist care facility, were abstracted for dates of initiation to care, first occurrence and frequency of the outcomes of interest (vaso-occlusive crises, acute splenic sequestration, acute chest syndrome, and infection). Patients were classified according to whether initiation of care was before (early) or after 5 months of age (late). Using standardized t-tests, χ2 tests, and a multiple-failure survival analysis the rates of acute events between groups were compared.ResultsOf the total study group (n= 290), homozygous sickle cell disease accounted for 97% and 95% of the early (n=113) and late groups (n=177) respectively. The mean age of presentation in the early and late group was 0.2 and 2.3 years (ppn=880) and acute chest syndrome (n= 571) together accounted for 91.6% of the total number of events (n=1584). The risk of vaso-occlusive crisis and acute chest syndrome (among patients who presented with these acute events) was significantly higher in the “late” group, by 43% (Incidence rate ratio, (IRR) = 1.43,pp=0.002), 95% CI (1.12-1.75) respectively compared to “early” group. There was no difference in risk between groups for acute splenic sequestration and infection among persons presenting with these events.ConclusionThe risk of acute events in children with sickle cell disease exposed to early care at a specialist care is significantly less. Therefore, widespread screening with rapid referral to a specialist center stands to reduce substantial morbidity in Jamaica and other regions with high prevalence of sickle cell disease.

The current study examines gender effects on disease knowledge and quality of life in adolescents with sickle cell disease (SCD) in Jamaica. We report the baseline results on 76 girls and 74 boys with mean age (16.9 ± 1.8 vs. 16.2 ±2.0 years), recruited in a larger intervention study. Girls had higher knowledge scores (15.3 ± 4.2 vs. 13.3 ± 4.2 p=.004), poorer overall QOL scores (70.1 ± 19.6 vs. 77.2 ± 17.8 p=0.02) but similar severity scores to boys. Girls also had significantly lower scores on many QOL domain scores: Pain occurrences over the course the past month (Pain and Hurt:77.49 ± 23.3 vs. 85.37 ± 17.13); concerns about seeking health services for pain (Worry1:63.73 ± 26.21 vs. 75.33 ± 24.62); confidence in self-managementtreatment effects (Treatment: 72.25 ± 23.6 vs. 80.73 ± 18.90) and SCD disclosureempathy from others (Communication II: 47.44 ± 1.02 vs. 61.71 ± 29.41). Knowledge was positively predicted by age, higher education, greater household possessions and was higher in girls; whereas QOL was lower in girls and those with greater disease severity and higher with higher education. In conclusion, there is a significant gender differential in disease knowledge and QOL among adolescents with SCD. Interventions will need to address the lower QOL in girls and lower disease knowledge among boys.

BACKGROUND Increasing knowledge and understanding of disease is known to improve outcomes in persons living with a chronic illness. In this paper, we aim to compare the disease knowledge of children with sickle cell disease (SCD), age 6-10 years, who received an intervention (an educational colouring book on SCD) geared towards improving disease knowledge, to those who did not received the colouring book. METHODS A quasi-experimental study was conducted where disease knowledge was determined in 56 children who had received the colouring book and compared to 60 children who did not receive this intervention. RESULTS The mean knowledge score was significantly higher in the intervention group (mean difference = 2.65; 95% CI [1.43, 3.86]), as well as in older children and in those in higher grades but there was no difference between sexes. In a multiple regression model (adjusted R2 : 0.39; p value

Introduction: Sickle cell disease (SCD) is a genetic red blood cell (RBC) disorder that causes chronic hemolytic anemia, progressive organ damage, and life-threatening acute complications such as painful vaso-occlusive crises. Allogeneic hematopoietic stem cell transplant (allo-HSCT) with myeloablative conditioning remains the only curative therapy for SCD but has several limitations including low donor availability and conditioning-related toxicity. Genetic modification of autologous hematopoietic system cells (HSCs) with reduced-intensity conditioning (RIC) using a high-potency drug product may address these limitations. ARU-1801 is a gene therapy that uses a modified γ-globin lentiviral vector to produce HbF G16D within autologous CD34+ HSCs. Preclinical studies in SCD mice have shown the G16D mutation enables γ-globin G16D to bind α-globin with higher affinity; lentiviral transfer of γ-globin G16D resulted in 1.5-2x more HbF per vector copy number (VCN) compared to analogous wild-type γ-globin vector. Early studies also suggested HbF G16D may be more potent for anti-sickling than HbF, lowering reticulocyte counts in SCD mice to a greater extent at similar protein levels. We hypothesize ARU-1801 with RIC could lessen toxicities and resource utilization relative to myeloablative approaches, allowing expanded access to gene therapy for a broader group of SCD patients. Updated data from patients in the ongoing Phase 1/2 study (NCT02186418) including laboratory and clinical markers of efficacy are presented here. Methods: Adults (18-45 years old) with severe SCD (defined by recurrent vaso-occlusive events [VOE] and acute chest syndrome) were screened for eligibility. Prior to ARU-1801 drug product (DP) infusion, all patients received a single IV dose of RIC melphalan (140 mg/m 2). Endpoints included measures of safety, engraftment, VCN, hemoglobin sub-fractions, and SCD-related outcomes. Patients were weaned off transfusions 3-6 months after DP infusion. Levels of anti-sickling globins (including HbF G16D) are presented as proportions of non-transfused total hemoglobin. Results: As of 28 July 2021, four patients (mean, 26 [19-35] years old) have been treated with ARU-1801 gene therapy for SCD with three patients followed for ≥12 months post-transplant. Transient neutropenia and thrombocytopenia were the predominant adverse events, lasting a median seven days each. There have been no other serious adverse events related to chemotherapy or ARU-1801 to date. At 36 months post-transplant, Patient 1 has shown stable HbF expression (27%) and 64% F-cells. Patient 2 has maintained 14% HbF and 37% F-cells at 36 months despite lower engraftment of ARU-1801 due to renal hyperfiltration (eGFR = 200 mL/min/1.73 m 2) at time of conditioning, which resulted in lower melphalan exposure. Both patients saw marked improvements in SCD manifestations, including 93% and 85% fewer annualized VOEs, respectively, in the two years after receiving ARU-1801 gene therapy compared to two years prior. Patient 3 received ARU-1801 manufactured with several process modifications (including improvements of HSC collection timing and lentiviral production) and has maintained 36% HbF at month 15 with pancellular distribution (96% F-cells). To date, Patient 3 has had no VOEs since ARU-1801 administration, representing 100% reduction from baseline. Conclusion: Amelioration of SCD phenotype and engraftment of ARU-1801 gene-modified HSCs is possible with a single RIC dose of melphalan, as demonstrated in three patients. The first patient shows 27% HbF expression at three years, and 93% reduction in VOEs. The second patient had lower HSC engraftment due to below-target melphalan exposure (likely caused by renal hyperfiltration), with 14% HbF and 5% HbA2 at three years. Nonetheless, an 85% reduction in VOEs in Patient 2 demonstrates significant clinical benefit. Dose-adjusted melphalan has the potential to improve engraftment in SCD patients with renal hyperfiltration. Following manufacturing process improvements, the third patient has shown the highest HbF (36%) at one year, the highest F-cells (96%), and no VOEs since receiving ARU-1801. ARU-1801, with RIC melphalan conditioning, is a promising alternative to myeloablative transplants for achieving durable responses with a favorable safety profile in patients with severe SCD. Longer follow-up and additional patients will be presented. Figure 1 Figure 1. Disclosures Asnani: Avicanna Ltd.: Research Funding; Aruvant Sciences: Research Funding. Lutzko: Aruvant Sciences: Patents & Royalties: preclinical vector development. Quinn: Forma Therapeutics: Consultancy; Emmaus Medical: Research Funding; Novo Nordisk: Consultancy; Aruvant: Research Funding. Lo: Aruvant Sciences: Current Employment. Little: Aruvant Sciences: Current Employment. Dong: Aruvant Sciences: Current Employment. Malik: Aruvant Sciences: Consultancy; Forma Therapeutics: Consultancy; Aruvant Sciences: Patents & Royalties; CSL Behring: Patents & Royalties. OffLabel Disclosure: Plerixafor was used for stem cell mobilization. Melphalan was used as chemotherapy conditioning prior to autologous transplant with ARU-1801

Introduction: ARU-1801 is a gene therapy consisting of autologous CD34+ hematopoietic stem cells and progenitors (HSCPs) transduced with a lentiviral vector (LV) encoding a modified γ-globinG16D gene. Preclinical studies in SCD mice have shown that g-globinG16D binds α-globin with higher affinity; hence, the g-globinG16D LV produces 1.5-2x more HbF/vector copy number (VCN) than a g-globin LV. Preliminary studies also show greater reduction in reticulocytes in SCD mice expressing HbFG16D compared to those expressing the same level of HbF, suggesting that HbFG16D may have a more potent anti-sickling effect than HbF. We hypothesized a high potency anti-sickling globin would allow ARU-1801 to be effective with reduced intensity conditioning (RIC). RIC would result in lower toxicities and resource utilization compared to myeloablative approaches, allowing access of gene therapy to a broader group of SCD patients. We previously reported early data from patient 1 (P1) and 2 (P2) in the ongoing Phase 1/2 study (NCT02186418), who were treated with drug product (DP) from the initial ARU-1801 manufacturing process (Process I). We now present the long-term data on these patients and early data from P3, the first patient treated with our new manufacturing process (Process II). Methods: Adults with severe SCD, as defined by recurrent vaso-occlusive events (VOE) and acute chest syndrome deemed eligible were enrolled. Manufacturing process improvements in Process II included optimized timing of HSCP collection after plerixafor mobilization, LV production and improved HSCP transduction. Prior to DP infusion, all patients received a single dose of IV melphalan (140 mg/m2 BSA) and were weaned off transfusions 3-6 months after DP infusion. Patients were monitored for safety, engraftment, VCN, anti-sickling Hb (ASG) expression, and hematological and clinical manifestations of SCD. Levels of ASG (including HbFG16D) are presented as fractions of endogenous Hb. Results: As of 28 July 2020, data from 3 patients treated with ARU-1801 are available. P1 (34yr old) has HbSβ0- and P2 (24yr old) has HbSβ+ thalassemia (2-3% HbA). Both have 30 months (mo) post-transplant (PT) follow up. P3 (19yr old) has HbSS genotype with 6 mo PT follow up. ARU-1801 demonstrated a favorable safety profile with no treatment-related adverse events to date. Time to neutrophil engraftment (ANC ≥500) was 9, 7, and 7 days PT, and time to platelet recovery (Plt >50,000) was 12, 7, and 6 days PT, in P1, P2, and P3, respectively. Figure 1 shows HSPC dose, conditioning exposure and gene transfer; Figure 2 shows ASG over time. Using Process I, P1 has shown stable expression of 20% HbFG16D, 31% ASG and 31%à64% F-cells over 2.5 years, despite a low DP VCN of 0.2 and low HSPC dose of 1.4 x106 cell/kg. P2 received a higher cell dose of 7.1 x106 cell/kg with a DP VCN of 0.47 but had below target melphalan exposure, likely due to rapid clearance from hyperfiltration (GFR= 200 mL/min/1.73m2). Despite lower engraftment and HbFG16D level, P2 maintains stable total ASG of 22% at 30 mo due to a compensatory increase in HbF. Using Process II, P3 received DP of 6.8 x106 cells/kg with a VCN of 1.0, and demonstrated an engrafted VCN of 0.74, 71% F-cells and 91% F-reticulocytes at 6 mo. As P3 is being weaned off transfusions, HbFG16D is progressively rising, showing the selective advantage to HbFG16D-containing RBCs. P1 and P2 have maintained improvements in VOEs, no VOE in P3 so far (data will be presented). Conclusion: We show that engraftment of ARU-1801 and amelioration of disease is possible with RIC using IV melphalan, with persistent stable ASG expression and meaningful improvement in VOEs in P1 and P2. P1 shows stable HbFG16D and high ASG despite low, albeit stable VCN. P2 had lower HSCP engraftment, which we hypothesize was due to below target melphalan exposure. Nevertheless, significant clinical benefit was observed in P2 due to stable ASG of 22% at mo 30. It is likely that the presence of this amount of HbFG16D has provided enough ASG to prevent sickling/ineffective erythropoiesis, resulting in the preferential survival of HbF+HbFG16D-expressing RBC. Process II DP in P3 resulted in 2-4X higher engraftment of transduced HSCPs at 6 mo. Additional process enhancements are under development for future treated patients. ARU-1801, administered with RIC, holds significant promise for achieving durable responses with a favorable safety profile in patients with severe SCD. Disclosures Asnani: Aruvant Sciences: Research Funding; Avicanna Ltd.: Research Funding. Lutzko:Aruvant Sciences: Patents & Royalties: pre-clinical vector development. Lo:Aruvant Sciences: Current Employment. Little:Aruvant Sciences: Current Employment. McIntosh:Aruvant: Current Employment, Current equity holder in private company. Malik:Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy; Aruvant Sciences, CSL Behring: Patents & Royalties. OffLabel Disclosure: Plerixafor - stem cell mobiliziation Melphalan - chemotherapy conditioning pre autologous transplant with ARU-1801

Objective To assess the feasibility of a problem-solving skills training intervention in improving psychological outcomes in mothers of infants with sickle cell disease (SCD). Design and methods This parallel randomized controlled trial recruited 64 babies with SCD, 6 to 12 months of age, and their mothers. Baseline measurements assessed mothers’ coping and problem-solving skills, depression, and parental stress before random assignment to intervention or control groups (n = 32 each). Problem-solving skills intervention was delivered through 6 monthly sessions, when babies attended for routine penicillin prophylaxis. All measurements were repeated for both groups at the end of the intervention period. Intention to treat analysis used repeated measures mixed models with the restricted estimation maximum likelihood approach. Results The problem-solving intervention had no significant effect on mothers’ problem-solving skills (adjusted treatment effect: -1.69 points (95% CI:-5.62 to 2.25)), coping behaviours (adjusted treatment effect: 0.65 points (95% CI:- -7.13 to 8.41)) or depressive symptoms (adjusted treatment effect: -0.41 (95% CI: -6.00 to 5.19)). It reduced mothers’ level of difficulty in managing stressful events by 9.5 points (95% CI (-16.86 to -2.16); effect size: 0.21 SD). In the subgroup of mothers at risk of depression (n = 31 at baseline), the intervention reduced depression scores with treatment effect of 10.4 points (95%CI: -18.83 to -1.88; effect size: 0.67 SD). Conclusion This problem-solving skills intervention study suggests feasibility and possible efficacy in improving some maternal outcomes. Further refinement and culturally appropriate adaptations of the intervention could lead to stronger effects.

Persons with sickle cell disease (SCD) experience multiple medical and physical complications; the disease also has numerous effects on their social and emotional well-being. We hypothesized that adults with SCD in Jamaica experience moderate levels of stigma and illness uncertainty and that these experiences may be associated with socio-demographic factors, such as gender, educational status and economic status.We surveyed 101 adults with SCD (54.5% female; mean age 31.6 ± 10.4 years; 72.2% homozygous SCD) using the Stigma in Sickle Cell Disease Scale (Adult), Mishel Uncertainty in Illness Scale (Adult) and a Socio-Demographic questionnaire.The mean stigma score was 33.6 ± 21.6 (range: 2-91) with no significant difference between males and females (32.3 ± 21.3 vs. 34.7 ± 21.9; p-value = 0.58). Illness uncertainty was greater in females than in males, though not statistically significant, (88.7 ± 13.5 vs. 82.6 ± 19.2; p-value: 0.07). Stigma and uncertainty had a significant positive correlation (r: 0.31; p-value: 0.01). In an age and sex controlled model, stigma scores were lower with higher numbers of household items (coef: -2.26; p-value: 0.001) and higher in those living in greater crowding (coef: 7.89; p-value: 0.002). Illness uncertainty was higher in females (coef: 6.94; p-value: 0.02) and lower with tertiary as compared with primary education (coef: -16.68; p-value: 0.03).The study highlights socioeconomic factors to be significant to the stigma and illness uncertainty experiences in SCD. Efforts by healthcare workers to reduce patient illness uncertainty may have additional impact, reducing their stigma.

The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease.In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed.A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).

Background We aim to assess the levels of agreement between parents, as proxies, and Jamaican adolescents living with sickle cell disease (SCD) in the reporting of the adolescent's quality of life. Procedures This cross-sectional study assessed 102 patient/proxy pairs on quality of life of adolescents with SCD using the PedsQL-SCD module. The level of agreement among pairs was assessed starting with broad group-level approaches (the Wilcoxon signed-rank test augmented by exploring percentage agreement) tapering to individual-level approaches (intraclass correlation coefficients [ICCs] supplemented with Bland-Altman plots). Results Most patients (76.5%) had homozygous SS disease (45.1% females; mean age 15.2 ± 1.5 years). Median total pediatric quality of life (PedsQL) scores were 79.1 (adolescent report) and 80.2 (parental report) (P = .60). There were 11.8% underestimation and 12.7% overestimation of overall health-related quality of life (HRQOL) by parents. The highest perfect agreement existed on the "pain and hurt" domain for both male and female adolescents (85.7% and 84.4%, respectively). Overestimation was highest on the "social communication" domain for both male and female adolescents (19.6% and 34.8%, respectively). Parents exhibited good agreement on total PedsQL scores in male adolescents (ICC = 0.70), but moderate agreement (ICC = 0.43) in female adolescents. Generally, parents underestimated their male child's functioning and overestimated the female child's functioning on the various domains. Conclusions Parents and adolescents exhibit fair agreement in assessment of the adolescent's overall HRQOL but differ on subjective domains. Agreement varies by sex of the affected teen where girls' HRQOL is generally overestimated by the parental proxy. Interventions to improve parents' understanding of their children's psychosocial needs are needed.

Author(s): Daya, Michelle; Rafaels, Nicholas; Brunetti, Tonya M; Chavan, Sameer; Levin, Albert M; Shetty, Aniket; Gignoux, Christopher R; Boorgula, Meher Preethi; Wojcik, Genevieve; Campbell, Monica; Vergara, Candelaria; Torgerson, Dara G; Ortega, Victor E; Doumatey, Ayo; Johnston, Henry Richard; Acevedo, Nathalie; Araujo, Maria Ilma; Avila, Pedro C; Belbin, Gillian; Bleecker, Eugene; Bustamante, Carlos; Caraballo, Luis; Cruz, Alvaro; Dunston, Georgia M; Eng, Celeste; Faruque, Mezbah U; Ferguson, Trevor S; Figueiredo, Camila; Ford, Jean G; Gan, Weiniu; Gourraud, Pierre-Antoine; Hansel, Nadia N; Hernandez, Ryan D; Herrera-Paz, Edwin Francisco; Jimenez, Silvia; Kenny, Eimear E; Knight-Madden, Jennifer; Kumar, Rajesh; Lange, Leslie A; Lange, Ethan M; Lizee, Antoine; Maul, Pissamai; Maul, Trevor; Mayorga, Alvaro; Meyers, Deborah; Nicolae, Dan L; O'Connor, Timothy D; Oliveira, Ricardo Riccio; Olopade, Christopher O; Olopade, Olufunmilayo; Qin, Zhaohui S; Rotimi, Charles; Vince, Nicolas; Watson, Harold; Wilks, Rainford J; Wilson, James G; Salzberg, Steven; Ober, Carole; Burchard, Esteban G; Williams, L Keoki; Beaty, Terri H; Taub, Margaret A; Ruczinski, Ingo; Mathias, Rasika A; Barnes, Kathleen C; CAAPA | Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Sickle cell disease (SCD) is one of the most common monogenic diseases in humans with multiple phenotypic expressions that can manifest as both acute and chronic complications. Although described more than a century ago, challenges in comprehensive disease management and collaborative research on this disease are compounded by the complex molecular and clinical phenotypes of SCD, environmental and psychosocial factors, limited therapeutic options and ambiguous terminology. This ambiguous terminology has hampered the integration and interoperability of existing SCD knowledge, and SCD research translation. The SCD Ontology (SCDO), which is a community-driven integrative and universal knowledge representation system for SCD, overcomes this issue by providing a controlled vocabulary developed by a group of experts in both SCD and ontology design. SCDO is the first and most comprehensive standardized human- and machine-readable resource that unambiguously represents terminology and concepts about SCD for researchers, patients and clinicians. It is built around the central concept ‘hemoglobinopathy’, allowing inclusion of non-SCD haemoglobinopathies, such as thalassaemias, which may interfere with or influence SCD phenotypic manifestations. This collaboratively developed ontology constitutes a comprehensive knowledge management system and standardized terminology of various SCD-related factors. The SCDO will promote interoperability of different research datasets, facilitate seamless data sharing and collaborations, including meta-analyses within the SCD community, and support the development and curation of data-basing and clinical informatics in SCD.

The region surrounding the Caribbean Sea is predominantly composed of island nations for its Eastern part and the American continental coast on its Western part. A large proportion of the population, particularly in the Caribbean islands, traces its ancestry to Africa as a consequence of the Atlantic slave trade during the XVI&ndash, XVIII centuries. As a result, sickle cell disease has been largely introduced in the region. Some Caribbean countries and/or territories, such as Jamaica and the French territories, initiated newborn screening (NBS) programs for sickle cell disease more than 20 years ago. They have demonstrated the major beneficial impact on mortality and morbidity resulting from early childhood care. However, similar programs have not been implemented in much of the region. This paper presents an update of the existing NBS programs and the prevalence of sickle cell disease in the Caribbean. It demonstrates the impact of the Caribbean Network of Researchers on Sickle Cell Disease and Thalassemia (CAREST) on the extension of these programs. The presented data illustrate the importance of advocacy in convincing policy makers of the feasibility and benefit of NBS for sickle cell disease when coupled to early care.

Introduction: sickle cell disease can result in visually threatening eye disease (proliferative sickle cell retinopathy). This can be prevented with timely eye screening. It is important for patients to understand their role. Our research is to determine the knowledge, beliefs and practices (KBP) regarding eye disease of Sickle Cell patients and the impact of genotype, demographic and socio-economic status. Methods: cross-sectional study at the Sickle Cell Unit, Jamaica during May 2016. Consecutive non-pregnant adults (>18 years of age) attendees, who were not acutely unwell, were invited to participate. A 26-item single interviewer administered questionnaire was used to obtain socio-demographic data, highest level of education completed, employment status, sickle cell genotype, if known, frequency of clinic attendance and patients' knowledge, beliefs and practices. Ten of these were yes/no questions, whereas eight required that they choose correct answers from four choices. Results: one hundred subjects were recruited, 72% had homozygous SS disease. Their ages ranged from 18-63 years (mean 34.1 years, SD11.3). Fifty six percent were female. Most (75%) had achieved at least secondary education. The majority (62%) were unemployed. The mean belief score was 3.6/6(60%) and the mean knowledge and practice scores were 3.3/7(47%) and 2.2/5(44%) respectively. Milder genotypes had higher knowledge scores vs the more severe genotypes (4.0 vs 3.2, P=0.013). Only 28% had regular eye examinations; less than 50% had seen an ophthalmologist in the past year. Practice scores were higher in employed than in unemployed patients (2.6 vs 1.9, (P=0.04)). Employed patients were more likely than the unemployed to see their eye doctor for regular eye "examinations" (42.1% vs 19.4%, χ2=6.0, P=0.02). The practice and knowledge scores correlated (r2=0.363, P

International audience; Sickle cell disease (SCD) is a debilitating single gene disorder caused by a single point mutation that results in physical deformation (i.e. sickling) of erythrocytes at reduced oxygen tensions. Up to 75% of SCD in newborns world-wide occurs in sub-Saharan Africa, where neonatal and childhood mortality from sickle cell related complications is high. While SCD research across the globe is tackling the disease on multiple fronts, advances have yet to significantly impact on the health and quality of life of SCD patients, due to lack of coordination of these disparate efforts. Ensuring data across studies is directly comparable through standardization is a necessary step towards realizing this goal. Such a standardization requires the development and implementation of a disease-specific ontology for SCD that is applicable globally. Ontology development is best achieved by bringing together experts in the domain to contribute their knowledge.The SCD community and H3ABioNet members joined forces at a recent SCD Ontology workshop to develop an ontology covering aspects of SCD under the classes: phenotype, diagnostics, therapeutics, quality of life, disease modifiers and disease stage. The aim of the workshop was for participants to contribute their expertise to development of the structure and contents of the SCD ontology. Here we describe the proceedings of the Sickle Cell Disease Ontology Workshop held in Cape Town South Africa in February 2016 and its outcomes. The objective of the workshop was to bring together experts in SCD from around the world to contribute their expertise to the development of various aspects of the SCD ontology.

Quality of life (QOL) and illness perceptions are important considerations when managing adolescents with sickle cell disease (SCD). This study aims to assess the psychometric properties of the SCD-specific paediatric quality of life (PedsQL™-SCD) and the revised illness perception questionnaires (IPQ-R) in Jamaican adolescents with SCD. One hundred and fifty Jamaican adolescents (M: 74, F: 76; mean age 16.1 ± 1.9 years, range: 13–19 years) completed the IPQ-R, PedsQL™-SCD (teen and parent forms) and a knowledge questionnaire. Socio-demographic and clinical data were also collected and the latter were used to create a severity index. Instruments’ structure, feasibility, reliability and construct validity were assessed. The Cronbach’s alpha for the 24-item knowledge questionnaire was 0.85; IPQ-R domains from 0.56 to 0.79 (except ‘treatment control’: 0.34); PedsQL teen-form domains from 0.70 to 0.93 and PedsQL parent-form domains from 0.72 to 0.95. All scales and subscales had low floor effects but ...

Background: Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by hemoglobin (Hb) polymerization and red blood cell sickling, leading to chronic hemolysis and anemia as well as episodic vaso-occlusion. These manifestations of SCD contribute to the cumulative organ damage that leads to disability and accelerated mortality. Voxelotor is a first-in-class therapy in development for the treatment of SCD that has been shown to increase Hb levels and reduce markers of hemolysis, consistent with inhibition of sickle Hb polymerization. The objective of this analysis was to evaluate the association between Hb response and markers of hemolysis in voxelotor-treated patients. Methods: The HOPE trial is a phase 3, randomized, placebo-controlled, double-blind, multicenter study comparing the efficacy and safety of voxelotor (1500 mg and 900 mg daily) versus placebo for ≥24 weeks in patients aged 12 to 65 years with SCD. The primary endpoint is the percentage of patients with a Hb response at week 24, defined as a >1.0 g/dL increase in Hb. Secondary endpoints include change in markers associated with hemolysis: absolute reticulocyte count and percentage of reticulocytes, indirect bilirubin level, and lactate dehydrogenase (LDH) level. The per-protocol population was defined as those who completed the week 24 visit of the assigned treatment regimen and who did not initiate hydroxyurea treatment between baseline and week 24. Pharmacokinetic/pharmacodynamic modeling was used to correlate voxelotor exposure with Hb response and measures of hemolysis. Results: A total of 229 patients (n=74, voxelotor 1500 mg; n=79, voxelotor 900 mg; n=76, placebo) were included in the per-protocol analysis. Among patients receiving voxelotor 1500 mg, all measures of hemolysis were consistently lower for those with changes in Hb of >1 g/dL compared with those with changes of ≤1 g/dL (Table 1). In the 900 mg group, percentage of reticulocytes, bilirubin, and LDH were lower for those with changes in Hb of >1 g/dL compared with those with changes of ≤1 g/dL; this pattern was not seen for absolute reticulocytes in this cohort. Generally, the degree of reduction in hemolysis markers was greater in the 1500 mg arm compared with the 900 mg arm. Linear relationships between voxelotor exposure and Hb and LDH response were observed. In addition, saturable relationships between reticulocytes and bilirubin were also observed. Conclusions: Among patients treated with voxelotor, those with Hb changes of >1.0 g/dL had the greatest reductions in the markers of hemolysis. In addition, patients with Hb changes of >1 g/dL and who received voxelotor 1500 mg had lower hemolytic markers than those who received voxelotor 900 mg, suggesting that exposure to a higher dose of voxelotor results in a greater decrease in hemolysis markers. Taken together, these results suggest that the mechanism by which voxelotor raises Hb is related to a reduction in hemolysis, which may modify the morbidity of SCD by improving hemolytic anemia. Disclosures Howard: Imara: Consultancy, Other: Travel grant; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Resonance Health: Other: Travel grant. Vichinsky:Global Blood Therapeutics: Consultancy; Agios: Research Funding; Pfizer: Research Funding. Knight-Madden:Global Blood Therapeutics: Research Funding; Nova Laboratories: Advisory Board on SCD 2017, Research Funding; Global Blood Therapeutics: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Addmedica: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; BlueBird Bio: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Abbott Nutrition: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Abbot International: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Nova Laboratories: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Pfizer: Other: Advisory Board on SCD 2017. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Washington:Global Blood Therapeutics: Employment, Equity Ownership. Tong:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Gordeuk:Emmaus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Imara: Research Funding; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Ironwood: Research Funding; Inctye: Research Funding; Pfizer: Research Funding; Inctye: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Consultancy, Honoraria; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Emmaus: Consultancy, Honoraria; Ironwood: Research Funding; Modus Therapeutics: Consultancy, Honoraria; Imara: Research Funding; Pfizer: Research Funding.

Incident stroke, both primary and recurrent are common in children with sickle cell anemia (SCA) in Jamaica with incidences of 7.8% by 14 years of age and 29/100 person-years respectively. Cerebral vasculopathy manifested by elevated transcranial doppler (TCD) velocity (>170 cm/sec) is the major risk factor for both with a prevalence of 19.8% among Jamaican children with SCA. Chronic blood transfusion is the standard of care to reduce stroke risk and recurrence in children with SCA in high income countries, but in low-resource settings where blood availability, safety and local acceptance are limited, hydroxyurea (HU) is emerging as a viable alternative. However, the efficacy of HU for incident stroke prevention in children with newly diagnosed severe cerebrovascular disease without the use of transfusions in a low resource setting like Jamaica is unclear. The EXpanding Treatment for Existing Neurological Disease (EXTEND) trial (ClinicalTrials.gov NCT02556099) was designed to investigate the effects of open label HU on TCD velocities after 18 months of treatment, compared to the pre-treatment value. Secondary aims included the effects of HU on the incidence of neurological events including magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) changes, non-neurological events, hematological responses and toxicity. We enrolled 43 children with SCA, 2 to 17 years of age , between Nov 2014 and April 2016, stratified into 3 groups: Low Risk Group (LRG) - On Hydroxyurea with TCD ≥170 cm/sec, N=12; Medium Risk Group (MRG) - HU naive with TCD ≥170 cm/sec, N=21; and High Risk Group (HRG) - Previous Stroke, N=10. All children received HU initially at 20 mg/kg/day followed by two monthly dose escalation using weight and pre-defined laboratory criteria to maximum tolerated dose (MTD) and thereafter 3 monthly visits. The average HU dose at MTD (mean±1SD) was 25.3±0.4 mg/kg. TCD was performed every 6 months according to the Stroke Prevention in Sickle Cell Anemia (STOP) protocol. The average age at enrollment was 7.7±2.6 years, with MRG significantly younger than HRG (6.7±2.0 years vs 9.2±3.7 years; p Laboratory benefits of HU included clinically significant increases in Hb (2.0±0.9 g/dl) and (1.7±0.7 g/dl) in MRG and HRG as well as increases in %HbF, (17.8±10.7 ) in MRG and (14.4±14) in HRG plus significant decreases in WBC (6.5±3.7 x 109/L) and (4.5±3.3 x 109/L) in MRG and HRG respectively. There were no significant changes in hematology for LRG. Overall, HU was well-tolerated with 0.53 recorded toxicities/year during 697.2 patient-months of treatment. Treatment with HU at MTD for 18 months in children at high risk for strokes was effective in lowering TCD velocities with laboratory benefits and was safe. However, while the overall incidence of new neurological events was low in children with elevated TCD velocities, children with previous stroke experienced higher rates of stroke recurrence on HU therapy. Thus, the incidence of neurological events in children with previous stroke may be related to severe vasculopathy that is challenging to manage using HU, transfusions, or newer disease-modifying therapies. Disclosures Rankine-Mullings: Nova Laboratories Limited, Martin House, Gloucester Crescent, Wigston, Leicester, LE18 4YL: Other: I am Principal investigator for the performance site at the University of the West Indies for the protocol A prospective open label, pharmacokinetic study of an oral Hydroxyurea solution in children with sickle cell anemia . Knight-Madden:Global Blood Therapeutics: Research Funding; Global Blood Therapeutics: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Addmedica: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; BlueBird Bio: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Nova Laboratories: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Abbot International: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Pfizer: Other: Advisory Board on SCD 2017; Abbott Nutrition: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Nova Laboratories: Advisory Board on SCD 2017, Research Funding. Adams:Bluebird: Consultancy; GBT: Consultancy, Other: consultancy to companies GBT and Blueburd Bio. Ware:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; 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; Novartis: Other: DSMB; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees.

Globally, the majority of persons born with sickle cell disease do not have access to hydroxyurea or more expensive interventions. The objectives were to estimate the survival in homozygous sickle cell disease, unbiased by symptomatic selection and to ascertain the causes of death in a pre-hydroxyurea population. The utility of early life biomarkers and genetically determined phenotypes to predict survival was assessed. A cohort study based on neonatal diagnosis was undertaken at the Sickle Cell Unit, a specialist clinic delivering care to persons with sickle cell disease in Jamaica. Screening of 100,000 deliveries detected 315 babies with homozygous sickle cell disease of whom 311 have been followed from birth for periods up to 43 years. Pneumococcal prophylaxis and teaching mothers splenic palpation were important, inexpensive interventions. Anticipatory guidance, routine care and out-patient acute care were provided. Each participant was classified as alive, dead, or defaulted (usually emigration). Causes of death were ascertained from clinical records and/or post-mortem reports. Survival was assessed using the Kaplan-Meier function. Sex-adjusted Cox semi-parametric proportional hazards and Weibull modelling were used to assess the effects on survival of biomarkers. Survival to 40 years was 55.5% (95% CI 48.7% to 61.7%). Acute Chest Syndrome (n = 31) and septicemia (n = 14) were significant causes of death at all ages. Acute splenic sequestration (n = 12) was the most common cause of early deaths. Survival was significantly shorter in those with lower hemoglobin at 1 year, high total nucleated count at 1 year, and a history of dactylitis ever. In these hydroxyurea naive patients, survival into midlife was common. Causes of death were often age specific and some may be preventable. Early life biomarkers predictive of decreased survival in SS disease identify a patient group likely to benefit from close clinical supervision and potentially high risk therapies.

We used a deeply sequenced dataset of 910 individuals, all of African descent, to construct a set of DNA sequences that is present in these individuals but missing from the reference human genome. We aligned 1.19 trillion reads from the 910 individuals to the reference genome (GRCh38), collected all reads that failed to align, and assembled these reads into contiguous sequences (contigs). We then compared all contigs to one another to identify a set of unique sequences representing regions of the African pan-genome missing from the reference genome. Our analysis revealed 296,485,284 bp in 125,715 distinct contigs present in the populations of African descent, demonstrating that the African pan-genome contains ~10% more DNA than the current human reference genome. Although the functional significance of nearly all of this sequence is unknown, 387 of the novel contigs fall within 315 distinct protein-coding genes, and the rest appear to be intergenic. Assembly of a pan-genome from 910 humans of African descent identifies 296.5 Mb of novel DNA mapping to 125,715 distinct contigs. This African pan-genome contains ~10% more DNA than the current human reference genome.

This study investigated the association of nutritional and haematological variables with maximum time-averaged mean velocity (TAMV) measured by transcranial Doppler (TCD) velocity and the agreement of classification between two protocols. TCD categories included: normal (

BACKGROUNDAsthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. One of the main goals of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to discover genes conferring risk to asthma in populations of African descent.METHODSWe performed a genome-wide meta-analysis of asthma across 11 CAAPA datasets (4,827 asthma cases and 5,397 controls), genotyped on the African Diaspora Power Chip (ADPC) and including existing GWAS array data. The genotype data were imputed up to a whole genome sequence reference panel from n=880 African ancestry individuals for a total of 61,904,576 SNPs. Statistical models appropriate to each study design were used to test for association, and results were combined using the weighted Z-score method. We also used admixture mapping as a complementary approach to identify loci involved in asthma pathogenesis in subjects of African ancestry.RESULTSSNPs rs787160 and rs17834780 on chromosome 2q22.3 were significantly associated with asthma (p=6.57 × 10−9 and 2.97 × 10−8, respectively). These SNPs lie in the intergenic region between the Rho GTPase Activating Protein 15 (ARHGAP15) and Glycosyltransferase Like Domain Containing 1 (GTDC1) genes. Four low frequency variants on chromosome 1q21.3, which may be involved in the “atopic march” and which are not polymorphic in Europeans, also showed evidence for association with asthma (1.18 ×10−6 ≤ p ≤ 3.06 ×10−6). SNP rs11264909 on chromosome 1q23.1, close to a region previously identified by the EVE asthma meta-analysis as having a putative African ancestry specific effect, only showed differences in counts in subjects homozygous for alleles of African ancestry. Admixture mapping also identified a significantly associated region on chromosome 6q23.2, which includes the Transcription Factor 21 (TCF21) gene, previously shown to be differentially expressed in bronchial tissues of asthmatics and non-asthmatics.CONCLUSIONSWe have identified a number of novel asthma association signals warranting further investigation.

Acute pulmonary problems in sickle cell disease (SCD) patients, in particular acute chest syndrome (ACS), cause significant mortality and morbidity. It is important to differentiate ACS from pneumonia to avoid inappropriate or inadequate treatment. Asthma may increase the risk of ACS and co-morbid asthma and SCD are associated with worse patient outcomes and, in preclinical models, more severe inflammation. Recurrent wheezing, however, can occur in the absence of a diagnosis of asthma; it is likely due to SCD related inflammation and additional therapies than those that treat asthma may be required. Further research is merited to clarify these issues.

In the version of this article initially published, the statement "there are no pan-genomes for any other animal or plant species" was incorrect. The statement has been corrected to "there are no reported pan-genomes for any other animal species, to our knowledge." We thank David Edwards for bringing this error to our attention. The error has been corrected in the HTML and PDF versions of the article.

Background: Genetic transfer of an anti-sickling β87-globin lentiviral vector (LV) into hematopoietic stem cells (HSC) followed by myeloablative transplant has cured one child with sickle cell anemia (SCA) (NEJM 2017), although it was not successful in 7 subsequent adult SCA patients, and modifications to intensify ablative conditioning, improve HSC dose, gene transfer are underway (Blood 130 Suppl 1: 527, 2017). Based upon our preclinical data (Blood 2009), we embarked upon a Reduced Intensity Conditioning (RIC) Phase I/II Pilot Study on Gene Transfer in Patients with SCA with a modified γ-Globin LV (NCT02186418), hypothesizing this approach will be safe, feasible and efficacious; Moreover, RIC will have significantly less toxicity, costs, and be implementable in many transplant centers, including those in some of the resource-poor countries, where supportive therapies for myeloablative transplants are unavailable, and where majority of SCA patients exist. Methods: Adult patients with severe SCA deemed eligible were transfused/erythrocytapheresed prior to HSC collection and transfused for 6 months post-transplant (PT) to Hb>10g/dl and HbS~30%. CD34+ HSC were collected via bone marrow harvest (BMH) and/or plerixafor mobilized Peripheral Blood Stem Collection (PBSC), selected for CD34+ cells and transduced. Patients received a single dose of IV melphalan (140mg/m2 BSA) 36hr prior to infusion of γ-globin modified (GM)-HSC. Patients were monitored for adverse events (AE), engraftment, vector copy number (VCN), modified HbF (HbF*) expression and clinical features of SCA. Results: Two SCA patients (35yo and 25yo) with HbS-β0 thalassemia genotype were treated. CD34+ HSC were collected via multiple BMH (P1) and BMH+PBSC (P2). Follow up data are available for 6 and 12mo on P1 and P2. P1 received 1x106 CD34+ cells/kgbw [vector copy number (VCN) 0.22], and P2 received 6.9x106 CD34+ cells/kgbw [VCN 0.46]. Time to neutrophil engraftment (ANC ≥ 500) was day 9 and 7 post-transplant (PT) in P1 and P2, respectively, and time to Plt recovery (Plt>50K) was day 14 PT in both. Patients included in this trial had severe disease and continued to have pre-existing chronic pain requiring significant opiates; hence ~80% of the AEs were pain events; other AEs were anticipated transient laboratory AEs associated with melphalan. Following GM-HSC infusion, both patients showed a progressive rise in HbF* (a point mutation in the γ-globin LV allows distinction from endogenous HbF by HPLC) starting from day 30 PT. Since patients had transfused HbA containing RBCs in the initial 6 months, HbF*/(HbF*+HbS) was calculated, and was 20% and 21% in P1 and P2 at day 180 PT and VCN 0.2-0.4, detected in all lineages. Integration site analysis, performed on the infused products (Day 0), at day 30 PT on P1 and P2, and on day 180 PT on P1 demonstrated highly polyclonal pattern of integration. At 1 yr PT, P1 had 20% HbF* (2.1g/dl HbF*, total Hb 10.6) with a stable VCN of 0.2-0.4 in multiple lineages in bone marrow and peripheral blood. The baseline Hb of P1 was 7.5-8.5g/dL prior to transplant. In the preceding 2 years prior to transplant, both patients were admitted for pain crises/acute chest >5-6 times/yr, and had chronic pain requiring chronic opiates. Chronic pain persisted for 4-5 months PT in P1, after which P1 has not required IV opiates, negligible oral opiates and has had no hospital visits/admissions with acute sickle events. P2 has required decreasing amounts of oral opiates for chronic back pain. Conclusions: Early results from 2 SCA adults treated with a modified γ-globin LV modified autologous HSC following RIC transplant showed excellent safety, feasibility, with minimal post-transplant toxicity, rapid count recovery, and sustained stable genetically modified cells in peripheral blood and bone marrow. The first patient shows significant clinical amelioration of the SCA phenotype at 1 year PT, with 20% vector-derived HbF (HbF*) that has caused amelioration of anemia, near elimination of chronic pain and absence of acute sickle events. The second patient, although still early post-transplant shows a similar HbF* trajectory. Additional study data will demonstrate whether this level of HbF* will provide consistent clinical benefit to patients with severe SCA. These early results, especially following a RIC transpant, are extremely promising; and if sustained, will provide a 'transportable' safe and feasible gene therapy for SCA. Disclosures Malik: CSL Behring: Patents & Royalties. Quinn:Global Blood Therapeutics: Research Funding; Silver Lake Research Corporation: Research Funding; Amgen: Research Funding.

We undertook a cost effectiveness analysis (CEA) of hydroxyurea (HU) in preventing stroke recurrence and/or death. We followed 43 children with sickle cell disease from 2000 to 2009 after having a first clinical stroke, of whom 10 opted for HU therapy. HU use led to decreased stroke recurrence and death without significantly increasing the annual cost of care per patient (J$83,250 vs. J$76,901, P = 0.491). The incremental cost effectiveness ratio (ICER) for prevention of stroke recurrence amounted to J$169,238 (US$1,900), while that for death prevention equalled J$635,843 (US$7,140). HU may be recommended when safe and affordable transfusion therapy is not feasible.

Characterization of genetic admixture of populations in the Americas and the Caribbean is of interest for anthropological, epidemiological, and historical reasons. Asthma has a higher prevalence and is more severe in populations with a high African component. Association of African ancestry with asthma has been demonstrated. We estimated admixture proportions of samples from six trihybrid populations of African descent and determined the relationship between African ancestry and asthma and total serum IgE levels (tIgE). We genotyped 237 ancestry informative markers in asthmatics and nonasthmatic controls from Barbados (190/277), Jamaica (177/529), Brazil (40/220), Colombia (508/625), African Americans from New York (207/171), and African Americans from Baltimore/Washington, D.C. (625/757). We estimated individual ancestries and evaluated genetic stratification using Structure and principal component analysis. Association of African ancestry and asthma and tIgE was evaluated by regression analysis. Mean ± SD African ancestry ranged from 0.76 ± 0.10 among Barbadians to 0.33 ± 0.13 in Colombians. The European component varied from 0.14 ± 0.05 among Jamaicans and Barbadians to 0.26 ± 0.08 among Colombians. African ancestry was associated with risk for asthma in Colombians (odds ratio (OR) = 4.5, P = 0.001) Brazilians (OR = 136.5, P = 0.003), and African Americans of New York (OR: 4.7; P = 0.040). African ancestry was also associated with higher tIgE levels among Colombians (β = 1.3, P = 0.04), Barbadians (β = 3.8, P = 0.03), and Brazilians (β = 1.6, P = 0.03). Our findings indicate that African ancestry can account for, at least in part, the association between asthma and its associated trait, tIgE levels.

Background: We aimed to estimate the relative risk for elevated blood pressure (BP ≥ 120/80 mmHg) for cardiovascular disease (CVD) risk factors among Afro-Caribbean youth in Jamaica and to evaluate the association between clustering of risk factors and elevated BP. Methods: We analysed data from 898 young adults, 18-20 years old (409 males; 489 females) from the Jamaica 1986 Birth Cohort Study. BP was measured with a mercury sphygmomanometer after the participant had been seated for 5 minutes. Anthropometric measurements were done and venous blood obtained to measure fasting glucose, lipids and insulin. Data on socioeconomic status (SES) were obtained via questionnaire. CVD risk factor status was defined using standard cut-points or the upper quintile of the distribution. Insulin resistance was estimated using the Homeostasis Model Assessment (HOMA-IR). Relative risks were computed using odds ratios (OR) from logistic regression models. Results: Prevalence of elevated BP was 30% among males and 13% among females (p Conclusion: Factors associated with elevated BP among Jamaican young adults include measures of obesity and insulin resistance, with significant differences by sex. Lower SES was associated with elevated BP among females. Clustering of risk factors was associated with markedly higher odds of elevated BP among males, but less so among females.

Background: Cerebral vasculopathy in sickle cell anemia (SCA) begins in childhood and features intracranial arterial stenosis with high risk of ischemic stroke. Stroke risk can be reduced by transcranial doppler (TCD) screening and chronic transfusion therapy; however, this approach is impractical in many developing countries. Accumulating evidence supports the use of hydroxyurea for the prevention and treatment of cerebrovascular disease in children with SCA. Recently we reported that hydroxyurea significantly reduced the conversion from conditional TCD velocities to abnormal velocities; whether hydroxyurea can be used for children with newly diagnosed severe cerebrovascular disease in place of starting transfusion therapy remains unknown. Objective: The primary objective of the EXpanding Treatment for Existing Neurological Disease (EXTEND) trial is to investigate the effect of open label hydroxyurea on the maximum time-averaged mean velocity (TAMV) after 18 months of treatment compared to the pre-treatment value. Secondary objectives include the effects of hydroxyurea on serial TCD velocities, the incidence of neurological and non-neurological events, quality of life (QOL), body composition and metabolism, toxicity and treatment response, changes to brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), genetic and serologic markers of disease severity, and cognitive and pulmonary function. Methods: This prospective Phase II trial will enroll children with SCA in Jamaica, between the ages of 2 and 17 years, with either conditional (170-199 cm/sec) or abnormal (? 200 cm/sec) TCD velocities. Oral hydroxyurea will be administered daily and escalated to the maximum tolerated dose (MTD). Participants will be seen in the Sickle Cell Unit (SCU) in Kingston, Jamaica monthly until achieving MTD, and then every 3 months. TCD will be performed every 6 months. Results: Currently, 43 participants have been enrolled out of a projected 50. There was one withdrawal due to immigration, with no permanent screen failures. Of the 43 enrolled, 37 participants have initiated study treatment. Conclusions: This trial investigates the effects of hydroxyurea treatment at MTD in children with conditional or abnormal TCD velocities before transfusion therapy and may represent an important advance towards establishing a suitable non-transfusion protocol for stroke prevention in children with SCA. The trial outcomes will have profound significance in developing countries where the disease burden is highest. Clinical Trial: ClinicalTrials.gov NCT02556099; https://clinicaltrials.gov/ct2/show/NCT02556099 (Archived by WebCite at http://www.webcitation.org/6k1yMAa9G) [JMIR Res Protoc 2016;5(3):e185]

International audience; Sickle cell disease (SCD) is a significant problem in the Caribbean, where many individuals have African and Asian forebears. However, reliable prevalence data and specific health care programs for SCD are often missing in this region. Closer collaboration between Caribbean territories initiated in 2006 to set up strategies to promote better equity in the health care system for SCD patients led to the formation of CAREST: the Caribbean Network of Researchers on Sickle Cell Disease and Thalassemia. We present the effectiveness of collaborations established by CAREST to promote SCD newborn screening programs and early childhood care, to facilitate health worker training and approaches for prevention and treatment of SCD complications, and to carry out inter-Caribbean research studies.

Background Although several studies have identified risk factors for high blood pressure (BP), data from Afro-Caribbean populations are limited. Additionally, less is known about how putative risk factors operate in young adults and how social factors influence the risk of high BP. In this study, we estimated the relative risk for elevated BP or hypertension (EBP/HTN), defined as BP ≥ 120/80 mmHg, among young adults with putative cardiovascular disease (CVD) risk factors in Jamaica and evaluated whether relative risks differed by sex. Methods Data from 898 young adults, 18–20 years old, were analysed. BP was measured with a mercury sphygmomanometer after participants had been seated for 5 min. Anthropometric measurements were obtained, and glucose, lipids and insulin measured from a fasting venous blood sample. Data on socioeconomic status (SES) were obtained via questionnaire. CVD risk factor status was defined using standard cut-points or the upper quintile of the distribution where the numbers meeting standard cut-points were small. Relative risks were estimated using odds ratios (OR) from logistic regression models. Results Prevalence of EBP/HTN was 30% among males and 13% among females (p p p = 0.008), while high HOMA-IR did not achieve statistical significance (OR 2.08, CI [0.94–4.58], p = 0.069). In similar models for women, high triglycerides (OR 1.98, CI [1.03–3.81], p = 0.040) and high HOMA-IR (OR 2.07, CI [1.03–4.12], p = 0.039) were positively associated with EBP/HTN. Lower SES was also associated with higher odds for EBP/HTN (OR 4.63, CI [1.31–16.4], p = 0.017, for moderate vs. high household possessions; OR 2.61, CI [0.70–9.77], p = 0.154 for low vs. high household possessions). Alcohol consumption was associated with lower odds of EBP/HTN among females only; OR 0.41 (CI [0.18–0.90], p = 0.026) for drinking p = 0.012) for drinking ≥3 times per week vs. never drinkers. Physical activity was inversely associated with EBP/HTN in both males and females. Conclusion Factors associated with EBP/HTN among Jamaican young adults include obesity, high glucose, high triglycerides and high HOMA-IR, with some significant differences by sex. Among women lower SES was positively associated with EBP/HTN, while moderate alcohol consumption was associated lower odds of EBP/HTN.

We undertook a cost effectiveness analysis (CEA) of hydroxyurea (HU) in preventing stroke recurrence and/or death. We followed 43 children with sickle cell disease from 2000 to 2009 after having a first clinical stroke, of whom 10 opted for HU therapy. HU use led to decreased stroke recurrence and death without significantly increasing the annual cost of care per patient (J$83,250 vs. J$76,901, P = 0.491). The incremental cost effectiveness ratio (ICER) for prevention of stroke recurrence amounted to J$169,238 (US$1,900), while that for death prevention equalled J$635,843 (US$7,140). HU may be recommended when safe and affordable transfusion therapy is not feasible.