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Children with sickle cell disease (SCD) frequently present to hospital acutely unwell and are often exposed to diagnostic chest X-rays (CXRs). Little evidence exists to determine when CXRs are clinically useful. Using electronic hospital records, we audited CXR use in children aged 0-18 who presented to hospital over the past 10 years in both an inpatient and emergency department setting. From a total of 915 first CXRs, only 28·2% of CXRs (n = 258) had clinically significant findings that altered management or final diagnosis. Of these abnormalities, consolidation represented 52·3%, effusion 8·9%, cardiomegaly 8·4% and sickle cell-related bone changes 6·3%. Indications for CXR of respiratory distress (OR = 3·74, 95% CI 2·28-6·13), hypoxia (OR = 1·86, 95% CI 1·50-2·31) and cough (OR = 1·64, 95% CI 1·33-2·02), were more likely to have significant CXR findings. Patients who had higher peak fever (38·4°C vs. 37·4°C, P = 0·001), higher peak CRP (156·4 vs. 46·1, P 0·001) and higher WCC (20·2 vs. 13·6, P 0·001) were more likely to have clinically significant abnormalities on CXR. We found a decision tool using either hypoxia, cough, respiratory distress, T 38°C, CRP 50 or WCC 15 × 10

We present case histories of three patients who had β-thalassemia (β-thal) trait with 'unusual severity' managed as β-thal intermedia (β-TI) where the basis of disease severity could not be explained with routine hematological and genetic investigations. The clinical diagnosis of 'thalassemia intermedia' was justifiable as they had a β-thal mutation and disease severity that did not fit in with either β-thal trait or with β-thal major (β-TM). As mutations of α, β, and γ genes could not explain the unusual severity of the disease, further analysis with next-generation sequencing (NGS) for red cell diseases was carried out, which led to the diagnosis of coexisting membranopathies. This case series highlights the inherent difficulty in the diagnosis of β-TI with certainty in some patients where the genetic basis is not clear-cut.

In the β-thalassemias, oxidative stress, resulting from chronic hemolysis, globin chain imbalance, iron overload and depleted antioxidant defences, likely contributes to cell death, organ damage, anemia, hypoxia and inflammation. We assessed variations in these parameters in β-thalassemia syndromes in Sri Lanka. Between November 2017 and June 2018, we assessed children and adults attending two thalassemia centres in Sri Lanka: 59 patients with HbE β-thalassemia, 50 β-thalassemia major, 40 β-thalassemia intermedia and 13 HbS β-thalassemia. Median age was 26.0 years (IQR 15.3-38.8), 101 (62.3%) were female and 152 (93.8%) of Sinhalese ethnicity. Methemoglobin, plasma hemoglobin, heme and ferritin were measured as sources of oxidants; plasma total antioxidant capacity, haptoglobin, hemopexin and vitamins C and E assessed antioxidant status; plasma thiobarbituric acid reactive substances and 8-hydroxy-2'-deoxyguanosine assessed oxidative damage; hemoglobin, plasma erythropoietin and transferrin receptor assessed anemia and hypoxia and plasma interleukin-6 and C-reactive protein assessed inflammation. Fruit and vegetable intake was determined by dietary recall. Physical fitness was investigated using the 6-min walk test and measurement of handgrip strength. Oxidant sources were frequently increased and antioxidants depleted, with consequent oxidative damage, anemia, hypoxia and inflammation. Biomarkers were generally most abnormal in HbE β-thalassemia and least abnormal in β-thalassemia intermedia but also varied markedly between individuals with the same thalassemia syndrome. Oxidative stress and damage were also more severe in splenectomized patients and/or those receiving iron chelation therapy. Less than 15% of patients ate fresh fruits or raw vegetables frequently, and plasma vitamins C and E were deficient in 132/160 (82.5%) and 140/160 (87.5%) patients respectively. Overall, physical fitness was poor in all syndromes and was likely due to anemic hypoxia. Studies of antioxidant supplements to improve outcomes in patients with thalassemia should consider individual patient variation in oxidative status both between and within the thalassemia syndromes.

Not available.

Liver involvement in sickle cell disease (SCD) is often referred to as sickle cell hepatopathy (SCH) and is a complication of SCD which may be associated with significant mortality. This review is based on a round-table workshop between paediatric and adult hepatologists and haematologists and review of the literature. The discussion was prompted by the lack of substantial data and guidance in managing these sometimes very challenging cases. This review provides a structured approach for the diagnosis and management of SCH in children and young adults. The term SCH describes any hepatobiliary dysfunction in the context of SCD. Diagnosis and management of biliary complications, acute hepatic crisis, acute hepatic sequestration and other manifestations of SCH are discussed, as well as the role of liver transplantation and haemopoietic stem cell transplantation in the management of SCH.

Objectives: We hypothesised that maternal diet-induced-obesity has adverse consequences for offspring energy expenditure and susceptibility to obesity in adulthood, and that the prebiotic polydextrose (PDX) would prevent the consequences of programming by maternal obesity. Methods: Female mice were fed a control (Con) or obesogenic diet (Ob) for 6 weeks prior to mating and throughout pregnancy and lactation. Half the obese dams were supplemented with 5% PDX (ObPDX) in drinking water throughout pregnancy and lactation. Offspring were weaned onto standard chow. At 3 and 6 months, offspring energy intake (EI) and energy expenditure (EE by indirect calorimetry) were measured, and a glucose-tolerance test performed. Offspring of control (OffCon), obese (OffOb) and PDX supplemented (OffObP) dams were subsequently challenged for 3 weeks with Ob, and energy balanced reassessed. Potential modifiers of offspring energy balance including gut microbiota and biomarkers of mitochondrial activity were also evaluated. Results: Six-month-old male OffOb demonstrated increased bodyweight (BW, P < 0.001) and white adipose tissue mass (P < 0.05), decreased brown adipose tissue mass (BAT, P < 0.01), lower night-time EE (P < 0.001) versus OffCon, which were prevented in OffObP. Both male and female OffOb showed abnormal glucose-tolerance test (peak [Glucose] P < 0.001; AUC, P < 0.05) which was prevented by PDX. The Ob challenge resulted in greater BW gain in both male and female OffOb versus OffCon (P < 0.05), also associated with increased EI (P < 0.05) and reduced EE in females (P < 0.01). OffObP were protected from accelerated BW gain on the OB diet compared with controls, associated with increased night-time EE in both male (P < 0.05) and female OffObP (P < 0.001). PDX also prevented an increase in skeletal muscle mtDNA copy number in OffOb versus OffCon (P < 0.01) and increased the percentage of Bacteroides cells in faecal samples from male OffObP relative to controls. Conclusions: Maternal obesity adversely influences adult offspring energy balance and propensity for obesity, which is ameliorated by maternal PDX treatment with associated changes in gut microbiota composition and skeletal muscle mitochondrial function.

Background: Ischemic stroke is a devastating complication affecting children with sickle cell anemia. Genetic factors are likely to be important in determining the risk of stroke but are poorly defined. Methods: We have studied a cohort of 19 children who had an overt ischemic stroke before 4 years of age. We predicted genetic determinants of stroke would be more prominent in this group. We performed whole exome sequencing on this cohort and applied 2 hypotheses to our variant filtering. First, we looked for strong, potentially mono- or oligogenic variants for ischemic stroke, and second, we considered that more common polygenic variants will be enriched in our cohort. Candidate variants emerging from both strategies were validated in a cohort of 283 patients with sickle cell anemia and known pediatric cerebrovascular outcomes. We used principal component analysis in this cohort to control for relatedness and population substructure. Results: Our primary finding was that the Apoliprotein E genotypes ε2/ε4 and ε4/ ε4, defined by the interplay of rs7412 and rs429358 , were associated with increased stroke risk, with an odds ratio of 4.35 ([95% CI, 1.85–10.0] P =0.0011) for ischemic stroke in the validation cohort. We also found that rs2297518 in NOS (NO synthase) 2 (odds ratio, 2.25 [95% CI, 1.21–4.19]; P =0.014) and rs2230123 in signal transducer and activator of transcription (odds ratio, 2.60 [95% CI, 1.30–5.20]; P =0.009) both had increased odds ratios for ischemic stroke, although these two variants were below the threshold for statistical significance after correction for multiple testing. Conclusions: These data identify new loci for future functional investigations into cerebrovascular disease in sickle cell anemia. Based on African population reference allele frequencies, the Apoliprotein E genotypes would be present in about 10% of children with sickle cell anemia and represent a genetic risk factor that is potentially modifiable by both dietary and pharmaceutical manipulation of its dyslipidemic effects.

ObjectiveTo evaluate the acceptability and safety profile of nocturnal long-term oxygen therapy (LTOT) in children with sickle cell disease (SCD) and chronic hypoxaemia.DesignRetrospective cohort study.Patients, setting and interventionChildren with SCD who started LTOT from 2014 to early 2019 in two tertiary hospitals in London, UK were retrospectively enrolled. Patients who started disease-modifying therapies Main outcome measuresMinor and major adverse events during LTOT were reported. Laboratory and clinical data, transcranial Doppler (TCD) scans and overnight oximetry studies performed at steady state within 12 months before and after starting LTOT were compared.ResultsNineteen children (10 males; median age 12 years, range 6–15) were included. Nearly half of them (9/19; 47%) were on hydroxyurea at baseline. No child discontinued LTOT because of intolerance or poor adherence. No major adverse events were reported. Laboratory data did not show significant changes in haemoglobin and reticulocyte count after 1 year of follow-up. No statistically significant change in the incidence of vaso-occlusive pain events was noted (median annual rate from 0.5 to 0 episode per patient/year; p=0.062). Overnight oximetry tests performed while on LTOT showed improvements in all oxygen saturation parameters (mean overnight and nadir SpO2, % of time spent with SpO2 ConclusionLTOT is a safe and feasible treatment option for children with SCD and chronic hypoxaemia.

Background Though case reports and limited case series of Sickle cell disease in Sri Lanka have been reported previously, no attempt has been made hitherto to undertake a comprehensive genotypic-phenotypic analysis of this “rare” group of patients. Results All accessible Sickle cell disease patients, totaling 60, including, 51 Sickle β-thalassaemia and 9 homozygous sickle patients were enrolled from seven thalassaemia treatment centres between December 2016 - March 2019. The majority of patients were of Sinhalese ethnicity (n=52, 86.67%). Geographically, two prominent clusters were identified and the distribution of Sickle haemoglobin in the island contrasted markedly with the other haemoglobinopathies. 3/ 9 homozygous sickle patients and 3/ 51 Sickle β-thalassaemia patients were receiving regular transfusion. Joint pain was the commonest clinical presentation among all sickle cell disease patients (n=39, 65.0%). Dactylitis was significantly more common in homozygous sickle patients compared with the Sickle β-thalassaemia groups (p 0.027). Two genetic backgrounds sickle mutation were identified namely, Arab Indian and Benin. Among the regulators of Foetal hemoglobin in Sickle patients of the present study rs1427407 G>T seemed to be the most prominent modifier, with a significant association with Foetal haemoglobin levels (p 0.04). Conclusions Overall, the clinical course of the Asian version of Sickle cell disease in Sri Lanka appears to be milder than that described in India.

The loss of red blood cell (RBC) deformability in sickle cell anaemia (SCA) is considered the primary factor responsible for episodes of acute pain and downstream progressive organ dysfunction. Oxygen gradient ektacytometry (Oxygenscan) is a recently commercialised functional assay that aims to describe the deformability of RBCs in SCA at differing oxygen tensions. So far, the Oxygenscan has been evaluated only by a small number of research groups and the validity and clinical value of Oxygenscan-derived biomarkers have not yet been fully established. In this study we examined RBC deformability measured with the Oxygenscan in 91 children with SCA at King’s College Hospital in London. We found a significant correlation between Oxygenscan-derived biomarkers and well-recognised modifiers of disease severity in SCA: haemoglobin F and co-inherited α-thalassaemia. We failed, however, to find any independent predictive value of the Oxygenscan in the clinical outcome measure of pain, as well as other important parameters such as hydroxycarbamide treatment. Although the Oxygenscan remains an intriguing tool for basic research, our results question whether it provides any additional information in predicting the clinical course in children with SCA, beyond measuring known markers of disease severity.

BACKGROUND\ud Worldwide, haemoglobin E β-thalassaemia is the most common genotype of severe β-thalassaemia. The paucity of long-term data for this form of thalassaemia makes evidence-based management challenging. We did a long-term observational study to define factors associated with survival and complications in patients with haemoglobin E thalassaemia.\ud \ud METHODS\ud In this prospective, longitudinal cohort study, we included all patients with haemoglobin E thalassaemia who attended the National Thalassaemia Centre in Kurunegala, Sri Lanka, between Jan 1, 1997, and Dec 31, 2001. Patients were assessed up to three times a year. Approaches to blood transfusions, splenectomy, and chelation therapy shifted during this period. Survival rates between groups were evaluated using Kaplan-Meier survival function estimate curves and Cox proportional hazards models were used to identify risk factors for mortality.\ud \ud FINDINGS\ud 109 patients (54 [50%] male; 55 [50%] female) were recruited and followed up for a median of 18 years (IQR 14-20). Median age at recruitment was 13 years (range 8-21). 32 (29%) patients died during follow-up. Median survival in all patients was 49 years (95% CI 45-not reached). Median survival was worse among male patients (hazard ratio [HR] 2·51, 95% CI 1·16-5·43), patients with a history of serious infections (adjusted HR 8·49, 2·90-24·84), and those with higher estimated body iron burdens as estimated by serum ferritin concentration (adjusted HR 1·03, 1·01-1·06 per 100 units). Splenectomy, while not associated with statistically significant increases in the risks of death or serious infections, ultimately did not eliminate a requirement for scheduled transfusions in 42 (58%) of 73 patients. Haemoglobin concentration less than or equal to 4·5 g/dL (vs concentration >4·5 g/dL), serum ferritin concentration more than 1300 μg/L (vs concentration ≤1300 μg/L), and liver iron concentration more than 5 mg/g dry weight of liver (vs concentration ≤5 mg/g) were associated with poorer survival.\ud \ud INTERPRETATION\ud Patients with haemoglobin E thalassaemia often had complications and shortened survival compared with that reported in high-resource countries for thalassaemia major and for thalassaemia intermedia not involving an allele for haemoglobin E. Approaches to management in this disorder remain uncertain and prospective studies should evaluate if altered transfusion regimens, with improved control of body iron, can improve survival.\ud \ud FUNDING\ud Wellcome Trust, Medical Research Council, US March of Dimes, Anthony Cerami and Ann Dunne Foundation for World Health, and Hemoglobal.

Introduction Acute hepatic porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in hepatic heme biosynthesis. ENVISION is an ongoing phase 3 study, evaluating efficacy and safety of givosiran in symptomatic AHP patients. Objective Describe efficacy and safety resuts of the ENVISION 18-month OLE period. Methods Exploratory efficacy (composite porphyria attacks, ALA/PBG levels, hemin use, and missed days of work) and safety measures in the OLE were assessed. Analyses were descriptive and represent the timepoint after which all patients completed at least their Month 18 visit (01/10/2020). Results Ninety-four patients completed the DB period, and 93 patients entered the OLE (placebo/givosiran = 46; givosiran/givosiran = 47). Mean exposure to givosiran was 12.97 [SD = 3.6] months for placebo/givosiran and 18.86 [3.6] months for givosiran/givosiran, with maximum exposure of 25.1 months. Continued treatment in givosiran/givosiran patients led to a median annualized attack rate (AAR) of 0.58 (range: 0–16.2) through Month 18. Patients in the placebo/givosiran group had an AAR of 1.62 (range: 0–11.8) after receiving givosiran for ≥12 months during the OLE period, compared with 10.65 (range: 0–51.6) whilst receiving placebo during the 6-month DB period. Sustained ALA/PBG lowering during the OLE was accompanied by sustained reductions in hemin use, and more than half of the placebo/givosiran patients experienced 0 days of hemin use. There was a decrease in the number of work days missed in the past 4 weeks at Month 6 (mean = 6.7 days [SD = 7.8], n = 20/46) compared with Month 18 (2.5 [5.1], n = 23/46), for patients in the placebo/givosiran group who were able to work. The most common related adverse events (AEs) observed during givosiran treatment were injection site reactions, nausea and fatigue. Hepatic and renal AEs were both reported in 17% of patients each during givosiran treatment. No new safety concerns occurred in the OLE period. Conclusion In the ongoing OLE period of the ENVISION study, patients receiving long-term treatment with givosiran demonstrated a durable response in clinical efficacy, across a wide range of clinical parameters. Following the initial 6 months of givosiran treatment during the OLE, placebo/givosiran patients had a similar clinical response to that observed in givosiran/givosiran patients in the OLE period through Month 18. The safety profile of givosiran remained acceptable and consistent with that previously observed.

Background Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA. Methods The Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3–7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry. Discussion Findings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA. Trial registration ClinicalTrials.govNCT04351698. Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020

Background: Sickle cell disease (SCD) is a group of genetic blood disorders characterized by hemolytic anemia, multi-organ damage and acutely painful events (vaso-occlusive crises [VOCs]) that can cause life-threatening complications. Vaso-occlusion is mediated, in part, by P-selectin, an adhesion molecule expressed on endothelial cells and platelets. Adults and children with SCD have similar P-selectin expression levels; however, disease severity worsens with increasing age because of cumulative endothelial damage caused by repeated vaso-occlusion events. Crizanlizumab is a humanized anti-P-selectin monoclonal antibody that binds P-selectin and blocks its interaction with its ligands. SUSTAIN, a Phase 2 study in adults with SCD, has shown that crizanlizumab, compared with placebo, is well tolerated and significantly decreases the number of VOCs requiring a healthcare visit (Ataga et al. N Engl J Med 2017). Aim: To describe the design of the first crizanlizumab study in pediatric patients (pts) with SCD and report demographics and baseline characteristics of a subset of enrolled pts (aged 6 to Methods: Primary objectives of this Phase 2, multicenter, open-label study are to confirm crizanlizumab dosing and assess safety. Pts aged 6 mo to Secondary objectives include assessment of crizanlizumab efficacy, measured by annualized rate of VOCs leading to a healthcare visit (clinic, emergency room [ER] or hospital), and annualized rate of VOCs managed at home. VOC subcategories (uncomplicated pain crisis, acute chest syndrome, hepatic and splenic sequestration, and priapism), overall hospitalizations and ER visits and dactylitis events are also assessed. Safety measures include frequency and severity of adverse events. Long-term PK and PD will also be characterized by measuring pre-dose concentrations and percentage of P-selectin inhibition prior to each study drug dose. Part A in each age group will confirm PK dose, beginning with ≥8 pts in G1. If unconfirmed, dose will be adjusted based on population PK model, and ≥8 additional pts enrolled. Once dose is confirmed, recruitment will be expanded for long-term safety and efficacy evaluation of the PK confirmed dose (Part B). This process will then repeat for G2 then G3 (2 to Results: As of January 28, 2020, 59 pts were enrolled: 46 pts in G1 (11 pts in Part A and 35 pts Part B) and 13 pts in G2 Part A. Pt demographics are available for Part A in G1 and 2 (Table), based on 2 Data Monitoring Committee analyses. The median age of G1 was 17.0 yr (range 13-17), 6 (54.5%) were male and 11 (100%) were Black/African American. 9 (81.8%) had HbSS disease, 1 (9.1%) HbSC and 1 (9.1%) HbSβ0. The median age of G2 was 9.0 yr (range 6-11), 8 (61.5%) were male, 7 (53.8%) were Black/African American, 4 (30.8%) were White, and 2 were of multiple race, specifically 'White, Asian' (n=1, 7.7%) and 'White, Black/African American' (n=1, 7.7%). 12 (92.3%) pts had HbSS disease and 1 (7.7%) had HbSC. Conclusions: This study aims to address an unmet treatment need in pediatric pts, exploring appropriate dosing and the safety of crizanlizumab. The annualized rates of VOCs, hospitalizations and ER visits will be assessed as secondary objectives. The primary analyses for Parts A and B of G1 and 2, and then G3, will occur consecutively when all pts enrolled in each group have either completed 26 weeks of treatment or discontinued the study treatment. Disclosures Heeney: UpToDate: Patents & Royalties: Author royalties; Micelle: Consultancy, Other; Keros: Consultancy; Novartis: Consultancy, Other; AstraZeneca: Consultancy, Other; Cyclerion: Consultancy, Other; Forma Therapeutics: Consultancy; Dova: Consultancy; Global Blood Therapeutics: Consultancy; Emerging Therapy Solutions (ETS): Consultancy. Rees:Alnylam Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AstraZeneca: Other: Data monitoring committee membership; Emmanus Medical: Consultancy, Honoraria; TauRx: Other: Data And Safety Monitoring. de Montalembert:Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees. Odame:Novo Nordisk: Other: Study Advisory Board; Global Blood Therapeutics: Other: Study Data Safety Monitoring Board; Novartis: Other: Study Steering Committee. Wali:Novartis: Research Funding. Nguyen:Novartis: Current Employment. Lam:Novartis: Current Employment. Herranz:Novartis: Current Employment. Kanter:NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; bluebird bio, inc: Consultancy, Honoraria; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Guidepoint Global: Honoraria; Cowen: Honoraria; Jeffries: Honoraria; Wells Fargo: Honoraria; Medscape: Honoraria; GLG: Honoraria; Sanofi: Consultancy. OffLabel Disclosure: Crizanlizumab is a monoclonal antibody to P-selectin indicated in the USA for the prevention of vaso-occlusive crises in patients aged 16 years and over with sickle cell disease. This abstract described the new pediatric trial of crizanlizumab, which is not indicated for patients aged less than 16 years of age

Objectives To determine the organisational resources in place; what blood was being transfused, why, how, where, when and by whom; whether laboratory support and policies met standards for patients with sickle cell disease (SCD). Background SCD affects 14 000 people in the United Kingdom (UK). Standards and guidelines do not cover all aspects of transfusion in SCD and there are no data on their use; people may become very sick without warning presenting to non-specialist hospitals; blood services are increasingly supplying units for transfusion in SCD with little data on their use. Methods A retrospective audit of transfusion services/practice for people with SCD who had received a transfusion in January-July 2014 in participating hospitals in the UK and Republic of Ireland (ROI). Results Eighty-four hospitals submitted 1290 cases, 75% of cases came from 18 hospitals submitting 25 or more cases. Transfusions (91.2% [1164/1276]) were administered to patients with HbSS, 60% (732/1227) of patients needed Rh CE negative blood. Transfusion episodes (4528) were recorded, of which 84% were elective. Stroke prevention accounted for 42% of all transfusions; adults received 56% of transfusions of which 50% were automated red cell exchange (RCE), children received 44% of transfusions of which 87% were simple transfusions. Conclusions There was a paucity of appropriate clinical management protocols, adequately trained staff and network arrangements. The high numbers of children being transfused, disparity in transfusion modality between children and adults and the high frequency of the CE negative Rh phenotype were noted.

To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points.

Background Erythrocyte pyruvate kinase is expressed under the control of the PKLR gene located on chromosome 1q21. Pyruvate kinase catalyzes the final steps of the glycolytic pathway and creates 50% of the red cell total adenosine triphosphate. Pyruvate kinase deficiency is the commonest glycolytic defect causing congenital non-spherocytic hemolytic anemia inherited in an autosomal recessive trait in which homozygotes and compound heterozygotes are common. Over 200 mutations have been described in patients with pyruvate kinase deficiency. This case report identifies a new pathogenic variant in PKLR gene detected in a patient with severe pyruvate kinase deficiency. Case presentation A Sri Lankan Sinhalese girl who developed neonatal anemia and jaundice within 24 hours of birth with mild hepatomegaly. She was from a nonconsanguineous marriage and had two siblings who had no hematological disorders. She had repeated admissions due to similar illnesses and at the age of 8 years was found to have pyruvate kinase deficiency associated with a novel homozygous pathogenic variant c.507+1delG in the PKLR gene. Conclusions A novel genetic variant in PKLR gene, consistent with pyruvate kinase deficiency, was detected in a Sri Lankan girl. This genetic variant may be specific to the Asian population and requires further studies.

Red cells from patients with sickle cell anaemia (SCA) contain the abnormal haemoglobin HbS. Under hypoxic conditions, HbS polymerises and causes red cell sickling, a rise in intracellular Ca2+ and exposure of phosphatidylserine (PS). These changes make sickle cells sticky and liable to lodge in the microvasculature, and so reduce their lifespan. The aim of the present work was to investigate how the peculiar conditions found in the renal medulla – hypoxia, acidosis, lactate, hypertonicity and high levels of urea – affect red cell behaviour. Results show that the first four conditions all increased sickling and PS exposure. The presence of urea at levels found in a healthy medulla during antidiuresis, however, markedly reduced sickling and PS exposure and would therefore protect against red cell adherence. Loss of the ability to concentrate urine, which occurs in sickle cell nephropathy would obviate this protective effect and may therefore contribute to pathogenesis.

Background Hydroxyurea and blood transfusion therapies remain the main therapeutic strategies for Sickle cell disease. Preliminary data suggest substantial variation and inconsistencies in practice of these two therapeutic modalities in South Asia. In this systematic review we searched Medline, Cochrane library and Scopus for articles on usage of hydroxyurea and blood transfusion therapies for sickle cell disease in South Asia published in English between October 2005 and October 2020. Results We selected 41 papers: 33 from India, 3 from Sri Lanka, 2 each from Pakistan and Bangladesh and one from Nepal. Only 14 prospective trials focused on hydroxyurea therapy from which majority (n = 10; 71.4%) adopted fixed low dose (10 mg/kg/day) regimen. With hydroxyurea therapy, 12 and 9 studies reported significant reductions in vaso-occlusive crises and transfusion requirement respectively. Severe anaemia (haemoglobin level Conclusions Published data on the hydroxyurea and transfusion therapies in South Asia are limited and heterogeneous. A clear gap of knowledge exists about the nature of the sickle cell disease in the Indian subcontinent particularly from countries outside India necessitating further evidence-based assessments and interventions.

Tonsillectomy and adenoidectomy (T&A) is frequently performed in children with sickle cell disease (SCD). Our aim was to evaluate the impact of this surgery on overnight oxygenation and rates of complications in these patients. Children with SCD who underwent T&A between 2008 and 2014 in two tertiary hospitals were retrospectively evaluated. Overnight oximetry and admission rates due to vaso-occlusive pain episodes (VOEs) and acute chest syndrome (ACS) in the year preceding and following the surgery were compared. 19 patients (10 males, 53%) with a median age of 6 years (range 3.5–8) were included. A significant increase of mean overnight arterial oxygen saturation measured by pulse oximetry (SpO2) (from 93±3.6% to 95.3±2.8%, p=0.001), nadir SpO2 (from 83.0±7.1% to 88±4.1%, p=0.004) and a reduction of 3% oxygen desaturation index (from a median value of 5.7 to 1.8, p=0.003) were shown. The mean annual rate of ACS decreased from 0.6±1.22 to 0.1±0.2 events per patient-year (p=0.003), while the mean cumulative rate of hospitalisations for all causes and the incidence of VOEs were not affected. T&A improved nocturnal oxygenation and was also associated with a reduction in the incidence of ACS at 1-year follow-up after surgery., In children with SCD, this retrospective analysis suggests that tonsillectomy and adenoidectomy may have a beneficial effect on nocturnal oxygenation level and the rate of ACS. This finding will need further confirmation in prospective and larger studies. https://bit.ly/3gL6gaU

Group model building (GMB) is a qualitative method aimed at engaging stakeholders to collectively consider the causes of complex problems. Tackling inequities in community nutrition is one such complex problem, as the causes are driven by a variety of interactions between individual factors, social structures, local environments and the global food system. This methods paper describes a GMB process that utilises three system mapping tools in a study with members of a multicultural, low-income community to explore declining fruit and vegetable intake in children. The tools were: 1) graphs over time, which captures the community&rsquo, s understanding of an issue, 2) cognitive mapping, which enables participants to think systemically about the causes and consequences of the issue, 3) causal loop diagrams, which describe feedback loops that reinforce the issue and identify potential actions. Cognitive mapping, a tool not usually associated with GMB, was added to the research process to support the gradual development of participants&rsquo, thinking and develops the skills needed to tackle an issue from a systems perspective. We evaluate the benefits and impact of these three tools, particularly in engaging participants and increasing understanding of systems thinking in order to develop and mobilise action. The tools could be adapted for use in other community-based research projects. Key learnings were the value of genuine partnership with a local organisation for longevity of the project, recruitment of key decisionmakers from the community early in the process, and allowing time to create sustainable change.

Acute hepatic porphyria comprises a group of rare, genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months prior to the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a healthcare facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased healthcare utilization. Conclusions: Patients experienced attacks often requiring treatment in a healthcare facility and/or with hemin, as well as chronic symptoms that adversely influence day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. This article is protected by copyright. All rights reserved.

ObjectivesTo investigate the agreement between pulse oximetry (SpO2) and oxygen saturation (SaO2) measured by CO-oximetry on arterialised earlobe blood gas (EBG) in children and adolescents with sickle cell disease (SCD).Design and settingWe retrospectively reviewed 39 simultaneous and paired SaO2 EBG and SpO2 measurements from 33 ambulatory patients with SCD (32 subjects with Haemoglobin SS and one with Haemoglobin Sß+, 52% male, mean±SD age 11.0±3.6, age range 5–18). Measurements were performed between 2012 and 2015 when participants were asymptomatic. Hypoxaemia was defined as SaO2 ≤93%. A Bland-Altman analysis was performed to assess the accuracy of SpO2 as compared with EBG SaO2.ResultsThe mean±SD SpO2 and SaO2 values in the same patients were, respectively, 93.6%±3.7% and 94.3%±2.9%. The bias SpO2–SaO2 was −0.7% (95% limits of agreement from −5.4% to 4.1%) and precision was 2.5%. In 9/39 (23%) cases, the difference in SpO2–SaO2 was greater than the expected error range ±2%, with SaO2 more often underestimated by SpO2 (6/9), especially at SpO2values ≤93%. Thirteen participants (33%) were hypoxaemic. The sensitivity of SpO2 for hypoxaemia was 100%, specificity 85% and positive predictive value 76%.ConclusionsPulse oximetry was inaccurate in almost a quarter of measurements in ambulatory paediatric patients with SCD, especially at SpO2values ≤93%. In these cases, oxygen saturation can be confirmed through EBG CO-oximetry, which is easier to perform and less painful than traditional arterial blood sampling.

Despite sickle cell disease (SCD) being the most common and severe inherited condition worldwide, therapeutic options are limited. To date, hydroxyurea remains the main treatment option in SCD. However, in the last decade the numbers of interventional clinical trials focussing on therapies for SCD have increased significantly. Many new drugs with various pharmacological targets have emerged and, although the majority have failed to show benefit in clinical trials, some have produced encouraging results. It seems probable that more drugs will soon become available for the treatment of SCD. Furthermore, promising clinical trials with improved outcomes have recently changed the perspective of curative therapies in SCD. Nevertheless, the application of novel therapeutic agents and potential curative treatments will most likely be limited to high-income countries and, thus, will remain unavailable for the majority of people with SCD in the foreseeable future.

BackgroundSickle Cell Disease (SCD) affects two in 100 Cameroonian new-borns, with 50-90% of affected children dying before their fifth birthday. Despite this burden, there is no national SCD programme in Cameroon. This study aimed to assess parents’ and physicians’ knowledge of SCD, their satisfaction with the quality of care and their recommendations to improve the treatment of SCD in Cameroon.MethodsA multi-centre cross-sectional survey was conducted in English and French, using structured questionnaires distributed in electronic format to physicians throughout Cameroon. Paper-based questionnaires were also administered to parents in the West and North West regions of Cameroon. Data were entered into Microsoft Excel and analysed using the SPSS statistical software.ResultsFifty-four parents and 205 physicians were recruited. We found that 72.2% of parents had good knowledge of SCD, 72.2% of parents were satisfied with the quality of care. Attending a sickle cell clinic (AOR 22, 95% CI 17.70-250) was significantly associated with having good knowledge. Just 14.2% of physicians had good knowledge and 23.3% of physicians were satisfied with the available management standards of SCD. Seeing more than five patients per month (AOR 3.17, 95% CI 1.23-8.20) was significantly associated with having good knowledge. Sickle cell clinics, national guidelines and subsidised treatment were the top three measures proposed by physicians and parents to improve the management of SCD.ConclusionKnowledge of SCD and satisfaction with care were poor among Cameroonian physicians. There is a need for a national programme and a comprehensive system of care for SCD in Cameroon.

ObjectiveThe purpose of this retrospective cross-sectional study was to investigate whether changes in white matter integrity are related to slower processing speed in sickle cell anemia.MethodsThirty-seven patients with silent cerebral infarction, 46 patients with normal MRI, and 32 sibling controls (age range 8–37 years) underwent cognitive assessment using the Wechsler scales and 3-tesla MRI. Tract-based spatial statistics analyses of diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) parameters were performed.ResultsProcessing speed index (PSI) was lower in patients than controls by 9.34 points (95% confidence interval: 4.635–14.855,p= 0.0003). Full Scale IQ was lower by 4.14 scaled points (95% confidence interval: −1.066 to 9.551,p= 0.1), but this difference was abolished when PSI was included as a covariate (p= 0.18). There were no differences in cognition between patients with and without silent cerebral infarction, and both groups had lower PSI than controls (bothp< 0.001). In patients, arterial oxygen content, socioeconomic status, age, and male sex were identified as predictors of PSI, and correlations were found between PSI and DTI scalars (fractional anisotropyr= 0.614,p< 0.00001;r= −0.457,p< 0.00001; mean diffusivityr= −0.341,p= 0.0016; radial diffusivityr= −0.457,p< 0.00001) and NODDI parameters (intracellular volume fractionr= 0.364,p= 0.0007) in widespread regions.ConclusionOur results extend previous reports of impairment that is independent of presence of infarction and may worsen with age. We identify processing speed as a vulnerable domain, with deficits potentially mediating difficulties across other domains, and provide evidence that reduced processing speed is related to the integrity of normal-appearing white matter using microstructure parameters from DTI and NODDI.

Caesarean section and instrumental delivery rates are increasing in many parts of the world due to a range of cultural and medical reasons, with limited consideration as to how ‘mode of delivery’ may impact on childhood and long-term health. However, babies born particularly by pre-labour caesarean section appear to have a subtly different physiology to those born by normal vaginal delivery, with both acute and chronic complications such as respiratory and other morbidities being apparent. It has been hypothesised that inherent mechanisms within the process of labour and vaginal delivery, far from being a passive mechanical process by which the fetus and placenta are expelled from the birth canal, may trigger certain protective developmental processes permissive for normal immunological and physiological development of the fetus postnatally. Traditionally the primary candidate mechanism has been the hormonal surges or stress response associated with labour and vaginal delivery, but there is increasing awareness that transfer of the maternal microbiome to the infant during parturition and transgenerational transmission of disease traits through epigenetics are also important. Interventions such as probiotics, neonatal gut seeding and different approaches to clinical care have potential to influence parturition physiology and improve outcomes for infants. This article is protected by copyright. All rights reserved

Sickle cell disease is one of the commonest serious inherited diseases in the world, and red cell transfusion is still one of the few effective treatments for acute and chronic complications. Transfusion corrects anaemia and dilutes out the number of red cells able to cause vaso-occlusion and vascular damage. Urgent red cell transfusions are used to correct acute anaemia, treat acute chest syndrome and patients with acute neurological symptoms. We use elective transfusions preoperatively for moderate risk surgery, and in some pregnant women. There is good evidence for the use of long-term regular transfusions in primary stroke prevention, with the aim of keeping the percentage of sickle haemoglobin below 30%. Long-term transfusions are also used in secondary stroke prevention, and the management of progressive organ damage, including renal impairment and pulmonary hypertension. Blood needs to be matched for ABO, RH and Kell, although alloantibodies may still develop and require more careful, extended cross-matching. Delayed haemolytic transfusion reactions are relatively common, difficult to diagnose and manage, and potentially fatal.

Background: Vaso-occlusive crises (VOCs) are the hallmark of SCD. The cell adhesion molecule P-selectin plays a key role in the multicellular interactions that can lead to VOCs. In the SUSTAIN trial in adults, crizanlizumab 5.0 mg/kg, a humanized monoclonal antibody that blocks P-selectin, significantly reduced the median annualized rate of VOCs vs placebo and had a favorable safety profile (Ataga et al. N Engl J Med 2017). Aim: To describe initial safety and efficacy results for patients (pts) with SCD aged 12- Methods: SOLACE-kids is a Phase II study to confirm and establish appropriate dosing and evaluate safety of crizanlizumab in pediatric pts with SCD (any genotype) and ≥1 VOC leading to a healthcare (HC) visit within 12 mo prior to screening. Pts (N≥100) are stratified by age: Group 1 (G1; 12- Results: As of 28 August 2020, 50 pts were enrolled in G1 of SOLACE-kids. Mean (SD) age of pts was 15.0 (1.92) yr, 29 (58%) were female, 44 (88%) had the HbSS genotype, 32 (64%) were Black/African American and 42 (84%) were receiving HU. Median (range) duration of exposure to crizanlizumab was 36.6 (6-98) wk; 44 (88%) pts received treatment for ≥26 wk. The most commonly reported AEs were headache (n=14 [28%]), vomiting (n=12 [24%]) and back pain (n=9 [18%]). Grade ≥3 AEs were reported in 13 (26%) pts; most common were anemia (n=3 [6%]) and back pain (n=2 [4%]). Serious AEs were reported in 11 (22%) pts; none were deemed related to treatment. Incidence of AEs of special interest (AESI) is shown in Table 1. No AESI led to treatment discontinuation except 1 pt who died of meningitis (not related to treatment). No infusion-related reactions were serious; all had resolved at data cut-off (except for 1 case of Grade 1 dizziness). No case of anaphylactic reaction to crizanlizumab was reported. Pain events on the day of crizanlizumab infusion suspected to be related to treatment were reported in 3 (6%) pts. All pain events, regardless of relationship to treatment, were Grade 1/2, except for two Grade 3 events reported in the same pt (back pain and pain in extremity), which resolved on day of onset. All hemorrhage events were mild and not considered related to treatment. Increase from baseline (BL) in total bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was reported in 29 (58%), 17 (34%) and 20 (40%) pts, respectively. 2 (4%) pts had Grade 4 total bilirubin significantly above normal (1 pt was Grade 4 and 1 pt was Grade 3 at BL); 21 (42%) pts had Grade 3 total bilirubin significantly above normal (5 pts were Grade 3 at BL). Grade 3 increase in ALT and AST was reported in 2 (4%) pts each. All reported liver function parameters did not meet study criteria for severe drug-induced liver injury. The median (range) number of VOCs leading to a HC visit was 3.0 (1.0-26.0) at BL and 1.6 (0.0-12.7) on treatment (median absolute reduction: 1.0 [range: -13.3 to 5.8]). 18 (36%) pts did not experience a VOC leading to a HC visit while on treatment. The median (range) annualized rate of hospitalizations/ER visits at BL was 4.0 (1.0-36.0) vs 1.54 (0.0-14.3) on treatment (median reduction: 2.35 [range: -21.7 to 5.3]) (Table 2). Conclusion: This initial analysis of SOLACE-kids shows crizanlizumab 5.0 mg/kg is safe and well tolerated in pts aged 12- Figure 1 Figure 1. Disclosures Heeney: FORMA: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vertex / Crispr Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; bluebird bio: Consultancy; Keros: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Cyclerion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rees: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Addmedica: Honoraria; TauRx: Membership on an entity's Board of Directors or advisory committees. De Montalembert: Vertex: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Odame: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Steering Committee; Global Blood Therapeutics: Other: DSMB. Brown: Imara: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Novo Nordisk: Consultancy; Forma Therapeutics: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Wali: Novatis Oncology: Research Funding. Nguyen: Novartis: Current Employment. Lam: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Pfender: Novartis: Current Employment, Current equity holder in publicly-traded company. Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy.

Background Sickle Cell Disease (SCD) is now one of the most common serious genetic condition in England. There is no reliable estimate of the total number of people living with SCD in the UK, to support commissioners and providers of services for people with SCD. Aim To obtain reliable data on the total number of people living with SCD in the UK in 2016. Method Information was requested from all national databases known to hold information on the number of people living with SCD in the UK. The information from each data source was first reviewed to estimate likely inaccuracies and then combined to provide a best estimate of people living with SCD in the UK. Conclusion This process indicated there are are about 14000 people living with SCD in the UK. This is equivalent to 1 in 4600 people.

This article provides an overview of neonatal screening for haematological conditions, with an emphasis on sickle cell disease and thalassaemia. We describe the clinical importance of haemoglobinopathies, developments in provision of care for such patients in England and update on clinical care for haemoglobinopathies sharing epidemiological data from the newborn screening programme. This shows that the birth prevalence of screen positive cases appears to have declined overall. The paper also provides useful links to a range of reports and resources which are of use to paediatricians, who are increasingly involved in the management of these conditions.

Studying different sickle cell genotypes may throw light on the pathogenesis of sickle cell disease (SCD). Here, the clinical profile, red cell sickling and K+ permeability in 29 SCD patients (15 patients with severe disease and 14 with a milder form) of HbA/S-Oman genotype were analysed. The super sickling nature of this Hb variant was confirmed. The red cell membrane permeability to K+ was markedly abnormal with elevated activities of Psickle , Gardos channel and KCl cotransporter (KCC). Results were consistent with Ca2+ entry and Mg2+ loss via Psickle stimulating Gardos channel and KCC activities. The abnormal red cell behaviour was similar to that in the commonest genotype of SCD, HbSS, in which the level of mutated Hb is considerably higher. Although activities of all three K+ transporters also correlated with the level of HbS-Oman, there was no association between transport phenotype and disease severity. The super sickling behaviour of HbS-Oman may obviate the need for solute loss and red cell dehydration to encourage Hb polymerisation, required in other SCD genotypes. Disease severity was reduced by concurrent α thalassaemia, as observed in other SCD genotypes, and represents an obvious genetic marker for prognostic tests of severity in young SCD patients of the HbA/S-Oman genotype.

Background: Sickle cell anaemia (SCA) is associated with frequent episodes of vaso-occlusive pain crises, but many patients also experience chronic daily pain, which may be due to avascular necrosis of joints, bone infarction, osteomyelitis or due to intractable chronic pain without obvious pathology2 or neuropathic pain3. Not all patients experience a significant chronic pain burden4. The impact of chronic sickle cell pain on the brain is not yet clear; a recent resting-state fMRI study showed a correlation between functional connectivity of the default-mode network and number of hospitalizations for pain5. In other chronic pain conditions, reduced grey matter volume has been noted in various cortical regions involved in pain processing such as the anterior6 and posterior7-9 cingulate cortex (ACC and PCC, respectively), primary motor cortex9 (M1), primary somatosensory cortex5,6 (S1) and insula cortex. The aim of this study is to investigate the relationship between daily pain and a priori selected grey matter regions. Methods: As part of the baseline assessments for the Prevention of Morbidity in Sickle Cell Anaemia (POMS2b) phase-II trial, 52 children and adults recorded baseline daily pain and underwent neuropsychological testing and MRI in the 14 days prior to randomisation. Daily pain was recorded on a numerical scale 0-10 for 14 days. Patients were split into "Low-Pain" group (50% of recorded days in pain). Neuropsychological assessment was carried out using: Wechsler full-scale IQ (FSIQ), working memory index (WMI) and processing speed index (PSI), Delis-Kaplan Executive Function System Tower and Sorting subtests. Patients underwent MRI on a 3T Siemens Prisma that included T2-weighted sequences to diagnose silent cerebral infarction and a 3D T1-weighted MPRAGE. Cortical parcellation was carried out using Freesurfer. A model was fitted to the imaging data variables to investigate differences between low-pain and highpain groups, controlling for age, gender and presence of SCI and socioeconomic status10 (Index of Multiple Deprivation decile by UK postcode). Results: Five children were excluded from analysis (poor quality data or braces artefact). The final sample was 47 children and adults with SCA. There was a significant correlation with percentage of days in pain and age (r = 0.53, p = 0.0001). In the low-pain group, 11 patients reported no pain during the recorded days. High-pain patients had significantly lower WMI and a trend for lower FSIQ, PSI, Sorting-correct sorts and Sorting-free sorting description. High-pain patients had significantly reduced cortical thickness in the mean cortex of the left and right hemispheres, and significantly thinner cortex in the bilateral precuenus, bilateral PCC, left M1 and right caudal ACC. There was a trend for positive correlation between average pain and right-hemisphere rostral ACC thickness. Conclusion: This study is the first to describe structural brain abnormalities in patients with high burden of sickle cell pain. These patients are part of a 6-month randomised controlled trial of overnight respiratory support with cognitive and pain endpoints as well as repeat MRI; this study may provide structural biomarkers that may parallel amelioration of chronic daily pain.

Background: DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) was a Phase 3, randomized, double-blind, placebo-controlled study conducted in children with sickle cell anemia at 51 sites in 13 countries across four continents. Procedure: Data from DOVE were assessed for regional differences in subject phenotype and treatment. Demographics, baseline clinical and laboratory data, hydroxyurea (HU) use, vaso-occlusive crisis (VOCs, composite endpoint of painful crisis or acute chest syndrome (ACS, Beijing, China)), serious adverse events (SAEs, Florence, Italy), hospitalization, and treatments were compared across the Americas, Europe, North Africa/Middle East, and Sub-Saharan Africa (SSA). Results: Race, body mass index, and blood pressures differed by region. Pre-enrollment VOCs were highest in the Americas. For subjects not on HU, baseline hemoglobin was lowest in SSA, reticulocyte count was lowest in the Americas. Within SSA, Kenya subjects presented higher baseline hemolysis. Painful crisis was the most common SAE, followed by ACS in the Americas and infections in other regions. VOC rate and percentage of VOC hospitalizations were highest in Europe. Regardless of region, most VOCs were treated with analgesics, approximately half were treated with intravenous fluids. The proportion of VOC-related transfusions was greatest in Europe. Lengths of hospital stay were similar across regions. Conclusions: Overall differences in SAEs and hospitalization for VOCs may be due to cultural diversities, resource utilization, disease severity, or a combination of factors. These data are of importance for the planning of future trials in SCA in a multinational setting.

IntroductionSickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and reduced life expectancy. Hydroxyurea (HU) has been shown to reduce the frequency and severity of vaso-occlusive episodes in SCD. Hypoxaemia and intermittent nocturnal oxygen desaturations occur frequently in children with SCD and contribute to the associated morbidity, including risk of cerebrovascular disease.ObjectiveTo evaluate the effect of HU on oxygen saturation (SpO2) overnight and on daytime SpO2 spot checks in children with SCD.MethodsA retrospective review of children with SCD and respiratory problems who attended two UK tertiary sickle respiratory clinics and were treated with HU. Longitudinal data were collected from 2 years prior and up to 3 years after the commencement of HU.ResultsForty-three children, 23 males (53%) with a median age of 9 (range 1.8–18) years were included. In the 21 children who had comparable sleep studies before and after starting HU, mean SpO2 was higher (95.2% from 93.5%, p=0.01) and nadir SpO2 was higher (87.2% from 84.3%, p=0.009) when taking HU. In 32 of the children, spot daytime oxygen saturations were also higher (96.3% from 93.5%, p=0.001).ConclusionChildren with SCD had higher oxygen saturation overnight and on daytime spot checks after starting HU. These data suggest HU may be helpful for treating persistent hypoxaemia in children with SCD pending more evidence from a randomised clinical trial.

The inherited disorders of hemoglobin, which include sickle cell disease and thalassemias, are the most common and widespread distributed monogenic disorders. Due to a selective advantage in malaria regions, these hemoglobin defects are particularly frequent in Africa, Asia, or in the Mediterranean areas, where malaria was endemic until the last century. In recent decades, the globalization of migration has contributed to generate multiethnic European societies. Due to migration from countries or regions with high hemoglobinopathy frequencies such as Africa, Middle East, or Asia, large numbers of patients with these disorders are living in almost every European country today. Furthermore, the numbers are increasing because of increasing refugee flows toward Europe. Additional requirements are the development of European recommendations and guidelines for diagnosis and effective therapeutic approaches. These, together with the advancement of clinical trials using new drugs and therapeutic procedures could ameliorate the quality of life of patients affected with these diseases and increase their life expectancy. Lastly, coordinated efforts should be made to develop diagnostic pathways for thalassemias and hemoglobinopathies, in order to plan interventions, including prenatal diagnosis and cure. For these reasons, the development of new tools to reliably diagnose anemias is urgently needed and fits well with the needs of personalized medicine. In the last 15 years, hematology research has made many big leaps forward. Our general aim will be to solve several hematologic problems using these new approaches. We expect that the development of such a diagnostic tool will improve timely diagnosis throughout Europe, especially in those countries where it is difficult to gain access to “classical” diagnostic tests.

Background Sickle Cell Disease (SCD) affects two in 100 Cameroonian newborns, with 50%–90% of affected children dying before their fifth birthday. Despite this burden, there is no national SCD programme in Cameroon. This study aimed to assess parents’ and physicians’ knowledge of SCD, their satisfaction with the quality of care and their recommendations to improve the treatment of SCD in Cameroon. Methods A cross-sectional study was conducted using structured questionnaires in English, and French, distributed in an electronic format to physicians throughout Cameroon. Paper-based questionnaires were also administered to parents in the West and North West regions of Cameroon. Data were entered into Microsoft Excel and analysed using the SPSS statistical package. Results Fifty-four parents and 205 physicians were recruited. 72.2% of parents had good knowledge of SCD, 72.2% of parents were satisfied with the quality of care. Attending a sickle cell clinic (AOR 22, 95% CI 17.70–250) was significantly associated with having good knowledge. 14.2% of physicians had good knowledge, 23.3% of physicians were satisfied with the management of SCD. Seeing more than five patients per month (AOR 3.17, 95% CI 1.23–8.20) was significantly associated with having good knowledge. Sickle cell clinics, national guidelines and subsidised treatment were the top three measures proposed by physicians and parents to improve the management of SCD in Cameroon. Conclusion Knowledge of SCD and satisfaction with care were poor among Cameroonian physicians. There is a need for a national programme and a comprehensive system of care for SCD in Cameroon.

Background Transcranial Doppler ultrasound is used to screen and assess the intracranial arteries of children with sickle cell disease. Recent findings suggest that extracranial internal carotid artery (eICA) stenosis is also a contributing factor to silent cerebral infarction. Stenosis has been measured using phased array transducers with no beam/flow angle correction and linear arrays with angle correction. Methods A total of 124 children undergoing TCD assessment were investigated for eICA velocities. Manual measurements of peak systolic velocity and TCD mean velocity were made with phased and linear array transducers. Results Peak systolic velocities ranged from 60 to 534 cm/s (median 126 cm/s) using the linear array and 53 to 394 cm/s (median 115 cm/s) using the phased array transducers. TCD mean ranged from 39 to 419 cm/s (median 81 cm/s) using the linear array and 34 to 295 cm/s (median 72 cm/s) using the phased array transducers. Conclusions There are advantages and disadvantages of each method, but stenoses were readily identified as focal velocity increases. We suggest thresholds for each transducer and recommend that imaging of the eICA forms part of screening for this group of children.

To detect and characterise different phenotypes of respiratory disease in children and young adults with sickle cell disease (SCD), 11 lung function and haematological biomarkers were analysed using k-means cluster analysis in a cohort of 114 subjects with SCD aged between 5 and 27 years. Three clusters were detected: cluster 1 had elevated pulmonary capillary blood volume, mixed obstructive/restrictive lung disease, hypoxia and moderately severe anaemia; cluster 2 were older patients with restrictive lung disease; and cluster 3 were younger patients with obstructive lung disease, elevated serum lactate dehydrogenase and bronchodilator reversibility. These results may inform more personalised management strategies to improve outcomes.

Introduction: Acute hepatic porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in hepatic heme biosynthesis. Induction of 5-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting step in heme biosynthesis, leads to accumulation of heme intermediates, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) that may result in neurovisceral attacks. ENVISION (NCT03338816) is an ongoing study, evaluating efficacy and safety of givosiran in symptomatic AHP patients in a 6-month double blind (DB) period and a 30-month open label extension (OLE) period. While the efficacy and safety profile of givosiran has previously been reported in the DB period, here its effect through Month 18 of the OLE period is reported. Methods: ENVISION is an ongoing Phase 3 global, randomized, placebo-controlled study. Exploratory efficacy outcome measures in the OLE included composite porphyria attacks (i.e. those requiring hospitalization, urgent care, or IV-hemin at home), ALA/PBG levels and hemin use. In addition, quality of life assessments (Physical Component Summary Short Form-12 [PCS SF-12], EuroQoL Visual analog scale [EQ-VAS]), the Porphyria Patient Experience Questionnaire (PPEQ), and missed days of work were assessed. Analyses were descriptive and represent the timepoint after which all patients completed at least their Month 18 visit (01/10/2020). Results: As of January 10, 2020, 94 patients completed the DB period and 93 patients entered the OLE (placebo/givosiran=46; givosiran/givosiran=47). Mean exposure to givosiran at data cutoff was 12.97 [SD=3.6] months for placebo/givosiran and 18.86 [3.6] months for givosiran/givosiran, with maximum exposure of 25.1 months. Continued treatment in givosiran/givosiran patients led to a median annualized attack rate (AAR) of 0.58 (range: 0-16.2) through Month 18. Patients in the placebo/givosiran group had an AAR of 1.62 (range: 0-11.8) after receiving givosiran for ≥12 months during the OLE period, compared with 10.65 (range: 0-51.6) whilst receiving placebo during the 6-month DB period. The average number of attacks per patient over time following givosiran treatment continued to decline during the OLE period for both groups (Figure 1). Sustained ALA/PBG lowering during the OLE was accompanied by sustained reductions in hemin use, and more than half of the placebo/givosiran patients experienced 0 days of hemin use. Improvements in PCS SF-12 scores at Month 6 (mean change from baseline=+5.1 [SD=9.0]) were maintained at Month 18 (mean change from baseline=+7.0 [7.0]) for givosiran/givosiran patients, with similar improvements observed in placebo/givosiran patients at Month 18 (mean change from baseline=+9.9 [8.2]). Continued givosiran treatment in givosiran/givosiran patients led to further improvements in EQ VAS compared with DB period (mean change from baseline 5.2 at completion of the DB period [SD=22.2] and 13.7 [22.5] at Month 18 during the OLE period), with placebo/givosiran patients also showing improvements at Month 18 (mean change from baseline 8.3 [SD=18.5]). Placebo/givosiran patients reported improvements in PPEQ scores (traveling, social activities, planning future events, household chores, exercise, and treatment satisfaction) since initiating givosiran, comparable to the improvement observed in the givosiran group during the DB period. Additionally there was a decrease in the number of work days missed due to porphyria in the past 4 weeks at Month 6 (mean=6.7 days [SD=7.8], n=20/46) compared with Month 18 (2.5 [5.1], n=23/46), for patients in the placebo/givosiran group who were able to work. The most common related adverse events (AEs) occurring during givosiran treatment were injection site reactions, nausea and fatigue. Hepatic and renal events were both reported in 17% of patients each during givosiran treatment. No new safety concerns occurred in the OLE compared with DB period. Conclusion: In the ongoing OLE period of the ENVISION study, patients receiving long-term treatment with givosiran demonstrated a durable response in clinical efficacy, across a wide range of clinical parameters. Following the initial 6 months of givosiran treatment during the OLE, placebo/givosiran patients had a similar clinical response to that observed in givosiran/givosiran patients in the OLE period through Month 18. The safety profile of givosiran remained acceptable and consistent with that previously observed. Disclosures Kuter: Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Dova: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Immunovant: Other: Travel Expenses, Research Funding; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Sanofi (Genzyme): Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Protalix Biotherapeutics: Consultancy; Principia: Consultancy, Research Funding; Shire: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Rees:AstraZeneca: Other: Data monitoring committee membership; Novartis: Consultancy, Honoraria; TauRx: Other: Data And Safety Monitoring; Alnylam Pharmaceuticals: Consultancy, Honoraria; Emmanus Medical: Consultancy, Honoraria. Ventura:Alnylam Pharmaceuticals: Consultancy, Honoraria; Recordati Rare Diseases: Consultancy, Honoraria. Balwani:Recordati Rare Diseases: Consultancy, Honoraria, Other: Disease information video recording; Alnylam Pharmaceuticals: Consultancy, Honoraria, Research Funding. Gouya:Alnylam Pharmaceuticals: Consultancy, Honoraria, Other: Scientific meeting. Simon:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Liu:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ko:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Rhyee:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silver:Alnylam Pharmaceuticals: Other: Travel reimbursement, Research Funding; Blue Care Network: Consultancy; Oncology Business Review: Speakers Bureau.