A homozygous frameshift variant expands the clinical spectrum of SAMD9 gene defects.

SAMD9, a ubiquitously expressed protein, is involved in several mechanisms, including endosome fusion, growth suppression and modulation of innate immune responses to stress and viral infections. While biallelic mutations in SAMD9 are linked to normophosphatemic familial tumoral calcinosis, heterozygous gain-of-function mutations in the same gene are responsible for MIRAGE, a multisystemic syndrome characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. A two-and-a-half-year-old girl, from a consanguineous Lebanese family, was included in this study. She presents with pre- and post-natal growth retardation, recurrent fevers, persistent diarrhea, elevated CRP and intermittent hypoglycemia. Whole genome sequencing revealed a homozygous frameshift variant in SAMD9 (NM_017654.4: c.480_481del; p.Val162Ilefs*5) in the proband. Sanger sequencing confirms its segregation with the disease in the family, and immunoblotting showed that the detected variant abolishes SAMD9 expression in the patient. Our findings expand the clinical spectrum linked to SAMD9 and highlight the importance of investigating further cases with mutations in this gene, as this will pave the way towards the understanding of the pathways driving these diseases.

Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study.

The phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor vs placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease (SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to receive weight-based doses of ticagrelor or matching placebo. The primary end point was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary end points included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory end points included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor, n = 101; placebo, n = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours' postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor vs placebo in these pediatric patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03615924.

Eltrombopag in pediatric chronic and refractory ITP: data from a retrospective multicenter study from Lebanon.

About 20% to 30% of pediatric patients with immune thrombocytopenia (ITP) develop chronic or refractory disease lasting 12 months or more that can be challenging to treat. Eltrombopag is being used after failure of previous lines of therapy with good results at tertiary healthcare centers in Lebanon, a developing country with available multidisciplinary treatment modalities. This is a retrospective multicenter observational study that analyzed data on pediatric patients with chronic or refractory ITP who were given eltrombopag as second- or third-line therapy in 6 large referral hospitals in Beirut (country capital located in mid Lebanon), South, North, and Mount Lebanon between October 2016 and May 2020. The primary end point of the study was a proportion of patients achieving platelet counts of ≥ 50 × 109/L for at least 6 weeks without requiring rescue therapy during the observation period. Data from 36 patients treated for chronic and refractory ITP, 20 (55.6%) males and 16 (44.4%) females, were analyzed. The median age at the eltrombopag dose was 11 years (2-18 years). All the patients had failure of the first-line therapy with steroids, 3 patients received eltrombopag as second-line therapy, and the remaining patients had failure of at least 2 previous lines of therapy, including steroids. The primary end point was achieved in 21 (58.3%) of 36 patients. The treatment was discontinued in 3 patients due to no response. Hepatotoxicity and all other adverse events (headache, weakness, and diarrhea) were mild and transient. All the patients who achieved the target platelet count of ≥ 50 × 109/L maintained the response for the treatment duration, which was a minimum of 5 months up to 3 years, with median/mean observation periods of 12 months and 14 months, respectively. This study confirms the findings of randomized controlled trials that eltrombopag as second- or third-line therapy in pediatric patients with chronic and refractory ITP is effective and safe, reinforcing its role in the real-world management of these patients.

Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4 to 11 years.

BACKGROUND: Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6 months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality. PROCEDURE: The HOPE-KIDS 1 trial (NCT02850406) is an ongoing four-part, phase 2a, open-label, single- and multiple-dose study to evaluate the pharmacokinetics, efficacy, and safety of voxelotor-a first-in-class HbS polymerization inhibitor-in patients aged 6 months to 17 years with SCD. Initial findings from a cohort of 45 patients aged 4 to 11 years who received voxelotor treatment for up to 48 weeks are reported. RESULTS: Hemoglobin (Hb) response, defined as a >1.0 g/dl increase from baseline, was achieved at week 24 by 47% (n = 16/34) of patients with Hb measurements at baseline and week 24. At week 24, 35% (n = 12/34) and 21% (n = 7/34) of patients had a >1.5 g/dl increase and a >2.0 g/dl increase from baseline in Hb concentration, respectively. Concurrent improvements in hemolytic markers were observed. Voxelotor was well tolerated in this young cohort, with no newly emerging safety signals. CONCLUSIONS: Based on its mechanism as an HbS polymerization inhibitor, voxelotor improves Hb levels and markers of hemolysis and has the potential to mitigate SCD-related complications; these results support its use in patients aged ≥4 years.

Pharmacokinetics and safety of ticagrelor in infants and toddlers with sickle cell disease aged <24 months.

Inhibition of platelet activation may reduce vaso-occlusion rates in patients with sickle cell disease (SCD). In the HESTIA4 (NCT03492931) study, 21 children with SCD received a single oral dose of the antiplatelet agent ticagrelor (0.1 mg/kg <6 months; 0.2 mg/kg ≥6 to <24 months). All patients had measurable ticagrelor plasma concentrations. Ticagrelor and active metabolite (AR-C124910XX) exposure were comparable across all groups (<6 months, ≥6 to <12 months and ≥12 to <24 months). Ticagrelor was well tolerated. Palatability was generally acceptable. These data will be used to enable dose selection for further investigations of ticagrelor efficacy and safety in children with SCD.

Clinical Features and Outcome of Sickle Cell Disease in a Tertiary Center in Northern Lebanon: A Retrospective Cohort Study in a Local, Hospital-Associated Registry.

Sickle cell disease affects more than 30 million people worldwide, including 0.1% of the population in Lebanon. It is characterized by unpredictable and painful vaso-occlusive crises (VOCs) that may lead to serious complications. This study describes the clinical burden of sickle cell disease in a cohort of patients treated at a comprehensive sickle cell disease referral center in Tripoli, Northern Lebanon. Patient demographics, clinical events, treatment, and survival were evaluated from a local, hospital-based registry of 334 sickle cell disease patients treated at the Nini Hospital, Tripoli, Lebanon, between 2009 and 2019. Mean age at sickle cell disease diagnosis and at first clinic visit was 2.9 and 8.5 years, respectively. Pain was the most common clinical event observed among all patients. Over the 10-year follow-up period, 15 (4.5%) patients died. Hydroxyurea (HU) and red blood cell (RBC) transfusions were the most commonly used therapies. One hundred and thirty-one (39.0%) patients were diagnosed with sickle cell disease at the Nini Hospital; the remaining patients were referred to and subsequently followed-up at the Nini Hospital. Eighty-seven (66.0%) Nini Hospital-diagnosed patients experienced a VOC. Seventy-four (85.0%) of these patients with a VOC event required HU during follow-up. Patients with a VOC required more RBC transfusions, cholecystectomy, and splenectomy than non-VOC patients. The high disease burden observed in this population of sickle cell disease patients illustrates a continued, unmet need to both prevent and manage VOC events and other sickle cell disease-associated complications.

Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.

Establishment of a formal program for retinoblastoma: Feasibility of clinical coordination across borders and impact on outcome.

Retinoblastoma is an ocular tumor that occurs in young children, in either heritable or sporadic manner. The relative rarity of retinoblastoma, and the need for expensive equipment, anesthesia, and pediatric ophthalmologic expertise, are barriers for effective treatment in developing countries. Also, with an average age-adjusted incidence of two to five cases per million children, patient number limits development of local expertise in countries with small populations. Lebanon is a small country with a population of approximately 4.5 million. In 2012, a comprehensive retinoblastoma program was formalized at the Children's Cancer Institute (CCI) at the American University of Beirut Medical Center, and resources were allocated for efficient interdisciplinary coordination to attract patients from neighboring countries such as Syria and Iraq, where such specialized therapy is also lacking. Through this program, care was coordinated across hospitals and borders such that patients would receive scheduled chemotherapy at their institution, and monthly retinal examinations and focal laser therapy at the CCI in Lebanon. Our results show the feasibility of successful collaboration across borders, with excellent patient and physician adherence to treatment plans. This was accompanied by an increase in patient referrals, which enables continued expertise development. However, the majority of patients presented with advanced intraocular disease, necessitating enucleation in 90% of eyes in unilateral cases, and more than 50% of eyes in bilateral cases. Future efforts need to focus on expanding the program that reaches to additional hospitals in both countries, and promoting early diagnosis, for further improvement of globe salvage rates.

One-year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation.

BACKGROUND: Iron overload is well documented in patients with ß-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. PROCEDURE: This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with ß-thalassemia major following HSCT. RESULTS: Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 ± 1.5 vs. -3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy. CONCLUSIONS: Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with ß- thalassemia major post-HSCT, with a manageable safety profile.

Transfusion Therapy in Children With Sickle Cell Disease.

Hydroxyurea, blood transfusions, and hematopoietic stem cell transplantation represent the 3 disease-modifying therapies in children with sickle cell disease (SCD). Blood transfusions play an increasingly important role in both prevention and management of SCD complications in this age group. This review will focus on the indications of blood transfusion in children with SCD and modalities of its administration. It will also highlight the complications of this life-saving therapy and ways of optimizing transfusion to minimize its associated risks.

13-valent pneumococcal conjugate vaccine (PCV13) is immunogenic and safe in children 6-17 years of age with sickle cell disease previously vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPSV23): Results of a phase 3 study.

BACKGROUND: A large population of older children with sickle cell disease (SCD) is currently vaccinated with only 23-valent pneumococcal polysaccharide vaccine (PPSV23). In immunocompetent adults, PPSV23 vaccination reduces immune responses to subsequent vaccination with a pneumococcal vaccine. The 13-valent pneumococcal conjugate vaccine (PCV13), which addresses this limitation, may offer an advantage to this population at high risk of pneumococcal disease. PROCEDURE: Children with SCD 6-17 years of age previously vaccinated with PPSV23 at least 6 months before study enrollment received two doses of PCV13 6 months apart. Anti-pneumococcal polysaccharide immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured before, 1 month after each administration, and 1 year after the second administration. RESULTS: Following each PCV13 administration, IgG GMCs and OPA GMTs significantly increased, and antibody levels after doses 1 and 2 were generally comparable. Antibody levels declined over the year following dose 2. At 1 year after the second administration, OPA GMTs for all and IgG GMCs for most serotypes remained above pre-vaccination levels. Most adverse events were due to vaso-occlusive crises, a characteristic of the underlying condition of SCD. CONCLUSIONS: Children with SCD who were previously vaccinated with PPSV23 responded well to 1 PCV13 dose, and a second dose did not increase antibody response. PCV13 antibodies persisted above pre-vaccination levels for all serotypes 1 year after dose 2. Children with SCD may benefit from at least one dose of PCV13.

A double-blind, placebo-controlled phase II study of the efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.

This placebo-controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), a fetal globin gene-inducing short-chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12-55 years) and 37 subjects (49%) were treated previously with hydroxycarbamide. Sixty subjects (79%) had Hb SS and 16 (21%) had S/ß(0) thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK-1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9% (95% confidence interval (CI): 0.1-1.6%) with HQK-1001 and 0.2% (95% CI: -0.7-1.1%) with placebo. Absolute increases in Hb F greater than 3% were noted in 9 of 38 subjects (24%) administered HQK-1001 and 1 of 38 subjects (3%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK-1001 and 1.7 with placebo. The most common adverse events in the HQK-1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK-1001 at this dose and schedule are not recommended in SCD. Intermittent HQK-1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation.

von Willebrand factor/factor VIII concentrate (Wilate) prophylaxis in children and adults with von Willebrand disease.

ABSTRACT: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the efficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run-in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was efficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively.

A randomized phase I/II trial of HQK-1001, an oral fetal globin gene inducer, in ß-thalassaemia intermedia and HbE/ß-thalassaemia.

ß-thalassaemia intermedia (BTI) syndromes cause haemolytic anaemia, ineffective erythropoiesis, and widespread complications. Higher fetal globin expression within genotypes reduces globin imbalance and ameliorates anaemia. Sodium 2,2 dimethylbutyrate (HQK-1001), an orally bioavailable short-chain fatty acid derivative, induces γ-globin expression experimentally and is well-tolerated in normal subjects. Accordingly, a randomized, blinded, placebo-controlled, Phase I/II trial was performed in 21 adult BTI patients (14 with HbE/ß(0) thalassaemia and seven with ß(+)/ß(0) thalassaemia intermedia, to determine effective doses for fetal globin induction, safety, and tolerability. HQK-1001 or placebo were administered once daily for 8 weeks at four dose levels (10, 20, 30, or 40 mg/kg per day), and subjects were monitored for laboratory and clinical events. Pharmacokinetic profiles demonstrated a t(1/2) of 10-12 h. Adverse events with HQK-1001 treatment were not significantly different from placebo treatment. The 20 mg/kg treatment doses increased median HbF above baseline levels by 6·6% and 4·4 g/l (P < 0·01) in 8/9 subjects; total haemoglobin (Hb) increased by a mean of 11 g/l in 4/9 subjects. These findings identified a safe oral therapeutic which induces fetal globin in BTI. Further investigation of HQK-1001 with longer dosing to definitively evaluate its haematological potential appears warranted.

A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.

2,2-Dimethylbutyrate (HQK-1001), an orally-bioavailable promoter-targeted fetal globin gene-inducing agent, was evaluated in an open-label, randomized dose-escalation study in 52 subjects with hemoglobin SS or S/ß(0) thalassemia. HQK-1001 was administered daily for 26 weeks at 30 mg/kg (n = 15), 40 mg/kg (n = 18) and 50 mg/kg (n = 19), either alone (n = 21) or with hydroxyurea (n = 31). The most common drug-related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose-limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non-compliance, only 25 subjects (48%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80%), and 12 (23%) had increases ≥4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8-3.2%] in 21 subjects receiving HQK-1001 alone and 2.7% (95% CI, 1.7-3.8%) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5-1.0 g/dL), and 13 subjects (25%) had increases ≥1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease. .

Identification of the first mutation in a BRE motif of the ß-globin gene and its inheritance with two other α-globin gene mutations in a Lebanese family.

A 7-year old boy presented with a history of recurrent respiratory infections and hypochromic microcytic anemia. Iron profiles were normal thereby prompting genetic analysis of α- and ß-globin mutations. The first mutation in a BRE motif of the ß-globin gene in the proband, sibling and the mother was identified. The proband and his sibling also inherited common α-globin mutations from the father and mother. In all cases, no serious thalassemia disease was detected.

Erratum: Rotavirus Genotypes and Vaccine Effectiveness from a Sentinel, Hospital-Based, Surveillance Study for Three Consecutive Rotavirus Seasons in Lebanon.

[This corrects the article DOI: 10.1371/journal.pone.0161345.].

HLA population genetics: a Lebanese population.

Human leukocyte antigen (HLA) typing was done in 426 Lebanese subjects of 88 families, in which 347 haplotypes were identified. The A, B, C, DRB1, DRB3/4/5, DQB1 and DPB1 loci were typed at high resolution. This study shows that information theory, as originally developed by Claude Shannon in 1948, provides a promising theoretical foundation to study the population genetics of a genetic system like HLA. Although Lebanese carry HLA alleles found in other populations, the association of these alleles into haplotypes is quite unique. Comparisons are made with the main ethnic groups. Two haplotypes well represented in the Lebanese population are not identified in any global population: L1 = {A*26:01:01 - B*35:01:01:01- C*04:01:01:01- DRB1*16:01:01 - DRB5*02:02 - DQB1*05:02:01} and L2 = {A*02:02 - B*41:01- C*17:01:01:01 -DRB1*11:04:01 - DRB3*02:02:01:01- DQB1*03:01:01:01}. By studying linkage disequilibrium in two blocks at a time, with the division of the blocks at different levels in consecutive cycles, conserved haplotypes in full linkage disequilibrium come to light, such as {A*26:01:01- B*35:01:01:01 - C*04:01:01:01 - DRB1*16:01:01 - DRB5*02:02 - DQB1*05:02:01- DPB1*03:01:01} and {A*33:01:01 - B*14:02:01 - C*08:02:01 - DRB1*01:02:01- DQB1*05:01:01:01 - DPB1*04:01:01:01}.

Iron in sickle-cell disease: what have we learned over the years?

Over the last four decades, monumental advances have been made in the understanding, assessment, and management of transfusion-dependent patients, which have translated into significant improvements in patient morbidity and mortality. Important lessons have been learned from extensive clinical experience of iron management in the thalassemias, but greater knowledge of key differences in the sickle-cell disease (SCD) population may impact on our approach to patient assessment and management. The unique pathophysiology of SCD is reflected in a distinct pattern of iron loading with minimal organ-specific injury. An appreciation and understanding of these differences should allow us to develop tailored management approaches that optimize patient outcomes.