Rafik Hariri University Hospital

Next-Generation Gene Therapy Few disciplines in contemporary clinical research have experienced the high expectations directed at the gene therapy field. However, gene therapy has been challenging to translate to the clinic, often because the therapeutic gene is expressed at insufficient levels in the patient or because the gene delivery vector integrates near protooncogenes, which can cause leukemia (see the Perspective by Verma ). Biffi et al. ( 1233158 , published online 11 July) and Aiuti et al. ( 1233151 ; published online 11 July) report progress on both fronts in gene therapy trials of three patients with metachromatic leukodystrophy (MLD), a neurodegenerative disorder, and three patients with Wiskott-Aldrich syndrome (WAS), an immunodeficiency disorder. Optimized lentiviral vectors were used to introduce functional MLD or WAS genes into the patients' hematopoietic stem cells (HSCs) ex vivo, and the transduced cells were then infused back into the patients, who were then monitored for up to 2 years. In both trials, the patients showed stable engraftment of the transduced HSC and high expression levels of functional MLD or WAS genes. Encouragingly, there was no evidence of lentiviral vector integration near proto-oncogenes, and the gene therapy treatment halted disease progression in most patients. A longer follow-up period will be needed to further validate efficacy and safety.

Colorectal cancer (CRC) is a significant cause of morbidity and mortality worldwide. However, colon cancer incidence and mortality is declining over the past decade owing to adoption of effective screening programs. Nevertheless, in some parts of the world, CRC incidence and mortality remain on the rise, likely due to factors including "westernized" diet, lifestyle, and lack of health-care infrastructure and resources. Participation and adherence to different national screening programs remain obstacles limiting the achievement of screening goals. Different modalities are available ranging from stool based tests to radiology and endoscopy with varying sensitivity and specificity. However, the availability of these tests is limited to areas with high economic resources. Recently, FDA approved a blood-based test (Epi procolon ) for CRC screening. This blood based test may serve to increase the participation and adherence rates. Hence, leading to increase in colon cancer detection and prevention. This article will discuss various CRC screening tests with a particular focus on the data regarding the new approved blood test. Finally, we will propose an algorithm for a simple cost-effective CRC screening program.

Twenty-three children with nonmalignant disorders received HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) after ex vivo elimination of αβ(+) T cells and CD19(+) B cells. The median number of CD34(+), αβ(+)CD3(+), and B cells infused was 16.8 × 10(6), 40 × 10(3), and 40 × 10(3) cells/kg, respectively. No patient received any posttransplantation pharmacologic prophylaxis for graft-versus-host disease (GVHD). All but 4 patients engrafted, these latter being rescued by a second allograft. Three patients experienced skin-only grade 1 to 2 acute GVHD. No patient developed visceral acute or chronic GVHD. Cumulative incidence of transplantation-related mortality was 9.3%. With a median follow-up of 18 months, 21 of 23 children are alive and disease-free, the 2-year probability of disease-free survival being 91.1%. Recovery of γδ(+) T cells was prompt, but αβ(+) T cells progressively ensued over time. Our data suggest that this novel graft manipulation strategy is safe and effective for haplo-HSCT. This trial was registered at www.clinicaltrials.gov as #NCT01810120.

PURPOSE Off-label use of vemurafenib (VMF) to treat BRAF V600E mutation–positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 ( P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAF V600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAF V600E clone. CONCLUSION VMF seemed safe and effective in children with refractory BRAF V600E -positive LCH. Additional studies are needed to find effective maintenance therapy approaches.

Allergic rhinitis affects the quality of life of millions of people worldwide. Air pollution not only causes morbidity, but nearly 3 million people per year die from unhealthy indoor air exposure. Furthermore, allergic rhinitis and air pollution interact. This report summarizes the discussion of an International Expert Consensus on the management of allergic rhinitis aggravated by air pollution. The report begins with a review of indoor and outdoor air pollutants followed by epidemiologic evidence showing the impact of air pollution and climate change on the upper airway and allergic rhinitis. Mechanisms, particularly oxidative stress, potentially explaining the interactions between air pollution and allergic rhinitis are discussed. Treatment for the management of allergic rhinitis aggravated by air pollution primarily involves treating allergic rhinitis by guidelines and reducing exposure to pollutants. Fexofenadine a non-sedating oral antihistamine improves AR symptoms aggravated by air pollution. However, more efficacy studies on other pharmacological therapy of coexisting AR and air pollution are currently lacking.

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.

Indoor environments contribute significantly to total human exposure to air pollutants, as people spend most of their time indoors. Household air pollution (HAP) resulting from cooking with polluting ("dirty") fuels, which include coal, kerosene, and biomass (wood, charcoal, crop residues, and animal manure) is a global environmental health problem. Indoor pollutants are gases, particulates, toxins, and microorganisms among others, that can have an impact especially on the health of children and adults through a combination of different mechanisms on oxidative stress and gene activation, epigenetic, cellular, and immunological systems. Air pollution is a major risk factor and contributor to morbidity and mortality from major chronic diseases. Children are significantly affected by the impact of the environment due to biological immaturity, prenatal and postnatal lung development. Poor air quality has been related to an increased prevalence of clinical manifestations of allergic asthma and rhinitis. Health professionals should increase their role in managing the exposure of children and adults to air pollution with better methods of care, prevention, and collective action. Interventions to reduce household pollutants may promote health and can be achieved with education, community, and health professional involvement.

PURPOSE: The frequency of valproate (VPA)-induced thrombocytopenia varied widely in previous studies, due to methodological differences. Our objective was to evaluate the relationship between trough VPA plasma levels and platelet counts and assess risk factors for the development of thrombocytopenia. METHODS: Patients with refractory partial epilepsy were enrolled in this double-blind, multicenter, concentration-response trial that evaluated the efficacy and safety of high versus low trough plasma VPA concentrations following administration of divalproex sodium as monotherapy. Trough VPA concentrations and concomitant platelet counts were drawn at baseline and intermittently throughout the 24-week trial. Bivariate correlations and multivariate stepwise regression analysis were performed between platelet counts and multiple variables. A logistic regression analysis was done to determine the probability of developing thrombocytopenia at various VPA levels. RESULTS: A total of 851 VPA levels and concomitant platelet counts were analyzed in 265 patients. Of these, 17.7% of patients experienced at least one episode of thrombocytopenia (platelet count < or = 100,000/microl) after exposure to divalproex sodium. A significant negative correlation was found between VPA levels and platelet counts. Women were significantly more likely to develop thrombocytopenia. The probability of developing thrombocytopenia substantially increased at trough VPA levels above 100 microg/ml in women and above 130 microg/ml in men. DISCUSSION: Our data strongly support a causal relationship between rising plasma VPA levels and reduced platelet counts, with additional risk factors including female gender and lower baseline platelet counts.

Antimicrobial resistance is closely linked to antimicrobial use and is a growing concern worldwide. Antimicrobial resistance increases healthcare costs substantially in many countries, including Lebanon. National data from Lebanon have, in the most part, been limited to a few academic hospitals. The Lebanese Society of Infectious Diseases conducted a retrospective study to better describe the antimicrobial susceptibility patterns of bacterial isolates in Lebanon. Data were based on records retrieved from the bacteriology laboratories of 16 different Lebanese hospitals between January 2011 and December 2013. The susceptibility results of a total 20684 Gram-positive and 55594 Gram-negative bacteria were analyzed. The prevalence rate of methicillin-resistant Staphylococcus aureus was 27.6% and of vancomycin-resistant Enterococcus spp was 1%. Streptococcus pneumoniae had susceptibilities of 46% to oxacillin, 63% to erythromycin, and 98% to levofloxacin. Streptococcus pyogenes had susceptibilities of 94% to erythromycin and 95% to clindamycin. The mean ampicillin susceptibility of Haemophilus influenzae, Salmonella spp, and Shigella spp isolates was 79%, 81.3%, and 62.2%, respectively. The extended-spectrum beta-lactamase production rate for Escherichia coli was 32.3% and for Klebsiella spp was 29.2%. Acinetobacter spp showed high resistance to most antimicrobials, with low resistance to colistin (17.1%). Pseudomonas spp susceptibilities to piperacillin-tazobactam and imipenem were lower than 80% (79.7% and 72.8%, respectively). This study provides population-specific data that are valuable in guiding antimicrobial use in Lebanon and neighbouring countries and will help in the establishment of a surveillance system for antimicrobial resistance following the implementation of a nationwide standardization of laboratory methods and data entry.

Mesenteric panniculitis is a rare, benign and chronic fibrosing inflammatory disease that affects the adipose tissue of the mesentery of the small intestine and colon. The specific etiology of the disease is unknown. The diagnosis is suggested by computed tomography and is usually confirmed by surgical biopsies. Treatment is empirical and based on a few selected drugs. Surgical resection is sometimes attempted for definitive therapy, although the surgical approach is often limited. We report two cases of mesenteric panniculitis with two different presentations and subsequently varying treatment regimens. Adequate response was obtained in both patients. We present details of these cases as well as a literature review to compare various presentations, etiologies and potential treatment modalities.

Managing patients with severe asthma during the coronavirus pandemic and COVID-19 is a challenge. Authorities and physicians are still learning how COVID-19 affects people with underlying diseases, and severe asthma is not an exception. Unless relevant data emerge that change our understanding of the relative safety of medications indicated in patients with asthma during this pandemic, clinicians must follow the recommendations of current evidence-based guidelines for preventing loss of control and exacerbations. Also, with the absence of data that would indicate any potential harm, current advice is to continue the administration of biological therapies during the COVID-19 pandemic in patients with asthma for whom such therapies are clearly indicated and have been effective. For patients with severe asthma infected by SARS-CoV-2, the decision to maintain or postpone biological therapy until the patient recovers should be a case-by-case based decision supported by a multidisciplinary team. A registry of cases of COVID-19 in patients with severe asthma, including those treated with biologics, will help to address a clinical challenge in which we have more questions than answers.

Aims: To compare the incidence of symptomatic hypoglycaemia in fasting Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan. Methods: Patients with type 2 diabetes (age ≥ 18 years) who were treated with a stable dose of a sulphonylurea with or without metformin for at least 3 months prior to screening, who had an HbA1c < 10% and who expressed their intention to daytime fast during Ramadan were eligible for this open-label study. Patients were randomised in a 1 : 1 ratio to either switch to sitagliptin 100 mg qd or to remain on their prestudy sulphonylurea. Patients completed daily diary cards to document information on hypoglycaemic symptoms and complications. The primary end-point was the overall incidence of symptomatic hypoglycaemia recorded during Ramadan. Results: Of the 1066 patients randomised, 1021 (n = 507 for sitagliptin and n = 514 for sulphonylurea) returned at least one completed diary card and were included in the analysis. The proportion of patients who recorded one or more symptomatic hypoglycaemic events during Ramadan was lower in the sitagliptin group (6.7%) compared with the sulphonylurea group (13.2%). The risk of symptomatic hypoglycaemia was significantly decreased with sitagliptin relative to sulphonylurea treatment (Mantel–Haenszel relative risk ratio [95% CI] = 0.51 [0.34, 0.75]; p < 0.001). There were no reported events that required medical assistance (i.e. visits to physician or emergency room or hospitalisations) or were considered severe (i.e. events that caused loss of consciousness, seizure, coma or physical injury) during Ramadan. Conclusions: In Muslim patients with type 2 diabetes who observed the fast during Ramadan, switching to a sitagliptin-based regimen decreased the risk of hypoglycaemia compared with remaining on a sulphonylurea-based regimen. The incidence of hypoglycaemia was lower with gliclazide relative to the other sulphonylurea agents and similar to that observed with sitagliptin.

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.

The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses. Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans.

There is a lack of official national antimicrobial resistance (AMR) data in Lebanon. Individual hospitals generate their own antibiotic susceptibility data in the form of yearly pamphlets. In this study, antibiotic susceptibility data from 13 hospitals distributed across different governorates of Lebanon were collected to conduct a compilation-based surveillance of AMR in Lebanon for the years 2015–2016. The findings were compared with those of a previous nationwide study in this country conducted between 2011 and 2013 as well as with similar data obtained from the 2015 and 2016 European surveillance reports of AMR. To provide a clear presentation of the AMR situation, mean percent susceptibility of different antibiotic–microbe combinations was calculated. During 2015–2016, the percent susceptibility of Enterobacteriaceae to third-generation cephalosporins and to carbapenems was 59 and 97%, respectively. Among Pseudomonas aeruginosa and Acinetobacter spp., carbapenem susceptibility reached 70 and 12%, respectively. Among Gram positive organisms, the percent susceptibility to methicillin in Staphylococcus aureus was 72%, that to vancomycin in Enterococcus spp. was 98% and that to penicillin in Streptococcus pneumoniae was 75%. Compared with results of 2011–2013, there was an overall trend of decreased susceptibility of bacteria to the tested antibiotics, with a variation of 5 to 10%. The antibiotic susceptibility data from Lebanon were found to be comparable with those from Eastern and South-eastern European countries. This study highlights the need to establish a robust national AMR surveillance system that enables data from Lebanon to be included in global AMR maps.

BACKGROUND: Childhood cancer is a highly curable disease when timely diagnosis and appropriate therapy are provided. A negative impact of the coronavirus disease 2019 (COVID-19) pandemic on access to care for children with cancer is likely but has not been evaluated. METHODS: A 34-item survey focusing on barriers to pediatric oncology management during the COVID-19 pandemic was distributed to heads of pediatric oncology units within the Pediatric Oncology East and Mediterranean (POEM) collaborative group, from the Middle East, North Africa, and West Asia. Responses were collected on April 11 through 22, 2020. Corresponding rates of proven COVID-19 cases and deaths were retrieved from the World Health Organization database. RESULTS: In total, 34 centers from 19 countries participated. Almost all centers applied guidelines to optimize resource utilization and safety, including delaying off-treatment visits, rotating and reducing staff, and implementing social distancing, hand hygiene measures, and personal protective equipment use. Essential treatments, including chemotherapy, surgery, and radiation therapy, were delayed in 29% to 44% of centers, and 24% of centers restricted acceptance of new patients. Clinical care delivery was reported as negatively affected in 28% of centers. Greater than 70% of centers reported shortages in blood products, and 47% to 62% reported interruptions in surgery and radiation as well as medication shortages. However, bed availability was affected in <30% of centers, reflecting the low rates of COVID-19 hospitalizations in the corresponding countries at the time of the survey. CONCLUSIONS: Mechanisms to approach childhood cancer treatment delivery during crises need to be re-evaluated, because treatment interruptions and delays are expected to affect patient outcomes in this otherwise largely curable disease.

Genome wide association studies (GWAS) and their replications that have associated DNA variants with myocardial infarction (MI) and/or coronary artery disease (CAD) are predominantly based on populations of European or Eastern Asian descent. Replication of the most significantly associated polymorphisms in multiple populations with distinctive genetic backgrounds and lifestyles is crucial to the understanding of the pathophysiology of a multifactorial disease like CAD. We have used our Lebanese cohort to perform a replication study of nine previously identified CAD/MI susceptibility loci (LTA, CDKN2A-CDKN2B, CELSR2-PSRC1-SORT1, CXCL12, MTHFD1L, WDR12, PCSK9, SH2B3, and SLC22A3), and 88 genes in related phenotypes. The study was conducted on 2,002 patients with detailed demographic, clinical characteristics, and cardiac catheterization results. One marker, rs6922269, in MTHFD1L was significantly protective against MI (OR=0.68, p=0.0035), while the variant rs4977574 in CDKN2A-CDKN2B was significantly associated with MI (OR=1.33, p=0.0086). Associations were detected after adjustment for family history of CAD, gender, hypertension, hyperlipidemia, diabetes, and smoking. The parallel study of 88 previously published genes in related phenotypes encompassed 20,225 markers, three quarters of which with imputed genotypes The study was based on our genome-wide genotype data set, with imputation across the whole genome to HapMap II release 22 using HapMap CEU population as a reference. Analysis was conducted on both the genotyped and imputed variants in the 88 regions covering selected genes. This approach replicated HNRNPA3P1-CXCL12 association with CAD and identified new significant associations of CDKAL1, ST6GAL1, and PTPRD with CAD. Our study provides evidence for the importance of the multifactorial aspect of CAD/MI and describes genes predisposing to their etiology.

AIMS: We aimed to describe the characteristics and care of participants with diabetes during Ramadan in the Middle East and North Africa (MENA). METHODS: In this prospective, observational study, we analysed the number of fasted days, number of participants fasting, glycemic control, rate of hypoglycemic events, and lifestyle patterns for participants with T2DM during Ramadan 2016. RESULTS: The population included 1749 participants with T2DM. The mean (SD) duration of fasting was 27.7 (5.0) days, and 57.3% of participants fasted for the full duration of Ramadan. Following Ramadan, a significant improvement in HbA1c, FPG, and PPG was observed (p < 0.0001). Confirmed hypoglycemia increased significantly from before to during Ramadan (incidence: 4.9% vs. 10.4%, p < 0.001; adverse events: 0.11 vs. 0.22 events/month/participant, p < 0.001) and was dependent on the treatment regimen. Severe hypoglycemia incidence was 0.2% before versus 0.9% during Ramadan (p = 0.031), whereas adverse events remained comparable (0.01 events/month/participant; p = 0.154). Most participants (97.4%) reported lifestyle changes during Ramadan. CONCLUSIONS: This prospective study is the first to describe the characteristics and care of participants with T2DM during Ramadan in MENA, and can be utilized in the development of evidence-based care to ensure the safety of participants who fast.

In patients suffering from transfusion-dependent anemia, excess iron secondary to regular transfusions cannot be physiologically excreted. This leads to a state of chronic iron overload with iron accumulating in the liver, heart, and endocrine organs, and ultimately results in significant morbidity and mortality. Historically, iron overload was assessed through measurement of serum ferritin or direct determination of liver iron concentration (LIC) by means of biopsy. Although both correlate well with iron overload severity, several limitations pertinent to both are of concern. This has led to the identification of novel noninvasive iron assessment measures, namely magnetic resonance imaging (MRI) R2 and T2*. Moreover, investigations of other potential indices like nontransferrin-bound iron (NTBI) and labile plasma iron (LPI) are yielding promising results. Optimal iron overload assessment and monitoring is a key element in the development of improved strategies of iron chelation therapy that can be tailored to meet the patient's specific needs.

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/β(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.