The evolution of the COVID-19 pandemic in paediatric patients with sickle cell disease: From Alpha to Omicron.

We compare the impact of SARS-CoV-2 variants on healthcare utilization and clinical presentation in paediatric patients with sickle cell disease (SCD). One hundred and ninety-one unique patients with SCD and positive SARS-CoV-2 polymerase chain reactions were identified between March 2020 and January 2022. Hospitalizations, which accounted for 42% (N = 81) of cases, were highest during the Delta dominant era (48%) and lowest during Omicron (36%) (p = 0.285). The most common SCD-related complication was vaso-occlusive pain (37%, N = 71), which accounted for 51% of all hospital admissions (N = 41), and acute chest was highest in the Alpha variant era (N = 15). Overall, COVID-19 remained mild in clinical severity within most paediatric SCD patients.

Clinical Impact of a Standardized Risk-Stratified Thromboprophylaxis Protocol for Multisystem Inflammatory Syndrome in Children.

OBJECTIVE: To evaluate the clinical impact of an institutional thromboprophylaxis protocol in patients with multisystem inflammatory syndrome in children (MIS-C), who are at increased risk for thromboembolism (TE). STUDY DESIGN: We conducted a single-center retrospective cohort study of children less than 18 years between March 2020 and December 2021. Eligible patients were confirmed with MIS-C and were managed with a standardized multidisciplinary treatment approach that included a thromboprophylaxis protocol to guide and unify clinical practice. For high-risk patients, prophylactic dose enoxaparin (target anti-Factor Xa 0.1-0.3 U/mL) was added. In high-risk patients with TE risk factors persistent at hospital discharge, thromboprophylaxis was prescribed for an additional 30 days. RESULTS: Of 135 patients with MIS-C, 124 (92%) required intensive care unit stay and 64 (47%) required a central venous catheter for a median duration of 5 days (IQR, 4-7). Prophylactic dose enoxaparin was initiated in 116 out of 121 patients (96%) deemed high-risk per our protocol at a median of 1 day after admission [IQR, 0-3] achieving target levels at a median of 1 day [IQR, 1-2]. The median initial anti-Factor Xa level was 0.13 u/mL [IQR, 0.05-0.19]. One patient (0.7%) developed symptomatic noncatheter related superficial vein thrombosis requiring therapeutic anticoagulation. Thromboprophylaxis was extended for 30 days after discharge in 108 out of 135 patients (80%). Bleeding events occurred in 5 patients during hospitalization (4.2%). All bleeding events were clinically relevant nonmajor bleeding. There were no deaths. CONCLUSIONS: Implementation of an institutional standardized thromboprophylaxis protocol in MIS-C was feasible and led to timely initiation of prophylactic anticoagulation and low rates of TEs and bleeding complications.

Red Blood Cell Vitamin C Concentration and Its Effect on Deformability in Pediatric Sickle Cell Disease.

Red cell rigidity is common in sickle cell disease (SCD). The contribution of oxidative stress on deformability remains unknown. This study investigated red blood cell (RBC) vitamin C concentrations in pediatric SCD (n=43) compared with healthy controls ( n =23) and developed a protocol to raise RBC vitamin C concentrations to measure the effect on deformability. Sickle cell RBC vitamin C concentrations seem low (20.5 µM, SD: 16.2 vs. 51.7 µM, SD: 15.8; P <0.0001). Vitamin C can be successfully loaded into sickle cell RBCs but seems to have minimal effect on deformability. Future studies are needed to understand the clinical implications of vitamin C deficiency in pediatric SCD.

Amino acid signature during sickle cell pain crisis shows significant alterations related to nitric oxide and energy metabolism.

Nitric oxide depletion secondary to arginase induced arginine deficiency has been shown to be important in the pathophysiology of vaso-occlusion in sickle cell pain crisis. Our objective of this study was to perform a comprehensive amino acid evaluation during sickle cell pain crisis. In a total of 58 subjects (29 in steady-state sickle cell disease and 29 with sickle cell pain crisis), the amino acids related to nitric oxide pathway was significantly decreased during sickle cell pain crisis compared to steady-state sickle cell disease: arginine (p = 0.001), citrulline (p = 0.012), and ornithine (p = 0.03). In addition, the amino acids related to energy metabolism was significantly decreased during a pain crisis: asparagine (p < 0.001), serine (p = 0.002), histidine (p = 0.017), alanine (p = 0.004), tyrosine (p = 0.012), methionine (p = 0.007), cystine (p = 0.016), isoleucine (p = 0.016) and lysine (p = 0.006). The amino acid related to oxidative stress were significantly higher during a sickle cell pain crisis (glutamic acid (p < 0.001). Furthermore, multivariate analysis with partial least squares-discriminant analysis (PLS-DA) showed that deficiencies of the amino acids arginine, asparagine, citrulline, methionine and alanine were the most important related to sickle cell pain crisis.

Multisystem Inflammatory Syndrome of Children: Subphenotypes, Risk Factors, Biomarkers, Cytokine Profiles, and Viral Sequencing.

OBJECTIVE: To assess demographic, clinical, and biomarker features distinguishing patients with multisystem inflammatory syndrome in children (MIS-C); compare MIS-C sub-phenotypes; identify cytokine biosignatures; and characterize viral genome sequences. STUDY DESIGN: We performed a prospective observational cohort study of 124 children hospitalized and treated under the institutional MIS-C Task Force protocol from March to September 2020 at Children's National, a quaternary freestanding children's hospital in Washington, DC. Of this cohort, 63 of the patients had the diagnosis of MIS-C (39 confirmed, 24 probable) and 61 were from the same cohort of admitted patients who subsequently had an alternative diagnosis (controls). RESULTS: Median age and sex were similar between MIS-C and controls. Black (46%) and Latino (35%) children were over-represented in the MIS-C cohort, with Black children at greatest risk (OR 4.62, 95% CI 1.151-14.10; P = .007). Cardiac complications were more frequent in critically ill patients with MIS-C (55% vs 28%; P = .04) including systolic myocardial dysfunction (39% vs 3%; P = .001) and valvular regurgitation (33% vs 7%; P = .01). Median cycle threshold was 31.8 (27.95-35.1 IQR) in MIS-C cases, significantly greater (indicating lower viral load) than in primary severe acute respiratory syndrome coronavirus 2 infection. Cytokines soluble interleukin 2 receptor, interleukin [IL]-10, and IL-6 were greater in patients with MIS-C compared with controls. Cytokine analysis revealed subphenotype differences between critically ill vs noncritically ill (IL-2, soluble interleukin 2 receptor, IL-10, IL-6); polymerase chain reaction positive vs negative (tumor necrosis factor-α, IL-10, IL-6); and presence vs absence of cardiac abnormalities (IL-17). Phylogenetic analysis of viral genome sequences revealed predominance of GH clade originating in Europe, with no differences comparing patients with MIS-C with patients with primary coronavirus disease 19. Treatment was well tolerated, and no children died. CONCLUSIONS: This study establishes a well-characterized large cohort of MIS-C evaluated and treated following a standardized protocol and identifies key clinical, biomarker, cytokine, viral load, and sequencing features. Long-term follow-up will provide opportunity for future insights into MIS-C and its sequelae.

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.

Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant.

BACKGROUND: The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. METHODS: We infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX-R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values. RESULTS: No serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady-state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow-up of 492 weeks among all the participants (range of follow-up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P=0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P=0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver-enzyme levels developed in 2 participants and resolved with short-term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion. CONCLUSIONS: We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene-derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092 .).

Parvovirus B19 infection in sickle cell disease: An analysis from the Centers for Disease Control haemoglobinopathy blood surveillance project.

OBJECTIVE: In the multicentre Haemoglobinopathy Blood Surveillance Project, to evaluate the seroprevalence of parvovirus B19 and DNA viral load in sickle cell disease (SCD). BACKGROUND: Although the epidemiology of parvovirus B19 seropositivity in SCD has been well documented, there are few studies that have assessed possible persistent parvovirus DNAemia and associated risk factors including blood transfusion. METHODS: A qualitative analysis of parvovirus B19 serology using ELISA and quantitative parvovirus B19 DNA by RT-PCR was performed in patients with SCD. RESULTS: Of 322 patients, 113 (35%) were parvovirus IgG positive and 119 (37%) were IgM positive at enrolment. The prevalence of IgG positivity increased with age. 71/322 (22%) were parvovirus DNA positive at enrolment with a mean viral load of 15 227 ± 55 227 SD. (range 72-329 238 IU/mL). Patients who were positive for parvovirus B19 DNA received a significantly higher red blood cell transfusion volume in the prior year compared to patients who were negative (mean RBC volume = 8310 mL vs 5435 mL, respectively; P = .0073). Seventy-seven patients had follow-up testing approximately 1 year after enrolment and 11/28 (39%) patients had persistently positive IgM. CONCLUSION: Further studies are needed to better understand the natural history of parvovirus B19 infection in SCD especially in relation to RBC transfusion as a risk factor, as well as disease outcome and severity.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Children with sickle cell anemia with normal transcranial Doppler ultrasounds and without silent infarcts have a low incidence of new strokes.

In a prospective cohort study, we tested the hypothesis that children with sickle cell anemia (SCA) with normal transcranial Doppler ultrasound (TCD) velocities and without silent cerebral infarcts (SCIs) would have a lower incidence rate of new neurological events (strokes, seizures or transient ischemic attacks) compared to children with normal TCD measurements and SCIs, not receiving regular blood transfusions. Nonrandomized participants from the silent cerebral infarct transfusion (SIT) Trial who had screening magnetic resonance imaging (MRI) of the brain and normal TCD measurements were included. Follow-up ended at the time of first neurological event (stroke, seizure or transient ischemic attack), start of regular blood transfusion, or loss to follow-up, whichever came first. The primary endpoint was a new neurological event. Of 421 participants included, 68 had suspected SCIs. Mean follow-up was 3.6 years. Incidence rates of new neurological events in nontransfused participants with normal TCD values with SCIs and without SCIs were 1.71 and 0.47 neurological events per 100 patient-years, respectively, P = .065. The absence of SCI(s) at baseline was associated with a decreased risk of a new neurological event (hazard ratio 0.231, 95% CI 0.062-0.858; P = .029). Local pediatric neurologists examined 67 of 68 participants with suspected SCIs and identified 2 with overt strokes classified as SCIs by local hematologists; subsequently one had a seizure and the other an ischemic stroke. Children with SCA, without SCIs, and normal TCD measurements have a significantly lower rate of new neurological events when compared to those with SCIs and normal TCD measurements. Pediatric neurology assessment may assist risk stratification.

Recurrent Acute Chest Syndrome in Pediatric Sickle Cell Disease: Clinical Features and Risk Factors.

Acute chest syndrome (ACS) is a common and serious lung complication in sickle cell disease. A retrospective medical chart review was performed over a 6-year period in all pediatric ACS patients to investigate whether factors during the initial hospitalization were associated with recurrent ACS episodes. There were 386 episodes of ACS: 149 had only 1 episode of ACS, and 76 had >1 episode of ACS; 172 (76.4%) had hemoglobin SS, and 39 (17.3%) had hemoglobin SC. The most common presenting features were fever (83%), pain (70%), and cough (61%), which changed with the number of ACS episodes. Children <4 years old were at greatest risk of recurrent ACS (P=0.018). In addition, history of asthma (adjusted incident rate ratio [IRR]=1.52; 95% confidence interval [CI], 1.22-1.98; P<0.0001), shortness of breath (IRR, 1.29; 95% CI, 1.02-1.62; P=0.033), and length of hospital stay (IRR, 1.04; 95% CI, 1.01-1.08; P=0.017) were significantly associated with prospective ACS events. Multiple episodes of ACS are common in sickle cell disease, and certain risk factors during the initial hospitalization are associated with recurrent ACS.

Malaria, Epstein-Barr virus infection and the pathogenesis of Burkitt's lymphoma.

A geographical and causal connection has long been recognized between malaria, Epstein-Barr virus (EBV) infection and Burkitt's lymphoma (BL), but the underlying mechanisms remain obscure. Potential clues are that the malaria parasite Plasmodium falciparum selectively absorbs vitamin A from the host and depends on it for its biological activities; secondly, alterations in vitamin A (retinoid) metabolism have been implicated in many forms of cancer, including BL. The first author has proposed that the merozoite-stage malaria parasite, emerging from the liver, uses its absorbed vitamin A as a cell membrane destabilizer to invade the red blood cells, causing anemia and other signs and symptoms of the disease as manifestations of an endogenous form of hypervitaminosis A (Mawson AR, Path Global Health 2013;107(3):122-9). Repeated episodes of malaria would therefore be expected to expose the tissues of affected individuals to potentially toxic doses of vitamin A. It is proposed that such episodes activate latent EBV infection, which in turn activates retinoid-responsive genes. Expression of these genes enhances viral replication and induces germinal center (GC) B cell expansion, activation-induced cytidine deaminase (AID) expression, and c-myc translocation, which in turn predisposes to BL. Thus, an endogenous form of retinoid toxicity related to malaria infection may be the common factor linking frequent malaria, EBV infection and BL, whereby prolonged exposure of lymphatic tissues to high concentrations of retinoids may combine to induce B-cell translocation and increase the risk of Burkitt's lymphoma.

Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia.

BACKGROUND: Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. METHODS: In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. RESULTS: A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04). CONCLUSIONS: Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Daily Pain, Physical Activity, and Home Fluid Intake in Pediatric Sickle Cell Disease.

Objectives: This study examined the temporal relationship between physical activity, fluid intake, and daily pain in children with sickle cell disease (SCD) with frequent pain. Methods: A total of 30 African American children ( M age = 13.9; 53% female; 76.3% type SS) who reported pain more than or equal to once every 2 weeks and their parents completed measures of pain and anxiety/depressive symptoms. Children then completed a daily pain diary and wore a physical activity Actiwatch for 14 days at home. Results: Contrary to physiological theory-based hypotheses, lower physical activity was associated with greater pain during the same day and the next day. Less pain was associated with greater physical activity the next day. There was no relationship between self-reported home fluid intake and daily pain ( p 's < .05). Conclusions: Results lend support for a complex bidirectional relationship between physical activity and daily pain in pediatric SCD, and identify physical activity as a target for future research.

Quality of life among pediatric patients with cancer: Contributions of time since diagnosis and parental chronic stress.

BACKGROUND: Pediatric cancer is associated with a host of negative psychosocial consequences; however, outcomes vary extensively suggesting a need to better understand this variation. Empirical research suggests a positive association between time since diagnosis (TSD) and Quality of Life (QoL). In addition to TSD, family stressors have been found to be particularly important in predicting QoL among children. The current study examined parental chronic stress beyond TSD in explanation of QoL functioning among a sample of pediatric patients with cancer. PROCEDURE: Participants included 43 pediatric patients aged 5-18 years (M(age) = 10.2 ± 3.6) who were undergoing oncological treatment. Parents reported on TSD, child's QoL, and their own chronic stress. RESULTS: TSD was associated with greater physical functioning (r = 0.30, P < 0.05). Parental chronic stress was associated with poorer emotional (r = -0.54, P < 0.01), physical (r = -0.41, P < 0.01), and social functioning (r = -0.44, P < 0.01). Further, hierarchal linear regression analyzes indicated parental chronic stress contributed incrementally beyond TSD in the explanation of physical (ß = -0.37, t = -2.58, P < 0.01), emotional (ß = -0.47, t = -3.51, P < 0.00), and social functioning (ß = -0.38, t = -2.67, P < 0.01). CONCLUSIONS: Parental chronic stress is associated with reduced levels of emotional, physical, and social functioning among pediatric patients. Future research is needed to further investigate the process by which chronic stress within the family interferes with adaptive coping among pediatric patients. In addition, clinical services may benefit from increased consideration of family factors, such as parental chronic stress, during oncological treatment.

Outcome of overt stroke in sickle cell anaemia, a single institution's experience.

Stroke is a traumatic complication in sickle cell anaemia (SCA) that is associated with significant morbidity and a risk of recurrent overt stroke of 2·2-6·4 events per 100 patient-years. A retrospective study was performed on all paediatric SCA patients diagnosed with a history of overt stroke between 1997 and 2010. A total of 31 children with SCA had new onset overt stroke. The mean age of the active patients (n = 27) was 17·9 years (range 6·8-27·6 years) with a total period of observation of 305 patient-years. Twenty-two of 27 (81%) were receiving long term red blood cell transfusions and 16 (59%) were taking the anti-platelet agent, aspirin, since diagnosis of the stroke. Two of 27 (7%) patients had a second overt stroke with an overall risk of recurrent stroke of 0·66/100 patient-years (one stroke was ischaemic and the other haemorrhagic). In patients taking aspirin with 180 patient-years of follow up, the recurrence rate of haemorrhagic stroke was 0·58/100 patient-years. We have an excellent outcome for overt stroke in paediatric SCA patients with a low rate of recurrent stroke. Further studies are needed to determine the risk-benefit ratio of aspirin therapy in the prevention of recurrent stroke in paediatric SCA.

Associations among emergency room visits, parenting styles, and psychopathology among pediatric patients with sickle cell.

BACKGROUND: To examine associations between frequency of emergency room (ER) visits and various parenting styles, both conjointly and interactively, and psychopathological outcomes among pediatric patients with sickle cell disease (SCD). PROCEDURES: Ninety-eight parents/caregivers of 6- to 18-year-old patients with SCD completed instruments assessing parenting style, child psychopathology, and reported on the frequency of ER visits during the previous year. RESULTS: ER visits were found to significantly explain Withdrawn/Depressed problems and parenting styles were found to incrementally contribute to the explanation of all forms of psychopathology. Further, Permissive parenting was found to explain Rule Breaking Behavior for those patients with low ER visit frequency but not for those with high ER visit frequency. CONCLUSIONS: Results of the current study confirm the importance of considering both the frequency of ER visits and parenting style in the explanation of psychopathology among pediatric patients with SCD. Results have important implications for both research and treatment.

Genetic variants and effect modifiers of QT interval prolongation in patients with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interval (QTc), a known risk factor for sudden cardiac death. Although numerous genetic variants have been identified as contributors to QT interval prolongation in the general population, their impact on SCD patients remains unclear. This study used an unweighted polygenic risk score (PRS) to validate the previously identified associations between SNPs and QTc interval in SCD patients, and to explore possible interactions with other factors that prolong QTc interval in AA individuals with SCD. METHODS: In SCD patients, candidate genetic variants associated with the QTc interval were genotyped. To identify any risk SNPs that may be correlated with QTc interval prolongation, linear regression was employed, and an unweighted PRS was subsequently constructed. The effect of PRS on the QTc interval was evaluated using linear regression, while stratification analysis was used to assess the influence of serum alanine transaminase (ALT), a biomarker for liver disease, on the PRS effect. We also evaluated the PRS with the two subcomponents of QTc, the QRS and JTc intervals. RESULTS: Out of 26 candidate SNPs, five risk SNPs were identified for QTc duration under the recessive model. For every unit increase in PRS, the QTc interval prolonged by 4.0 ms (95% CI: [2.0, 6.1]; p-value: <0.001) in the additive model and 9.4 ms in the recessive model (95% CI: [4.6, 14.1]; p-value: <0.001). Serum ALT showed a modification effect on PRS-QTc prolongation under the recessive model. In the normal ALT group, each PRS unit increased QTc interval by 11.7 ms (95% CI: [6.3, 17.1]; p-value: 2.60E-5), whereas this effect was not observed in the elevated ALT group (0.9 ms; 95% CI: [-7.0, 8.8]; p-value: 0.823). CONCLUSION: Several candidate genetic variants are associated with QTc interval prolongation in SCD patients, and serum ALT acts as a modifying factor. The association of a CPS1 gene variant in both QTc and JTc duration adds to NOS1AP as evidence of involvement of the urea cycle and nitric oxide metabolism in cardiac repolarization in SCD. Larger replication studies are needed to confirm these findings and elucidate the underlying mechanisms.