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.)

WHAT'S KNOWN ON THIS SUBJECT: Obstructive sleep apnea syndrome (OSAS) prevalence in children with sickle cell anemia is not well described. Although these children often experience nocturnal oxygen desaturation, it is unclear whether they are more likely to have OSAS.WHAT THIS STUDY ADDS: Children with sickle cell anemia have a high prevalence of OSAS with typical symptoms, beyond just nocturnal oxyhemoglobin desaturation. This study supports the need for increased efforts to screen for, diagnose, and treat OSAS in this vulnerable population. abstract OBJECTIVE: To ascertain the prevalence of and risk factors for obstructive sleep apnea syndrome (OSAS) in children with sickle cell anemia (SCA). METHODS:Cross-sectional baseline data were analyzed from the Sleep and Asthma Cohort Study, a multicenter prospective study designed to evaluate the contribution of sleep and breathing abnormalities to SCArelated morbidity in children ages 4 to 18 years, unselected for OSAS symptoms or asthma. Multivariable logistic regression assessed the relationships between OSAS status on the basis of overnight inlaboratory polysomnography and putative risk factors obtained from questionnaires and direct measurements. RESULTS:Participants included 243 children with a median age of 10 years; 50% were boys, 99% were of African heritage, and 95% were homozygous for b S hemoglobin. OSAS, defined by obstructive apnea hypopnea indices, was present in 100 (41%) or 25 (10%) children at cutpoints of $1 or $5, respectively. In univariate analyses, OSAS was associated with higher levels of habitual snoring, lower waking pulse oxygen saturation (SpO 2 ), reduced lung function, less caretaker education, and non-preterm birth. Lower sleep-related SpO 2 metrics were also associated with higher obstructive apnea hypopnea indices. In multivariable analyses, habitual snoring and lower waking SpO 2 remained risk factors for OSAS in children with SCA. CONCLUSIONS:The prevalence of OSAS in children with SCA is higher than in the general pediatric population. Habitual snoring and lower waking SpO 2 values, data easily obtained in routine care, were the strongest OSAS risk factors. Because OSAS is a treatable condition with adverse health outcomes, greater efforts are needed to screen, diagnose, and treat OSAS in this high-risk, vulnerable population.

Summary Haemophilia A carriers have historically been thought to demonstrate normal haemostasis. However, recent data demonstrates that despite normal factor VIII, haemophilia A carriers demonstrate an increased bleeding tendency. We tested the hypothesis that obligate haemophilia carriers demonstrate an increase in bleeding symptoms. A cross sectional study was performed comparing haemophilia A carriers to normal women. Questionnaire assessment included a general bleeding questionnaire, condensed MCMDM-1VWD bleeding assessment tool and Pictorial Bleeding Assessment Chart (PBAC). Laboratory assessment included complete blood count, prothrombin time, activated partial thromboplastin time, fibrinogen activity, FVIII activity (FVIII:C), von Willebrand factor antigen level, ristocetin cofactor, platelet function analyser-100™ and ABO blood type. 44 haemophilia A carriers and 43 controls were included. Demographic features were similar. Laboratory results demonstrated a statistically significant difference only in FVIII:C (82.5 versus 134%, p value < 0.001). Carriers reported a higher number of bleeding events, and both condensed MCMDM-1 VWD bleeding scores (5 versus 1, p value < 0.001) and PBAC scores (423 versus 182.5, p value = 0.018) were significantly higher in carriers. Haemophilia A carriers exhibit increased bleeding symptoms when compared to normal women. Further studies are necessary to fully understand the bleeding phenotype in this population and optimize clinical management.

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Heritability, the proportion of phenotypic variance explained by genetic factors, can be estimated from pedigree data 1 , but such estimates are uninformative with respect to the underlying genetic architecture. Analyses of data from genome-wide association studies (GWAS) on unrelated individuals have shown that for human traits and disease, approximately one-third to two-thirds of heritability is captured by common SNPs 2-5 . It is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular if the causal variants are rare, or other reasons such as overestimation of heritability from pedigree data. Here we show that pedigree heritability for height and body mass index (BMI) appears to be fully recovered from whole-genome sequence (WGS) data on 21,620 unrelated individuals of European ancestry. We assigned 47.1 million genetic variants to groups based upon their minor allele frequencies (MAF) and linkage disequilibrium (LD) with variants nearby, and estimated and partitioned variation accordingly. The estimated heritability was 0.79 (SE 0.09) for height and 0.40 (SE 0.09) for BMI, consistent with pedigree estimates. Low-MAF variants in low LD with neighbouring variants were enriched for heritability, to a greater extent for protein altering variants, consistent with negative selection thereon. Cumulatively variants in the MAF range of 0.0001 to 0.1 explained 0.54 (SE 0.05) and 0.51 (SE 0.11) of heritability for height and BMI, respectively. Our results imply that the still missing heritability of complex traits and disease is accounted for by rare variants, in particular those in regions of low LD.

Premature death and cardiac abnormalities are described in individuals with sickle cell disease (SCD), but the mechanisms are not well characterized. We tested the hypothesis that cardiac abnormalities in children with SCD are related to sleep-disordered breathing. We enrolled 44 children with SCD (mean age, 10.1 years; range, 4-18 years) in an observational study. Standard and tissue Doppler echocardiography, waking oxygen saturation averaged over 5 minutes, and overnight polysomnography were obtained in participants, each within 7 days. Eccentric left ventricular (LV) hypertrophy was present in 46% of our cohort. After multivariable adjustment, LV mass index was inversely related to average asleep and waking oxygen saturation. For every 1% drop in the average asleep oxygen saturation, there was a 2.1 g/m 2.7 increase in LV mass index. LV diastolic dysfunction, as measured by the E/E ratio, was present in our subjects and was also associated with low oxygen saturation (sleep or waking). Elevated tricuspid regurgitant velocity (> 2.5 m/sec), a measure of pulmonary hypertension, was not predicted by either oxygen saturation or sleep variables with multivariable logistic regression analysis. These data provide evidence that low asleep and waking oxygen saturations are associated with LV abnormalities in children with SCD. (Blood. 2010;116(1):16-21)

Background Pregnancy in women with sickle-cell disease (SCD) is associated with increased adverse outcomes. Findings on the association between SCD and adverse pregnancy outcomes are conflicting, and the results do not address whether these associations are similar in both low-and high-income countries.Objectives We conducted a systematic review and meta-analysis to evaluate pregnancy outcomes associated with SCD.Search strategy The MEDLINE database was searched using medical subject headings (MeSH) and keywords for articles on pregnancy outcomes in women with SCD.Selection criteria We used full research articles published in English that compared women with SCD with women who did not have SCD, as controls.Data collection and analysis Data were abstracted and analysed using comprehensive Meta-analysis 2.2. The primary outcomes were intrauterine growth restriction and perinatal mortality. Secondary outcomes were rates of caesarean sections, preeclampsia, eclampsia, postpartum haemorrhage, maternal mortality, prematurity, and low birthweight. Random-effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (95% CIs).Main results Sixteen studies met all of the selection criteria and were included in the analysis. SCD was associated with intrauterine growth restriction (pooled OR 2.79, 95% CI 1.85-4.21), perinatal mortality (pooled OR 3.76, 95% CI 2.34-6.06), and low birthweight (pooled OR 2.00, 95% CI 1.42-2.83). SCD was also associated with an increased risk of pre-eclampsia (pooled OR 2.05, 95% CI 1.47-2.85), maternal mortality (pooled OR 10.91, 95% CI 1.83-65.11, P = 0.009), and eclampsia (pooled OR 3.02, 95% CI 1.20-7.58).Conclusion Pregnancy in women with SCD is associated with increased risks of adverse perinatal and maternal outcomes in both low-and high-income countries.Keywords Maternal and perinatal outcome, pregnancy, sickle-cell disease.Tweetable abstract This meta-analysis showed worse pregnancy outcomes in women with sickle-cell disease compared with controls.Please cite this paper as: Boafor TK, Olayemi E, Galadanci N, Hayfron-Benjamin C, Dei-Adomakoh Y, Segbefia C, Kassim AA, Aliyu MH, Galadanci H, Tuuli MG, Rodeghier M, DeBaun M, Oppong SA. Pregnancy outcomes in women with sickle-cell disease: a systematic review and meta-analysis. BJOG 2016;123:691-698.

Study Hypothesis Demographic factors and emergency provider attitudes are associated with adherence to national guidelines for the management of acute SCD pain. Methods We conducted a cross sectional survey of emergency providers at the 2011 annual American College of Emergency Physicians scientific assembly using a validated instrument to assess provider attitudes and self-reported analgesic practices towards patients with SCD. Multivariable, relative risk regressions were used to identify factors associated with adherence to guidelines. Results There were 722 eligible participants with a 93% complete response rate. Most providers self-reported adherence to the cornerstones of SCD pain management including parenteral opioids (90%) and re-dosing opioids within 30 minutes if analgesia is inadequate (85%). Self-reported adherence was lower for other recommendations including use of patient-controlled analgesia (PCA), acetaminophen, NSAIDs and hypotonic fluids when euvolemic. Emergency providers in the highest quartile of negative attitudes were 20% less likely to re-dose opioids within 30 minutes for inadequate analgesia (risk ratio 0.8, 95% CI 0.7 – 0.9). High volume providers (those who see more than one SCD patient per week), were less likely to re-dose opioids within 30 minutes for inadequate analgesia (RR 0.9, 95% CI 0.8 – 0.9). Pediatric providers were 6.6 times more likely to use PCA for analgesia (95%CI 2.6 – 16.6). Conclusions The majority of emergency providers report that they adhere to national guidelines regarding use of opioids for SCD-related acute pain episodes. Other recommendations have less penetration. Negative attitudes towards individuals with SCD are associated with lower adherence to guidelines.