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Sickle cell disease is associated with progressive and increased neurological morbidity throughout the lifespan. In people with sickle cell anaemia (the most common and severe type of sickle cell disease), silent cerebral infarcts are found in more than a third of adolescents by age 18 years and roughly half of young adults by age 30 years, many of whom have cognitive impairment despite having few or no conventional stroke risk factors. Common anatomical neuroimaging in individuals with sickle disease can assess structural brain injury, such as stroke and silent cerebral infarcts; however, emerging advanced neuroimaging methods can provide novel insights into the pathophysiology of sickle cell disease, including insights into the cerebral haemodynamic and metabolic contributors of neurological injury. Advanced neuroimaging methods, particularly methods that report on aberrant cerebral blood flow and oxygen delivery, have potential for triaging patients for appropriate disease-modifying or curative therapies before they have irreversible neurological injury, and for confirming the benefit of new therapies on brain health in clinical trials. [ABSTRACT FROM AUTHOR]

• Neurologic complications in children under five years of age with SCD are common. • Diagnosis of neurologic complications is difficult in young children with SCD. • Silent cerebral infarct and cognitive impairment are the most common neurologic complications. • Detection of overt stroke in very young children is challenging. Sickle Cell Disease (SCD) is one of the most common genetic diseases in the world affecting every organ. The major challenge in the medical care of children with SCD is preventing end-organ dysfunction, particularly the brain. Major neurologic complications in children less than five years with SCD include, but are not limited to, Silent cerebral infarct, cerebral sinus thrombosis, epilepsy, reversible encephalopathy syndrome, and ischemic and hemorrhagic stroke. Recurrent headaches and migraine are not rare in children under five years with SCD. This review will focus on the neurologic complications and the description of the modifiable risk factors in children less than 5 years of age with emphasis on differences between high and low resource settings. Neurologic complications of children under 5 years of age and the modifiable risk factors. The PUBMED database was searched using medical subject headings (MeSH) and keywords for articles regarding neurologic complications in children under 5 years of age. Neurologic complications in children under five years of age with SCD may be more frequent than currently reported, among which Silent cerebral infarct and cognitive impairment are the most common. [ABSTRACT FROM AUTHOR]

Background: To improve the quality of care for children with sickle cell anemia in Kano, Nigeria, we initiated a standard care protocol in 2014 to manage children with strokes at Aminu Kano Teaching Hospital.Methods: The standard care protocol requires that children with acute strokes be treated with hydroxyurea at a fixed dose of 20 mg/kg/day within two months of the stroke.Results: Twenty-nine children with sickle cell anemia and initial stroke were identified based on clinical World Health Organization criteria from 2014 to 2017. Follow-up was a median of 1.04 years (interquartile range 0.43 to 1.83 years) to either July 2017 or a second stroke, corresponding to an initial stroke incidence rate of 0.88 per 100 patient-years. Eight children had a recurrent stroke, six of whom were prescribed hydroxyurea 20 mg/kg/day by two months after initial stroke. Two children died. Six of the recurrent strokes occurred within six months of the initial stroke, two before hydroxyurea prescription. The stroke recurrence rate was 17.4 events per 100 patient-years. Adherence was approximately 60%, partly because families had to pay for hydroxyurea. Stroke incidence is probably underestimated because despite formal training for stroke detection during the quality improvement period, no participant had assessment using a standardized pediatric stroke scale and neuroimaging was not available.Conclusions: In children with sickle cell anemia, a high rate of initial and recurrent strokes exists in a low-resource setting. Ongoing needs include training to detect strokes with an objective stroke assessment and government-supported free access to hydroxyurea for stroke prevention. [ABSTRACT FROM AUTHOR]

Children and adults with sickle cell anemia (SCA) have a higher risk of strokes compared to age- and race-matched peers. Velocity in the middle cerebral or distal internal carotid artery as measured by transcranial Doppler ultrasound is a recognized method to identify children but not adults with SCA at high-risk for first stroke. For both children and adults with SCA that have had a stroke, no methods clearly identify individuals at highest risk of recurrent strokes or an initial silent stroke, the most common neurological injury. Methods to assess cerebral hemodynamics in SCA have been utilized for decades but often required radiotracers making them not feasible for screening and longitudinal follow-up. MRI approaches that do not require exogenous contrast have been introduced and are appealing in both clinical and research scenarios. Improved neuroimaging strategies hold promise for identifying individuals with SCA at increased risk of initial and recurrent infarcts, justifying more aggressive risk-based therapy. We review the epidemiology of stroke in SCA, the impact of strokes, stroke mechanisms, and potential imaging strategies including regional and global oxygen extraction fraction, cerebral blood flow, and vessel wall imaging to identify individuals at high-risk of stroke. [ABSTRACT FROM AUTHOR]

The article examines whether genetic approaches are still necessary to cure sickle cell disease (SCD). Topics covered include the allogeneic blood or marrow transplantation (alloBMT) approach, the gene therapy, and the nonmyeloablative haploidentical BMT as a curative option for adults with SCD who have pre-existing heart, lung, and kidney dysfunction.

The article informs Sickle cell disease (SCD), is a heritable disorder of hemoglobin that affects newborns babies in the U.S. Topic include allogeneic blood or marrow transplantation is the only cure for patients with SCD; and harvesting of hematopoietic stem/progenitor cells (HSPCs), ex vivo transduction using a retroviral vector carrying a γ-globin or β-globin transgene, and reinfusion of transduced HSPCs following myeloablative chemotherapy.

The article discusses a study focusing on the role of silent cerebral infarcts (SCI) in causing morbidity in children with sickle cell anaemia (SCA). Topics discussed include intracranial vasculopathy and infarct recurrence in children with SCA; the magnetic resonance angiography (MRA) performed on the children under study; and the increased risk of SCI in children with intracranial vasculopathy.

Acute chest syndrome is a frequent cause of acute lung disease in children with sickle-cell disease. Asthma is common in children with sickle-cell disease and is associated with increased incidence of vaso-occlusive pain events, acute chest syndrome episodes, and earlier death. Risk factors for asthma exacerbation and an acute chest syndrome episode are similar, and both can present with shortness of breath, chest pain, cough, and wheezing. Despite overlapping risk factors and symptoms, an acute exacerbation of asthma or an episode of acute chest syndrome are two distinct entities that need disease-specific management strategies. Although understanding has increased about asthma as a comorbidity in sickle-cell disease and its effects on morbidity, substantial gaps remain in knowledge about best management. [ABSTRACT FROM AUTHOR]

With advances in brain imaging and completion of randomized clinical trials (RCTs) for primary and secondary stroke prevention, the natural history of central nervous system (CNS) complications in sickle cell disease (SCD) is evolving. In order of current prevalence, the primary CNS complications include silent cerebral infarcts (39% by 18 years), headache (both acute and chronic: 36% in children with sickle cell anemia [SCA]), ischemic stroke (as low as 1% in children with SCA with effective screening and prophylaxis, but ∼11% in children with SCA without screening), and hemorrhagic stroke in children and adults with SCA (3% and 10%, respectively). In high-income countries, RCTs (Stroke Prevention in Sickle Cell Anemia [STOP], STOP II) have demonstrated that regular blood transfusion therapy (typically monthly) achieves primary stroke prevention in children with SCA and high transcranial Doppler (TCD) velocities; after at least a year, hydroxycarbamide may be substituted (TCD With Transfusions Changing to Hydroxyurea [TWiTCH]). Also in high-income countries, RCTs have demonstrated that regular blood transfusion is the optimal current therapy for secondary prevention of infarcts for children with SCA and strokes (Stroke With Transfusions Changing to Hydroxyurea [SWiTCH]) or silent cerebral infarcts (Silent Infarct Transfusion [SIT] Trial). For adults with SCD, CNS complications continue to be a major cause of morbidity and mortality, with no evidence-based strategy for prevention. [ABSTRACT FROM AUTHOR]

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 SCA-related 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 in-laboratory 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 βS 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 (SpO2), reduced lung function, less caretaker education, and non–preterm birth. Lower sleep-related SpO2 metrics were also associated with higher obstructive apnea hypopnea indices. In multivariable analyses, habitual snoring and lower waking SpO2 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 SpO2 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. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is caused by a mutation in both beta globin genes, resulting in chronic hemolysis and multiorgan disease that ultimately leads to premature death. Although hemoglobin S (HbS) polymerization and vaso-occlusion are central to the pathogenesis of SCD, overlapping pathways implicated in SCD-related endothelial dysfunction include hemolysis, defects in nitric oxide metabolism, ischemia-reperfusion injury, oxidative stress, increased cell-to-cell adhesion, and proinflammatory and coagulation mediators. Progression of organ-specific vasculopathy often precedes organ dysfunction and may provide targets for therapeutic intervention. SCD-related vasculopathies include, but are not limited to, moyamoya that often precedes cerebral infarcts or hemorrhage, proliferative retinopathy prior to loss of eyesight, pulmonary vasculopathy associated with pulmonary hypertension, and renal vasculopathy prior to the onset of chronic renal disease. This review evaluates evidence that SCD vasculopathy is a harbinger for organ dysfunction and reviews the potential for targeted antivasculopathy therapies. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD), the most common genetic disease screened for in the newborn period, occurs in ~1 in 2400 newborns in the general population and 1 in 400 individuals of African descent in the United States. Despite the relative high prevalence and low pediatric mortality rate of SCD when compared with other genetic diseases or chronic diseases in pediatrics, few evidence-based guidelines have been developed to facilitate the transition from pediatrics to an internal medicine or family practice environment. As with any pediatric transition program, common educational, social, and health systems themes exist to prepare for the next phase of health care; however, unique features characterizing the experience of adolescents with SCD must also be addressed. These challenges include, but are not limited to, a higher proportion of SCD adolescents receiving public health insurance when compared with any other pediatric genetic or chronic diseases; the high proportion of overt strokes or silent cerebral infarcts (~30%) affecting cognition; risk of low high school graduation; and a high rate of comorbid disease, including asthma. Young adults with SCD are living longer; consequently, the importance of transitioning from a pediatric primary care provider to adult primary care physician has become a critical step in the health care management plan. We identify how the primary care physicians in tandem with the pediatric specialist can enhance transition interventions for children and adolescents with SCD. [ABSTRACT FROM AUTHOR]

Silent cerebral Infarct (SCI) is the most common form of neurologic disease in children with sickle cell anemia (SCA). SCI is defined as abnormal magnetic resonance imaging (MRI) of the brain in the setting of a normal neurologic examination without a history or physical findings associated with an overt stroke. SCI occurs in 27% of this population before their sixth, and 37% by their 14th birthdays. In adults with SCA, the clinical history of SCI is poorly defined, although recent evidence suggests that they too may have ongoing risk of progressive injury. Risk factors for SCI include male sex, lower baseline hemoglobin concentration, higher baseline systolic blood pressure, and previous seizures. Specific morbidity associated with SCI includes a decrement in general intellectual abilities, poor academic achievement, progression to overt stroke, and progressive SCI. In addition, children with previous stroke continue to have both overt strokes and new SCI despite receiving regular blood transfusion therapy for secondary stroke prevention. Studies that only include overt stroke as a measure of CNS injury significantly underestimate the total cerebral injury burden in this population. In this review, we describe the epidemiology, natural history, morbidity, medical management, and potential therapeutic options for SCI in SCA. [ABSTRACT FROM AUTHOR]

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbS|V thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure ( P = . 0 1 8 ), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761. [ABSTRACT FROM AUTHOR]

The most devastating complication of sickle cell anemia is cerebral infarction, affecting ∼30% of all individuals with sickle cell anemia. Despite being one of the most common causes of stroke in infants and children, the mechanism of cerebral infarction in this population has not been extensively studied and is poorly understood. Multiple, synergistic factors are important in the pathogenesis of stroke including the hemodynamic effects of cerebral arterial occlusive disease, viscosity, chronic and acute anemia and acute medical events. This review focuses on the relationship between these factors in order to provide a foundation for further study of the etiology of strokes in this high-risk population. MRDD Research Reviews 2006;12:192–199. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Beckwith-Wiedemann syndrome (BWS), which causes prenatal overgrowth, midline abdominal wall defects, macroglossia, and embryonal tumors, is a model for understanding the relationship between genomic imprinting, human development, and cancer. The causes are heterogeneous, involving multiple genes on 11p15 and including infrequent mutation of p57KIP2 or loss of imprinting of either of two imprinted gene domains on 11p5: LIT1, which is near p57KIP2, or H19/IGF2. Unlike Prader-Willi and Angelman syndromes, no chromosomal deletions have yet been identified. Here we report a microdeletion including the entire LIT1 gene, providing genetic confirmation of the importance of this gene region in BWS. When inherited maternally, the deletion causes BWS with silencing of p57KIP2, indicating deletion of an element important for the regulation of p57KIP2 expression. When inherited paternally, there is no phenotype, suggesting that the LIT1 RNA itself is not necessary for normal development in humans. [ABSTRACT FROM AUTHOR]

Studies the association of in vitro fertilization with Beckwith-Wiedemann Syndrome and epigenetic alterations of the H19 and LIT1 genes. Key issues of interest; Analysis of pertinent topics and relevant issues; Implications on human genetics.

Beckwith-Wiedemann syndrome (BWS) is a congenital cancer-predisposition syndrome associated with embryonal cancers, macroglossia, macrosomia, ear pits or ear creases, and midline abdominal-wall defects. The most common constitutional abnormalities in BWS are epigenetic, involving abnormal methylation of either H19 or LIT1, which encode untranslated RNAs on 11p15. We hypothesized that different epigenetic alterations would be associated with specific phenotypes in BWS. To test this hypothesis, we performed a case-cohort study, using the BWS Registry. The cohort consisted of 92 patients with BWS and molecular analysis of both H19 and LIT1, and these patients showed the same frequency of clinical phenotypes as those patients in the Registry from whom biological samples were not available. The frequency of altered DNA methylation of H19 in patients with cancer was significantly higher, 56% (9/16), than the frequency in patients without cancer, 17% (13/76; P = .002), and cancer was not associated with LIT1 alterations. Furthermore, the frequency of altered DNA methylation of LIT1 in patients with midline abdominal-wall defects and macrosomia was significantly higher, 65% (41/63) and 60% (46/77), respectively, than in patients without such defects, 34% (10/29) and 18% (2/11), respectively ( P = .012 and P = .02, respectively). Additionally, paternal uniparental disomy (UPD) of 11p15 was associated with hemihypertrophy (P = .003 ), cancer ( P = .03), and hypoglycemia (P = .05 ). These results define an epigenotype-phenotype relationship in BWS, in which aberrant methylation of H19 and LIT1 and UPD are strongly associated with cancer risk and specific birth defects. [ABSTRACT FROM AUTHOR]

Presents information on a study which focused on the role of genomic imprinting in cancer and some hereditary diseases, including Beckwith-Wiedemann syndrome, a disorder of prenatal overgrowth and predisposition to embryonal malignancies. Materials and methods; Results and discussion.

Abstract. Erythrocyte protoporphyrin (EP) was introduced in the 1970s as an inexpensive screening test for lead poisoning. As greater knowledge of lead poisoning has accumulated, the recommended EP level at which further evaluation for lead poisoning should be initiated has been lowered from Is greater than or equal to 50 micro g/dL to Is greater than or equal to 35 micro g/dL. The purpose of this study was to evaluate the utility of this EP threshold. A receiver operator characteristic curve was constructed to assess the relationship between the true-positive rate and false-positive rate of EP at various decision thresholds. The receiver operator characteristic curve was constructed with data from the second National Health and Nutrition Examination Survey from 1976 to 1980, which included 2673 children 6 years of age or younger who had both blood lead and EP level determinations. Decision analysis was then used to determine the optimal EP decision threshold for detecting a blood lead level Is greater than or equal to 25 micro g/dL. The receiver operator... [ABSTRACT FROM AUTHOR]

Summary. Bone marrow failure is believed to be the underlying condition that drives the expansion of the paroxysmal nocturnal haemoglobinuria (PNH) clone. Indeed, circulating PNH blood cells have been identified in patients with acquired aplastic anaemia and with hypoplastic myelodysplasia. Whether PNH blood cells are also present in patients with inherited aplastic anaemia has not been reported. We screened a large group of patients diagnosed with Shwachman–Diamond Syndrome (SDS) for PNH blood cells. None of the patients analysed had detectable circulating PNH blood cells, indicating that bone marrow failure in SDS does not select for PNH progenitor cells. [ABSTRACT FROM AUTHOR]

The article presents the result of the study on primary stroke prevention in children with sickle cell anaemia and high transcranial Doppler (TCD) flow velocities. It state that transfusion therapy confer 92 percent relative risk reduction and 14.8 percent absolute risk reduction for stroke after completion of trial. It mentions that the results will help fill knowledge gaps that allows care for children with sickle cell anaemia with TCD.

Background: Optimal strategies for regular blood transfusion therapy are not well defined in sickle cell disease (SCD). This analysis tested the hypothesis that in the first of year of regular transfusions, when chelation therapy use is minimal, automated exchange transfusion would be the superior method for attenuating the rise in ferritin levels compared to simple and manual exchange transfusions. Study design and methods: The Silent Cerebral Infarct Multi‐Center Clinical Trial randomly allocated children with SCD and silent cerebral infarcts to receive standard care or regular transfusions with a target pre‐transfusion HbS concentration ≤ 30% and minimum hemoglobin level > 9.0 g/dL. Participants with at least nine transfusions and sufficient ferritin testing in the first year of the trial were included in a planned secondary analysis. Ferritin levels by the end of the first study year were compared between participants receiving automatic exchange transfusion, manual exchange transfusion, and simple transfusion. Results: A total of 83 participants were analyzed. During the first year of the study, 75.9% of the participants had >80% of transfusions via one transfusion method. At baseline no significant differences in ferritin levels were observed in the three transfusion groups (p = 0.1). After 1 year of transfusions the median (interquartile range) ferritin levels in the simple transfusion (n = 40), manual exchange transfusion (n = 34) and automatic exchange transfusion (n = 9) groups were 1800 ng/mL (1426‐2204 ng/mL), 1530 ng/mL (1205‐1805 ng/mL), and 355 ng/mL (179‐579 ng/mL), respectively (p < 0.001). Conclusion: Automated exchange transfusion, when compared to other transfusion methods, is the optimal transfusion strategy for attenuating increase in ferritin levels in children with SCD. [ABSTRACT FROM AUTHOR]

A reply by Michael R. DeBaun et al to a letter to the editor about their article "Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia" in the August 21, 2014 issue is presented.

The author comments on the National Heart, Lung, and Blood Institute's (NHLBI) guideline for the management of sickle cell disease (SCD) in the U.S. Topics discussed include the challenges in developing guidelines for people with uncommon disease, key recommendations from the Institute of Medicine (IOM) adopted by NHLBI for guideline creation and IOM recommendations that NHLBI did not follow.

The author discusses the quality of life of children treated for sickle cell disease in high-income countries. He mentions the risk of brain injury and academic performance of the children, blood transfusions preventing overt strokes, and issues like organ failure. Routine health checkups and decreasing associated diseases after treatment are mentioned.

Mendelian randomization (MR) is increasingly employed as a technique to assess the causation of a risk factor on an outcome using observational data. The two-stage least-squares (2SLS) procedure is commonly used to examine the causation using genetic variants as the instrument variables. The validity of 2SLS relies on a representative sample randomly selected from a study cohort or a population for genome-wide association study (GWAS), which is not always true in practice. For example, the extreme phenotype sequencing (EPS) design is widely used to investigate genetic determinants of an outcome in GWAS as it bears many advantages such as efficiency, low sequencing or genotyping cost, and large power in detecting the involvement of rare genetic variants in disease etiology. In this paper, we develop a novel, versatile, and efficient approach, namely MR analysis under Extreme or random Phenotype Sampling (MREPS), for one-sample MR analysis based on samples drawn through either the random sampling design or the nonrandom EPS design. In simulations, MREPS provides unbiased estimates for causal effects, correct type I errors for causal effect testing. Furthermore, it is robust under different study designs and has high power. These results demonstrate the superiority of MREPS over the widely used standard 2SLS approach. We applied MREPS to assess and highlight the causal effect of total fetal hemoglobin on anemia risk in patients with sickle cell anemia using two independent cohort studies. A user-friendly Shiny app web interface was implemented for professionals to easily explore the MREPS. [ABSTRACT FROM AUTHOR]

The main objective of this study was to demonstrate that computational fluid dynamics (CFD) modeling can be used to study the contribution of covert and overt vascular architecture to the risk for cerebrovascular disease in sickle cell disease (SCD) and to determine the mechanisms of response to therapy such as chronic red blood cell (cRBC) transfusions. We analyzed baseline (screening), pre-randomization and study exit magnetic resonance angiogram (MRA) images from 10 (5 each from the transfusion and observation arms) pediatric sickle SCD participants in the silent cerebral infarct transfusion (SIT) trial using CFD modeling. We reconstructed the intracranial portion of the internal carotid artery and branches and extracted the geometry using 3D Slicer. We cut specific portions of the large intracranial artery to include segments of the internal carotid, middle, anterior, and posterior cerebral arteries such that the vessel segment analyzed extended from the intracranial beginning of the internal carotid artery up to immediately after (~0.25 inches) the middle cerebral artery branching point. Cut models were imported into Ansys 2021R2/2022R1 and laminar and time-dependent flow simulation was performed. Change in time averaged mean velocity, wall shear stress, and vessel tortuosity were compared between the observation and cRBC arms. We did not observe a correlation between time averaged mean velocity (TAMV) and mean transcranial Doppler (TCD) velocity at study entry. There was also no difference in change in time average mean velocity, wall shear stress (WSS), and vessel tortuosity between the observation and cRBC transfusion arms. WSS and TAMV were abnormal for 2 (developed TIA) out of the 3 participants (one participant had silent cerebral infarctions) that developed neurovascular outcomes. CFD approaches allow for the evaluation of vascular topology and hemodynamics in SCD using MRA images. In this proof of principle study, we show that CFD could be a useful tool and we intend to carry out future studies with a larger sample to enable more robust conclusions. [ABSTRACT FROM AUTHOR]

The goal of curing children and adults with sickle cell disease (SCD) is to maximize benefits and minimize intermediate and long-term adverse outcomes so that individuals can live an average life span with a high quality of life. While greater than 2000 individuals with SCD have been treated with curative therapy, systematic studies have not been performed to evaluate the long-term health effects of hematopoietic stem cell transplant (HSCT) in this population. Individuals with SCD suffer progressive heart, lung, and kidney disease prior to curative therapy. In adults, these sequalae are associated with earlier death. In comparison, individuals who undergo HSCT for cancer are heavily pretreated with chemotherapy, resulting in potential acute and chronic heart, lung, and kidney disease. The long-term health effects on the heart, lung, and kidney for children and adults undergoing HSCT for cancer have been extensively investigated. These studies provide the best available data to extrapolate the possible late health effects after curative therapy for SCD. Future research is needed to evaluate whether HSCT abates, stabilizes, or exacerbates heart, lung, kidney, and other diseases in children and adults with SCD receiving myeloablative and non-myeloablative conditioning regimens for curative therapy. [ABSTRACT FROM AUTHOR]

Haemophilia A carriers have historically been thought to exhibit normal haemostasis. However, recent data demonstrates that, despite normal factor VIII (FVIII), haemophilia A carriers demonstrate an increased bleeding tendency. We tested the hypothesis that obligate haemophilia carriers exhibit an increase in clinically relevant bleeding. 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-100TM and ABO blood type. Forty-four 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 vs. 134%, P < 0.001). Carriers reported a higher number of bleeding events, and both condensed MCMDM-1 VWD bleeding scores (5 vs. 1, P < 0.001) and PBAC scores (423 vs. 182.5, P = 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. [ABSTRACT FROM AUTHOR]

Objectives: Evidence-based practice for stroke prevention in high-income countries involves screening for abnormal transcranial Doppler (TCD) velocity and initiating regular blood transfusions for at least 1 year, followed by treatment with hydroxyurea. This practice has not been transferred to low-resource settings like Nigeria, the country with the highest global population density of SCD. Following a multi-center randomized controlled trial among children with SCA in northern Nigeria, screening for stroke and initiation of hydroxyurea was established as standard of care at the clinical trial sites and other locations. We aim to describe the critical steps we took in translating research into practice for stroke prevention in SCA in Nigeria. Guided by the PRISM framework, we describe how we translated results from a randomized controlled trial for primary prevention of stroke in children with sickle cell anemia into usual care for children with SCA in Kaduna, Nigeria. Results: Findings from this study demonstrate the importance of organizational support and stakeholder involvement from the onset of a clinical trial. Having the dual objective of conducting an efficacy trial while simultaneously focusing on strategies for future implementation can significantly decrease the lag time between discovery and routine practice. [ABSTRACT FROM AUTHOR]

Background: Nigeria has the highest proportion of children with sickle cell anemia (SCA) globally; an estimated 150,000 infants with SCA are born annually. Primary stroke prevention in children with SCA must include Nigeria. We describe capacity-building strategies in conjunction with two National Institutes of Health-funded primary stroke prevention trials (a feasibility trial and phase III randomized controlled trial) with initial hydroxyurea treatment for children with SCA and abnormal transcranial Doppler (TCD) velocities in Nigeria. We anticipated challenges to conducting clinical trials in a low-resource setting with a local team that had not previously been involved in clinical research and sought a sustainable strategy for primary stroke prevention.Methods: This is a descriptive, prospective study of challenges, solutions, and research teams in two trials that enrolled a total of 679 children with SCA.Results: As part of the capacity-building component of the trials, over eight years, 23 research personnel (physicians, nurses, research coordinators, a statistician, and a pharmacist) completed a one-month research governance and ethics training program at Vanderbilt University Medical Center, USA. A lead research coordinator for each site completed the Society of Clinical Research Professionals certification. TCD machines were donated; radiologists and nonradiologists were trained and certified to perform TCD. A scalable E-prescription was implemented to track hydroxyurea treatment. We worked with regional government officials to support ongoing TCD-based screening and funding for hydroxyurea for children with SCA at a high risk of stroke.Conclusions: Our trials and capacity building demonstrate a sustainable strategy to initiate and maintain pediatric SCA primary stroke prevention programs in Africa. [ABSTRACT FROM AUTHOR]

Summary This review will focus on the strengths and limitations associated with the current standard of care for primary prevention of ischaemic strokes in children with sickle cell anaemia (SCA) - transcranial Doppler ultrasound (TCD) screening followed by regular blood transfusion therapy when TCD measurement is above a threshold defined by a randomized clinical trial (RCT). The theoretical basis for potential alternative strategies for primary prevention of neurological injury in SCA is also discussed. These strategies will include, but will not be limited to: immunizations to prevent bacterial infections, particularly in low income countries; management of elevated blood pressure; and targeted strategies to increase baseline haemoglobin levels with therapies such as hyroxycarbamide or potentially definitive haematopoietic stem cell transplant. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease. Methodology/Principal Findings: Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology. Conclusions: These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease. [ABSTRACT FROM AUTHOR]

OBJECTIVES. Primary hemorrhagic stroke is an uncommon complication of sickle cell disease, with reported mortality rates of 24% to 65%. Most reported cases are in adults; little is known about its occurrence in children. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and hypertransfusion. We performed a retrospective case-control study to evaluate risk and prognostic factors for primary hemorrhagic stroke among children with sickle cell disease. PATIENTS AND METHODS. Case subjects (sickle cell disease and primary hemorrhagic stroke) and control subjects (sickle cell disease and ischemic stroke) were identified at 2 children's hospitals from January 1979 to December 2004 by reviewing divisional records and the discharge databases. RESULTS. We identified 15 case subjects (mean age: 10.4 ± 1.3 years) and 29 control subjects (mean age: 5.2 ± 0.4 years). An increased risk of hemorrhagic stroke was associated with a history of hypertension and recent (in the last 14 days) transfusion, treatment with corticosteroids, and possibly nonsteroidal antiinflammatory drugs. Average blood pressures at well visits (adjusted for age and gender) were similar between the 2 groups, suggesting that hypertension was intermittent CONCLUSIONS. In this group of children with sickle cell disease, hemorrhagic stroke was associated with a history of hypertension or antecedent events including transfusion or treatment with corticosteroids. Improved understanding of risk and prognostic factors, especially those that are modifiable, may help prevent this devastating complication in children with sickle cell disease. [ABSTRACT FROM AUTHOR]

Health-related quality of life (HRQL) is an outcome that may be used to measure the impact of sickle cell disease on the child and their family but has not been routinely assessed in this disease. The objective of this study was to describe the HRQL of children with sickle cell disease as reported by the parent and the child, to compare the relationship between the two, and to determine the association of parent, child and disease characteristics on HRQL. Ninety-five parents completed the Child Health Questionnaire (CHQ)-Parent Form28 and 53 children completed the CHQ-Child Form87. Compared with the child report, parents reported worse HRQL in the overall perception of health, physical functioning, behaviour and self esteem domains of HRQL ( P < 0·005). Parent and child reports of HRQL correlated strongly in assessment of the impact of bodily pain ( r = 0·58) on HRQL and moderately in physical functioning ( r = 0·44), behaviour ( r = 0·45), general health ( r = 0·44), self esteem ( r = 0·40) and changes in health ( r = 0·33) domains. Disease status, neurobehavioral co-morbidities, and parent education were associated with the HRQL of the child. Both the parent and child perspectives are needed to fully understand the impact of sickle cell disease on the HRQL of the child and effect of this disease on the family. [ABSTRACT FROM AUTHOR]

Background: Prevalence and contribution of intracranial and extracranial arterial stenosis to stroke risk were assessed prospectively in children and young adults with sickle cell disease.Methods: In this cross-sectional study, children and young adults (mean = 19.4 years) with sickle cell disease underwent neurological examination, brain MRI, and magnetic resonance angiography of the head and neck. Two neuroradiologists independently recorded infarcts and arterial stenosis. Clinical features and stroke outcomes were compared between participants with and without stenosis and between children and young adults. Logistic regression analysis assessed the association of variables of interest with overt stroke and silent cerebral infarct.Results: Of 167 participants (79 children and 88 young adults), 20 (12.0%) had intracranial stenosis, all in the anterior circulation, and nine had concurrent extracranial stenosis. No participants had isolated extracranial stenosis. Participants with intracranial stenosis were more likely than those without stenosis to have an overt stroke (70% vs 5%, P < 0.001) or silent cerebral infarct (95% vs 35%, P < 0.001). Logistic regression analysis indicated that intracranial stenosis was strongly associated with overt stroke when compared with participants with silent cerebral infarct alone and strongly associated with silent cerebral infarct when compared with participants with normal brain MRI; male sex and age were also significant predictors of silent cerebral infarct.Conclusions: Intracranial stenosis was strongly associated with both overt stroke and silent cerebral infarct; prevalence of intracranial stenosis was similar to prior estimates in sickle cell disease. Extracranial stenosis without concurrent intracranial stenosis did not occur and thus could not be evaluated as an independent risk factor for stroke. [ABSTRACT FROM AUTHOR]

Summary: Severe anaemia, defined as haemoglobin level < 6·0 g/dl, is an independent risk factor for death in individuals with sickle cell disease living in resource‐limited settings. We conducted a cross‐sectional study of 941 children with sickle cell anaemia, who had been defined as phenotype HbSS or HbSβ0 thalassaemia, aged five to 12 years, and were screened for enrollment into a large primary stroke prevention trial in Nigeria (SPRING; NCT02560935). The main aim of the study was to determine the prevalence and risk factors for severe anaemia. We found severe anaemia to be present in 3·9% (37 of 941) of the SPRING study participants. Severe anaemia was significantly associated with the lower educational level of the head of the household (P = 0·003), as a proxy for poverty, and a greater number of children per room in the household (P = 0·004). Body mass index was not associated with severe anaemia. The etiology of severe anaemia in children living with sickle cell anaemia in Nigeria is likely to be multifactorial with an interplay between an individual's disease severity and other socio‐economic factors related to poverty. [ABSTRACT FROM AUTHOR]

Objective Recurrent vaso-occlusive pain episodes, the most common complication of sickle cell disease (SCD), cause frequent health care utilization. Studies exploring associations between patient activation and acute health care utilization for pain are lacking. We tested the hypothesis that increased activation and self-efficacy are associated with decreased health care utilization for pain in SCD. Methods In this cross-sectional study of adults with SCD at a tertiary medical center, we collected demographics, SCD phenotype, Patient Activation Measure levels, and self-efficacy scores using structured questionnaires. We reviewed charts to obtain disease-modifying therapy and acute health care utilization, defined as emergency room visits and hospitalizations, for vaso-occlusive pain episodes. Negative binomial regression analyses were used to test the hypothesis. Results We surveyed 67 adults with SCD. The median age was 27.0 years, 53.7% were female, and 95.5% were African American. Median health care utilization for pain over one year (range) was 2.0 (0–24). Only one-third of participants (38.8%) were at the highest activation level (median [range] = 3 [1–4]). Two-thirds (65.7%) of participants had high self-efficacy (median [range] = 32.0 [13–45]). Regressions showed significant association between health care utilization and activation (incidence rate ratio [IRR] = 0.663, P  = 0.045), self-efficacy (IRR = 0.947, P  = 0.038), and male sex (IRR = 0.390, P  = 0.003). Two outliers with high activation, self-efficacy, and health care utilization also had addictive behavior. Conclusions Many individuals with SCD have suboptimal activation and reduced self-efficacy. Higher activation and self-efficacy were associated with lower health care utilization for pain. Additional studies are needed to evaluate interventions to improve activation and self-efficacy and reduce acute health care utilization for pain. [ABSTRACT FROM AUTHOR]

Children with sickle cell anemia (SCA) have elevated cerebral blood velocity relative to healthy peers. The primary aim of this study was to evaluate the association between cerebral blood velocity, measured by transcranial Doppler (TCD) ultrasound, age, and gender with cognitive function in children with SCA in Nigeria. Eighty-three children (Mage = 9.10, SD = 1.90 years; 55% female) with SCA in Nigeria completed cognitive assessments and a TCD ultrasound. The association between TCD velocity and measures of perceptual reasoning (Raven's Progressive Matrices), working memory (WISC-IV Digit Span), and executive planning (Tower of London, TOL) were assessed. Results showed that elevated TCD velocity significantly predicted lower scores on TOL Time Violations and Total Problem-Solving Time when controlling for BMI, hemoglobin level, and parent education, suggesting that TCD velocity is related to the efficiency of executive function. Further, age was negatively related to children's performance on the Ravens Matrices and TOL Total Correct, and boys showed greater deficits on the TOL Total Correct relative to girls. Moderation analyses for gender showed that there was a conditional negative association between TCD velocity and Digit Span for boys, but not for girls. Findings suggest that children with SCA in Nigeria with elevated TCD velocity are at risk for deficits in efficiency of executive planning, and boys with elevated TCD velocity are particularly at increased risk for deficits in auditory working memory. Implications of this study are important for interventions to reduce cerebral blood velocity and the use of TCD in this population. [ABSTRACT FROM AUTHOR]

Background: Although Latinos, African-Americans, and American Indians/Alaska Natives comprise 34% of Americans, these under-represented minorities (URMs) account for only 7% of US medical-school faculty. Even when URMs become faculty, they face many substantial challenges to success. Little has been published, however, on keys to academic success for URM young faculty investigators. Methods: The Research in Academic Pediatrics Initiative on Diversity (RAPID) goal is to enhance the professional advancement of URM junior faculty pursuing research careers in general academic pediatrics. One important RAPID component is the annual mentoring/career-development conference, which targets URM residents, fellows, and junior faculty, and has included 62 URM participants since its 2013 inception. A conference highlight is the panel discussion on keys to academic success for URM young investigators, conducted by the RAPID National Advisory Committee, a diverse group of leading senior researchers. The article aim was to provide a guide to academic success for URM young investigators using the 2018 RAPID Conference panel discussion. A modified Delphi technique was used to provide a systematic approach to obtaining answers to six key questions using an expert panel: the single most important key to success for URM young investigators; ensuring optimal mentorship; how to respond when patients/families say, "I don't want you to see my child because you are ____"; best strategies for maximizing funding success; how to balance serving on time-consuming committees with enough time to advance research/career objectives; and the single thing you wish someone had told you which would have substantially enhanced your success early on. Results/Conclusions: This is the first published practical guide on keys to academic success for URM young investigators. Identified keys to success included having multiple mentors, writing prolifically, being tenaciously persistent, having mentors who are invested in you, dealing with families who do not want you to care for their child because of your race/ethnicity by seeking to understand the reasons and debriefing with colleagues, seeking non-traditional funding streams, balancing committee work with having enough time to advance one's research and career by using these opportunities to generate scholarly products, and asking for all needed resources when negotiating for new jobs. [ABSTRACT FROM AUTHOR]

• Multicenter learning collaborative model of haploidentical bone marrow transplantation (BMT) for sickle cell disease (SCD). • Using haploidentical BMT as curative therapy for SCD increases the donor pool. • Haploidentical BMT with post-transplantation cyclophosphamide (PTCy) plus thiotepa increases donor engraftment in SCD. • Event-free survival and overall survival are improved following haplo-BMT with PTCy plus thiotepa. Comparison of contemporary approaches to hematopoietic bone marrow transplant for severe sickle cell disease. MRD-BMT (Matched Related Donor-Bone Marrow Transplant), based on data from Bernaudin et al. Blood 2007 Oct 1;110(7):2749-56.; MUD-BMT (Matched Unrelated Donor-Bone Marrow Transplant), based on data from Shenoy et al. Blood, 2016. 128(21): p. 2561-2567 and Haplo-BMT (Haploidentical-Bone Marrow Transplant), based on our current data. SCD, Sickle cell disease; EFS, Event free survival; OS, Overall survival, TRM, Transplant related mortality; GVHD, Graft-versus-Host-Disease. Image, graphical abstract Curative therapy for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor has been frustratingly elusive. In with the goal of improving engraftment while minimizing transplantation-related morbidity, a multi-institutional learning collaborative was developed in the context of a Phase II clinical trial of nonmyeloablative, related HLA-haploidentical (haplo) bone marrow transplantation (BMT) with post-transplantation cyclophosphamide. All eligible participants had hemoglobin SS, and 89% (16 of 18) had an identifiable donor. The median patient age was 20.9 years (IQR, 12.1 to 26.0 years), and the most common indication for transplantation was overt stroke (in 69%; 11 of 16). In the first 3 patients, the conditioning regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and low-dose total body irradiation. Graft-versus-host disease (GVHD) prophylaxis included post-transplantation cyclophosphamide, mycophenolate mofetil, and sirolimus. Primary graft rejection occurred in 2 of the 3 patients (67%), which triggered the study-stopping rule. To reduce graft rejection risk, thiotepa was added to the conditioning regimen, and then 15 patients (including 2 with previous graft rejection) underwent haplo-BMT with this thiotepa-augmented conditioning regimen. At a median follow-up of 13.3 months (interquartile range [IQR], 3.8 to 23.1 months), 93% (14 of 15) had >95% stable donor engraftment at 6 months, with 100% overall survival. The median time to neutrophil engraftment (>500) was 22 days (IQR, 19 to 27 days), and that for platelet engraftment (>50 x 109/L) was 28 days (IQR, 27 days to not reached). Two patients had grade III-IV acute GVHD, 1 patient had mild chronic GVHD, and 86% of patients (6 of 7) were off immunosuppression therapy by 1-year post-transplantation. Our data suggest that haplo-BMT with post-transplantation cyclophosphamide and thiotepa improves donor engraftment without significantly increasing morbidity or mortality and could dramatically expand curative options for individuals with SCD. [ABSTRACT FROM AUTHOR]

The article discusses the HbSS and HbSb0 thalassaemia which are two sickle cell disease (SCD) phenotypes that are believed to be so similar in disease severity basing the major paediatric National Institute of Health randomized controlled trials. It states that a significant proportion of children of African descent with HbSb0 thalassaemia are inaccurately diagnosed basing the phenotypic analyses alone.

Objectives: Women with sickle cell disease (SCD) are living longer as a result of advances in the care of their underlying disease. With the population growing of women living with SCD, reproductive health issues in this population have become an emphasized area of medical care. We sought to describe current patterns of contraception use, menstruation, and quality-of-life (QOL) measures in women with SCD.Methods: Using a cross-sectional study design, we administered paper surveys at two academic medical centers to women aged 10 to 55 years with SCD to capture current contraceptive use, characteristics of menstrual cycles, and QOL metrics.Results: Of the 103 women who participated, 12.7% (13/102) experienced a duration of menses >7 days (defined here as prolonged menstrual bleeding). Approximately half of women (51.5%, 53/103) used some form of contraception, with depot medroxyprogesterone acetate injections and condoms being the most common. During their last menstrual periods, women with both dysmenorrhea and prolonged menstrual bleeding (6.9%, 7/102) were more likely to experience more days of poor QOL, with more nights with sleep disturbance (P = 0.001) and more days with trouble taking care of themselves (P = 0.003), as well as being unable to do things they previously enjoyed (P = 0.001), compared with those with neither phenomenon (28.2%, 29/103).Conclusions: Dysmenorrhea and prolonged menstrual bleeding negatively affect the QOL of women with SCD. Menstrual histories and preventive measures for menstruation-related morbidity should be incorporated into routine evaluations of women with SCD. [ABSTRACT FROM AUTHOR]

Background: Acute vaso-occlusive pain episodes in sickle cell disease (SCD) are associated with increased rates of hospitalization and early mortality. Despite the observation that women have higher rates of acute vaso-occlusive pain episodes than men, sex-specific risk factors for acute vaso-occlusive pain have not been identified. We tested the hypothesis that acute vaso-occlusive pain is temporally associated with the onset of menstruation in women with SCD. Methods: Initially, using a cross-sectional study design, we administered questionnaires, including validated measures of SCD pain frequency and severity within the last 30 days, as well as menstrual symptoms in a discovery group (n = 103). We then confirmed our findings by administering the same questionnaires online in a replication group (n = 118). A validated questionnaire was used to define dysmenorrhea. Results: In the initial discovery group, 28% (29 of 103) reported acute vaso-occlusive pain episodes temporally associated with menstruation, and 72% (74 of 103) did not. Of the 29 reporting acute vaso-occlusive pain associated with menstruation, 90% (26) and 10% (3) did and did not meet criteria for dysmenorrhea, respectively. In the replication group, 36% (43 of 118) reported acute vaso-occlusive pain temporally associated with menstruation. Of the 43 reporting acute vaso-occlusive pain associated with menstruation, 60% (26) and 40% (17) did and did not meet criteria for dysmenorrhea, respectively. Conclusions: In both the discovery and replication groups, we demonstrate that acute vaso-occlusive pain is temporally associated with the onset of menstruation that women with SCD can distinguish from dysmenorrhea. [ABSTRACT FROM AUTHOR]