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Detecting silent cerebral infarcts on magnetic resonance images (MRIs) in children with sickle cell anemia is challenging, yet reproducibility of readings has not been examined in this population. We evaluated consensus rating, inter-, and intra-grader agreement associated with detecting silent cerebral infarct on screening MRI in the Silent Infarct Transfusion Trial. Three neuroradiologists provided consensus decisions for 1073 MRIs. A random sample of 53 scans was reanalyzed in blinded fashion. Agreement between first and second consensus ratings was substantial (κ = 0.70, P < .0001), as was overall intergrader agreement (κ = 0.76, P < .0001). In the test-retest sample, intragrader agreement ranged from κ of 0.57 to 0.76. Consensus decisions were more concordant when MRIs contained more than one larger lesions. Routine use of MRI to screen for silent cerebral infarcts in the research setting is reproducible in sickle cell anemia and agreement among neuroradiologists is sufficient. [ABSTRACT FROM PUBLISHER]

In children, levels of play, physical activity, and fitness are key indicators of health and disease and closely tied to optimal growth and development. Cardiopulmonary exercise testing (CPET) provides clinicians with biomarkers of disease and effectiveness of therapy, and researchers with novel insights into fundamental biological mechanisms reflecting an integrated physiological response that is hidden when the child is at rest. Yet the growth of clinical trials utilizing CPET in pediatrics remains stunted despite the current emphasis on preventative medicine and the growing recognition that therapies used in children should be clinically tested in children. There exists a translational gap between basic discovery and clinical application in this essential component of child health. To address this gap, the NIH provided funding through the Clinical and Translational Science Award (CTSA) program to convene a panel of experts. This report summarizes our major findings and outlines next steps necessary to enhance child health exercise medicine translational research. We present specific plans to bolster data interoperability, improve child health CPET reference values, stimulate formal training in exercise medicine for child health care professionals, and outline innovative approaches through which exercise medicine can become more accessible and advance therapeutics across the broad spectrum of child health. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is a genetic disorder characterized by complex pathophysiological mechanisms leading to vaso-occlusive crisis, chronic pain, chronic hemolytic anemia, and vascular complications, which require considerations for exercise and physical activity. This review aims to elucidate the safety, potential benefits, and recommendations regarding exercise and training in individuals with SCD. SCD patients are characterized by decreased exercise capacity and tolerance. Acute intense exercise may be accompanied by biological changes (acidosis, increased oxidative stress, and dehydration) that could increase the risk of red blood cell sickling and acute clinical complications. However, recent findings suggest that controlled exercise training is safe and well tolerated by SCD patients and could confer benefits in disease management. Regular endurance exercises of submaximal intensity or exercise interventions incorporating resistance training have been shown to improve cardiorespiratory and muscle function in SCD, which may improve quality of life. Recommendations for exercise prescription in SCD should be based on accurate clinical and functional evaluations, taking into account disease phenotype and cardiorespiratory status at rest and in response to exercise. Exercise programs should include gradual progression, incorporating adequate warm-up, cool-down, and hydration strategies. Exercise training represents promising therapeutic strategy in the management of SCD. It is now time to move through the investigation of long-term biological, physiological, and clinical effects of regular physical activity in SCD patients., (© 2024 Wiley Periodicals LLC.)

Cardiopulmonary exercise testing (CPET) provides clinicians with information vital to the management of pediatric cardiology patients. CPET can also be used to measure cardiorespiratory fitness (CRF) in these patients. CRF is a robust marker of overall health in children. However, a complete understanding of CRF in pediatric cardiology patients is limited by lack of large, standardized CPET databases. Our purpose was to develop a standardized CPET database, describe available data at our institution, and discuss challenges and opportunities associated with this project. CPETs performed from 1993 to present in an urban pediatric hospital were collected and compiled into a research database. Historical data included demographic and clinical variables and CPET outcomes, and additional variables were calculated and coded to facilitate analyses in these cohorts. Patient diagnoses were coded to facilitate sub-analyses of specific cohorts. Quality assurance protocols were established to ensure future database contributions and promote inter-institutional collaborations. This database includes 10,319 CPETs (56.1% male), predominantly using the Bruce Protocol. Patients ranging from ages 6 to 18 years comprise 86.8% of available CPETs. Diagnosis classification scheme includes patients with structurally normal hearts (n = 3,454), congenital heart disease (n = 3,614), electrophysiological abnormalities (n = 2,082), heart transplant or cardiomyopathy (n = 833), and other diagnoses (n = 336). Historically, clinicians were provided with suboptimal interpretive resources for CPET, often generalizing inferences from these resources to non-representative clinical populations. This database supports representative CRF comparisons and establishes a framework for future CRF-based registries in pediatric patients referred for CPET, ultimately improving clinical decision-making regarding fitness in these populations., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sickle cell anaemia (SCA) patients display elevated levels of circulating pro-inflammatory cytokines and endothelial activation markers compared to healthy peers. The impact of exercise on the pro-inflammatory state in SCA remains unclear. This study aimed to characterize the whole-blood transcriptome profile in response to an acute bout of exercise in paediatric SCA patients. Twenty-three SCA participants (13 ± 3 years, 52% girls) and 17 healthy controls (14 ± 3 years, 29% girls) performed eight 2-min bouts of cycle ergometry interspersed with 1-min rest intervals. Whole-blood transcriptome profile (RNA-seq) was performed before and after exercise. At baseline, gene pathways associated with gas transport in erythrocytes were up-regulated in SCA patients compared to controls. Following exercise, gene pathways associated with innate immunity were altered in both groups. Interaction analyses revealed 160 annotated genes (101 up- and 59 down-regulated) that differentially altered by exercise in SCA patients. Moreover, genes that exhibited a blunted response to exercise in SCA patients were enriched in the IL-17 signalling pathway, suggesting an impaired innate immune response to exercise. This data will contribute to the development of evidence-based exercise prescription guidelines for this patient population., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A ., Methods: We conducted a phase 3, single-group, open-label study of exa-cel in patients 12 to 35 years of age with sickle cell disease who had had at least two severe vaso-occlusive crises in each of the 2 years before screening. CD34+ HSPCs were edited with the use of CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary end point was freedom from inpatient hospitalization for severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed., Results: A total of 44 patients received exa-cel, and the median follow-up was 19.3 months (range, 0.8 to 48.1). Neutrophils and platelets engrafted in each patient. Of the 30 patients who had sufficient follow-up to be evaluated, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months, and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers occurred., Conclusions: Treatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. (CLIMB SCD-121; ClinicalTrials.gov number, NCT03745287.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis through ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of the erythroid-specific enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs)., Methods: We conducted an open-label, single-group, phase 3 study of exa-cel in patients 12 to 35 years of age with transfusion-dependent β-thalassemia and a β 0 /β 0 , β 0 /β 0 -like, or non-β 0 /β 0 -like genotype. CD34+ HSPCs were edited by means of CRISPR-Cas9 with a guide mRNA. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was transfusion independence, defined as a weighted average hemoglobin level of 9 g per deciliter or higher without red-cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed., Results: A total of 52 patients with transfusion-dependent β-thalassemia received exa-cel and were included in this prespecified interim analysis; the median follow-up was 20.4 months (range, 2.1 to 48.1). Neutrophils and platelets engrafted in each patient. Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence occurred in 32 (91%; 95% confidence interval, 77 to 98; P<0.001 against the null hypothesis of a 50% response). During transfusion independence, the mean total hemoglobin level was 13.1 g per deciliter and the mean fetal hemoglobin level was 11.9 g per deciliter, and fetal hemoglobin had a pancellular distribution (≥94% of red cells). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred., Conclusions: Treatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent β-thalassemia. (Supported by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-111 ClinicalTrials.gov number, NCT03655678.)., (Copyright © 2024 Massachusetts Medical Society.)

Pediatric patients are often referred to cardiopulmonary exercise testing (CPET) laboratories for assessment of exercise-related symptoms. For clinicians to understand results in the context of performance relative to peers, adequate fitness-based prediction equations must be available. However, reference equations for prediction of peak oxygen uptake (VO 2peak ) in pediatrics are largely developed from field-based testing, and equations derived from CPET are primarily developed using adult data. Our objective was to develop a pediatric reference equation for VO 2peak . Clinical CPET data from a validation cohort of 1,383 pediatric patients aged 6 to 18 years who achieved a peak respiratory exchange ratio ≥1.00 were analyzed to identify clinical and exercise testing factors that contributed to the prediction of VO 2peak from tests performed using the Bruce protocol. The resultant prediction equation was applied to a cross-validation cohort of 1,367 pediatric patients. Exercise duration, gender, weight, and age contributed to the prediction of VO 2peak , generating the following prediction equation: (R 2  = 0.645, p <0.001, standard error of the estimate = 6.19 ml/kg/min): VO 2peak (ml/kg/min) =16.411+ 3.423 (exercise duration [minutes]) - 5.145 (gender [0 = male, 1 = female]) - 0.121 (weight [kg]) + 0.179 (age [years]). This equation was stable across the age range included in the present study, with differences ≤0.5 ml/kg/min between mean measured and predicted VO 2peak in all age groups. In conclusion, this study represents what we believe is the largest pediatric CPET-derived VO 2peak prediction effort to date, and this VO 2peak prediction equation provides clinicians who perform and interpret exercise tests in pediatric patients with a resource with which to better quantify fitness when CPET is not available., Competing Interests: Declaration of Competing Interest The authors have no competing interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To develop reference values for cardiorespiratory fitness, as quantified by peak oxygen uptake (VO 2peak ) and treadmill time, in patients aged 6 through 18 years referred for cardiopulmonary exercise testing (CPET)., Study Design: We reviewed a clinical pediatric CPET database for fitness data in children aged 6-18 years with no underlying heart disease. CPET was obtained via the Bruce protocol utilizing objectively confirmed maximal effort via respiratory exchange ratio. Fitness data (VO 2peak and treadmill test duration) were analyzed to determine age- and sex-specific reference values for this pediatric cohort., Results: Data from 2025 pediatric CPETs (53.2% female) were included in the analyses. VO 2peak increased with age in males, but not females. Treadmill test duration increased with age in both males and females. Fitness was generally higher in males when compared with females in the same age groups., Conclusions: Our study provides extensive reference values for both VO 2peak and total treadmill test time via the Bruce protocol for a pediatric population without known cardiac disease. Furthermore, the inclusion of objectively confirmed maximal exercise effort increases confidence in these findings compared with prior studies in this area. Clinicians performing CPET in pediatric populations can utilize these reference values to characterize test results according to representative peer data., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The electronic health record, data science advances, and dynamic environmental and infectious threats to child health highlight the need for harmonized and interoperable approaches to pediatric cardiopulmonary exercise testing (CPET). Accordingly, we developed a terminology harmonization in exercise medicine and exercise science domain analysis model (THEMES DAM) to structure CPET data elements., Methods: THEMES DAM identified 114 data elements, including participant information, calibration, equipment, protocols, laboratory personnel, encouragement strategies, and analysis procedures. We used the THEMES DAM, vetted by the international data standards organization HL7, to construct a current-state survey of pediatric CPET centers in the United States. Forty-eight of 101 centers responded to a questionnaire covering seven major topic areas (38 items)., Results: Centers predominantly performed between 100 and 500 tests annually. Cardiac disease represented 55% of referrals. Almost all centers calibrated gas concentrations and flow daily, but 42% never calibrated their treadmill or cycle ergometers. All centers measured V̇O2peakbut calculated differently. Centers used a variety of protocols (e.g., for treadmill: 61%, Bruce; 43%, modified Bruce; 59%, other); 44% calculated CPET slopes from submaximal portions of CPET (e.g., V̇O2-HR). All centers verbally encouraged participants, but only 40% used a standardized approach. The interpretation of CPET was done by physicians (60%), exercise physiologists (25%), exercise technicians (10%), nurses (1%), or others (4%). Ninety-one percent would agree to collaborate in multicenter research, 89% to establish dynamic reference values, and 83% to better interpret CPET., Conclusions: The survey data and the implementation of THEMES DAM could accelerate interoperability across multiple centers. This would facilitate a nimble approach to create pediatric reference values responsive to the constantly changing health environment and stimulate novel approaches to CPET research and clinical application., (Copyright © 2022 by the American College of Sports Medicine.)

Background: Critically ill infants are susceptible to thrombosis due to several risk factors. The aim of this study was to identify risk factors associated with venous and arterial thrombosis in neonates admitted to the neonatal intensive care unit (NICU) and to identify differences in risk factors for venous versus arterial thrombosis., Methods: We conducted a case-control study at 31 level IV NICUs using the Children's Hospital Neonatal Database between Jan 1, 2010, and Dec 13, 2016, in the USA. Cases were identified on the basis of having an outcome of venous or arterial thrombosis. Controls were matched by gestational age, presence of a central access device (CAD), hospital, and admission year. Four controls per case (1:4) were randomly selected. Bivariable and multivariable regression analyses were performed to examine the associations between potential risk factors and venous or arterial thrombosis. CAD-related risk factors were analysed in the subset of neonates with a CAD., Findings: We identified 118 952 new admissions to 31 NICUs. The overall thrombosis incidence was 15·5 per 1000 NICU admissions (95% CI 14·8-16·2). After exclusion of patients with a length of hospitalisation longer than 3 days or heart disease, the study included 1326 thrombosis cases (1022 with venous thrombosis and 362 with arterial thrombosis; 58 patients had both types of thrombosis and are included within both of these numbers) and 5304 randomly selected controls. Venous thrombosis was independently associated with bloodstream infection (odds ratio 2·07, 95% CI 1·72-2·49; p<0·0001), maternal diabetes (1·62, 1·30-2·03; p<0·0001), abdominal or gastrointestinal surgery (1·36, 1·17-1·58; p<0·0001), thrombocytopenia (2·44, 2·02-2·94; p<0·0001), prolonged mechanical ventilation (1·27, 1·10-1·46; p=0·0014), and age 7 days or older at admission (1·49, 1·28-1·74; p<0·0001). Arterial thrombosis was independently associated with maternal hypertension (1·42, 1·05-1·91; p=0·030), thrombocytopenia (2·20, 1·59-3·06; p<0·0001), prolonged mechanical ventilation (1·58, 1·24-2·01; p=0·0002), age 7 days or older at admission (1·35, 1·05-1·74; p=0·0018), and small for gestational age (1·56, 1·13-2·16; p=0·0003). In the CAD subset analysis, CAD duration of 21 days or longer (venous thrombosis: 1·52, 1·15-2·01, p=0·0034; arterial thrombosis: 1·98, 1·25-3·14, p=0·035) and CAD in both the upper and lower body (venous thrombosis: 2·43, 1·92-3·08, p<0·0001; arterial thrombosis: 1·58, 1·02-2·45, p=0·040) were associated with higher odds of thrombosis., Interpretation: Identification of thrombosis-associated risk factors will be useful in developing a risk prediction model to prevent thrombosis and in improving outcomes. The study results add to the knowledge of the differences in risk factors for venous versus arterial thrombosis in neonates and to the understanding of the associations of CAD characteristics with neonatal thrombosis., Funding: Bristol-Myers Squibb-Pfizer Alliance., Competing Interests: Declaration of interests RB received an investigator-initiated grant from Bristol-Myers Squibb–Pfizer Alliance for this study, and travel support from Bristol-Myers Squibb–Pfizer Alliance to present the study at the International Society on Thrombosis and Haemostasis 2020. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Sickle cell disease (SCD) is a life-limiting inherited hemoglobinopathy that results in significant complications and affects quality of life. Hematopoietic stem cell transplantation (HSCT) is currently the only curative intervention for SCD; however, guidelines are needed to inform how to apply HSCT in clinical practice., Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and health professionals in their decisions about HSCT for SCD., Methods: The multidisciplinary guideline panel formed by ASH included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews (through 2019). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment., Results: The panel agreed on 8 recommendations to help patients and providers assess how individuals with SCD should consider the timing and type of HSCT., Conclusions: The evidence review yielded no randomized controlled clinical trials for HSCT in SCD; therefore, all recommendations are based on very low certainty in the evidence. Key recommendations include considering HSCT for those with neurologic injury or recurrent acute chest syndrome at an early age and to improve nonmyeloablative regimens. Future research should include the development of a robust SCD registry to serve as a comparator for HSCT studies., (© 2021 by The American Society of Hematology.)

Patients with sickle cell disease (SCD) and thalassemia experience several complications across their lifespan that lead to impairment in different health-related quality of life (HRQOL) domains. There is increasing interest in curative therapies for patients with SCD and thalassemia, including hematopoietic stem cell transplant (HSCT) and gene therapy; however, the effect of these therapies on various HRQOL domains remains unclear. Our objective was to systematically evaluate the most recent evidence for the effect of HSCT and gene therapy on HRQOL in patients with SCD and thalassemia. A systematic search of medical literature databases was conducted. A total of 16 studies (thalassemia, n = 9; SCD, n = 6; both, n = 1) involving 517 participants met inclusion criteria (thalassemia, n = 416; SCD, n = 101). HSCT was associated with a small to large positive effects in most HRQOL domains (Cohen's d; mean = 0.47; median = 0.37; range, 0.27-2.05). In thalassemia, HSCT was frequently associated with large positive effects in physical and emotional HRQOL domains (median d = 0.79 and d = 0.57, respectively). In SCD, HSCT was associated with large positive effects in all HRQOL domains. Emerging data suggest improvement in HRQOL outcomes across different domains following gene therapy in thalassemia and SCD. The quality of evidence was moderate in 13 studies (81%). HSCT has a positive impact on several HRQOL domains in patients with SCD and thalassemia; however, more longitudinal studies are warranted to assess the sustainability of these effects. Reporting HRQOL outcomes from ongoing gene therapy or gene-editing trials in SCD and thalassemia is key to better understand the benefits of such therapies., (© 2021 by The American Society of Hematology.)

Purpose: Sickle cell disease (SCD) is associated with high acute healthcare utilization. The purpose of this study was to examine whether Medicaid expansion in California increased Medicaid enrollment, increased hydroxyurea prescriptions filled, and decreased acute healthcare utilization in SCD., Methods: Individuals with SCD (≤65 years and enrolled in Medicaid for ≥6 total calendar months any year between 2011 and 2016) were identified in a multisource database maintained by the California Sickle Cell Data Collection Program. We describe trends and changes in Medicaid enrollment, hydroxyurea prescriptions filled, and emergency department (ED) visits and hospital admissions before (2011-2013) and after (2014-2016) Medicaid expansion in California., Results: The cohort included 3635 individuals. Enrollment was highest in 2014 and lowest in 2016 with a 2.8% annual decease postexpansion. Although <20% of the cohort had a hydroxyurea prescription filled, the percentage increased by 5.2% annually after 2014. The ED visit rate was highest in 2014 and decreased slightly in 2016, decreasing by 1.1% annually postexpansion. Hospital admission rates were similar during the pre- and postexpansion periods. Young adults and adults had higher ED and hospital admission rates than children and adolescents., Conclusions: Medicaid expansion does not appear to have improved enrollment or acute healthcare utilization among individuals with SCD in California. Future studies should explore whether individuals with SCD transitioned to other insurance plans or became uninsured postexpansion, the underlying reasons for low hydroxyurea utilization, and the lack of effect on hospital admissions despite a modest effect on ED visits., (© 2020 Wiley Periodicals, Inc.)

The American Society of Hematology (ASH) convened 5 guideline panels to develop clinical practice recommendations addressing 5 management areas of highest importance to individuals living with sickle cell disease: pain, cerebrovascular complications, pulmonary and kidney complications, transfusion, and hematopoietic stem cell transplant. Panels were multidisciplinary and consisted of patient representatives, content experts, and methodologists. The Mayo Clinic Evidence-Based Practice Center conducted systematic reviews based on a priori selected questions. In this exposition, we describe the process used by ASH, including the GRADE approach (Grades of Recommendations, Assessment, Development and Evaluation) for rating certainty of the evidence and the GRADE Evidence to Decision Framework. We also describe several unique challenges faced by the guideline panels and the specific innovations and solutions used to address them, including a curriculum to train patients to engage in guideline development, dealing with the opioid crisis, and working with indirect and noncomparative evidence.

Background: Prevention and management of end-organ disease represent major challenges facing providers of children and adults with sickle cell disease (SCD). Uncertainty and variability in the screening, diagnosis, and management of cardiopulmonary and renal complications in SCD lead to varying outcomes for affected individuals., Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD., Methods: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews up to September 2017. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment., Results: The panel agreed on 10 recommendations for screening, diagnosis, and management of cardiopulmonary and renal complications of SCD. Recommendations related to anticoagulation duration for adults with SCD and venous thromboembolism were also developed., Conclusions: Most recommendations were conditional due to a paucity of direct, high-quality evidence for outcomes of interest. Future research was identified, including the need for prospective studies to better understand the natural history of cardiopulmonary and renal disease, their relationship to patient-important outcomes, and optimal management., (© 2019 by The American Society of Hematology.)

Acute chest syndrome (ACS) and transfusion requirements are common and difficult to predict during hospitalizations for acute vaso-occlusive episodes (VOE) among individuals with sickle cell disease (SCD). This study examined the relationship between nucleated red blood cell (NRBC) counts during hospitalization for VOE and development of ACS or transfusion requirement among children with SCD. Retrospective chart review was performed for 264 encounters of patients with SCD hospitalized for uncomplicated VOE who had NRBC count data at admission during a 5-year period. Multivariable logistic regression analysis was conducted to determine the relationship of admission and change in NRBC ([INCREMENT]NRBC) to ACS/transfusion requirement. Overall, 44 of 264 (16.7%) encounters resulted in ACS, transfusion, or both. Admission NRBC was not associated with development of ACS/transfusion requirement. Among 125 of 264 (47.3%) encounters in which a subsequent CBC was obtained, greater increases in NRBCs and greater decrease in hemoglobin were significantly associated with ACS/transfusion requirement (OR, 2.72; 95% CI, 1.16, 6.35; P=0.02 and OR, 2.52; 95% CI, 1.08, 5.89; P=0.03, respectively). Our finding that an increase in NRBC counts was associated with development of ACS/transfusion requirement suggests that [INCREMENT]NRBCs may represent a useful biomarker for predicting complications in children with SCD hospitalized for VOE.

Background: Hydroxyurea reduces complications and improves health-related quality of life (HRQOL) in sickle cell disease (SCD) patients, however adherence remains suboptimal. Understanding patients' views of hydroxyurea is critical to optimize adherence, particularly in adolescents and young adults (AYA). Study objectives were to assess beliefs about hydroxyurea using the Beliefs about Medicines Questionnaire (BMQ), and to examine the relationship of patients' beliefs to their hydroxyurea adherence and HRQOL., Methods: Thirty-four AYA with SCD participated in a cross-sectional study January-December 2015. Study assessments included BMQ to examine beliefs about hydroxyurea; Visual Analogue Scale (VAS) to assess hydroxyurea adherence; and Patient Reported Outcomes Measurement Information System (PROMIS®) to evaluate HRQOL., Results: Participants (41% female, 91% Black) had median age of 13.5 (IQR 12-18) years. Participants' concerns about overuse of medications correlated with concerns about hydroxyurea (r s  = 0.36, p = 0.04) and overall harm of medications (r s  = 0.5, p = 0.003). Participants' age positively correlated with the necessity of hydroxyurea (r s  = 0.45, p = 0.007). Participants' concerns about hydroxyurea and overuse of medications positively correlated with anxiety (r s  = 0.41, p = 0.02; r s  = 0.44, p = 0.01) and depression (r s  = 0.37, p = 0.04; r s  = 0.54, p = 0.001), but inversely correlated with peer relationships (r s  = -0.45, p = 0.03; r s  = -0.44, p = 0.03), respectively, suggesting better HRQOL with concerns. Fifty percent of participants reported low hydroxyurea adherence (VAS < 80%), which was more seen in patients with higher concerns about hydroxyurea (p = 0.02)., Conclusions: Beliefs about hydroxyurea correlated with HRQOL scores and adherence levels. Addressing patients' concern about hydroxyurea and medications overall as well as routine assessment of adherence and beliefs could help to overcome adherence barriers., (Copyright © 2018 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Objective: To identify risk factors associated with venous and arterial thrombosis in sick neonates admitted to the neonatal intensive care unit., Study Design: A case-control study was conducted at 2 centers between January 2010 and March 2014 using the Children's Hospital Neonatal Database dataset. Cases were neonates diagnosed with either arterial or venous thrombosis during their neonatal intensive care unit stay; controls were matched in a 1:4 ratio by gestational age and presence or absence of central access devices. Bivariable and conditional logistic regression analyses for venous and arterial thrombosis were performed separately., Results: The overall incidence of neonatal thrombosis was 15.0 per 1000 admissions. A higher proportion of neonates with thrombosis had presence of central vascular access devices (75% vs 49%; P < .01) were of extremely preterm gestational age (22-27 weeks; 26% vs 15.0%; P <.05) and stayed ≥31 days in the neonatal intensive care unit (53% vs 32.9%; P <.01), when compared with neonates without thrombosis. A final group of 64 eligible patients with thrombosis and 4623 controls were analyzed. In a conditional multivariable logistic regression model, venous thrombosis was significantly associated with male sex (AOR, 2.12; 95% CI, 1.03-4.35; P = .04) and blood stream infection (AOR, 3.47; 95% CI, 1.30-9.24; P = .01)., Conclusions: The incidence of thrombosis was higher in our neonatal population than in previous reports. After matching for central vascular access device and gestational age, male sex and blood stream infection represent independent risk factors of neonatal venous thrombosis. A larger cohort gleaned from multicenter data should be used to confirm the study results and to develop thrombosis prevention strategies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The contribution of sickle cell trait (SCT) to racial disparities in cardiopulmonary fitness is not known, despite concerns that SCT is associated with exertion-related sudden death. We evaluated the association of SCT status with cross-sectional and longitudinal changes in fitness and risk for hypertension, diabetes, and metabolic syndrome over the course of 25 years among 1995 African Americans (56% women, 18-30 years old) in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Overall, the prevalence of SCT was 6.8% (136/1995) in CARDIA, and over the course of 25 years, 46% (738/1590), 18% (288/1631), and 40% (645/1,611) of all participants developed hypertension, diabetes, and metabolic syndrome, respectively. Compared with participants without SCT, participants with SCT had similar baseline measures of fitness in cross-section, including exercise duration (535 vs 540 seconds; P = .62), estimated metabolic equivalent of tasks (METs; 11.6 vs 11.7; P = .80), maximum heart rate (174 vs 175 beats/min; P = .41), and heart rate at 2 minutes recovery (44 vs 43 beats/min; P = .28). In our secondary analysis, there was neither an association of SCT status with longitudinal changes in fitness nor an association with development of hypertension, diabetes, or metabolic syndrome after adjustment for sex, baseline age, body mass index, fitness, and physical activity. SCT is not associated with reduced fitness in this longitudinal study of young African American adults, suggesting the increased risk for exertion-related sudden death in SCT carriers is unlikely related to fitness. SCT status also is not an independent risk factor for developing hypertension, diabetes, or metabolic syndrome., (© 2017 by The American Society of Hematology.)

Peak oxygen uptake (peak V ˙ O 2 ) measured by clinical exercise testing is the benchmark for aerobic fitness. Aerobic fitness, estimated from maximal treadmill exercise, is a predictor of mortality in adults. Peak V ˙ O 2 was shown to predict longevity in patients aged 7-35 years with cystic fibrosis over 25 years ago. A surge of exercise studies in young adults with congenital heart disease over the past decade has revealed significant prognostic information. Three years ago, the first clinical trial in children with pulmonary arterial hypertension used peak V ˙ O 2 as an endpoint that likewise delivered clinically relevant data. Cardiopulmonary exercise testing provides clinicians with biomarkers and clinical outcomes, and researchers with novel insights into fundamental biological mechanisms reflecting an integrated physiological response hidden at rest. Momentum from these pioneering observations in multiple disease states should impel clinicians to employ similar methods in other patient populations; e.g., sickle cell disease. Advances in pediatric exercise science will elucidate new pathways that may identify novel biomarkers. Our initial aim of this essay is to highlight the clinical relevance of exercise testing to determine peak V ˙ O 2 , and thereby convince clinicians of its merit, stimulating future clinical investigators to broaden the application of exercise testing in pediatrics., Competing Interests: The authors declare that they have no competing interests.

Although individuals with sickle cell anaemia (SCA) have elevated baseline inflammation and endothelial activation, the acute phase response to maximal exercise has not been evaluated among children with SCA. We measured the acute phase response to maximal exercise testing for soluble vascular cell adhesion molecule (sVCAM) as well as interleukin 6 (IL6), total white blood cell (WBC) count, C-reactive protein (CRP) and D-dimer in a cohort of children with SCA and matched controls at baseline, immediately after, and 30, 60 and 120 min following exercise. Despite higher baseline levels of all biomarkers except CRP, the acute phase response from baseline to immediately after exercise was significantly greater in subjects versus controls for CRP (2·1 vs. 0·2 mg/l, P = 0·02) and D-dimer (160 vs. 10 μg/l, P < 0·01) only. Similar between-group trends were observed over time for all biomarkers, including sVCAM, IL6, total WBC, CRP and D-dimer. Lower fitness, defined by peak oxygen consumption (VO2 ), was independently associated with greater acute phase responses to exercise for sVCAM. Our results suggest maximal exercise may not be associated with any greater escalation of endothelial activation or inflammation in SCA and provide preliminary biomarker evidence for the safety of brief, high-intensity physical exertion in children with SCA., (© 2015 John Wiley & Sons Ltd.)

Background: Few studies have investigated factors influencing participation rates for minority children with a chronic disease in clinical trials. The Silent Cerebral Infarct Multi-Center Clinical (SIT) Trial provides an opportunity to study the impact of demographic and socio-economic factors on randomization in a clinical trial among Black children. Our primary objective was to characterize the factors associated with successful randomization of children with sickle cell disease (SCD) and silent cerebral infarct (SCI) in the SIT Trial after initial consent., Procedure: Differences in socio-economic and demographic variables, family history and disease-related variables were determined between eligible participants who were successfully randomized and those who were not randomized following initial consent. Head of household educational level and family income were examined separately for US versus non-US sites., Results: Of 1,176 children enrolled in the SIT Trial, 1,016 (86%) completed screening. Of 208 (20%) children with qualifying SCI on pre-randomization MRI, 196 (94%) were successfully randomized. There were no differences in socio-economic, demographic, or disease-related variables between children who were or were not randomized. Participants from non-US sites were more likely to be randomized (22% vs. 12%, P = 0.011); although, randomization by country was associated with neither head of household education nor family income., Conclusion: In the SIT Trial, acceptance of random allocation was not associated with socio-economic or demographic factors. Although these factors may represent barriers for some participants, they should not bias investigators caring for children with SCD in their approach to recruitment for clinical trial participation., (© 2014 Wiley Periodicals, Inc.)

Tricuspid regurgitant jet velocity (TRJV) >or= 2.5 m/sec. on echocardiography is a surrogate marker for pulmonary hypertension (PHT) in adults with sickle cell disease (SCD). We prospectively examined the relationship between TRJV and laboratory markers of hemolysis in 51 children and young adults with SCD at baseline. We found significant correlations between TRJV and lactate dehydrogenase (LDH), hemoglobin (Hb), reticulocyte count (retic) and aspartate aminotransferase (AST). LDH, retic and AST were significantly higher and Hb was lower in subjects with TRJV >or= 2.5 m/sec. We conclude that hemolysis significantly contributes to TRJV elevation in children and young adults with SCD.

Alpha-hemoglobin-stabilizing protein (AHSP) is an erythroid protein that binds and stabilizes alpha-hemoglobin during normal erythropoiesis and in pathological states of alpha-hemoglobin excess. AHSP has been proposed as a candidate gene in some Heinz body hemolytic anemias and as a modifier gene in the beta-thalassemia syndromes. To gain additional insight into the molecular mechanisms controlling the erythroid-specific expression of the AHSP gene and provide the necessary tools for further genetic studies of these disorders, we have initiated identification and characterization of the regulatory elements controlling the human AHSP gene. We mapped the 5'-end of the AHSP erythroid cDNA and cloned the 5'-flanking genomic DNA containing the putative AHSP gene promoter. In vitro studies using transfection of promoter/reporter plasmids in human tissue culture cell lines, DNase I footprinting analyses and gel mobility shift assays, identified an AHSP gene erythroid promoter with functionally important binding sites for GATA-1- and Oct-1-related proteins. In transgenic mice, a reporter gene directed by a minimal human AHSP promoter was expressed in bone marrow, spleen, and reticulocytes, but not in nonerythroid tissues. In vivo studies using chromatin immunoprecipitation assays demonstrated hyperacetylation of the promoter region and occupancy by GATA-1. The AHSP promoter is an excellent candidate region for mutations associated with decreased AHSP gene expression.