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Summary 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Transfusional iron overload represents a substantial challenge in the management of patients with sickle cell disease ( SCD) who receive chronic or episodic red blood cell transfusions. Iron-induced cardiomyopathy is a leading cause of death in other chronically transfused populations but rarely seen in SCD. Study objectives were to: (i) examine the extent of myocardial and hepatic siderosis using magnetic resonance imaging ( MRI) in chronically transfused SCD patients, and (ii) evaluate the relationship between long-term (over the 5 years prior to enrolment) mean serum ferritin ( MSF), spot-ferritin values and liver iron content ( LIC) measured using MRI and liver biopsy. Thirty-two SCD patients (median age 15 years) with transfusional iron overload were recruited from two U.S. institutions. Long-term MSF and spot-ferritin values significantly correlated with LIC by MRI-R2* ( r = 0·77, P < 0·001; r = 0·82, P < 0·001, respectively). LIC by MRI-R2* had strong positive correlation with LIC by liver biopsy ( r = 0·98, P < 0·001) but modest inverse correlation with cardiac MRI-T2* ( r = −0·41, P = 0·02). Moderate to severe transfusional iron overload in SCD was not associated with aberrations in other measures of cardiac function based on echocardiogram or serum biomarkers. Our results suggest that SCD patients receiving chronic transfusions may not demonstrate significant cardiac iron loading irrespective of ferritin trends, LIC and erythropoiesis suppression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Physiologic contributors to reduced exercise capacity in individuals with sickle cell anemia (SCA) are not well understood. The objective of this study was to characterize the cardiopulmonary response to maximal cardiopulmonary exercise testing (CPET) and determine factors associated with reduced exercise capacity among children and young adults with SCA. A cross-sectional cohort of 60 children and young adults (mean 15.1 ± 3.4 years) with hemoglobin SS or S/β0 thalassemia and 30 matched controls (mean 14.6 ± 3.5 years) without SCA or sickle cell trait underwent maximal CPET by a graded, symptom-limited cycle ergometry protocol with breath-by-breath, gas exchange analysis. Compared to controls without SCA, subjects with SCA demonstrated significantly lower peak VO2 (26.9 ± 6.9 vs. 37.0 ± 9.2 mL/kg/min, P < 0.001). Subjects demonstrated slower oxygen uptake (ΔVO2/ΔWR, 9 ± 2 vs. 12 ± 2 mL/min/watt, P < 0.001) and lower oxygen pulse (ΔVO2/ΔHR, 12 ± 4 vs. 20 ± 7 mL/beat, P < 0.001) as well as reduced oxygen uptake efficiency (Δ VE/ΔVO2, 42 ± 8 vs. 32 ± 5, P < 0.001) and ventilation efficiency (Δ VE/ΔVCO2, 30.3 ± 3.7 vs. 27.3 ± 2.5, P < 0.001) during CPET. Peak VO2 remained significantly lower in subjects with SCA after adjusting for age, sex, body mass index (BMI), and hemoglobin, which were independent predictors of peak VO2 for subjects with SCA. In the largest study to date using maximal CPET in SCA, we demonstrate that children and young adults with SCA have reduced exercise capacity attributable to factors independent of anemia. Complex derangements in gas exchange and oxygen uptake during maximal exercise are common in this population. [ABSTRACT FROM AUTHOR]

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]

The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222 hour. The typical apparent volume of distribution was 21.8 L and the apparent systemic clearance was 6.88 L/h for an average weight patient of 30.7 kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6 hours post-dose and AUC with the most significant (R2 = 0.71) observed at 1.5 hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 hours after an oral dose of the drug were highly predictive of systemic drug exposure. [ABSTRACT FROM AUTHOR]

Red blood cell ( RBC) transfusions can be life-sustaining in chronic inherited anaemias, such as thalassaemia, and the indications for blood transfusions in patients with sickle cell disease continue to expand. Complications of transfusions, such as allosensitization, can create significant medical challenges in the management of patients with haemoglobinopathies. This review summarizes key findings from the medical literature related to alloimmunization in haemoglobinopathies and examines potential measures to mitigate these risks. Areas where future studies are needed are also addressed. [ABSTRACT FROM AUTHOR]

α-Hemoglobin-stabilizing protein (AHSP) is an erythroid protein that binds and stabilizes α-hemoglobin during normal erythropoiesis and in pathological states of α-hemoglobin excess. AHSP has been proposed as a candidate gene in some Heinz body hemolytic anemias and as a modifier gene in the β-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. [ABSTRACT FROM AUTHOR]

Summary: We examined heart rate variability (HRV) during exercise testing in 20 children with sickle cell anaemia (SCA) and 12 controls. Subjects achieved lower median HRV at peak exercise [standard deviation of R‐wave to R‐wave intervals (SDNN), 2·3 vs 2·9 ms, P = 0·027; logarithmic transformation of high frequency power (lnHF), 0·9 vs 1·3 ln(ms2), P = 0·047] and had lower post‐exercise HRV across minute‐by‐minute analysis of recovery. After adjustment for haemoglobin, fitness and SCA status, subjects had lower HRV at the end of recovery with differences increasing as baseline HRV increased. Further investigation of HRV and exercise safety in SCA is warranted. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) state level surveillance data are limited. We performed a retrospective review of emergency department (ED) visits and hospitalizations from individuals with SCD in Illinois (2016–2020) using the Illinois Health and Hospital Association's Comparative Health Care and Hospital Data Reporting Services. There were 48,094 outpatient ED visits and 31,686 hospitalizations. Most visits (67%) occurred in Cook County, were covered by public insurance (77%) and were from individuals with medium high (40.3%) or high (36.1%) poverty levels. SCD healthcare utilization remains high and surveillance data may inform SCD program development and resource allocation at the state level. Abbreviations CDC Centers for Disease Control and Prevention ED Emergency Department FDA Food & Drug Administration ICD International Classification of Diseases IL Illinois SCD Sickle cell disease [ABSTRACT FROM AUTHOR]

Summary: We used near‐infrared spectroscopy to examine tissue oxygenation (StO2) during exercise in 17 children and young adults with sickle cell anaemia (SCA) and 13 controls. Patients had lower cerebral StO2 at all exercise stages and demonstrated significantly greater decreases in cerebral StO2 later during exercise. Quadriceps StO2 increased similarly in patients and controls during early exercise, but decreases from baseline were greater in patients during later exercise. At similar workloads, patients demonstrated lower cerebral StO2 (69·2 ± 6·6 vs. 79·5 ± 5·3%, P < 0·001) and trended towards lower quadriceps StO2 (67·7 ± 9·0 vs. 73·2 ± 7·9%, P = 0·09). Further studies of tissue oxygenation during exercise in SCA are warranted. [ABSTRACT FROM AUTHOR]

Defects of the ankyrin-1 gene are the most common cause in humans of hereditary spherocytosis, an inherited anemia that affects patients of all ethnic groups. In some kindreds, linked -108/-153 nucleotide substitutions have been found in the upstream region of the ankyrin gene promoter that is active in erythroid cells. In vivo, the ankyrin erythroid promoter and its upstream region direct position-independent, uniform expression, a property of barrier insulators. Using human erythroid cell lines and primary cells and transgenic mice, here we have demonstrated that a region upstream of the erythroid promoter is a barrier insulator in vivo in erythroid cells. The region exhibited both functional and structural characteristics of a barrier, including prevention of gene silencing in an in vivo functional assay, appropriate chromatin configuration, and occupancy by barrier-associated proteins. Fragments with the -108/-153 spherocytosis-associated mutations failed to function as barrier insulators in vivo and demonstrated perturbations in barrier-associated chromatin configuration. In transgenic mice, flanking a mutant -108/-153 ankyrin gene promoter with the well-characterized chicken HS4 barrier insulator restored position-independent, uniform expression at levels comparable to wild-type. These data indicate that an upstream region of the ankyrin-1 erythroid promoter acts as a barrier insulator and identify disruption of the barrier element as a potential pathogenetic mechanism of human disease. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To determine the factors associated with exercise capacity in adults with sickle cell disease (SCD) and its relationship to hospitalizations and mortality. Methods: A total of 223 participants in the Cooperative Study of Sickle Cell Disease (CSSCD) (64% female, 70% hemoglobin SS/Sβ0 thalassemia, mean age 43.3 ± 7.5 years) underwent maximal exercise testing using a treadmill protocol with a mean duration of 11.6 ± 5.2 minutes. Results: Female sex (β = −3.34, 95% CI [−1.80, −4.88], P < 0.001), older age (β = −0.14, 95% CI [−0.24, −0.04], P = 0.005), higher body mass index (β = −0.23, 95% CI [−0.37, −0.10]; P = 0.001), and lower hemoglobin (β = 0.56, 95% CI [0.08, 1.04], P = 0.02) were independently associated with lower fitness, while there was a trend with abnormal pulmonary function testing (β = −1.42, 95% CI [−2.92, 0.07]; P = 0.06). Lower percent‐predicted forced expiratory volume in 1 second (FEV1) was independently associated with lower fitness (β = 0.08, 95% CI [0.03, 0.13], P = 0.001). Genotype and hospitalization rates for pain and acute chest syndrome (ACS) prior to testing were not associated with exercise capacity. Baseline exercise capacity predicted neither future pain or ACS nor survival in our cohort. Adults with SCD tolerated maximal exercise testing. Conclusions: Prospective studies are needed to further evaluate the impact of regular exercise and improved fitness on clinical outcomes and mortality in SCD. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease (SCD) complications lead to poor health-related quality of life (HRQOL) and increased healthcare utilization in this population, which could be mitigated with hydroxyurea therapy; however, adherence is suboptimal. We assessed the relationship of healthcare utilization to hydroxyurea adherence and HRQOL amongst youth with SCD. Methods: Thirty-four patients with SCD (median age 14 years, IQR 12-18) on hydroxyurea participated in this cross-sectional study and completed Morisky Adherence Scale 8-items and Patient Reported Outcomes Measurement Information System (PROMIS®) HRQOL measures. A medical chart review was conducted to assess healthcare utilization. Results: Participants with more frequent hospitalizations and emergency room (ER) visits and longer length of stay (LOS) had significantly lower fetal hemoglobin (rs=-0.44; rs=-0.45; rs=-0.46, p < 0.05) and mean corpuscular volume (rs=-0.47; rs=-0.42; rs=-0.48, p < 0.05), respectively. More frequent hospitalizations and ER visits and longer LOS correlated significantly with worse fatigue (rs=0.51; rs=0.41; rs=0.53, p < 0.05), pain (rs=0.41; rs=0.38; rs=0.47, p < 0.05), physical function mobility (rs=-0.67; rs=-0.59; rs=-0.67, p < 0.05), depression (rs=0.38; rs=0.31; rs=0.42, p < 0.05), and social isolation (rs=0.76; rs=0.76; rs=-0.84, p < 0.05), respectively. Conclusions: We conclude that increased healthcare utilization in youth with SCD is associated with low adherence to hydroxyurea and worse HRQOL domain scores. It is important emphasize the clinical benefits of high adherence to hydroxyurea, particularly among youth with SCD. Future longitudinal studies are warranted to assess the directionality of these relationships, and may reveal modifiable behavioral factors associated with early changes in hydroxyurea adherence levels. [ABSTRACT FROM AUTHOR]

Background: Little is known about red blood cell (RBC) transfusion practices for children hospitalized for a sickle cell vaso-occlusive pain crisis (VOC). We hypothesized that transfusion would be associated with the development of acute chest syndrome (ACS), lower hemoglobin (Hb) concentration, and lack of hydroxyurea therapy.Study Design and Methods: This is a secondary analysis of all children admitted for a sickle cell pain crisis enrolled in the Magnesium in Crisis (MAGiC) randomized trial; all had HbSS or S-β0 thalassemia. ACS development and transfusion administration were prospectively collected during the parent trial. All Hb values during the hospitalization were recorded, as was parent report of child receiving hydroxyurea. Relative risks (RRs) of transfusion were compared between groups.Results: Of 204 enrolled children, 40 (19.6%) received a transfusion. Of the 30 children who developed ACS, 22 (73.3%) received transfusions compared to 18 of 174 (10.3%) without ACS: the RR of transfusion in children with ACS was 7.1 (95% confidence interval [CI], 4.4-11.5). Among those without ACS, the lowest Hb was most strongly associated with transfusions: RR was 3.1 (95% CI 2.0 - 4.7) for each 1 g/dL decrease in lowest Hb. In a binary recursive partitioning model for those without ACS, a lowest recorded Hb level of less than 6.3 g/dL was significantly associated with transfusion during admission (p < 0.01). Hydroxyurea use was not associated with transfusions in any analysis.Conclusion: ACS increased the RR of transfusion in children hospitalized for VOC sevenfold. In children without ACS, transfusion was associated with lowest Hb concentration, particularly Hb concentration of less than 6.3 g/dL. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease (SCD) patients have impaired domains of health-related quality of life (HRQOL). Hydroxyurea is safe and efficacious in SCD; however, adherence is suboptimal, and patients' perceptions are poorly understood amongst adolescents and young adults (AYA). Study objectives were to: (1) examine patients' perceptions of SCD and hydroxyurea; and (2) explore the relationship of their perceptions to clinical characteristics, HRQOL domains and hydroxyurea adherence.Methods: Thirty-four SCD patients on hydroxyurea (≥6 months) participated in a single-institution study. Study measures included Brief-Illness Perceptions Questionnaire, ©Modified Morisky Adherence Scale 8-items, and Patient Reported Outcomes Measurement Information System (PROMIS®). We assessed the relationship of patients' perceptions to hydroxyurea adherence using Wilcoxon rank-sum test, the number of hospitalizations using Kruskal-Wallis test, and the number of ED visits, adherence level, HRQOL domain scores using Spearman's rho correlations. We conducted a sub-analysis in HbSS patients to evaluate the relationship of patients' perceptions to laboratory markers of hydroxyurea adherence.Results: Participants were 59% male and 91% Black, and had a median age of 13.5 (range 12-18) years. Participants with ≥4 hospitalizations over 1-year prior (using electronic medical chart review) reported more negative perceptions of SCD-related symptoms and emotional response, and perceived hydroxyurea as less beneficial; all p-values ≤0.01. Most participants (74%) reported low hydroxyurea adherence. Participants with higher hydroxyurea adherence perceived more hydroxyurea benefits (r s = 0.44, p < 0.01) and had better emotional response to SCD (r s = -0.44, p = 0.01). In a sub-analysis of HbSS patients, perceived benefits of hydroxyurea positively correlated with HbF (r s = 0.37, p = 0.05) and MCV values (r s = 0.35, p = 0.05). Participants with more negative perceptions of SCD-related consequences, concerns, and emotional response, and fewer perceived hydroxyurea benefits reported worse fatigue (r s = 0.68; r s = 0.44; r s = 0.74; r s = -0.60), pain (r s = 0.56; r s = 0.54; r s = 0.63; r s = -0.39), anxiety (r s = 0.55; r s = 0.58; r s = 0.56; r s = -0.47), and depression (r s = 0.64; r s = 0.49; r s = 0.70; r s = -0.62), respectively, all p-values <0.05.Conclusions: Dynamics influencing hydroxyurea adherence are multifactorial, and understanding patients' perceptions is critical to overcoming adherence barriers. Patients' favorable perceptions correlated with greater adherence and better HRQOL domain scores. Prospective evaluation of patients' perceptions of SCD and hydroxyurea in relation adherence, HRQOL domains and clinical outcomes is warranted. [ABSTRACT FROM AUTHOR]

Background: Detecting change in health status over time and ascertaining meaningful changes are critical elements when using health-related quality of life (HRQL) instruments to measure patient-centered outcomes. The PedsQL™ Sickle Cell Disease module, a disease specific HRQL instrument, has previously been shown to be valid and reliable. Our objectives were to determine the longitudinal validity of the PedsQL™ Sickle Cell Disease module and the change in HRQL that is meaningful to patients.Methods: An ancillary study was conducted utilizing a multi-center prospective trial design. Children ages 4-21 years with sickle cell disease admitted to the hospital for an acute painful vaso-oclusive crisis were eligible. Children completed HRQL assessments at three time points (in the Emergency Department, one week post-discharge, and at return to baseline (One to three months post-discharge). The primary outcome was change in HRQL score. Both distribution (effect size, standard error of measurement (SEM)) and anchor (global change assessment) based methods were used to determine the longitudinal validity and meaningful change in HRQL. Changes in HRQL meaningful to patients were identified by anchoring the change scores to the patient's perception of global improvement in pain.Results: Moderate effect sizes (0.20-0.80) were determined for all domains except the Communication I and Cognitive Fatigue domains. The value of 1 SEM varied from 3.8-14.6 across all domains. Over 50% of patients improved by at least 1 SEM in Total HRQL score. A HRQL change score of 7-10 in the pain domains represented minimal perceived improvement in HRQL and a HRQL change score of 18 or greater represented moderate to large improvement.Conclusions: The PedsQL™ Sickle Cell Disease Module is responsive to changes in HRQL in patients experiencing acute painful vaso-occlusive crises. The study data establish longitudinal validity and meaningful change parameters for the PedsQL™ Sickle Cell Disease Module.Trial Registration: ClinicalTrials.gov (study identifier: NCT01197417 ). Date of registration: 08/30/2010. [ABSTRACT FROM AUTHOR]

Objectives To identify barriers to hydroxyurea adherence (negative beliefs, access, and/or recall barriers), and their relationship to adherence rates and health-related quality of life ( HRQOL) among adolescents and young adults ( AYA) with sickle cell disease ( SCD). Methods A cross-sectional survey was administered to 34 AYAs (12-22 years old) in SCD clinics from January to December 2015. Study measures included Brief Medication Questionnaire, Modified Morisky Adherence Scale 8-items, visual analog scale, and Patient Reported Outcomes Measurement Information System. Results Participants (59% male; 91% Black) had a median age of 13.5 years ( IQR 12-18). Participants reported negative beliefs (32%), recall barriers (44%), and access barriers (32%). Participants with recall barriers reported worse pain ( P=.02), fatigue ( P=.05), and depression ( P=.05). The number of adherence barriers inversely correlated with adherence level using © MMAS-8 ( rs=−.38, P=.02) and VASdose ( rs=−.25, P=.14) as well as MCV ( rs=−.45, P=.01) and HbF% ( rs=−.36, P=.05), suggesting higher hydroxyurea adherence in patients with fewer barriers. Conclusions Patients with fewer barriers to hydroxyurea adherence were more likely to have higher adherence rates and better HRQOL scores. Routine assessment of hydroxyurea adherence and its related barriers could provide actionable information to improve adherence rates, HRQOL, and other clinical outcomes. [ABSTRACT FROM AUTHOR]

Importance: Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it.Objective: To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans.Design, Setting, and Participants: Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures.Exposures: Presence of SCT.Main Outcomes and Measures: Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure.Results: The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, -0.29%; 95% CI, -0.35% to -0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of -0.30% (95% CI, -0.39% to -0.21%). The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons).Conclusions and Relevance: Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation. [ABSTRACT FROM AUTHOR]

Magnesium, a vasodilator, anti-inflammatory, and pain reliever, could alter the pathophysiology of sickle cell pain crises. We hypothesized that intravenous magnesium would shorten length of stay, decrease opioid use, and improve health-related quality of life (HRQL) for pediatric patients hospitalized with sickle cell pain crises. The Magnesium for Children in Crisis (MAGiC) study was a randomized, double-blind, placebo-controlled trial of intravenous magnesium vs normal saline placebo conducted at 8 sites within the Pediatric Emergency Care Applied Research Network (PECARN). Children 4 to 21 years old with hemoglobin SS or Sβ0 thalassemia requiring hospitalization for pain were eligible. Children received 40 mg/kg of magnesium or placebo every 8 hours for up to 6 doses plus standard therapy. The primary outcome was length of stay in hours from the time of first study drug infusion, compared using a Van Elteren test. Secondary outcomes included opioid use and HRQL. Of 208 children enrolled, 204 received the study drug (101 magnesium, 103 placebo). Between-group demographics and prerandomization treatment were similar. The median interquartile range (IQR) length of stay was 56.0 (27.0-109.0) hours for magnesium vs 47.0 (24.0-99.0) hours for placebo (P 5 .24). Magnesium patients received 1.46 mg/kg morphine equivalents vs 1.28 mg/kg for placebo (P 5 .12). Changes in HRQL before discharge and 1 week after discharge were similar (P > .05 for all comparisons). The addition of intravenous magnesium did not shorten length of stay, reduce opioid use, or improve quality of life in children hospitalized for sickle cell pain crisis. This trial was registered at www. clinicaltrials.gov as #NCT01197417. [ABSTRACT FROM AUTHOR]

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]