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BACKGROUND: Adolescent and young adult (AYA) women with sickle cell disease (SCD) have increased pregnancy-related health risks and are prescribed potentially teratogenic medications, yet limited data are available regarding pediatric SCD provider contraceptive practices. We aimed to assess pediatric hematology providers’ beliefs, practices, motivators, and barriers for providing contraceptive care to female AYA with SCD. METHODS: Guided by the Health Belief Model (HBM), we developed a 25-question, web-based survey to assess practices. Survey links were distributed nation-wide to pediatric SCD and/or general hematology providers through their publicly available emails and by request to directors of U.S. accredited Pediatric Hematology-Oncology fellowship programs for distribution to their SCD providers. Data analysis included descriptive statistics, chi-square analysis, logistic regression. RESULTS: Of 177 respondents, 160 surveys meeting inclusion criteria were analyzed. Most providers reported counseling (77.5%) and referring female AYA patients for contraception (90.8%), but fewer reported prescribing contraception (41.8%). Proportionally fewer trainees provided counseling compared to established providers (54% vs. 85%, p

PURPOSE To evaluate different T2 -oxygenation calibrations for estimating venous oxygenation in people with sickle cell anemia (SCA). METHODS Blood T2 values were measured at 3 T in the internal jugular veins of 12 healthy volunteers and 11 SCA participants with no history of stroke, recent transfusion, or renal impairment. T2 -oxygenation relationships of both sickled and normal blood samples were calibrated individually and compared with values generated from published models. After converting venous T2 values to venous oxygenation, whole-brain oxygen extraction fraction and cerebral metabolic rate of oxygen were calculated. RESULTS Sickle blood samples' oxygenation values calculated from our individual calibrations agreed well with measurements using a blood analyzer, whereas previous T2 calibrations based on normal blood samples showed 13%-19% underestimation. Meanwhile, oxygenation values calculated from previous grouped T2 calibration for sickle blood agreed well with experimental measurement on averaged values, but showed up to 20% variation for several individual samples. Using individual T2 calibrations, the whole-brain oxygen extraction fraction and cerebral metabolic rate of oxygen of SCA participants were 0.38 ± 0.08 and 172 ± 42 µmol/min/100 g, respectively, which were comparable to those values measured on healthy volunteers. CONCLUSION Our results confirm that sickle blood T2 values not only depend on the hematocrit and oxygenation values, but also on other hematological factors. The individual T2 calibrations minimized the effect of heterogeneity of sickle blood between different SCA populations and improved the accuracy of T2 -based oximetry. The measured oxygen extraction fraction and cerebral metabolic rate of oxygen of this group of SCA participants were found to not differ significantly from those of healthy individuals.

Baseline hematocrit fraction (Hct) is a determinant for baseline cerebral blood flow (CBF) and between-subject variation of Hct thus causes variation in task-based BOLD fMRI signal changes. We first verified in healthy volunteers (n = 12) that Hct values can be derived reliably from venous blood T1 values by comparison with the conventional lab test. Together with CBF measured using phase-contrast MRI, this noninvasive estimation of Hct, instead of using a population-averaged Hct value, enabled more individual determination of oxygen delivery (DO2), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2). The inverse correlation of CBF and Hct explained about 80% of between-subject variation of CBF in this relatively uniform cohort of subjects, as expected based on the regulation of DO2 to maintain constant CMRO2. Furthermore, we compared the relationships of visual task-evoked BOLD response with Hct and CBF. We showed that Hct and CBF contributed 22%–33% of variance in BOLD signal and removing the positive correlation with Hct and negative correlation with CBF allowed normalization of BOLD signal with 16%–22% lower variability. The results of this study suggest that adjustment for Hct effects is useful for studies of MRI perfusion and BOLD fMRI. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

BACKGROUND Factor (F)XIII deficiency is a rare inherited bleeding disorder, but can also be acquired due to the development of inhibitors. CASE REPORT A 17-year-old female with systemic lupus erythematosus and end-stage kidney disease secondary to Class IV lupus nephritis developed spontaneous subcutaneous and muscular hematomas and delayed major bleeding after invasive procedures. She had abnormal kaolin thromboelastography (kTEG; decreased maximal amplitude, representative of clot strength) initially attributed to thrombocytopenia and uremic platelet dysfunction, but her FXIII activity was undetectable, and a high-titer antibody against FXIII was identified. She had improvement in clinical bleeding and in kaolin thromboelastogram result and transient improvement in FXIII activity after each dose of plasma-derived FXIII concentrate (Corifact) or cryoprecipitate. Her inhibitor titers gradually improved with multiple immunosuppressive therapies and plasma exchange. While her FXIII activity level remained mildly decreased, she has not had additional significant bleeding. CONCLUSION Treatment with either plasma-derived FXIII or cryoprecipitate is an effective treatment to normalize the kTEG variables and clinical bleeding diatheses associated with acquired FXIII inhibitors. Higher doses may be needed in patients with high-titer inhibitor.

The transition period from pediatric care to adult care for patients with sickle cell disease (SCD) is associated with increased mortality and morbidity. Identification of risk factors for unsuccessful transition may aid in developing strategies to improve the transition process and health outcomes in this population. We examined factors associated with unsuccessful transition from pediatric to adult care for patients with SCD at the Johns Hopkins Hospital. We found that public insurance and increased hospitalization rates were associated with poor transition to adult care. The findings provide possible areas of intervention.

Paradoxical' embolization via intracardiac or intrapulmonary right-to-left shunts (RLS) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in sickle cell anaemia (SCA), predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke (SCA + stroke) have an increased prevalence of potential RLS. We performed contrasted transthoracic echocardiograms on 147 children (aged 2-19 years) with SCA + stroke) mean age 12·7 ± 4·8 years, 54·4% male) and a control group without SCA or stroke (n = 123; mean age 12·1 ± 4·9 years, 53·3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA+stroke group than controls (45·6% vs. 23·6%, P < 0·001). The odds ratio for potential RLS in the SCA + stroke group was 2·7 (95% confidence interval: 1·6-4·6) vs controls. In post hoc analyses, the SCA + stroke group had a higher prevalence of intrapulmonary (23·8% vs. 5·7%, P < 0·001) but not intracardiac shunting (21·8% vs. 18·7%, P = 0·533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent and potentially modifiable risk factor for stroke in SCA.

Purpose To develop a fast protocol for measuring T1 values in the internal carotid artery (ICA), to validate this technique with in vitro measurements, and to evaluate its reproducibility. Methods A modified Look–Locker sequence was optimized to enable rapid determination of T1 in the ICA at 3T. T1 values from the ICA were compared with in vitro measurements on individually sampled venous blood oxygenated to arterial levels. A test–retest reproducibility study was also conducted. Results The group-averaged arterial blood T1 value was 1908 ± 77 ms for six women (hematocrit = 0.39 ± 0.03) and 1785 ± 55 ms for seven men (hematocrit = 0.45 ± 0.02), which is 100–200 ms longer than the widely adopted value obtained from bovine blood experiments. The arterial T1 value per subject correlated significantly with individual hematocrit values. The intrasession and intersession coefficients of variation were 1.1% and 2.1%, respectively, indicating good precision and reproducibility of our method. Reasonable agreement was observed between the in vivo and in vitro results with a correlation coefficient of 0.78. Conclusion The proposed method can provide fast arterial T1 measurement on individual subjects. When not performing such a subject-specific measurement, we recommend the use of 1908 ms and 1785 ms for healthy women and men, respectively, or 1841 ms for adults in general. Magn Reson Med 77:2296–2302, 2017. © 2016 International Society for Magnetic Resonance in Medicine

Tobacco smoke exposure has been associated with more frequent hospitalizations in children with sickle cell disease (SCD), but previous studies have not quantified the exposure by objective methods. We enrolled 50 children and young adults with SCD in a retrospective and prospective cohort study and quantified tobacco smoke exposure by objective (salivary cotinine) and survey measures. We used a multivariable negative binomial regression model to evaluate the association between salivary cotinine and hospital admissions. Forty-five percent (22/49) of participants had significant elevation of salivary cotinine (≥ 0.5 ng/ml). The incidence risk ratio (IRR) for hospital admission for those with elevated cotinine was 3.7 (95% CI 1.8-8). Those exposed to secondhand smoke but not primary smokers (cotinine between 0.5 and 10 ng/ml) had a similarly increased risk of hospitalization [IRR 4.3 (95% CI 1.8-10)]. We show that an objective measure of tobacco smoke exposure, salivary cotinine, is strongly associated with the rate of hospital admissions in children and young adults with SCD. This association underscores the importance of screening for tobacco smoke exposure in people with SCD. Further investigation is warranted to determine the mechanisms of and to evaluate interventions to decrease tobacco smoke exposure.

The completion of the Multicenter Silent Infarct Transfusion Trial demonstrated that children with pre-existing silent cerebral infarct and sickle cell anemia (SCA) who received regular blood transfusion therapy had a 58% relative risk reduction of infarct recurrence when compared to observation. However, the total benefit of blood transfusion therapy, as assessed by the parents, was not measured against the burden of monthly blood transfusion therapy. In this planned ancillary study, we tested the hypothesis that a patient centered outcome, health-related quality of life (HRQL), would be greater in participants randomly assigned to the blood transfusion therapy group than the observation group. A total of 89% (175 of 196) of the randomly allocated participants had evaluable entry and exit HRQL evaluations. The increase in Change in Health, measured as the child's health being better, was significantly greater for the transfusion group than the observation group (difference estimate = -0.54, P ≤ 0.001). This study provides the first evidence that children with SCA who received regular blood transfusion therapy felt better and had better overall HRQL than those who did not receive transfusion therapy.

Children with sickle cell anemia have a higher-than-expected prevalence of poor educational attainment. We test two key hypotheses about educational attainment among students with sickle cell anemia, as measured by grade retention and use of special education services: (1) lower household per capita income is associated with lower educational attainment; (2) the presence of a silent cerebral infarct is associated with lower educational attainment. We conducted a multicenter, cross-sectional study of cases from 22 U.S. sites included in the Silent Infarct Transfusion Trial. During screening, parents completed a questionnaire that included sociodemographic information and details of their child's academic status. Of 835 students, 670 were evaluable; 536 had data on all covariates and were used for analysis. The students' mean age was 9.4 years (range: 5-15) with 52.2% male; 17.5% of students were retained one grade level and 18.3% received special education services. A multiple variable logistic regression model identified that lower household per capita income (odds ratio [OR] of quartile 1 = 6.36, OR of quartile 2 = 4.7, OR of quartile 3 = 3.87; P = 0.001 for linear trend), age (OR = 1.3; P < 0.001), and male gender (OR, 2.2; P = 0.001) were associated with grade retention; silent cerebral infarct (P = 0.31) and painful episodes (P = 0.60) were not. Among students with sickle cell anemia, household per capita income is associated with grade retention, whereas the presence of a silent cerebral infarct is not. Future educational interventions will need to address both the medical and socioeconomic issues that affect students with sickle cell anemia.

Children with sickle cell anemia have a high prevalence of silent cerebral infarcts (SCIs) that are associated with decreased full-scale intelligence quotient (FSIQ). While the educational attainment of parents is a known strong predictor of the cognitive development of children in general, the role of parental education in sickle cell anemia along with other factors that adversely affect cognitive function (anemia, cerebral infarcts) is not known. We tested the hypothesis that both the presence of SCI and parental education would impact FSIQ in children with sickle cell anemia. A multicenter, cross-sectional study was conducted in 19 US sites of the Silent Infarct Transfusion Trial among children with sickle cell anemia, age 5-15 years. All were screened for SCIs. Participants with and without SCI were administered the Wechsler Abbreviated Scale of Intelligence. A total of 150 participants (107 with and 43 without SCIs) were included in the analysis. In a multivariable linear regression model for FSIQ, the absence of college education for the head of household was associated with a decrease of 6.2 points (P = 0.005); presence of SCI with a 5.2 point decrease (P = 0.017); each $1000 of family income per capita with a 0.33 point increase (P = 0.023); each increase of 1 year in age with a 0.96 point decrease (P = 0.023); and each 1% (absolute) decrease in hemoglobin oxygen saturation with 0.75 point decrease (P = 0.030). In conclusion, FSIQ in children with sickle cell anemia is best accounted for by a multivariate model that includes both biologic and socioenvironmental factors.

Background Respiratory syncytial virus (RSV) is a cause of acute chest syndrome (ACS) in sickle cell disease (SCD), but its clinical course and acute complications have not been well characterized. We compared RSV to seasonal influenza infections in children with SCD. Procedure We defined cases as laboratory-confirmed RSV or seasonal influenza infection in inpatients and outpatients

Hydroxyurea is the only approved medication in the United States for the treatment of sickle cell anemia (HbSS) and is widely used in children despite an indication limited to adults. We review the evidence of efficacy and safety in children with reference to pivotal adult studies. This evidence and expert opinion form the basis for recommended guidelines for the use of hydroxyurea in children including indications, dosing, therapeutic and safety monitoring, and interventions to improve adherence. However, there are substantial gaps in our knowledge to be addressed by on-going and planned studies in children.

Background Sickle cell disease (SCD) requires coordinated ambulatory care from generalists and hematologists. We examined when children with SCD establish ambulatory care connections, whether these connections are maintained, and how these connections are used before and after hospitalizations. Procedure We conducted a retrospective cohort study of Medicaid-insured Maryland children with SCD from 2002 to 2008. For children enrolled from birth, time to first, second, and third generalist and first hematologist visits was plotted. For all children, we analyzed ambulatory visits by age group, by emergency department (ED) and hospital use, and before and after hospitalizations. Results The overall study cohort comprised 851 children; 178 provided data from birth. Ambulatory care connections to generalists were made rapidly; connections to hematologists occurred more slowly, if at all (38% of children had not seen a hematologist by age 2 years). Visits with generalists decreased as patients aged, as did visits with hematologists (54% of children in the 12–17 year age group had no hematology visits in 2 years). Children with higher numbers of ED visits or hospitalizations also had higher numbers of ambulatory visits (generalist and hematologist). Most children had visits with neither generalists nor hematologists in the 30 days before and after hospitalizations. Conclusions Medicaid-insured children with SCD rapidly connect with generalists after birth; connections to hematologists occur more slowly. The observation that connections to generalists and hematologists diminish with time and are infrequently used around hospitalizations suggests that the ambulatory care of many Medicaid-insured children with SCD may be inadequate. Pediatr Blood Cancer 2012; 59: 888–894. © 2012 Wiley Periodicals, Inc.

BACKGROUND: Data on sentinel lymph node (SLN) biopsy in children with melanoma are limited. In this study, the authors compared the factors associated with SLN biopsy use and metastases in pediatric and young adult patients with melanoma. METHODS: The 2008 Surveillance, Epidemiology, and End Results (SEER) databases were used to examine melanoma cases from 2003 to 2008. Data extracted include age, sex, race, stage, tumor thickness, ulceration, lymph node status, surgical treatment, and survival. Logistic regression models were used for adjusted analyses. RESULTS: In total, 717 children (age 1 mm vs ≤1 mm), but not younger age (OR, 1.3; 95% CI, 0.94-1.8) in adjusted analyses. SLN metastasis was correlated with ulceration (OR, 3.0; 95% CI, 1.6-5.8), increased thickness (OR, 6.8; 95% CI, 3.1-15 for 2.01-4.0 mm vs ≤1 mm), and for the interaction between age

Current T(1) values for blood at 3T largely came from in vitro studies on animal blood or freshly drawn human blood. Measurement of blood T(1) in vivo could provide more specific information, e.g., for individuals with abnormal blood composition. Here, blood T(1) at 3T was measured rapidly (

We present the cases of two patients with severe congenital neutropenia (SCN) who both developed generalized adenopathy. Although both had recent histories that placed infection high on the differential of causes for the adenopathy, biopsies demonstrated acute myeloid leukemia (AML) as the etiology. The risk of malignant transformation in SCN is known to be significantly elevated, and these cases illustrate the need for physicians of such patients to keep myelodysplastic syndrome (MDS) and AML high on the differential when patients manifest atypical symptoms.

Background Acute chest syndrome (ACS) is a frequent cause of hospitalization and mortality in children with sickle cell disease. Transfusion is often required to prevent respiratory failure and treatment with dexamethasone may reduce the length of admission and the need for transfusions. We performed a retrospective cohort study to evaluate risk factors for readmission and prolonged hospitalization after different treatments for ACS.

Most patients with renal medullary carcinoma (RMC) have advanced disease at presentation and rarely respond to radiation or chemotherapy. We describe two adolescents with metastatic disease who had significant responses to cisplatin or carboplatin in combination with gemcitabine and paclitaxel.

BACKGROUND Individuals with sickle cell disease (SCD) have an increased risk of cholelithiasis from bilirubin stones. Symptomatic biliary tract disease (BTD) includes acute and chronic cholecystitis, obstruction of the common bile duct (CBD), cholangitis, and gallstone pancreatitis. Cholecystectomy is the main treatment strategy for symptomatic patients; however, the prevalence of recurrent BTD following cholecystectomy has not been systematically evaluated. We conducted a retrospective cohort study to describe the recurrence of BTD after cholecystectomy and characterize risk factors for recurrent disease.

Drug-induced immune thrombocytopenia (DITP) is often unrecognized; failure to diagnose this condition can result in unintended re-exposure to the drug and bleeding risk.[1] Here we report three children with DITP due Trimethoprim Sulfamethoxazole (TMP/SMX) dependent, platelet-reactive antibodies. With the increased use of TMP/SMX over the past several years, these cases highlight the need for heightened awareness of this potential adverse reaction in children.

To the Editor: Venous thromboembolism (VTE), including both deep venous thrombosis (DVT) and pulmonary embolism (PE), is an important cause of morbidity and mortality in children. Although there is heightened awareness of this disease and its risk factors in children, there has been minimal evaluation of diagnostic tests (clinical prediction models, imaging modalities, and D-dimer assays) in children compared to adults.(1) ELISA based D-dimer assays have excellent sensitivity for the diagnosis of VTE in adults and this may permit the exclusion of VTE.(2) However, the utility of D-dimer assays for VTE in children has not been evaluated. We performed a retrospective chart review of patients ≤21 years of age at Johns Hopkins Hospital with suspected VTE, imaging studies, and quantitative D-dimer. We used a discharge and billing database to identify patients and extracted information on potential risk factors, clinical findings, laboratory and imaging studies, and treatment. D-dimer was measured with an immunoturbidimetric assay on a Blood Coagulation System (BCS) analyzer (Advanced D-dimer; Dade-Behring) per the manufacturer's specifications. We identified 33 patients (20 male and 13 female) with diagnostic imaging studies and measurement of D-dimer within 72 hours. Twenty-six had acute VTE (15 DVT, 3 PE and 8 both], 6 with unchanged chronic VTE (5 DVT and 1 PE), and 1 without VTE (suspected PE). Most patients had multiple acquired risk factors for VTE with central venous catheters (54%), infections (40%), and immobility (42%) most frequent. D-dimer was significantly elevated in children with VTE (median 5.0, IQR 2.05-16.44) compared to children with negative evaluations for acute VTE (median 1.58, IQR 1.46-3.11, P 40 years old, 0.43-2.24 mg/L) and children (2-12 years old, 0.4-2.27 mg/L). Figure 1 D-dimer (log-scale) by diagnosis and the normal range for children 2 – 12 years of age We found that the D-dimer test was sensitive but only moderately specific for the diagnosis of VTE in children, and that the performance varied with the chosen cut-off. This assay is approved for the diagnosis of VTE in adults; the cut-off is 1.6 mg/L as the normal range is significantly higher than many D-dimer assays.(3) A D-dimer 1.75 mg/L was 92% sensitive (95% CI 75 – 99) and 57% specific (95% CI 18 – 90). Raising the threshold of the D-dimer to >2 mg/dl decreased the sensitivity to 77% (95% CI 56 – 91) while increasing the specificity to 71% (95% CI 29 – 96) for the diagnosis of VTE (Table 1). In a previous study of hospitalized adults from our institution,(4) the sensitivity of this test at a threshold of 2 mg/L was comparable (70% in adults versus 77% in children), however the specificity was considerably lower (42% in adults versus 71% in children). We calculated the area under the ROC [0.86 (95% CI 0.72-1.0)] to assess the performance of the D-dimer test to diagnose VTE. The greater the area under the curve, the better the performance of the diagnostic test with an area of 0.5 corresponding to a test that performs no better than flipping a coin. Table 1 Diagnostic Test Characteristics by Cut-Off (95% CI) While the utility of the D-dimer testing has been studied extensively in adults, its performance for the diagnosis of VTE in pediatric patients has not been evaluated. A report of children with PE from a single institution described elevated levels of D-dimer in 6 of 10, but the normal range was not described.(5) In children with acute thrombotic events, elevated D-dimer was found to be predictive of poor outcome (persistent thrombosis, VTE recurrence, or post-thrombotic syndrome); however, measurement of D-dimer was semi-quantitative and its predictive value for the diagnosis of VTE was not reported.(6) In both adults and children, an elevated D-dimer after treatment of VTE appears to be a risk factor for recurrent thrombus.(6-8) To our knowledge, this is the first report that describes the sensitivity of D-dimer measurements for the diagnosis of VTE in children. The incidence of VTE is significantly lower in children than adults, but perhaps even more challenging to diagnose. Compression ultrasonography of the lower extremities (sensitivity 91% and specificity 99%)(9) and MR venography (sensitivity 92% and specificity 95%)(10) have only been validated against the gold standard (contrast venography) in adults. D-dimer assays, in particular automated assays with rapid turn around times like the immunoturbidimetric assay used in this study, offer several advantages over other diagnostic modalities for VTE. They are relatively inexpensive and readily available in the outpatient and inpatient setting. A normal level in adults may potentially exclude VTE and avoid the need for expensive and time consuming imaging studies. Further prospective trials are necessary to validate our findings in children, as well as to address the utility of the D-dimer in selected subsets of pediatric patients.