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We report a case of a 69-year-old male who was planned for a transcatheter aortic valve replacement (TAVR) with a 26 mm Sapien 3 Valve (Edwards Lifesciences, Irvine, California) for the treatment of symptomatic severe aortic stenosis. During rapid ventricular pacing and implantation of the TAVR valve, there was a loss of pacing capture and subsequent embolization of the valve into the aortic arch. Retrieval of the embolized valve was attempted unsuccessfully using several techniques. Finally, by using a 34 mm Evolut R Valve (Medtronic, Minneapolis, Minnesota), we were able to secure the embolized valve in the transverse segment of the aortic arch without compromising the branch vessels. To our knowledge, this is the first reported case of using a valve-in-valve approach to fixate an embolized valve in the transverse aorta.

The purpose of this study is to perform and evaluate baseline abdominal ultrasound in infants with sickle cell anemia who participated in the BABY HUG multiinstitutional randomized placebo-controlled trial of hydroxyurea therapy and to examine the potential relationships among ultrasound results and clinical, nuclear medicine, and laboratory data.After local institutional review board approval and with informed guardian consent, 116 girls and 87 boys (age range, 7.5-18 months) with sickle cell anemia underwent standardized abdominal sonography at 14 institutions. Imaging was centrally reviewed by one radiologist who assessed and measured the spleen, kidneys, gallbladder, and common bile duct. Baseline physical assessment of spleen size, serum alanine aminotransferase and bilirubin levels, (99m)Tc sulfur colloid liver-spleen scans, and (99m)Tc diethylenetriaminepentaacetic acid clearance glomerular filtration rates (GFRs) were obtained. Analysis of variance and the Student test were performed to compare sonographic findings to published results in healthy children and to clinical and laboratory findings.The mean (± SD) spleen volume (108 ± 47 mL) was significantly greater than published normal control values (30 ± 14 mL; p0.0001). There was no correlation between spleen volume and function assessed by liver-spleen scan. The mean GFR (125 ± 34 mL/min/1.73 m(2)) was elevated compared with control GFRs (92 ± 18 mL/min/1.73 m(2)). Renal volumes (right kidney, 29 ± 8 mL; left kidney, 31 ± 9 mL) were significantly greater than control volumes (right kidney, 27 ± 3 mL; left kidney, 27 ± 3 mL; p0.0001) and were positively correlated with GFR (p = 0.0009). Five percent of patients had sonographic biliary abnormalities (sludge, n = 6; dilated common bile duct, n = 2; and cholelithiasis and thickened gallbladder wall, n = 1 each). There was no correlation between biliary sonographic findings and laboratory results.In infants with sickle cell anemia, sonographic spleen volume does not reflect function, but increased renal volume correlates with GFR and is consistent with hyperfiltration. Sonographic biliary abnormalities can occur early in life, while remaining clinically silent.

Background Transcranial Doppler ultrasonography (TCD) is used to predict stroke risk in children with sickle cell anemia (SCA), but has not been adequately studied in children under age 2 years. Procedure TCD was performed on infants with SCA enrolled in the BABY HUG trial. Subjects were 7–17 months of age (mean 12.6 months). TCD examinations were successfully performed in 94% of subjects (n = 192). Results No patient had an abnormal TCD as defined in the older child (time averaged maximum mean TAMM velocity ≥200 cm/sec) and only four subjects (2%) had velocities in the conditional range (170–199 cm/sec). TCD velocities were inversely related to hemoglobin (Hb) concentration and directly related to increasing age. Conclusion Determination of whether the TCD values in this very young cohort of infants with SCA can be used to predict stroke risk later in childhood will require analysis of exit TCD's and long-term follow-up, which is ongoing (ClinicalTrials.gov number, NCT00006400). Pediatr Blood Cancer 2010;54:256–259. © 2009 Wiley-Liss, Inc.

To evaluate serial hormone concentrations in subjects treated with vaginally administered misoprostol for early pregnancy failure.As part of a randomized clinical trial, serum was collected on treatment days 1, 3, 8, and 15.Multicenter clinical trial.Women with a nonviable first-trimester pregnancy.Serum concentrations of human chorionic gonadotropin (hCG), progesterone, and sex hormone binding globulin (SHBG) were evaluated.A logistic regression model was constructed to assess the associations of percent and complete expulsion of the gestational sac and/or successful management.The percent change from the day of treatment until the first follow-up visit was predictive for complete expulsion for progesterone (P) (P.005) and hCG (P.005), but not for SHBG. The actual value was not significantly associated with complete expulsion or successful management. A decrease (day 1-3) of 79% for both hCG and P was associated with a 90% probability of complete passage of the gestational sac. A 90% probability of successful management was noted if P decreased by 78% on day 3 or 59% on day 7, or hCG decreased by 74% on day 3 or 78% on day 7 compared with pretreatment values.Percent change, but not absolute change, in serial hormone values are strongly associated with both the complete expulsion of the gestational sac with one dose of misoprostol and ultimate success.

Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects.This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sβ(0)thalassaemia, were aged 9-18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on (99)Tc spleen scan) and renal function (glomerular filtration rate by (99m)Tc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2-4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00006400.96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m(2), p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia.On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia.The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development.

Subject retention and adherence are essential to maintain the power and validity of the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG). We designed a study to assess adherence with study medication administration and study visits and to evaluate socioeconomic factors (SES) that may influence these measurements of adherence. These data are important for assessing impact of adherence on BABY HUG trial outcome and defining impact of SES on adherence.Each subject's median study medication (MedAd) and mean visit adherence (VAd) were evaluated. We examined associations of adherence with SES of participating families.MedAd data were available on 153 of the 191 subjects who started randomized study medication. MedAd was 101.7% of volume prescribed, with 88.9% of subjects taking at least 80% of doses. VAd data were available on 185 of the 191 subjects who started randomized study medication. VAd was 97.3%, with 82.2% of subjects having no missed visits. During dose titration, subjects had on average 12.9% higher medication adherence than subjects who were on a stable dose and had less frequent study visits. MedAd and VAd were not significantly associated with SES.Subjects in the BABY HUG trial have had excellent adherence. SES was not associated with adherence, suggesting that SES should not be used as a criterion for enrolment in clinical trials. Additional efforts are needed to maintain medication adherence, particularly when the interval between scheduled visits increases. (ClinicalTrials.gov number, NCT00006400).

To compare the safety, efficacy, postprocedure quality of life, and acceptability of manual vacuum aspiration (MVA) performed as an outpatient with electric vacuum aspiration (EVA) performed in a hospital in women experiencing a first-trimester miscarriage.From a randomized multicenter trial comparing misoprostol with vacuum aspiration for first-trimester loss, data were extracted comparing the safety, efficacy, and acceptability of MVA in an office setting with local anesthesia with EVA in an operating room environment with spinal or general anesthesia or monitored anesthesia care (MAC).One hundred fifty-seven women underwent EVA or MVA. Efficacy and safety were similar in both groups. Physical and emotional role functioning scores were better in patients undergoing MVA (p=0.01), and fewer patients undergoing MVA missed work or required help at home (p0.01). However, pain severity scores were better in the EVA arm of the study (p=0.03). There was a trend toward fewer MVA patients recommending or using this procedure again.In patients with early pregnancy loss, treatment with MVA as an outpatient with local anesthesia is an effective and safe alternative to EVA performed in a hospital with conscious sedation or spinal or general anesthesia. Treatment in the outpatient setting allows for a better physical and emotional quality of life postprocedure.

BABY HUG is an NHLBI/NICHD-sponsored Phase III randomized double-blinded placebo-controlled clinical trial (NCT00006400) to test the hypothesis that hydroxyurea can prevent chronic organ damage in very young children with sickle cell anemia (SCA). Renal and splenic function measures are the co-primary endpoints. Renal disease in SCA begins early in life with impaired urine concentration and acidification, along with glomerular hyperfiltration; some patients will progress to microalbuminuria, glomerulosclerosis, macroalbuminuria, and even renal failure. In BABY HUG, glomerular filtration rate (GFR) elevation was selected as a primary endpoint, to be measured quantitatively by plasma clearance of injected 99mTc-DTPA and also estimated by the Schwartz equation where GFR = (height × 0.55)/(serum creatinine), with creatinine measured by HPLC to .01 mg/dL precision. Of 233 enrolled subjects, 193 completed screening and were randomized to study treatment. Quantitative GFR measurement was successful in most cases: 176 of 182 (97%) of DTPA clearance studies were adequate and 157 subjects had both baseline DTPA and Schwartz GFR values available for analysis. The average age at GFR measurement was 13.7 ± 2.6 months (range 9–19 months) and 59% of subjects were female. Baseline mean (± 1SD) hematological parameters included hemoglobin = 9.0 ± 1.4 gm/dL, absolute reticulocytes = 295.3 ± 137.4 × 109/L, WBC = 14.3 ± 5.8 × 109/L, and fetal hemoglobin (HbF) = 25.6 ± 8.8%. Baseline past medical history included dactylitis (34%), splenic sequestration (7%), and acute chest syndrome (5%). The average baseline quantitative GFR measurement determined by DTPA clearance was elevated at 125.4 ± 34.4 mL/min/1.73m2, (range 40.2 – 300.9 mL/min/1.73m2, normal value 100 ± 20 mL/min/1.73m2). The average baseline GFR estimate by Schwartz equation was substantially higher at 193.9 ± 53.8 mL/min/1.73m2, range 65.8 – 350.0 mL/min/1.73m2. In univariate analysis, the DTPA GFR value was positively correlated with the Schwartz GFR estimate (r=0.22, p=0.0059, slope=0.145) as well as age, weight, height (all p≤.001) but not with hemoglobin, HbF, WBC, reticulocytes, previous sickle cell-related events, or measures of splenic function including liver-spleen scan and quantitation of pitted erythrocytes and micronuclei. The Schwartz GFR estimate was positively correlated with age, height, WBC, and splenic function, and negatively correlated with hemoglobin and HbF. Using a quantitative GFR threshold of 120 mL/min/1.73m2 and an age threshold of 15 months, higher GFR values were observed in older infants, p=0.026. These data indicate that renal dysfunction measured by GFR elevation may begin early in life in SCA; quantitative GFR measurement is feasible but highly variable in this very young patient population; (3) the Schwartz and DTPA GFR values are strongly correlated, but the Schwartz estimate is usually greater and only modestly agrees with the quantitative DTPA GFR value. These baseline GFR measurements in BABY HUG support the hypothesis of age- and disease-related glomerular hyperfiltration in SCA. BABY HUG should yield important information regarding the ability of hydroxyurea to prevent renal damage among infants with SCA.

Abnormal early pregnancy is a common experience for women. Approximately 1 in 4 women will experience a miscarriage during her lifetime.1 Between 15% and 20% of clinically recognized pregnancies are diagnosed as abnormal in the first or early second trimester.2 For more than 50 years, the standard management of early pregnancy failure has been a dilation and curettage (D&C). Typically, the procedure is performed in an operating room, which significantly increases cost. In recent years, the medical community began to question whether immediate evacuation by surgical intervention is truly necessary for most cases of early pregnancy failure.3–5 Misoprostol, a prostaglandin E1 analogue, has garnered attention over the past few decades, both in regimens for medical abortion and by itself for early pregnancy failure.6 Overall, comparison of trials using misoprostol for early pregnancy failure is difficult because the studies included various patient populations and dosing regimens (for example, repeat dosing every 3–4 hours or every 24 hours), different routes of administration (oral or vaginal), varying definitions of success (the time allowed until dilation and curettage was performed),7 and a misunderstanding of how to use ultrasonography to define both inclusion and success.8–10 Additionally, most of the large studies involve inpatient admission for medical management, a scenario that would be unlikely in the United States.11,12 To address these weaknesses, we conducted a multicenter randomized trial including 491 women treated with misoprostol 800 μg vaginally and 161 women who had a vacuum aspiration procedure for early pregnancy failure.13 Misoprostol treatment success was 71% (95% confidence interval [CI] 67–75%) after one dose and 84% (95% CI 81–87%) overall. Although this overall success was statistically equivalent to the 97% (95% CI 94–100%) for vacuum aspiration, the rates are clinically quite different. There may be easily identifiable subgroups for whom misoprostol treatment will be more or less effective and, ideally, some women for whom the success rates may more closely approximate those of vacuum aspiration. This report details the findings of a planned substudy of this multicenter trial to evaluate factors related to success with misoprostol treatment.