MaryAnn O'Riordan

Increased carotid intima media thickness and cardiac biomarkers in Hiv infected children

Objectives:To assess carotid intima media thickness (IMT) and cardiac biomarkers in HIV infected children on antiretroviral therapy (ART). Methods:This was a single site, cross sectional, controlled observational study. We assessed carotid IMT, homocysteine, high-sensitivity C-reactive protein and myeloperoxidase levels in HIV infected children on stable ART for ≥ 6 months. Carotid IMT was reported as internal carotid artery (ICA) and common carotid artery (CCA) thickness; left and right sides were measured separately. Groups were compared using appropriate two-sample tests. Results:Of the 62 subjects enrolled, 31 were HIV positive (50%), 66% were female, and 69% were African–American. Median CD4% was 32% and 26 patients (84%) had HIV-1 RNA< 400 copies/ml. Sixteen patients had been taking protease inhibitors for a median duration of 27 months. None had hypertension or smoked. HIV infected children had higher HOMA-IR, waist-to-hip ratio, cholesterol, triglycerides, myeloperoxidase and lower homocysteine levels. Left and right CCA IMT, and left and right ICA IMT were significantly higher in the HIV infected group. Significant predictors of carotid IMT measurements in uninfected controls were body mass index and homocysteine, but only the duration of ARV therapy was predictive of IMT in the HIV infected group. Conclusion:Higher levels of carotid IMT and some cardiac markers were found in ART treated HIV infected children when compared to matched uninfected controls. These results suggest that HIV infected children receiving ART may be at increased risk of cardiovascular disease.

Performance of an Automated Immature Granulocyte Count as a Predictor of Neonatal Sepsis

Neonatologists use immature granulocytes (IG) in manual differential counts as an indicator of sepsis. This study was designed to compare the predictive ability of automated vs manual IG counts for neonatal sepsis. Infants undergoing sepsis evaluation were identified prospectively for study if a CBC count was obtained in temporal proximity to the blood culture. Automated IG counts were obtained from the research software of the Sysmex XE-2100 (Sysmex, Kobe, Japan). Manual average IG counts were obtained from two 100-cell manual differential counts independently performed by a technologist and a hematopathology resident. A comparative analysis of manual and automated IG counts showed considerable overlap of ranges. The highest positive blood culture rate occurred in the nonneutropenic preterm subset of infant older than 7 days (21/55 [38%]). For these infants, elevated IG counts by manual and automated methods were associated significantly with positive blood culture results (odds ratio, manual, 3.74; odds ratio, automated, 3.63), albeit with low sensitivity.

Development and Validation of a Questionnaire to Assess Carbohydrate and Insulin-Dosing Knowledge in Youth With Type 1 Diabetes

OBJECTIVE The American Diabetes Association advocates insulin regimens for youth with type 1 diabetes that involve adjusting insulin dose based on carbohydrate intake and blood glucose level. Implementing these regimens requires knowledge about carbohydrate content of foods and subsequent calculations of insulin dose, skills that may be difficult to gauge in practice. Therefore, we sought to develop and validate a questionnaire, the PedCarbQuiz (PCQ), to assess carbohydrate and insulin-dosing knowledge in youth with type 1 diabetes. RESEARCH DESIGN AND METHODS After development by an expert panel, the PCQ was administered to 75 youth with type 1 diabetes or their parents. Reliability was assessed by Cronbach α and split-half testing. To assess validity, scores were correlated with A1C, expert assessments, parent educational level, and complexity of insulin regimen. RESULTS PCQ mean score was 87 ± 9.7% (range 42–98%). Cronbach α was 0.88, and correlation of split halves was 0.59 (P < 0.0001). Higher PCQ scores correlated significantly with lower A1C (r = −0.29, P = 0.01) and expert assessments (r = 0.56, P < 0.001). Scores were significantly higher in parents with college degrees than in those without (P = 0.01) and in participants with more complex insulin regimens (P = 0.003). CONCLUSIONS The PCQ is a novel, easily administered instrument to assess knowledge about carbohydrates and insulin dosing calculations. Initial analyses support the reliability and validity of the PCQ.

Changes in Fat Mitochondrial DNA and Function in Subjects Randomized to Abacavir/Lamivudine or Tenofovir DF/Emtricitabine with Atazanavir/Ritonavir or Efavirenz: AIDS Clinical Trials Group Study A5224s, substudy of A5202

BACKGROUND The effect of nonthymidine nucleoside reverse-transcriptase inhibitors (NRTIs) on fat mitochondrial DNA (mtDNA) content and function is unclear. METHODS A5202 randomized antiretroviral therapy-naive human immunodeficiency virus-infected subjects to abacavir-lamivudine (ABC/3TC) versus tenofovir DF-emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir-ritonavir (ATV/r). A5224s, substudy of A5202, enrolled 269 subjects with fat measurements by dual-energy x-ray absorptiometry and computed tomography. A subset of subjects underwent fat biopsies at baseline and week 96 for mtDNA content (real-time polymerase chain reaction) and oxidative phosphorylation nicotinamide adenine dinucleotide (reduced) dehydrogenase (complex I) and cytochrome c oxidase (complex IV) activity levels (immunoassays). Intent-to-treat analyses were performed using analysis of variance and paired t tests. RESULTS Fifty-six subjects (87% male; median age, 39 years) were included; their median body mass index, CD4 cell count, and fat mtDNA level were 26 kg/m(2), 227 cells/μL, and 1197 copies/cell, respectively. Fat mtDNA content decreased within the ABC/3TC and TDF/FTC groups (combining EFV and ATV/r arms; median change, -341 [interquartile range, -848 to 190; P = .03] and -400 [-661 to -221; P < .001] copies/cell, respectively), but these changes did not differ significantly between the 2 groups (P = .57). Complex I and IV activity decreased significantly in the TDF/FTC group (median change, -12.45 [interquartile range, -24.70 to 2.90; P = .003] and -8.25 [-13.90 to -1.30; P < .001], optical density × 10(3)/µg, respectively) but not the ABC/3TC group. Differences between the ABC/3TC and TDF/FTC groups were significant for complex I (P = .03). CONCLUSIONS ABC/3TC and TDF/FTC significantly and similarly decreased fat mtDNA content, but only TDF/FTC decreased complex I and complex IV activity levels. CLINICAL TRIALS REGISTRATION NCT00118898.

Salsalate is poorly tolerated and fails to improve endothelial function in virologically suppressed HIV-infected adults

In this 13-week, open-label, randomized study of the anti-inflammatory salsalate versus usual care, there were no significant improvements in flow-mediated dilation of the brachial artery, endothelial activation, inflammation or coagulation markers, homeostasis model assessment of insulin resistance or lipoproteins with salsalate or between groups in virologically suppressed, HIV-infected adults on antiretrovirals. Tinnitus and transaminitis occurred frequently in the salsalate group. Dose reduction due to toxicities encountered and low level of inflammation may explain these results.

Mitochondrial function, inflammation, fat and bone in HIV lipoatrophy: randomized study of uridine supplementation or switch to tenofovir.

BACKGROUND Lipoatrophy modestly improves when the thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI) is removed. In vitro, uridine (NucleomaxX(®); Pharma Nord, Vojens, Denmark) reversed tNRTI mitochondrial toxicity. METHODS All patients had lipoatrophy on a tNRTI-containing regimen with HIV RNA<400 copies/ml. A randomized 48-week study switched patients from tNRTI to tenofovir (TDF) or added uridine (continuing tNRTI). End points were changes in limb fat (DEXA), subcutaneous abdominal fat mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), inflammation markers (soluble tumour necrosis factor receptors, high-sensitivity C reactive protein [hsCRP], interleukin-6 [IL-6], soluble vascular cell adhesion molecule 1), bone mineral density (BMD) of the hip and spine, HIV-1 RNA, CD4(+) T-cells and fasting metabolic parameters. RESULTS Fifty patients were enrolled (n=24 TDF switch; n=26 uridine); median age 48 years; 54% white; 86% male; limb fat 4,494 g. Baseline characteristics were similar between groups. In the NucleomaxX(®) arm, mtRNA increased (all P<0.001), hsCRP and IL-6 increased (both P=0.02), whereas fat mtDNA decreased without changes in limb fat. In the TDF-switch arm, fat mtDNA and inflammation markers did not change; however, significant increases in mtRNAs (P<0.001), limb fat (409 g; IQR -59-1,155) and CD4(+) T-cell count (P=0.03), and decreases in total and hip BMD (median -3.3%; IQR -5.1-0; P=0.005) were observed. Between-group changes were significant for fat mtDNA, hsCRP, IL-6, limb fat and hip BMD. No correlation was found between changes in limb fat and those of fat mtRNA, inflammation markers or protease inhibitor duration. CONCLUSIONS In HIV lipoatrophy, NucleomaxX(®) improved mtRNA, but worsened inflammation markers and fat mtDNA without changes in limb fat. Switching from a tNRTI to TDF for 48 weeks increased limb fat and fat mtRNA. Large decreases in total and hip BMD were seen after TDF switch.
ClinicalTrials.gov identifier: NCT00119379.

Pharmacokinetic properties and tolerability of single-dose terbutaline in patients with severe asthma treated in the pediatric intensive care unit

BACKGROUND Asthmatic children requiring treatment in the pediatric intensive care unit (PICU) receive aggressive drug therapy that may include IV administration of β 2-receptor agonists to prevent progression to life-threatening respiratory failure. The only pharmacologic agent in this class currently available for parenteral use in the United States is terbutaline. Study of IV dosing of terbutaline in the pediatric population has been limited. OBJECTIVE The aim of this study was to determine the pharmacokinetic (PK) properties and tolerability of single-dose terbutaline in pediatric patients across a broad age range who were admitted to the PICU and were receiving maximal conventional asthma drug therapy. METHODS This study was conducted at the PICU at Rainbow Babies and Childrens Hospital (Cleveland, Ohio). Patients aged 6 months to 16 years with severe exacerbation of reactive airways disease and who were undergoing maximal conventional therapy and had an arterial catheter were enrolled. Patients were arbitrarily assigned to receive a single IV infusion of 1 of 3 doses of terbutaline (10, 20, or 30 μg/kg), infused over 5 minutes. Blood samples were obtained for the determination of plasma terbutaline concentrations just before terbutaline was administered (baseline), immediately on completion of the IV infusion, and at 10, 20, and 40 minutes and 1, 2, 4, 8, 16, 32, 48, and 72 hours after the 5-minute infusion. PK properties (elimination half-life [tl2], mean residence time [MRT], apparent steady-state volume of distribution [Vdss], and total body clearance [CI]) were determined and adverse effects were recorded. RESULTS The determination of terbutaline PK properties was possible in 50 of 56 enrolled patients (31 boys, 19 girls; mean [SD] age, 6.5 [4.5] years). The PK properties of terbutaline were linear over the dose range studied and, with the exception of the expected dose-dependent increases in peak terbutaline plasma concentration and area under the terbutaline plasma concentration-time curve, no statistically significant differences were observed in PK relative to dose. Therefore, we pooled the data for all subsequent analyses. Statistically significant correlations with patient age were observed with tl2 (r = 0.4, P < 0.006), MRT (r = 0.4, P < 0.002), and Vdss (r = 0.33, P < 0.02), but not C1 (r = -0.03, P = NS). Single-dose terbutaline administration was generally well tolerated. CONCLUSIONS Single-dose IV terbutaline was well tolerated in this study. In maximally treated asthmatic patients in the PICU, terbutaline elimination may be more rapid than in nonacutely ill children. These PK data suggest that if the drug is to be administered intravenously, the continuous IV infusion method, including loading doses for any subsequent dose escalations, may be the most appropriate. The influence of age and safety of long-term, continuous terbutaline IV infusion requires further study.

Plasma Sclerostin in HIV-Infected Adults on Effective Antiretroviral Therapy.

Sclerostin is linked to bone physiology and cardiovascular disease through the Wnt/β-catenin signaling pathway. The goal of this study was to determine if sclerostin is related to bone physiology and cardiovascular disease during antiretroviral treatment in HIV-infected persons. This was a cross-sectional analysis from study entry into the Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN in HIV (SATURN) trial, an ongoing randomized trial comparing rosuvastatin to placebo in HIV-infected adults on antiretroviral therapy. Plasma sclerostin was measured at study entry by ELISA from participants with available samples. Spearman correlation and multivariable linear regression were used to test relationships between sclerostin and bone density or bone turnover and cardiovascular disease. Among 139 HIV-infected participants (median age 46 years, CD4 lymphocyte count 614 cells/μl), the median plasma sclerostin level was 444.1 (IQR 330.3, 570.1) pg/ml. Correlations were detected between sclerostin and age (r=0.26), lumbar spine Z-score (r=0.31), RANKL (r=-0.21), carotid intima-media thickness (CIMT, r=0.19), and sVCAM-1 (r=0.27), p<0.05. No significant correlations were detected between sclerostin and current (r=0.006) or nadir CD4 count (r=0.11). While associations between sclerostin, lumbar spine Z-score, and sVCAM-1 were robust to covariate adjustment (p<0.01), association with CIMT was no longer significant (p=0.08). Our findings provide preliminary support for a relationship between sclerostin and bone mineral density in HIV-infected persons. The Wnt/β-catenin pathway should be investigated as a potential mechanism for loss of bone mineral density in treated HIV infection.