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BACKGROUND - Cardiopulmonary bypass (CPB) lyses erythrocytes and induces lipid peroxidation, indicated by increasing plasma concentrations of free hemoglobin, F2-isoprostanes, and isofurans. Acetaminophen attenuates hemeprotein-mediated lipid peroxidation, reduces plasma and urine concentrations of F2-isoprostanes, and preserves kidney function in an animal model of rhabdomyolysis. Acetaminophen also attenuates plasma concentrations of isofurans in children undergoing CPB. The effect of acetaminophen on lipid peroxidation in adults has not been studied. This was a pilot study designed to test the hypothesis that acetaminophen attenuates lipid peroxidation in adults undergoing CPB and to generate data for a clinical trial aimed to reduce acute kidney injury following cardiac surgery.
METHODS AND RESULTS - In a prospective double-blind placebo-controlled clinical trial, sixty adult patients were randomized to receive intravenous acetaminophen or placebo starting prior to initiation of CPB and for every 6 hours for 4 doses. Acetaminophen concentrations measured 30 min into CPB and post-CPB were 11.9 ± 0.6 μg/mL (78.9 ± 3.9 μM) and 8.7 ± 0.3 μg/mL (57.6 ± 2.0 μM), respectively. Plasma free hemoglobin increased more than 15-fold during CPB, and haptoglobin decreased 73%, indicating hemolysis. Plasma and urinary markers of lipid peroxidation also increased during CPB but returned to baseline by the first postoperative day. Acetaminophen reduced plasma isofuran concentrations over the duration of the study (P = 0.05), and the intraoperative plasma isofuran concentrations that corresponded to peak hemolysis were attenuated in those subjects randomized to acetaminophen (P = 0.03). Perioperative acetaminophen did not affect plasma concentrations of F2-isoprostanes or urinary markers of lipid peroxidation.
CONCLUSIONS - Intravenous acetaminophen attenuates the increase in intraoperative plasma isofuran concentrations that occurs during CPB, while urinary markers were unaffected.
TRIAL REGISTRATION - ClinicalTrials.gov NCT01366976.
BACKGROUND - This study sought to assess the feasibility of conducting a phase III HIV prevention trial using a multivalent human papillomavirus (HPV) vaccine (Gardasil; Merck, Whitehouse Station, NJ).
METHODS - A total of 479 sexually active women aged 16-24 years in the Western Cape, South Africa, were enrolled in the Efficacy of HPV Vaccine to Reduce HIV Infection (EVRI) Trial. Of these, 402 were HIV negative, nonpregnant, and randomized 1:1 to receive Gardasil or a saline placebo vaccine. Vaccine doses were administered at enrollment, month 2, and month 6, and participants were followed for 1 month after the third dose. Enrollment HIV, HPV, other sexually transmitted infections (STIs), and cervical cytology were evaluated. Rates of accrual, vaccine compliance, and adherence to protocol were monitored.
RESULTS - High rates of accrual of eligible females to study (93%) and completion of the 3-dose vaccine series (91%) were noted, with few protocol violations. Ineligibility due to reported HIV positivity was 19%, and another 12% of those enrolled tested HIV positive. STI prevalence was high, with 6.2%, 10.9%, and 32.8% testing positive for syphilis, gonorrhea, and chlamydia, respectively. Cervical prevalence of ≥1 of 37 HPV types was 71%. STI and HPV prevalence was highest among the youngest women (<19 years).
CONCLUSIONS - Feasibility (successful accrual, retention, and vaccination) of conducting randomized placebo-controlled trials of HPV vaccines among HIV high-risk women in South Africa was demonstrated. This work demonstrates that phase III HIV prevention trials need to intervene at young ages and screen and treat multiple STIs concurrently to have a measurable impact on HIV acquisition.
Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority. In a phase I/II, placebo-controlled trial, healthy, HIV-1-negative adults were randomized to receive one of 5 vaccine regimens: LIPO-5 (combination of 5 lipopeptides) alone (250 μg), ALVAC-HIV (vCP1452) alone, or 3 groups of ALVAC-HIV (vCP1452) followed by ALVAC-HIV (vCP1452) plus LIPO-5 (250, 750, and 2,500 μg). Only 73/174 participants (42%) received all four vaccinations due to a study halt related to myelitis. There were no significant differences in systemic reactions between groups or in local reactogenicity between groups receiving ALVAC-HIV (vCP1452). Significant differences in local reactogenicity occurred between groups receiving LIPO-5 (P ≤ 0.05). Gag and Env antibodies were undetectable by ELISA 2 weeks after the fourth vaccination for all but one recipient. Antibodies to Gag and Env were present in 32% and 24% of recipients of ALVAC-HIV (vCP1452) alone and in 47% and 35% of ALVAC-HIV (vCP1452)+LIPO recipients, respectively. Coadministration of LIPO-5 did not significantly increase the response rate compared to ALVAC-HIV (vCP1452) alone, nor was there a significant relationship between dose and antibody responses among ALVAC-HIV (vCP1452)+LIPO groups. Over 90% of study participants had no positive gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses to any peptide pool at any time point. The study was halted due to a case of myelitis possibly related to the LIPO-5 vaccine; this case of myelitis remains an isolated event. In general, there was no appreciable cell-mediated immunity detected in response to the vaccines used in this study, and antibody responses were limited. The clinical trial is registered on ClinicalTrials.gov with registry number NCT00076063.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
OBJECTIVE - This planned secondary analysis of the Outcomes Following Vaginal Prolapse Repairs and Midurethral Sling trial assessed whether treatment knowledge differed between randomized groups at 12 months and whether treatment success was affected by treatment perception.
STUDY DESIGN - Sham suprapubic tension-free vaginal tape (TVT) incisions were made in the Outcomes Following Vaginal Prolapse Repairs and Midurethral Sling trial participants randomized to no-TVT. Primary surgical outcomes and maintenance of blinding was assessed at 12 months. Knowledge of treatment assignment was compared between groups, and the relationship with treatment success rates was assessed.
RESULTS - Prior to the 12 month postoperative visit, only 4% of treated participants (13 of 336) formally reported unmasking. At 12 months, 94% of the randomized participants (315 of 336) provided treatment knowledge data. Sixteen TVT participants (10%) reported treatment knowledge; most (n = 15, 94%) were correct; 17 of the sham participants (11%) reported treatment knowledge; half (n = 8, 47%) were correct. Similar proportions of unmasked participants who reported no treatment knowledge correctly guessed/perceived treatment assignment (sham, 46 [33%] vs TVT, 44 [33%]). We did not detect significant differences in treatment success rates based on perception within and across received treatment groups (perceived sham vs TVT overall [P = .76]). Of those receiving TVT, more participants perceiving TVT had treatment success compared with those who perceived sham (84% vs 74%; P = .29). Among sham participants, more participants perceiving sham had success compared with those who perceived receiving TVT (65% vs 56%; P = .42).
CONCLUSION - Sham surgical incisions effectively mask TVT randomization. These findings may help to inform future surgical trial designs.
Copyright © 2014 Elsevier Inc. All rights reserved.
BACKGROUND - The management of hyperphosphatemia in patients with moderate to severe chronic kidney disease (CKD) includes dietary phosphate restriction and/or prescription of phosphate binders. Measuring phosphate intake in CKD is important for monitoring dietary adherence and for the effectiveness of therapeutic interventions. The 24-hour urine collection is the gold standard method for determining phosphate intake; however, timed urine collections are cumbersome and prone to error. We investigated the precision and accuracy of spot urine phosphate measurements, compared to 24-hour urine phosphate (24hUrP) collection.
STUDY DESIGN, SETTING, AND PARTICIPANTS - We evaluated simultaneous spot and 24hUrP measurements, collected on multiple occasions, from 143 participants in the Phosphate Normalization Trial, a randomized trial of phosphate binders versus placebo among persons with an estimated glomerular filtration rate between 20-45 mL/minute per 1.73 m2. We used residual analyses and graphical methods to model the functional relationship of spot urine phosphate and creatinine measurements with 24hUrP. We used multiple linear regression to test whether additional covariates improved model prediction, including treatment assignment, age, sex, height, weight, urine collection time, and last meal time. We internally validated results using leave-one-out cross-validation, and externally validated in an independent replication cohort.
RESULTS - A log-log relation between the spot urine phosphate-to-creatinine ratio and 24hUrP excretion yielded the best model fit. In addition to spot urine phosphate and creatinine concentrations, inclusion of age, sex, and weight significantly improved prediction of 24hUrP. Compared with a spot urine phosphate-to-creatinine ratio alone (r2 = 0.12, P < .001), the new equation more accurately predicted 24hUrP (leave-one-out validation r2 = 0.43, P < .001, independent validation r2 = 0.39, P < .001).
CONCLUSION - We describe a novel equation to predict 24hUrP excretion using spot urine phosphate and creatinine, age, sex, and weight. The equation is more accurate and precise than the urine phosphate-to-creatinine ratio alone, and it provides a simple method for estimating 24hUrP excretion in patients with nondialysis-requiring CKD.
Copyright © 2014 National Kidney Foundation, Inc. All rights reserved.
Postural tachycardia syndrome (POTS) is characterized by excessive increases in heart rate (HR) upon standing. Previous studies have shown that standing HR decreases over time in POTS patients given placebo. We hypothesized that this reduction is due to cardiovascular physiological alteration, as opposed to psychological benefit from perceived therapy. To prospectively test this hypothesis, we examined the effects of an open-label 'no treatment' intervention (NoRx) compared with a patient-blinded placebo on standing HR in POTS patients. Twenty-one POTS patients participated in a randomized cross-over trial with oral placebo versus NoRx administered at 0900 h. Seated blood pressure (BP) and HR were measured at baseline and every hour for 4 h. Similarly, BP and HR were measured while patients stood for 10 min at these time points. Standing HR decreased significantly over time with both NoRx (112±13 and 103±16 b.p.m. at baseline and 4 h, respectively) and placebo (112±14 and 102±16 b.p.m. at baseline and 4 h, respectively; Ptime<0.001), but this effect was not different between interventions (Pdrug=0.771). Postural tachycardia syndrome patients have exaggerated orthostatic tachycardia in the morning that decreases over time with either placebo or NoRx interventions, suggesting this phenomenon is due to cardiovascular physiological variation. These data highlight the need for a placebo arm in haemodynamic clinical trials in POTS and may have important implications for the diagnosis of these patients.
© 2014 Wiley Publishing Asia Pty Ltd.
OBJECTIVE - Inflammation, insulin resistance and vascular dysfunction characterize obesity and predict development of cardiovascular disease (CVD). Although women experience CVD events at an older age, vascular dysfunction is evident 10years prior to coronary artery disease. Questions remain whether replacing SFA entirely with MUFA or PUFA is the optimal approach for cardiometabolic benefits. This study tested the hypotheses that: a) body composition, inflammation and vascular function would improve with a high fat diet (HFD) when type of fat is balanced as 1/3 SFA, 1/3 MUFA and 1/3 PUFA; and b) body composition, inflammation and vascular function would improve more when balanced HFD is supplemented with 18C fatty acids, in proportion to the degree of 18C unsaturation.
METHODS - Obese premenopausal women were stabilized on balanced HFD and randomized to consume 9g/d of encapsulated stearate (18:0), oleate (18:1), linoleate (18:2) or placebo.
RESULTS - Significant improvements occurred in fat oxidation rate (↑6%), body composition (%fat: ↓2.5±2.1%; %lean: ↑2.5±2.1%), inflammation (↓ IL-1α, IL-1β, 1L-12, Il-17, IFNγ, TNFα, TNFβ) and vascular function (↓BP, ↓PAI-1, ↑tPA activity). When compared to HFD+placebo, HFD+stearate had the greatest effect on reducing IFNγ (↓74%) and HFD+linoleate had the greatest effect on reducing PAI-1 (↓31%).
CONCLUSIONS - Balancing the type of dietary fat consumed (SFA/MUFA/PUFA) is a feasible strategy to positively affect markers of CVD risk. Moreover, reductions in inflammatory molecules involved in vascular function might be enhanced when intake of certain 18C fatty acids is supplemented. Long term effects need to be determined for this approach.
Copyright © 2014 Elsevier Inc. All rights reserved.
BACKGROUND - Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope glycoprotein (Env) were tested in a phase 2a trial in human immunodeficiency virus (HIV)-uninfected adults for safety, immunogenicity, and 6-month durability of immune responses.
METHODS - A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the MMM regimen); or placebo injections.
RESULTS - At peak response, 93.2% of the DDMM group and 98.4% of the MMM group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gp120) of Env. For both regimens, response rates were higher for CD4(+) T cells (66.4% in the DDMM group and 43.1% in the MMM group) than for CD8(+) T cells (21.8% in the DDMM group and 14.9% in the MMM group). Responding CD4(+) and CD8(+) T cells were biased toward Gag, and >70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon γ, interleukin 2, tumor necrosis factor α, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold.
CONCLUSIONS - DDMM and MMM vaccinations with virus-like particle-expressing immunogens elicited durable antibody and T-cell responses.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: firstname.lastname@example.org.
OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Of 112 subjects (ages 6-36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome-baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years-showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months. RESULTS C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168-0.268) and 0.141 nmol/L (95% CI 0.071-0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months' delay with abatacept. Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years. CONCLUSIONS Costimulation modulation with abatacept slowed decline of β-cell function and improved HbA1c in recent-onset T1D. The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.
OBJECTIVES - To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation.
DESIGN - Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial.
SETTING - Two hundred and thirty-three ICUs in 17 countries.
PATIENTS - All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score.
INTERVENTIONS - Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity.
MEASUREMENTS AND MAIN RESULTS - A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline.
CONCLUSIONS - ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.