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Prediction of Residual Risk by Ceramide-Phospholipid Score in Patients With Stable Coronary Heart Disease on Optimal Medical Therapy.
Hilvo, M, Wallentin, L, Ghukasyan Lakic, T, Held, C, Kauhanen, D, Jylhä, A, Lindbäck, J, Siegbahn, A, Granger, CB, Koenig, W, et al
Journal of the American Heart Association. 2020;(10):e015258
Abstract
Background Identification of patients with stable coronary heart disease who are at significant residual risk could be helpful for targeted prevention. Our aim was to determine the prognostic value of the recently introduced ceramide- and phospholipid-based risk score, the Cardiovascular Event Risk Test (CERT2), in patients with stable coronary heart disease on optimal medical therapy and to identify biological processes that contribute to the CERT2 score. Methods and Results Plasma samples (n=11 222) obtained from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were analyzed using a tandem liquid chromatography-mass spectrometry method. STABILITY was a trial in patients with stable coronary heart disease randomized to the lipoprotein-associated phospholipase A2 inhibitor darapladib or placebo on optimized medical therapy at baseline, with a median follow-up of 3.7 years. Hazard ratios per SD for the CERT2 risk score were 1.32 (95% CI, 1.25-1.39) for major adverse cardiovascular event, 1.47 (95% CI, 1.35-1.59) for cardiovascular death, 1.32 (95% CI, 1.16-1.49) for stroke, 1.23 (95% CI, 1.14-1.33) for myocardial infarction, and 1.56 (95% CI, 1.39-1.76) for hospitalization due to heart failure, when adjusted for traditional cardiovascular risk factors. CERT2 showed correlation (P<0.001, r>0.2) with inflammatory markers high-sensitivity C-reactive protein, interleukin 6, the heart failure marker N-terminal pro-B-type natriuretic peptide, and low-density lipoprotein cholesterol. After also adjusting for levels of other prognostic biomarkers, the CERT2 score was still independently related to the risk of cardiovascular death but not to nonfatal events. Conclusions The CERT2 risk score can detect residual risk in patients with stable coronary heart disease and is associated with biomarkers indicating inflammation, myocardial necrosis, myocardial dysfunction, renal dysfunction, and dyslipidemia. REGISTRATION URL https://www.clinicaltrials.gov. Unique identifier: NCT00799903.
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Using joint models to disentangle intervention effect types and baseline confounding: an application within an intervention study in prodromal Alzheimer's disease with Fortasyn Connect.
van Oudenhoven, FM, Swinkels, SHN, Hartmann, T, Soininen, H, van Hees, AMJ, Rizopoulos, D
BMC medical research methodology. 2019;(1):163
Abstract
BACKGROUND Many prodromal Alzheimer's disease trials collect two types of data: the time until clinical diagnosis of dementia and longitudinal patient information. These data are often analysed separately, although they are strongly associated. By combining the longitudinal and survival data into a single statistical model, joint models can account for the dependencies between the two types of data. METHODS We illustrate the major steps in a joint modelling approach, motivated by data from a prodromal Alzheimer's disease study: the LipiDiDiet trial. RESULTS By using joint models we are able to disentangle baseline confounding from the intervention effect and moreover, to investigate the association between longitudinal patient information and the time until clinical dementia diagnosis. CONCLUSIONS Joint models provide a valuable tool in the statistical analysis of clinical studies with longitudinal and survival data, such as in prodromal Alzheimer's disease trials, and have several added values compared to separate analyses.
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Association of Mild to Moderate Aortic Valve Stenosis Progression With Higher Lipoprotein(a) and Oxidized Phospholipid Levels: Secondary Analysis of a Randomized Clinical Trial.
Capoulade, R, Yeang, C, Chan, KL, Pibarot, P, Tsimikas, S
JAMA cardiology. 2018;(12):1212-1217
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Abstract
IMPORTANCE Several studies have reported an association of levels of lipoprotein(a) (Lp[a]) and the content of oxidized phospholipids on apolipoprotein B (OxPL-apoB) and apolipoprotein(a) (OxPL-apo[a]) with faster calcific aortic valve stenosis (CAVS) progression. However, whether this association is threshold or linear remains unclear. OBJECTIVE To determine whether the plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) have a linear association with a faster rate of CAVS progression. DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of a randomized clinical trial tested the association of baseline plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) with the rate of CAVS progression. Participants were included from the ASTRONOMER (Effects of Rosuvastatin on Aortic Stenosis Progression) trial, a multicenter study conducted in 23 Canadian sites designed to test the effect of statin therapy (median follow-up, 3.5 years [interquartile range, 2.9-4.5 years]). Patients with mild to moderate CAVS defined by peak aortic jet velocity ranging from 2.5 to 4.0 m/s were recruited; those with peak aortic jet velocity of less than 2.5 m/s or with an indication for statin therapy were excluded. Data were collected from January 1, 2002, through December 31, 2005, and underwent ad hoc analysis from April 1 through September 1, 2018. INTERVENTIONS After the randomization process, patients were followed up by means of echocardiography for 3 to 5 years. MAIN OUTCOMES AND MEASURES Progression rate of CAVS as assessed by annualized progression of peak aortic jet velocity. RESULTS In this cohort of 220 patients (60.0% male; mean [SD] age, 58 [13] years), a linear association was found between plasma levels of Lp(a) (odds ratio [OR] per 10-mg/dL increase, 1.10; 95% CI, 1.03-1.19; P = .006), OxPL-apoB (OR per 1-nM increase, 1.06; 95% CI, 1.01-1.12; P = .02), and OxPL-apo(a) (OR per 10-nM increase, 1.16; 95% CI, 1.05-1.27; P = .002) and faster CAVS progression, which is marked in younger patients (OR for Lp[a] level per 10-mg/dL increase, 1.19 [95% CI, 1.07-1.33; P = .002]; OR for OxPL-apoB level per 1-nM increase, 1.06 [95% CI, 1.02-1.17; P = .01]; and OR for OxPL-apo[a] level per 10-nM increase, 1.26 [95% CI, 1.10-1.45; P = .001]) and remained statistically significant after comprehensive multivariable adjustment (β coefficient, ≥ 0.25; SE, ≤ 0.004 [P ≤ .005]; OR, ≥1.10 [P ≤ .007]). CONCLUSIONS AND RELEVANCE This study demonstrates that the association of Lp(a) levels and its content in OxPL with faster CAVS progression is linear, reinforcing the concept that Lp(a) levels should be measured in patients with mild to moderate CAVS to enhance management and risk stratification. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00800800.
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NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study): Randomized Controlled Contrast-Enhanced Sonothrombolysis in an Unselected Acute Ischemic Stroke Population.
Nacu, A, Kvistad, CE, Naess, H, Øygarden, H, Logallo, N, Assmus, J, Waje-Andreassen, U, Kurz, KD, Neckelmann, G, Thomassen, L
Stroke. 2017;(2):335-341
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Abstract
BACKGROUND AND PURPOSE The NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study) aimed to assess effect and safety of contrast-enhanced ultrasound treatment in an unselected acute ischemic stroke population. METHODS Patients treated with intravenous thrombolysis within 4.5 hours after symptom onset were randomized 1:1 to either contrast-enhanced sonothrombolysis (CEST) or sham CEST. A visible arterial occlusion on baseline computed tomography angiography was not a prerequisite for inclusion. Pulse-wave 2 MHz ultrasound was given for 1 hour and contrast (SonoVue) as an infusion for ≈30 minutes. Magnetic resonance imaging and angiography were performed after 24 to 36 hours. Primary study end points were neurological improvement at 24 hours defined as National Institutes of Health Stroke Scale score 0 or reduction of ≥4 National Institutes of Health Stroke Scale points compared with baseline National Institutes of Health Stroke Scale and favorable functional outcome at 90 days defined as modified Rankin scale score 0 to 1. RESULTS A total of 183 patients were randomly assigned to either CEST (93 patient) or sham CEST (90 patients). The rates of symptomatic intracerebral hemorrhage, asymptomatic intracerebral hemorrhage, or mortality were not increased in the CEST group. Neurological improvement at 24 hours and functional outcome at 90 days was similar in the 2 groups both in the intention-to-treat analysis and in the per-protocol analysis. CONCLUSIONS CEST is safe among unselected ischemic stroke patients with or without a visible occlusion on computed tomography angiography and with varying grades of clinical severity. There was, however, statistically no significant clinical effect of sonothrombolysis in this prematurely stopped trial. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01949961.
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Preventing the Progression of Intestinal Failure-Associated Liver Disease in Infants Using a Composite Lipid Emulsion: A Pilot Randomized Controlled Trial of SMOFlipid.
Diamond, IR, Grant, RC, Pencharz, PB, de Silva, N, Feldman, BM, Fitzgerald, P, Sigalet, D, Dicken, B, Turner, J, Marchand, V, et al
JPEN. Journal of parenteral and enteral nutrition. 2017;(5):866-877
Abstract
BACKGROUND To examine whether SMOFlipid prevents progression of intestinal failure-associated liver disease (IFALD) in parenteral nutrition (PN)-dependent infants with early IFALD (conjugated bilirubin 17-50 µmol/L, 1-3 mg/dL). STUDY DESIGN Pilot multicenter blinded randomized controlled trial comparing SMOFlipid with Intralipid. Patients received the trial lipid for up to 12 weeks, unless they achieved full enteral tolerance sooner. The primary clinical outcome was the serum conjugated bilirubin. RESULTS Twenty-four infants (mean age, 6 weeks) participated in the trial (13 Intralipid and 11 SMOFlipid). At the time of trial enrollment, patients in both groups were receiving 90% of their calories by PN. Mean duration on trial was 8 weeks and did not differ according to treatment ( P = .99). At trial conclusion, patients who received SMOFlipid had a lower conjugated bilirubin than those who received Intralipid (mean difference, -59 µmol/L; P = .03). Patients receiving SMOFlipid were also more likely to have a decrease in serum conjugated bilirubin to 0 µmol/L than those in the Intralipid group over the entire observation period (hazard ratio, 10.6; 95%; P = .03). The time to achievement of full enteral tolerance did not differ statistically (hazard ratio, 1.3; P = .59) between the groups. There was no significant difference in safety outcomes between the groups. CONCLUSIONS Compared with Intralipid, SMOFlipid reduces the risk of progressive IFALD in children with intestinal failure. This trial was registered at clinicaltrials.gov as NCT00793195.
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Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma.
Klein, O, Davis, ID, McArthur, GA, Chen, L, Haydon, A, Parente, P, Dimopoulos, N, Jackson, H, Xiao, K, Maraskovsky, E, et al
Cancer immunology, immunotherapy : CII. 2015;(4):507-18
Abstract
Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08); however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest that the alkylating agent cyclophosphamide can enhance immune responses by depleting Tregs. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine. The combination treatment led to a significant increase in vaccine-induced NY-ESO-1-specific CD4(+) T cell responses compared with the first trial cohort treated with vaccine alone. We could not detect a significant decline in regulatory T cells in peripheral blood of patients 14 days after cyclophosphamide administration, although a decline at an earlier time point cannot be excluded. Our observations support the inclusion of cyclophosphamide in combination trials with vaccines and other immune-modulatory agents.
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A nutritional approach to ameliorate altered phospholipid metabolism in Alzheimer's disease.
Hartmann, T, van Wijk, N, Wurtman, RJ, Olde Rikkert, MG, Sijben, JW, Soininen, H, Vellas, B, Scheltens, P
Journal of Alzheimer's disease : JAD. 2014;(3):715-7
Abstract
Recently, a biomarker panel of 10 plasma lipids, including 8 phosphatidylcholine species, was identified that could predict phenoconversion from cognitive normal aged adults to amnestic mild cognitive impairment or Alzheimer's disease (AD) within 2-3 years with >90% accuracy. The reduced levels of these plasma phospholipids could reflect altered phospholipid metabolism in the brain and periphery. We show that a 24-week nutritional intervention in drug-naïve patients with very mild to mild AD significantly increased 5 of the 7 measured biomarker phosphatidylcholine species. By providing nutrients which normally rate-limit phospholipid synthesis, this nutritional intervention could be useful in asymptomatic subjects with a plasma lipid biomarker profile prognostic of AD.
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Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma.
Nicholaou, T, Ebert, LM, Davis, ID, McArthur, GA, Jackson, H, Dimopoulos, N, Tan, B, Maraskovsky, E, Miloradovic, L, Hopkins, W, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2009;(6):2166-73
Abstract
PURPOSE NY-ESO-1 is a highly immunogenic antigen expressed in a variety of malignancies, making it an excellent target for cancer vaccination. We recently developed a vaccine consisting of full-length recombinant NY-ESO-1 protein formulated with ISCOMATRIX adjuvant, which generated strong humoral and T-cell-mediated immune responses and seemed to reduce the risk of disease relapse in patients with fully resected melanoma. This study examines the clinical and immunologic efficacy of the same vaccine in patients with advanced metastatic melanoma. EXPERIMENTAL DESIGN Delayed-type hypersensitivity responses, circulating NY-ESO-1-specific CD4(+) and CD8(+) T cells, and proportions of regulatory T cells (Treg) were assessed in patients. RESULTS In contrast to patients with minimal residual disease, advanced melanoma patients showed no clinical responses to vaccination. Although strong antibody responses were mounted, the generation of delayed-type hypersensitivity responses was significantly impaired. The proportion of patients with circulating NY-ESO-1-specific CD4(+) T cells was also reduced, and although many patients had CD8(+) T cells specific to a broad range of NY-ESO-1 epitopes, the majority of these responses were preexisting. Tregs were enumerated in the blood by flow cytometric detection of cells with a CD4(+)CD25(+)FoxP3(+) and CD4(+)CD25(+)CD127(-) phenotype. Patients with advanced melanoma had a significantly higher proportion of circulating Treg compared with those with minimal residual disease. CONCLUSIONS Our results point to a tumor-induced systemic immune suppression, showing a clear association between the stage of melanoma progression, the number of Treg in the blood, and the clinical and immunologic efficacy of the NY-ESO-1 ISCOMATRIX cancer vaccine.
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Effects of specific CLA isomers on plasma fatty acid profile and expression of desaturases in humans.
Thijssen, MA, Malpuech-Brugère, C, Gregoire, S, Chardigny, JM, Sébédio, JL, Mensink, RP
Lipids. 2005;(2):137-45
Abstract
Human studies suggest that CLA changes metabolism, possibly through effects on mRNA expression of desaturase and elongase enzymes. In this respect, differential effects of the two most common dietary CLA isomers, cis-9,trans-11 (c9,t11) and trans-10,cis-12 (t10,c12) CLA, have hardly been studied. We therefore gave 25 healthy, overweight men and women daily for 6 wk a drinkable dairy product containing 3 g of oil that was rich in oleic acid. For the next 18 wk, the control group (n = 7) continued to use this product, whereas the second (n = 9) and third groups (n = 9) received products with 3 g of purified c9,t11 CLA or t10,c12 CLA. For each gram of c9,t11 CLA consumed, the proportion in plasma phospholipids increased by 0.26%. For t10, c12 CLA, this value was 0.20%. The t10,c12 CLA isomer increased plasma TAG levels of conjugated 18:3, whereas c9,t11 CLA increased those of both conjugated 18:3 and 20:3. In plasma phospholipids, the delta9 desaturation index of 18:0 (18:1 n-9/18:0) was decreased by t10,c12 CLA (P= 0.03 for diet effects), and the delta6 desaturation index [(18:3n-6 + 20:3n-6)/18:2n-6] was decreased by both CLA isomers (P < 0.01 for diet effects). The delta5 desaturation index (20:4n-6/20:3n-6) and the delta9 desaturation index of 16:0 (16:1 n-7/16:0) were not affected. No effects were seen on mRNA expression of desaturases and elongase in peripheral blood mononuclear cells (PBMC). We therefore conclude that incorporation of c9,t11 and t10,c12 CLA into plasma lipids reflects dietary intakes. Compared with oleic acid, delta9 and delta6 desaturation indices in plasma phospholipids are decreased after consumption of c9,t11 or t10,c12 CLA. Effects on desaturation indices were, however, not reflected by changes at the transcriptional level for the various desaturases and elongase enzymes in PBMC.
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SonoVue in transcranial Doppler investigations of the cerebral arteries.
Kaps, M, Legemate, DA, Ries, F, Ackerstaff, RG, Markus, H, Pezzoll, C, Llull, JB, Spinazzi, A
Journal of neuroimaging : official journal of the American Society of Neuroimaging. 2001;(3):261-7
Abstract
BACKGROUND AND PURPOSE The authors investigated the safety and diagnostic potential of a new ultrasound contrast agent (SonoVue) using transcranial color-coded duplex sonography (TCCS). METHODS Forty patients were enrolled in a multicenter, open-label (on-site), blind (off-site), randomized, dose-ranging crossover study. SonoVue was administered as an intravenous bolus injection of 4 different dosages (0.3, 0.6, 1.2, and 2.4 mL). Efficacy was evaluated as (1) off-site assessment of global quality of the Doppler investigation (based on color or power Doppler images and spectral analysis) at baseline and following each dose of SonoVue according to a 4-point scale (from very poor to excellent imaging of blood flow) and (2) duration of clinically useful signal enhancement and color or power Doppler visualization of blood flow. Additional on-site efficacy assessments performed following each dose of SonoVue included confidence in diagnosis and global consequences of contrast enhancement on diagnosis. Safety evaluations included clinical laboratory tests, neurological examination, injection site tolerability, and incidence of adverse events and their relationship to the study agent. RESULTS All doses of SonoVue significantly improved the global quality of Doppler examinations (P < .05). The median duration of clinically useful enhancement was dose related (P < .001) and ranged from 2 to 6 minutes at the highest dose. The administration of the contrast agent changed a nondiagnostic study to a diagnostic one in 66% of patients and increased the confidence in diagnosis in 74% of cases. No serious adverse events were recorded following SonoVue administration. The observed adverse reactions were all transient and mild in intensity. CONCLUSIONS The results obtained from this multicenter study demonstrate that the administration of SonoVue to patients with ischemic cerebrovascular disease who undergo TCCS examination of cerebral vessels improves the visualization of intracranial arteries, providing a dose-dependent contrast enhancement and a clinically useful duration of signal enhancement related to the dose. During this multicenter study, SonoVue proved to be a safe and well-tolerated compound.