A community assessment to inform a multi-level intervention to reduce CVD risk and risk disparities in a rural community

In order to complete a formative evaluation to identify community-level assets and barriers to healthy lifestyle choices, we conducted qualitative interviews, community audits, and secondary data analyses. We solicited local leaders’ perspectives regarding ‘win-ability’ of obesity prevention policy options. Participants noted that many resources were available, yet a barrier was high cost. There were more parks per capita in low-income areas, but they were of lower quality. The most winnable obesity prevention policy was incentives for use of food from local farms. Results are being used to inform an intervention to reduce CVD risk in a rural eastern North Carolina

Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: A randomized trial

AIM: High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. OBJECTIVE: To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). DESIGN AND SETTING: A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion. PATIENTS: Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. INTERVENTION: Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. MAIN OUTCOME MEASURES: The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. RESULTS: The nominal change in the total atheroma volume (adjusted means) was -2.71, -3.13, -1.50, and -3.05 mm(3) with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, -0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was -0.022, -0.036, -0.022, and -0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was -0.51, 2.65, 0.71, and -0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. CONCLUSION: CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2; TRIAL REGISTRATION NUMBER: NCT01201837

Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial†

Aim High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. Objective To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). Design and setting A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion. Patients Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. Intervention Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. Main outcome measures The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. Results The nominal change in the total atheroma volume (adjusted means) was −2.71, −3.13, −1.50, and −3.05 mm3 with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, −0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was −0.022, −0.036, −0.022, and −0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was −0.51, 2.65, 0.71, and −0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. Conclusion CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2; Trial registration number: NCT0120183

Clinical tolerability and safety profile of CER-001, a novel bio-engineered pre-\u3b2 HDL-mimetic, across the clinical development programme

Background: The main protective effect of HDL against atherosclerosis is its ability to mobilise cholesterol from lipid-rich atherosclerotic plaques. Cerenis Therapeutics has developed CER-001, an engineered discoidal particle comprising recombinant human ApoA-I and phospholipids mimicking the natural nascent, discoidal pre-\uf062 HDL particle. In preclinical studies, CER-001 promotes cholesterol efflux from macrophages and from atherosclerotic plaques. In clinical trials in patients with familial hypercholesterolaemia or hypoalphalipoproteinaemia, CER-001 reduced carotid wall thickness and enhanced ex vivo cholesterol efflux capacity, thus affecting atherosclerotic burden. Several clinical development programs are underway. Purpose: To report the clinical tolerability and safety findings observed with CER-001 across the clinical development programs performed to date. Methods: Adverse event (AE), serious AE (SAE) and other safety-related data were collated to evaluate the safety profile of CER-001 to determine whether any specific treatment-related AEs emerge as clinical experience with the product increases. Results: In the Phase I study, no treatment-related AEs were reported with single IV doses of CER-001 (0.25 to 45 mg/kg). There were no deaths, SAEs or AEs that led to withdrawal. There were no adverse findings associated with CER-001, relative to placebo, on vital signs, ECGs, clinical chemistry, haematology, immunogenicity and coagulation parameters. In multiple dose studies involving CER-001 (3 to 12 mg/kg), there have been no unusual or particularly concerning AEs reported to date. After six administrations, one each week, in post-ACS patients, no antibodies against ApoA-I were detected at 6 months. AE data from 530 subjects in Phase II studies, including type and incidence of AEs, SAEs and AEs causing withdrawal from study treatment, shows a safety profile comparable with placebo except for infusion reactions, which occurred more frequently with CER-001. Treatment-related infusion reactions occurred in 16 of 410 subjects (4%) treated with CER-001 in Phase II studies. These were reversible in all cases and either resolved spontaneously or after management with antihistamines, steroids and/or IV fluids. In studies evaluating liver enzymes (ALT, AST), no 3-times upper limit of normal elevations were seen during CER-001 therapy. Conclusions: To date, CER-001 appears to have a clinical safety profile similar to placebo in terms of type and incidence of AEs, SAEs and AEs causing withdrawal from study treatment. CER-001 was not associated with any adverse impact on hepatic safety. Not unusually, a slightly higher incidence of infusion reactions has been reported and clinical study sites should be aware of the possibility of infrequent infusion reactions and be prepared to provide supportive care if necessary. Safety support is continuing with CER-001 clinical development for short- and long-term treatment

The influence of the eugenics movement on physical education in the United States

L'imprégnation de la culture américaine par les idées, les thèmes, les concepts eugéniques ou issus de l'eugénisme (primauté de l'anthropométrie, darwinisme social, hygiène raciale, éducation sexuelle, stéréotypes raciaux, lutte contre la dégénérescence de la race, dépistage des caractéristiques héréditaires et croyance en les progrès de la génétique...), et leur influence dans la naissance et le développement de l'éducation physique aux Etats-Unis

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE^-/- Mice: Evidence of ABCA1 Down-Regulation

<div><p>Objective</p><p>CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression <i>in vitro</i> and <i>in vivo</i> in the presence of CER-001 and native HDL (HDL3).</p><p>Methods and Results</p><p>CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL₃ compared to non-lipidated apoA-I. <i>In vivo</i>, in an apoE^-/- mouse “flow cessation model,” in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively.</p><p>Conclusions</p><p>These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE^-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both <i>in vitro</i> and <i>in vivo</i>. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression.</p></div

No benefit of HDL mimetic CER-001 on carotid atherosclerosis in patients with genetically determined very low HDL levels

Background and aims: Infusion of high-density lipoprotein (HDL) mimetics failed to induce regression of atherosclerosis in recent randomized clinical trials. However, patients in these previous trials had normal levels of HDL-cholesterol, which potentially limited efficacy. Patients with very low levels of HDL-cholesterol and impaired cholesterol efflux capacity can be expected to derive the most potential benefit from infusion of HDL mimetics. This randomized clinical trial evaluated the efficacy of infusions of the HDL mimetic CER-001 in patients with genetically determined very low levels of HDL cholesterol. Methods: In this multicenter, randomized clinical trial, we recruited patients with familial hypoalphalipoproteinemia (due to ABCA1 and/or APOA1 loss-of-function variants). Participants were randomized to intravenous infusions of 8 mg/kg CER-001 or placebo (2:1 ratio), comprising 9 weekly infusions followed by infusions every two weeks. Patients underwent repeated 3T-MRI to assess mean vessel wall area and 18F-FDG PET/CT to quantify arterial wall inflammation. Results: A total of 30 patients with a mean age of 52.7 ± 7.4 years and HDL-cholesterol of 0.35 ± 0.25 mmol/L were recruited. After 24 weeks, the absolute change in mean vessel wall area was not significantly different in the CER-001 group compared with placebo (n = 27; treatment difference: 0.77 mm2, p = 0.21). Furthermore, there was no significant difference in carotid arterial wall inflammation (n = 24, treatment difference: 0.10 target-to-background ratio of the most diseased segment, p = 0.33) after 24 weeks. Conclusion: In patients with genetically determined very low HDL-cholesterol, 24 weeks of treatment with HDL mimetic CER-001 did not reduce carotid vessel wall dimensions or arterial wall inflammation, compared with placebo

cAMP stimulated-ABCA1 specific efflux decrease in J774 macrophages following CER-001 and HDL3 incubation.

<p>J774 macrophages were incubated with cAMP to increase the ABCA1 expression and then CER-001 and HDL3 at 25 μg/ml were added in the cell culture medium and the specific cAMP cholesterol efflux was determined. apoA-I (25 μg/ml) was used as reference for specific ABCA1-cholesterol efflux in the experiment. ** p<0.01, ***p<0.001.</p

Effect of dose-response of CER-001 and HDL3 in atherosclerotic plaque progression in ligatured carotid of apoE^-/- mice.

<p>The left carotid of apoE^-/- mice (n = 12) was ligatured, fed with HCD and treated (retro-orbital injection) every second day with different concentrations of CER-001 or HDL3 (8 infusions). The carotids were lipid extracted and cholesterol concentrations were determined by HPLC. Panel A; unesterified cholesterol. Panel B; total cholesterol. Panel C; protein level of ABCA1 was measured in the ligatured carotids using Western blot analysis as described in material and methods section. The data represent the means of ABCA1 expression from at least 5 different carotids. Representative Western-blot for carotid analysis was resolved with anti-ABCA1 antibody (1/1000 dilution) and anti-Calnexin antibody (1/1000). * p<0.05, ** p<0.01, ***p<0.005, ****p<0.001, *****p<0.0001</p