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Background: CSL112 is a new formulation of human apolipoprotein A-I (apoA-I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double-blind, multicenter, dose-ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease., Methods and Results: Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2-hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug-related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA-I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7-, 3.4-, and 6.8-g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (>3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7-, 3.4-, and 6.8-g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion-site bruising. CSL112 resulted in rapid (T(max)≈2 hours) and dose-dependent increases in apoA-I (145% increase in the 6.8-g group) and total cholesterol efflux (up to 3.1-fold higher than placebo) (P<0.001)., Conclusions: CSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA-I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation., Clinical Trial Registration: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Many anti-psychotic medications produce marked weight gain. In this study, we estimate the expected impact of degrees of antipsychotic-induced weight gain on selected mortality rate and incidence rates of impaired glucose tolerance (IGT) and hypertension (HTN) among US adults. Using raw data from 5209 respondents from the Framingham Heart Study's public use data set and national statistics on population demographics, we estimated the expected effect of weight gain on number of deaths and incident cases of IGT and HTN for a 10-year period commencing in 1999. Results indicated that the estimated deleterious effects of weight gain were greater for people with higher BMIs at baseline, for greater degrees of weight gain, for men than women, and for older than younger persons. Because there is a 'U-shaped' relation between BMI and mortality rate, small to moderate weight gains among people with baseline BMIs less than 23 were predicted to decrease mortality rates, whereas weight gains among people with baseline BMIs above that level were expected to increase mortality rates. However, the relations of IGT and HTN with BMI are monotonically increasing. Thus, the anticipated effect of weight gain on IGT and HTN is deleterious regardless of baseline BMI. Because it is unclear whether the beneficial effects of the atypical agents on, for example, reducing suicide mortality, outweigh the putative increase in mortality due to weight gain, we estimate the beneficial effects due to decreased death from suicide with the potential deleterious effects due to a 10-kg weight gain. We found that 492 suicide deaths per 100,000 schizophrenic patients would be prevented over 10 years with the use of clozapine compared to 416 additional deaths due to antipsychotic induced weight gain. Although this estimate is rather crude and should be seen only as offering a sense of the likely situation, results suggest that the lives saved via clozapine may essentially be offset by the deaths due to weight gain. As we discuss, it is not possible to provide definitive estimates of the effect of antipsychotic-induced weight gain on health and mortality, but our findings suggest that the magnitude of weight gains induced by many antipsychotic agents is likely to have important deleterious effects on mortality and health.

The Expanded Clinical Evaluation of Lovastatin study, a randomized, double-blind, placebo- and diet-controlled multicenter trial, evaluated the efficacy and tolerability of lovastatin over 48 weeks in 8,245 patients with moderately severe hypercholesterolemia. During year 1 of follow-up of the full cohort, lovastatin at 20 or 40 mg/day, or 20 or 40 mg twice daily, produced dose-dependent decreases in low-density lipoprotein (LDL) cholesterol (24% to 40%) and triglyceride levels (10% to 19%), and increases in high-density lipoprotein (HDL) cholesterol (6.6% to 9.5%). In all, 977 patients continued their original blinded treatment for an additional year. In year 2, the LDL cholesterol response to lovastatin was maintained, the triglyceride reductions were somewhat less, and the increases in HDL cholesterol were moderately greater than in year 1. Successive transaminase elevations > 3 times the upper limit of normal were observed in only 1 patient in year 2, yielding a cumulative 2-year incidence of from 0.1% (placebo or lovastatin 20 mg/day) to 1.9% (lovastatin 80 mg/day). Myopathy occurred in only 1 patient during year 2, and over the 2-year study was observed rarely and only at lovastatin dosages of 40 and 80 mg/day. This study indicates that lovastatin maintains its efficacy over long-term follow-up, particularly in effectively lowering LDL cholesterol, is generally well tolerated, and has a favorable safety profile.

Coronary artery disease (CAD) primary end point definitions used in previous prevention trials are reviewed, as well as trends over time for CAD mortality, incidence and hospital discharges to see if new primary end points should be considered. CAD mortality has shown a dramatic decline in the U.S. in the last 20 years, whereas the decrease in the incidence of acute myocardial infarction (AMI) is less consistent. The decline in CAD incidence and mortality has been attributed to changes in lifestyle and increased medical/surgical intervention. Hospital discharge rates for CAD have risen during the past decade. In addition, although the rate of discharge for AMI appears to have stabilized, the rates for angina, and more dramatically for unstable angina, have increased. Unstable angina made up 4% of CAD discharges in 1980, and increased to 25% of CAD discharges in 1989. Because of these trends, future trials that rely solely on AMI as a primary end point will not reflect the actual experience with CAD presentation in the U.S. Given the greater availability of methods to diagnose unstable angina more accurately, and because of its high risk pathology, it is concluded that unstable angina should receive serious consideration as a primary end point in future primary prevention trials.

Shellfishborne disease control in the United States began in the 1920's. The water quality standard promulgated at that time to reduce the incidence of shellfishborne disease has never been adequately evaluated. Evidence suggesting such an evaluation is needed comes from 1) the frequency of shellfishborne disease outbreaks, 2) the changing nature of disease agents, 3) reports of shellfishborne disease in non-outbreak settings, and 4) microbiological studies indicating a lack of correlation between the standard and potential pathogenic organisms. A proper evaluation will define the standard's ability to protect human health and allow for the harvesting of an important food resource.

Ambulatory encounters in a community-based family practice residency program were analyzed using diagnosis clusters. During an 18-month period (July 1982 through December 1983), demographic information and clinical diagnoses for 44,453 successive patient visits were collected and stored in a computerized data base. The 30 most frequent diagnosis clusters accounted for 70% of all recorded clinical diagnoses. Comparison with NAMCS, USC-MAMP (Western Region) and Virginia studies revealed a younger, more indigent population with a higher frequency of visits for hypertension, prenatal and postnatal care, diabetes, chronic respiratory illness and congestive heart failure. Consistent with the other large ambulatory data sets, the general medical examination, hypertension and acute upper respiratory conditions were the most frequent diagnosis clusters. Differences with other reported data sets reflected the site-specific demographic characteristics of patients and providers, regional and environmental influences on the incidence of specific disease states and the relative abundance of other subspecialist physicians. Such local or regional data bases not only provide valuable information as to clinical content but also may help in identifying previously unrecognized health problems.