Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)

BACKGROUND: The Scandinavian Simvastatin Survival Study (4S) randomized 4444 patients with coronary heart disease (CHD) and serum cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with triglycerides < or =2.5 mmol/L (220 mg/dL) to simvastatin 20 to 40 mg or placebo once daily. Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction, P<.00001). Simvastatin produced substantial changes in several lipoprotein components, which we have attempted to relate to the beneficial effects observed. METHODS AND RESULTS: The Cox proportional hazards model was used to assess the relationship between lipid values (baseline, year 1, and percent change from baseline at year 1) and MCEs. The reduction in MCEs within the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total and LDL cholesterol, apolipoprotein B, and less so with HDL cholesterol, but there was no clear relationship with triglycerides. We estimate that each additional 1% reduction in LDL cholesterol reduces MCE risk by 1.7% (95% CI, 1.0% to 2.4%; P<.00001). CONCLUSIONS: These analyses suggest that the beneficial effect of simvastatin in individual patients in 4S was determined mainly by the magnitude of the change in LDL cholesterol, and they are consistent with current guidelines that emphasize aggressive reduction of this lipid in CHD patients.     

Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial

CONTEXT: Alendronate sodium reduces fracture risk in postmenopausal women who have vertebral fractures, but its effects on fracture risk have not been studied for women without vertebral fractures. OBJECTIVE: To test the hypothesis that 4 years of alendronate would decrease the risk of clinical and vertebral fractures in women who have low bone mineral density (BMD) but no vertebral fractures. DESIGN: Randomized, blinded, placebo-controlled trial. SETTING: Eleven community-based clinical research centers. SUBJECTS: Women aged 54 to 81 years with a femoral neck BMD of 0.68 g/cm2 or less (Hologic Inc, Waltham, Mass) but no vertebral fracture; 4432 were randomized to alendronate or placebo and 4272 (96%) completed outcome measurements at the final visit (an average of 4.2 years later). INTERVENTION: All participants reporting calcium intakes of 1000 mg/d or less received a supplement containing 500 mg of calcium and 250 IU of cholecalciferol. Subjects were randomly assigned to either placebo or 5 mg/d of alendronate sodium for 2 years followed by 10 mg/d for the remainder of the trial. MAIN OUTCOME MEASURES: Clinical fractures confirmed by x-ray reports, new vertebral deformities detected by morphometric measurements on radiographs, and BMD measured by dual x-ray absorptiometry. RESULTS: Alendronate increased BMD at all sites studied (P<.001) and reduced clinical fractures from 312 in the placebo group to 272 in the intervention group, but not significantly so (14% reduction; relative hazard [RH], 0.86; 95% confidence interval [CI], 0.73-1.01). Alendronate reduced clinical fractures by 36% in women with baseline osteoporosis at the femoral neck (>2.5 SDs below the normal young adult mean; RH, 0.64; 95% CI, 0.50-0.82; treatment-control difference, 6.5%; number needed to treat [NNT], 15), but there was no significant reduction among those with higher BMD (RH, 1.08; 95% CI, 0.87-1.35). Alendronate decreased the risk of radiographic vertebral fractures by 44% overall (relative risk, 0.56; 95% CI, 0.39-0.80; treatment-control difference, 1.7%; NNT, 60). Alendronate did not increase the risk of gastrointestinal or other adverse effects. CONCLUSIONS: In women with low BMD but without vertebral fractures, 4 years of alendronate safely increased BMD and decreased the risk of first vertebral deformity. Alendronate significantly reduced the risk of clinical fractures among women with osteoporosis but not among women with higher BMD.     

A loop acceleration technique to speed up verification of automatically generated plans

The CIRCA planning system automatically creates reactive plans and uses formal verification techniques to prove that those plans will preserve system safety. CIRCA’s timed automata verification system is highly efficient, yet can display pathologically bad behavior when reasoning about reaction loops, a particular form of interacting cycles of states. In this paper, we describe a loop acceleration technique that recognizes these state-space structures during the verification process and bypasses the process of expanding an arbitrarily large cycle of states, effectively compressing loops of arbitrary size into a compact, finite set of states. The resulting performance improvement can be very dramatic: in domains where tight loops of short-duration transitions interact with long-duration transitions, our new loop acceleration methods can reduce verification time (and hence planning time) from hours to below a second.     

Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S)

BACKGROUND: The Scandinavian Simvastatin Survival Study (4S) demonstrated pronounced reductions in mortality and major coronary events in a cohort of patients with established coronary heart disease (CHD). The present study provides a detailed, post hoc assessment of the efficacy and safety of simvastatin therapy in the following subgroups of 4S patients: those > or = 65 years of age, those < 65 years of age, women, and men. METHODS AND RESULTS: The 4S cohort of 4444 CHD patients included 827 women and 1021 patients > or = 65 years of age. Total cholesterol at baseline was 5.5 to 8.0 mmol/L with triglycerides < or = 2.5 mmol/L. Patients were randomized to therapy with simvastatin 20 to 40 mg daily or placebo for a median follow-up period of 5.4 years. End points consisted of all-cause and CHD mortality, major coronary events (primarily CHD death and nonfatal myocardial infarction), other acute CHD and atherosclerotic events, hospitalizations for CHD and cardiovascular events, and coronary revascularization procedures. Mean changes in serum lipids were similar in the different subgroups. In patients > or = 65 years of age in the simvastatin group, relative risks (95% confidence intervals) for clinical events were as follows: all-cause mortality, 0.66 (0.48 to 0.90); CHD mortality, 0.57 (0.39 to 0.83); major coronary events, 0.66 (0.52 to 0.84); any atherosclerosis-related event, 0.67 (0.56 to 0.81); and revascularization procedures, 0.59 (0.41 to 0.84). In women, the corresponding figures were 1.16 (0.68 to 1.99); 0.86 (0.42 to 1.74), 0.66 (0.48 to 0.91), 0.71 (0.56 to 0.91), and 0.51 (0.30 to 0.86), respectively. CONCLUSIONS: Cholesterol lowering with simvastatin produced similar reductions in relative risk for major coronary events in women compared with men and in elderly (> or = 65 years of age) compared with younger patients. There were too few female deaths to assess the effects on mortality in women. Because mortality rates increased substantially with age, the absolute risk reduction for both all-cause and CHD mortality in simvastatin-treated subjects was approximately twice as great in the older patients.     

Cost savings from home and community-based services: Arizona's capitated Medicaid long-term care program

The Arizona Long-Term Care System is the first capitated, long-term care Medicaid program in the nation to operate statewide. It promotes an extensive home and community-based services program intended to lower long-term care costs by substituting home care for institutional care. Because the program is statewide, finding a suitable control group to evaluate it was a serious problem. A substitute strategy was chosen that compares actual costs incurred to an estimate of what costs would have been in the absence of home and community-based (HCB) services. To estimate the likelihood of institutionalizing clients in the absence of HCB services, coefficients for institutionalization risk factors were estimated in a logistic regression model developed using national data. These were applied to characteristics of Arizona clients. The model assigned approximately 75 percent of the program's clients to a category with traits that were determined to resemble nursing home residents' traits. A similar methodology was used to estimate lengths of nursing home stays. Lengths of stay by the program's nursing home patients were regressed on their characteristics using an event history analysis model. Coefficients for these characteristics from the regression analysis were then applied to HCB services clients to estimate how long their nursing home stays would have lasted, had they been institutionalized. These estimated nursing home stays were generally shorter than these same patients' observed home and community stays. Risk of institutionalization was then multiplied by estimated length of stay and by monthly nursing home costs to estimate what costs would have been without the HCB services option. The expected costs were compared to actual costs to judge cost savings. Home and community-based services appeared to save substantial amounts on costs of nursing home care. Estimates of savings were very robust and did not appear to be declining as the program matured. Savings probably came from several sources: the assessment teams that judged client eligibility were employed by a state agency and thus were independent from the program contractors; clients were required to be in need of at least a three-month nursing home stay; a cap was placed on the number of HCB services clients contractors were allowed to serve each month; the capitated payment methodology forced managed care contractors to hold down average HCB services costs or lose money; and the HCB services and nursing home costs were blended in the capitated rate, so that plans that failed to place clients in HCB services would lose money by using more nursing home days than their monthly capitated rate allowed.     

The challenges of real-time AI

The research agendas of artificial intelligence and real-time systems are converging as AI methods move toward domains that require real-time responses, and real-time systems move toward complex applications that require intelligent behavior. They meet at the crossroads in an exciting new subfield commonly called “real-time AI.” This subfield is still being defined, and the precise goals for various real-time AI systems are in flux. Our goal is to identify promising areas for future research in both real-time and AI techniques. We describe an organizing conceptual structure for current real-time AI research, exploring the meanings this term has acquired. We then identify the goals of real-time AI research and specify some necessary steps for reaching them