Fifth Pivotal Research in Cardiology in the Elderly (PRICE-V) Symposium: Preventive Cardiology in the Elderly—Executive Summary. Part II: Afternoon Session

Authors

  • Michael W. Rich MD,

    1. From the Washington University School of Medicine, St Louis, MO ; 1 and the Centers for Disease Control and Prevention, Atlanta, GA2
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  • 1 George A. Mensah MD,

    1. From the Washington University School of Medicine, St Louis, MO ; 1 and the Centers for Disease Control and Prevention, Atlanta, GA2
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  • and 2 for the PRICE-V Investigators

    1. From the Washington University School of Medicine, St Louis, MO ; 1 and the Centers for Disease Control and Prevention, Atlanta, GA2
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    • *

      PRICE-V Investigators: C. Noel Bairey Merz, Cedars-Sinai Medical Center, Los Angeles, CA; George Bakris, University of Chicago, Chicago, IL; Dan Berkowitz, Johns Hopkins University, Baltimore, MD; Dan R. Berlowitz, Bedford VA Hospital, Bedford, MA; David M. Buchner, University of Illinois, Urbana-Champaign, IL; Carmen Castaneda-Sceppa, Northeastern University, Boston, MA; Ricki J. Colman, University of Wisconsin, Madison, WI; Gregg Fonarow, University of California, Los Angeles, CA; Edward D. Frohlich, Ochsner Clinic, New Orleans, LA; Gary H. Gibbons, Morehouse School of Medicine, Atlanta, GA; David G. Harrison, Emory University, Atlanta, GA; Stephen B. Kritchevsky, Wake Forest University, Winston-Salem, NC; Daniel Levy, National Heart Lung and Blood Institute, Bethesda, MD; Emanuele Marzetti, University of Florida, Gainesville, FL; George A. Mensah, Centers for Disease Control and Prevention, Atlanta, GA; Anne B. Newman, University of Pittsburgh, Pittsburgh, PA; Elizabeth O. Ofili, Morehouse School of Medicine, Atlanta, GA; Eric D. Peterson, Duke University, Raleigh-Durham, NC; Thomas G. Pickering, Columbia University, New York, NY; Eric Ravussin, Louisiana State University, Baton Rouge, LA; Leanne M. Redman, Louisiana State University, Baton Rouge, LA; Michael W. Rich, Washington University School of Medicine, St Louis, MO; Paul M. Ridker, Harvard Medical School, Boston, MA; Mark A. Williams, Creighton University, Omaha, NE; Susan Zieman, Johns Hopkins University, Baltimore, MD.


Address for correspondence: Michael W. Rich, MD, Professor of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8086, St Louis, MO 63110
E-mail: mrich@wustl.edu

Session IV

Inflammation, Oxidation, and Atherogenesis in the Elderly

Moderator: David G. Harrison, MD

  • A. Lipids, inflammation, and atherosclerosis
  • Paul M. Ridker, MD, MPH

  • B. Aging and vascular function: molecular mediators and clinical implications
  • Gary Gibbons, MD

  • C. Role of reactive oxygen species in vascular disease
  • David G. Harrison, MD

In the past decade, abundant laboratory and clinical data have accumulated linking inflammation and atherosclerosis. Indeed, as pointed out by Dr Ridker, inflammation appears to be involved in all stages of the atherosclerotic process and is likely to play a major role in plaque vulnerability. In addition, biomarkers of inflammation, such as high-sensitivity C-reactive protein (hsCRP) and interleukin 6, have been shown to independently predict incident cardiovascular disease across all strata of total and low-density lipoprotein (LDL) cholesterol levels. Similarly, elevated hsCRP level has been associated with increased risk for developing the metabolic syndrome and diabetes mellitus. Moreover, reduction in inflammatory markers appears to significantly contribute to the favorable effects of regular exercise on incident cardiovascular disease. There is also evidence that the beneficial effects of statins in reducing cardiovascular risk may be mediated in part by attenuation of inflammatory processes. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, for example, statin therapy had the greatest benefit in reducing the risk of death or myocardial infarction among patients who achieved both an LDL cholesterol level <70 mg/dL and an hsCRP level <2 mg/L. More recently, the JUPITER trial demonstrated a significant reduction in cardiovascular disease events among individuals with LDL cholesterol levels <130 mg/dL but with hsCRP levels ≥2 mg/L, suggesting that patients with evidence for active inflammation may benefit from statin therapy even when the LDL cholesterol levels are within the target range recommended by current guidelines. In summary, although additional research is required to elucidate the molecular and vascular biological mechanisms responsible for the association between inflammation and atherosclerosis, the clinical importance of this link is clearly established, and there is emerging evidence that inflammation per se may serve as an appropriate therapeutic target for reducing cardiovascular disease risk.

The interaction between aging and vascular function is complex, involving genetic, environmental, and behavioral factors, with further modulation by comorbid conditions. As discussed by Dr Gibbons, aging is associated with increased vascular stiffness and endothelial dysfunction, mediated in part by oxidative stress, inflammation, and angiotensin II. Obesity accelerates these processes, leading to premature vascular aging, even during childhood and adolescence. Similarly, hypertension, dyslipidemia, and diabetes mellitus facilitate the development of atherosclerosis. Conversely, findings from the Heart Outcomes Prevention Evaluation (HOPE) and European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA) trials suggest that angiotensin-converting enzyme inhibitors may exert favorable effects on vascular function. The influence of genomic and epigenomic variations on the vasculature is an area of ongoing investigation, and preliminary evidence suggests that blood vessels may have an “epigenetic memory” that could modulate vascular aging and therefore serve as a potential therapeutic target. Additional research is needed, however, to further characterize the relationships between aging, traditional cardiovascular risk factors, diet, environmental factors, and genomic and epigenetic variations with respect to their impact on the vascular transcriptome and vascular function.

Hypertension, diabetes mellitus, dyslipidemia, cigarette smoking, and aging all contribute to increased oxidative stress through generation of superoxide radicals and hydrogen peroxide. As discussed by Dr Harrison, the production of oxidative moieties is mediated by several enzymes, including xanthine oxidase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and nitric oxide synthases. Increased oxidative stress, in turn, leads to lipid oxidation, adhesion molecule expression, matrix metalloproteinase activation, growth of vascular smooth muscle cells, altered vasomotion, and apoptosis, all of which contribute to endothelial dysfunction and atherogenesis. However, despite the strong association between oxidative stress and atherosclerosis, clinical trials of antioxidant vitamins, including vitamin C, vitamin E, and beta-carotene, have failed to show a beneficial effect of these agents on cardiovascular outcomes. These observations have led to a reassessment of the mechanisms underlying the relationship between oxidative stress and vascular disease. In this regard, recent studies from Dr Harrison’s laboratory suggest that tetrahydrobiopterin (BH4) may play an important role in regulating the response to oxidative stress, and that therapy with BH4 reduces blood pressure in both hypertensive mice and humans. Other recent studies focusing on NADPH oxidase isoforms have provided novel insights into the role of these enzymes in the pathogenesis of oxidative stress-mediated vascular dysfunction. In addition, studies in mice and humans indicate that a feedback mechanism contributes to the regulation of the interaction between endothelial nitric oxide synthase (eNOS) and extracellular superoxide dismutase (ecSOD), and that regular exercise significantly increases both eNOS and ecSOD expression, perhaps contributing to the beneficial effect of exercise on atherogenesis.

Research Recommendations

Additional basic research is needed to elucidate the fundamental molecular, biochemical, and cellular mechanisms responsible for the complex interactions between aging, inflammation, oxidative stress, endothelial dysfunction, and atherogenesis. Improved understanding of the mechanisms whereby hypertension, diabetes, dyslipidemia, smoking, obesity, physical inactivity, and other novel risk factors, as well as common comorbid conditions (eg, renal insufficiency, heart failure, pulmonary disease, arthritis), modulate the relationship between age and vascular function is also needed. Additional investigation to discern the influence of genomic and epigenomic factors on vascular aging and their role as potential therapeutic targets is also warranted. Similarly, further characterization of the potential role of specific therapies for reducing oxidative stress and their impact on clinical outcomes is needed. Clinical trials are needed to determine the effects of novel anti-inflammatory agents on vascular disease and clinical outcomes, to better define which patients might benefit from such therapies, to determine optimal levels of biomarkers (eg, LDL cholesterol, hsCRP) for reducing cardiovascular risk across a broad range of patient populations (including octogenarians and beyond), and to assess the long-term cost-effectiveness of these interventions. Pending the results of preliminary investigations, clinical studies will also be required to determine the effectiveness of novel therapies aimed at modulating age-related endothelial dysfunction and the deleterious effects of oxidative stress; such studies should include adequate representation of older patients of both sexes and all major racial and ethnic groups.

Session V

Calorie Restriction: Potential Role in the Prevention of Cardiovascular Disease

Moderator: Eric Ravussin, PhD

  • A. Cellular mechanisms of cardioprotection by calorie restriction
  • Emanuele Marzetti, MD, PhD

  • B. Effects of calorie restriction on cardiovascular aging in non-human primates
  • Ricki J. Colman, PhD

  • C. Beneficial effects of calorie restriction on cardiovascular function and metabolism in humans
  • Leanne M. Redman, PhD

As discussed above, aging is associated with multiple changes that adversely affect cardiovascular structure and function, leading to a progressive decline in cardiovascular reserve. Conversely, calorie restriction has been shown to attenuate many of these processes in multiple species, thereby slowing the rate of aging, reducing the risk of age-related diseases, including cardiovascular disease and cancer, and resulting in an increase in longevity of up to 60%. Thus, as reviewed by Dr Marzetti, moderate calorie restriction (ie, 30%–40% less than baseline) decreases systemic levels of oxidative stress and inflammation as well as proinflammatory enzymes and adhesion molecules, all of which contribute to cellular and vascular aging. Additional mechanisms whereby calorie restriction exerts cardioprotective effects include suppression of structural protein deposition (including collagen and other extracellular matrix components), modulation of the immune response, reduction in DNA damage, induction of DNA repair genes, and a decrease in cellular apoptosis. Taken together, these effects serve to preserve myocardial and mitochondrial structural integrity and function. Resveratrol, a naturally occurring antioxidant, antithrombotic, and anti-inflammatory compound found in nuts and red wine appears to mimic the effects of calorie restriction. Resveratrol supplementation has been shown to markedly reduce the adverse cardiovascular effects of a high-calorie diet and to improve survival in adult mice. While preliminary, these findings suggest that the apparently beneficial effects of calorie restriction may be partially achievable through pharmacologic interventions, potentially obviating the need to reduce caloric intake.

In 1989, a longitudinal study was initiated at the Wisconsin National Primate Research Center to assess the effects of a 30% calorie-restricted diet on various age-related physiologic parameters and clinical outcomes in rhesus monkeys. As discussed by Dr Colman, the initial cohort included 30 men; later, 30 women and 16 men were added. All animals were 6 to 14 years of age upon entry into the study (ie, equivalent to young adult). The median lifespan of captive rhesus monkeys fed a normal diet is 26 years, with fewer than 30% surviving 30 years. Study animals undergo comprehensive evaluations at yearly intervals supplemented by additional tests (eg, echocardiography, magnetic resonance imaging) at prespecified time points. Findings to date indicate that compared with control animals, those fed a calorie-restricted diet demonstrate reductions in basal glucose and insulin concentrations; increased insulin sensitivity; favorable effects on LDL cholesterol, triglycerides, and C-reactive protein levels; modest reductions in blood pressure; and attenuation of age-related alterations in cardiac valve structure and function. In addition, a marked reduction in glucoregulatory impairment was demonstrated in the calorie-restricted group, along with reductions in the incidence of neoplasia and endometriosis, and a possible trend for less cardiovascular disease. Furthermore, an apparent reduction in aging-related mortality was observed, along with a trend toward lower all-cause mortality. Although these studies are ongoing, the data suggest that the anti-aging effects of caloric restriction observed in mice and rats extend to nonhuman primates.

To evaluate the effects of calorie restriction in nonobese humans, in 2002 the National Institute on Aging initiated the multicenter Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) trial, a prospective randomized study in which 48 healthy men and women 25 to 49 years of age were allocated to 1 of 4 groups (12 patients per group): weight maintenance (control group), 25% calorie restriction below baseline, 12.5% calorie restriction plus 12.5% increased energy expenditure through structured exercise, or a very low calorie diet (890 Kcal/d) to achieve a 15% reduction in body weight. Serial assessments of body composition, lipids, insulin sensitivity, aerobic capacity, and other parameters were performed. Preliminary findings from the first 3 groups were presented by Dr Redman. Baseline characteristics, including demographics and metabolic profile, were similar. During the 24-week study period, mean weight loss was about 10% in the 25% calorie restriction group and in the calorie restriction plus exercise group, as compared with 1% in the control group. These changes were associated with significant reductions in total body and visceral fat content. Intrahepatic but not intramyocellular lipid deposition was reduced, while insulin secretion and sensitivity were improved. Diastolic blood pressure decreased 5% in the calorie restriction plus exercise group but not in the 25% calorie restriction group. Similarly, improved aerobic capacity occurred only in the calorie restriction plus exercise group. Thus, although 24 weeks of 25% calorie restriction had favorable effects on body composition, glucose metabolism, and overall cardiovascular risk, the combination of 12.5% calorie restriction plus 12.5% increased caloric expenditure through regular exercise had a greater impact on cardiovascular risk factors than calorie restriction alone.

Research Recommendations

Additional research is needed to establish the molecular, biochemical, and cellular mechanisms whereby calorie restriction attenuates the aging process. Further studies are needed in laboratory animals, including nonhuman primates, to determine the effects of calorie restriction on longevity; to identify factors, such as exercise, that may modulate the relationships between calorie restriction, aging, and life expectancy; and to gain insight into the effects of dietary composition, dietary patterns, and the “dose–response” relationship between calorie reduction, aging, and clinical outcomes. Identification of surrogate markers that could potentially assess the impact of calorie restriction during a shorter time horizon would be valuable. Studies of calorie restriction in humans are needed in larger and more diverse populations, including younger and older patients, patients with prevalent cardiovascular risk factors (including diabetes mellitus and obesity), and patients with established cardiovascular disease. In addition to examining the effects of calorie restriction on risk factors and metabolic parameters, large longitudinal studies and clinical trials will eventually be needed to determine whether calorie restriction reduces the risk of age-related diseases and fosters a longer and healthier lifespan. As with laboratory animals, it will also be important to assess the impact of dietary composition, degree of calorie restriction required to produce a beneficial effect, and the role of other modulating factors in influencing the association between calorie restriction and cardiovascular risk factors as well as clinical outcomes. In particular, the interaction between physical activity and calorie restriction requires additional study. Further investigation is needed on pharmacologic interventions, such as resveratrol, that simulate the effects of calorie restriction in humans, including randomized clinical trials in the event that preliminary data appear promising.

Session VI

Therapeutic Inertia and Quality of Cardiovascular Care in the Elderly

Moderator: C. Noel Bairey Merz, MD

  • A. Evidence for therapeutic inertia in primary prevention with increasing age
  • Eric D. Peterson, MD, MPH

  • B. Implications of therapeutic inertia on the cardiovascular disease burden in older adults: morbidity, mortality, and costs
  • Thomas G. Pickering, MD

  • C. Strategies for increasing implementation of preventive measures to reduce the burden of cardiovascular disease in older adults
  • Dan R. Berlowitz, MD

Despite the fact that the prevalence of cardiovascular risk factors and disease increases with age, and that cardiovascular disease is by far the leading cause of death in the very elderly, much less is known about the prevention of cardiovascular disease in older compared with younger individuals. However, as reviewed by Dr Peterson, available data indicate that the absolute benefit of treating cardiovascular risk factors, especially hypertension and hyperlipidemia, is at least as great in older as in younger patients. Nonetheless, numerous studies have documented an “age gradient” in treatment patterns, such that increasing age is associated with progressively decreasing utilization of both pharmacologic and nonpharmacologic interventions aimed at reducing cardiovascular risk. Potential factors contributing to this “therapeutic inertia” include limited efficacy data in elderly patients, physician and patient concerns about possible adverse effects, “polypharmacy” and the associated risk of drug–drug interactions and increased cost of treatment, high prevalence of competing comorbidities, and “ageism” (ie, devaluation of the importance and quality of life of elderly patients). Taken together, these factors often make it difficult to accurately balance the potential benefits and risks of preventive interventions, especially since elderly patients with significant coexisting conditions have almost uniformly been excluded from randomized clinical trials. This problem is compounded by the fact that outcomes evaluated in clinical trials, such as cardiac event rates or mortality, may not reflect the outcomes that are important to older patients, who may be more concerned about the impact of an intervention on quality of life. These considerations imply that novel strategies are needed to overcome therapeutic inertia and to implement effective preventive measures in older patients with or at risk for cardiovascular disease.

According to the American Heart Association, the estimated total direct and indirect cost of cardiovascular disease in the United States in 2008 was $448.5 billion. Antihypertensive therapy prevents more than 80,000 premature deaths per year; decreases hospitalization rates; significantly reduces morbidity due to stroke, coronary heart disease, heart failure, and renal failure; and has a benefit-cost ratio of 6:1. However, despite these benefits and the widespread availability of a diverse array of effective antihypertensive medications, hypertension control rates in the United States have remained at 30% to 35% for the past 20 years. Moreover, older age is the strongest independent risk factor for both underdiagnosis and inadequate treatment of hypertension, as a result of which the clinical and economic burden of uncontrolled hypertension is greatest in the older adult population. As discussed by Dr Pickering, physician inertia (ie, failure to treat high blood pressure or to adjust the medication regimen when the blood pressure remains elevated) and patient inertia (ie, failure to adhere to the prescribed treatment) both contribute to the problem of poor blood pressure control. In one study, 87% of clinic visits in which the blood pressure was >140/90 mm Hg did not result in a change in medications. Not surprisingly, blood pressure control rates on subsequent visits were significantly higher among patients whose medication regimen was intensified. Newer approaches to overcoming therapeutic inertia at both the physician and patient levels include home blood pressure monitoring, internet-based management, and multidisciplinary interventions involving a pharmacist or nurse.

The reasons for therapeutic inertia and potential strategies for overcoming it were further explored by Dr Berlowitz. Several factors add to the complexity of therapeutic inertia in older patients. The benefits of a specific intervention, such as statins for hyperlipidemia, are often uncertain in very elderly patients, especially those older than 80 or 85 years with multiple competing comorbidities. Conversely, the potential for side effects and adverse drug interactions is greater in this population. There also may be a conflict between prevention of future events vs preservation of quality of life in patients with relatively limited life expectancy. Consequently, what appears to be therapeutic inertia may in fact represent “appropriate inaction,” particularly when considering patients’ complexity, competing demands for care, and other uncertainties. Therapeutic inertia may then represent a conscious decision not to intervene based on careful consideration of the potential benefits and risks. A further factor confounding the process is consideration of patient preferences. Thus, even when the physician recommends a specific action, the patient may elect to forego additional therapy. Integral to this decision is the patient’s perception of what is important. For example, in one study only half of older patients with hypertension placed greater importance on reducing cardiovascular events than on the potential for increased fall risk and other side effects from antihypertensive medications. Despite these complexities, 2 practical guidelines for overcoming therapeutic inertia are useful. First, the physician should make an objective determination of whether the patient is at goal (ie, is the blood pressure <140/90 mm Hg? Is the LDL cholesterol level <100 mg/dL?) before considering the potential impact of other issues. Second, if the patient is not at goal, prompt intensification of therapy should be implemented unless contraindicated. Additional strategies for improving care include provider-based interventions (education, reminders/decision support, audits with feedback, financial incentives), patient-based interventions (education, promotion of self-management), and system or organizational change. At present, there is no consensus regarding what strategy is most effective, but approaches that focus on provider reminders, patient education, and organizational change appear to result in significant improvements.

Research Recommendations

Studies are needed to better understand the reasons for therapeutic inertia, focusing specifically on the unique challenges in elderly patients. In examining the mechanisms of therapeutic inertia, both quantitative and qualitative analyses are required and both physician and patient perspectives must be considered. Metrics for measuring and quantifying therapeutic inertia need to be developed and tested. Such metrics will need to consider the issue of appropriate inaction vs therapeutic inertia, especially in older patients with multiple comorbid conditions and/or limited life expectancy. There is also a need to determine the extent to which variations in therapeutic inertia occur across health care settings and regions and the reasons for such variations. Additional study is needed to better define the effects of therapeutic inertia on clinical outcomes and health care costs, as well as the potential impact of reducing therapeutic inertia on these outcomes. Interventions directed at overcoming therapeutic inertia need to be developed and tested in various clinical settings involving a broad spectrum of patients, including, but not limited to, the elderly and very elderly. Studies are also needed that address the integration of interventions focused on therapeutic inertia into an overall strategy for improving cardiovascular care and outcomes.

Closing Plenary Lecture

Aging and Preventive Cardiology in the United States: A Framework for Action

George A. Mensah, MD

The aging process, an unavoidable phenomenon that begins at birth and accelerates with advancing age, is a powerful independent risk factor for cardiovascular diseases. Scientific evidence presented at this symposium suggests that although the process is unavoidable, its pathophysiologic derangements are accelerated in the setting of adverse psychosocial, environmental, behavioral, and biological risk factors. Most prominent among these are physical inactivity, poor nutrition, obesity, tobacco use, hypertension, diabetes, and dyslipidemia. Not surprisingly, the aging of the US population coupled with the high prevalence of obesity and other risk factors has led to an increasing burden of cardiovascular morbidity, disability, and frailty, especially in the elderly.

The good news is that effective strategies exist for the prevention and control of these risk factors and for effective promotion of high-quality cardiovascular health, overall well-being, and prevention of premature frailty. The 6 plenary sessions in this conference addressed many of these strategies. The central challenge for preventive cardiology is how best to translate these scientific advances into practice. What is an ideal framework for translating the basic, clinical, and population science research findings to the desired outcomes of reducing mortality, increasing quality of life, eliminating disparities, and preventing frailty in the elderly?

The American College of Cardiology, in its 33rd Bethesda conference (Preventive Cardiology: How Can We Do Better?),1 tackled this issue. Similarly, the American Heart Association, the World Heart Federation, and the World Health Organization have produced documents and scientific statements that provide guidance on promoting “active aging” or “healthy aging.” In the United States, several federal agencies, including the National Institute of Aging at the National Institutes of Health and the Centers for Disease Control and Prevention, have emphasized the importance of translating science into practice and have supported continued research in this arena. The multiple lessons learned from these endeavors have provided the basis for the conceptual framework for action addressed in the closing plenary lecture.

Key elements of the framework include: (1) major inputs, (2) strategic actions, (3) short- and intermediate-term outcomes, and (4) long-term outcomes. The projected manpower need for the preventive cardiology health care work force is a crucial input, especially as the first wave of baby boomers turns 65 in 2011. An effective network of federal, state, and local health departments as well as cardiology practices, health care centers, and community resources constitute additional inputs. Strategic actions include awareness and education campaigns, core essential preventive services, direct patient care, collaborative self-management support, and supportive health care policy and legislation. Well-defined short- and intermediate-term indicators measurable at the individual, health system, and societal levels are essential. Examples of such indicators include blood pressure and lipid control rates, the proportion of individuals who smoke, and the proportion who engage in regular physical activity. Improvements in quality of life and reductions in preventable mortality, frailty, and health disparities are appropriate long-term outcome measures.

It must be emphasized that this framework is only the initial phase of a model designed to help move science into clinical and public health practice for effective preventive cardiology. Active participation of governmental and nongovernmental partners from across multiple sectors and the keen commitment of policymakers, planners, practitioners, patients, and the public are essential to make the endeavor successful. Most importantly, continued surveillance and evaluation are necessary to ensure that intermediate- and long-term outcome objectives are being met and that broad support for the model inputs and strategic actions exist at the national, state, and local levels.

Disclosure:

The findings and conclusions in this executive summary are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the National Institutes of Health. Supported by a grant from the National Institute on Aging (R13 AG23743, Michael W. Rich, MD, Principal Investigator).

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