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Meeting Reports

American Heart Association's Scientific Sessions 2012 (AHA)
November 4 - 7, 2012
Los Angeles, CA

CARDIOVASCULAR INNOVATIONS: THE FUTURE IS NOW


Nanomaterials are materials in which 50% or more of the contained particles are in the range of 1 nm to 100 nm. They have several potential clinical applications, including antithrombotic therapy, cell therapy, treatment of atherosclerosis, drug delivery, and nanorods for induction of angiogenesis. Sanjay Misra, MD, Mayo Clinic, Rochester, Minnesota, USA, discussed the targets and therapies of nanotechnology.

Karagkiozaki et al. [Int J Nanomedicine 2010] found that the surface nanotopography of stent nanocoating influences the behavior of platelets, and this is a key factor for biomaterial thrombogenicity. Patra et al. [Nano Lett 2011] demonstrated that europium hydroxide nanorods (inorganic nanorods) with a diameter of 35 nm to 50 nm and a length of 200 nm to 300 nm cause an increase in proangiogenic cytokines, such as vascular endothelial growth factor-A and basic fibroblast growth factor.

Various nanoscale technologies are being applied to the field of stem cell therapy for the treatment of cardiovascular diseases. Other promising applications include the prevention, imaging, and treatment of atherosclerosis [Psarros C et al. Nanomedicine 2012] and the use of copolymer-stabilized micro- and nanobubbles as vectors for the anticancer drug doxorubicin [Rapoport N et al. J Natl Cancer Inst 2007]. Valenzuela and Simon [Nanomedicine 2012] describe a micellar estradiol formulation that serves as an alternative transdermal delivery system for hormone replacement therapy. According to Dr. Misra, nanotechnologies have far reaching implications for the practice of medicine in a wide range of fields.


Next-Generation Ventricular Assist Devices

Mark S. Slaughter, MD, University of Louisville, Louisville, Kentucky, USA, presented information on next-generation ventricular assist devices (VADs), heart valves, and other devices. All of the products he discussed are in various stages of development, and none are FDA-approved.

As VAD technology evolves it is increasingly being applied as destination therapy rather than exclusively as a bridge to transplant. Kirklin et al. [J Thorac Cardiovasc Surg 2012] reported that the average 2-year survival after cardiac transplantation is ~80%. However, evolution from pulsatile to continuous flow technology has dramatically improved 1- and 2-year survival, and important subsets of patients with continuous flow destination therapy now enjoy survival that is comparable with heart transplantation out to 2 years. After discussing a breakthrough technology that delivers nitric oxide from a novel liquid source, he said that new VAD technology should reduce operative trauma, thus reducing overall adverse events.


Next-Generation Valves and Devices

Next-generation valve companies are making use of the small intestine submucosa-extracellular matrix (SIS-ECM) to improve their products and potentially improve postoperative outcomes. CorMatrix Cardiovascular is testing tissue-engineered ECM for pericardial repair; the product comes from porcine-derived SIS.

SIS-ECM is obtained from the submucosa of the small intestine of pigs and consists of a complex matrix of collagen; the submucose is found between the mucosal and muscular layers of the small intestine. It provides strength to the intestine and also serves as a reservoir for cytokines that support the growth and differentiation of intestinal epithelial cells.

Transapical aortic valve implantation has evolved as a treatment option for high-risk patients who have severe aortic stenosis. While much of the focus has been on improving valves and the delivery systems, issues of vascular access and safe closure remain important and of great interest.

Dr. Slaughter reported that a first-in-human clinical trial [NCT01721642] of the Apica ASC transapical access and closure device had successful access and closure, with no device-related complications to date.

Dr. Slaughter said that natural scaffolds that repopulate with native cells might fix the problem of durability of bioprosthetic valves; that safe, reliable, and near bloodless access to the LV apex could improve outcomes and approach to both aortic and mitral valve replacements; that the ability to deliver a predetermined dose of cells/matrix to a specific area could improve clinical efficacy of regenerative medicine; and that new delivery systems for nitric oxide could allow chronic treatment in patients who are not candidates for other therapies.


Drug-Coated Balloons and Bioabsorbable Stents

Bruno Scheller, MD, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany, focused on drug-coated balloons and bioabsorbable stents—vascular restoration therapy, ie, the fourth revolution in interventional cardiology, according to Wykrzykowska et al. [EuroIntervention2009].

Long-term (>10 years) clinical outcomes of a first-in-human study of a fully biodegradable poly-l-lactic acid coronary stent found rates free of all-cause death, cardiac death, and major adverse cardiac events at 10 years of 87%, 98%, and 50%, respectively [Nishio S et al. Circulation 2012]. Intravascular ultrasound data suggest that the stent struts mostly disappear within 3 years. The external elastic membrane area and stent area did not change.

ABSORB Clinical Investigation, Cohort B [ABSORB B; NCT00856856], a multicenter, single-arm trial, assessed the safety and performance of an everolimus-eluting bioresorbable vascular scaffold [Ormiston JA et al. Circ Cardiovasc Interv2012]. Forty-five patients underwent serial invasive imaging at 6 and 24 months of follow-up. Struts still recognizable on optical coherence tomography at 2 years showed 99% neointimal coverage with optical and ultrasonic signs of bioresorption accompanied by an increase in mean scaffold area compared with baseline. The 2-year major cardiac event rate was 6.8% without any scaffold thrombosis, confirming the medium-term safety and efficacy of the new device. However, randomized controlled clinical trials are missing for bioabsorbable stents.

Drug-coated balloon catheters have been studied in a variety of randomized studies and large registries, especially paclitaxel-iopromide- and paclitaxel-urea coated balloons. For patients with peripheral artery disease, a meta-analysis of randomized trials compared target lesion revascularization using paclitaxel-coated balloon angioplasty versus conventional uncoated balloon angioplasty showed superior antirestenotic efficacy compared with uncoated balloon angioplasty (Table 1) [Cassese S et al. Circ Cardiovasc Interv 2012]. Other studies in coronary arteries have had similar findings in the treatment of in-stent restenosis and de novo lesions [Unverdorben M et al. Circulation 2009; Wöhrle J et al. J Am Coll Cardiol 2012]. Dr. Scheller said that drug-coated balloons are not a replacement for drug-eluting stents, but a new option in endovascular and coronary interventions and potentially useful in areas of the leg where stenting is typically avoided due to joint motion. Both drug-coated balloons and bioabsorbable stents represent the technology for a new age of vascular therapy that leaves no permanent implants behind.


Table 1. Target Lesion Revascularization.



PCB=paclitaxel-coated balloon; UCB=uncoated balloon. Adapted from Cassesse S et al. Paclitaxel-Coated Versus Uncoated Balloon Angioplasty Reduces Target Lesion Revascularization in Patients With Femoropopliteal Arterial Disease: A Meta-Analysis of Randomized Trials, Circ Cardiovasc Interv 2012;5(4): 582-589.




FRUGAL INNOVATION: THE FUTURE OF CARDIOVASCULAR MEDICINE


Stephen MacMahon, MD, DSc, George Institute for Global Health at the University of Sydney, Sydney, Australia, presented the Lewis A. Conner Memorial Lecture. The theme of Prof. MacMahon’s presentation was frugal innovation, an approach he believes will be essential for the future of cardiovascular (CV) medicine in the 21st century. "Despite the many innovations in the treatment and prevention of cardiovascular disease [CVD], the benefits have been felt by few of the many individuals that are actually in need,” said Prof. MacMahon.

A major challenge today is how to provide basic care for the 7 billion people on the planet, 3 billion of whom are likely to develop serious CVD sometime in their life. Currently, 5 billion individuals have no reliable access to essential CV health care. In a study conducted in India, the prevalence of coronary heart disease (CHD) and cerebrovascular disease was estimated to be 4.8% and 2.0%, respectively. Among individuals with either diagnosis, 14% reported taking aspirin, 41% took a blood pressure-lowering medication, and only 5% reported using a cholesterol-lowering medication [Joshi R et al. Circulation2009].

Similar findings were reported in the Prospective Urban Rural Epidemiological [PURE] study, in which the use of secondary prevention medications was low worldwide but especially in low-income countries and rural areas [Yusuf S et al. Lancet2011]. Many people in the world with serious CVD receive no treatment whatsoever because most of the world’s high-risk individuals live in resource-poor regions. Of the individuals who are at risk of CVD, 80 million live in high-income regions and 250 million live in the rest of world. Those in the high-income areas have access to a CV drug budget of $100 billion compared with <$20 million in the poorer regions. The same disparity holds true for quality of care and the distribution of physicians. Cost is another major issue. In a study in China, workers without health insurance were 7 times more likely to experience catastrophic payments (defined as ≥30% of total household annual income) than workers with insurance [Heeley E et al. Stroke2009].

There are vast numbers of unmet CV healthcare needs that are related to inadequate workforce and resources. There is a great variation in the global quality of care and high cost relative to the ability to pay. Consequently, many tens of millions of individuals die prematurely and unnecessarily every decade from preventable CV causes. Radical action is needed to avert this consequence. Prof. MacMahon proposed the need to embrace the notion of frugal innovation, which includes solutions that are affordable to the >3 billion individuals living on less than $2.50/day. These innovations need to be economically disruptive and lead to fundamental market changes, ie, a model that is low margin, high volume.

Prof. MacMahon discussed three frugal innovation approaches that might help alleviate the unmet needs for CVD prevention and treatment.

Primary care workforce models developed in high-income countries are impractical and unaffordable elsewhere. Physician-centered care is not the solution as there are too few physicians, and they are too expensive, difficult to retain, and display a wide variation in the quality of care. For example, there are 500,000 doctors in India today; if India were to adopt a US-style approach to health care, 3 million physicians would be required.

To meet the demands of individuals in low-income regions, the medical workforce needs to be larger and more affordable, and deliver care with consistent quality. An alternative is to equip and train an allied work force to provide basic, essential cardiac care. In a government-funded program in India, high school graduates were trained to be multipurpose health workers. They were trained using an algorithm-based screening and treatment approach for secondary prevention and high-risk primary prevention of CVD, the leading cause of death in India. These workers were able to detect and identify high-risk individuals at a higher rate than physicians. There was also good agreement between the health workers and physicians regarding treatment of patients with CHD, ie, the prescribing of angiotensin-converting enzyme inhibitors, β-blockers, statins, and aspirin (Figure 1) [Joshi R et al. J Am Coll Cardiol 2012]. There is a similar program ongoing in China for patients at high risk of stroke.


 

Figure 1. Identification of High-Risk Individuals by Multipurpose Healthworker.

 






Adapted from S MacMahon, MD. AHA 2012.

 

Another approach is the development of low-cost technologies, in part to facilitate the expansion of the medical work force, but also to improve the quality of care. The Systematic Medical Assessment Referral and Treatment (SMART) program is an example of an electronic decision support system used for patient assessment, diagnosis, treatment, follow-up, referral, and quality control regarding primary and secondary prevention of stroke, heart disease, and kidney disease. Low-cost remote electronic sensors for mobile phones are being developed that can collect a range of information regarding CV markers, eg, blood pressure, heart rate, electrocardiogram, and heart sounds. Another technological development underway is consumer devices for monitoring CV risk, early warning signs, and symptoms. These devices also contain programs that remind patients to takemedication, keep track of weight loss, choose healthy foods, and schedule appointments.

Pharmaceutical innovation is particularly important for emerging markets. Low-cost drugs in fixed-dose once-a-day combinations can help meet the demands for drugs in low-income regions. This requires a shift to low margins with high volume. Efforts are underway to develop drugs that are low-cost, fixed-dose, once-a-day combinations for CVD. The Programme to Improve Life and Longevity [PILL] pilot study conducted by Prof. MacMahon was a 12-week placebo-controlled trial using a fixed-dose combination pill for stroke prevention [PILL Collaborative Group. PLoS ONE 2011]. The pill was a combination of aspirin (75 mg), simvastatin (20 mg), lisinopril (10 mg), and hydrochlorothiazide (12.5 mg) taken daily. The estimated effects for patients continuing long-term treatment of the combined pill produced included a ~60% reduction for risk of CHD and ischemic stroke (Table 1) at a cost significantly less than the sum of the individual ingredients.



Table 1. Estimated Reductions in Cardiovascular Risk for Those Remaining on Treatment.

Adapted from PILL Collaborative Group. An International Randomised Placebo-Controlled Trial of a Four-Component Combination Pill ("Polypill”) in People with Raised Cardiovascular Risk. PLoS ONE 2011;6(5): e19857.


Ongoing efforts like these have the potential to reduce the disease burden while preventing a sharp rise in worldwide costs.


IMPACT OF LX4211 ON CARDIOVASCULAR RISK FACTORS IN TYPE 2 DIABETES


LX4211, a dual inhibitor of sodium glucose transporters 1 and 2 (SGLT1/2), demonstrated a clear dose reduction in plasma glucose concentration (HbA1C) in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy in the Safety and Efficacy of LX4211 with Metformin in T2DM Patients with Inadequate Glycemic Control on Metformin study. SGLT1 is primarily responsible for gastrointestinal (GI) glucose absorption, while SGLT2 is primarily responsible for renal glucose reabsorption, leading to reductions in blood glucose levels and weight loss. Julio Rosenstock, MD, Dallas Diabetes and Endocrine Center, Dallas, Texas, USA, who presented this study believes that LX4211 has the potential to address multiple cardiovascular disease risk factors in diabetic patients.

The study was designed to evaluate the dose-range efficacy and safety of LX4211 versus placebo from baseline to Week 12 in patients with T2DM inadequately controlled on metformin monotherapy. Additional eligibility criteria included being aged 18 to 75 years with a body mass index ≤45 kg/m2, and HbA1C ≥7% to ≤10.5%. After 2 weeks of screening, subjects were randomly assigned to treatment with placebo or 1 of 4 LX4211 dosages (75 mg QD, 200 mg QD, 200 mg BID, or 400 mg QD) for 12 weeks and followed for an additional 2 weeks. The primary study endpoint was the change in HbA1C from baseline to Week 12. Secondary outcomes included percentage of patients reaching target HbA1C of ≤7% at Week 12, fasting plasma glucose change from baseline to Week 12, body weight change, blood pressure (BP) change, urinary glucose change, and safety.

Randomized patients (n=299) were mean age 56 years, 42% female, and had a BMI of 32 to 34 kg/m2, and HbA1C of 7.9% to 8.3 %. Patients had normal blood pressure (BP) and lipid levels. All doses of LX411 significantly reduced HbA1C compared with baseline, with dose related changes from 0.4% to 0.9%. Baseline characteristics were balanced between randomization groups. Relative to placebo after 12 weeks of treatment; LX411 reduced HbA1C beginning at Week 1 and continuing out to Week 12 (p<0.001 for the 200-mg BID and 400-mg QD doses; p<0.05 for 75-mg and 200-mg QD doses). Maximum effect on urinary glucose excretion was achieved with 200 mg QD at Weeks 4, 8, and 12. No further glucose excretion was achieved with the 200-mg BID or 400-mg QD doses. However, further reductions in HbA1C were evident with the higher doses of LX411, which probably indicates further inhibition of SGLT1. Weight loss was achieved with all doses except for the 75-mg dose, up to 2.5 kg at Week 12 with 200 mg BID (p<0.001). Compared with placebo, systolic BP was significantly (p<0.05) reduced with the 200-mg BID and 400-mg QD doses over the 12-week period. Diastolic BP was not significantly changed. No clinically meaningful changes in high- or low-density lipoprotein cholesterol levels over baseline or compared with placebo were evident.

Adverse events (AEs) were well balanced across the treatment arms and similar in frequency to those seen with placebo. Common AEs associated with LX4211 were vaginal infections (3% to 5%), GI disorders, and headaches. There were no dose-related differences in drug discontinuation due to AEs.

In poorly controlled patients with T2DM on metformin, dual SGLT 1 and 2 inhibition with LX2411 improved glucose control and was associated with consistent reductions in systolic BP and body weight without an increase in hypoglycemia. Dr. Rosenstock concluded that, because of its insulin-independent effects, LX4211 can potentially address multiple cardiovascular risk factors in patients with T2DM and it warrants further study.

All novel oral glycemic agents are now required to undergo Phase 3 study evaluations to determine whether they affect clinical cardiovascular endpoints, including heart failure and ischemic events. In addition, these Phase 3 trials are often longer than the initial studies investigating glucose control and are helpful to evaluate, serious AEs, such as hypoglycemia, hypotension, or off-target effects. With this particular class of diabetic agents, an increase in genitourinary infections may be plausible since glycosuria is increased with this therapy.



MULTIVITAMINS FOR THE PREVENTION OF CARDIOVASCULAR DISEASE IN MEN


Basic research has suggested that some individual vitamin and mineral components of multivitamins might reduce the risk of cardiovascular disease (CVD). However, no large-scale, long-term randomized trials have tested the effect of multivitamins. Howard D. Sesso, ScD, MPH, Brigham and Women’s Hospital, Boston, Massachusetts, USA, presented results from the Physicians’ Health Study II (PHS II) on the long-term risks and benefits of multivitamin use in male physicians [Sesso HD et al. JAMA2012].

PHS II was a randomized, double-blind, placebo-controlled, 2x2x2x2 factorial trial testing multivitamin, vitamin E, vitamin C, and beta-carotene. It was conducted by mail in 14,641 male physicians aged ≥50 years. A total of 7641 PHS I participants and 7000 new physicians were randomized to take an active multivitamin or its placebo, as well as for the other vitamin arms. For the multivitamin component, the primary cardiovascular (CV) endpoint was major CV events (nonfatal myocardial infarction [MI], nonfatal stroke, and CV death). The secondary endpoints were total and fatal MI, total and fatal stroke, ischemic and hemorrhagic stroke, CVD mortality, and total mortality. The participants were followed for a mean of 11.2 years, resulting in 164,000 person-years of follow-up.

Multivitamin compliance was 77% at 4 years, 72% at 8 years, and 67% at study end. Baseline characteristics were well balanced between the multivitamin and placebo groups. The cumulative incidence of major CV events at study end was not significantly different between the 2 groups (HR, 1.01; 95% CI, 0.91 to 1.10; crude log-rank p=0.69; Figure 1). Similarly, no significant differences were seen in the incidences of secondary endpoints (Table 1). There was a borderline significant reduction in MI death (27% vs 43%; HR, 0.61; 95% CI, 0.38 to 0.995; p= 0.048) that may have been due to chance, given its small case counts.


Figure 1. Major CV Events: Active Versus Placebo Multivitamins During 11.2 Years of Follow-Up.


Copyright © 2001 American Medical Association. All rights reserved.



Table 1. Association Between Randomized Multivitamin Assignment and Risk of Major CV Events and Mortality.


CV=cardiovascular; MI=myocardial infarction; aMean follow-up of 11.2 years for all 14,641 men through June 1, 2011; bAdjusted for age, Physicians' Health Study (PHS) cohort (original PHS I participant, new PHS II participant), randomized beta-carotene assignment, randomized vitamin E assignment, and randomoized vitamin C assignment and stratified on CV disease at baseline; cDefined as a composite endpoint consisting of the first of any of the following individual events: normal MI, nonfatal stroke, and CV death. The individual events do not sum to the total because each individual analysis assess the first event that occurs during follow-up. Therefore, a participant who for example has an MI and then dies of CV disease would be counted for both individual events but only once for the primary end point of major CV events; dIncludes both fatal and nonfatal events; eStroke type was unknown for 6 men in the active multivitamin group and for 16 men in the placebo group; fAdditionally stratified on baseline cancer. Copyright © 2001 American Medical Association. All rights reserved.



Notably, the total number of cancers—the other primary endpoint of the multivitamin component of the trial—was modestly but significantly reduced, with 1290 in the multivitamin group versus 1379 in the placebo group (HR, 0.92; 95% CI, 0.86 to 0.998; p=0.04). The total number of incident cancers among participants with a baseline history of cancer was also significantly lower in the multivitamin group (95) versus the placebo group (126; HR, 0.73; 95% CI, 0.56 to 0.96; p=0.02) but was not significantly lower among participants without a baseline history of cancer (1195 vs 1253; HR, 0.94; 95% CI, 0.87 to 1.02; p=0.15).

The results of the PHS II trial demonstrated no effect of long-term multivitamin use on CVD in men. The main reason to take a daily multivitamin is still for the prevention of vitamin and mineral deficiency, along with the potential reductions on total cancer. The investigators will provide additional results on the effects of multivitamins on the secondary endpoints of eye disease and cognitive function, and other important analyses of CV and cancer outcomes, along with extended follow-up of this trial cohort.



THE FREEDOM TRIAL: CABG SUPERIOR TO PCI IN DIABETIC PATIENTS WITH CAD


In the United States alone, ~700,000 patients undergo multivessel coronary revascularization yearly. Of these, 25% have diabetes [Smith SC et al. Circulation2002]. Valentin Fuster, MD, PhD, Mount Sinai School of Medicine, New York, New York, USA, presented results from the Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals with Diabetes [FREEDOM] trial.

According to Dr. Fuster, the FREEDOM trial was the largest prospective study of revascularization strategy in patients with diabetes and multivessel coronary artery disease (CAD) undergoing intensive medical treatment. Its purpose was to compare mortality and major adverse cardiovascular events in diabetic individuals with multivessel CAD randomized to either coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). The primary outcome measure was a composite of death from any cause, nonfatal myocardial infarction (MI), and nonfatal stroke [Farkouh ME et al. N Engl J Med2012].

FREEDOM was sponsored by the National Heart, Lung, and Blood Institute, and inclusion criteria were a diagnosis of diabetes as defined by the American Diabetes Association guidelines: angiographically confirmed multivessel CAD with severe (>70%) lesions in at least 2 major epicardial vessels, and an indication for revascularization based on symptoms of angina and/or objective evidence of myocardial ischemia. Prior to randomization, all qualifying angiograms were reviewed by a study-related interventionalist and surgeon.

A total of 1900 patients with diabetes and multivessel CAD were enrolled from 2005 through 2010 from 140 international centers, and randomized to undergo either PCI with drug-eluting stents or CABG. Patients were followed for a minimum of 2 years (median among survivors, 3.8 years) and all patients were recommended to be prescribed currently indicated antidiabetic, antihypertensive, and lipid-lowering therapy by their treating physicians [Farkouh ME et al. N Engl J Med 2012].

The mean patient age was 63 years, 29% were women, 83% had three-vessel disease, and mean ejection fraction was 66%. As compared with PCI, the primary outcome was significantly reduced with CABG at 5 years (18.7% vs 26.6%; absolute difference, 7.9 percentage points; 95% CI, 3.3 to 12.5; p=0.005). The benefit of CABG was driven by differences in rates of both MI (p<0.001) and death from any cause (p=0.049). Stroke was more frequent in the CABG group, with 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (p=0.03). There was no statistical interaction between the benefit of CABG on the primary endpoint and Synergy Between PCI with TAXUS and Cardiac Surgery (SYNTAX) score or any other prespecified subgroup.

Dr. Fuster concluded that, in patients with diabetes and multivessel coronary disease, CABG was of significant benefit compared with PCI and it is the preferred method of revascularization in this setting. He noted that FREEDOM was relatively short-term—7 years, with a minimum of 2 years and a median of 3.8—and long-term follow-up would provide a better understanding of the comparative benefit of CABG, specifically on mortality.

Elizabeth A. Magnuson, MD, University of Missouri-Kansas City, Kansas City, Missouri, USA, presented a cost-effectiveness analysis of the FREEDOM trial. While CABG was associated with higher initial costs (~$9000) compared with PCI, this cost difference was partially offset by lower costs associated with repeat revascularization and, to a lesser extent, cardiac medications.

At 5 years, CABG improved quality-adjusted life expectancy by ~0.03 years while increasing total costs by ~$3600 per patient. Over a lifetime, CABG was associated with 0.66 quality-adjusted life year (QALY) gained and ~$5400 per patient higher costs yielding an incremental cost-effectiveness ratio of $8132 per QALY gained.

According to Dr. Magnuson, results were robust under various sensitivity analyses regarding the duration of the CABG effect on both survival and costs. Results were also consistent across a wide range of subgroups. Based on these findings, she concluded that CABG provides better long-term clinical outcomes than drug-eluting stent PCI for patients with diabetes and multivessel CAD, and these benefits are achieved at an overall cost that represents an attractive use of societal healthcare resources. The outcomes also provide additional support for existing guidelines that recommend CABG for diabetic patients with multivessel CAD.


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