risk

  • 00:34:40

    #81: The Risk Syndrome: Part 1-Why Clients Hesitate (And How To Overcome the Hesitation)

    · The Three Month Vacation Podcast: Online Small Business|Marketing Strategy Plan| Sean D'Souza | Psychotactics

    If you were to boil down marketing to a single word, it would be "risk". When a client is ready to buy they still hesitate. Even when there's a sense of urgency on their part, they still go through a series of steps before they come to a decision. What are those steps? Why do clients seem to back away at the last minute? In this two-part series, we examine the "big boy"?risk. And we find out how it sits on its end of the see-saw and dominates the buying process. We then use The Brain Audit (yes, it's a book you should read) to remove those barriers that cause risk. Find out for yourself how we get to the end point and do so much more than just risk-reversal! -------------------------- In ‘part 1 of this 2-part series’ Sean talks about Part 1: Why Clients Don’t Buy (Understanding The Elements of Risk)Part 2: Why The Risk Factor Changes With Every Version Of Your Product/ServicePart 3: How Pre-sell Dramatically Ramps Down Risk Right click here and ‘save as’ to download this episode to your computer. Useful Resources The Brain Audit: Why Customers Buy (And Why They Don’t)5000bc: How to get reliable answers to your complex marketing problemsRead or listen to: How To Attract Truckloads of Clients -------------------------- Last month I decided to buy some software for sound editing. And with that decision, I started a merry dance.You know that dance, don’t you? It’s called the “should I, shouldn’t I” dance. First, I spent an enormous amount of time reading up on what I was about to buy. Did it fit my needs? Was it just a duplication of the software I already had in place? Would it be easy enough to learn? Then, I delved deep into the testimonials. 20 minutes later, I was still reading—not quite sure what I was looking for, when every testimonial clearly seemed to signal the software was right for me. Almost an hour later, not entirely sure of my decision, I pressed the “buy now” button. So what was the price of the software? It was $350. And you think—“Ah, that makes sense You have to do a fair bit of research before plonking down that much money.” And you’d be right. When faced with a slightly risky decision, we have to make sure we do our due diligence, don’t we? I spent another hour going through the very same process: The features, benefits, testimonials, comparison—all while assessing whether I needed the product. The only issue was this new product was priced at two dollars and ninety-nine cents! So why spend the same amount of time and effort on a product that costs less than the price of a coffee? Welcome to the tangled universe of risk, where logic seems to go into a blackhole. Where we spend as much time debating whether to go ahead with a decision, even if a product or service is offered free. We explore why risk isn’t always connected to money, or even the size of the transaction. And while it may seem that we behave unpredictably, our actions are remarkably consistent every time we have to make a decision. Worst of all, despite knowing it’s pointless spending hours debating whether a $2.99 purchase is worth it, we can’t help ourselves. We go through similar actions over and over again. If we’re so hopeless when we’re aware of our actions, how can we predict the behaviour of our clients? And how do we reduce or even eliminate risk? How do we get to the stage where the client doesn’t even read your sales page and buys your product completely on trust—even when it’s an expensive purchase? Let’s dig into this crazy universe of risk—shall we? We’ll delve deep into three topics – Why Clients Don’t Buy (Understanding The Elements of Risk)– Why The Risk Factor Changes With Every Version Of Your Product/Service– How Pre-sell Dramatically Ramps Down Risk Part 1: Why Clients Don’t Buy (Understanding The Elements of Risk) Modern see-saws are kind of boring. You don’t even need someone to sit on the other side. They have all these fancy spring mechanisms so that—in effect—you could see saw your way to your heart’s content. What the modern see-saw misses is the fun that came with understanding balance. As kids, the see-saw mechanism was quick to demonstrate how balance made an enormous difference. And when we decide to look at risk, we must first understand balance. Now if you’ve read The Brain Audit, you’ll know that you need seven elements to take the client from “hmmm” to “yes, I want to buy your product or service”. The first three of those seven are the problem, solution and target profile. The next four are objections, testimonials, risk reversal and uniqueness. What we’re experiencing in The Brain Audit is a factor of balance. The first three elements of problem, solution and target profile balance out the next four elements. The first three elements are all about attraction—the next four are about risk. Risk, as you can see, is the big boy on the see-saw No matter how good you are at attracting a prospect, there’s an enormous risk factor always lurking on the sales playground. To understand how we need to reduce that risk, let’s examine each of those four elements, one at a time. On our list, we have objections, testimonials, risk-reversal and uniqueness. And of course, that list makes no sense at all, does it? Because we just saw risk-reversal as one of the elements in the list. If this topic is about risk, then isn’t risk-reversal supposed to take care of the risk? Interestingly, no. Risk-reversal is only a part of the whole “gang of four”. Let’s start with the first of the four—objections Objections are the harbinger of risk. They’re like vultures waiting to land and chomp off the sale. But just like vultures, the reputation of objections is misplaced. Every possible purchase has not one—but many objections. But even if we were to sidestep the sales process and just look at your life, you’d see that objections play a big role. If someone said to you: Come over on Sunday—notice, notice how your brain goes for a little spin. That’s because your brain is bringing up the objections—even if you you’re semi-keen to go over. Is it just a “come over” situation, you wonder. Or will there be lunch? Will you have to have lunch in advance. All these questions go circling madly in your brain. Should you make an excuse, and just stay home, you wonder? And the moment you do all of this wondering, you’ve entered the world of objections. There are two big reasons why objections show up The first—and most important reason objections are roused—is because necessary information is missing. As we noticed in the “come over to my place” situation, the complete lack of information drives the prospect crazy. Most objections arise directly from the fact that you’ve held back the most important information—the information needed to make the sale. Whether you’re buying a car or software for $2.99, the objections are what will hold the client back repeatedly. And we may say, “I know this stuff. Objections are marketing 101”. And yet, time and time again, a client will come right to the point of buying the product or service—and then back away. In some cases, this is because the information is not available, but in today’s world, there’s also a pretty good chance that the client hasn’t seen the information. Because we’re all drowning in information, we start to skim—and miss out on certain points—points important to us. This builds up the risk tremendously—and more so for an expensive product or service. At this point in time, the Article Writing Course is about $3000 $3000 is a fair bit of money, even when you’re absolutely sure of the results. There are a ton of objections that come up almost immediately. – Will Sean be present at all times?– Will there be specific assignments and will they be looked at daily?– Will the group I’m in work out—after all, I don’t know any of them!– Will there be specific guidelines for the course? The answer to all of this is yes, yes and yes. And yes. The sales page must, in graphics and text—take apart the objections. And this brings us to a very important juncture. No matter what you say on your sales page, it’s just you saying stuff to sell your course. What an audience looks at, right after you’ve reduced their risk is the very next element—testimonials. Testimonials are the opposite of objections Yup, you heard right. Testimonials are not the wonderful things client write about your business. Instead, they have a clear and definite purpose. That purpose is to destroy the objections—and the risk—but from a third party point of view. Which is why you need first to list all the objections you receive—and continue to receive from clients. Once you get these objections, get your current clients to address the risk with their testimonials. When you look at the Article Writing Course, for instance, we realise that it’s expensive. We realise there are courses that are $1000 or even $500. They may not be the competition for Psychotactics, but you have to know that first hand from a client who’s done the course. Someone who’s taken the journey. They need to tell you how the course has tiny increments; how it has groups that magically work together; that I—Sean am there all the time, almost never sleeping, always hovering, always moving you ahead. But they also need to compare it with courses they’ve done before; experiences they’ve been through and found to be less than satisfactory. And to make sure this happens, we ask the alumni of every course as many as 17 questions. In return, we get a 1500 word answer. Notice what’s happening to you as you skim through the prospectus? You suddenly notice there are over 80 pages of testimonials. You read maybe one or two, possibly even getting to three—but those walls of risk are coming down very quickly indeed. But why? Because the testimonial attacked the risk from three angles—first it took on the objection head on, it was a third-party experience, but most importantly, it wasn’t just a few lines. 1500 words mean a lot to a prospect. They paint a picture that 20-30 words could never do. And the risk factor starts to reduce considerably. But we’re not done yet—because we’ve only dealt with the objections and testimonials. Part 2: Why The Risk Factor Changes With Every Version Of Your Product/Service It’s now time for the risk reversal Seems odd, doesn’t it? Why have a risk-reversal when you’re already dealing with the objections? This is the question we had to ask ourselves as well when we ran into the concept of risk-reversal. Back in the early days of Psychotactics, we would sell home study versions of our courses and workshops. Back then in the good ol’ days, clients were more than happy to get a big box in the mail. That box would contain a binder with a ton of notes and yes, CDs. As we continued to sell the product, we’d get a few returns now and then (every product gets returns). When we’d open the returned products, we were foxed at how immaculate the contents of the boxes happened to be. The CDs looked like they’d never been touched—or touched and wiped clean. The notes—not a smear or tear in place. The boxes looked almost identical to the condition they were shipped out. And that made us realise that risk-reversal is not the same as objections. Risk-reversal is the biggest fear the client has—a fear that must be addressed and put in bold, bright lights so it can’t be missed. The risk wasn’t that clients wanted their money back The risk was they were afraid to go through the package in detail as they feared they wouldn’t get their money back if the materials were soiled in any way. From that came the “The Lawn Mower Guarantee”. A guarantee that stated: If you don’t like the product, you’re free to take your lawn mower, run over the CDs and notes—then put them in the box and ship it back. The moment clients set their eyes on that guarantee; the sales went up exponentially. When Zappos.com started selling shoes online, there were smirks Who would buy shoes online? Sure, shoes were a $40 billion market, but shoes online? As you can see, Tony Hsieh, CEO of Zappos.com was voicing his objections. But his eventual partner, Nick Swinmurn, was prepared. “It’s a $40 billion market”, Swinmurn repeated, and the most interesting thing was that 5% of shoe sales was already being sold by mail order catalogs. But what was their risk-reversal? A money back guarantee, right? After all, shoes may not fit; they may not look as good as they do online—or you may just change your mind. But no, that wasn’t the guarantee The risk was that you’d have to figure out how to ship the shoes back. So Zappos put in a 365-day return policy with free shipping both ways. Free shipping both ways! That’s the biggest risk of all. And this is the part that most of us may not take the time to figure out. What is the client’s most significant risk? In some cases, it’s a simple money back guarantee, but in most cases, the clients will voice their biggest risk. To find the real risk, you have to dig. To find the biggest risk, you have to get clients to list all the possible risks and objections—and get the clients to pick their greatest risk.And sometimes even that may not be enough. The packages that came back to us untouched told us a precise story—a story that the client might never have voiced. To get to a real risk-reversal and reduce that risk, you can’t just hope that a shiny money-back guarantee will work. You have to dig, and dig deep. But nothing needs more digging than the last element—the uniqueness We’ve covered objections, testimonials and risk-reversal, but all that does is set up a client to go to the competition. And that’s where uniqueness comes in. Once you’ve covered all the other elements, the client needs to know why they should buy from you and not from anyone else. If we were to drag the Article Writing Course back into the picture, we’d notice that the competition may be offering courses at a far lower rate—and promising quicker results. After all the Article Writing Course takes 12 weeks—that’s three whole months. You have assignments, and these are checked daily. This means you have to run your business and do your assignments every single day. This makes the course baby-tough So what’s baby-tough. If you have a cat, you have to put out their food, their water, and that’s probably all you need in terms of work. A dog—now that would involve a walk, some play time—it’s a lot more work. A baby on the other hand—a newborn—that means you’re sleep deprived for quite a while. That is the uniqueness of the Article Writing Course. It’s baby-tough. It means you work extremely hard for the three months—and that hard work shows up as a skill on the other side. Right before we had this uniqueness in place, it was a lot harder to sell the course We tackled the objections, had reams of testimonials and the risk-reversal (not money-back, but that you’d only tackle tiny increments every day). Still, it was a lot harder to sell the course. The moment we added the uniqueness, the seats were filled in a day, then half a day and in some cases as little as 25 minutes. A client wants to get the most unique product or service possible. To get anything but the best is hardly acceptable. The moment the Article Writing Course became baby-tough, the clients knew they were in for some real work. And real results. The other courses with their “easy” and “quick” results now became a liability. In fact, uniqueness can stand alone—and clients may ignore the other elements of risk if the uniqueness is strong enough. When you think of Domino’s pizza delivering in “30 minutes or it’s free”, there could have been many other objections, zero testimonials, and well, we’ll accept the risk-reversal. But it’s the uniqueness of screamingly quick delivery that got the attention of the client. When you look at products and services that clients choose—even when they’re not the best in the market place, it’s usually because of the uniqueness. And that’s because the uniqueness creates extreme clarity. When you’re faced with why you chose one computer over the next, why you chose one chartered accountant over the other—you don’t need muddiness. The more fuzzy the message, the less likely your audience is to pick you over the other. Working on your uniqueness is your top priority, and every product or service should have their uniqueness. The company may have one level of uniqueness, but every product or service needs to have their uniqueness as well. When we think of risk, it’s easy to isolate ourselves to just the risk-reversal There’s no doubt the risk-reversal is very important—once you find the real risk involved. Just like Zappos figured out the both-ways free shipping was more important, you too have to dig into the nuances of your product or service. The objections can’t be left out because they cause too much chaos in the mind of the client. Even a simple Sunday outing without the proper information, becomes a matter of “should I, shouldn’t I?”. And testimonials are a science that’s worth delving into. Getting long, detailed answers turn your testimonials into an experience, not just some sugary, nice things your client is saying about your product or service. But what’s the one thing you need to work on as quickly as possible? It’s always the uniqueness. What makes your product or service unique? What makes it different from the competition? That’s the question clients want you to answer right away as it creates clarity. The client can justify to themselves and others in their world, why they bought the product or service. In The Brain Audit, there are two distinct parts: the attraction factor—and the risk.It’s like a see-saw—an old-fashioned see-saw. It’s fun when both sides are balanced—well, almost balanced! Coming Next: Part 2—How Pre-sell Plays A Crucial Role In Risk-Reduction. http://www.psychotactics.com/82

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  • 00:20:59

    Circulation May 30, 2017 Issue

    · Circulation on the Run

    Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. Our featured paper this week confirms the clinical utility of a polygenic risk score of common variants of cardiovascular disease. More soon after this week’s summary of articles.                                 The first original article describes distinct cell-specific roles for NADPH oxidase, or Nox2, in blood pressure regulation. This paper from first author, Dr. Sag, corresponding author, Dr. Shah, colleagues from King's College London British Heart Foundation Center of Excellence in the United Kingdom. The authors used novel gene modified mouse models to show that Nox2 in myeloid cells modulates basal blood pressure whereas endothelial cell Nox2 is involved in angiotensin II-dependent hypertension. The finding that Nox2 in different cell types has distinct effects on blood pressure, suggest that different diseases conditions may alter blood pressure through effects on Nox2 in different cell types. For example, it is conceivable that the effects on myeloid cells on basal blood pressure may be enhanced in inflammatory settings, whereas endothelial cell Nox2 activation may be more relevant to renin-angiotensin system-dependent hypertension. The current results are therefore relevant to the design of novel therapeutic approaches for hypertension by targeting NADPH oxidases.                                 The next paper provides a new, more accurate atherosclerotic cardiovascular disease risk prediction tool in familial hypercholesterolemia that may increase the efficiency of care and use of newer lipid lowering therapies. Co-corresponding authors, Dr. Mata and Pérez de Isla, from Hospital Clinicals San Carlos in Madrid, Spain, use data from SAFEHEART, a multicenter, nationwide, long-term prospective cohort study of 2,404 adult patients with molecularly-defined familial hypercholesterolemia and who have followed up for a mean of 5.5 years. They developed a robust risk prediction equation for incident atherosclerotic cardiovascular disease based on the following independent predictors; age, male gender, history of previous atherosclerotic cardiovascular disease, high blood pressure, increased body mass index, active smoking, LDL cholesterol and LPA levels. The new SAFEHEART risk equation performed better with a Harrell C index of 0.81 compared to 0.78 for the modified Framingham's risk equation and 0.8 for the ACC/AHA Pooled Cohort risk Equations. The authors therefore concluded that the risk of incident atherosclerotic cardiovascular disease may be estimated in familiar hypercholesterolemia patients, using simple clinical predictors, and that these findings may improve re-stratification and could be utilized to guide therapy in patients with familiar hypercholesterolemia.                                 The next study tells us that late gadolinium enhancement cardiovascular magnetic residents identifies patients with dilated cardiomyopathy but without severe left ventricular systolic dysfunction, who are still at high risk of sudden cardiac death. In this study, by first author Dr. Halliday, corresponding author Dr. Pennell, from Royal Brompton Hospital in London, United Kingdom, the authors prospectively investigated the association between mid-wall late gadolinium enhancement and the primary composite outcome of sudden cardiac death or aborted sudden cardiac death, among 399 consecutive referrals with dilated cardiomyopathy and a left ventricular ejection fraction above 40% seen at their center between 2000 and 2011. These patients were followed for a median of 4.6 years. 17.8% of patients with late gadolinium enhancement reached the pre-specified end point, compared to only 2.3% without late gadolinium enhancement.                                 Furthermore, following adjustment, late gadolinium enhancement predicted the composite end point, with a hazards ratio of 9.3. Thus, patients with dilated cardiomyopathy and mid-wall late gadolinium enhancement, and mild or moderate reductions of left ventricular ejection fraction should still be recognized as having a high risk of sudden cardiac death. This is important because these patients are not currently offered ICDs for the primary prevention of sudden cardiac death, based on current guidelines. Due to the low competing risk of death from non-sudden causes, it is possible that these patients will benefit from ICD implantation, but randomized trials are now required. These issues are discussed in an accompanying editorial from Dr. Markman of Johns Hopkins University, and Dr. Nazarian, Hospital of University of Pennsylvania.                                 The next study enhances our understanding of the role of immunity in hypertension. Now, the innate antigen-presenting cells and adaptive immune T-cells have long been implicated in the development of hypertension, however, the T-lymphocytes subsets involved in the pathophysiology of hypertension remain unclear. A small subset of innate-like T-cells expressing the gamma-delta T-cell receptor, rather than the more commonly expressed alpha-beta T-cell receptor, could play a role, and these were the focus in today's paper by first author Dr. Caillon, corresponding author Dr. Schiffrin, and colleagues from Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Canada. In experimental models, the authors showed than angiotensin-2 infusion increased gamma-delta T-cell numbers and activation in the spleen of wall tite mice, as well as in increased the systolic blood pressure, and decreased mesentric artery endothelial function in wild type mice, but not in mice devoid of gamma-delta T-cells, or in mice depleted of gamma-delta T-cells by depleting antibody injections.                                 Furthermore, angiotensin-2 induced T-cell activation in the spleen and peri-vascular adipose tissue was blunted in null mice. In humans, there was an association between systolic blood pressure and gamma-delta T-cells. In summary, this is the first in-vivo demonstration that gamma-delta T-cells, a subpopulation of T-cells, play a fundamental role in the development of hypertension and vascular damage. These results will help design novel treatments to limit the progression of hypertension and vascular damage.                                 The final paper describes a novel multi-modality strategy for cardiovascular risk assessment. Dr. de Lemos and colleagues from UT Southwestern Medical Center in Dallas, Texas, hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic cardiovascular disease risk assessments among individuals without known cardiovascular disease. These modalities included: left ventricular hypertrophy by electrocardiogram, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high sensitivity cardiac troponin-T, and high sensitivity C-reactive protein.                                 Using data from 6,621 individuals of the multi-ethnic study of atherosclerosis, or MESA, as well as 2,202 individuals from the Dallas heart study, the authors evaluated the association of test results with the global composite cardiovascular disease outcome, and that would include cardiovascular death, myocardial infarction, stroke, coronary or periphery revascularization, incident heart failure or atrial fibrillation, as well as atherosclerotic cardiovascular disease outcomes, which included fatal or non-fatal myocardial infarction or stroke. Over more than 10 years of follow-up, the authors found that each test result was independently associated with the global composite cardiovascular disease events in MESA. When the 5 tests were added to a base model, the C statistic improved, that was significant integrated discrimination improvement, and net reclassification improvement, and the model was well-calibrated. Using a simple integer score counting the number of abnormal tests, they showed that global cardiovascular disease risk increased with increasing score in a graded fashion. These findings were replicated in the Dallas heart study, and were similar for the atherosclerotic cardiovascular disease outcome.                                 This study therefore supports the potential value of a multi-modality testing strategy in selected individuals, in whom additional risk stratification is desired, beyond measurement of traditional atherosclerosis risk factors. The authors do highlight that additional studies are needed to validate the present findings, determine the optimal approach to implementation, and address direct and indirect cost implications of the additional testing.                                 Well, that wraps it up for your summaries. Now for our feature discussion.                                 Our feature paper today tells us that a polygenic risk score identifies a group of individuals with a higher burden of atherosclerosis, and greater relative benefit from statin therapy in the primary prevention setting. But perhaps even more significant, is that it addresses the fact that even relatively small effect sizes of common snips gathered together in a genetic risk score may have clinical utility in the prediction of cardiovascular disease, and to discuss this I'm so pleased to have the first author, Dr. Pradeep Natarajan from Massachusetts General Hospital, and Dr. Anand Rohatgi, associate editor from UT Southwestern. Welcome, gentlemen. Dr. Pradeep Natarajan:  Thank you very much, Carolyn. Dr. Anand Rohatgi:          Thank you, Carolyn. Dr. Carolyn Lam:               Pradeep, could you start by telling us what you did? This was a tour de force, please. Dr. Pradeep Natarajan:  Yeah, thanks so much for the invitation and the enthusiasm. So, briefly, large-scale, genome-wide association studies have discovered genetic risk variants in the population that individually associate with coronary disease risk. Many others have shown that an aggregate of these genetic risk variants predisposes to an increased risk for coronary disease by about 60%. But we sought to, with this study, understand how primary preventive statins could influence that risk, and whether these insights could be helpful in refining statin eligibility. So, among the individual variants that had been associated with coronary disease, we developed a risk score. This encapsulated 57 individual genetic variants. This risk score is independent of traditional cardiovascular risk factors, and identified individuals with a greater burden of sub-clinical atherosclerosis, defined as coronary artery calcium and carotid plaque, and two observational cohorts in individuals with a greater absolute and relative benefit from statin therapy from a subgroup analysis within the WOSCOPS clinical trial.                                 What we were surprised by is that the conventional wisdom, that all previously described subgroups within statin trials had the same relative benefit, and statins per unit of alveol cholesterol lowering. So, about 20 to 25% lowering of risk per 40mg per deciliter of alveol cholesterol. So we clinically identify individuals who just start out at high absolute risk, assume that the relative benefit will be the same across everyone, and optimize the number needed to treat simply by just finding individuals at high risk. But, here we didn't see the expected 20 to 25% lowering in the high genetic risk group, we saw actually a 44% relative risk reduction for the same lowering of alveol cholesterol. And we have now observed that across three different clinical trials, and these individuals are at high baseline risk, so this translates into an even more optimized number needed to treat, and really the opportunity to identify individuals earlier with an age independent biomarker. Dr. Carolyn Lam:               That's really cool, in fact, the number needed to treat in the high-risk score group was impressively low at 13. Dr. Pradeep Natarajan:  That's correct. Now, overall in the WOSCOPS trial, if you look at all individuals, it's about 38, so it is a high risk primary preventive group of men with, you know, substantial hyperlipidemia, but if you look at at least a relative difference between the two, going from 38 to 13, that's about a three-fold improvement of the number needed to treat. Dr. Carolyn Lam:               You know, what you said about it not correlating with exactly what you expected with the drop in LDL and so on, does that mean that this genetic risk score, that a lot of the snips are probably associated with LDL levels, but that a lot of them may be giving more information beyond LDL? Is that what it means? Dr. Pradeep Natarajan:  Yeah, you know, it's interesting. Most of the genetic variants that are associated with coronary disease actually do not seem to clearly influence traditional cardiovascular risk factors. The latest best estimate of that is about 39% of them associate with traditional cardiovascular risk factors, and then a subset with LDL cholesterol. So the aggregate score actually does not associate with traditional risk factors, and including with LDL cholesterol. Dr. Carolyn Lam:               Wow, and Anand, I'm sure we had so many discussions with the editors about the paper. Could you share some thoughts? Dr. Anand Rohatgi:          Yes, Carolyn. Circulation as a journal represents the best in cardiovascular science, and we're always interested in the highest-level articles related to atherosclerotic cardiovascular disease. So, when we received this manuscript from Pradeep and Sekar’s group, really leaders in the field, we were really excited, and as we went through the review process we got even more excited because it, as you said, Carolyn, it really was a tour de force, it was a high-quality article and it combined multiple things, and that's what we're really interested in seeing at Circulation, is combining several aspects, in this case genetics, sub-clinical atherosclerotic imaging, and also treatment effect.                                 And, you know, it's interesting because several recent manuscripts looking at genetic risk scores, they were associated with coronary disease but it wasn't clear that they were improving what we call risk prediction performance indices, at least enough to meet the bar of incorporating them into guideline-type recommendations. So I think the field wasn't sure how to move forwards with this type of information, but now I think this study really demonstrates that this type of risk score, this genetic risk score, really can inform treatment decisions in a big way. And so we were really excited to talk about that and then see it move forward. Dr. Carolyn Lam:               So a question for both of you now. Can these data be extrapolated to other cohorts of patients? I mean, WOSCOPS was predominantly white, and all were males, right? So, Pradeep, would you like to take that first? Dr. Pradeep Natarajan:  That's an excellent observation, and I think ... A clear limitation in the field, but an outstanding question that I think can be addressed going forwards. So, the main challenge is that the epidemiological cohorts that were used for genetic analysis largely have been of European ancestry, and we know that genetic background and a variety of non-genetic factors influence cardiovascular disease risk, so in genetic analysis of European individuals the influencers of coronary disease risk may not influence cardiovascular disease the same in non-European ethnicities. And, you know, we've done some work of this specifically in African-Americans, and there are some differences. You know, African-Americans are largely mixed of both African and European ancestry, some of that seems to also influence how you interpret the cardiovascular genetic risk score.                                 Ideally you would have a risk score that is not influenced by the genetic background, and so the next step going forward are one to look to see how well this risk score predicts in non-European ancestry, because, obviously, not as much statin clinical trial information in non-European cohorts, but I think looking at the treatment effect in non-Europeans will be important. And then, you know, the third step is we and others are participating in several now large ongoing efforts to really define what the genetic influences are in non-European ancestries, and I think that will be a very important next step that's really critical before the clinical implementation. Dr. Carolyn Lam:               Yeah, talking to you from Asia, that's music to my ears, obviously. Anand, did you have any questions for Pradeep or anything else to add about the paper? Dr. Anand Rohatgi:          Yeah, I wanted to add one or two comments. One thing that this study demonstrates is that the genetic risk scores, whether they relate to traditional risk factors or lipids, that doesn't necessarily translate to what it might mean in terms of treatment benefit, and so I think that concept is generalizable and now it needs to be tested in other ethnicities, other types of subgroups, but I think you can disentangle a relationship with risk factors and lipids to its treatment effect and this study really nicely shows that.                                 And I think just to take a step back, we know statins work in intermediate-risk patients, maybe even low-risk patients with the most recent studies, but at a public policy level, and just as a cognition, we really want to narrow the focus, it's something called precision medicine that the American Heart Association is promoting as a concept, and I think that this study really demonstrates that here we have now another tool that can reduce this number needed to treat, make this choice for statins more precise, maximizing the benefits and limiting cost. So, I think that concept is very generalizable, it needs to be tested now in multiple populations, like Pradeep said, and I guess one of the questions I had had for the authors is: how do we incorporate this finding that they saw with sub-clinical atherosclerosis, which we thought was very fascinating among the editors at Circulation, that now they're also linking with sub-clinical atherosclerosis, is that something that the investigators think needs to be pursued further? Would that be something that would be used clinically as well? Dr. Pradeep Natarajan:  I think there are lots of opportunities for this going forward, you know, in prior work we've done the genetic architecture for clinical coronary disease is actually very similar to sub-clinical coronary disease, and there are many influences for sub-clinical coronary disease, and clinical coronary-disease, that are both genetic and environmental, and the aggregate effect from the polygenic risk on sub-clinical atherosclerosis suggests that it's obviously not absolute and there are other factors that influence sub-clinical atherosclerosis. Dr. Carolyn Lam:               Well, listeners, you heard it right here. Thank you for joining us this week, tell all your friends about it, and don't forget to tune in again next week.

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  • 00:24:57

    Circulation November 8, 2016 Issue

    · Circulation on the Run

      Dr. Carolyn Lam:             Welcome to circulation on the run. Your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam associate editor for the National heart center and Duke National University of Singapore. Our podcast is really going around the world, and today's feature interview comes to you live from China. Where we will be discussing the prediction of ten year risks of cardiovascular disease in the Chinese population. So now to all our Chinese colleagues out there: Chinese dialect     First here's your summary of this week's journal. The first study challenges the assumption that all patients with vascular disease are at high risk of recurrent vascular events. First author Dr. Kasenbrud corresponding author Dr. Viceren and colleagues form the University Medical center Utric in the Netherlands, provide new data on the estimation of ten year risk of recurrent vascular events and a secondary prevention population. In other words, in patients with established cardiovascular disease they applied the second manifestations of arterial disease or 'smart' score for the ten year risk prediction of myocardial infarction, stoke or vascular death in more than six thousand-nine hundred Dutch patients with vascular diseases ranging for coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm and poly-vascular disease. Predictors included in the SMART risk score included age, sex, current smoking, diabetes, systolic blood pressure, total cholesterol, HGL cholesterol, presence of coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm, estimated glomariaol fruition rate, high sensitivity CRP and years since the first manifestation of vascular disease. They further externally validated the risk score in more than eighteen thousand four hundred patients with various types of vascular disease fro the TNT ideals Sparkle and Capri trials.     The overall findings was that the external performance of the SMART risk score was reasonable apart from over-estimation of risk in patients which a ten year risk of more than forty percent. What was striking was the substantial variation in the estimated ten year risk. The median ten year risk of a reoccurring major vascular event was 17 percent but this varied for less than 10 percent in 18 percent to more than 30 percent in 22 percent of patients.     The authors further estimated residual risk at guideline recommend targets by applying the relative risk reductions form meta-analysis to estimated risks for targets for systolic pressure, LDL, smoking, physical activity and use of anti-thrombotic agents. They found that if all modifiable risk factors were at guideline recommend targets only half of the patients would have ten year risk of less than 10 percent. Even with optimal treatment many patients with vascular disease appear to remain at more than a 20 percent or even more than 30 percent of a ten year risk.     The take home message is that a single secondary prevention strategy for all patients with vascular disease may not be appropriate. Instead novel risk stratification approaches may be helpful to individualize secondary prevention by identifying high risk patient which may derive the greatest benefit from novel interventions.                       The next study provides experimental evidence that an indigenous-gastro transmitter hydrogen sulfide may potentially be a therapeutic target in diabetic patients with cardiovascular diseases. In this paper by first author Dr. Chen, corresponding author Dr.Kisher and Colleagues from the Louis Cat's school of medicine Temple University in Philadelphia. Authors aim to evaluate the role of hydrogen sulfide deficiency in diabetes induced bone marrow cell dysfunction and to examine the therapeutic effects of restoring hydrogen sulfide production in diabetic bone marrow cells on ischemic high limb injury in diabetic DBDB mice. They further specifically investigated the effects of hydrogen sulfide deficiency on the nitric oxide pathways under conditions of high glucose. They found that bone marrow cells for diabetic DBDB mice had decreased hydrogen sulfide production and lower levels cystathonine gamma lyaze which is the primary enzyme that produces hydrogen sulfide in the cardiovascular system. Administration of a stable hydrogen sulfide donor and over expression of cystathonine gamma lyaze in diabetic bone marrow cells restore their functional and restorative properties. Further more they demonstrated that the therapeutic actions of hydrogen sulfide were mediated by nitric oxide pathway involving endothelial nitric oxide synthase PT495.     In summary these results support the hypothesis that hydrogen sulfide deficiency plays critical role in diabetes induced bone marrow cell dysfunction and suggests that modulating hydrogen sulfide production in diabetic bone marrow cells may have transformational value in treating critical limbs ischemia.     The next study reinforces the importance of hypertension as a critical risk factor for inter-cerebral hemorrhage, and suggests that Blacks and Hispanics may be a particularly high risk. In this study by DR. Walsh and colleagues for the University of Cincinnati, authors conducted the largest case controlled study to date on treated and untreated hypertension as a risk factor for inter-cerebral hemorrhage. They also investigated whether there was variation by ethnicity. The ethnic racial variations of inter-cerebral hemorrhage or eriche study is a prospective multi-center case controlled study of inter-cerebral hemorrhage among Whites, Blacks and Hispanics. Cases were enrolled from 42 recruitment cites, controls were matched cases one to one by age, sex, ethnicity and metropolitan area. A total of 958 white, 880 black and 766 Hispanic cases of inter-cerebral hemorrhage were enrolled. Untreated hypertension was more highly prevalent in Blacks at almost 44 percent and Hispanics at almost 47 percent compared to whites at 33 percent. Treated hypertension was a significant independent risk factor and untreated hypertension was substantially greater risk factor for all three ethnic groups and across all locations. There was a striking interaction between ethnicity and risk of inter-cerebral hemorrhage, such that untreated hypertension conferred a greater risk of inter-cerebral hemorrhage in Blacks and Hispanics relative to Whites.                         The nest study provides the first prospective multi-centered data on mortality and morbidity in rheumatic heart disease from low and middle income countries. First author Dr. Zulky, corresponding author Dr. Mayoci and authors from Gertrude hospital and University of Cape Town in South Africa present the results of two year follow up of the global rheumatic heart disease registry or remedy study in 3343 children and adults with rheumatic heart disease from 14 low and middle income countries. They found that although patients were young with a median age of only 28 years the 2 year case fatality rate was high at almost 17 percent. The median age at death was 28.7 years. Mortality was higher in low income and low middle income regions compared to upper middle income countries. Independent predictors of death was severe valve disease, more advanced functional class, atrial fibrillation and older age. Where as post primary education and female sex were associated with a lower risk of death. The authors carefully noted that apart from age and gender the independent risk factors for mortality such as severity of valve disease heart failure, atrial fibrillation and low education were all modifiable and thus they called for programs focused on the early detection and treatment on clinical rheumatic heart disease.     Well that's it for the summaries, now lets go over to China     For our feature interview today we are going all the way to Beijing at the great Wall meeting where we will be meeting authors as well as editors. So here we have first and corresponding author Professor {Dong Fen Gu} and co-author Professor {Sherliang} both from {Fu Y} hospital Chinese academy of medical sciences in Beijing. Welcome   Dr.Gu: Welcome we are so delighted to be interviewed by you   Dr. Carolyn Lam:   Thank you so much we are so excited to be talking about your paper predicting the ten year risks of cardiovascular disease in the Chinese population. And here we have as well editor in chief Dr. Joe Hill as well as Dr. Amid Kira digital strategies editor and associate editor. Gentlemen how is it in Beijing? And I hear that you have a Chinese greeting for everyone as well.   Joe Hill: {Ni how} and {nuchme and senchmen}   Amid Kira: I can't top that but I agree with what Joe said   Dr. Carolyn Lam: Dr. Gu, could you please tell us what is it that is so different about cardiovascular disease in China compared to what we heard about in the western world.   Dr.Gu: Okay cardiovascular disease is both leading cause of death in China and in United States as well in European countries. However the patterns for components of cardiovascular disease including coronary arteries and stroke are still quite different in the Chinese populations compared united states. For example there are coronary arteries mortality rate in the united states is along the 100 thousand per year and this is the first leading cause of death in the united states. And for stroke the annual mortality rate is along 36 per 100 thousand in the united states populations. However in china the stroke mortality rate among Chinese populations is around the 160 per 100 thousand, so that almost 3.5 to 4 as high as in untied states. Obviously for our lifestyle in including battery behavior quite different you can easily identify one kind of difference in the united states and the Europe restaurants from Chinese restaurants and some western style restaurants you can figure it out.             And another example, smoking rate is major component for risk of cardiovascular disease it is very high in Chinese adult men. It over 50 percent right now but in the united states in the past 50 years it declined immensely. And around maybe less than around 20 percent and from the previous experiment from studies by Dr. Liu Chin from and my colleague Dr.WU they used the questions for predictions of coronary arteries compared to equations and also use the similar prediction model compares that its chemical cardiovascular disease from the united states population and the Chinese population. That to over estimation if we use the united states produced this kind of equation. So based on this kind of scenario we based on Chinese long term larger scales cohort to precede and study our own prediction model.   Dr. Carolyn Lam: Wow that is really fascinating Dr. Gu and I really could not agree with you more because I sort of trained in the united states for quite some time and then I moved back to Singapore and saw for myself in Asia the tremendously high rates of stroke. I was also very struck by the relative youth of the patients suffering cardiovascular disease and the differences in risk factors, the smoking but not just that, obesity is almost defined on a different scale in our relatively sized smaller Chinese population compared to that in the western. Congratulations to you and your team for a successful amazing effort. Could you or Dr. Yang now just let us know what are your main findings.   Dr. Yang:           Well I think there are 2 major finding for our work. First we developed a new prediction risk model you know after analysis is for high risk score or equations released by AJ and ACC and is some other risk scores. We included 6 conditional risk factors in combination with our previous knowledge that included age, treated or untreated ISBP, total classical, HDLC current smoking and diabetes. So this traditional risk factors were set up as a base model and then we use the predefined statistical to include new additional variables they were Chinese special elements. Finally in our model there were rates as constraints and geographic region which means northern part versus the southern part in China and also organization is rural or urban area. And finally the forth one is family history as a CVD so this for additional variables in our model suggest that we maybe as a Chinese prediction and equations has something special. For example we feel more attention for central obesity in primary prevention in Chinese populations and also you know the norther part and the southern part there are large differences in the risk profiles. And so maybe according to our risk prediction model we pay more attentions for the residence living in northern part in China.     And then for the second points I think we found that PCE equation which shows for equations was not appropriate to predict ten year risk of in Chinese populations. For example in our revelation cohort we found that our model just slightly over predicts severity risk by 17 percent in Chinese man but when we use the PCE models released form AHA the over-estimation come to 50 percent so maybe equations from western populations are not appropriate to Chinese populations.   Dr. Carolyn Lam: Thank you so much Dr. Yang I mean those are just such important findings applicable to a huge population in china, like you said. And just as important as the second point that the pooled equations derived from western populations may not be the most appropriate for certain other ethnic populations. I think that a very important message and that why we are so proud to be publishing this in Circulation. Could I ask then are you applying these new equations in your personal clinical practice?   Dr.Gu:   Risk assessment is a fundamental components for prevention of ASSVD. In Chinese we question {turn the PA on} provide a valuable to identify high risk individuals in Chinese populations. And not with just complicated [inaudible 00:18:02] for further analysis. And propose three levels of groups of risk stratification could be identified by cut off 5 percent and 10 percent. So lower risk individuals with predicted activity risk of less than 5 percent should be offered lifestyle wise to maintain the lower risk status. While the moderate risk individual is predicted risk of 5 to 10 percentage for intensive therapeutic lifestyle change wit drug therapy if necessary. For the high individual risk high or large 10 percent teheraph of clinical aliment taken account for physicians recommendation should be required with therapy for the lifestyle modification. Then annually clinic up, including an echocardiographic information for carotid artery back and even for outer [inaudible 00:19:09] CT examinations for coronary artery are recommended. Also blood pressure, lipids, glucose measurement if necessary are suggest according to Chinese guideline. While cardiovascular disease prevention as well as for the epidemic of this kind a lines. For ACVD patients those are different kinds of risk assessment we could know whether their risk profile had been improved or be progressed so that appropriate clinical elements should be taken in clinical practice.   Dr. Carolyn Lam: Thank you very much Dr. Gu so that just show that these findings are immediately clinically applicable and I trust that means you're suing it in your clinics too, and once again were so happy to be publishing this in Circulation so in the rest of the time in going to now direct questions at Joe and Amid.     How's China been? How are your chopstick skills and any word on how Circulation is being received there?   Joe Hill: Well Carolyn its a delight to be here this is a bustling media that get better and better every year. In about 2 hours we have our first ever Circulation session, we brought several editors here to discuss the types of content that we are looking to publish, the type of work across prevention and population and electrophysiology of heart failure. This is an extraordinary media that is now internationally acclaimed and as we've heard here, the face of cardiovascular disease in Asia is changing. And as you pointed out 60percent of the human race lives in Asia and we want to do everything we can to be here on the ground, in Asia trying to address this curve that is already present and is worsening by the day.   Dr. Carolyn Lam: Amid, you know you've seen the latest statistic on our podcasts and you highlighted that we have quite a number of listeners over there as well. Would you like to tell me how this is all blending it to the digital strategies and anything else you might want to highlight?   Amid Kira: Sure its been an incredible meeting and we get to meet great colleagues like our colleagues today on this podcast and learning so much from this meeting. Our podcast as you pointed out quite a sizable and growing cadre of people in Asia and Japan and China who are listening and we truly want to enhance that as Joe mentioned with the large splurge of cardiovascular disease and the great science that is going on here. Want to make sure that we are able to be apart of that conversation and interact with researcher and clinitions here. In addition to podcast, we are exploring some other options involving social media, specifically in China so stayed tuned in how those develop but we certainly appreciate the importance of being her and interacting where so much of cardiovascular disease and cardiovascular science is occurring.   Dr. Carolyn Lam: That's so great. Joe or Amid now there's a specific we would like to highlight to our listeners the doodle, either of you want to pick that up a bit about blipping the doodle?   Amid Kira: So there is as you know Circulation now has this doodle where we change it periodically and its sort of a fun themed thing. Right now I think it Halloween and we've had several other ones that people have designed to sort of keep thing fresh and light and interesting. There's a new app called blippar which you can download from iTunes or android stores and you can essentially scroll that over with your phone with the doodle and that will take you to new content either table of contents of videos, different kinds of content that it can navigate you to. So I hope people will not only enjoy the doodle kind of anticipate what's next in terms of seasons but will take the time t blip the doodle when they get a chance.   Dr. Carolyn Lam: That great and that blippar- B l I P P A R. You really c should check it out, anyone who is listening to this really check it out you'll be floored. Joe could I just turn the mic to you for any last words about the global outreach of Circulation, I mean its just so amazing that you're there in China   Joe Hill: Well heart disease Carolyn knows no boundaries nor does Circulation. There was a day when cardiovascular disease was largely an issue in the developed world that is long since gone and that's why the study that we are talking about today with these authors is so important because the face of cardiovascular disease is different than in the west, the ways in which it is  evolving id different here than in the west and I like many others foresee an increase a significant increase in the types and prevalence of heart disease here in Asia. for all the reasons that we have been talking about, hypertension, obesity, type two diabetes, smoking the environment all of these challenges I fear are going to lead to a substantial increase in the prevalence of heart disease in Asia and that why we're here on the ground with Circulation in Asia that's why we have one of our major leaders Chong Shong Ma who is here in Beijing. Circulation is in China everyday, it’s in Beijing everyday to try and address this problem.   Dr. Carolyn Lam: And you heard it from our editor and chief, so thank you everyone for listening to this episode of Circulation on run. Tune in next week.      

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  • 00:25:35

    Circulation January 17, 2017 Issue

    · Circulation on the Run

      Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.                                                 In today's episode, we are discussing very important new data regarding stroke risk stratification in patients with atrial fibrillation. First though, let me give you the highlights of this week's journal.                                                 The first paper provides mechanistic evidence that endothelial-derived microparticles may play a key role in the development of endothelial dysfunction following acute coronary syndrome. In this paper from first author, Dr. Abbas, co-corresponding authors, Dr. Toti and Morel from the University of Strasbourg in France, authors expose core sign coronary artery endothelial cells to microparticles shed from senescent cells, or circulating microparticles from patients with acute coronary syndrome.                                                 They showed that exposure to these microparticles induced increase senescence-associated beta-galactosidase activity, oxidative stress, and early phosphorylation of MAP kinases and AKT, and upregulation of p53, p21 and p16. Depletion of endothelial-derived microparticles from acute coronary syndrome patients reduced the induction of senescence.                                                 On the other hand, pro-senescent microparticles promoted endothelial cell thrombogenicity. These microparticles exhibited angiotensin-converting enzyme activity and upregulated AT1 receptors and ACE in endothelial cells. Losartan and AT1 receptor antagonist and inhibitors of either MAT kinases or PI3-kinase prevented the microparticle-induced endothelial senescence.                                                  In summary, these findings indicate that endothelial-derived microparticles from acute coronary syndrome patients induce premature endothelial senescence and thrombogenicity suggesting that targeting endothil-derived microparticles and their bioactivity may be a promising therapeutic strategy to limit the development of endothelial dysfunction post-acute coronary syndrome.                                                 The next study is the first large and prospective study showing that NT-proBNP is associated with cardiovascular events in patients with adult congenital heart disease independent of multiple clinical and echocardiographic variables.                                                 This is a study from first author, Dr. Bekan; and corresponding author, Dr. Roos-Hesselink and colleagues from the Erasmus University Medical Center in Rotterdam, the Netherlands. The author studied 595 clinically stable patients with adult congenital heart disease who attended the outpatient clinic between 2011 and 2013.                                                 All patients underwent clinical assessment, electrocardiography, echocardiography and biomarker measurement, including NT-proBNP, high-sensitivity troponin T and growth differentiation factor 15. Patients were prospectively followed over a median of 42 months for the occurrence of cardiovascular events including death, heart failure, hospitalization, arrhythmia, thromboembolic events and reintervention.                                                 They found that of the three evaluated biomarkers, NT-proBNP was most strongly associated with cardiovascular events. Importantly, patients with a low-risk of death and heart failure could be accurately identified with a high negative predictive value.                                                 In patients with elevated NT-proBNP, elevations of high sensitivity troponin T and growth differentiation factor 15 identified those patients at highest risk of cardiovascular events.                                                 In summary, these biomarkers may play an important role in the monitoring and management of patients with adult congenital heart disease.                                                 The next study describes heart failure stages among older adults in the community. Dr. Shah and colleagues from the Brigham and Women's Hospital in Boston Massachusets classified more than 6,000 participants in the atherosclerosis risk and community study into heart failure stages. These were stage A; asymptomatic individuals with heart failure risk factors, but no cardiac structural or functional abnormalities. Stage B; asymptomatic individuals with structural abnormalities such as left ventricle hypertrophy, dilation, dysfunction, or valve disease. Stage C1; clinical heart failure without prior hospitalization. Stage C2; clinical heart failure with prior hospitalization.                                                 They found that only 5% of examined participants were free of heart failure risk factors or structural heart disease. 52% were categorized as stage A, 30% stage B, 7% stage C1, and 6% stage C2. Worst heart failure stage was associated with a greater risk of incident heart failure hospitalization or death at a median follow up of 608 days.                                                 Left ventricular ejection fraction was preserved in 77% of stage C1 and 65% of stage C2 respectively. In corporation of longitudinal strain measurements and diastolic dysfunction into the stage B definition, reclassified 14% of the sample from stage A to B.                                                 Abnormal LV structure, systolic function, whether based on ejection fraction of longitudinal strain, and diastolic dysfunction, were each independently and additively associated with the risk of incident heart failure hospitalization or death in stage A and B participants.                                                 The authors concluded that the majority of older adults in the community are at risk of heart failure, appreciably more compared to previous reports in younger community-based samples. The study also highlighted the burden of heart failure with preserved ejection fraction in the elderly and provided evidence that left ventricular diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and ejection fraction in identifying patient at risk of heart failure hospitalization or death.                                                 The next study sheds light on the association of the LPA gene, ethnicity and cardiovascular events. First author, Dr. Lee; corresponding author Dr. Tsimikas and colleagues from University of California San Diego studied 1,792 black, 1,030 white, and 597 Hispanic subjects all enrolled in the Dallas Heart Study. They measured LPA snips, apolipoprotein A isoforms, LP(a) and oxidized phospholipids on apolipoprotein B100.                                                 These individuals were also followed for a median of 9.5 years for major adverse cardiovascular events. The authors found that the prevalence of LPA snips and apolipoprotein A isoforms were very different across ethnic groups. LPA snips that were associated with elevated LP(a) in whites were associated with low LP(a) in Hispanics mainly due to differences in apoliproprotein A isoforms size.                                                 After multi-variable adjustment, LP(a) and oxidized phospholipids on apolipoprotein B were both predictors of major adverse cardiovascular events. Conversely, LPA snips and apolipoprotein A isoforms did not add predictive value to models and did not show clinical utility in this study.                                                 These data suggests that much of LP(s) mediated major adverse coronary events is driven by oxidized phospholipids. Importantly, elevated LP(a) and oxidized phospholipids on apolipoprotein B must be recognized as important predictors of major adverse cardiovascular events across racial groups.                                                 The final study addresses the question of the optimal antithrombotic regimen for longterm management of patients with symptomatic peripheral artery disease, or PAD, with a history of limb revascularization. To answer this question, Dr. Jones and colleagues from Duke Clinical Research Institute looked at the EUCLID trial, or examining use of ticagrelor in PAD trial, which randomized patients with PAD to treatment with ticagrelor 90 milligrams twice daily, or clopidogrel 75 milligrams daily.                                                 As a reminder, patients in EUCLID were enrolled based on a normal ankle-brachial index of less .8, or a prior lower extremity revascularization. The current paper really focus on the subset of 7,875 patients who were enrolled based on a prior lower extremity revascularization criterion.                                                 The authors found that after adjustment for baseline characteristics, patients enrolled based on prior revascularization for PAD had higher higher rates of myocardial infarction and acute limb ischemia with similar composite rates of cardiovascular death, myocardial infarction and stroke when compared with patients enrolled based on the ankle brachial index criterion.                                                 Overall, there were no significant differences between ticagrelor and clopidogrel for the reduction of cardiovascular or acute limb events.                                                 Those were your highlights. Now, for our featured discussion.                                                 On today's podcast, we are discussing the very, very important issue of stroke risk in patients with atrial fibrillation. Most of us use the international guidelines for anticoagulation in atrial fibrillation that mostly suggest that we use the CHADS VASc scoring system to determine the stroke risk in a particular patient and then determine whether or not this patient meets the threshold for anticoagulation.                                                 This assumes that the CHADS VASc score corresponds to a fixed stroke rate. Today, in our journal, we have very, very interesting results from a paper with corresponding author, Dr. Daniel Singer who really suggest that we may need to rethink that. Dr. Daniel Singer joins us today from Massachusets General Hospital.                                                 Welcome Daniel. Dr. Daniel Singer:             Thank you for having me. Dr. Carolyn Lam:               Great. Today, we also have Dr. Sana Al-Khatib who's the associate editor from Duke University who managed this paper. Welcome Sana. Dr. Sana Al-Khatib :         Thank you Dr. Carolyn, I'm happy to be here. Dr. Carolyn Lam:               Daniel, could we start by you letting us know what you sought to do in your study and what you found? Dr. Daniel Singer:             We all know that anticoagulants are extraordinarily effective at preventing stroke in patients with atrial fibrillation, but they also raise the risk of bleeding, and sometimes that bleeding could be quite serious and even fatal. As a result, for that past 10, 15 years, we have used a risk-based approach to the decision about whether to start a patient on anticoagulation, and that risk is the stroke risk that a patient faces if they weren't taking anticoagulants. Then we figured that anticoagulants will reduce it by about two-thirds.                                                 There are formal decision analysis and then a more informal sense that a patient has to face an anticoagulated risk of stroke of about 2%, some people might say 1% to 2% before anticoagulation results in an expected net clinical benefit that the effect in reducing ischemic stroke will exceed the risk of increasing bleeding.                                                 While the CHADs VASc score has been widely accepted as the basis for estimating that risk, it became apparent to us as we looked across the studies that were underlying that assumption, that the risk that were associated with various CHADs VASc scores were extremely variable. Many of these risks actually were less than that 1% or 2% threshold for anticoagulation.                                                 What I mean is that the stroke risk associated with CHADs VASc score of one, or two, which is the basis for the guideline threshold for anticoagulation actually corresponded to risk less than 1% in many of these very large studies. We have conducted a systematic review just to be sure that we were capturing the overall evidence base for this, and that's what we report in our paper. Dr. Carolyn Lam:               Perhaps you could start by letting us know exactly how far off are we in our stroke risk estimation. Dr. Daniel Singer:             We looked at 34 studies that were quite large and then we zeroed in on the largest one. If you looked at the rate for stroke overall, they varied enormously in terms of the overall stroke rate. Then when we focused down on CHADs VASc score of 1, or 2, we found that the majority of these studies, actually, for CHADs VASc 1, was less than 1% per year. For CHADs VASc 2 score was in the majority these studies less than 2% per year.                                                 Both of those stroke risks have raised us the question where are these patients could gain in that clinical benefit from being anti-coagulated, because those stroke risk, if they were reduced by two-thirds, would really be a very small reduction in risk and yet they'd still face the bleeding risk.                                                 Among the most interesting findings actually is that we found that a Swedish national database and the large Danish national database came up with threefold difference in their estimate of stroke rates. The Swedish database produced lower risk, and the Danish database produced substantially higher risk.                                                 If you think about it, there are probably no two countries in the world that are more similar in terms of gene, social environmental, medical care systems, and that raises the specific question of, "Is it underlying rates that vary across different cohorts and different geographies, or is it a different in methodology?"                                                 We think a lot of the differences are due to methodologic difference, and that we need to standardize these differences together, better handle on what the real stroke rate is among patients with these low CHADs VASc scores. Dr. Carolyn Lam:               The variability that you pointed on your paper is really striking, but another possibility, do you think, is that maybe stroke risk isn't static. Dr. Daniel Singer:             Yeah. If that's the case, we face a great difficulty in developing predictions rules of what the stroke risk could be. I think most people feel it's the function of their age, and whether they've had a prior stroke, and whether they have the comorbidity, hypertension, and diabetes, and so on, that are incorporated into the various stroke risk scores, in particular, CHADs VASc.                                                 We tend to think that that's pretty fixed until you get older or until you accumulated another comorbidity. I think the striking difference is that, one, that we actually anticipated in the beginning, was that the stroke rates in people with atrial fibrillation were also coming down. The stroke rates in general have been dramatically decreasing for decades now.                                                 One issue is whether that applies as well to atrial fibrillation associated stroke. There is a suggestion of that, but the variability across the cohorts is so great that you can't pick up a strong signal in terms of calendar time. Although I suspect that there is a strong calendar effect. Exactly why that is, we could speculate. I suspect a lot of it is control of blood pressure, but that's speculation. Dr. Carolyn Lam:               Daniel, congratulations again for that fascinating and really very sobering findings.                                                 Sana, you managed this paper. It's very important paper. In fact, important enough that you invited an editorial. Could you please share some of your thoughts? Dr. Sana Al-Khatib :         Oh, yeah. Absolutely. First, I'd like to start by congratulating Daniel and his team on conducting this really important study. I enjoyed reading it and managing it. Definitely, congratulations.                                                 A couple of thoughts that I have. I completely agree with this really important finding, that there is a lot of variability in the rates of stroke that come from different patient populations and databases. As you pointed out Daniel, I think this is indeed largely due to differences in methodology in terms of how the information was selected, how certain things were defined.                                                 I agree with you there. You called for standardization of this, and I wonder if you have any thoughts about how we can go about doing that. I also want to bring up some of the newer studies now that are showing some significance in terms of biomarkers. Is that really adding significantly to the predictive ability of risk prediction models? I wanted to get your thoughts on that as well. Dr. Daniel Singer:             Let me address your last question, which is simply you state that the CHADs VASc score, the CHAD score and so on, are based on very simple clinical features, and it would be unusual for them to be highly predictive. In fact, they're only mediocrely predictive, and the addition of biomarkers high-sensitivity troponin proBNP, now, people have suggested the imaging biomarkers like magnetic resonance to asses fibrosis in the left atrium. These are all very, very promising in terms of getting better models.                                                 The problem is to do that on a very scale such that we can get precise and well-calibrated predictions. We've found when we're analyzing to pair risk scores, we found that the most important issue is the underlying risk, so that, yes, you can get a great model, but if you have high variability in the underlying rate, you can have a problem specifying an individual with a stroke risk.                                                 We have to standardize and improve the quality of bringing people into these cohorts, and of interrogating the cohorts and databases and making sure that we have the same approach to assessing outcomes.                                                 This could probably be best done in very big scientific prospective registry studies, but it's tough to get all that information. There are some registry studies now ongoing, the ORBIT registries, the GARFIELD registries that may help us a lot with specifying stroke risk, but they don't have the biomarkers embedded in them. I'm hopeful that with better message, and large studies, and incorporating biomarkers, that we'll really get down to very accurate and generalizable stroke risk.                                                 I think the CHADs VASc and similar simple stroke risk scores will be in the rear-view mirror. Dr. Sana Al-Khatib :         That's great. Can I ask one other question, because I completely agree with you looking at your numbers and the data that you presented, is that when you look, especially at the CHADs VASc score 1 patient, the risk seems to be pretty low.                                                 As you very well know, the guideline documents don't really ... At least, for the American AHA/ACC guideline document, they don't really verbalize very definitively the need to anticoagulate patients with a CHADs VASc score of 1.                                                 If you look at the numbers related to a CHADs VASc score of 2, I'm not sure that I completely agree that the risk is very low. Certainly, there was 33% of the studies reported stroke rates of greater than 2% per year. I think maybe different people have different thresholds. While I completely agree with you on the CHADs VASc score of 1 patients, I find that the findings on patients with a CHADs VASc score of 2 a bit more concerning.                                                 In fact, if anything, I would want based even on your data, not on the guidelines to offer anticoagulation to patients with CHADs VASc score of 2. What would you say to that? Dr. Daniel Singer:             I'm looking at our table that has this, and a lot of the CHADs VASc 2 scores are under 2%, but they're in mid 1%. In the North American cohorts in particular, the rates tend to be lower. That said, I think the heart of the problem here is that we have focused on the threshold for anticoagulation. I think there's an argument to be made that you lay out the risks and benefits to the patients and engage them in a decision, particularly with regards to these lower CHADs VASc scores.                                                 At least you make a lot of, perhaps, even more emphasis on being sure that the higher CHADs VASc scores, that anticoagulation is the net benefits of anticoagulation are made very clear to the patient, and that we don't have large fractions of patients who can take anticoagulants not taking them.                                                 We know from the pinnacle registry and other registries, that even at high CHADs VASc scores, we have 40% plus of atrial fibrillation patients who are not getting anticoagulants. I think that's where we have a lot more assurance that the net benefit is positive and that we can make a different both in terms of a patient in front of us, and in terms of the overall public health aspects of atrial fibrillation and stroke. Dr. Sana Al-Khatib :         I do believe that this is really important, but it is also important to keep in mind that with the novel novel oral anticoagulants, I think the whole landscape has changed. Not only do patients have different options to consider, but certainly, the risk of bleeding, which is the other part of this equation, has gone down significantly with the novel agents.                                                 I think as we engage in shared decision making with patients, I think it is really important to highlight these really very remarkable features about the agents that have really changed the care of patients with atrial fibrillation.                                                 One thing to add to this whole topic is, really, all the new advances that we're seeing in this field that has been really life-changing for us and for our patients. Dr. Carolyn Lam:               Indeed Sana. I was about to bring up the bleeding risk part, the flip side of the coin as well. Also, the point that most of my patients with atrial fibrillation, they really strongly value the avoidance of stroke even more than avoidance of bleeding. Someone, that needs to be taken into consideration as well.                                                 Daniel, I'd love to give you the last words. You mentioned that you like to highlight, maybe, some more of the implications of your findings. Dr. Daniel Singer:             I guess I would say there's a scientific implication, which is what we've ben discussing, which is the importance of trying to get these rates down correctly and accurately, and maybe we have to get people together to say how they're doing these studies.                                                 The second is, for the individual patient, that we should engage them in this discussion. Maybe patients who are perfectly willing to a novel anticoagulant and CHADs VASc score of zero. That would come out of a discussion with the patient. That our emphasis at this point since we're a little unsure about the threshold level, our emphasis both at the individual patient level, and then from the public heath perspective should be on the higher CHADs VASc scores where we know that we can expect a net clinical benefit from the vast majority of patients with AF.                                                 I agree with Dr. Al-Khatib, that the novel anticoagulants post an important advantage in the sense not so much in their overall bleeding, but particularly in terms of their intercranial bleeding, which is the lethal bleeding we most want to avoid. Dr. Carolyn Lam:               Thank you both for joining us. Thank you listeners for joining us. Don't forget to tune in next week.  

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  • The Strengths and Limitations of Risk Assessment: Professor Susan Turner of the University of California-Irvine

    · The Center for Court Innovation - Podcasts

    In this podcast recorded at the Courts, Community Engagement, and Innovative Practices in a Changing Landscape symposium held in Anaheim in December 2015, Susan Turner, professor in the department of Criminology, Law & Society at the University of California-Irvine, explains how risk assessment tools are developed and discusses the strengths and limitations of risk assessment. RAPHAEL POPE-SUSSMAN: This is Raphael Pope Sussman, with the Center for Court Innovation. This podcast is part of a series of dispatches from the Court's Community Engagement and Innovative Practices in a Changing Landscape Symposium held in Anaheim in December 2015. The conference focused on justice reforms, including recent developments in California, public safety realignment and Proposition 47. Public safety realignment refers to changes brought about by 2011 legislation that shifted responsibility for certain populations of offenders from the State to the county level. Proposition 47, a ballot initiative passed by referendum in 2014 reclassified certain low level felonies as misdemeanors. I hope you enjoy listening. Hi, this is Raphael Pope Sussman, with the Center for Court Innovation, and I'm here today at the Court's Community Engagement and Innovative Practices in a Changing Landscape Conference in Anaheim. Right now I'm sitting with Susan Turner, professor in the Department of Criminology, Law and Society at University of California, Irvine. Susan, thank you for speaking with me today. SUSAN TURNER: Glad to be here. POPE-SUSSMAN: What's the process for developing a new risk assessment tool? TURNER: Well, risk assessment tools can be developed by an organization. There are also ones that are available that have been developed by others, so some of the first decisions that jurisdictions make is whether to do it home grown or whether or not to buy something that's been developed and is available for purchase, or is perhaps free. If you're interested in developing a risk tool for your jurisdiction, one of first things you need to decide is what are you interested in predicting? Most jurisdictions in risk assessment are interested in predicting some kind of recidivism behavior, such as arrest or incarceration or conviction. Then we generally use a set of variables that are related to an offender's prior record, age or gender, and then some other factors that may be related to their drug use, mental health status, their association with criminal peers. You basically need to make sure that you have the data for your left hand and your right hand side of the equation. You gather the information on an individual level, so for every person you're interested in, you gather information on whatever outcome and then their record, their variables such as their gender, their age, and their prior record. You want to have a sample that's large enough. You put them generally in a regression equation, where you try to figure out whether or not these factors are predictive. You're able to gather weights for the variables based on these mocks. For example, if you're predicting whether somebody would be convicted, you might have age and you'd have a weight of 5, gender you'd have a weight of 3, different prior record variables would have various weights. You can just imagine sort of scoring everybody up, and the higher the scores, generally the more likely someone will recidivate. Once you do that on one half of your sample, you build your model. Then you do something called validation on a separate set of data that you haven't looked at before and that tells you whether or not what you've developed on your first sample validates or is predictive on your second sample. That's basically a kind of simplistic view, but the overall gist is that you have data available, you develop your instrument on one half of the sample and test it on the second. POPE-SUSSMAN: What are the limitations of these tools? TURNER: Well, there's a lot of good things about the tools and there are, of course, always limitations with any kind of tool. Risk assessment for recidivism is, like many other risk tools, we have risk tools in our regular lives. You think of your car insurance premiums that you pay are based on risk assessment tools. Risk assessments tools are only as good as the data that are behind them, number one. Another limitation to risk assessments tools that we all need to be aware of is that they're never 100% accurate, and probably will never be 100% accurate. They generally are what's referred to as a moderately good predictor, but because of the nature of human behavior and variables that we don't know why people do the things we do, we can never gain 100% accuracy, which sometimes gets us into trouble with say politicians who have very high standards for whether or not you want to use an instrument. Sometimes so high that they're really not practical. POPE-SUSSMAN: What are the great strengths? TURNER: Great strengths are that we normally discuss risk assessments tools contrasted with what we refer to clinical judgment, or some people call it gut. The research has shown that actuarial tools or risk prediction instruments are more accurate than gut or clinical experience. Many people don't like to believe that because they're often trained in a clinical background, or you can imagine a parole agent with 30 years of experience is sometimes looking askew at risk assessments tool, but they're more accurate. They can also result in decision making that's more consistent, because you can imagine the great variability if everyone follows their own gut. You have lots of different ways the same person might be scored, so there's consistency. There's also, with some risk assessments tools the advantage of time. Some of them are automated so for large numbers of people they can be scored pretty quickly, allowing an agency to be able to get actuarial tool on a number of offenders without the resources that may be required for, say, 45 or 50 minute instruments that are collected individually. POPE-SUSSMAN: What roles do you see for risk assessments tools in the larger project of decarceration? TURNER: One of the things we've talked about here today was the use of risk assessment and one of the things I mentioned was that risk assessment's been around for a long time. It's got a resurgence nowadays, I think partly because we're trying to reduce the current populations that we have incarcerated and we don't have enough money to be able to keep everyone locked up. Money is driving a lot of decisions and one of them I think actually may be risk assessment. We need to decide who are the highest risk people, the ones that we need to devote our resources to, our public safety resources, and to not spend the resources on the ones who are the lower risk. POPE-SUSSMAN: How do we ensure that risk tools don't show bias against individuals and communities that may have disproportionate rates of established risk factors, like housing or employment or disability? TURNER: Very good question. I think there are a number of people who are concerned with risk assessments tools based on dimensions that may impact certain groups unfairly. Many risk assessments tools use an offender's prior record as a major variable in their recidivism outcomes. Then there's obviously the question, if prior records are somehow biased in their very creation within communities of color, what does that mean in terms of risk assessments tools. It's a very valid question. One of the ways that we help address this is when we develop tools, we take a look at and see how well the tools works with the different populations of interest. For example, when we developed a tool for the California Department of Corrections and Rehabilitation, we were particularly concerned about whether the tool predicted for females as well as males, because there's a lot of work suggesting that some of the risk factors for women are different and for men. Also, we were concerned about whether the risk tool worked equally well for blacks and Hispanics and whites and other groups. What we do with those is that we separate the samples into the groups of interest and check to see whether the tool is as predictive in each of the groups. If you find a tool that doesn't work very well in one of the segments that you're interested in, then you need to go back to the drawing board. POPE-SUSSMAN: I've heard that misdemeanor populations are particularly difficult to assess. Why is that? TURNER: Well, the discussion of misdemeanor risk assessments has really come into the light here in California with proposition 47. Traditionally, most of us deal with risk assessments in the felony world. All the risk assessments tools I've done are pretty much predicting felony recidivism. There is a question, are these tools good for misdemeanors. There are tools out there that have been developed for misdemeanors. There's a tool for misdemeanor DUIs and some tools that are developed by the University of Cincinnati team have established one that's for misdemeanors. They basically work the same as the felony tools. They're predicting a different kind of an outcome, which is maybe a lower level of behavior. What we find with our risk tools is that these tools can be very robust to different populations and different kind of outcomes. POPE-SUSSMAN: Do you have any big vision going forward, the next step for risk assessment? TURNER: Well, one of the risk assessment has always been used pretrial for a long time. It's been used the last 20 or 30 years at the probation stage. I think more recently it's being considered at the sentencing stage, which I think in many ways has a little more ethical issues, whether or not in sentencing actually considering risk as opposed to the sentence type. POPE-SUSSMAN: What do you mean by ethical issues? TURNER: I mean, what's the purpose of sentencing and some people say the purpose of sentencing is that it should be proportionate to the crime that was committed and that our statutes are based, sentences are based on perceived severity of violent offences being more serious that property offenses and you reserve the highest sentence lengths for the more violent. If you move to a risk based system and you say, well as we found in our research, people convicted of violent crimes are not necessarily the most likely to re-offend, so you basically a conflict going with what is the justice based, in terms of the offense, versus a risk based, which is about future behavior. That's sort of conflict that you've got to figure out how you're going to deal with. In our own development of the risk tool for the State, in our training and discussion of the tool, we've come across people who are very perplexed by our findings that show that people who have convictions for violent offenses, there's actually what we refer to as negative weights on that, so that people with violent offenses are actually less likely to have recidivism than those that don't, which is very counter-intuitive. POPE-SUSSMAN: I guess that would also get to people's ideas about what the justice system is supposed to do. Is it supposed to be punitive? Is it supposed to be rehabilitative? Is it supposed to be utilitarian? TURNER: Yeah, I think, as I teach my students, a couple things you have to remember. If you remember a couple of things, you go out after school it'll be very helpful. One of the them is to remember always the different purposes of punishment. One is deterrence, and that's what we we think risk based decision making is based on. But there's retribution, incapacitation. Yeah, there's many philosophies of what the goal of punishment is. I think risk prediction sets you straight in the cross hairs of some of the other theories of punishment. POPE-SUSSMAN: Well, thank you. I really appreciate you taking the time to speak with me. TURNER: Thank you very much for the opportunity. POPE-SUSSMAN: This is Raphael Pope Sussman, of the Center for Court Innovation, and I've been speaking with Susan Turner, Professor in the Department of Criminology, Law and Society at the University of California, Irvine. For more information on the Center for Court Innovation, visit www.courtinnovation.org  

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  • 00:19:16

    Circulation November 29, 2016 Issue

    · Circulation on the Run

      Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our feature discussion today is about the validation of a novel biomarker-based stroke risk score for atrial fibrillation, the ABC stroke score. But first, here's your summary of this week's journal.     The first paper provides experimental insights into endothelial nitric oxide synthase uncoupling in endothelial dysfunction. In this paper by first author Dr. Lee, corresponding author Dr. Wong and colleagues from Qilu Hospital of Shandong University in China, authors assessed endothelial function in animal models of hyperglycemia, hyperhomocysteinemia, and a dyslipidemia. They demonstrated that GTP cyclohydrolase 1 is the target of the microRNA-133a and that it's a topic expression and endothelial cells mediates endothelial dysfunction.     Furthermore, Lovastatin up-regulated GTP cyclohydrolase 1 and tetrahydrobiopterin and re-coupled endothelial nitric oxide synthase in stress endothelial cells. These actions of Lovastatin were abolished by enforced micro RNA 133A expression and mirrored by a mir-133a-antagomir. Finally, the beneficial effect of Lovastatin in mice were abrogated by in vivo mir-133A over-expression or by GTP cyclohydrolase 1 knockdown. In summary, this paper offers a mechanistic basis for targeting micro RNA 133A as a therapeutic approach to correct endothelial nitric oxide synthase dysfunction. It also provides further support to the role of statins in combating endothelial dysfunction.     The next study shows us that in hypertrophic cardiomyopathy, calcium mishandling may be the potential link between the primary genetic cause and downstream signaling cascade that leads to hypertrophy and arrythmias. In this study, Dr. Helms and colleagues from University of Michigan analyzed gene expression, protein levels and functional essays for calcium regulatory pathways in 35 human hypertrophic cardiomyopathy surgical samples with and without sarcomere mutations and compared that with 8 control hearts. They found a marked reduction in circa2 abundance, which correlated with reduced circa2 function in hypertrophic cardiomyopathy compared to controlled hearts regardless of the underlying genetic etiology.     However, calcium calmodulin depend protein kinase type 2 or cam2, which is a calcium sensing kinase, was deferentially activated only in the sarcomere gene mutation positive samples. Activation of chem kinase 2 was associated with an increase in phospholamb and phosphorylation in hypertrophic cardiomyopathy. However, neither calcineurin MRNA nor MEF2 activity was increased, suggesting that calcineurin pathway activation was not an upstream cause of increased chem kinase 2 protein abundance or activation.     In summary, this paper demonstrated that calcium mishandling occurs through both genotype specific and common pathways in human hypertrophic cardiomyopathy. Post-translational activation of chem kinase 2 pathway is specific to sarcomere mutation positive hypertrophic cardiomyopathy. While Sarco 2 abundance and sarcoplasmic reticulum calcium uptake are depressed in both sarcomere positive and negative hypertrophic cardiomyopathy. Thus, chem kinase pathway inhibition may improve aberrant calcium cycling in hypertrophic cardiomyopathy. This is discussed further in an accompanying editorial by Dr. Jill Tardiff.     The third study suggests that in patients with a dilated aortic route and trileaflet aortic valve, a ratio of aortic route area to height provides independent and improved stratification for prediction of death. First author Dr. Masry, corresponding author Dr. Desai and colleagues from the Center for Aortic Disease, Heart and Vascular Institute of Cleveland Clinic, studied consecutive patients with a dilated aortic route of greater or equal to 4 centimeters who underwent echocardiography and gated contrast enhanced thoracic aortic computer tomography or magnetic resonance and geography between 2003 and 2007.     A ratio of aortic route area over height was calculated on tomography and a cutoff of 10 squared centimeters per meter of height was chosen as abnormal. In 771 patients with trileaflet aortic valve and concomitant aortopathy, there was incremental prognostic value for indexing aortic route or ascending aortic area to patient height rather than using an unindexed aortic diameter. Incorporation of the ratio significantly and independently reclassified the risk for death and at normal ratio was independently associated with higher long-term mortality while cardiovascular surgery was associated with improved survival. Importantly, a sizable minority of patients with aortic route diameters between 4.5 and 5.5 centimeters had an abnormal aortic route when indexed to height ratio. 78 percent of deaths in this subgroup occurred in those with an abnormal aortic route area to height ratio. Findings were similar when ascending aortic measurements were considered. The take home message is that an aortic route area to height ratio above 10 squared centimeters per meter of height has significant and independent prognostic utility and may be used to re-stratify patients with trileaflet aortic valve and a dilated aorta.     The final study provides pre-clinical data to show that Ticagrelor reduces cardio damage post myocardial infarction to a greater extent than Clopidogrel by an adenosine induced organ protective response. First author Dr. Villaher, corresponding author Dr. Bademan and colleagues from the Cardiovascular Research Center in Barcelona, Spain studied a close-chest swine model of ischemia reperfusion in which myocardial infarction was induced by 1 hour balloon occlusion of the mid-left anterior descending coronary artery followed by 24 hours of re-flow. Prior to occlusion, the animals were randomly assigned to receive either placebo, a loading does of Clopidogrel, a loading does of Ticagrelor or a loading does of Ticagrelor followed by an A1 A2 receptor antagonist. Edema infarc size left ventricular size and left ventricular function were assessed by three T cardiomagnetic resonance imaging. Inhibition of platelet aggregation was the same between the groups receiving a P2Y-12 inhibitor.     Yet, Ticagrelor reduced infarc size to a significantly greater extent than Clopidogrel, reducing it by a further 23.5 percent, an effect supported by troponin eye assessment and histopathological analysis. Furthermore, compared to Clopidogrel, Ticagrelor significantly diminished myocardial edema by 24.5 percent, which correlated with infarced mass. Administration of an adenosine A1 A2 antagonist abolished the cardio protective effects of Ticagrelor over Clopidogrel. At a molecular level, aquaporin 4 expression decreased and the expression and activation of AMP kinase cyclin and COX-2 increased in the ischemic myocardium of Ticagrelor versus Clopidogrel treated animals. In summary, this study shows that Ticagrelor exerts cardio protective effects beyond its anti-platelet efficacy by adenosine dependent mechanisms, which reduce necrotic injury and edema formation. This is discussed in an accompanying editorial by Drs. Gerbel, Jung and Tantry. That wraps it up for the summaries. Now for our feature discussion.     Today, we are going to be discussing the performance of the ABC score for stroke in atrial fibrillation. And as a reminder for all our listeners there, ABC stands for A for age, B for biomarkers, that's NT-proBNP and high-sensitivity troponin, and C for clinical history of prior stroke. And again as a reminder, this risk score was originally derived in the Aristotle trial. However, we have new results about its performance and validation today from first and corresponding author Dr. Jonas Oldgren from Uppsala Clinical Research Center in Sweden. Welcome, Jonas.   Speaker 2: Thank you very much.   Carolyn Lam: We also have today the associate editor who managed this paper, Dr. Sandeep Das from UT Southwestern. Hi Sandeep.   Speaker 3: Hi Carolyn, thanks for having me.   Carolyn Lam: So Jonas, could you start off by telling us why you did this study and what you found?   Speaker 2: We did this study to validate the recently derived ABC stroke risk score. We have had risk scores for predicting stroke in patients with atrial fibrillation derived since the late 1990's and refined later on. But those risk scores have only used clinical markers for risk. We have for several years developed new risk prediction models with biomarkers and now we are combine them in a very simple biomarker based risk score, taking into account age as a clinical variable and the clinical history of prior stroke and only two common used biomarkers. And by that we can predict the risk of stroke with better precision than previous clinical risk scores.   Carolyn Lam: Yeah, I like what you said. I mean it is literally as simple as ABC. So tell us how you validated it and what you found.   Speaker 2: It was derived in a large cohort of patients participating in a clinical trial with new or relapsed coagulant compared to Warfarin and we now validated in almost a full size group participating it another clinical trial. So we have large data sets of very well described patients where we have good outcome data. Very solid data to rely on. Now we can see that the ABC risk score is now validated but the good precision and good collaboration of the discriminatory abilities is high and better than the previously used clinical risk scores.   Carolyn Lam: Could you give us some numbers behind that that are clinically meaningful? Everyone's going to be wondering compared to the chads-vasc score for example, how does this ABC score perform in that validation test set?   Speaker 2: We can adjust that by several different aspects. One is of course to calculate the C index which is a statistical method to see how good we can predict risk and the C indices for the ABC stroke score both in the duration and now in the validation cohort is higher than for the chads-vasc and atrial risk scores. But we can also look at what we have in this paper in circulation ... we can look at predicted outcome rates and observed outcome rates and can see that they clearly overlap both in the duration and validation court. So if you predict a risk that is less than 1 percent per year, it is observed also a risk that is less than 1 percent a year. Does this always ... the thing is when you derive risk or but when you validate it in another cohort, you need to show that it's a similar result.   Carolyn Lam: Yeah, that's true. Sandeep, you are managing this paper. It's very important. How do you think that clinicians should be taking the results?   Speaker 3: I think that clearly using anticoagulation and selected patients at high risk for stroke with atrial fibrillation is one of the best things we do in cardiology. You know in terms of reducing the risk of an important harm to patients. I think there's a fair bit of dissatisfaction out there with currently sort of standard, which is chads-vasc. Especially in people with a chads-vasc ... men with a chads-vasc of 1 or women with a chads-vasc of 1 to 2 where there's a bit of struggling over how to decide. So I think that one real advantage of this score in addition to the fact that it predicts better by the higher C statistic, which is fantastic and pretty uncommon, right? Lars sort of buried the lead a little bit by not emphasizing that it's relatively rare that we're able to move a c statistic by a point of 5 in the modern era.     But the other thing is that it helps give us an ability to come up with good estimates in people at low risk, which I think has been a challenge and something that people are a little concerned clinically. So I think that this is easily available, biomarkers that we routinely check all the time and it doesn't have the sort of gender challenge with chads-vasc where you're trying to figure out whether your low risk woman really needs to be on Warfarin or anticoagulation. So I think that it has a lot of clinical utility right out of the box, which is nice.   Carolyn Lam: Actually, Jonas could you let us know is there any sex differences in the performance of the score?   [00:14:46] Speaker 2:   There are no differences in the performance of the score. So we looked ... the advantage of this score is when we derived it in the original model, we looked at all important clinical and biomarker risk factors and we can see that these were the foremost interesting markers. So we only used those. So we can predict much better and as pointed out so nicely by Sandeep, for patients at the lower end of the risk spectrum, we can find patients or have higher or lower risk even within patients with chads-vasc 1 or chads-vasc 2. And I think it's also important to see what about patients at higher risk despite proper anticoagulation. We did not know how to treat them but in the future we might perhaps tailor treatment also for those patients with residual high risk of stroke despite proper anticoagulation treatment. For instance, if the left atrial appendage occluded devices are shown in the future to be a good option for those patients, we can find them also by this risk score. So both in the higher and lower end of the risk spectrum.   Carolyn Lam: That's a really good point. On that note, I'm just curious. What do you think is in the future? What more knowledge do we need to address before we put this into practice or are you already using this? Or do you think it should enter guidelines for example? Maybe Sandeep, I could ask for your opinion first.   Speaker 3: We see a lot of biomarkers associated with increased risk kind of studies come out in the literature. You know probably every week you see several of these things come out. So what's really interesting about this is that it's obviously methodologically extremely well done but its been derived and validated in two large cohorts, which is pretty much best practice right? You want to see people validate these risk scores in large and distinct cohorts of patients to build up sort of clinical validity to the reader or consumer. So I think, from my standpoint, this is ready for prime time. I'm really intrigued by the fact that biomarkers, especially troponin, are predicting stroke in this population and there have been some observational reports out there that have showed an association between troponin and increased risk of stroke or worse outcomes after stroke. So I'd be really curious as to what Jonas thinks about why troponin would be predictive of stroke in this population.   Speaker 2: We were extremely intrigued by the finding when we first did those single observations of only troponin as a risk marker because we know that troponin is a very specific protein found in the myocardium. But the clinic predicts risk for stroke also and there are several explanations but they are mainly hypotheses about aging and myocardial function really to identify patients of risk. But the clear cut explanation is still not there.   Carolyn Lam: It's likely that these biomarkers are incorporating aspects that we don't fully understand, which is why they are better predictors isn't it? I mean to your point Sandeep.   Speaker 3: Yeah, no absolutely. And I think that's great.   Carolyn Lam: Exactly. It really opens a lot of other questions that need to be answered in the meantime. Jonas, any other last words about how you may be applying this clinically in your own patients?   Speaker 2: We have no solid data supporting the use of this clinical risk score and as already pointed out, which I think is very good, all clinic risk scores should of course be in the best world validated as useful decision support truth and really in clinics trial seeing that they improve outcomes. This is to my knowledge never been down with a clinical risk scores. We have never used them prospectively to guide treatment and to improve outcomes. Actually, we are aiming to do that. We hope to start a clinical trial next year with ABC score guided treatment compared to standard of care. But it's a very huge undertake of course to that we can improve treatment by risk or guided management.   Carolyn Lam: That's excellent. So remember everyone, you heard it right here. A new trial that they're engaging. I really congratulate you first for this study, as well as this future efforts which are clearly going to be very important.     Thank you very much both of you for joining us today and thank you listeners for listening. Don't forget to tune in next week.  

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  • The Potential for Bias in Risk-Assessment Tools: A Conversation

    · The Center for Court Innovation - Podcasts

    In this New Thinking podcast, Reuben J. Miller, assistant professor of social work at the University of Michigan, and his research collaborator Hazelette Crosby-Robinson discuss some of the criticisms that have been leveled against risk assessment tools. Those criticisms include placing too much emphasis on geography and criminal history, which can distort the actual risk for clients from neighborhoods that experience an above-average presence of policing and social services. "Geography is often a proxy for race," Miller says. Miller and Crosby-Robinson spoke with the Center for Court Innovation's Director of Communications Robert V. Wolf after they participated in a panel on the "The Risk-Needs-Responsivity Framework"  at Justice Innovation in Times of Change, a regional summit on Sept. 30, 2016 in North Haven, Conn.Reuben J. Miller, assistant professor of social work at the University of Michigan, and his research collaborator Hazelette Crosby-Robinson participate in a panel at "Justice Innovation in Times of Change," a regional summit. WOLF: Hi, I'm Rob Wolf, Director of Communications at the Center for Court Innovation and today with me at the Justice Innovation in Times of Change Conference here at the Quinnipiac School of Law in North Haven, Connecticut are two of the panelists who participated in a discussion about risk needs assessment tools. They are Professor Reuben Miller, who is an assistant professor of social work at the School of Social Work at the University of Michigan and his research assistant at the School of Social Work, Hazelette Crosby-Robinson.  Thank you so much for taking the time after your panel to sit down and talk with me. MILLER: Thank you for having us. WOLF: So, I wanted to just start off talking about the risk assessment tools and some of the criticisms that have been leveled against them because, as we heard on the panel from Sarah Fritsche, a colleague of mine at the Center for Court Innovation, their use has exploded and they've been embraced as a decision-making tool in the criminal justice setting. MILLER: Sure. WOLF: But you raised some potential concerns about them and some of their limitations and I wondered if you could share what some of those limitations are as you see them. MILLER: Sure, I'm happy to. So, Hazelette is my research associate and collaborator. She's super modest. So, I'd like to first preface this by saying, some scholars have suggested that we've really entered an actuarial age. So it's not just risk assessment in criminal justice, but a whole cost benefits calculus, a whole risk calculus that's based on actuarial models that try to predict future harm. So they try to predict, much like an insurance company would try to predict the future risk of a car accident. In a criminal justice setting, these risk needs assessments are trying to, one, gauge the needs of incarcerated individuals or people who have been convicted of a crime to try to figure out where they could shore up deficits in their skill sets or in their general stability. So for example, they might examine things like housing stability, or whether or not one was employed, or what kinds of service needs they may have. So for example, if one has a history of substance use and abuse, that would indicate that they need treatment or some sort of intervention based around these things. And at the same time, they're trying to gauge the risk of re-offense, so the risk that they will commit a crime. So there are a number of criticisms. The literature that engages this is fairly long. I tend to think about some of the movers and shakers in this field, Kelly Hannah-Moffat, Bernard Harcourt, Sonia Star, Faye Taxman. Faye Taxman's work is actually helping us to think about important ways that we can implement risk assessment that reduce some of the biases that are sort of baked into it, but just to talk about some of the critiques that have come from this literature and of course my own, on the one hand there are static factors like where one lives, so geography, their prior criminal history. These are things that they can't avoid. And the privileging of recidivism as an indicator of success. These are all problematic for the following reasons. So geography is often a proxy for race. We know that we live in a country that has a pattern of residential racial segregation. And we know that policing and criminal justice resources of all kinds are overwhelmingly distributed in areas where poor people of color tend to live. The problem is, people are now being arrested from, returned to, and even given programs designed to rehabilitate them all within low income communities. Very bounded geographic districts. And so what you get is, you get the overwhelming concentration of criminal justice resources, and you get a signaling of what that all means. So if the substance abuse treatment house is located in a neighborhood, then that tells me that there's substance abusers there. Right? And so that signals narcotics forces to the community. It says something about the community. Halfway houses are also overwhelmingly there. And so one must think about what the concentration of these things do. So now okay, as it relates to risk. Being in a neighborhood like this triggers a higher risk score. It is indeed one of the measures of risk, and so in that way it's a proxy for race. Sorry, I know I'm talking quite a bit, but - WOLF: No, and just to kind of summarize though, or to recap what you've said so far, the way risk assessment tools work, they place a high value on the location someone's from. They place a high value on their history with arrest. MILLER: That's absolutely right. WOLF: And so, if there's a preponderance of enforcement there, some people are more likely to have an arrest record or - MILLER: The study from Stop and Frisk made this abundantly clear. That even when people aren't doing anything wrong they're being overwhelmingly stopped if they're black or Latino. And so we know that criminal justice contact increases the likelihood that one will be arrested. And so anyway, this is a big problem of using prior arrest records for example and even prior conviction records, so now you've got a bunch of arrests. By the time you get to the prosecuting attorney, they’re going to say, Look, you've been arrested 14 times. "Well, I've been arrested 14 times but never charged." No, but you have a history of arrest, and so I'm going to now charge you because I see a pattern. This is how statistical discrimination might work, or does in fact work in practice. So now the prosecuting attorney sees a pattern. Sends it before the judge, who looks at this pattern and interprets it to make a decision about the length of the sentence when the conviction is read, as is a jury if it ever goes to trial. 97% of cases never go to trial, but when it goes to trial, juries are presented with the same evidence of patterns which have more to do with where the police are concentrated than what people are actually doing. WOLF: So what do you say to the notion that these instruments are validated? That they predict? This information, whether there's a potential bias incorporated into them, they still can predict six months to a year out whether someone is going to recommit a crime. MILLER: Yes, with great reliability. But it's a population being normed against itself. And so, overwhelmingly concentrate criminal justice resources in a particular neighborhood, which leads to more arrests, which leads to more convictions, which leads to more imprisonment. Then I look at those who were imprisoned, and I use that to validate my measures. So the problem, is this sort of self-fulfilling prophecy, this feedback loop, this is one problem. Another problem is that, and Kelly Hannah-Moffat points this out brilliantly, correlation and causation are very different things. It's like the standard social science response that any bench chair social scientist gives when they look at two relationships and people use that as some sort of cause, but likelihood that particular groups of people are more likely to commit a crime, doesn't mean that having committed a crime in the past means you actually will commit a crime. And so what we're doing is, we're treating relationship as if it's a cause, as if it's a fact. And so I will sentence you now based on my assumption of your future danger to commit a crime based on a set of assumptions that I use to justify the overwhelming concentration of police to begin with. Police aren't the culprits here. It's a rationality, it’s a way to approach problems, that I think must be critically investigated. WOLF: And you also pointed out in your presentation that perhaps the cultural context, the environment and the changing policy culture where for instance, marijuana arrest which were so vigorously pursued several years ago are now considered a low priority, or they're not even being done anymore. And yet, people have a record of those arrests and if history of arrest is a factor, someone in the audience also questioned this, should we drop those particular kind of arrests as a factor because we don't care about them anymore? Do they indicate further likelihood of going against the law or are they just something someone did because they like marijuana and that's it? MILLER: That's right. And this is a part of the rigidity of risk assessment. This is rigidity of risk categories. So to place one in a category, you are an offender. And in Michigan, where I've done a lot of research and where I've worked, habitual offenses ... and it's not like this in Michigan, but it's like this in many, many states, most states I would argue ... being a habitual offender means more time, greater risk, more punishment. CROSBY-ROBINSON: Up to life. MILLER: Absolutely. So what does it mean to habituate? What am I looking at? Well, if I'm not being careful about the criminal codes, if I'm not carefully examining what I considered a crime at a given moment in time, and adjusting my instrument for that. Which must happen, probably, annually. If I’m not adjusting my instrument for that, if not quarterly. If I'm not adjusting that for different understandings of what is right and wrong, then what I'll end up doing is habituating someone. Giving them longer sentences, giving them harsher treatment, deeper levels of punishment, or indicating they need deeper levels of intervention. WOLF: So tell me what recommendations you'd make. Because you also made a point in the panel that there are some good things about risk assessment. They do take away discretion form judges or people whose own bias might lead them to make the wrong decisions? MILLER: Absolutely. The benefit of risk assessment is to use it to avoid the criminal record to begin with. This one bit of it. So if you have low risk, low leverages, as my colleague pointed out earlier today, then you are not indicated for intervention of any kind. And it's better to just release these folks without intervention of any kind. WOLF: Right, and that's what the research supports. MILLER: The research supports it, absolutely. So what risk assessment allows ... the careful prosecutor, judge, public defender, et cetera to do is to remove some of the discretion, because much of the decisions that are being made are based on a gut feeling. So I am reading something in the defendant. They don't have remorse, or they haven't shown accountability for their actions, or they have, as one of the panelists raised, belligerent interactions, let's say with their parent or the prosecuting attorney or the defendant. And my assessment is happening divorced from what it means to actually be in court in that moment in time. How might a child, 17 years old, respond to facing 20 years in prison? How should they respond? Should they be depressed, sad, angry, avoidant? What are our expectations in this moment. And so risk assessment, what it allows us to do is say, Okay, let me take a step back, let me look at what actually happened. Let me get away from my intuition, let me think about a more objective way to assess how this defendant should be treated. An interesting note ... So here it is. We can use smart risk assessments to think carefully and critically about how we treat offenders, what level of intervention that we lay out whether that intervention be prison, or jail time, or a diversion program, or a treatment group. There's no perfect way to do this which is why constant reevaluation is necessary. You can't settle, this is the instrument for me. You can’t settle. It's not the instrument for you - CROSBY-ROBINSON: Continuous improvement. MILLER: Continuous improvement. WOLF: And maybe testing ... if I understood what Sarah Fritchey said, my colleague the researcher for the Center of Court Innovation, that you also can test these instruments within certain populations and see, are they producing more negative outcomes for an African-American population? And ask these questions that you're asking to weed out the bias that might be built into that. MILLER: Absolutely. The questions that we're raising are in some ways a set of philosophical questions but they're questions about the application, the use of, the embrace of, instruments to determine whether or not someone is a future danger. Perhaps this is just the wrong approach altogether. Not the risk assessment ... not that one doesn't need to think about ways that they can help predict behaviors of individuals. I think that's useful in some ways, but it certainly needs to be challenged, it needs to be questioned. What am I predicting? Who am I predicting this for? What are the possibilities for this person once these predictions are made? These are questions that need to be addressed. WOLF: So, Miss Crosby-Robinson, let me ask you, as we talk about these kinds of assessments, you bring to bear your own set of experiences with the correctional system as a researcher and you're own past history which you refer to on the panel as someone who had been formerly incarcerated. And I wonder what insights that had allowed you to bring to bear to this notion? Presumably a long time ago they didn't have these risk assessments, I don't know ... when you were initially had your first contact with the correctional system, the justice system. And now they do and you've had a lot of contact and opportunity to interview and spend time with people are incarcerated and I wonder where you come down on this issue? CROSBY-ROBINSON: Well, first of all, I think it's a good idea to have a risk assessment, as Ruben has said earlier, because it removes some of this pressure from judges and prosecutors to make these decisions based on their own personal bias or how they're feeling at the time. But what it does not account for are all of the little various innuendos that a person is going through when they come out. Family reunification can create a stressor. If somebody's coming out and they have to be paroled to a family address, a suitable relative for placement. So they're coming to this family address, but the family address that the parole officers decided that the person can parole to is not really the best environment, and sometimes the issues that they had that led to their incarceration stem from the family issues that they were having at the time. Or it's not in the right environment or they don't have really enough support from their family. And things happen because lives are fluid and things change. For instance, we interviewed a person who was 17 years old and she was pregnant. She had a mental illness, she'd been in the mental health system since she was 8 years old. She lived with her grandmother. We interviewed people three times, as soon as they were discharged and then 30 days after they'd been out. Then 60 days and 90 days. And so, following her, by the time we got to her third interview, her grandmother dies. She's living in her grandmother's house. This is the only stable person she's known in her life. Her grandmother has raised her since 9 years old. She just had a baby, the baby isn't even a year old yet. Now she's 18 years old, she has a mental illness, and she's relying on that system to become her support now where her grandmother was everything. Well, these are things that a risk assessment would just not pick up. Because you never know what's going to happen. So now what happens to this individual? We're at the end of the time that we follow this person for our study. But you know, the question is in our mind, what happens? And another thing that I find frustrating, is no matter what your risk assessment is and if you get it right or not, then when a person who gets out into the community, whatever the risk assessment decided that they need as a support or an intervention, there's no community resource for that. WOLF: The theme I'm hearing from both of you is that these risk needs assessment tools cannot be judged or effectively used apart from the environment, whether it's the environment that created the measurements of risk, or the needs. Because if you can identify the needs and say great, but if you don't have the resources in the community it's meaningless information. MILLER: So, Faye Taxman has a great paper. She finds that, on the need side of things, substance abuse treatment is indicated in about 90% of the folks who were justice involved, but the capacity to provide the treatment, either in prison or out. Something like 25% of folks in prison were able to actively engage in regular substance abuse treatment that needed it. And so what this does is it creates another deficiency that one might judge or regard as a part of the risk of this individual recidivate. Did you complete programming? What was programming available, either in prison or out? WOLF: Well, this had been a very vigorous and interesting conversation and I really appreciate you're both taking the time to speak to me about your work. MILLER: Yeah, thanks for having us. WOLF: So, I've been speaking with Professor Reuben Miller, assistant professor of social work at the School of Social Work at the University of Michigan and his research assistant and collaborator, Hazelette Crosby-Robinson and we're all here today in New Haven at Quinnipiac University school of law for the Conference of Justice Innovation in Times of Change, which is sponsored by the Center for Court Innovation and the Department of Justice's Bureau of Justice Assistance and hosted by Quinnipiac University. You can find out more about risk needs assessment and criminal justice reform in general at our website, www.courtinnovation.org. I'm Rob Wolf, thanks for listening.   

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  • 00:18:33

    Circulation May 2, 2017 Issue

    · Circulation on the Run

    Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Doctor Carolyn Lam, associate editor for the National Heart Center and Duke National University of Singapore. Our feature paper today presents the first information on the impact of cardiovascular health in middle age and the burden of mobility in older age. This exciting data is from the Chicago Heart Association study. First, let me give you your summary of this week's journal.                                                 The first study tells us that patients with long QT syndrome type II are at increased risk of hypoglycemia. First author, Doctor Hilton Cavallius, co-corresponding authors Doctor Tarakov and Hanson from University of Copenhagen, Denmark, noticed that loss of function mutations in HERG, which encodes the voltage gate at potassium channel 11.1, causes long QT syndrome II, but that the specific voltage gate at potassium channels are also present in pancreatic alpha and beta cells and intestinal L and K cells, which secrete glucagon, insulin, and the incretins, glucagon-like peptide one or GLP1, and glucose-dependent insulinotropic polypeptide, or GIP.                                                 All these hormones are crucial for glucose regulation. The authors therefore hypothesize that patients with long QT syndrome II may have increased incretin and beta cell, but decreased alpha cell function and thus, lower glucose levels. To test this hypothesis, they measured secretion of these hormones and cardiac repolarization in response to a six-hour, 75 gram oral glucose tolerance test in 11 patients with long QT syndrome II with functional mutations in HERG with 22 matched healthy participants.                                                 They found that following glucose ingestion, patients with long QT syndrome II displayed exaggerated incretin and endocrine pancreatic function with more than 50% increased levelsq of circulating insulin, GLP1 , and GIP and defective glucagon secretion, causing low plasma glucose levels and thus, increased risk of symptomatic reactive hypoglycemia following the glucose load.                                                 Furthermore, in rats, pharmacological blockade of these voltage gate at potassium channel 11.1 with [inaudible 00:02:43] had similar effects and inhibition of HERG in beta and L cells increased insulin and GLP1  secretion up to 50%. Finally, glucose ingestion aggravated cardiac repolarization disturbances in patients with long QT syndrome II with a 122% greater increase in QT interval in these patients compared to controls. The take home message is that clinicians should be more aware of the risk of hypoglycemia with glucose ingestion in patients with long QT II syndrome and also recognize that this reactive hypoglycemia can further increase the risk of malignant arrhythmia in these patients.                                                 The next paper is the first study to describe the risk of myocardial infarction after discontinuation of thienopyridine therapy in the DAPT study, or dual antiplatelet therapy study. As a reminder, in this trial, after PCI and 12 months of clopidogrel or prasugrel plus aspirin, eligible patients remained on aspirin and were randomized to continue thienopyridine  versus placebo for 18 months. At 30 months, patients stopped the study drug and were observed for three months. In the current study by first author Doctor Schmidt, corresponding author Doctor Mauri, and colleagues from Brigham and Women's Hospital in Boston, Massachusetts. The authors looked at cumulative incidents of myocardial infarction assessed over three months after randomization and three months after study drug discontinuation. They found that discontinuing thienopyridine after either 12 or 30 months was associated with an early increase in myocardial infarction risk, mainly unrelated though to stent thrombosis. The magnitude of risk was highest in the early time frame and lower in patients not treated with the [inaudible 00:04:47] eluting stents.                                                 The authors further compared pateints with DAPT scores above or below 2, and showed that both groups had lower rates of myocardial infarction with continued thienopyridine . Thus, while higher DAPT scores identify patients with a greater absolute ischemic benefit relative to bleeding with continued thienopyridine therapy, discontinuation at 12 months increases the myocardial infarction hazard regardless of DAPT score group.                                                 The next paper describes the impact of depression treatment on one year mortality following acute myocardial infarction. Doctor [inaudible 00:05:28] and colleagues from the University of Missouri School of Medicine in Kansas City looked at the TRIUMPH study, which is an observational multicenter cohort study that enrolled more than 4000 patients with acute myocardial infarction between 2005 and 2008 from 24 US hospitals.                                                 Patients were administered the patient health questionnaire 9 during the index myocardial infarction admission and depression was defined by a score of 10 or above. This was categorized as treated if there was a documentation of a discharged diagnosis, medication prescribed for depression, or referral for counseling, and is untreated if none of these three criteria were documented. Overall, 18.7% of patients met criteria for depression and 30.4% were treated. Compared without depression, patients with treated depression had one year mortality rates that were not different. However, patients with untreated depression had a higher one year mortality when compared to patients without depression. In summary, this study really shows that the association between depression following myocardial infarction and increased mortality differs by depression treatment status at the time of the index myocardial infarction. Patients with untreated depression have a 70 to 90% higher risk of dying at one year after the myocardial infarction than patients without depression or patients with treated depression. These findings should therefore encourage further research to examine the impact of depression recognition and treatment at the time of an acute myocardial infarction.                                                 The final study provides insight into the paradox that folate deficiency is an independent risk factor for congenital heart disease, yet the maternal plasma folate level is paradoxically not a good diagnostic marker of this risk. In the current study by first author Doctor Wang, co corresponding authors Doctors Chow and Wang, from Fudan University, Shanghai, China. The authors examined six folate related polymorphisms in three independent case control groups comprising 1489 patients with congenital heart disease and 1745 healthy individuals from the Han Chinese population. They found that a specific fidgetin intronic 4 variant was associated with decreased circulating folate levels and increased protection against congenital heart disease. They further showed that increased fidgetin expression inhibited proteasomal degradation of reduced folate carrier 1 and dihydrofolate reductase, thus facilitating [inaudible 00:08:29] uptake and metabolism of folate. Their results therefore demonstrated that folate utilization, rather than the circulating folate levels, determined the preventive effects of folate against congenital heart disease. These findings provide new insights into the relationship of circulating folate levels with congenital heart disease and potentially other folate associated diseases.                                                 Well, that wraps it up for your summaries. Now, for our feature discussion.                                                 Today's feature paper really represents the first data we have that tells us what our cardiovascular health in middle age is doing to us in older age, in terms of both morbidity and longevity. To discuss this paper today, I'm so happy to have the first and corresponding author, Doctor Norrina Allen from Northwestern University in Chicago and Doctor Jarett Berry, associate editor from UT Southwestern. Welcome, both. Dr Norrina Allen:              Thank you very much. Dr Jarett Berry:                 Thanks, Carolyn. Dr Carolyn Lam:                Norrina, could I start with you? This represents the 40 year follow up of the Chicago Heart Association detection project and industry. Could you maybe start by telling us a little bit about the Chicago Heart Association study? Dr Norrina Allen:              The Chicago Heart Association study was a large study that recruited almost 40,000 individuals who were employed in Chicago. They did a baseline exam between 1967 and 1973. After that baseline exam, we followed those individuals for over 40 years using their Medicare records, so we've been able to monitor their healthcare utilization and the incidence of disease across their lifetime up through 2010. Dr Carolyn Lam:                Then you measured their cardiovascular health by specific measurements, right? Could you tell us how that was defined and then also how was morbidity burden defined? Dr Norrina Allen:              Of course. We really think the overall burden of cardiovascular health tells us something more than looking at individual risk factors, so we classified each of the CHA participants into one of four groups, and each of those groups was defined by the level of main cardiovascular risk factors, including blood pressure, BMI, diabetes, smoking, and cholesterol level. We identified people who had favorable levels of all of those risk factors, individuals who had one elevated but not clinically of those high risk factors, individuals who had one high level, or individuals who had two or more high levels. That was based on their baseline exam. Overall we found that about 6% of the CHA participants had favorable levels of all of the risk factors at baseline, 19% had one or more that was elevated, 40% had one high, and 35% had two or more high risk factors, and again this was at the baseline exam when they were young to middle aged.                                                 We then followed them, as I mentioned, using Medicare data and we identified the burden of whole morbidity based on the ICD9 codes in their Medicare record, and we identified the level of morbidity for each year of age, from entry into Medicare, [inaudible 00:11:54] all the way to their death. Dr Carolyn Lam:                And now, drum roll, your findings, they were pretty stunning. Dr Norrina Allen:              Yeah. As you mentioned when you introduced the study, this study is really the first to look at the whole of an individual's later life, meaning not just looking at the incidence of disease or longevity but taking those both into account. What we were particularly interested in was looking at the cumulative burden of morbidity in older age and the relative proportion of life that people live with cardiovascular or all cause morbidity. What we found was that individuals, who at baseline in young and middle age and favorable levels of all major cardiovascular risk factors, lived longer by almost four years but they also delayed the onset of all cause and cardiovascular morbidity by 4 and a half and almost 7 years respectively. What that means is that the proportion of their life that they live with morbidity was much shorter, they lived longer and healthier as compared to individuals who had one or two more high risk factors. Dr Carolyn Lam:                What an important public health message. Jarett, this concept of morbidity compression, tell us your thoughts. Dr Jarett Berry:                 This is a really important paper. We've known for a long time, of course, that low risk individuals live longer, but the question of whether or not low risk individuals lived better throughout their life has been incompletely understood. The problem is that because low risk individuals live longer, the question that many have asked is that when we live longer is there a so-called expansion of misery, which some have talked about? That we live longer, but we have the same burden of disease or is that extended time horizon with the extended life span ... is the burden of morbidity compressed into a shorter period of time? In order to do that you need a couple things. You need a very large study that's followed for a very long time. Importantly, not just follow them for a long period of time, but follow enough individuals all the way until death so you know not just the first part of the story but we know the end of the story.                                                 It really wasn't until [inaudible 00:15:18] paper, with not only the very large sample side but the very long term follow up until death, that we've been able to understand that actually low risk status in middle age does actually compress morbidity. This question of morbidity compression is not just an academic question but it actually has potential implications for cost savings and how we think about health care costs in our health care system. It'd be nice to hear [inaudible 00:15:18] thoughts about that as well, what else she found in regard to the Medicare costs. Dr Norrina Allen:              Right. As Jarett mentioned, not only from an individual perspective but at a societal level, what we're interested in is whether being in favorable cardiovascular health actually lowers healthcare costs at the same time as increasing an individual's health and longevity. What we found was that not only do the individuals in favorable health live longer and healthier, but they also have lower cumulative and annual healthcare costs, meaning that from a societal standpoint the compression of morbidity results in healthcare savings. We really think this is a strong method that provides support for earlier prevention efforts not only to improve an individual's quality of life but to reduce the healthcare costs associated with later life morbidity. Dr Carolyn Lam:                Indeed, what an important message to live longer and better and to save societal cost we need to get healthier cardiovascularly in middle age. Now, what really scares me though, is the statistic you told us a bit earlier. Only 6% of the individuals that you studied had a favorable level of all factors. What do you think this implies? What do you think needs to be done? Dr Norrina Allen:              Unfortunately, at this point, it's relatively rare in our population to reach middle age, 40 to 50 years of age, with favorable levels of all major cardiovascular risk factors. I think ... my research is really focused on trying to identify ways and times to intervene, to really help promote cardiovascular health early in life. I really think that we need to work hard to prevent the occurrence of these risk factors and the elevation of these risk factors much earlier in life. That means, even before the age of 40 and much earlier than that, we really need to be focusing on preserving cardiovascular health so that by the time individuals reach later life they can have a good quality of life and a longer, healthier life. Dr Jarett Berry:                 I think the issue of the fact that low risk status is rare is that's a challenge that we continue to wrestle with as a society and as investagators interested in this are and how to improve that. When you look at your data, Norrina, I guess one silver lining here is we do see that ... when you look across the strata of risk groups ... it wasn't just the low risk individuals that seemed to benefit. It seemed that there was a little bit of a dose response. The goal obviously is to promote low risk status, but if we could limit the prevalence of those at the highest risk and shift them down a little bit, that could also have potential implications. I'd be interested to hear your thoughts about that. Dr Norrina Allen:              I think that's very accurate. There really is kind of a dose response level, so that every risk factor that's favorable adds a benefit and the more we can do to reduce the high risk factors over time, the better the long term outcomes are likely to be. I do really think prevention doesn't only have to exist before the development of the risk factors, but also there's a benefit to reducing risk factors that may have already developed or are elevated, and to try and reduce their level. I would say that I think that's an interesting next step that we really want to look at and try and think about how best to intervene even at middle age and help improve outcomes much later in life. Dr Carolyn Lam:                Thank you, listeners, for joining us today. I'm sure you agree, it's such an important message. Share it with your friends and tune in next week.

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  • 00:18:16

    Circulation March 28, 2017 Issue

    · Circulation on the Run

    Caroline:                              Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Up next, we are discussing the featured paper in this week's journal regarding the increased risk of cerebrovascular events in young cancer survivors, the downside perhaps of surviving cancer, so to speak. But first, here's your summary of this week's journal.                                                 The first paper describes the US national trends in atrial fibrillation hospitalization, readmission, and mortality. This paper from Dr. Freeman and colleagues of Yale University School of Medicine in New Haven, Connecticut used data from all Medicare fee-for-service beneficiaries between 1999 and 2013, and found that the adjusted rates of hospitalization for atrial fibrillation increased by almost 1% per year. Median hospital length of stay remained unchanged at three days, but median Medicare inpatient expenditure per beneficiary increased from $2,932 to $4,719 per stay.                                                 During the same period, the rate of inpatient mortality during hospitalization for atrial fibrillation decreased by 4% per year, and the rate of 30-day readmission also decreased by 1% per year, while the rates of 30-day and one-year mortality decreased more modestly by 0.5% and 0.26% per year, respectively. Thus, between 1999 and 2013, among Medicare fee-for-service beneficiaries, rates of hospitalization for atrial fibrillation and the cost of those inpatient stays increased substantially, but this was associated with improved outcomes, including lower rates of readmission and mortality. These findings suggest that increased hospitalization and more costly contemporary treatments, such as atrial fibrillation catheter ablation, may be associated with improved outcomes.                                                 The next study provides insights into the mechanisms underlying augmentation of muscle blood flow by ultrasound cavitation of microbubbles. Now, this is a promising approach for rapidly correcting tissue profusion in acute ischemic syndromes or for treating chronic ischemic symptoms. In this paper by first author Dr. Belsik, corresponding author Dr. Linder, and colleagues from Night Cardiovascular Institute Oregon Health and Science University in Portland, Oregon, the authors hypothesized that pure endergic signaling may be responsible for sheer dependent increases in muscle profusion during therapeutic ultrasound cavitation.                                                 To test this hypothesis, the authors studied unilateral exposure of the proximal hind limb of mice with and without ischemia produced by iliac ligation, to therapeutic ultrasound after intravenous injection of lipid microbubbles. They further performed a proof of concept study with twelve patients with stable sickle cell disease. They found that therapeutic ultrasound cavitation increased muscle profusion by seven-fold in normal mice, reversed tissue ischemia for up to 24 hours in the murine model of peripheral artery disease, and doubled muscle profusion in patients with sickle cell disease.                                                 Augmentation inflow extended well beyond the region of ultrasound exposure. Ultrasound cavitation produced a nearly forty-fold focal and sustained increase in ATP, the source of which included both endothelial cells and erythrocytes. Inhibitory studies indicated that ATP was a critical mediator of flow augmentation. Furthermore, combined indomethacin and inhibition of eNOS abolish the effects of therapeutic ultrasound, indicating downstream signaling through both nitric oxide and prostaglandins. Thus, the authors concluded that therapeutic ultrasounds using microbubble cavitation to increase muscle profusion relies on sheer dependent increases in ATP, which can act through a diverse portfolio of purinergic signaling pathways. Cavitation-related release of ATP may further serve to explain ultrasound's role in other therapeutic applications, such as wound and bone healing, and ultrasound facilitated drug or gene uptake.                                                 The final original paper describes the age-specific trends of heart failure in Denmark over the last two decades. Dr. Christiansen and colleagues of University of Copenhagen in Denmark studied more that 210,000 Danish individuals over the age of 18 years, with a first time in-hospital diagnosis of heart failure from three nation-wide Danish registries.                                                 They found that the incidents of ischemic and non-ischemic heart failure in Denmark declined by approximately 50% among older adults more than 50 years old, but increased by about 50% among younger individuals, or individuals less than 50 years old, between 1995 and 2012. Furthermore, they observed a concomitant increasing trend of various treated co-morbid conditions, including hypertension, diabetes, and ischemic heart disease in the population. These findings from Denmark imply a change in the profile of the heart failure community and portend a higher burden of heart failure in the future. The increasing trend of incident heart failure among young individuals especially warrants further investigation.                                                 Well, those were the original papers this week. Now, for our feature discussion.                                                 Our feature paper today discusses a hugely important modern issue that may seem like good news at first sight. We know that survival in cancers has rapidly improved with advances in early detection and treatment, however the improved survival also extends the window for the occurrence of long-term complications such as psycho-social effects, fertility problems, secondary malignancies, and, as highlighted in today's paper, the risk for cerebrovascular events. I'm so pleased to have with us first, author Chloe Bright from University of Birmingham, United Kingdom, as well as associate editor Dr. Graeme Hankey from University of Western Australia. Welcome, Chloe and Grim! Chloe Bright:                      Thank you for having me. Graeme Hankey:              Thank you Caroline. Caroline:                              Chloe, what an interesting and important focus on cerebrovascular events following survival from cancer. Please, can you share your inspiration for looking at this and what you found? Chloe Bright:                      As you've just said, the five year survival rate from teenage and young adult cancer has been increasing and increasing, and it's over 80% now, which means there's such a large population of survivors who are at increased risk, or potentially increased risk, of developing adverse health outcomes. So, as you know, cerebrovascular disease can be potentially fatal so it's really important that we estimate how much teenage and young cancer survivors are at risk of this. So to start of with our group in Birmingham actually set up the teenage and young adult cancer survivor cohort study. And this is a cohort of over 200,000 five year survivors of cancer who were diagnosed between 15 and 39 years of age. And this was set up because there's hardly any literature regarding the adverse health outcomes of teenagers and young adults who have had cancer.                                                 So, as I said, cerebrovascular disease is a really important outcome to look at. So we decided we've got this resource in the UK, which is the Hospital Episode Statistics, and this carries information on all the inpatient hospitalizations in England. So from this we were able to determine how many people with teenage and young adult cancer had been hospitalized for cerebrovascular events and compare this to what we would expect to see in the general population to see if they had an increased risk or not. So from limited previous literature that was out there we did know that TYA cancer survivors had an increased risk of developing a cerebrovascular event. However, we were unsure how this risk varied with certain explanatory factors, such as age of cancer diagnosis or the decade of cancer diagnosis, gender, and attained age, so that's the age at which a stroke event might occur. So the main aim of our study was to quantify this. Caroline:                              Yes and to put some numbers to that increased risk. It was a 40% increased risk, wasn't it? That is striking. Chloe Bright:                      We observed almost 2,800 cerebrovascular events. That related to a 40% increased risk of being hospitalized compared to what we would expect to see in the general population, which is really quite substantial. Caroline:                              Now, were there particular risk factors that were associated with more cerebrovascular complications like certain types of tumors or certain types of therapies and so on? Chloe Bright:                      Survivors of central nervous system tumors, head and neck tumors, and leukemia were all at the greatest risk compared to the general population. And this is probably related to radiotherapy that they had for their initial treatment. So radiotherapy to the neck, which could involve damage to the carotid artery, or radiation to the head which again could cause damage to the cerebral arteries in the brain. And then also we found that the risk increased dramatically as people aged for neck tumor survivors and CNS tumor survivors. So specifically cerebral infarctions, the additional number that we saw was a lot greater in, say, survivors over age 60. And this is probably because this is when strokes in the general population are becoming more incident.                                                 And actually an interesting finding, we observed that males actually had a higher number of excess infarctions than females, and this was especially among head and neck tumor survivors. So we can't confirm this, but this could potentially be due to difference in smoking habits because there could be a said etiology between smoking and the risk of head neck cancer and also smoking and the risk of stroke. Unfortunately, we didn't have the information on smoking status to confirm this. Caroline:                              This is a huge study. It shows a substantial increased risk of stroke in these young cancer survivors, and also sheds light on the possible underlying mechanisms. What you mention about vasculopathy following radiotherapy really reminds me about what we learn about breast cancer radiotherapy and the risk of myocardial infarction.                                                 Graeme, what are your perspectives on this paper please? Graeme Hankey:              Well as an editor, as everyone knows, what we're really looking for are four main points. Firstly that the study was ethical, which it was. Secondly that the results are valid, internally and also externally. And we're very confident in the validity of the results. This was a very large study of 180,000 people, and more importantly had 2,800 cerebrovascular events so that's a lot of [inaudible 00:12:25] and the followup was pretty rigorous over 11 years, and the outcome events were [inaudible 00:12:32] by a data linkage through the hospitalization for the cerebrovascular events.                                                 The other two key features of course is are the results novel and are they important? And these are novel results. There's only been one previous similar study of a Danish cohort that was only 43,000 but one quarter the size of this study, and one year survivors of teenage and young adult cancer from 1943 to 2009 and followed up. And the results were actually very similar, showing a 1.3 or 30% increased risk of hospitalization for cerebrovascular events. Again supporting the validity of this recent study to obtain similar results, but in a four times greater population and in a more contemporary population whose patients were recruited between 1971 and 2006 and followed up from 1997 to 2012.                                                 And the other thing is it's not just ethical, valid, and novel, but it's important because it really has big implications for stroke prevention in young adult survivors of cancer. And it has implications for once they get the diagnosis and they're through their treatment to really focus on what were their pre-morbid vascular risk factors? Are they actually causal risk factors and not just cancer but also for future stroke like smoking and alcohol, and hypertension and diabetes? Secondly to try and recognize what is their absolute risk? Are they men who are at higher risk? Have they had previous irradiation that probably puts them at higher risk, as well as their current respective profile?                                                 Thirdly for them to then realize what's the impact of their cancer diagnosis on their future behaviors if they become depressed or change their diet or taking other treatments, or abusing drugs, and could that increase their vascular risk? And fourthly, what should be done? Should they just control their vascular risk factors through lifestyle? Or should we actually have a randomized trial of risk factor control, and/or antiplatelet therapy and/or statins and/or blood pressure lowering in these high risk survivors of cancer who are sill in their forties or fifties. Should they actually be taking antiplatelet therapy or statins? We probably need a randomized trial because they're high risk, we would think, or certainly a sub-population. Caroline:                              Thanks Graeme for framing that so excellently. You're absolutely right that these are the things we look for in a paper as editors. And for our listeners to hear that is just so important.                                                 Well, I'd like to hand it over to you now Chloe. What are the next steps in your mind? What are the remaining gaps in knowledge you'd like to address? Chloe Bright:                      I really think it relates to what Graeme just said. We need to get the information on the specific radiotherapy, the doses that have been used, the potential lifestyle factors of these individuals to see how much of an effect that has on the risk of stroke. So potentially conduct a case control study while we're able to get this information and then use that. And then, as Graeme said, once there is more information potentially a randomized control trial might be useful. But again, I think we need some more information before we can get the go ahead to doing that. Caroline:                              Great. Just one more quick question please. You know, Chloe, you found that those who were more recently treated had a higher risk of cerebral hemorrhage than among survivors diagnosed earlier. Now, did you have any postulations on why this was the case? Chloe Bright:                      This increase in the hemorrhage with more recent diagnosis was actually restricted to glial tumor survivors. So one explanation that we thought might explain this was that in recent years due to advances in treatments those glial tumor survivors, glial tumors who had more advanced stage at diagnosis, potentially surviving a little bit longer, so reaching five year survival which would enter them into our study. However they potentially might be having another occurrence, which would be causing them to have a hemorrhage, which in the previous decades perhaps they wouldn't have survived that long in the first place. That's just one of many ideas. Graeme Hankey:              I think the recurrence of not just glioma but perhaps also melanoma that the survival is much greater now with new immunomodulating therapies for melanoma, we'll probably see longer survival in melanoma which typically when it metastasizes is hemorrhagic and perhaps also leukemia with thrombocytopenia, with more hemorrhage and other metathesis. The other thing it could be though is a diagnostic ascertainment bias in that I'm 60 now, and when I started neurology 35 years ago we didn't really have much brain imaging and couldn't diagnose intracerebral hemorrhage very well. And clinical diagnosis wasn't very reliable. Now the imaging which can actually distinguish hemorrhagic from ischemic stroke is much more widely available. And I suspect there's a greater increase in the diagnosis of cerebral hemorrhage now because of better imaging. We've seen that in other epidemiologic studies with that diagnostic trend. Caroline:                              What excellent points. Thank you so much Chloe and Graeme.                                                 Well you've been listening to Circulation on the Run. Thanks for joining us today and don't forget to tune in next week.    

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  • 00:19:48

    Risk It for the Biscuit: How to Work out What your Risk Tolerance is, and What is Risk Profiling?

    · The Rentvesting Podcast | Smart Investor | Real Estate Investing Couch | Australian Property Talk

    On this week's episode of the Rentvesting Podcast we're talking about risk profiling. This episode is based on a question from Chris, looking at a bird's eye view of how you can be thinking of investing. We're breaking down why people make decisions and what risk profiling is based on. The question was around where someone should really be investing, as opposed to where someone does invest.   We'll run through what determines that individual preference along with what it should be A lot of people who have lost money in the share market are now moving to property. This is based on psychology, if you're risk tolerant and don't mind things like gambling, running with scissors, swimming after you've just eaten - these sorts of people are considered risk tolerant. The other On the other side of this are those considered risk adverse, they don't like taking risks in life. Based on that fact, that starts to determine where, if they're looking to invest, they do. If someone is risk tolerant they might go for penny shares where those companies could go up or down a lot. While someone who is risk averse might just keep all their money in cash.   What's the risk reward concept? There's low risk like cash, then there a high risk. In financial markets or investment, risk isn't like everyday risk. Risk is considered through volatility. The risk-return equation says the higher the volatility you accept, the more movement that can occur, the higher your return should be. For instance cash, cash can't lose value unless hyperinflation occurs. Cash doesn't move up and down, it will get you different interest rates but as you go down the chain of assets that have higher growth components because they go up and down, they now have volatility. The greater they go up, the greater they can go down. If we break it down on the chain as far as what's the least and most volatile: Bonds have a slight volatility, but generally, they're more an income asset. Property and shares, when they have growth components to them - you can break it down to high or low growth depending on the area. You can buy in blue chip suburbs where the yield might be lower, but high-risk suburbs like mining towns could have high yield but also could drop and then you could be at risk. As for companies, the banks don't move so much but smaller companies have more risk involved and that volatility can be at 80% a day.   How do people determine when they invest in that risk profile? Generally, people just determine it on their own, they invest in what they feel is right for them. Sometimes it's easy to miss the point though and what you're trying to achieve. Individual needs + psychology = risk profile. Someone who is young and can handle the risk could go for property, because they have time to invest in a long-term investment. While someone who is defensive in retirement should go for 30% growth and 70% defensive.   Are there any one size fits all rules? Not really, it depends on the individual. I've seen some 20-year-olds who don't want to invest in any shares and they think they're too risky. Then I've seen some individuals in their 70's have invested in their shares all their life and love the up and down changes of it. While even though they need more defensive assets at that time. Although there might be broad profiling depending on the age and time you're at in your life, it really depends on the person. For myself, when I try to figure out where funds should be invested the first thing we look at is their individual means and how long they want to be investing the money for. If it's for a home deposit that's 2 - 4 years and those funds shouldn't be invested as it's too short term. But if it's for long term 30 - 40 years that can allow a lot of growth, especially if there are regular investments, it's better to split out the investments over time.   What are some questions on how you determine a risk profile? Return requirements Return requirements mean that planning and forecasting are required in order to get 8% return per annum. So working back from how much you need in your super, we look at how much you need as an underlying return. If you cut out growth from the equation: Income + Growth = Return. You've halved a lot of the equation and if you're defensively invested, you'll be getting income from cash and bonds and a little bit of growth. But if you get that solely, you're likely to get a lower percent return than if you've got more growth allocation over the long term. So that's the first one looking at return requirements. How much to invest If you've got a lot to invest and more money to diversify, that can often allow for a bit more risk to be taken on. Just generally, we ask them what their reaction to case scenarios would look like. For example, if your investment goes down by 50% how would you react? What's the max level of volatility you want to accept in a portfolio? This is looking at their psychology of how tolerant they are. This is looking at their psychology of how tolerant they are. Figure out what sort of needs you're after. We also test their understanding with questions like - say the portfolio does drop by 25% how would you react? Would you invest more? So that one helps determine a lot of their knowledge around investment So that one helps determine a lot of their knowledge around investment and volatility. It's about re-educating, as volatility occurs, so the best thing to do is not to sell, because selling when it goes down guarantees you will lose money. If a share goes from 100 to 50, it then needs to go up by 100% to go back where it was. If you invest at that point, then your upwards return isn't that great. So if you added another 50, then any additional growth after is just a plus. In summary, shares are the highest risk - between shares, property, fixed interest and cash.   Case Study Looking at case studies at a high level, if Bob is a young investor and has only invested once (30 years old), what is the portfolio for someone who is a bit risk averse but wants to grow? As this person has probably been burnt by investments before, they probably will try and avoid it. For this individual, it would be about reeducating them. If you're in your 20's and your investment is in super, let's have a look at the difference between keeping your funds in cash or taking on additional risk over a 30 year period. First of all, don't sell! If you have a surplus of cash or you manage them wisely, they shouldn't drop that much. Long term, the market does recover.   On the other side, Sarah loves to gamble, she's a bit older, the late 50's and has a decent amount of money. Is it bad for her to go high growth, high risk? It's up to her. If she's about to retire, what will she live on? If Sarah has a decent amount of money to retire on and draw an income, it's probably better for her to be more defensive. If she's 100% invested in shares, then 40% of their value could go down.   Key takeaways Risk profiling is based on your individual needs and not what your friends are doing or what the market does. It's based on your individual profile - answering the above questions, understanding what you can handle if it goes up or down. Changing the perception of letting external things determine where you invest and looking at what is the right thing for you towards your long term goal. Don't forget to leave a review on iTunes!

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  • Prosecutors Explore New Solutions to Public Safety Concerns: A Conversation about the 'Smart Prosecution Initiative'

    · The Center for Court Innovation - Podcasts

    The Bureau of Justice Assistance at U.S. Department of Justice created the Smart Prosecution Initiative to encourage prosecutors to explore new solutions to public safety problems. Grant recipients work with researchers to document outcomes and develop effective, economical, and innovative responses to crime. In this podcast, Denise O'Donnell, the director of the Bureau of Justice Assistance, sits down with Jose Egurbide of the Los Angeles City Attorney's Office and Mark Kammerer of the Cook County State’s Attorney’s Office to talk about their Smart Prosecution programs, which use risk assessment tools to divert low-level offenders from court. The conversation took place while the three were in Chicago to attend Community Justice 2016.At Community Justice 2016: Above, Denise O'Donnell, director of the Bureau of Justice Assistance, delivers her keynote address. Below left, Jose Egurbide of the Los Angeles City Attorney's Office participates in a panel on Restorative Justice. Right, Mark Kammerer of the Cook County State's Attorney's Office discusses Risk/Needs Assessments on a panel.   ROB WOLF: Hi. This is Rob Wolf, director of Communications at the Center for Court Innovation. We are at Community Justice 2016 where 400 people have gathered in Chicago for 3 days to share ideas about justice reform. With me are 3 people who are leaders of efforts to improve justice systems both locally and nationally: Denise O'Donnell is the director of the Bureau of Justice Assistance at the Department of Justice; Mark Kammerer is the Supervisor of Alternative Prosecution and the Sentencing Unit at the Cook County State's Attorney's Office; and Jose Egurbide is the Supervising Attorney in the Los Angeles City Attorney's Office. Something you all have in common is a grant program supported by the Bureau of Justice Assistance called the Smart Prosecution Initiative. Denise O'Donnell, I thought maybe you could explain what the Smart Prosecution Initiative is and how the Bureau is using it to support innovation and test new ideas. DENISE O’DONNELL: Sure. I'm a former prosecutor, and when I came to BJA I felt we really didn't have enough focus on prosecutors and the role prosecutors can play in justice reform. We had a great program called Smart Policing that had been operating for a number of years that actually funded police practitioner partnerships- research partnerships to look at innovative approaches and collect data, analyze them and assess the outcomes of the program. We brainstormed a little about that and thought it was a great model for prosecutors as well. So prosecutors can innovate. They can try new approaches. They can work with a researcher, collect data and work on programs like diversion programs, like community justice centers, and so many other initiatives. It's now part of a smart suite of programs at BJA. We now have 9 programs working in this model to really promote criminal justice innovation. WOLF: Mark and Jose, now both of you have grants under the Smart Prosecution Initiative. They're similar in that they're both helping divert offenders from more traditional sentences. Let me ask you both, why would a prosecutor's office be interested in diverting people from punishments that would get them more deeply involved in the justice system? Mark, do you want to go first? MARK KAMMERER: Sure. We've actually been involved in diversion for decades. When I came to the office in 2000, there was a drug diversion program that had been around since the 70's, but one of the things we found with a lot of our alternative sentencing, basically treatment courts, is that people had engaged in significant criminal activity before they got to treatment court. What we wanted to do was possibly intervene with people at an earlier stage, with the hope being we could interrupt the cycle before they got to the point where they had significant background that would warrant being in an intensive 24 month probation program. Our office has been, especially in the last 4 or 5 years, very involved in diverting people out of the system as early as possible. We've implemented a medical model that people are diverted at the earliest point with the least amount of intervention possible, knowing that we have a whole system- a whole continuum that we could advance to another level if needs be. The Smart Prosecution process, the grant that we received with that, was to ... We were able to involve risk assessment in our process. One of my experiences from working in healthcare is you really need to objectify things as much as possible so we know who it is that we're working with, and why we're working with them, and what would be the best interventions. That was one of the gaps in our system, was we did not have sufficient risk assessment involvement. That was a cornerstone of the proposal that we made to BJA that was funded. WOLF: I know, Jose, your initiative as well, you're diverting people and you're also doing risk assessment. Let me just ask you, I thought prosecutors classically are interested in guilt and innocence. What does a risk assessment tool, like both your programs use, do for you? JOSE EGURBIDE: Thanks, Rob. We're very excited to be here. Of course we're very grateful for BJA's leadership and the opportunities that that's creating as well as the CCI risk and needs assessment tool. What that's doing for us is, it's giving us an alternative to an already congested court system where we can focus more on rehabilitation and, as Mark said, looking at it at the front end. You often see a lot of rehabilitation happening upon reentry.  We also believe that when you talk about alternative prosecution, when you talk about restorative justice, you need to restore the victim, you need to restore the community, but you also need to restore the offender to a position where they'll be a more productive member of society going forward. WOLF: Let's talk a little bit specifically about what a risk assessment tool is. You both use a similar tool that the Center for Court Innovation developed with Bureau of Justice Assistance support. It's evidence based, it's been tested, but tell me how it actually functions. What does it tell you and what does it allow you to do? EGURBIDE: A needs and risk assessment tool ... and now there are some tools that are just risk assessment. The Center for Court Innovation tool that we use was selected specifically because it also focuses on a needs assessment. So again, when you talk about restorative justice, our program, the Neighborhood Justice Program, intercepts those individuals at the pre-filing stage, before a case- a criminal case is ever filed against them.  That allows us to take a look at needs responsivity, take a look at what are some of the dynamic risk factors that this individual exhibits and be able to fashion out either resources or obligations that will address those needs and that risk. I think when you're talking about, as Denise was mentioning, Smart Prosecution, this is an evidence based approach that will lead to better outcomes. It will lead to a lower level of recidivism. WOLF: So Mark, what do you do? You get the results of the assessment and then what kinds of sentences, or I guess they're not formal sentences because it's diversion, but what kind of services are you linking the offenders to? KAMMERER: One of the things that we were able to do with our Smart Prosecution grant program was to give specific types of interventions to people based on the level of their risk. What had happened in the past, we had a misdemeanor diversion program without risk assessment and everybody that was eligible for other reasons, all received the exact same intervention with the exact same expectations. Now with this program, we divide- the CCI tool divides people into low, medium and high risk levels and so we have a different expectation of people, what they need to do in order to have their case dismissed based on the level of their risk. What we do is, people at the lowest levels have an intervention and maybe an assessment and a referral to services; at the high end, are required to be engaged in a cognitive behavioral therapy program. We're looking at changing criminogenic thinking for people that are higher risk. A side benefit for us has been the ability... is to show that people with a higher level of risk can be just as successful in a program like this as the people with a low level of risk. We've actually been able to expand our eligibility criteria in terms of charging within the time period that we've been with this grant funding. People who would not have been eligible when we started this program, now are eligible because we've been able to show people with a little higher risk are not really a higher risk, they just need a different intervention. WOLF: Just for people who are listening who might not be familiar with the risk needs responsivity theory, which is what this whole model is based on, that a response or treatment in order for it to be effective, it needs to match the offenders risk of re-offending. Someone at a higher risk of re-offending should have a higher intensity intervention. KAMMERER: I'm sorry to interrupt, but that's exactly what we designed. People with a higher level of risk have a higher expectation. You're exactly right. O’DONNELL: You know, I just want to add from BJA's perspective, risk needs assessment tools have been around for a long time, but what CCI did was develop a tool specifically for low level and misdemeanor offenses which tailors the kind of response to fit the offense since individuals might normally face a couple days in jail or a week or two in jail, so do the interventions or the alternatives match that level of accountability. Referrals to services instead of spending 2 days in jail hopefully has a much better return on our investment. WOLF: Let me ask you, Denise O'Donnell, the Bureau of Justice Assistance, as you said, this program links the prosecutors also with a research [partners 00:10:29] and you're encouraging prosecutors and other justice practitioners to use evidence based tools. Obviously, there's a theme here that using evidence based strategies is important. Maybe you could talk a little bit about why it's important and you think, obviously these guys here and their offices have gotten that message, but is that message getting out as far and as wide as you'd like it to get out to prosecutors and courts and such? O’DONNELL: Well, it's always a struggle to reach everyone, but I think this conference is a good example. 400 people here participating in community justice programs. We had a recent grant solicitation for community justice programs and had 70 different jurisdictions want to establish those programs. We can only fund 10 of them. The demand is certainly increasing but what we see in Smart On Crime solutions is that you have to really have pilot programs. Like we see, beyond pilot programs, but you have to have programs that you evaluate and look at the outcomes. I think that is what convinces people that a) we can expand the model because we have some really good results or other jurisdictions become interested in trying to replicate what has been successfully done in Los Angeles or here in Cook County. WOLF: Jose, you wanted to say something? EGURBIDE: I just wanted to say that, just to echo Denise's comments, that through our City Attorney, Mike Feuer, who really embraces restorative justice and transformational as opposed to transactional approach to addressing these offenses, I think that we're really changing the way that our traditional criminal justice system works. We're alleviating an already congested system, but we're doing it in a way where, as Mark said, we're able to fashion out specific engagement strategies for each individual because we're using Smart Prosecution, because we're using a risk and needs assessment tools that's specifically designed for low level offenders. I think it's great and I think that the tool, for those listeners that may not be familiar with it, allows you to identify either housing issues, education issues or other challenges that an individual might have and be able to link them to those services. At the end, what you have is a person who's being held accountable but also comes out of the process a little bit better without the negative consequences of a conviction or something that's going to hinder them from going forward in a positive way. WOLF: I think that nicely summarizes what the Smart Prosecution Initiative is all about. I want to thank you, all 3 of you, for taking the time out from the Community Justice 2016 to speak with me. EGURBIDE: Thank you, Rob. O’DONNELL: Thank you. KAMMERER: Thanks for asking us. WOLF: I've been speaking with Denise O'Donnell who's the Director of the Bureau of Justice Assistance at the Department of Justice, Mark Kammerer, Supervisor of Alternative Prosecution and the Sentencing Unit at the Cook County State's Attorney's office here in Chicago and Jose Egurbide who is the Supervising Attorney in the Los Angeles City Attorney's office. I'm Rob Wolf, Director of Communications at the Center for Count Innovation. Thanks for listening.    

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  • Using Evidence-Based Assessment To Create Problem-Solving Interventions

    · The Center for Court Innovation - Podcasts

    Center for Court Innovation researcher Sarah Picard-Fritsche discusses the risk-need-responsivity model for working with offenders and the Center's efforts to develop a screening tool for misdemeanor offenders.The following is a transcript   Raphael: Hi. I'm Raphael Pope-Sussman at the Center for Court Innovation and in today's podcast, we're looking at risk-need assessment tools for offenders. Our guest is Sarah Fritsche, associate director of research here at the Center. Sarah, thank you for speaking with me today and welcome. SARAH FRITSCHE: Thanks. Happy to be here. RAPHAEL POPE-SUSSMAN: Wonderful. What is risk-need? FRITSCHE:  Well, risk-need-responsivity theory is essentially a theory of crime prevention which has three core components. The risk principle, which suggests that courts and treatment programs that are interested in reducing the risk of offenders should focus on those individuals coming through the system who are at the highest risk for re-offense--as opposed to what we sometimes see happening, which is lower risk offenders, we focus our resources on them based on an idea that they deserve a second chance or that the higher risk offender is a lost cause. All of those ideas are quite intuitive but actually research evidence shows us that when we focus our resources on treating and intervening with and supervising the higher risk group, that is when we achieve risk reductions and when we are able to get people out of the revolving door where they keep coming through the jails over and over again. When we focus our resources on lower risk offenders, ironically enough or perhaps it's not really an irony, I don't know, but unfortunately when we do that, what happens is that we sometimes increase risk because we put folks who have pro-social networks and not very serious drug problems who just were in the wrong place at the wrong time. We put them into intensive treatment and that exposes them to anti-social networks, that takes them away from their job, that takes them away from their family, and this increases their risk for future offense and future involvement in the justice system. POPE-SUSSMAN: What's the origin of this theory? FRITSCHE:  The theory originates with two Canadian psychologists in the late '80s, early '90s, James Bonta and his partner's name was Andrews. They were actually developing an assessment tool which is now one of the longest-used assessment tools in the field, called the “Level of Services Inventory.” Their theories of criminal conduct are essentially psychological. Individual theories of criminal conduct were what undergirded the assessment tool that they created. They came up with a theory-- the main and most tested principle in the theory is the risk principle, but there's also two other components. One is the need principle, which tells us that we should try to understand the specific needs of each individual person coming through the justice system in order to give them the correct targeted treatment. It's that part that is intuitive. But without the correct assessment tools, we can't figure out what that is. The third component is responsivity, which means that we should develop treatment programs or therapeutic intervention programs that respond to people's learning styles and some clinical needs that might interfere with their ability to recover, such as mental illness or trauma. POPE-SUSSMAN: Can you talk a little bit about what you're working on in the Center and what is the Center's focus right now in terms of risk-need assessment? FRITSCHE: Sure. I started working in this area about five years ago and my interest in it grew out of one of the first studies that I did here at the Center, which was a study of Brooklyn's program, which they call the Universal Screening for Drug Court, for people in the criminal court who might have the need for drug treatment. They were trying to find as many people as they could and send them into drug court as an alternative to maybe a short-term jail sentence that they might get. They had a screening system that was effectively just based on present charge. I guess my response to the system was that it was well intentioned but that based on the research that I did that they probably needed a little more information to identify the individuals that were most appropriate for drug court programming. A little more clinical information, maybe a little more criminal history information. I started looking around to see if anybody else had had that idea and that's where I ran into risk-need-responsivity theory. One of our first projects here that's really about this theory is testing the LSI-R, which I just described to you as one of the earliest tools in ... POPE-SUSSMAN: Just for listeners who aren't so savvy, what does LSI-R stand for? FRITSCHE: Oh, it stands for the Level of Services Inventory and it's just a 54-item assessment tool that they developed to assess individual offenders along the areas that we know may be related to re-offense. We wrote a proposal to the National Institute of Justice to do a randomized controlled trial where we looked at whether ... we're looking, we're actually now analyzing and writing up the data, at whether the treatment plans and outcomes of a drug court participant that was assessed using the LSI-R would be any different than those where they didn't get a standardized or RNR-based assessment. That was our first project that began in 2010 and is ongoing and will be reported on soon. Then shortly following that project, the world of evidence-based assessment, evidence-based practice just however coincidentally really exploded and a lot of the federal government agencies that we worked with and other non-profit organizations that work in the justice system became very interested in some of these concepts-- whether we could use evidence-based validated assessments to learn more about what keeps offenders caught in this revolving door of being incarcerated and re-offending very quickly. And whether we could then use that information or evidence to develop better programs that are therapeutic interventions. The Center has a long history of trying to create therapeutic or problem-solving interventions for offenders. This foray into this field was very natural for us. Since the evidence-based assessment research in the drug court started, we have picked up several new projects that are in this area. At the moment, we are looking at a different assessment tool that's similar to the LSI-R called the COMPAS. Don't ask me what that stands for because nobody really knows, but it's a similar tool and we're looking at that specifically in a sub-population of mentally ill offenders because there's a lot of questions in the field as to whether these validated assessments that have been historically used to predict outcomes for general felony populations will work in some of the sub-populations that are important in the justice system, mentally ill offenders being one of them. Then the other project that's very important in this field that we're doing right now began specifically from misdemeanor offenders, which is another important and understudied subgroup. We have, nationally in our justice system, about 10 million individuals per year that come through our criminal courts on misdemeanor charges. We have a very underdeveloped understanding or comprehension of what the clinical and social service needs and criminal risk of these individuals is. That gap in the research is what brought us to develop and seek funding for the Misdemeanor Assessment Project, which is a two-part project. First, to develop an assessment tool that can accurately give us a profile of the risk and needs of misdemeanor offenders rooted in risk-need-responsivity theory, and secondly to develop an intervention that we hope will effectively reduce risk for re-arrest in this population. Because the misdemeanor population is also quite tricky in terms of therapeutic intervention because they may have very high needs. They may have very serious drug problems. They may have mental illness. They may be traumatized. They may have long rap sheets. Their current charge will not allow you to put them in a two-year drug treatment program such as a drug court no matter how badly they may need it. We have to maintain legal proportionality. The second part of the Misdemeanor Assessment Project is specifically to develop short-term interventions including evidence-based cognitive behavioral treatments for this population that we hope will at least advance the ball for them somewhat in terms of reducing the clinical and social structural factors that cause them to come back into the system so quickly. POPE-SUSSMAN: Are there specific projects that we’re rolling out? FRITSCHE:Yes. The Misdemeanor Assessment Project is a specific project. We're at a stage now where we have developed a short screening tool that we feel is feasible for people in criminal courts here in New York City and nationally to try to get an idea of what the profile of their low-level offender population is in terms of risk and needs. This short screening tool is currently being used in Cook County, which is essentially Chicago, with a pilot test of a program they have for misdemeanor offenders who have been diverted from jail from traditional processing, court processing, and are given some level of treatment. Based on our screening tool, they're going to make an assessment of whether to give them a high level of treatment because they're high risk, or something a little less if they're a moderate risk, or basically just refer them to services if they're low risk. In Cook County, we're using this tool as a test of the risk principle, basically. The same short assessment tool is being rolled out in New York City, in Brooklyn and Manhattan criminal courts as a part of a larger research study to re-validate whether the items and domains that we think are predicting re-arrest in this population in New York City … we're going to test them again. We tested them once last year and we're going to test them again. That's one product that we have that we're refining but we're also giving to the field to use and test and then at the same time, we're developing a short-term intervention for misdemeanor offenders that we're going to pilot test in the community courts in Manhattan, the Bronx, and Brooklyn over the next six months. POPE-SUSSMAN: Great. Longer term on the horizon, are there any further plans? FRITSCHE: Yes. I think it's sometimes a little hard to see past the next six months especially for those of us who do research because we're oftentimes quite reticent to make claims. I think that there's definitely a demand on the ground for concrete tools, curriculums, assessment instruments that can help people move the needle from their default response to a lot of criminal behavior and overloaded criminal dockets--which is to put people into short-term stays and detention--to having more evidence-based responses to this kind of crime that have the potential to reduce risk. I think that it's a very timely field not just for practitioners but politically and especially socially here in the United States, that there's currently a public debate about whether incarceration is an effective response to crime, especially low-level crime. I think that our focus on these issues is really going to become ... I hope it will become a part of practical solutions and a part of the national conversation on alternatives to incarceration. POPE-SUSSMAN: That's very exciting. Well, thank you so much for talking to me today. I'm Raphael Pope-Sussman. I've been speaking with Sarah Fritsche, associate director of research at the Center for Court Innovation about risk/need assessment tools. To learn more about the Center for Court Innovation, please visit www.courtinnovation.org. Thank you for listening. FRITSCHE: Thanks.

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  • 00:23:23

    Circulation January 3, 2017 Issue

    · Circulation on the Run

    Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Caroline Lam, associate editor from The National Heart Center and Duke National University of Singapore. Today we will be discussing the results of an individual level meta-analysis regarding venous thromboembolism and its risk factors, but first, here's your summary of this week's issue. The first paper provides insights into paracrine signalling pathways that regulate epicardial adipose tissue formation. That is, referring to the adipose tissue located between the epicardium and underlying myocardium that is known to be strongly associated with coronary artery disease. In the current study from Dr. Lira of Icahn School of Medicine at Mount Sinai, New York, Dr. Pu from Boston Children's Hospital, Dr. [Chien 00:00:56] from Karolinska Institute and colleagues, the authors used a novel modified mRNA screening approach to probe the effect of individual paracrine factors on epicardial progenitors in the heart. Using two independent lineage tracing strategies in murine models, they showed that cells originating from the WT1-positive mesothelial lineage, which includes epicardial cells, differentiate into epicardial adipose tissue following myocardial infarction. This differentiation process required WT1 expression and was stimulated by insulin-like growth factor 1 receptor activation. Insulin-like growth factor 1 receptor inhibition significantly reduced its adipogenic differentiation and reduced WT1 lineage cell differentiation into adipocytes following myocardial infarction. These results thus establish insulin-like growth factor 1 receptor signalling as a key pathway that governs epicardial adipose tissue formation in the context of myocardial injury. And it does this by redirecting the fate of WT1-positive lineage cells. The study also demonstrates the utility of a modified RNA based paracrine library screening to dissect signalling pathways in homeostasis and disease. The next study brings us closer to understanding the mechanisms underlying diabetes-associated heart failure. In this study by first author, Dr. Wang, corresponding authors, Dr. Abel and Xiang from University of California, Davis and colleagues. High-fat diet feeding was used to induce obesity and diabetes in wild-type mice or mice lacking the beta-2 adrenergic receptor or beta-arrestin 2. High-fat diet feeding was found to selectively increase the expression of phosphodiesterase 4D in the mouse hearts in concert with the reduced phosphokinase A phosphorylation of phospholamban which contributed to systolic and diastolic dysfunction. The expression of phosphodiesterase 4D was also elevated in human hearts with diabetes. The induction of phosphodiesterase 4D expression was mediated by an insulin receptor and substrate as well as by beta-arrestin-2 dependent activation of a beta adrenergic receptor, ERK signalling cascade. Genetic deletion of beta-2 adrenergic receptor or beta-arrestin-2 or pharmacological inhibition of beta-2 adrenergic receptor with carvedilol or G-protein receptor kinase 2 with paroxetine all significantly attenuated insulin-induced phosphorylation of ERK and phosphodiesterase 4D induction thus preventing diabetes-related systolic dysfunction. Thus, targeting the insulin beta-2 adrenergic receptor pathway may be a novel way to prevent diabetes-associated heart failure. The next study addresses the gap in care pertaining to implantable cardioverter-defibrillator or ICD use among Medicare patients with low ejection fraction following myocardial infarction. Dr. Pokorny and colleagues from Duke University Medical Center examined rates of post-discharge ejection fraction assessment and ICD implantation among more than 10,280 Medicare-insured patients age 65 years above with an ejection fraction 35% and below during an index myocardial infarction admission in the ACTION Registry Get With the Guidelines. They found that the cumulative incidence of ejection fraction reassessment within one year of myocardial infarction was 66.8%. Within the first year of post-myocardial infarction, 11% of patients who had an ejection fraction reassessment underwent ICD implantation which was significantly higher than patients without an ejection fraction reassessment. After multivariable adjustment, ejection fraction reassessment remained significantly associated with a higher likelihood of ICD implantation within one year in both revascularized and non-revascularized patients. Based on these findings, the authors recommend that all patients who are potential candidates for ICD therapy be scheduled for follow-up outpatient ejection fraction assessment prior to hospital discharge to bridge these currently observed gaps in care. The next study is the first multi-institutional study in Asia describing current treatment strategies for total anomalous pulmonary venous connection. This retrospective study of 768 patients with total anomalous pulmonary venous connection operated on between 2005 and 2014 is from first authors Dr. Shi, Zhu, and Chen, corresponding authors, Dr. Chen and Zhuang and colleagues from the Shanghai Children's Medical Center and Guangdong General Hospital in China. While most patients underwent conventional repair, a sutureless patient was technique was employed in 10% of patients. Over a median follow-up of 23 months, there were 38 intraoperative deaths and 13 late deaths. A younger age at the time of repair, next an infracardiac total anomalous venous connections, pre-operative pulmonary venous obstruction, prolonged cardiopulmonary bypass time and longer duration of ventilation were all factors associated with increased mortality. Among these 717 survivors, recurrent pulmonary venous obstruction was found in 15% or 111 patients. Risk factors for recurrent pulmonary venous obstruction included pre-operative pulmonary venous obstruction, infracardiac total anomalous pulmonary connection, mixed venous connections and prolonged cardiopulmonary bypass time, a sutureless technique was associated with a lower restenosis rate compared to conventional repair in patients with pre-operative pulmonary venous obstruction but not in newborn patients. Thus, this study provides an important data on the outcomes following surgical correction and risk factors for poor prognosis in total anomalous pulmonary venous connection in Asia. The final study is the first systematic review and meta-analysis on the association of genetic polymorphisms and outcome of clopidogrel-treated patients with ischemic stroke or transient ischemic attacks. In this paper from first author, Dr. Pan, corresponding author, Dr. Wang and colleagues from Beijing Tiantan Hospital, Capital Medical University in Beijing, China. Authors looked at 15 studies of 4,762 patients with stroke or transient ischemic attack treated with clopidogrel and this included 3 studies from Europe and 12 studies from East Asia. They found that carriers of the CYP2C19 loss-of-function alleles were at increased risk of stroke compared to noncarriers. Composite vascular events were also more frequent in carriers compared to noncarriers while bleeding rates were similar. There was no evidence of statistical heterogeneity among the included studies for stroke but there was for composite vascular events suggesting that publication bias cannot be ruled out. Genetic variance other than CYP2C19 were not associated with clinical outcomes. The author suggested that their findings may justify genetic testing when clopidogrel is otherwise considered the preferred treatment modality, especially in East Asian patient populations in whom the prevalence of CYP2C19 loss-of-function allele is high. In an accompanying editorial, Dr. Simon and [inaudible 00:10:11] suggest it maybe time to consider a prospective trial of personalized medicine using CYP2C19 genotyping in acute ischemic stroke and perhaps considering alternative medications in poor or intermediate metabolizers such as in the popular ongoing genetics trial in STEMI patients undergoing PCI. That wraps it up for the summaries this week. Now for our feature discussion. Today's feature paper talks about the association of traditional cardiovascular risk factors with venous thromboembolism. And it is the first individual level meta-analysis of prospective studies. I am so delighted to have the first and corresponding author here with us, Dr. Bhaktawar Khan Mahmoodie from San Antonio's Hospital in the Netherlands. Hi Khan, thanks for being here. Dr. Bhaktawar Khan Mahmoodie:             Thank you for inviting me. Thanks a lot. Dr. Carolyn Lam:               And I am particularly delighted to have associate editor, Dr. Josh Beckman from Vanderbilt University joining us today as well. Welcome Josh. Dr. Josh Beckman:           Caroline, it is such a pleasure to be here with you. I've been listening to these podcasts and they have been incredible. I've been waiting to be able to jump in and today's paper is an awesome place to start. Dr. Carolyn Lam:               It certainly is. Congratulations on managing such an important paper. Khan, maybe I could start with you. Venous thromboembolism versus arterial thromboembolism. We're very familiar with the latter. We know it comprises coronary heart disease, stroke, peripheral artery disease. We're very familiar with the risk factors such as hypertension, hyperlipidemia, diabetes, smoking. But here you're asking, are these same risk factors applicable in venous thromboembolism. That would include deep venous thrombosis, pulmonary embolism, where we traditionally classify it into provoked events that is triggered by things we know well like immobilization, surgery and so on. And then there are the unprovoked events that don't have any risk factors. So could you, first of all, point out ... you were looking at venous thromboembolism. What was your hypothesis with regards to the traditional cardiovascular risk factors? Dr. Bhaktawar Khan Mahmoodie:             Many researchers in the last 10, 15 years, they go questions whether there is connection between venous and arterial thromboembolism. Since then, several studies published on that with controversial results. So our hypothesis for this paper was to see whether there is real associations or are we looking at some kind of associations due to confounding factors such as age and overweight which are risk factors for both. Dr. Carolyn Lam:               Yeah. And yours is actually the first individual level meta-analyses of prospective studies dealing with this. Tell us what you found in ... Were you surprised by your findings? Dr. Bhaktawar Khan Mahmoodie:             What we found that actually traditional, modifiable, cardiovascular risk factors like hypertension, diabetes and hyperlipidemia were not risk factors for venous thromboembolism. The exception was smoking, current smoking, which was particularly associated with provoked venous thromboembolism which is probably pro its association with cancer. And cancer itself is a strong risk factor for venous thromboembolism. About whether I was surprised, I was not surprised at all. We saw in several cohort studies and well-defined cohort studies that the association disappeared after adjustment for age and body mass index which are important confounders in these [inaudible 00:14:06]. That's what I expected and we found it and it is confirmed with this large individual level meta-analysis. Dr. Carolyn Lam:               Great. But what did you think of the association of higher systolic blood pressure not with higher but with lower risk of venous thromboembolism? Dr. Bhaktawar Khan Mahmoodie:             That was a bit surprising for us too but I think the best explanation we can give at the moment is probably that we have some kind of competing risk. And one suggestion that we gave in the paper as well is that maybe what we already know is that higher blood pressure is a strong risk factor for atrial fibrillation. Most of these people they receive oral anticoagulants. That is subsequently probably a protective factor for venous thromboembolism. We probably deal with some kind of competing risk from another condition like the atrial fibrillation and use of anticoagulants which we could not unfortunately adjust for in this analysis. Dr. Carolyn Lam:               Sure. That makes sense. Josh, can I bring you into this? I mean I remember well our multiple and long discussions at the editors meetings. This is one of those papers that is extremely important for its negative, neutral associations isn't it? Dr. Josh Beckman:           I think this is one of the more important papers in this field in a long time. I am one of those people who has followed this literature and believed, based on the best previous publications, that there was a link between many of the arterial thrombosis or atherothrombotic risk factors and venous thromboembolism. In fact, Circulation published one of these meta-analyses, and I'm going to say only because this little paper is so large with only 21,000 patients demonstrating a clear association. So the first question I would have, we published that back at 2008, the first question I would have is can you describe for the general readership what such a large series of patients allows you to do that was not permitted by the other meta-analyses of say twenty to thirty thousand patients that have been previously in the literature. Dr. Bhaktawar Khan Mahmoodie:             Thank you Dr. Beckman and thank you also for managing this paper. This is an important question and I think what we were able to do compared to the previous analysis in 2008, we were able to adjust for confounding risk factors. In the course, we included were all with validated venous thromboembolism events and also the events are temporal character, like all the risk factors were measured and then followed-up for event. While in that paper, there were many case-controlled studies added and the results were not adjusted for age and also not adjusted for body mass index. And if we do the same with what's done there, then we have the same results like in our [inaudible 00:17:14] associations, all of these risk factors were indeed positively associated with risk for venous thromboembolism. Dr. Carolyn Lam:               Let me just state, I mean, there were almost 245,000 participants in your study. With 4,910 thromboembolism events, so this is really huge and gives you a lot of power to look at this thing very carefully. Dr. Josh Beckman:           It was a 10-fold increase from any of the major publications in this area. It was almost geometrically larger in size which is why, I think its conclusion will be accepted differently than all the previous analyses. Now, let me ask one question about what you already identified in your discussion as a possible limitation. Is this study applicable to all populations around the globe or do you think it is a bit more focused? Dr. Bhaktawar Khan Mahmoodie:             I think it is focused at least. We don't have Asian population in these analyses and also the proportion of African-Americans were limited which was only limited to some U.S. cohorts so I think that there is a limitation which is results are probably only applicable for Caucasian population. Dr. Josh Beckman:           I guess my other question is, one of the reasons that people, I think, advance the argument that there may be overlap between the two kinds thrombosis is that there was evidence that the medication, statin, may ... to a much smaller degree, reduce venous thrombosis as well as reducing arterial thrombosis. Do you think that this is evidence of some common pathophysiology? Or is it like smoking, it's truly working separately from arterial disease? Dr. Bhaktawar Khan Mahmoodie:             Personally, I think that this association or the finding of statins reduce the risk of thromboembolism could be due to some pleiotropic effects of statins. Like even for stroke, we know that the association of cholesterol with stroke is not so clear-cut as it is with myocardial infarction but still it reduces risk of stroke. And also for venous thromboembolism, the risk reduction of venous thrombosis in the JUPITER trial was like 50%, which is very high, even better than aspirin. But I think that may not be directly related cholesterol levels but more to another pleiotropic effects of statins. It could influence levels of various coagulation [inaudible 00:19:56] in the endothelial stabilization which may be also important risk factors for venous thrombosis. Dr. Josh Beckman:           One of the reasons that this paper is very important is that we begin to look for therapies and risk factors based on what the disease is caused by. And so the fact that you guys were able to establish, in my opinion, quite clearly what does and what does not contribute to venous thrombosis allows us to begin to think about the disease differently and approach it differently. I would like to provide congratulations. My one little ask of you is that one of the things that I think this podcast is great for is to explain to the readership what goes into this kind of work. Everybody thinks that someone else's research is easier to do than their own, which of course is a ridiculous thing. But can you describe for us what it's like and how long it took from the study initiation to when you completed it? How much work went into trying to get all these studies together to create this individual patient level data? Dr. Bhaktawar Khan Mahmoodie:             Yeah. That was a great amount of work. Actually, I did a systematic review of the only PubMed publications back in 2014 and it took almost 2 years at least. I was not always active the whole 2 years but still I had to visit several PIs of the studies to get them so far to share their data. Eventually, I had to develop a code that will make it possible without sharing the individual level data by using the same definitions and the same categorization of variables so we call it a two-stage meta-analysis similar to one-stage if the definitions are similar. And eventually, I think that the real part of the analysis and inclusion of studies took like half a year or so. There was a lot of work. Dr. Josh Beckman:           I think this is a tremendous amount of work and for those members of our readership who do basic research, or translational work, or practice in the clinics, it really needs to be made clear that this is a heroic effort of hundreds and hundreds of hours. And that getting together all of these studies is just an enormous undertaking. And that even though, we can read the paper in 10 minutes and gleam the most important part. It is an incredible amount of work for which you guys are to be congratulated. Dr. Bhaktawar Khan Mahmoodie:             Thank you for acknowledging this. Thanks a lot. Dr. Carolyn Lam:               Josh, I couldn't agree with you more and I truly couldn't have said it any better. Thank you both of you for making this just one of the best discussions we've had on this podcast. I'm sure the listeners all agree what a wonderful time we've had. You've been listening to Circulation on the Run. Please remember to tune in next week.  

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  • Reducing New York City's Jail Population

    · The Center for Court Innovation - Podcasts

    New York City's incarceration rates have been dropping steadily, but a new report from the Center for Court Innovation, in collaboration with the Vera Institute of Justice, suggests the city’s jail population can still be brought significantly lower. The report looks in detail at key decision-points along the path from arrest through bail to sentencing and makes concrete suggestions for how to improve the system, especially for those defendants detained awaiting trial. In this New Thinking podcast, Matthew Watkins speaks with Michael Rempel, the report's lead author and the Center's research director.MATTHEW WATKINS: Hi, I'm Matthew Watkins and you're listening to the New Thinking podcast from the Center for Court Innovation. Both crime and incarceration rates have been dropping steadily in New York City, but a new report from the Center, in collaboration with the Vera Institute of Justice, suggests the city's jail population can still be brought lower; a move that could also cut costs substantially. The report looks in detail at the process, from arrest to sentencing, and makes concrete suggestions on how to improve the system. To discuss the report, I'm joined today by its lead author, Mike Rempel. Mike is also the Director of Research here at the center. Mike, thanks so much for joining me today. MIKE REMPEL: Good to be with you. WATKINS: This report relies principally on industrial amounts of data. What kinds of conclusions, what kinds of perspectives can you get on a system as complex as the New York City correctional system, from looking at the data, that you might not be able to get without access to those kinds of numbers? REMPEL: We can learn a lot. One of the advantages we have in New York City is that we actually have outstanding data sources available to us. We have the state’s Criminal Justice Agency, which is one of the best in the country at maintaining a very clean data set. Then, we merged that data with a variety of local data sources. The idea for the project was actually developed by senior staff at the Mayor's Office of Criminal Justice in the city. What they wanted was something that they called a path analysis. What this meant, and what we did, was that we looked at the flow of criminal cases from where they start, at the point of arrest, to the next step, which is the arraignment. That's the very first appearance in court. To the next step, which is the whole processing of a case that takes place, from the arraignment until the final court appearance, which is the disposition. WATKINS: There can often be a long gap in between. REMPEL: There can often be long gaps in between, so this is the path we took. Then, the purpose of the project ... The purposes were essentially two-fold, to describe what happens at each of these decision points. Second, to critically analyze what happens at each of these decision points, and whether what happens is what we think logically should happen. For example, are individuals sent to jail who are in fact low risk and could be better supervised in the community? Or, are there delays in the process that is causing people to spend excessive trips to court or excessive time in Rikers Island, potentially? We looked at facts in each stage. Those were our two questions. WATKINS: If we start with the first decision point, that would be the arrest decision point. What does your research suggest is happening at the arrest stage currently, and what's unexploited in terms of trying to reduce, safely, the number of people going to jail in New York City? REMPEL: At arrest we focused on two potential decisions that a law enforcement officer could make. The first is whether to make what we call a custodial arrest, where the defendant is actually taken into custody and after booking at the precinct, is sent to a holding cell in the criminal court until arraignment, which happens within 24 hours. Essentially they'll spend a night in a holding cell. WATKINS: Custodial arrest for a layperson just means arrest? REMPEL: Arrest and taken into custody. WATKINS: Okay. REMPEL: There's a second kind of arrest where they are booked. They're taken to the precinct, but then they do no spend a night in a holding cell. Instead, they're given a ticket. They're released, and they can come back for their first court date, the arraignment, sometime later. As it happens, it's several months later. That's the first decision that we looked at. Should law enforcement make a custodial arrest? Or rather, we looked at the extent to which law enforcement makes a custodial arrest or issues a ticket. This focuses mainly on misdemeanors. Those are the cases that are eligible potentially for a ticket. Second, we looked at whether there are certain kinds of cases that would be appropriate for neither of those two outcomes, and instead could be appropriate for diversion. Where in fact, the law enforcement officer might send an individual directly to a program of some kind. In effect, they could complete that program, the case could then never be forwarded, and never appear in court. We looked at that second potential decision as well. WATKINS: Broadly speaking, how is the system doing right now in terms of diverting those people it's able to divert, or giving desk appearance tickets to those people who don't need to have a custodial arrest? REMPEL: Let's start with diversion. Right now diversion at the police stage is very, very new. It's actually been a focus of the current mayoral administration. There are a couple of very small scale pilot programs. WATKINS: They could be doing more diversion, in essence. That's what the numbers suggested. REMPEL: There could, in theory, be more on diversion. What we actually found is that one could make a credible, statistical case for more diversion. What we found is that there are a great number of criminal cases that go through the courts whether it's through a desk appearance ticket, a night in the holding cell, making one court appearance, or sometimes making multiple court appearances. Potentially, with each court appearance requiring a day, potentially, waiting in court. None of us ... We found that we can statistically isolate certain categories of cases, that at the end of this process are extremely likely to have the case dismissed. For example, a first-time, non-violent, misdemeanor defendant, ages 16-24, has an 80% likelihood of having the case dismissed. Since we know these cases are overwhelmingly likely to be dismissed anyway, instead of putting them through a process that could undermine their confidence in our justice system. They might be an appropriate candidate for diversion out of court, where they go to a program, perform several hours of something, and then are released. WATKINS: Right, particularly at such a young age when the interactions with the criminal justice system can be so damaging and consequential. REMPEL: Exactly. It's interesting, the justice system. It's actually responsive to the young age. That's why in the end these cases of young people are particularly likely to be dismissed, but the lack of responsiveness is in the process leading up to the dismissal, that perhaps could be circumvented. WATKINS: Right, so we need to go the extra step of actually diverting them before we just dismiss their cases. REMPEL: Right. Unlike diversion, desk appearance tickets are already very common. There are 10's of 1000's issued each year. What we actually found is that law enforcement, by no means, overuses desk appearance tickets. In fact, we found that only 1% of individuals who currently receive a desk appearance ticket pose a high risk of committing a future crime. In other words, it's very low-risk individuals who are sent right back out and told to return to court at a later time. On the other hand, we actually found that desk appearance tickets are arguably underutilized. We did find racial dis-proportionalities in their use because black and Hispanic defendants are less likely to receive a ticket than white defendants, even if they have comparable characteristics.   WATKINS: If we turn to look at the question of arraignments, as related to these desk appearance tickets, there's often a long wait in-between the issuance of the ticket and the arraignment. Is that correct? REMPEL: Right. We had some fascinating findings on that. Again, remember that the desk appearance ticket is supposed to be a positive for the defendant because they avoid the overnight in the holding cell. They basically are released on their own and they can go home several hours after the arrest. However, what we found is that the court date, when the have to return to court for their arraignment, averages two months later city-wide, and three months later in the Bronx. This long gap between the arrest and the court date leads many individuals to forget that they have the court date. They don't appear. A warrant is issued. They're re-arrested. We then found that even though these are primarily very low-level misdemeanor cases— they wouldn't have received the ticket in the first place if it was not a low-level case— We found that if this process happens and in the end they warrant, because they neglected their court date, when they are returned to court they actually are potentially exposed to serving jail time pre-trial. WATKINS: Let's turn a little bit to look at this question of risk assessments. Maybe you could explain for people a little bit what a risk assessment is? Then, what your study found about how defendants of different risks levels are being treated by the system, and where there are some unexploited areas, in terms of reducing jail numbers. REMPEL: Great. Risk assessments are used currently across the country. The purpose of a risk assessment is to use statistical information that is accurate for large groups of individuals, and to apply them to specific cases in order to understand their likelihood of re-offending.  Now, typically risk assessments will look at different types of risk. One type of risk might be Person-X has a low or high-risk of committing some future offense. Very often people are not just interested in that, because what they're interested in is a serious crime against the person. Often, risk assessments will focus on risk of violence, which really raises the question of risk to public safety. That's risk assessment in a nutshell. What we did in this study is, we didn't use a risk assessment that is currently in use. In effect, we created our own risk assessment tool based on data we had, in order to in-turn critically examine who's going through the system. Some the most interesting findings from that came during the pre-trial period where we found that a majority of those who currently are sent to jail prior to a conviction, actually pose a relatively lower, at most moderate, risk of re-offending. That led to a key area of reform, in terms of recognizing that there are large numbers that actually could be safely supervised in the community. WATKINS: Essentially the suggestion from the numbers is that the current system is being too conservative, in terms of alternatives to detention vis-à vis risk levels. REMPEL: As of several years ago, the current system was definitely being extremely conservative. Just to give you a sense of some of the statistics, we found that of those who are sent to jail prior to a conviction, right now 64% of them are in a minimal, low, or at most moderate-risk category. That's misdemeanors. Then among the felonies it's 59% in these low-risk categories. This is a pool that's ripe for diversion. This has been the case for years. The city currently is piloting a solution to this very problem. What our findings speak to is the idea that this solution could actually be used with very, very large numbers of individuals. WATKINS: Let's turn to look a little bit at the question of bail, which your report goes into in some detail. Let's say a defendant is ordered by a judge to pay a set amount of cash bail at his/her arraignment. What happens at that point? Is it easy for the person to then pay their bail? The bail is supposed to keep them out of jail, right? REMPEL: The decision to set bail, as you indicated, happens right at the arraignment court appearance. The defendant can't pay the bail because right after the arraignment court appearance the defendant is then escorted to the back and prepared for transport to a city jail. What actually happens is that a family member or friend, who ideally is in the audience at arraignment, hears the bail amount. Then, they have a certain number of hours, potentially, to pay the bail at a window in the courthouse. Now, what we found is that in point-of-fact, in only 11% of cases where bail is set, does the family member or friend actually pay bail successfully before the defendant is transported to a city jail. The reasons for this are many. It could be that a family member or friend was not in the courtroom. It could be they were not notified. It could be that the defendant didn't have an opportunity to call a contact that the defendant had. It could be that the friend or family member was in the courtroom, but because of how quickly the proceedings move, didn't actually catch or understand what the bail amount was, didn't know where to go. It could also be that in any given case, because of the schedules of when the buses leave the courthouses to go to jail, that their window of time ... Which is theory could be up to three hours, was actually much shorter. The family member or friend could have paid bail right at the courthouse, but the defendant left the courthouse and was bused to jail before that could happen. There are number of reasons this happens, but the up-shot is that it's a gap in the system that only about 1 in 10 defendants, for whom bail is set, can get it paid and avoid any jail time. WATKINS: Again, this is another decision point in the system you've identified that is leading, arguably, to unnecessary detention. REMPEL: Correct. What we found in a lot of cases, what happens is the defendants do have the financial wherewithal to get bail paid. What will happen after several days— They will spend several days in jail. They will have the experience that one has in jail, which is an experience that can be deeply scarring psychologically. Then, after several days later they will be released because they were in fact able to make bail. WATKINS: Now, there's a larger debate about cash bail going on in this country that we're not going to get into here. I can see the relief on your face. The idea behind bail is it's meant to guard against either someone being a flight risk, failing to appear at their next court date, or being a risk to public safety. When your research looks at why bail is being set in the New York City system currently, is that how the system is actually functioning? REMPEL: No, it's not. It's actually interesting, legally the justification for bail in New York State is to secure court attendance. In other words, you pay bail and since you're going to lose the bail money you paid if you don't show up for your court dates, you're incentivized to show up for your court dates. Not our research, but what research by others has shown, is that actually about 15% of New York City defendants fail to appear at one of their court dates. Actually, most of those who fail to appear for a court date, they probably forgot. In the end, they tend to show up to court soon thereafter. Only about 5% of defendants both fail to appear for one of their court dates and have still disappeared 30 days later. Others have actually found that fail-to-appear is not a great problem in the city. However, in our study we looked at what really drives bail decisions. We found that it was the charge. When we compared misdemeanor defendants to non-violent felony defendants to violent felony defendants, the likelihood that the prosecutors will request bail and that the judges will set bail goes much higher. We found other factors related to criminal history were also important. Everything was dwarfed by the paramount importance of charge. Even though charge is actually unrelated to one's likelihood of not appearing for a scheduled court date. It is somewhat related, but not strongly related, to future risk to public safety. WATKINS: If we just turn to look at sentencing now, your report looked for example, specifically at misdemeanor offenses. Often those sentences are very, very brief. What does that suggest to you in terms of another decision point in the system? REMPEL: We should pause for a moment on that, and just observe that in some ways the quite low use of jail at the sentencing stage for misdemeanors is a strength of the system. We found that of those that have a conviction, only 16% of misdemeanors have a jail sentence. That means New York City is not drastically overusing jail at the sentencing stage. However, we found that when jail is sentenced with misdemeanors, at the sentencing stage, in 4 out of 5 cases, the sentence is 30 days or less. A jail sentence of 30 days or less, on its face, is too short to incapacitate the defendant for a meaningful enough period of time to prevent future criminal behavior. On the other hand, it's not too short to potentially increase the likelihood that these defendants will actually engage in criminal behavior after they are released, as a negative effect of the exposure to others who are also involved in the criminal justice system while they are in jail who, in some cases, may be up on more serious charges, may have more serious criminal histories, or may be higher-risk individuals. While the strength of the system is the low use of jail, we found that even the use that exists probably could, and should, be avoided because it's so short, to produce no meaningful benefit. WATKINS: And could be counter-productive. REMPEL: And could be counter-productive. WATKINS: Right. If we just want to turn lastly to the topic that will interest a lot of people, I'm sure, and that is cost. It sounds like you've identified a number of decision points in the system that would allow New York City to safely reduce its jail population, potentially quite significantly. What kinds of cost savings could that produce, do you think? REMPEL: Cost savings that are significant, but not as significant as one might expect in the short term. The reasons are as follows. Jail is extremely expensive in New York City. On average it costs about $208,000 to incarcerate someone at a local jail per year. Less than a year, then prorate that on a daily basis. WATKINS: That's far above the national rate. REMPEL: That's far above the national rate. Jail is extremely expensive. In the long term, slashing the jail population would reap tremendous fiscal benefits to the city. In the short term, one should candidly understand that you don't get a defendant per defendant reduction in costs just because you now are no longer filling a jail bed. A lot of the costs are what we call, fixed. You still have to maintain the jail. You still, unless you drastically reduce the jail population, are not going to shrink your workforce. You're still going to pay the pension to people who use to be in the work force. You're still going to pay everyone's salaries. You're still going to have to have subsidiary contracts with health and mental health providers for individuals in the jail. A lot of the costs change slow. People should understand that you could slash the jail population in half. If you do that, the fiscal savings will be overwhelming in the long term, but it may take some time. WATKINS: That's great. Mike, thanks so much. REMPEL: Sure, thank you. WATKINS: I've been speaking with Mike Rempel. He's the Director of Research here at the Center for Court Innovation. Mike is the lead author of a new study called Jail in New York City: Evidence-Based Opportunities for Reform. It's available on our website, CourtInnovation.org. My name is Matt Watkins. Thanks for listening to the New Thinking podcast.   

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  • 00:36:54

    MI in Children

    · Pediatric Emergency Playbook

    Myocardial infarction (MI) in children is uncommon, but underdiagnosed.  This is due to two main factors: the etiologies are varied; and the presenting symptoms are “atypical”. We need a mental metal detector!  Case examples Congenital Two main presentations of MI due to congenital lesions: novel and known.  The novel presentation is at risk for underdiagnosis, due to its uncommonness and vague, atypical symptoms.  There are usually some red flags with a careful H&P.  The known presentation is a child with a history of congenital heart disease, addressed by corrective or palliative surgery.  This child is at risk for expected complications, as well as overdiagnosis and iatrogenia.  Risk stratify, collaborate with specialists. The fussy, sweaty feeder: ALCAPA Anomalous Left Coronary Artery from the Pulmonary Artery (ALCAPA) is an example of what can go wrong during fetal development: any abnormality in the number, origin, course, or morphology of the coronary arteries can present as a neonate with sweating during feeds (steal syndrome), an infant in CHF, or an older child with failure to thrive or poor exercise tolerance. The stable child with chest pain: myocardial bridge Normal coronary arteries run along the epicardial surface of the heart, with projections into the myocardium.  If part of the artery’s course runs within the myocardium (i.e. the artery weaves into and/or out of the myocardium), then there is a myocardial bridge of the coronary artery.  With every systolic contraction, the artery is occluded.  Although a myocardial bridge may not cause symptoms (especially at distal portions), the area it supplies is at risk. With any minor trauma or exertion, demand may outpace supply, resulting in ischemia.  Diagnosis is made on coronary angiography. The unwell child post-cardiac surgery: Fontan problems The child with single ventricle physiology may have a Norwood procedure at birth (creation of a neoaorta, atrial septectomy, and Blalock-Taussig shunt), a Bidirectional Glenn procedure at 3-6 months (shunt removed, superior vena cava connected to pulmonary arteries), and a Fontan procedure at about 2-3 years of age (inferior vena cava blood flow is shunted into the pulmonary arteries). These children depend on their preload to run blood passively into the pulmonary circuit; afterload reduction is also important to compensate for a poor left ejection fraction, as well as to avoid the development of pulmonary hypertension.  They are typically on an anticoagulant (often aspirin), a diuretic (e.g. furosemide), and an afterload reduction agent (e.g. enalapril).  Any disturbance in volume status (hyper- or hypovolemia), anticoagulation, or afterload may cause myocardial strain or infarction.  Take the child s/p Fontan seriously and involve his specialists early with any concerns. Autoimmune The body’s inflammatory-mediated reaction to a real or perceived insult can cause short- and long-term cardiac sequelae.  Find out how well the underlying disease is controlled, and what complications the child has had in the past. The red, hot, crispy, flaky child: acute Kawasaki disease Kawasaki disease (KD) is an acute systemic vasculitis, diagnosed by the presence of fever for five or more days accompanied by four or more criteria:  bilateral conjunctival injection, mucositis, cervical lymphadenopathy, polymorphous rash, and palmar or sole desquamation.  The criteria may occur (and disappear) at any time during the illness. Infants are under double jeopardy with Kawasaki Disease.  They are more likely to have incomplete KD (i.e. not fulfill strict criteria) and if they have KD, they are more likely to suffer the dangerous consequences of aneurysm formation (chiefly coronary arteries, but also brain, kidney).  Have a low threshold for investigation. Treatment includes 2 g/kg/day IVIG and high-dose aspirin (30-50 mg/kg/day) acutely, then low-dose aspirin (5 mg/kg/day) for weeks to months.  Regular and long-term follow-up with Cardiology is required. The aftermath: sequelae of Kawasaki disease The family and child with a history of KD may have psychological trauma and continuous anxiety about the child’s risk of MI.  Approximately 4.7% of children who were promptly diagnosed and correctly treated will go on to have cardiac sequelae. Children who have no detected cardiac sequelae by 8 weeks, typically continue to be asymptomatic up to 20 years later.  Smaller aneurysms tend to regress over time, especially those < 6 mm. Thrombi may calcify, or the lumen may become stenotic due to myofibroblast proliferation.  Children with any coronary artery dilatation from KD should be followed indefinitely. Giant aneurysms (≥8 mm) connote the highest risk for MI.  Parents often are concerned about recurrence, and any subsequent fever can be distressing.  There is a low rate of recurrence for KD: approximately 2%.  Infants who have coronary aneurysms are at the highest risk for recurrence. The older child with vague chest complaints and hypercoagulability: Systemic Lupus Erythematosus and Anti-Phospholipid Syndrome Up to 15% of cases of SLE begin in childhood.  Adult criteria are used, with the caveat that the diagnosis of SLE in children can be challenging; many children only manifest a few of the criteria initially before going on to develop further systemic involvement. The Systemic Lupus International Collaborating Clinics (SLICC) revised the criteria in 2012.  The patient should have ≥4/17 clinical and/or immunologic criteria.  The clinical criteria are: acute cutaneous (malar); chronic cutaneous (discoid); oral; alopecia; synovitis; serositis; renal; neurologic; hemolytic anemia; leukopenia; or thrombocytopenia.  The immunologic criteria are: ANA; anti-dsDNA; anti-Sm; antiphospholipid; low complement; and/or Direct Coombs (in absence of hemolytic anemia).  At least one criterion should be clinical, and at least one should be immunologic.  Children with antiphospholipid syndrome (APS) may occur with or without SLE.  Patients are at risk for venous and arterial thrombi formation.  APS may also cause structural damage, such as valvular thickening and valvular nodes (Libman-Sacks endocarditis).  Mitral and aortic valves are at the highest risk. Although most children with chest pain will not have MI, those with comorbidities should be investigated carefully. Trauma Direct, blunt trauma to the chest can cause myocardial stunning, dysrhythmias, or an asymptomatic rise in Troponin I.  However, some children are at risk for disproportionate harm due to a previously unknown risk factor.  Clinically significant cardiac injury occurs in up to 20% of patients with non-penetrating thoracic trauma. The motor vehicle collision: blunt myocardial injury Direct trauma (steering wheel, airbag, seatbelt), especially in fast acceleration-deceleration injury, may cause compression of the heart between the sternum and the thoracic spine. Electrocardiography (ECG) should be performed on any patient with significant blunt chest injury.  A negative ECG is highly consistent with no significant blunt myocardial injury. Any patient with a new abnormality on ECG (dysrhythmia, heart block, or signs of ischemia) should be admitted for continuous ECG monitoring. Elevation in troponin is common, but not predicted.  A solitary elevated troponin without ECG abnormality is of unclear significance.  Author’s advice: obtain troponin testing if there is an abnormal ECG, more than fleeting suspicion of BCI, and/or the child will be admitted for monitoring. Hemodynamically labile children should be resuscitated and a stat transesophageal echocardiogram obtained. The high-velocity object: coronary artery dissection or thrombus Direct trauma (e.g. MVC, baseball, high-velocity soccer ball) may cause damage to the left anterior descending artery or left circumflex artery, at the highest risk due to their proximity to the chest wall.  Thrombosis and/or dissection may result, often presenting in a focal pattern of ischemia on the ECG. Echocardiography may reveal valvular damage related to the injury, as well as effusion and ejection fraction.  Since there is often a need to investigate the coronary anatomy, percutaneous coronary intervention (PCI) is recommended. The minor trauma with disproportionate complaint: myocardial bridge As mentioned in the congenital section (above), a known variation of a coronary artery’s course involves weaving in and out of the myocardium, creating a baseline risk for ischemia.  Even minor trauma in a child with a myocardial bridge may cause acute thrombus, or slow stenosis from resulting edema.  Unfortunately, the presence of myocardial bridging is often unknown at the time of injury.  Approximately 25% of the population may have myocardial bridging, based on autopsy studies. Take the child seriously who has disproportionate symptoms to what should be a minor injury. Hematologic Coagulopathic and thrombophilic states may predispose children to focal cardiac ischemia.  The best documented cormorbidity is sickle cell disease, although other pro-thrombotic conditions also put the child at risk. The child with sickle cell disease and chest pain: when it’s not acute chest syndrome Sickle cell disease (SCD) can affect any organ system, although the heart is traditionally considered a lower-risk target organ for direct sickling and ischemia.  The major cardiac morbidity in sickle cell is from strain, high-output failure and multiple, serial increases in myocardial demand, causing left ventricular hypertrophy and congestive heart failure. However, there is mounting evidence that acute myocardial ischemia in sickle cell disease may be underappreciated and/or attributed to other causes of chest pain. Other cardiac sequelae from SCD include pulmonary hypertension, left ventricular dysfunction, right ventricular dysfunction, and chronic iron overload. Evidence of myocardial ischemia/infarction in children with SCD has been demonstrated on single-photon emission computed tomography (SPECT) scan. The puffy faced child with chest pain: nephrotic syndrome hypercoagulability Children who suffer from nephrotic syndrome lose proteins that contribute to the coagulation cascade.  In addition, lipoprotein profiles are altered: there is a rise in the very low-density lipoproteins (LDL), contributing to accelerated atherosclerosis.  Typically nephrotic patients have normal levels of high-density lipoproteins (HDL), unless there is profuse proteinuria. Children with difficult-to-control nephrotic syndrome (typically steroid-resistant) may form accelerated plaques that rupture, causing focal MI, as early as school age. The previously well child now decompensated: undiagnosed thrombophilia Asymptomatic patent foramen ovale (PFO) is the cause of some cases of cryptogenic vascular disease, such as stroke and MI.  However, the presence of PFO alone does not connote higher risk.  When paired with an inherited or acquired thrombogenic condition, the venous thrombus may travel from the right-sided circulation to the left, causing distal ischemia.  Many of these cases are unknown until a complication arises. The chronically worried, now with a reason: hypercholesterolemia A family history of adult-onset hypercholesterolemia is not necessarily a risk factor for early complications in children, provided the child does not have the same acquired risk factors as adults (e.g. obesity, sedentary lifestyle, smoking, etc).  Parents may seek help in the ED for children with chest pain and no risk factors, but adult parents who have poor cholesterol profiles. The exception is the child with familial hypercholesterolemia, who is at risk for accelerated atherosclerosis and MI. Infectious Myocarditis has varied etiologies, including infectious, medications (chemotherapy agents), immunologic (rheumatologic, transplant rejection), toxins (arsenic, carbon monoxide, heavy metals such as iron or copper), or physical stress (electrical injury, heat illness, radiation). In children, the most common cause of myocarditis is infectious (viruses, protozoa, bacteria, fungal, parasites).  Of these, viral causes are the most common (adenovirus, enterovirus, echovirus, rubella, HHV6). The verbal child may complain of typical chest complaints, or may come in with flu-like illness and tachycardia or ill appearance out of proportion to presumed viral illness. The most common presenting features in children with myocarditis are: shortness of breath, vomiting, poor feeding, hepatomegaly, respiratory distress, and fever. The infant in shock after a ‘cold’: myocarditis Beware of the poor feeding, tachycardic, ill appearing infant who “has a cold” because everyone else around him has a ‘cold’.  That may very well be true, but any virus can be invasive with myocardial involvement.  Infants are only able to increase their cardiac output through increasing their heart rate; they cannot respond to increased demands through ionotropy.  Look for signs of acute heart failure, such as hepatomegaly, respiratory distress, and sacral edema. The child with tachycardia out of proportion to complaint: myocarditis The previously healthy child with “a bad flu” may simply be very symptomatic from influenza-like illness, or he may be developing myocarditis.  Look for chest pain and tachycardia out of proportion to presumed illness, and constant chest pain, not just associated with cough. The “pneumonia” with suspicious chest x-ray: myocarditis Acute heart failure may mimic viral pneumonia.  Look for disproportionate signs and symptoms. Toxins Younger children may get into others’ medications, be given dangerous home remedies, take drugs recreationally, have environmental exposures (heavy metals), suffer from a consequence of a comorbidity (iron or copper overload) or have adverse events from generally safe medications. The hyperactive boy with a hyperactive precordium: methylphenidate Attention deficit hyperactivity disorder (ADHD) is growing in rate of diagnosis and use of medications.  As the only medical diagnosis based on self-reported criteria, many children are given stimulants regardless of actual neurologic disorder; with a higher proportion of children exposed to stimulants, adverse effects are seen more commonly. Methylphenidate is related to amphetamine, and they both are dopaminergic drugs.  Their mechanisms of action are different, however.  Methylphenidate increases neuronal firing rate.  Methamphetamine reduces neuronal firing rate; cardiovascular sequelae such as MI and CHF are more common in chronic methamphetamine use. Although methylphenidate is typically well tolerated, risks include dysrhythmias such as ventricular tachycardia. The child with seizure disorder and chest pain: anti-epileptics Some anti-epileptic agents, such as carbamazepine, promote a poor lipid profile, leading to atherosclerosis and early MI.  Case reports include school-aged children on carbamazepine who have foamy cells in the coronary arteries, aorta, and vasa vasorum on autopsy.  It is unclear whether this is a strong association. The spice trader: synthetic cannabinoids Synthetic cannabinoids are notoriously difficult to regulate and study, as the manufacturers label them as “not for human consumption”.  Once reports surface of abuse of a certain compound, the formula is altered slightly and repackaged, often in a colorful or mysterious way that is attractive to teenagers. The misperceptions are: are a) synthetics are related to marijuana and therefore safe and b) marijuana is inherently “safe”. Both tend to steer unwitting teens to take these unknown entities.  Some suffer MI as a result. Exposure to tetrahydrocannabinol (THC) in high-potency marijuana has been linked to myocardial ischemia, ventricular tachycardia, and ventricular fibrillation.  Marijuana can increase the heart rate from 20-100%, depending on the amount ingested. K2 (“kush 2.0”) or Spice (Zohai, Genie, K3, Bliss, Nice, Black Mamba, fake weed, etc) is a mixture of plant leaves doused in synthetic chemicals, including cannabinoids and fertilizer (JWH-108), none of which are tested or safe for human consumption.  Synthetic cannabinoids have a higher affinity to cannabinoid receptors, conferring higher potency, and therefore worse adverse effects.  They are thought to be 100 to 800 times more potent as marijuana. Bath salts (Purple Wave, Zoom, Cloud Nine, etc) can be ingested, snorted, or injected.  They typically include some form of cathinone, such as mephedrone, similar to the substance found in the naturally occurring khat plant. Hallucinations, palpitations, tachycardia, MI, and dysrhythmias have been reported from their use as a recreational drug. Chest pain with marijuana, synthetic cannabinoid, or bath salt ingestion should be investigated and/or monitored. Riding that train: high on cocaine Cocaine is a well-known cause of acute MI in young people.  In addition to the direct stimulant causes acutely, such as hypertension, tachycardia, and impaired judgement (coingestions, risky behavior), chronic cocaine use has long-term sequelae.  Cocaine causes accelerated atherosclerosis.  That, in conjunction with arterial vasospasm and platelet activation, is a recipe for acute MI in the young. Cranky: methamphetamine Methamphetamine is a highly addictive stimulant that is relatively inexpensive and widely available.  Repeated use causes multiple psychiatric, personality, and neurologic changes.  Risky behavior, violence, and motor vehicle accidents are all linked to this drug.  Like cocaine, methamphetamine may cause fatal dysrhythmias, acute MI from demand ischemia, and long-term sequelae such as congestive heart failure. Summary Acute MI is a challenging presentation in children: Easily missed: uncommon and atypical Varied etiology Respect vague symptoms with a non-reassuring H&P Try to detect it: CATH IT! References Congenital AboulHosn JA et al. Fontan Operation and the Single Ventricle. Congenit Heart Dis. 2007; 2:2-11. Aliku TO et al. A case of anomalous origin of the left coronary artery presenting with acute myocardial infarction and cardiovascular collapse. African Health Sci. 2014; 14(1): 23-227. Andrews RE et al. Acute myocardial infarction as a cause of death in palliated hypoplastic left heart syndrome. Heart. 2004; 90:e17. Canale LS et al. Surgical treatment of anomalous coronary artery arising from the pulmonary artery. Interactive Cardiovascaulr and Thoracic Surgery. 2009; 8:67-69. Güvenç O et al. Correctable Cause of Dilated Cardiomyopathy in an Infant with Heart Failure: ALCAPA Syndrome. J Curr Pediatr. 2017; 15:47-50. Hastings RS et al. Embolic Myocardial Infarction in a Patient with a Fontan Circulation. World Journal for Pediatric Congenital Heart Surgery. 2014; 5(4)L631-634. Hoffman JIE et al. Electrocardiogram of Anomalous Left Coronary Artery From the Pulmonary Artery in Infants. Pediatr Cardiol. 2013; 34(3):489-491. Kei et al. Rare Case of Myocardial Infarction in a 19-Year-Old Caused by a Paradoxical Coronary Artery Embolism. Perm J.2015; 19(2):e107-e109. Liu Y, Miller BW. ALCAPA Presents in an Adult with Exercise Inlerance but Preserved Cardiac Function. Case Reports Cardiol. 2012; AID 471759. Möhlenkamp S et al. Update on Myocardial Bridging.Circulation. 2002;106:2616-2622. Murgan SJ et al. Acute myocardial infraction n the neonatal period. Cardiol Young. 2002; 12:411-413. Sieweke JT et al. Myocardial infarction in grown up patients with congenital heart disease: an emergening high-risk combination. International Journal of Cardiology. 2016; 203:138-140. Schwerzmann M et al. Anomalous Origin of the Left Coronary Artery From the Main Pulmonary Artery in Adults. Circulation. 2004; 110:e511-e513. Tomkewicz-Pajak L et al. Arterial stiffness in adult patients after Fontan procedure. Cardiovasculr Ultrasound. 2014; 12:15. Varghese MJ et al. The caveats in the diagnosis of anomalous origin of left coronary artery from pulmonary artery (ALCAPA). Images Paediatr Cardiol. 2010; 12(3): 3–8. Autoimmune Ayala et al. Acute Myocardial Infarction in a Child with Systemic Lupus Erythematosus and Antiphospholipid Syndrome. Turk J Rheumatol. 2009; 24:156-8. Nakano H et al. Clinical characteristics of myocardial infarction following Kawasaki disease: Report of 11 cases. J Pediatr. 1986; 108(2):198-203. Pongratz G et al. Myocardial infarction in an adult resulting from coronary aneurysms previously documented in childhood after an acute episode of Kawasaki’s disease. European Heart J. 1994. 15:1002-1004. Newburger JW et al.  Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease. A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747-2771. Son MB et al. Kawaski Disease. Pediatr Rev. 2013; 34(4). Yuan S. Cardiac surgical procedures for the coronary sequelae of Kawasaki disease. Libyan J Med. 2012; 7:19796. Trauma Abdolrahim SA et al. Acute Myocardial Infarction Following Blunt Chest Trauma and Coronary Artery Dissection. J Clin Diagnost Res. 2016; 10(6):14-15. Galiuto L et al. Post-traumatic myocardial infarction with hemorrhage and microvascular damage in a child with myocardial bridge: is coronary anatomy actor or bystander. Signa Vitae. 2013; 8(2):61-63. Janella BL et al. Acute Myocardial Infarction related to Blunt Thoracic Trauma. Arq Bras Cardiol. 2006; 87:e168-e171. Liu X et al. Acute myocardial infarction in a child with myocardial bridge World J Emerg Med. 2011; 2(1):70-72. Long WA et al. Childhood Traumatic Infarction Causing Left Ventricular Aneurysm: Diagnosis by Two-Dimensional Echocardiography. JACC. 1985; 5(6):1478-83. Smith S. Right Bundle Branch Block after Blunt Trauma: A Tragic Case. [Blog Post] July 22, 2012. Retrievable at: http://hqmeded-ecg.blogspot.com/2012/07/right-bundle-branch-block-after-blunt.html. Hematologic Carano N et al. Acute Myocardial Infarction in a Child: Possible Pathogenic Role of Patent Foramen Ovale Associated with Heritable Thrombophilia. Pediatr. 2004; 114(2):255-258.      Chacko P et al. Myocardial Infarction in Sickle Cell Disease. J Cardiovascl Transl Res. 2013; 6(5):752-761. De Montalembert M et al. Myocardial ischaemia in children with sickle cell disease. Arch Dis Child. 2004; 89:359-362. Gladwin MT et al. Cardiovascular Abnormalities in Sickle Cell Disease. JACC. 2012; 59(13):1123-1133. Osula S et al. Acute myocardial infarction in young adults: causes and management. Postgrad Med J. 2002; 78:27-30. Silva JMP et al. Premature acute myocardial infarction in a child with nephrotic syndrome. Pediatr Nephrol. 2002; 17:169-172. Suryawanshi SP. Myocardial infarction in children: Two interesting cases. Ann Pediatr Cardiol. 2011 Jan-Jun; 4(1): 81–83. Infectious Cunningham R et al. Viral myocarditis Presenting with Seizure and Electrocardiographic Findings of Acute Myocardial Infarction in a 14-Month-Old Child. Ann Emerg Med. 2000; 35(6):618-622. De Vettten L et al. Neonatal Myocardial Infarction or Myocarditis? Pediatr Cardiol. 2011; 32:492-497. Durani Y et al. Pediatric myocarditis: presenting clinical characteristics. Am J Emerg Med. 2009; 27:942-947. Erden I et al. Acute myocarditis mimicking acute myocardial infarction associated with pandemic 2009 (H1N1) influenza virus. Cardiol J. 2011; 552-555. Hover MH et al. Acute Myocarditis Simulating Myocardial Infarction in a Child. Pediatr. 1191; 87(2):250-252. Lachant D et al. Meningococcemia Presenting as a Myocardial Infarction. Case Reports in Critical Care. 2015; AID 953826. Laissy JP et al. Differentating Myocardial Infarction from Myocarditis. Radiology. 2005; 237(1):75-82. Miranda CH et al. Evaluation of Cardiac Involvement During Dengue Viral Infection. CID. 2013; 57:812-819. Rettig JS et al. Myocarditis in Children Requiring Critical Care Transport. In:  "Diagnosis and Treatment of Myocarditis", Milei J, Ambrosio G (Eds). DOI: 10.5772/56177. Toxins De Chadarévian JP et al. Epilepsy, Atherosclerosis, Myocardial Infarction, and Carbamazepine. J Child Neurol. 2003; 18(2):150-151. McIlroy G et al. Acute myocardial infarction, associated with the use of a synthetic adamantly-canabinoid: a case report. BMC Pharmacology and Toxicology. 2016; 17:2. Mir A et al. Myocardial Infarction Associated with Use of the Synthetic Cannabinoid K2. Pediatr. 2011; 128(6):1-6 Munk K et al. Cardiac Arrest following a Myocardial Infarction in a Child Treated with Methylphenidate. Case Reports Pediatr. 2015; AID 905097. Rezkalla SH et al. Cocaine-Induced Acte Mycardial Infarction. Clin Med Res. 2007; 5(3):172-176. Schelleman H et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry. 2012 Feb;169(2):178-85. Sheridan J et al. Injury associated with methamphetamine use: a review of the literature. Harm Reduction Journal, 2006; 3(14):1-18. Stiefel G et al. Cardiovascular effects of methylphenidate, amphetamines and atomoxetine in the treatment of attention-deficit hyperactivity disorder. Drug Saf. 2010 Oct 1;33(10):821-42.   This post and podcast are dedicated to Edwin Leap, MD for his sanity and humanity in the practice of Emergency Medicine.  Thank you, Dr Leap for all that you do.

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  • 00:18:25

    Circulation March 21, 2017 Issue

    · Circulation on the Run

    Dr. Lam:                               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. In this week's issue, we are discussing if public placement of defibrillators in the community can be improved. First, here's your summary of this week's Journal.                                                 Stroke incidents, prevalence, and risk factors have been changing over the past 50 years so do we need a more contemporaneous revised Framingham Stroke Risk profile to reflect these trends? Well the first paper in our issue looks at this and this is from first author Dr. Dufouil, corresponding author Dr. Seshadri and colleagues from the Boston University School of Medicine.                                                 Let's first recall that the Framingham Stroke Risk profile was originally described in 1991 and integrates the effect of age, sex, and baseline measurements of various vascular risk factors such as systolic blood pressure, use of anti-hypertensive medications, left ventricular hypertrophy on ECG, prevalent cardiovascular disease, current smoking status, atrial fibrillation and diabetes all to describe the 10-year probability of incident stroke.                                                 In the current paper, the authors updated the Framingham Stroke Risk profile using the means of risk factors that reflect current prevalence, the estimate of incident stroke to reflect current rates, and the hazards ratio that reflect current associations. They used the same risk factors identified in the original stroke risk profile with the exception of left ventricular hypertrophy. The authors compared the accuracy of the standard old risk profile with the revised new risk profile in predicting the risk of [alt 00:01:58] and ischemic stroke and validated the new risk profile in two external cohorts, the three cities and regards or reasons for geographic and ethnic differences in stroke studies.                                                 They found that the new stroke risk profile was a better predictor of current stroke risks in all three samples than the original old Framingham Stroke Risk profile. The new stroke risk profile was also a better predictor among whites compared to blacks in the regard study. The authors therefore concluded that a more contemporaneous revised Framingham Stroke Risk profile could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors.                                                 The next study provides preclinical proof of principle that an apelin receptor agonist may be of therapeutic use in pulmonary arterial hypertension. And the agonist in this case is  Elabela/Toddler or ELA, first identified as an essential peptide in the development of the heart in Zebrafish, and subsequently proposed as a second endogenous ligand at the G-protien coupled apelin receptor, which works at this receptor despite a lack of sequence similarity to the established ligand, apelin.                                                 In this study from first author Dr. Yang, corresponding author Dr. Davenport and colleagues  from University of Cambridge in the United Kingdom, ELA competed for binding of apelin in human hearts with overlap of the two peptides indicated by encyclical modeling. ELA activated G-protein and β-arrestin dependent pathways and as expression was detectable in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, cardiac output, and elicited vasodilatation in rats in vivo.                                                  ELA expression was reduced in cardiopulmonary tissues from patients with pulmonary arterial hypertension and in rat models. Finally, ELA treatment significantly attenuated the elevation of right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in monocrotaline exposed rats. Thus, these results suggest that a selective agonist that mimics the action of indulgence ligand apelin or Elabela/Toddler, ELA, may be a promising therapeutic strategy in the treatment of pulmonary arterial hypertension.                                                 The final paper looks at sudden cardiac death after coronary artery bypass grafting, its incidents, timing, and clinical predictors. First author Dr. Rao, corresponding author Dr. Velazquez and colleagues from Duke Clinical Research Institute in Durham, North Carolina, looked at the patients enrolled in the STICH, or Surgical Treatment of Ischemic Heart Failure Trial who underwent coronary artery bypass grafting with or without surgical ventricular reconstruction. They excluded patients with a prior ICD and those randomized only to medical therapy. Over a median followup of 46 months, 113 out of 1,411 patients who received coronary artery bypass surgery, had sudden cardiac death while 311 died of other causes.                                                 The five-year cumulative incidence of sudden cardiac death was 8.5%. In the first 30 days after bypass surgery, sudden cardiac death accounted for 7% of all the deaths. The numerically greatest monthly rate of sudden cardiac death was in the 31 to 90 day time period. In multivariable analysis end-systolic volume index and BNP were the most strongly associated with sudden cardiac death. Thus, this study shows that the monthly risk of sudden cardiac death shortly after bypass surgery among patients with a low ejection fraction is highest between the first and third months, suggesting that risk stratification for sudden cardiac death should occur early in the post-operative period, particularly in patients with an increased preoperative end-systolic volume index and/or an increased BNP.                                                 Well, that wraps it up for you summaries, let's turn to our feature paper.                                                 I love our feature paper this week. You know why? It actually tells us what Tim Hortons, Starbucks, Second Cup and ATMs may have in common and may have to do with sudden cardiac death. Indeed, our feature paper actually tells us that coffee shops and ATMs may be the best spots to place AEDs at, well at least in Toronto. And to discuss this really interesting paper, I have the corresponding author, Dr. Timothy Chan from University of Toronto as well as Dr. Sana Al-Khatib, welcome again Sana, Associate Editor from Duke University, welcome to you both. Dr. Al-Khatib:                     Thank you, my pleasure. Dr. Chan:                             Thank you, very nice to be here. Dr. Lam:                               So Tim, was that an interesting enough lead up? I mean you have to tell us about your study, it is so fascinating. Dr. Chan:                             I'm very pleased that you find it interesting and not just us. So we undertook this study, we started this actually a couple of years ago, and we've been working on this issue of defibrillator location optimization for several years, and we've been talking and we have meetings in coffee shops and we were just wondering one day, what would be the risk or the coverage provided by all these different well-recognized location types around the city, and that was really the motivation that got us started looking at this study. Dr. Lam:                               Tell us what you did and also how it differs from the study you did that was published in 2016 where you also reported on the spatial temporal analysis of registered AEDs in Toronto. The current study clearly extends it, but could you clarify to us all how it does? Dr. Chan:                             Maybe just give a little bit of a background and context with regards to other literature that's similar. There have been studies in the past that looked at what we would call spatial coverage of cardiac arrest, so they looked at different broad location types and they tried to calculate, they basically calculated how many cardiac arrests happened, let's say within 100 meters of those location types. And what we've done here is we've extended that in a couple of directions. The first direction is looking at spatial temporal coverage and so this is not just in the nearby vicinity, IE, 100 meters, but also that cardiac arrests happen when that nearby location that had the AED was open. So if a cardiac arrest happens, but for example, let's say there's a coffee shop that actually has an AED and that coffee shop is closed, it's almost as if that AED is not even there. So one of the major things we made sure to include was this idea of temporal coverage as well, on top of the spatial.                                                 The second major difference I would say would be the fact that we're really looking at more granular location types, so you mentioned a few businesses in your opening such as Tim Hortons and Starbucks and so on, which are coffee shops, and so one of the things that we find is when we look at very broad location types, we tend to aggregate together lots of different types of businesses. For example, if you think about a restaurant, there are many different types of restaurants that get lumped in to this category, and they do have different cardiac arrest coverage associated with them. So by breaking it up into smaller location types, we wanted to get a better idea of the risk at different locations and if you also think about one of the long term goals of this work would be to try and help policy makers identify promising partners to partner with for, let's say public access defibrillation programs, by identifying specific businesses or municipal locations, it might actually give them better targets to try and pursue rather than let's say a group of different businesses. Dr. Lam:                               That makes so much sense and it really just seems like such an important public health message as well. The sensible part being of course, if you have an out of hospital cardiac arrest, you need an AED that's both nearby and available, so that was really clever. Sana, could you give us your take on the public health implications of Tim's findings? Dr. Al-Khatib:                     I think the public health implications of this work can be vast and if you look at what he's done in terms of ascending to out of hospital cardiac arrests a lot of initiatives have been launched to try to improve the outcomes of patients who have the out of hospital cardiac arrests. Unfortunately despite all the work that has been done and all the wonderful initiatives that have been launched, we still have a lot of work to do to improve the survival of those victims. So certainly a crucial step is how we deploy AEDs in a strategic way based on data and evidence such as these data that are provided to us by Tim and his colleagues.                                                 I think this is very clever, I do agree that we have to be more strategic in how we deploy AEDs and having the data such as these will only help us improve and get better of course. Everybody has limited resources, and so if we can be more selective in terms of how we deploy AEDs I think that would help everybody. I realize this was done within Toronto and some of these findings may not be generalizable to other cities, but I think this is definitely a great way to make us reshape our thinking in terms of how we do this, and so a question I have for Tim if I may, are you aware of any similar studies that have been done looking at this in other cities and then if not, how do we encourage other groups to do similar work? Dr. Chan:                             There have been similar studies done that have focused really on the spatial side of things, so doing this 100 meter radius and counting cardiac arrests that have been nearby, there's actually been fairly little work that's been done on the spatial temporal side. And a couple of exceptions that I will note that I think are important to point out is there was a very nice study that was done out of a group in Copenhagen, and they were looking at actually spatial temporal coverage, particularly the loss in coverage that you experience when you go from looking at spatial to spatial temporal. For example if you count all of the cardiac arrests that happen nearby a registered AED based only on 100 meters, and then you count the same number, but you have to now layer on top of that when the building that the AED is in is open, then you tend to get a big loss. They found quite striking numbers, I think they found a 50% loss, when you look at evenings and weekends I believe, in Copenhagen. So basically all the cardiac arrests that happened where you thought there was an AED nearby, there's actually only one in two is actually nearby and accessible when you looked into hours of operation.                                                 And this actually comes back to the earlier question from Carolyn about how our study relates to our previous study in 2016, so we actually replicated that Copenhagen study in Toronto where we measured spatial coverage and we measured spatial temporal coverage and we measured that loss, and we found a similar loss overall, about 20%, so 1 in 5 cardiac arrests happened where there was an AED nearby, but that AED was not available because that location was closed. So that was one of the impetuses for leading us to do this study where we start to examine specifically the different location types and the specific businesses that were involved. Dr. Lam:                               Wow, that's just really inspiring Tim, I mean I'm kind of thinking about the Singapore situation too and I think it's actually applicable and I would love if we had local data similar to yours, so congratulations, I really share what Sana said. Thinking though about the public health and the larger implications of what you're talking about, what do both of you think of the implications for a public commercial partnership in these things if it is coffee stores or banks that seem to be the best locations, perhaps these have implications to how the public and private should collaborate to make these things happen, what do you think? Dr. Chan:                             I completely agree. These types of public private partnerships, specifically for AED deployment are not necessarily new, they already happen in some parts of the world. One of the examples I always like to bring out is if you go to Japan and they have vending machines everywhere in Japan and then you'll often run into vending machines that have an AED right in them, so one of the benefits is that first the vending machines are everywhere and second, if you're a citizen there, you probably know where the vending machines are where you travel in your day to day life and so I would say that would be a very similar thing here in North America, whether it be coffee shops or ATMs, if someone were to put me in a random part of the city and ask me, "Hey Tim, do you know where the nearest AED is?" I'd probably have a lot of trouble, but if they said could you figure out where the nearest ATM is for your bank or where the nearest Starbucks is you know, there's pretty much one on every corner. It would be much easier to identify and find, so I think there are significant benefits to partnering with these companies or these businesses that have very broad name recognition and brand recognition, are geographically well spread and located in populated areas.                                                 I should also mention, I feel like there's a few other benefits for these types of locations, so for example for ATMs, I think there's a lot of secondary benefits, so for example, there's a built in security component, there's a video camera there, that might be able to help make sure that no one's vandalizing or stealing an AED. There's perhaps built in weather protection because there's electricity there already, so in a cold climate like Toronto where you might worry about putting an AED outside, you could have potentially a heating cabinet that would be fed by the electricity for the ATM and so on. So I think there's actually a lot of benefits if we could actually operationalize a system like this. Dr. Lam:                               Sana, do you think there are some more unanswered questions? Dr. Al-Khatib:                     I did want to agree with Tim on what he said, that these public private partnerships have been in place. Unfortunately we haven't been able to make much progress. As I said, I do see the results of this study as being potentially a catalyst to improve the work that we are doing and ensuring stronger partnerships and collaborations to help us achieve what we want to achieve which is basically improve the survival rate of out of hospital cardiac arrests, so I completely agree with that and I loved your idea, Tim, when you talked about now people may not recall where AEDs might be, but if you link them with teller machines or coffee shops, I think that would be much easier to remember.                                                 You know of course there are a lot of questions that remain unanswered unfortunately. Again as was stated by Tim and his colleagues in the paper and on the call, how we can translate these findings to other locations I think is really key and then of course doing the work, meaning let's use these data to deploy more AEDs and then really looking at the impact of that. Ultimately we want to make sure that if we hypothesize that by doing this we can improve outcomes for these victims, we would want to prove that. So I think the next steps would be to see if this can be replicated in other places, but also even within Toronto, if we can accomplish some of this and then examining the impact, I think would be extremely beneficial. Dr. Lam:                               Fabulous, thank you so much Sana, thank you so much Tim for sharing your thoughts today.                                                 Listeners, you heard it right here on Circulation on the Run. Don't forget to tell all your friends about this podcast and tune in next week.                                                                                

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  • 00:20:18

    Circulation October 3, 2017 Issue

    · Circulation on the Run

    Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.                                                 Today's issue features striking results from the ASSERT 2 trial of the prevalence of subclinical atrial fibrillation detected with implantable monitors in a group of high-risk older individuals. Much more soon, right after these summaries.                                                 The first original paper in this weeks' journal shows for the first time that myocardial edema, in the week after STEMI in humans, is a bimodal phenomenon. First off, there is Dr. Fernandez Jimenez and Barreiro-Perez, corresponding author Dr. Ibañez, and colleagues from CNIC in Madrid, Spain, evaluate that the time course of edema reaction in 16 patients with anterior STEMIs successfully treated by primary angioplasty compared to 16 matched controls using cardiac magnetic resonance and assessing its implications for myocardium at risk quantification. The STEMI patients were scanned serially within the first three hours after reperfusion and at, one, four, seven and 40 days, while controls were scanned once. Furthermore, they performed an experimental study of 20 pigs undergoing 40 minute ischemia reperfusion, followed by serial cardiac magnetic residence exams at 120 minutes, one, four and seven days after reperfusion.                                                 The authors found that am initial wave of edema appeared abruptly at reperfusion, but it was significantly attenuated by 24 hours. The initial wave of edema was followed by a second or differed healing related wave of edema several days after reperfusion, reaching a plateau around four to seven days after myocardial infarction. Of note, cardiac magnetic resonance myocardium at risk quantification at 24 hours post-reperfusion severely underestimated the infarct size.                                                 In summary, post-MI edema in patients follows a bimodal pattern, which affects cardiac magnetic resonance in estimates of myocardium at risk. The dynamic changes in post-STEMI edema, highlight the need for standardization of cardiac magnetic resonance timing to retrospectively delineate myocardium at risk and quantify myocardial salvage. According to the present clinical and experimental data, a time window between day four and seven, post-MI, seems a good compromise for standardization. However, further studies are needed to study the effect of other factors on these variables.                                                 The next paper sheds light on molecular mechanisms underline the progression of atherosclerosis, involving multiple inflammatory events, as well as the counteraction by inflammatory responses in cells such as the endothelium, circulating monocytes and resident macrophages in the arterial wall.                                                 Co-first authors, Dr. Li and Martin, corresponding author Dr. Shyy from Xi’an Jiaotong University Health Science Center and University Health Science Center and University of California, San Diego and colleagues, analyzed RNA seek data to identify cholesterol oxidation and e-flux genes regulated by Kruppel-like factor 4, which is a key anti-inflammatory transcription factor. They found that Kruppel-like factor 4 upregulates cholesterol 25 hydroxylase and liver X receptor in vascular endothelial cells and macrophages. In further in vitro and in vivo experiments, they show that access enhanced reverse cholesterol transport from the vascular wall, mitigated inflammation through suppression of sterile regulatory binding protein two and NOD-like receptor family hiring pyrin domain containing protein three inflammasome in endothelial cells and also promoted cholesterol e-flux in M1 to M2 transition in macrophages.                                                 In summary, Kruppel-like factor 4 trans-activates cholesterol 25 hydroxylase and liver X receptor, promoting the synergistic effects between individual cells and macrophages to protect against atherosclerosis susceptibility, and this may therefore be a therapeutic target for cardiovascular disease.                                                 The next study provides data on the safety and efficacy of a novel cobalt alloy-based coronary stent eluting the antiproliferative agent, ridaforolimus, for treatment of patients with coronary artery disease.                                                 Dr. Kandzari from Piedmont Heart Institute in Atlanta, Georgia and colleagues, reported the primary results of the bionics trial, which was a prospective international, one-to-one randomized trial conducted to evaluate in a noninferiority design, the relative safety and efficacy of ridaforolimus-eluting stents compared to slow release zotarolimus-eluting stents among 1,919 patients at 76 centers undergoing PCI. At 12 months, the primary endpoint of target lesion failure was 5.4% for both devices, thus meeting the prespecified criteria of noninferiority of ridaforolimus stent compared to the zotarolimus stent.                                                 Angiographic and intravascular ultrasound measures of restenosis, late lumen loss and nepintimal hyperplasia measured at 13 months, were similar in both devices. Treatment with the ridaforolimus-eluting stent resulted in low rates of myocardial infarction, repeat revascularization and stent thrombosis, and results were consistent in predefined patients and lesion groups. The authors therefore concluded that these results support the safety and efficacy of ridaforolimus-eluting stents in patients representative of every day clinical practice.                                                 Well, that wraps it up for your summaries. Now, for our future discussion.                                                 Today for our future discussion, we are going to talk about a true global public health problem. It's a condition that affects 33 million people worldwide, a number that is expected to double by 2050, and what we're talking about is atrial fibrillation. Those are the numbers of just what we know of detected atrial fibrillation, but today's paper deals with silent subclinical atrial fibrillation and the results of the ASSERT 2 trial. I'm so pleased I have the first and corresponding author with us today, Dr. Jeff Healey from Population Health Research Institute at McMaster University in Hamilton, Ontario. Welcome, Jeff. Dr. Jeff Healey:                 Good morning. Dr. Carolyn Lam:               Also on the show today is Dr. Sami Viskin, associate editor from Tel Aviv Medical Center. Hi, Sami. Dr. Sami Viskin:                 Hi. Hello, everybody. Dr. Carolyn Lam:               Jeff, from ASSERT to ASSERT 2, could you give us a bit of the picture of what made you do ASSERT 2 and what have we learned? Dr. Jeff Healey:                 The ASSERT trial was a large 2,500 patient trial in patients in with pacemakers and also implantable defibrillators and it was really an easy first place to study this entity of sub-clinical atrial fibrillation because, of course all of these patient had implanted devices with electrodes in their atrial where they could report all of the internal activity continuously for many years at a time. This was done with really no incremental costs or inconvenience to the patient, the data were already being collected, so in ASSERT we asked the question, how common is atrial fibrillation as it is not detected clinically and is it associated with stroke? What we found was that over time, somewhere between 30% and 40% of patients with an implemented device developed atrial fibrillation, which we termed subclinical atrial fibrillation, because this was not detected by the usual clinical mean. Great results, very interesting, but begged the question, is this a unique entity that we see only in pacemaker patients or if you just took older individuals in the more general population, would you see subclinical atrial fibrillation as well? That was really the impetus for doing that ASSERT 2 trial in patients who are over the age of 65, had cardiovascular condition, placed them at increased risk or stroke in atrial fibrillation, but did not have implanted devices. Dr. Carolyn Lam:               Indeed, Jeff. That's a beautiful set up. The ASSERT was really quite a landmark study suggesting that what we know as clinical may be just the tip of the iceberg, isn't it? Now you've extended it, and I think it'd be really important for the audience to understand that ASSERT 2 was really a high risk cohort. Could you maybe tell us a little bit more of what you did and what more we learned? Dr. Jeff Healey:                 Sure. These were typical patients who might be attending a cardiology clinic, an outpatient general medicine clinic who did not have pacemakers and did not have any history of atrial arrhythmias, but you're right, they were high-risk. These were patients over 65 who have had clinical risk factors, things like hypertension, or diabetes, but also some other marker of increased risk such as a BNP that was elevated or left atrial enlargement. Dr. Carolyn Lam:               Yeah and your findings were so striking. Tell us. Dr. Jeff Healey:                 What was quite was surprising was, indeed, we found that in the non-pacemaker, non-defibrillator population from ASSERT 2, we also found high prevalence of subclinical atrial fibrillation. This was really quite surprising. In fact, it was many times higher than we had predicted. We found that over time, the annual risk of developing atrial fibrillation in this cohort was 34.4% per year, which is truly astounding number of patients who developed atrial fibrillation. Dr. Carolyn Lam:               That's like one in three of such patients experiencing at least one of these episodes lasting at least five minutes? That's really impressive. Dr. Jeff Healey:                 It was high.  You could look into that study and find groups where the risk was even higher, so we chose to cut off left atrial volume of 58 millimeters and not correspondent with the median volume of the population series of Olmstead County for people over the age of 65 who came in for an echocardiogram, and that was the minimum left atrial size to get into the trial. If you then looked at within the ASSERT 2 trial and looked at the volumes within the trial, somewhere around 72 1/2 milliliters, if you looked at the patients who had the top of atrial size, that risk was as high 50% per year, so one in two. Dr. Carolyn Lam:               Another thing I noticed though about your results is that the frequency of these episodes, it's not that frequent, and so what we would do typically in a 24-hour monitoring or even a seven-day monitoring would have captured only a small proportion of these. Isn't that the case, Jeff? Could you give us some numbers there? Dr. Jeff Healey:                 Yes, of course. The episodes that qualified were at last five minutes in duration, we then do longer episodes in course, but these were much less frequent in the single digit percent risk, and what we found was there were, as you say, quite infrequent. So with the standard 24-hour halter monitor, for example, you would have had a very low pickup. It really goes to show that the longer you monitor, the more you will find. I think that's the key message out of this study and other studies like it.                                                 I think conversely, you also have to realize that the more you look, or the harder you look, you may be uncovering atrial fibrillation that behaves differently than atrial fibrillation you find, for example, in the single 12 lead ECG. We have found, and others have found, that the risk of stroke we find when we would have short episode picked up only with long term continuous monitoring is real but it's much lower than we see with atrial fibrillation that was picked up by ECB where patients are presenting in emergency rooms stroke with symptoms. Dr. Carolyn Lam:               That's such relevant points, and it really brings up the unanswered questions perhaps, exactly what is the correlation with stroke risk? What should we do about it? Sami, I'm sure you have other questions when you handle this paper and we had so many discussions among the editor, would you like to just start the ball rolling in some of these considerations? Dr. Sami Viskin:                 Well, actually, we understood from the beginning of the study was not powered to show any difference in outcome by intervention, by treating any of these patients that had discovered atrial fibrillation with anticoagulation, so we took this paper as what it is, a paper that shows the unexpectedly high privileges of atrial fibrillation in patients who have neither symptoms nor electrocardiographic documentation of atrial fibrillation when they undergo implantation of our recording device. So we took this paper for what it is, a very interesting finding that opens the door for new studies, testing perhaps the value of intervention with anticoagulation at an earlier stage. Dr. Carolyn Lam:               Yeah, I agree. I'd love to hear Jeff’s thoughts on what those next steps may be, but just to point out to the audience, I mean, at the moment, our decisions on whether to anti-coagulate, like the CHADSVASC score and so on, doesn’t really take into account the type of atrial fibrillation or the duration of atrial fibrillation? Does it? What do we do now? What do we do in the context of the fact that results, like the COMPASS trial, that maybe just based on the presence of vascular disease, we should anti-coagulate, right? Jeff, how about your thoughts? What are the next steps? Dr. Jeff Healey:                 You're right. I mean, is there a value for empirically anticoagulating individuals. That's really going to boil down to the individuals with an absolute risk of stroke and how well they do on anticoagulants. Good question.                                                 In the post-stroke world or post-cryptogenic stroke, which we now report to as [inaudible 00:16:48], these individuals are being evaluated with two large clinical trials, looking at this idea of just empiric anticoagulation with low dose, NOAC in comparison to aspirin.  These trials are ongoing, and they expect to report findings by the end of 2018.                                                 In the general population, no such large scale trial is ongoing at the present time. You mentioned COMPASS and the big COMPASS results were clearly a big result at the European Society meeting, but it must be clarified that the dose of NOAC or rivaroxaban used in COMPASS was not the typical dose that we would use in the treatment of patients with atrial fibrillation, so much lower. I think we have to be careful when we're talking about doses that may be different 5 to 10 fold and what is then coagulating a patient and what is not. I think, certainly, I would not consider the COMPASS tests right now to be an effective atrial fibrillation dose, but as we've discussed, subclinical atrial fibrillation is different and we may have further data in the future.                                                 Now, how do we get there? I think many people are aware of two ongoing trials, the ARTESIA trial, which is run by our group, the NOAH-AF Trial run by Kirchof and the group from Birmingham and the AF-NET organization, and these two ongoing trials have taken this question back again, so the pacemaker population that we are enrolling thousands of patients with pacemakers and defibrillators who have these short episodes, and they're being randomized treatment with a full dose new oral anticoagulant vs aspirin. These trials are ongoing, and I think these trials and the pacemaker population will actually give us the answer to what is the risk benefit for treating, so interesting course of event. We started in the pacemaker population to show there was risk for these short episodes, that this was hotly debated 10 - 15 years ago, and now we take ASSERT 2 and other trials into the non-pacemaker population to show that this is actually a problem for older individuals in general, and now the third step, go back into the pacemaker clinic again and to do trials to study the effectiveness in therapy. Dr. Carolyn Lam:               Great point and great takeaways. How about, Sami? What do you think would be the take-home message for clinicians at this moment based on what we know now and based on this new data? Dr. Sami Viskin:                 Well, the message is clear, the message is that atrial fibrillation is far more prevalent than what we think it is, the message is that for every event of atrial fibrillation that we feel we probably have many events that we don't feel we should be distrustful about judging the decision to anti-coagulate or not based on symptoms, and I'm referring now to patients who already have one event documented of atrial fibrillation and are waiting until they feel the next one, before they start taking anti-coagulations. This is another warning about how we should be careful about trusting symptoms when deciding to treat and when not to treat. I just said this opens a new door for a new line of studies, looking at how early to intervene with anticoagulation, what dosage should be used for these patients who probably have lower burden of atrial fibrillation. If you can see that the patients who have atrial fibrillation documented on the electric cardiogram, as patients who simply have a higher burden and therefore they are more likely to come up with documentation on a regular ACG, so perhaps those only have subclinical atrial fibrillation have a lower burden, perhaps they can benefit from lower doses of anticoagulation, but these are all fit, that need to be proven by trials. Dr. Jeff Healey:                 It is not only an issue for implanted devices but with the implantable cardiac monitors, this is now relevant for many other patients who have these devices implanted for things like syncope, but also there's been a lot of progress in the last 5 to 10 years on surface-attached based monitors or other types of monitors that can be with patients for days, weeks and even months, and we're all grappling with this in clinical medicine, what to do with a person with 25 beats of an atrial tachycardia or 37 seconds on a 30-day monitor? It's all an issue of the density, the burden of arrhythmia, and we do believe there is some gradience in the risk of stroke ... You're right, the treatment is not obvious, but we should take our treatment for patients who are in atrial fibrillation a lot or all the time, and simply apply it upstream like, that we may have very different treatment or approaches that are more tailored to individual patient risk. Dr. Carolyn Lam:               Thanks, Jeff, and thank you so much, Sami. Congratulations, Jeff. We discussed a lot of other questions that need to be answered, but you've really opened the door to look at some of these questions with your paper today and we're really very proud to be publishing your paper in this week's journal.                                                 Thank you very much, listeners for joining us this week. Don't forget to tune in again next week.  

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  • 00:35:03

    Which chest pain patients can be discharged?

    · ERCAST

    Ryan Radecki from EM Lit of Note is here to deconstruct the HEART score, utility of stress tests in low risk patients, and his approach to low risk chest pain. As a bonus, Ryan is also the wordsmith for the show notes. Important stuff mentioned on this show Amal Mattu's low risk chest pain ADP Code for 3 months of free EM:RAP   ERTHANKS The Show notes... There is no such thing as “zero-risk” chest pain: Once you learn to stop worrying and love again, where are we going with “low-risk” chest pain? Simply put, most of our observation chest pain evaluations represent low-value care: In a study comparing CCTA and rapid stress-testing for rule-out of “low-risk” patients, only a handful had positive results. In a study reviewing two years of chest pain rule-outs, again, just 1.7% of stress tests performed were positive, and 1/3rd of those were false positives. No “low-risk” patients had a positive stress. A study reviewing stress test outcomes in an intermediate risk cohort (mean age 60) resulted in ~25% positive of indeterminate results, with a third of those referred for angiography – half of which received an intervention.At the micro level, why should we care? Patients make their free choice to come for comprehensive evaluation.However, on a macro level, it’s unsustainable. And, as more and more patients are shifted to HMO and ACO care and payment models – the Kaisers, Geisengers, Intermountains, Partners of the world – there will be, essentially, mandates to reduce such low-value care.So, how do we do this safely?Step 1: Highly-sensitive troponin assays.The evidence, of which there is ample, is of reasonable quality. Much of it, unfortunately, is sponsored by the manufactures of the assays involved, which degrades some confidence in the results. But, there are a few main summary points: Sensitivity for nSTEMI is about 90% at ED presentation. Specificity of any troponin elevation, however, is 50-60%. The longer the time from onset of symptoms, the more reliable the sensitivity. Repeating a troponin 1- or 2-hours after presentation, particularly for thosepresenting early in symptoms, will increase sensitivity for late rise – and likewise improve specificity by ruling out AMI for patients’ whose troponins do not increase. Step 2: Shared decision-making.After making a diagnosis regarding acute MI in the Emergency Department – or, at least, to the extent hs-Troponin permits such an answer – outcome prognostication begins. Most folks are familiar with TIMI for risk-stratification, despite not being derived in the Emergency Department. While it is still a reasonable to assess overall risk with TIMI, most folks are moving to the HEART score, while a few other protocols/algorihtms – EDACS, MACS, Vancouver, modified Goldman – are also vying for use. There’s a lovely synergy between identifying a patient as “low risk” and the negative predictive value of negative troponin testing in the Emergency Department. Patients discharged with negative – particularly undetectable troponins – will have event rates at a fraction of a percent, and even lower if only AMI or cardiac-death are included. This is why HEART is described, primarily, as a single-troponin strategy. These are the sorts of numbers to present to patients in the context of shared decision-making as part of changing the routine conversation about admission into one about discharge. Returning autonomy to the patient to make an informed choice about further care – and documenting such – allows the patient to assume the risks of their self-determination. Adding mention of the frequency of false- positives in a low-risk population – roughly as frequent as the true positives – is also valuable. There are still quirks with HEART – mostly that patients, in theory, can have ischemic EKGs or elevated troponins and still remain “low risk”. These instances ought to be extremely rare in practice – and clinicians will have to make prudent individualized decisions given the clinical context. The fantastic Stephen Smith, of Hennepin County, also frequently reminds me true unstable angina is still an important troponin-negative. These are near-critical occlusions of the coronary circulation, and the key to diagnosis – and missed diagnosis – is correctly interpreting the EKG and performing serial EKGs in the Emergency Department. Lastly, it is important to note the AHA Guidelines, as well as prudent longitudinal medical care, recommend patients still have follow-up for additional diagnostics or management, as indicated. Patients at low-risk and with negative biomarkers are at profoundly low-risk for events in, at least, the very short term. Of 11,230 patients observed and with negative biomarkers in Ohio community hospitals, only 20 had a potentially preventable poor outcome related to hospitalization. Narrowed down to the 7,266 patients with entirely normal EKGs and vital signs, 4 had poor outcomes – 2 of which were noncardiac, and 2 of which were iatrogenic. Patients, particularly low-risk, are almost certainly safer outside the hospital than in! Stress Test Utility Citations:"Safety of a rapid diagnostic protocol with accelerated stress testing"  “The Association Between Pretest Probability of Coronary Artery Disease and Stress Test Utilization and Outcomes in a Chest Pain Observation Unit”  “The incremental value of stress testing in patients with acute chest pain beyond serial cardiac troponin testing” hs-Troponin Citations:“Multicenter Evaluation of a 0-Hour/1-Hour Algorithm in the Diagnosis of Myocardial Infarction With High-Sensitivity Cardiac Troponin T” “High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study” “Implications of Introducing High-Sensitivity Cardiac Troponin T Into Clinical Practice” “Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a high-sensitivity cardiac troponin T assay” “Does undetectable troponin I at presentation using a contemporary sensitive assay rule out myocardial infarction? A cohort study” “Troponin Elevations Only Detected With a High-sensitivity Assay: Clinical Correlations and Prognostic Significance”  “High-sensitivity versus conventional troponin for management and prognosis assessment of patients with acute chest pain”  “Undetectable High Sensitivity Cardiac Troponin T Level in the Emergency Department and Risk of Myocardial Infarction”  "Validation of High-Sensitivity Troponin I in a 2-Hour Diagnostic Strategy to Assess 30-Day Outcomes in Emergency Department Patients With Possible Acute Coronary Syndrome" "Early rule out of acute myocardial infarction in ED patients: value of combined high-sensitivity cardiac troponin T and ultrasensitive copeptin assays at admission" "Increasingly Sensitive Assays for Cardiac Troponins" “One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T.” "High-sensitivity troponin T for early rule-out of myocardial infarction in recent onset chest pain" “Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction.” HEART Score Citations:“Identifying Patients Suitable for Discharge After a Single-Presentation High- Sensitivity Troponin Result: A Comparison of Five Established Risk Scores and Two High-Sensitivity Assays” “The HEART Pathway Randomized Trial – Identifying Emergency Department Patients With Acute Chest Pain for Early Discharge” “2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines”  "A prospective validation of the HEART score for chest pain patients at the emergency department" "Improving risk stratification in patients with chest pain: the Erlanger HEARTS3 score" Unstable Angina Citations:“Unstable angina still exists. Beware.”  “A Case of Clinical Unstable Angina in the ED” “Unstable Angina: Dr. Braunwald asks if it is time for a Requiem” Safety of Chest Pain Discharge Citation: “Risk for Clinically Relevant Adverse Cardiac Events in Patients With Chest Pain at Hospital Admission”

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  • 00:23:05

    Circulation September 19, 2017 Issue

    · Circulation on the Run

    Dr. Carolyn Lam:               Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.                                 Today we will be discussing the cost effectiveness of statin use guidelines for the prime and prevention of coronary heart disease and stroke. Comparing the 2013 American College of Cardiology American Heart Association guidelines with the adult treatment panel three guidelines. A very important and current discussion that you don't want to miss. All coming up right after these summaries.                                 The first original paper in this week's journal is the largest study yet reported that assessed the long term outcome of Takayasu's Arthritis. First author, Dr. Comarmond, and corresponding author Dr. Saadoun and colleagues from Hospital Pitie-Salpetriere in Paris performed a retrospective, multi-centered study of 318 patients from the French Takayasu network including patients with Takayasu Arthritis fulfilling the American college of Rheumatology and/or Ishikawa criteria. They found that, firstly, 50% of  Takayasu arthritis patients relapse and experienced a vascular complication at ten years. Secondly, male sex, elevated CRP, and carotidynia were independently associated with relapse and with a two-fold higher risk of relapse. And thirdly, patients at high risk for vascular complications could be identified according to presence of two or more of the following risk factors: progressive clinical course diagnosis, thoracic aortic involvement, and or retinopathy. In summary, these factors identify patients with a high risk of relapse or vascular complications and may therefore serve to adjust more aggressive management and close follow up in Takayasu's Arthritis.                                 The next study provides experimental evidence for a pathogenic role of the transcription factor interferon regulatory factor five or IRF-5 in atherosclerosis. In this study from co-first authors, Dr. Seneviratne and Dr. Edsfeldt, corresponding author Dr. Monoco from Kennedy Institute of Rheumatology in Oxford, United Kingdom, and colleagues. The authors showed that atherosclerosis prone apple-E negative mice who were also deficient in IRF-5 showed reduced atherosclerosis lesions and necrotic core formation. They found that the development of the lesion necrotic core was controlled by IRF-5 through impairment of macrophage dead cell removal, or spherocytosis. They further demonstrated that the CD-11C gene was a direct target of IRF-5 in macrophages and that IRF-5 was important in maintaining CD-11C positive macrophages in atherosclerotic lesions. In summary IRF-5 was shown to be a potential therapeutic target since its inhibition could reduce plaque inflammation and necrotic core size, thus potentially promoting a stable plaque phenotype with a lower risk of acute clinical complications.                                 The next study is the first to assemble a transcriptomic framework of multiple cardiac cell populations during post natal development and following injury, thus enabling comparative analysis of the regenerative or new natal state, compared to the non regenerative or adult state. In this study from first author Dr. Quaife-Ryan and co- corresponding authors Dr. Porrello from the Royal Children's Hospital and Dr. Hudson from the University of Queensland, Australia. The authors isolated cardiomyocytes, fibroblasts, leukocytes and endothelial cells from infarct and non infarct neonatal and adult mouse hearts. The then performed RNA sequencing on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair and regeneration. They further, surveyed the epigenetic landscape of cardiomyocytes during post natal maturation by performing deep sequencing of assessable chromatin regions. This comprehensive profiling of cardiomyocytes and non myocyte transcriptional programs uncovered several injury responsive genes across regenerative and non regenerative time points. The majority of transcriptional changes in all cardiac cell types resulted from development maturation from neo natal stages to adulthood. Rather that activation of a distinct regeneration specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state.                                 But in contrast cardiomyocytes failed to reactive the neonatal proliferative network following infarction which was associated with loss of chromatin accessibility around cell cycle genes during post natal maturation. In summary these findings are significant because they defined a regulatory program underpinning the neonatal regenerative state and identified chromatin modifications in adult myocytes that could restrict cardiac regenerative potential after birth and may need to be overcome to facilitate cell cycle re entry in adults.                                 The final study reports results of two studies investigating the pharmicokinetic and clinical outcomes of a new drug coated balloon to treat femoral popliteal disease. The first study is the Illuminate pivotal study in which 300 symptomatic patients were randomized to stellarex drug coated balloon or standard angioplasty. The primary safety outcome was freedom from device and procedure related death through 30 days and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months. The primary effectiveness endpoint was primary patency through 12 months. The second study was the illuminate pharmicokinetic study in which paclitaxel plasma concentrations were measured after last balloon deployment and at pre specified times until no longer detectable. In this report my first in corresponding Dr. Krishnan from Mount Sinai Medical Center in New York. In the pivotal study the primary safety endpoint and the primary patency rate was significantly higher with the drug coated balloon. The rate of clinically driven target lesion revascularization was significantly lower in the drug coated balloon cohort. pharmicokinetic outcomes showed that all patients had detectable Placitexal levels after drug coated balloon deployment that declined within the first hour.                                 In summary these findings demonstrate the safety profile and superior patency of the stellarex drug coated balloon for femoral popliteal disease compared to standard angioplasty. This therefore suggests that this drug coated balloon may be a valuable treatment option for patients with superficial femoral and popliteal artery disease.                                 Well those were your summaries now for our feature discussion.                                 Today we are discussing the highly relevant and also highly controversial issue of Statins for primary prevention of cardiovascular disease and when do we start a statin. How cost effective is it, and of course all this discussion really began with the 2013 ACC/AHA guidelines that expanded the recommended statin use. I am so pleased because this week’s journal actually provides, for the first time, some cost effectiveness data that may help us in making this decision and in facing our patients. I can't tell you the number of times I've had an individual patient come to me and just want to discuss all the pros and cons of starting a statin for primary prevention and I'm sure, listeners out there you identify with this. Well hang because today we have the corresponding author of today's feature paper Dr. Kirsten Bibbins-Domingo from University of California, San Francisco  as well as the editorial list on this wonderful paper, Dr. Rodney Hayward from University of Michigan and VA Ann Arbor. Welcome Kirsten and Rod. Dr. Kirsten Bibbins:          Thank you. Dr. Rodney Hayward:     Great to be here. Dr. Carolyn Lam:               Kirsten, could you please tell us the top line results of what you found in this paper, it's such an important paper. Dr. Kirsten Bibbins:          We use simulation modeling to compare three approaches to giving Statins for primary prevention. The older guideline in the US called ATP-3, the one that you mentioned in your introduction the ACC/AHA guideline that broadened the use of Statins to many many more people and then an even broader strategy where we don't look at cardiovascular risk, and in each of these approaches we found that the use of Statins for primary prevention was very effective and in fact cost saving, when we did a cost effectiveness analysis. And regardless of the assumptions that we made about more side effects then we had known from the literature or could anticipate or regardless of the parameters that we put into the model we found that, pretty much that the broad use of these medications is effective and, in fact, cost saving. Dr. Carolyn Lam:               Could you give us an idea of what you used in that simulation model, what population was it, how applicable is it to people outside the US, for example. Dr. Kirsten Bibbins:          Simulation modeling is a way to take the evidence that we have from multiple types of studies and to try to synthesize that evidence and apply it to, in this case, the population of the US. So our simulation model uses the demographics of the US and takes the primary studies and the effect rises that we know from those studies and using that model we found that each of these three approaches had both health benefits and cost saving benefits. It's applicability might be somewhat variable if this were applied to a different population, but the effects are pretty substantial and so it suggests that Statins are likely to be beneficial using these approaches in a broad array of populations. Dr. Carolyn Lam:               Could you give us an idea of the estimated effect size, you know, when you say cost effective, for example, how, how much and for what. Give us everyday clinician some kind of take home of numbers that would make sense for them. Dr. Kirsten Bibbins:          One way to think about these types of cost effectiveness analysis is that often times they give us numbers that suggest that we have to pay a certain amount to get the type of health benefit that we want. In this case because we found that they were cost savings, it actually suggests that the amount that we pay for Statins, to give Statins to a broad population of individuals actually saves us money. It saves us money in terms of the heart attacks that are avoided, and the other types of health care costs that are avoided and probably a number that might be relevant to your audience might be that the number that one would need to treat in order get one additional year of life, through using these Statins for primary prevention, is on the order of about 35 individuals and so that's a small number that we would be treating in a primary care practice in order for an additional quality adjusted year of life. Dr. Carolyn Lam:               I thought that was really one of the most remarkable figures, you know, that the ATP-3 guidelines would result in 8.8 million more statin users than the status quo and that was an entity of 35 per quality of life. Was that correct? Dr. Kirsten Bibbns:           That's exactly right. Dr. Carolyn Lam:               Whereas the ACC/AHA guidelines could potentially result up to 12.3 million more statin users than the ATP-3 guidelines with a marginal number needed of 68 per quality of life. So very, very useful figures, but you know, I began by saying my individual patient. These feel like population bases statistics, you know, and my individual patient kind of wants to know but for me, what's a long term risk and so on. And these are issues that you have discussed so elegantly, Rod, in your editorial. Could you enlighten us a bit on these considerations. Dr. Rodney Hayward:     Sometimes decisions that we have to make in policy are inherently population based decisions, like putting fluoride in the water, in which the average benefit of cost for population is what you have. Cause you can't treat individual separately with that type of intervention, but with a statin, the average that a population gets is not the important thing to our patients across the room. And it's sort of the number needed to treat for them, how likely are they to benefit. And what I think this paper establishes very well, and I think it's important to start with why the areas of agreement here, this establishes that the new guidelines are a great idea. There's no assumptions in this model that would change that starting people on a statin between 7.5 and 10 % ten year risk isn't a good idea. And that aspect of the paper even some of the issues I have about some of the assumptions are not going to be relevant, where it starts to become concerning, and will always be controversial is how low of risk to start it at. Do we go from 7.5 to a 5% risk? Do we start putting everyone at age forty on a statin?                                 And at that case, certain elements of this simulation model are very important, the likelihood of an individual benefiting becomes very, very small. And even a small dislike of the medicine, would outweigh that. But also you have to assume in this model that we know all the bad things of a statin at 20-25 years, because you're starting to put people on a daily medicine that's biologically active for 30 years. And it's impossible statistically, epidemiologically, to know with any degree of certainty whether or not being on these medicines for 20-30 years would have unheard effects. We don't have that ability, currently, even if we had the databases so how should individuals think about that, well my feeling is that is part of the shared decision making of how much a patient worries about unknowns, about being on a medicine long-term versus they worry more about the potential for a heart attack prevention which are likely there. I want to emphasize again these are not relevant concerns when we're talking about the current guidelines, these are only concerns when we start pushing it down to a 5% risk or everyone over 40 where you're extending to tens of millions more people, in which the population benefits would be substantial.                                 As long as people don't mind taking a pill every day at those ages and we know all of the harms being on a statin for 20 years. And that's something that no one knows. Dr. Carolyn Lam:               Rod that was just so eloquently stated, and listeners out there, you just have to read this editorial. It states these things very clearly, and I think it's really helpful in our thinking of what to tell patients when we do see them. Kirsten, I'd love to invite your thoughts on what Rod just said, you acknowledge this, fully in your paper. Curious, any steps you took to maybe address this and what you would say as a take home message for clinicians? Dr. Kirsten Bibbins:          I think that Rod's bringing out exactly the point. And, I think, we have seen the shift from the earlier guideline to the most recent guideline in putting more people on Statins and these medications certainly have the benefit, but as you bring more and more people on who have lower overall cardiovascular risk, their likelihood of benefiting while there, is always smaller. And so then other things do come in to play, and I think the thing that probably was most surprising to us as we put this work together, was how sensitive our results were to, essentially, a patients preference as we moved down into including more of these lower risk individuals. That means that an individual who's lower risk may not directly benefit or their likelihood of benefiting in terms of avoiding a heart attack is lower, and so therefore the facts that their tolerance for taking a daily medication is in fact, then becomes relevant in to their particular trade off for taking this medication. And I think that is clinically important as we think about including more and more lower risk people into these types preventative guidelines, the threshold for any given individuals tolerance for taking a daily medication and of course, as Rod said, if you're doing this over many years and decades the fact that we don't actually know what will happen over the long term, also becomes relevant. Dr. Carolyn Lam:               Just maybe one last question for both of you. What do you think our next step is here, what more do we need? Dr. Kirsten Bibbins:          I just think we still want to continue to expand our understanding of what the long term effects and side effects of daily use of statin therapies are, again I'd want to emphasize as you said it's always important to understand patients preference, but, as Rod said, our current guidelines which really have focused on higher risk individuals, I wouldn't want it to be lost that these medications are in fact very effective and so I think having an understanding of the long term use of these medications and what the potential side effects when used over a long period time are, I think that's a critically important area. As well as really developing continuing to develop the tools that can help doctors and patients together engage in the conversation about the trade off for given individual. Dr. Rodney Hayward:     I would definitely agree with that, but I would focus on three bits of science. That are critically important for refining this issue. The one is something we currently don't have and that's post marketing surveillance of medicines long term. That when you look at the data we have, that, most of them follow patients either a short period of time and don't have enough continuity or their smaller studies in which outcomes that are long term might be found. And this is a place where big data, but also combining and sharing data across health systems could really help us monitor. This is not just an issue for Statins but as more medicines are recommended for younger individuals with life expectancy we need to work on that. Two the results are insensitive meaning that it always looks good, for people in the current guidelines but two elements of the model for people at a 5% risk or starting people at age 40 are assumptions that are being made with the best available data now, but have some considerable concerns and could be improved.                                 One is, we don't know the impact of a non fatal heart attack on future outcomes, my personal opinion is the assumption in this model, is probably an overestimate. Unimportant for the current guidelines but would be critically important for these younger risk people and ways to really understand the impact of non fatal events on future risk are epidemiologically tricky and it's very easy to pick up things that are markers that aren't causal and then when you run your models you think you're extending life years where you really aren't. And the other is we still don't know how much a Statins relative benefit varies by a persons LDL level, that might seem astounding but there's evidence on both sides. That it is related to baseline LDL and it's not. This is a completely solvable question, the CTT group has the data and we really need them to publish and tell us how much the relative risk of a statin varies by that. The current assumption in the ACC/AHA guidelines is that it is not correlated, the assumption in Kirsten's model is that it is.                                 Either could be correct, my personal opinion is it's probably in between, those two, but that would help us in terms of thinking of extending to the lower people. If LDL is a partial factor that probably should be considered, if it's not then only risks should be considered. That is completely answerable for those that have access to the RCT data and I'm hoping that this paper may encourage that publication. Dr. Carolyn Lam:               Wow, those were such insightful comments, I can't thank you enough, Rod and Kirsten for joining us today.                                 Listeners I'm sure you enjoyed that and learned so much just like I did. Don't forget to join us again next week.

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  • 00:39:37

    Neonatal Jaundice

    · Pediatric Emergency Playbook

    Most newborns will have some jaundice.  Most jaundice is benign. So, how can we sort through the various presentations and keep our newborns safe? Pathologic Jaundice When a baby is born with jaundice, it’s always bad.  This is pathologic jaundice, and it’s almost always caught before the baby goes home.  Think about ABO-incompatbility, G6PD deficiency, Crigler-Najjar, metabolic disturbances, and infections to name a few.  Newborns are typically screened and managed. Physiologic Jaundice Physiologic jaundice, on the other hand, is usually fine, until it’s not. All babies have some inclination to develop jaundice.  Their livers are immature.  They may get a little dehydrated, especially if mother’s milk is late to come in.  In today’s practice, we are challenged to catch those at risk for developing complications from rising bilirubin levels. Hyperbilirubinemia is the result of at least one of three processes: you make too much, you don’t process it enough, or you don’t get rid of it fast enough. Increased production Bilirubin mostly comes from the recycling of red blood cells. Heme is broken down in in the liver and spleen to biliverdin then bilirubin. Normal, full term babies without jaundice run a little high -- bilirubin production is two to three times higher than in adults, because they are born with a higher hematocrit.  Also, fetal hemoglobin is great at holding on to oxygen, but has a shorter life span, and high turn-over rate, producing more bilirubin. Impaired conjugation Think of bilirubin as your email.  Unconjugated bilirubin is your unread email.  To process it or get rid of it – you have to open it.  Of course, the more unread messages that accumulate, the more unwell you feel. Conjugated bilirubin is your opened and processed email.  So much easier to sort out, deal with, and get rid of. Decreased excretion Both unread email and unconjugated bilirubin continue to float around in your inbox.  Unconjugated bilirubin keeps getting reabsorbed in the intestinal mucosa through enterohepatic circulation. Processed email and conjugated bilirubin are easier to sort out.  Conjugated bilirubin is water soluble, so it goes right into the read folder in your gallbladder, and is excreted off your inbox.  Later on down the line in the intestine, conjugated bilirubin can’t be reabsorbed through the intestinal mucosa.  Like when you open an email and forget about it – it passes on through, out of your system. Newborns are terrible at answering emails.  There is a lot of unread unconjugated bilirubin is floating around.  The liver and spleen are just not able to keep up. Also, newborns have a double-whammy administrative load.  Normally, bacteria in the gut can further break down conjugated bilirubin to urobilin and get excreted in the urine.  The infant’s gut is relatively sterile, so no admin assistance there.  Just to add to the workload a poor little newborn has to do – he is being sabotaged by extra beta-glucuronidase which will take his hard-earned conjugated bilirubin and unconjugate it again, then recycle it, just like email you “mark as unread”. How Does this All Go Down? The recommended followup is 48 hours after discharge from the nursery for a routine bilirubin check, often in clinic, and often via the transcutaneous route. More Specifically: Infant Discharged Should Be Seen by Age Before age 24 h 72 h Between 24 and 48 h 96 h Between 48 and 72 h 120 h The neonate will end up in your ED off hours, if there is concern, if his status deteriorates, or simply by chance.  We need to know how to manage this presentation, because time is of the essence to avoid complications if hyperbilirubinemia is present. Critical Action #1: Assess risk for developing severe hyperbilirubinemia. This will tell you: check now in ED or defer to clinic (default is to check). Risk Factors for Developing Hyperbilirubinemia Total serum bilirubin/Transcutaneous bilirubin in high-risk zone Jaundice in first 24 hours ABO incompatibility with positive direct Coombs, known hemolytic disease, or elevated ETCO Gestational age 35-36 weeks Prior sibling had phototherapy Cephalohematoma or bruising Exclusive breastfeeding, especially with poor feeding or weight loss East Asian Race Critical Action #2 Check bilirubin and match this with how old the child is -- in hours of life -- at the time of bilirubin measurement. This will tell you: home or admission. Use the Bilitool or Bhutani Nomogram (below).   Can I go Home Now? Risk Stratification for Developing Severe Hyperbilirubinemia. Bhutani et al. Pediatrics. 1999. In general, babies at low-risk and low-intermediate risk can go home (see below).  Babies at high-intermediate or high risk are admitted (see below). Critical Action #3: Assess risk for developing subsequent neurotoxicity. This will tell you: a) phototherapy or b) exchange transfusion     Phototherapy Now?     Exchange Transfusion Now? Threshold for Initiating Exchange Transfusion by Risk Stratum. Bhutani et al. Pediatrics. 1999. Home care The neonate who is safe to go home is well appearing, and not dehydrated.  His total bilirubin is in the low to low-intermediate risk for developing severe hyperbilirubinemia, and he is not at high risk for neurotoxicity based on risk factors. Babies need to stay hydrated.  Breast feeding mothers need encouragement and need to offer feeds 8-12 times/day – an exhausting regimen.  The main message is: stick with it.  Make sure to enlist the family's help and support to keep Mom hydrated, eating well, and resting whenever she can.  Supplementing with formula or expressed breast milk is not routinely needed.  Be explicit that the neonate should not receive water or sugar water – it can cause dangerous hyponatremia.  A moment of solid precautionary advice could avert a disaster in the making. The child’s pediatrician will help more with this, and you can remind nursing mothers of the excellent La Leche League – an international group for breastfeeding support.  They have local groups everywhere, including a hotline to call. Nursery Care If the baby is at high intermediate or high risk for hyperbilirubinemia, then he should be admitted for hydration, often IV.  Most babies with hyperbilirubinemia are dehydrated, which just exacerbates the problem. Bililights or biliblankets, provide the baby with the right blue spectrum of light to isomerize bilirubin to the more soluble form.  Traditionally, we have thought them to be more effective or safer than filtered sunlight.  A recent randomized control trial by Slusher et al. in the New England Journal of Medicine compared filtered sunlight versus conventional phototherapy for safety and efficacy in a resource-poor environment.  These were all term babies with clinically significant jaundice in Nigeria.  To standardize the intervention, they used commercial phototherapy canopies that remove most UV rays. None of them became dehydrated or became sunburned.  The filtered sunlight resulted in a 93% successful treatment versus 90% for conventional phototherapy.  My take away: we now have some evidence basis for using filtered sunlight as an adjunct for babies well enough to go home. Critical Care Although rare, the critically ill neonate with hyperbilirubinemia requires immediate intervention. He will be dehydrated – possibly in shock.  He will be irritable. Or, he may just have a dangerously high bilirubin level – at any minute he could develop bilirubin induced neurologic dysfunction, or BIND, especially when bilirubin concentrations reach or surpass 25 mg/dL (428 micromol/L).  The bilirubin is so concentrated that it leeches past the blood brain barrier and causes neuronal apoptosis.  BIND is a spectrum from acute bilirubin encephalopathy to kernicterus, all involving some disorder in vision, hearing, and later gait, speech, and cognition. Acute bilirubin encephalopathy starts subtly.  The neonate may be sleepy but hypotonic or have a high-pitched cry; he maybe irritable or inconsolable, jittery or lethergic. The dehydration and neurologic dysfnction from the hyperbilirubinemia may even cause fever.  Check the bilirubin in any neonate you are working up for sepsis. Acute bilirubin encephalopathy may progress to an abnormal neurologic exam, seizures, apnea, or coma. Kernicterus is the final, permanent result of bilirubin encephalpathy.  The child may have choreoathetoid cerebral palsy with chorea, tremor, ballismus, and dystonia.  He may have sensorineural hearting loss, or cognitive dysfunction. It is for this reason that any child sick enough to be admitted should be considered for exchange transfusion.  Most babies need just a little gentle rehydration and bililights, but to be sure, the admitting team will look at a separate nomogram to gage the child’s risk and decide whether to pull the trigger on exchange transfusion.  For our purposes, a ballpark estimate is that if the total serum bilirubin is 5 mg/dL above the phototherapy threshold, or if they have any red flag signs or symptoms, then exchange transfusion should be started. Exchange transfusion involves taking small aliquots of blood from the baby and replacing them with donor blood.  It’s often a manual procedure, done with careful monitoring.  It can be done with any combination of umbilical arteries or veins with peripheral arteries or veins.  In general, arteries are the output, veins are for transfusion. The baby may need a double-volume exchange, which ends up replacing about 85% of circulating blood, a single-voume exchange, replacing about 60% of blood, or any fraction of that with apartial volume exchange.  It is a very delicate procedure that requires multiple hours and often multiple staff. For our pruposes, just be aware that the jaundiced baby in front of you may need escalation of his care. Summary Find out the hour of life of the baby at the time of bilirubin measurement.  Identify risk factors for developing severe hyperbilirubinemia and/or neurotoxicity The child with low to low-intermediate risk may be a good outpatient candidate provided he is well, not dehydrated, and follow-up is assured. The child with high-intermediate to high-risk for developing severe hyperbilirubinemia should be admitted for hydration, bililights, and/or assessment for exchange transfusion. The unwell child with or without current neurologic findings should have immediate exchange transfusion. References Benitz WE. Hospital Stay for Healthy Term Newborn Infants. Pediatrics. 2015; 135(5):948-53. Bhutani V et al. Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. Pediatrics. 2004; 114(1). Bhutani VK, Wong RJ. Bilirubin Neurotoxicity in Preterm Infants: Risk and Prevention. J Clin Neonatol. 2013 Apr-Jun; 2(2): 61–69. Bosschaart N et al. Limitations and Opportunities of Transcutaneous Bilirubin Measurements. Pediatrics. 2012; 129(4). Colletti JE, Kothari S, Jackson DM, Kilgore KP, Barringer K. An emergency medicine approach to neonatal hyperbilirubinemia. Emerg Med Clin North Am. 2007 Nov;25(4):1117-35, vii. Gamaleldin R et al. Risk Factors for Neurotoxicity in Newborns With Severe Neonatal Hyperbilirubinemia. Pediatrics. 2011; 128(4):825-31. Lauer BJ, Spector ND. Hyperbilirubinemia in the Newborn. Pediatrics in Review. 2011; 32(8):341-9. Maisels J et al. Hyperbilirubinemia in the Newborn Infant ≥35 Weeks’ Gestation: An Update With Clarifications. Pediatrics. 2009; 124(4):1193-6. Smitherman H, Stark AR, Bhutani VK. Early recognition of neonatal hyperbilirubinemia and its emergent management.  Semin Fetal Neonatal Med. 2006 Jun;11(3):214-24. Vandborg PK, Hansen BM, Greisen G, Ebbesen F. Dose-response relationship of phototherapy for hyperbilirubinemia. Pediatrics. 2012 Aug;130(2):e352-7. This post and podcast are dedicated to Gita Pensa, MD, for her commitment to #FOAMed and passion for asynchronous learning and education innovation.

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