"I Have Macular Degeneration...Now What?"
Transcript of Teleconference with Priyatham (Prithu) S. Mettu, M.D.
August 26, 2015
1:00 – 2:00 p.m. EDT
Please note: This chat was edited for clarity and brevity.
GUY EAKIN: Hello, everyone, and welcome to our monthly BrightFocus Chat, presented by the BrightFocus Foundation (BFF). My name is Guy Eakin; I’m the Vice President for Scientific Affairs at BrightFocus.
So, today I’d like to welcome our speaker, Dr. Prithu S. Mettu, who is an ophthalmologist who treats diseases such as macular degeneration, and he does this at the prestigious Duke University Eye Center. Dr. Mettu is also a BrightFocus-funded researcher working to understand how the immune system makes wet macular degeneration possibly worse. So Dr. Mettu, thank you so much for joining us from North Carolina today
PRITHU METTU: Well, Guy, thank you very much for having me, and thanks to you and BrightFocus, and it’s quite a delight to be with you and to be able to speak to everyone who is with us on the call today.
GUY EAKIN: Well absolutely. Before we get to the call I’d like to mention if you have a question that you would like to ask Dr. Mettu at any time during today’s call, please press *3 and you can submit your question to an operator, and if for any reason you are disconnected from the call, the number to call back in is 877-229-8493 and you will need to punch in an ID code, that’s 112435. So, that’s 877-229-8493 and an ID code of 112435.
Dr. Mettu, as you already know, in this chat we cover clinical topics about AMD; every couple of months, we alternate those with lifestyle and sort of in-the-home types of information. But in case there are some new participants on the line, I was hoping you could give us a broad strokes overview of what macular degeneration is and what, as an ophthalmologist, do you see that makes you suspect that this eye may have macular degeneration.
PRITHU METTU: Ok, sure. Age related macular degeneration is a disease that affects the macula, which is the central part of the retina. What I often say is that the macula is the prime real estate of the retina; it’s responsible for allowing us to have good, fine central vision. It’s the kind of thing that allows you to thread a needle, or to focus and see detail when reading or trying to do any kind of fine detail work.
That’s contrasted to peripheral vision, which is kind of the side vision. In macular degeneration, what happens is that over time, patients can initially develop some visual disturbances, sometimes they say, “I see a blurry spot in my vision,” or “Things look a little distorted or fuzzy or unclear,” and then over time those symptoms can worsen to actually result in frank loss in central vision. The kind of symptoms patients may initially present with are really—they may come in and say, “When I’m reading there is a spot that drops out,” “I’m not able to see all those letters,” or “When I cover one eye, the eye that I’m looking through it looks like things are just distorted or there is a dark spot right in the center.”
Those are the symptoms that make us think that there could be something going on in the macula, which, in patients who are ages 60 and older, often times can be due to age-related macular degeneration.
GUY EAKIN: Well in some of our prior discussions, you mentioned there might be some symptoms you might not notice and that there might be things that when you talk to your patient and prompt them and say, “Have you seen something in this area,” and they might say, “Oh yeah, you know, come to think of it, I have.” What did you mean by that?
PRITHU METTU: Thank you for mentioning that. When talking with patients, one of the things we notice as we begin to understand more about their disease is that they oftentimes do have symptoms that they may not always notice first, and that can be, “Well, when I’m in a restaurant and I’m trying to read a menu, I’m not able to see as well unless I have the right kind of lighting,” or, “I’m outside and it’s bright and I walk inside, I have trouble adjusting to the lower light conditions.” Or perhaps when they are reading something, they have difficulty just trying to read when there is not sufficient contrast between the background and the letters. And so, these are some of the more kind of subtle visual symptoms that can appear early, which can also be caused by macular degeneration.
These are things that can be very frustrating, because oftentimes when we are checking the vision at the clinic, or just checking regular measures of vision function, the vision may be quite good, but systematically, these problems with vision may still present quite a challenge to our patients.
GUY EAKIN: Thank you for sharing that. So, as we talk a little bit about the introduction of what macular degeneration is, the theme for today is, “I Have Macular Degeneration…Now What?” So, could you talk about, for someone who is newly diagnosed, what are the expectations around the timeline for progression and what does progression look like to a patient?
PRITHU METTU: In terms of the question, “Now what?” when you first get that diagnosis it can be quite a challenging time, because you hear the term “macular degeneration” and you think “Gosh, I’m going to lose my vision.” Well, I think the reality is that the disease is one in which vision changes typically are gradual over time. There are really two forms of the disease, there is—everybody starts out with dry macular degeneration, and that’s characterized by deposits that form underneath the macular called drusen. And in the earliest forms, there may be the kinds of subtle vision complaints that I mentioned, or for some patients they may not notice many changes at all with their vision.
As dry macular degeneration can progress, that’s when some of these more specific symptoms can occur—so, blind spots, distortions etc. Any time during dry, a patient can actually convert or progress to wet macular degeneration. And when that happens, there is usually a more remarkable shift in the vision.
So, I mentioned for patients who have dry, their vision changes are typically gradual. When wet macular degeneration occurs, typically patients experience a sudden change in the vision—so, they wake up one morning and they notice that there is a dark spot they hadn’t appreciated before, and that’s typically because there is a new abnormal blood vessel that has grown underneath the macula. That blood vessel can actually leak fluid, bleed, or scar, and it’s the activity of the abnormal blood vessel that can actually compromise vision and create a form of relative central vision loss.
GUY EAKIN: When something comes up as soon as, say, overnight, for your patients that have either dry form or wet form, is there a typical frequency that you ask them to come in for a visit, check-up beyond their home monitoring?
PRITHU METTU: For patients who have dry, what we typically recommend is that at first diagnosis, they come in at least every 6 months. We are talking about the early form of dry macular degeneration. In the intervals between those visits, we typically recommend that patients do a form of home monitoring with what’s called an Amsler grid—I’m sure many on the call have heard about it or actively using it. And it’s a grid that allows the individual to test each eye individually and look for any signs that there may be a focus of distortion or a focus that dropped out of their vision and detect any changes. And there have been more recent developments for home monitoring, which we could potentially talk about.
These more recent technologies, such as the ForeseeHome device, allow us to potentially pick up changes in the disease at the earliest possible point. What we typically say, for patients who do notice changes, is that they should call the office to try and schedule an urgent appointment and check to see if there has been any change in their disease. And I usually counsel my patients that you would rather have a false alarm than to potentially miss a change that we could potentially address sooner.
For wet macular degeneration, it’s a little bit different because once that’s diagnosed—fortunately we do have treatments, and so visits to the office then become more frequent to treat the condition and to monitor the response to treatment.
GUY EAKIN: So you mentioned the Amsler grid for home monitoring, which certainly if anyone hasn’t heard of the Amsler grid, they are welcome to come on our website at BrightFocus.org or call us at 1-800-437-2423, and we’d be happy to give one to you. You also mentioned the ForeseeHome monitoring device, and we have some information we would be happy to supply you at that same telephone number, 800-437-2423. Would you mind telling us about the advances in home monitoring?
PRITHU METTU: Sure. So, this is fairly recent, but the manufacturers of the device partner with the team that was studying the AREDS2 vitamin supplements to look at patients with dry macular degeneration and see whether their monitoring device could actually detect disease earlier. And some of the findings that were recently published suggest that patients who were being monitored at home were able to have their disease detected earlier than those who were just doing the typical, standard care with the Amsler grid.
That’s important because what we know is that the best predictor of vision for patients with wet macular degeneration is the vision at the time of their diagnosis. So, generally speaking, patients who have good vision at the time that their disease is diagnosed, if they are promptly treated, can retain that good vision. Once the vision decreases, particularly when it decreases to lower levels, it’s harder to reverse that. So, there is utility in being able to detect it accurately, but more importantly, detect it early.
GUY EAKIN: Thank you. So, this is just hot off the press, the availability of these devices. So, how would you engage your doctor in finding out if it’s something that is appropriate for your own visual conditions?
PRITHU METTU: It’s a good question to ask the doctor, and it’s typically—it can vary from practice to practice, or doctor to doctor—it’s typically a device that, in theory, could be prescribed by any ophthalmologist. But it typically is prescribed by someone who has a focus in retinal diseases. With this prescription, there is then an interaction with Notal Vision, which is the company that makes the device. They can essentially set the patient up with the device itself, which is something that is kept at home; it’s typically connected to a computer or to a line that would allow a communication from the home to a central monitoring service.
The central monitoring service is able to—without getting into too much detail—is able to take information from the patient’s home screen, which involves interacting with the device to look for patterns that would suggest a change. If there is such a pattern, the monitoring service then alerts the patient’s doctor, and the patient as well, to try to come in to get checked. This is something that is generally pretty well known by retina specialists. As far as one of the issues that is still being worked out, is whether that would be covered insurance versus what would need to be paid out of pocket. That may vary a little bit based on what area of the country you live in or what type of insurance coverage you have.
GUY EAKIN: Thank you. So, I might shift gears a little bit, and we are talking a little bit about people who may be more recently diagnosed with the disease. And certainly on this call, as well as in your practice, you have had a lot of people with the disease for many years, so what does “Now what?” mean for them and how do you approach these patients in your own practice?
PRITHU METTU: When patients first get the diagnosis, as you might imagine, there is a variety of responses. Many people have heard about the disease, may have had a family member or relative who have had the disease. And often times these experiences affect them, and often times we hear the questions, “Am I going to go blind, and if so, is that going to happen tomorrow?”
The first thing is to understand that every patient’s experience is different. Some patients have a very mild course in terms of never having any significant visual changes, and then some can have a more rapid course. The key is for the patient, and also myself as the physician, to understand that patient’s individual disease. We typically try to go over some of the key components of the disease, but also to really get a sense of where they are in understanding how it might impact them, and helping them cope with that.
I can’t stress enough the importance of having a good support system with family and friends and others in the community that can provide that support. And then at that point, it’s really about providing education and addressing the concerns to get them up to speed about what could happen from here and what to expect.
GUY EAKIN: Thank you. We do have questions coming in. I want to give everyone a reminder that if you press *3 you can submit a question to Dr. Mettu. It will take you off line for a few minutes, where you will talk to one of our operators, and then you will rejoin the call. But before we move into that question and answer portion of the chat, Dr. Mettu, can I ask you to talk a little about the future of treatments and what’s on the horizon for macular degeneration as a pharmaceutical and as an eye care provider? What, in particular, are you looking forward to?
PRITHU METTU: So, that’s a great question. I will start by just talking about dry macular degeneration, because that’s currently the form of the disease that we don’t really have effective treatments for—we are, at the moment, really restricted to the AREDS vitamins. I think that there are a number of promising types of treatments on the horizon, some of which are currently in clinical trials and some of which may be coming in to trial soon. I’ll highlight a few of those.
What we know right now that is currently in trial is a type of drug that blocks a portion of the immune response. That drug is currently in the late phase 3 of clinical trial at various sites throughout the country. It’s a potential drug made by the company Genentech and that type of treatment involves injecting medications into the eye much as the medications we inject—same approach, different drug, but same approach—as what we do for wet macular degeneration.
GUY EAKIN: Does that drug have a human understandable name yet, is that something that we can listen for in the news?
PRITHU METTU: Not yet, but you might hear it as a type of complement inhibitor. There has been a lot of interest in understanding the complement system, which is one aspect of the immune system. But there is some thought that the complement—a highly activated complement system may contribute to macular degeneration. So, this is a drug that is designed to block that aspect of the immune system within the retina and see if it can slow the progression of dry macular degeneration
GUY EAKIN: Before Dr. Mettu goes on to some of the other things that are on the horizon, I do want to remind people that we will have a transcript, and so if there are words that you’re hearing in the course of this conversation that you are having a hard time understanding or would like to see in print, give us a week or two and you can call in at 1-800-437-2423 or look at www.brightfocus.org. We will get a transcript up for you. So Dr. Mettu, anything else on the horizon for therapies for macular degeneration?
PRITHU METTU: Yes, so there’s also some interest in—this is a question I hear a lot from my patients—there is also some interest in stem cells. That has received a lot of attention. There are several companies right now that are trying to develop stem cell–based treatments to replace retina that is lost over course of the disease. We are still a few years away from seeing how well that approach will pan out. Though there is kind of a twist on that approach, which is to try to inject cells that aren’t going to replace the tissue we lost, but actually will boost the existing tissue and try to preserve what’s there—preserve the tissue—and keep it from dying as a part of the disease. I think that may actually bear some promise. There are some clinical trials: there is an early phase that was completed for that and there are some continuing clinical trials that are under development as a part of that as well.
GUY EAKIN: Well I’d like to segue into the question and answer portion of the call, ask a few questions on the topic of research that’s been submitted by our audience members. But first, a reminder you can ask a question by pressing *3, and if you’re disconnected from the call, the number to call back in is 877-299-8493, and you’ll need that ID code of 112435.
So, we have a bunch of questions coming in, and one of the ones that is most frequent is probably summarized by Ken from New York, who is asking how unusual it is for the condition of AMD to develop in one eye and not the other. So, is it possible to have AMD in one eye and not the other, or at different stages?
PRITHU METTU: It is certainly possible to have AMD in one eye and not the other, though not common for that to remain the case over the course of one’s life. What we see, not infrequently, is that one eye may develop the disease earlier than the other, so they may be at different stages. Along those lines, it’s not unusual to have one eye have the dry form of the disease, and the other eye to develop wet. For that to remain the case for several years before—and in some cases, some of those patients don’t actually see the conversion to wet in the other eye—there is about a 10 percent risk for patients who have wet macular degeneration in one eye…There is about a 10 percent per year risk of developing wet macular degeneration in the unaffected, dry eye.
GUY EAKIN: Thank you, so I hope that helps those callers. We have a question, couple of questions from callers in Idaho and Chicago, asking what causes the disease. No one in their family has ever been diagnosed with AMD—is it genetic?
PRITHU METTU: Very good question. There’s debate, actually, among doctors and scientists about the causes. What we believe—and I’m involved in a research group here at Duke that is studying the disease—what we believe is that the disease is a disease of the environment, and particularly of western society; so, what we believe is it’s the accumulative exposures to different things in our environment. That can run the gamut from certain pollutants in the air to cigarette smoke to certain things in our diets—so, high fat, high cholesterol diet.
Over time, exposures to the things we eat and breathe or are around could cause injury to the macula, and as a result, the disease reflects that. There are a lot of questions about the genetics of the disease, and the genetics are a little different than how people classically think of genetics. Often times I hear, “Well, my mom had the disease and my brother had the disease, does that mean I’m going to get the disease too?” The disease isn’t really passed along in the typical genetic fashion, but what we think is there can be genetic factors that change our susceptibility. So, how that translates is that it may be that when people have certain types of genes, they see the onset of that disease sooner, and what we know to be true as we look across the population—as you look at the older groups in the population, people in their 70s, people in their 80s, people in their 90s—the relative prevalence or the relative percentage of people who have the disease goes up. So, there is some component we were exposed to in the environment, and then there can be some susceptibility factors in our genes that can modulate when and if we get that disease.
GUY EAKIN: Of course, we hear all the time that smoking is one of those factors in our environment that greatly contribute to macular degeneration, so our talking points always note that the advice in the medical community is to avoid smoking.
PRITHU METTU: I completely agree with that.
GUY EAKIN: Alright, Ida from New York is asking—she has wet macular degeneration and is receiving injections—is wondering, now that her leakage has been stabilized, how important is it to continue the injections? How might her treatment profile change?
PRITHU METTU: That’s a good question, so I’ll start with the caveat that every patient’s experience is different. But that being said, what we know in general is that this is a disease that requires treatment for life. And so that’s something I tell my patients. If we look at the studies, most of the studies that have studied the drugs are only 1 to 2 year studies, and the reality is that this is a disease that goes well beyond that.
All of the studies that have looked at how people do over time show that as the frequency of treatment drops off, or if people stop treatment, whatever vision was gained during the initial period can gradually dwindle over time. For the vast majority of patients, they need continued treatment. It may not be every month, it may be less frequent than that, but the vast majority of patients need continued treatment for life. There are a few exceptions. There are some patients that the disease can go quiet or dormant, and they do okay without treatment, but that is very rare. That is certainly less than 10 percent, maybe even fewer than that.
GUY EAKIN: We have a couple of questions about dry macular degeneration and essentially the AREDS supplements. So, we have a caller from Connecticut and a caller from my home state of Kentucky who submitted questions asking what can be done to help with dry AMD. Is there anything out there beyond the supplements? And our caller from Connecticut is asking, are there supplements to layer on top of the supplements? Is there anything she should be taking with the AREDS in terms of other vitamins, or even—she mentioned kale, if we are trying to eat more nutritiously, is there a special way to be cooking things like kale?
PRITHU METTU: Very good question. The short and general answer, as it relates to what’s been studied, is that the only proven supplement to have a beneficial effect in slowing the disease progression is the AREDS vitamins, and so you typically see that at the supermarket or the drug store as Ocuvite or a variation of that. Now with the AREDS2 there have been some additions to that with lutein and omega-3 fatty acids. I typically tell patients that those are the good ones to be on, provided that there’s nothing in the AREDS vitamins that their medical doctor wouldn’t [shouldn’t this be “would object to”??] object to because of some other medical condition. As far as other supplements or other things to do, there is no proven supplement, although I do have a number of patients who are very motivated to take supplements they think may have antioxidant effects. I typically tell them that, for the most part, it would certainly not hurt; it might help. The studies haven’t really been done on that.
More generally with diet, I think green leafy vegetables are excellent. Kale is a great choice, spinach, fresh vegetables are particularly good. A lot of fresh salads. If you had to think about different styles of cooking, there is some thought that you get nutrient retention there. Again, these are things that are more subtle nuances, and I think if you have that attention to your diet and what you’re taking, that’s already half the battle.
GUY EAKIN: I think these questions kind of hit on the scarcity of options within dry AMD. Trula from Idaho is writing in to ask us—it seems the wet macular degeneration has more medical studies and advancement than dry, and she asks if that is true or is that just perception, and if it is, is there a reason for that?
PRITHU METTU: Very good questions, that is true. That is a true statement. We do have a series of classes of treatments called anti-VEGF; that’s the molecule we think is the key driver for wet macular degeneration. We have drugs that block that molecule that are quite effective for the wet form of the disease.
We don’t have good medical treatments for dry macular degeneration. The reasons for that are complex, but I’ll try to simplify by saying that we were very fortunate, based upon the work of the pioneers in the field, to get a better understanding of the factors that drive wet macular degeneration. There was a recognition that this molecule, VEGF, was a key driver of the wet form of the disease. We’ve had those drugs for about 10 years, and it has really been a transformative treatment for patients with the disease, because prior to that, patients with the disease were almost doomed to losing their central vision. Now we have an opportunity to preserve it in many cases, and perhaps boost it.
For dry macular degeneration, our limitations of treatment have been related to the fact that we haven’t had as strong of an understanding of what drives the disease, but I think that’s improving. And I think that, as our knowledge continues to improve, I think we will see more and more drugs that are being tested in clinical trials. And from there, I think within the next—5 may be optimistic—the next 5 or 10 years, I would not be surprised to see one of the things that is in clinical trials show some benefit for patients and give some hope and promise to people who are affected with the disease.
GUY EAKIN: Sounds like you’re saying that the toehold that was necessary to get some understanding about dry macular degeneration, has recently been found. And you mentioned the immune complement system, whereas the wet macular degeneration, they’ve had the knowledge of this VEGF molecule for many, many years. Is that fair to say?
PRITHU METTU: That’s absolutely fair. I think there’s a lead time from the moment you make a discovery about a potential drug target to seeing that drug in the clinic, and I think that lead time varies—it’s probably at least 10 years. I think that was the case for the drugs for wet macular degeneration. We are in that lead time period right now. It’s an exciting time, because there are a number of promising targets and promising options that are being studied. We are looking forward to seeing what comes from these efforts.
GUY EAKIN: Well, we may have time for two more questions. We have a caller who is asking about an eye that—she has dry AMD in that eye, and that eye keeps watering, and she says she is currently taking drops but they don’t seem to be helping. So I know this is a frequent concern, but are these related conditions, or is this probably just coincidence?
PRITHU METTU: I think it’s likely to be unrelated. I think that these things are not infrequently coincidences, because dry eye essentially affects the surface of the eye whereas dry macular degeneration—completely different disease—affects the retinal tissue in the back of the eye. But these diseases both occur in older patients, and so it’s not uncommon for someone to have macular degeneration and also to be afflicted with dry eye. That is a little bit beyond the scope of what we are talking about here, but I would encourage those individuals who are affected by both to talk to their doctors about what effective treatment options would be available for dry eye. It seems a little counterintuitive, because people think my eye is dry, why should it be watering, but watering is typically a reflex response of the eye to dryness.
GUY EAKIN: I think Connie from Michigan may have the last question of the day, and she’s asking if there are behaviors that might speed up the progression. I know we talked about behaviors that might slow down the progression of the disease, but she asks if excessive use of the eye with macular degeneration, and maybe things like reading, might be speed up the progression, and will other things like particular glasses—prism glasses, for instance—be helpful?
PRITHU METTU: Very good question. To the best of my knowledge, there aren’t specific eye usage behaviors that would speed up the disease. It’s typically other modifiable behaviors, like we were talking about smoking—most especially smoking and diet—and those sorts of risk factors that can change the rate of disease progression. Using the eye or reading or just general day-to-day activities don’t typically affect the disease. I think there was a second part to that question.
GUY EAKIN: Yes, she had also asked about specific glasses and whether or not they might affect the progression, prism glasses in her case. Are there glasses or devices that may help people with macular degeneration?
PRITHU METTU: In some cases, yes, so as medical doctors we’re very focused on treating and monitoring the disease and trying to intervene on the disease process when we can. But there is a whole other kind of aspect of eye care, which is about maximizing visual function, and within that realm are a whole host of visual aid devices, and sometimes that can include glasses with certain types of prisms. It just depends on the need of the individual patient.
There are specialists who specialize in vision rehab and low vision, many of whom have formal optometric or ophthalmic training, and their whole focus is on trying to maximize the vision that the patient has to optimize their function. So with many patients with macular degeneration, seeing one of those types of specialists—again, in terms of low vision specialist or vision rehab specialist—seeing one of those individuals can be quite beneficial and complimentary to seeing the specialist who is taking care of their disease.
GUY EAKIN: Well thank you so much, Dr. Mettu, for all the time you’ve taken to speak with us today. And I’d like to thank everyone who joined the call and asked us questions. I mentioned earlier, we will have a transcript here in about a week, so you can either find that on our website or you can call in at 1-800-437-2423 to order print transcript.
But before we conclude, I’d like to ask everybody a question, and you can use your phone to send us a response. So, we want to ask quite simply, how you would rate this telephone chat. And if you found the chat helpful, please take a moment to press 1 on your phone; if you only found this chat only somewhat helpful, please press the number 2; and if you didn’t find the chat helpful at all, if you’re still around, please press 3.
Again, thank you, Dr. Mettu, for talking with us today. Our next chat will be on healthy living with low vision, a nice segue from the last question, and we encourage you to register and submit questions in advance and we will be sending anyone who is registered a reminder email. So, if you’d like to register for that September chat right now, or request any of the free materials from BrightFocus Foundation—we mentioned the magnetic Amsler grid, we also have materials about the at-home monitoring devices that we talked about in today’s call—but you can stay on the line right after the call concludes and leave a message or again call us at 800-437-2423. You can always find these resources on our website at www.brightfocus.org.
Again, thank you so much, Dr. Mettu, you covered a ton of information and I know there are many people out there who have the answers they were looking for. Thank you to everyone listening on the call today. And again, if you’d like to leave a comment after the call, just stay on the line. Thank you from all of us at BrightFocus, have a great day!
The information provided in this transcription is a public service of BrightFocus Foundation and is not intended to constitute medical advice. Please consult your physician for personalized medical, dietary, and/or exercise advice. Any medications or supplements should be taken only under medical supervision. BrightFocus Foundation does not endorse any medical products or therapies.
Useful Resources and Key Terms
- BrightFocus Foundation, 1-800-437-2423, or visit us at www.brightfocus.org
- Common Treatments for Macular Degeneration
- Macular Degeneration: Essential Facts
- Macular Degeneration Treatments Fact Sheet
- Macular Degeneration: Frequently Asked Questions
- VEGF inhibitors currently available: Avastin, Lucentis, Eylea
- Home monitoring devices: Amsler grid; ForeseeHome device by Notal Vision
- Future treatment options being researched: A complement inhibitor by Genentech (currently in Phase 3 clinical trials); Injecting cells into the retina to try to preserve existing tissue (currently in early phase clinical trials)
- Supplements and good nutritional practice: AREDS vitamins (typically sold as Ocuvite or a variation of that), AREDS2 vitamins (added lutein and omega-3 fatty acids), Green leafy vegetables
- Rehab and low vision specialists can recommend devices, such as prism glasses, to help maximize visual function
This content was last updated on: February 29, 2016