Bioresorbable Stents and Polymers: Do We Need Better DES?

Editor’s Note: In the fall of 2015, the first drug-eluting stent with a bioresorbable polymer was approved by the US Food and Drug Administration (FDA) for use in the United States, and in July 2016, the US got its first totally bioresorbable stent. European interventional cardiologists have experience with many more stent types than their American counterparts, so | Medscape interviewed Dr Robert Byrne from Deutsches Herzzentrum, Munich, about the rationale behind the various technologies and whether there is a need for a better drug-eluting stent (DES).

cardiologists have experience with many more stent types than their American counterparts, so | Medscape interviewed Dr Robert Byrne from Deutsches Herzzentrum, Munich, about the rationale behind the various technologies and whether there is a need for a better drug-eluting stent (DES).

Robert A. Byrne, MB BCh, PhD | Medscape: Let’s first discuss the bioresorbable polymer stent. This is a permanent metal DES with a polymer that breaks down over time. What is the reason for developing such a stent?

Robert A. Byrne, MB BCh, PhD: The background, of course, is the issue of delayed arterial healing with DES, which is behind many problems, including late stent thrombosis, late restenosis, and neoatherosclerosis. Although the causes are multifactorial, it seems that a central component is a latent inflammatory reaction to the permanent polymer coatings on the original FDA-approved DES, which were mostly methacrylate based. That makes the concept of a stent coated with a bioabsorbable or a biodegradable polymer attractive. It’s there when you need it to control the drug release in the first 30 days, and then it’s broken down usually from poly-L lactide (PLLA) or poly-lactic-co-glycolic acid (PLGA) into carbon dioxide and water after sometime between 3 and 24 months, depending on the technology [approximately 3 months for the Synergy™ stent]. What’s left behind is essentially a bare metal stent. | Medscape: The US has one DES with a bioresorbable polymer (Synergy), but there are others available in Europe.

Dr Byrne: In Europe, we have a large number of bioabsorbable or biodegradable polymer-based stents. At my center, we’ve had good experience with the BioMatrix biolimus stent (Biosensors International) one of the first biodegradable polymer stents to receive CE mark approval. It was the stent used in the LEADERS trial[1] published in 2008 and it has a somewhat thicker structure than other DES.

The other notable ones are the Orsiro stent (Biotronik) and the Ultimaster® (Terumo), which was the follow-on stent to the Nabori® stent. Both of these are biolimus eluting with very similar drug-release kinetics to the BioMatrix stent. Deutsches Herzzentrum was involved in the development of the Yukon® Choice PC (Translumina therapeutics), which is a thin-strut polylactic acid–based sirolimus-eluting stent. | Medscape: Given the potential disadvantages of polymers, what experience do you have with polymer-free stents?

Dr Byrne: It would be nice to work completely polymer-free because it seems that the polymer is the nidus for persistent inflammation which drives these late adverse events. We and other investigators have had quite a lot of experience with completely polymer-free DES, where you use other mechanisms to control the drug release—for example, surface modification with micropores or wells on the surface of the stent and a higher drug dosage. The goal is to compensate for inferior drug-release kinetics and achieve good antirestenotic efficacy. But by and large, it hasn’t worked out so far.

The goal [for polymer-free stents] is to compensate for inferior drug-release kinetics and achieve good antirestenotic efficacy. But by and large, it hasn’t worked out so far.
We published a number of studies from the ISAR-TEST stent program[2] showing a late luminal loss of between 0.45 mm and 0.50 mm, which is clearly inferior to the best-in-class DES in broadly inclusive patient populations, where you normally get 0.20-0.30 mm. It’s still better than the old bare metal stents (BMS) that had late lumen loss of 0.8 mm to 1.0 cm. Interestingly, the original Endeavor® zotarolimus-eluting stent (Medtronic) had a polymer that made the drug release even quicker than if you had no polymer at all, and that stent was associated with quite high late luminal loss (approximately 0.6 mm).[3] This underlines the importance of drug release kinetics in determining late loss. | Medscape: I should note that polymer-free stents are not approved for use in the United States, but there are a few with CE mark available in Europe.

Dr Byrne: We have a number of CE mark–approved stents that are completely polymer-free, but as I said, these are associated with a somewhat suboptimal anti-restenotic efficacy. Interestingly, the BioFreedom stent studied in the LEADERS FREE trial[4] uses a surface-modified backbone. They then apply the drug without polymer directly to the stent. They chose biolimus A9™ as the drug (also called umirolimus); it seems to be able to overcome the shortcomings of not having a polymer, to some extent. They have showed a late luminal loss that is more encouraging than our experience.

The other approach is to use a second drug on the stent backbone. Basically, you accept the suboptimal antirestenotic efficacy compared with a regular sirolimus application and you add a second drug to attack a different element of the restenotic response cascade. Preclinical work suggested that estrogen may promote endothelial healing and reduce restenosis,[6] but when we tested this on a stent in clinical studies, it didn’t pan out.[7] We had some success with probucol, which is a powerful antioxidant that was shown to reduce restenosis in the patients undergoing angioplasty if they took it in pill form before the angioplasty and then for a period of weeks after the angioplasty.[8]

 We tested a probucol stent in a large-scale randomized controlled trial against a best-in-class Resolute stent (Medtronic) in the ISAR TEST 5 study,[9] which, at the time it was published, was the largest DES trial in the literature, with 3002 patients. The probucol stent proved to be noninferior to the durable-polymer DES at 12 months. We recently published a 5-year follow-up of this technology[10] hoping to detect an improvement in late outcomes, but we didn’t see that. Instead, the results with both stents were excellent, with very low rates of adverse events with both the durable polymer zotarolimus-eluting Resolute stent and this dual-drug, polymer-free stent. One of the problems for any new stent technology is that the new-generation durable-polymer DES have set the bar very high. | Medscape: Given that the bar is so high and the results are very good for contemporary DES, is it still worth trying to develop something better?

Dr Byrne: That question comes up a lot. The outcomes with the new-generation DES are excellent out to 1 year, but their Achilles heel is this small rate of late catchup restenosis and late stent thrombosis, which probably works out as around about 0.2%-0.3% per year. In terms of absolute risk, that’s very small, but we know that stent thrombosis is often a catastrophic event, invariably associated with myocardial infarction (often quite large) and a not inconsiderable rate of mortality.

 We also know from autopsy studies[11] and from optical coherence tomography[12] follow-up of patients that a dominant cause of late stent failure is neoatherosclerosis, which is new atherosclerosis forming inside the stent. This is definitely accelerated in comparison with a BMS. It could be that the inflammatory reaction to polymer is driving this process. This is the rationale for pursuing advances in these technologies even though the bar is high. | Medscape: Back in 2006, it was suggested that DES have a higher risk for late-stent thrombosis than BMS and that that is why BMS continued to be used. Later analyses seem to suggest that on balance, DES are safer than BMS[13] and that any risk for late stent thrombosis may be tied to first-generation DES.[14] Is that a fair assessment?

Dr Byrne: I think so. DES were a game changer in interventional cardiology and enabled us to attack a really complex disease pattern that was formerly treated very conservatively or was the preserve of the cardiac surgeon. The two issues which impeded their universal uptake were delayed arterial healing and its consequences (as I mentioned earlier), and cost. The iteration of this technology has leveraged three important advances: thinner stent struts; a lower drug dose and a switch to exclusively sirolimus-based analogs which lead to better healing profiles; and a move toward more biocompatible polymers.

 A biodegradable polymer is a good example of a development to address the first problem. In terms of cost, both in Europe and in the United States, the cost came down dramatically. For this reason, the use of DES at our institution has been 100% for the past 6-8 years or more. | Medscape: You don’t use any BMS?

Dr Byrne: We don’t use BMS. Maybe for a niche indication—for example, very, very large vessels where you have to use a stent that is developed for the peripheral arterial system. That would be our only indication nowadays for a BMS implantation. The reason for our adoption of DES is the dramatic reduction in restenosis. Restenosis rates are 50%-70% lower[15] compared with BMS. That’s a paradigm shift. | Medscape: The first-generation paclitaxel-eluting TAXUS™ (Boston Scientific) stent is generally accepted as a lower-performing DES; however, there are data that the first-generation sirolimus-eluting Cypher (Cordis) stent (now discontinued) has performed better in contemporary studies[16,17] versus earlier studies indicating that issues beyond the stent, such as improved technique and longer duration of dual antiplatelet therapy, affect outcomes. Do you think that next-generation DES are a real advance over first-generation DES if you exclude the TAXUS stent?

 Dr Byrne: It’s an interesting question, but the short answer is that I believe definite progress has been made in outcomes for next-generation DES over first-generation stent technology, and not just progress over and above the TAXUS stent. It’s correct to point out that there was a differential efficacy (seen in many studies and registries) in that the Cypher stent was better than TAXUS probably in the acute phase and definitely in the late–follow-up setting. But we now have good evidence from meta-analyses,[18] large-scale randomized controlled trials,[19] and registry data[20] (although there are outliers) which show that current-generation gold-standard DES have surpassed the performance of the Cypher stent.

Now, in parallel to that, there have been developments in the stent backbones—mainly a switch toward thinner stent struts. We know that thinner stent struts cause less injury at the time of implantation,[21]are associated with lower rates of neointimal hyperplasia,[22] and cause less flow disturbance[23] after implantation. They’re probably associated with lower rates of thrombosis in the acute phase. Thinner struts also enable a much lower crossing profile when the stent is crimped on the balloon, which has made a dramatic improvement in the deliverability of stents over the past 10 years. So it’s not just progress in terms of better drug elution but also in relation to stent backbone development. | Medscape: That brings us to fully bioresorbable stents. The backbone of the bioresorbable stents/scaffold has thicker struts than contemporary DES and most are made with plastic, correct?

 Dr Byrne: Yes. The challenge with this technology to-date has been to deliver a device with a radial strength that approaches that of conventional metallic backbone DES. Plastic just doesn’t have as high a radial strength as metal alloys. The technologies that leverage lactic acid tend to have considerably thicker stent struts, of the order of 150 µm, which doesn’t compare favorably with the 50-90 µm of traditional metallic stents.

These thicker struts cause more injury at the time of implantation. They are more difficult to deploy into the vessel wall. The analogy used is that of a snowshoe: If you’ve got a broad surface area, of course it’s more difficult to sink into the snow, and a broad surface area in a stent makes it more difficult to implant into the vessel wall. That may be the cause of flow disturbances after implantation, and that might be a trigger for the slightly increased thrombotic risk with these stents.

The second factor is that despite these modifications [thicker struts], the radial strength is not as good as with metallic DES. When you look at the six randomized controlled trials[24,26-30]that are available now and you look at the mean minimal luminal diameter after implantation, it favors the metallic DES. And we know that mean minimal luminal diameter is an important determinant of stent thrombosis.[31] I think these two factors contribute to the slightly higher rate of stent thrombosis we see with these devices compared with metallic DES. | Medscape: In the United States, the Absorb™ bioresorbable vascular scaffold (Abbott Vascular) is the only one available, but there are a few others with CE mark. Can you tell us about those?

Dr Byrne: In addition to Absorb, the DESolve™ Myolimus-Eluting Bioresorbable Coronary Scaffold System (Elixir Medical Corporation) is CE mark approved. It hasn’t had widespread commercial rollout but is available in some jurisdictions. Just recently, the Magmaris magnesium absorbable stent (previously called Dreams [Biotronik]) was released. Cardiologists in Europe are just getting their hands on this stent. We haven’t implanted any at Deutsches Herzzentrum. It will be interesting to see how this stent performs outside the setting of highly selected patients in a single-arm trial.[32,33] | Medscape: The argument in favor of bioresorbable stents is that any benefits will be accrued over the long haul.

Dr Byrne: In many respects, it’s a no-brainer: All things being equal, it would be preferable to have a stent with sufficient mechanical strength to deliver maximal performance in the first 30 days to 1 year after implantation and then have it dissolve or break down, leaving no backbone in the vessel wall. There are many potential benefits, including restoration of vasomotion, removing the nidus for late stent-related adverse events, and allowing future bypass grafting of the vessel segment (if needed). I don’t think many of us need much convincing that that would be preferable. The problem is that all things are not equal, so how much of an inferiority are we going to accept compared with current-generation DES? As I said earlier, the bar is high.

It would be nice to have data showing definitive late benefit with these [bioresorbable] stents, but we are probably not going to have long-term data from large-scale trials until 2020 or 2021. | Medscape: When I interviewed you last year about bioresorbable stents, you said that about 10%-20% of the patients might be appropriate candidates. Has that changed?

 Dr Byrne: We’re probably treating about 5%-10% of patients with bioresorbable stents. The patients who are potentially going to derive maximum benefit over time are younger patients who would otherwise have to deal with the adverse effects of a permanent metallic stent in the vessel wall over the decades remaining in their lifespan. And the types of patients would be those with straightforward lesions. We certainly avoid deploying bioresorbable stents in lesions with heavy calcification because of the issues of radial strength. Even if you perform a very aggressive lesion preparation, you can have a suboptimal result. We also tend to avoid bifurcations, where a two-stent technique is possible or maybe needed. We don’t have a good solution yet with the bioabsorbable stents in the bifurcation area. | Medscape: And are you still recommending that patients with bioresorbable vascular stents/scaffolds be enrolled in clinical trials or postimplantation surveillance studies?

Dr Byrne: I think that’s important. We need more data with these stents, and if we are implanting these, ideally we should try to enroll the patients in a randomized trial, or at least have a systematic follow-up protocol so that we can gather more information, especially on late outcomes. | Medscape: How do you discuss the different stent options with patients?

Dr Byrne: You have to take some time to discuss the issue. The bioresorbable stents are certainly intuitively attractive for patients. As more experience has been gathered in Europe over the past few years, some patients are already aware from the lay media of potential issues in regard to stent thrombosis with these devices. Many of the patients are quite well informed, and you have to give a fair appraisal of the data and say that these stents require further study. It would be nice to have data showing definitive late benefit with these stents, but we are probably not going to have long-term data from large-scale trials until 2020 or 2021, when the ABSORB 4 dataset should be available. | Medscape: Are there any other upcoming stent data that we should look out for?

Dr Byrne: I am very much looking forward to the ABSORB 3-year results. These will serve as a proof of concept if you want to see whether vasomotion is improved within 3 years with the bioresorbable stent as compared with the regular metallic DES. We should have some results in 2016. The AIDA study is the first large-scale study comparing bioresorbable stents with conventional DES in more broadly based patient populations.[34] That could be very interesting; we might have some data this year.

Getting back to your earlier question about DES vs BMS, the largest study examining this, theNORSTENT trial, will present results in more than 9000 patients at the upcoming European Society of Cardiology meeting in Rome. | Medscape: A conversation about stents would not be complete without mentioning duration of dual antiplatelet therapy (DAPT). How much does the stent type factor into the decision about duration of DAPT, or is it more patient/lesion-related? Would you ever say, “This is a polymer-free stent, so 3 months of DAPT is enough, but if this were a regular DES it should be 12 months”?

Dr Byrne: The patient—and the lesion, in particular—have to be taken into account. You have to consider cases that are more likely to have stent thrombosis; this could be bifurcation stenting, long-segment stenting, or small-vessel stenting. And there are lesions where the consequences of late stent thrombosis are likely to be dire, such as the left main stem or proximal left anterior descending artery. We consider prolonged DAPT out to 24 months in patients who we perceive to be at either high risk or high jeopardy from their stent implantation. The time scale in the DAPT study[35] was 30 months, so it’s somewhere in the time window of 24-30 months for these patients.

Of course, you also have to factor in the risk of bleeding. In high–bleeding-risk patients, we would probably aim for 6- to 12-month duration, even if they have high-risk ischemic risk.

Does the stent type itself play a role in that judgment? I think it does, but I would also say that between the currently available generation durable or biodegradable polymer metallic DES, I don’t think that there is much difference in terms of late performance. Now, if you are talking about fully bioresorbable stents, then I think there might be a difference. Certainly our practice is to continue DAPT for 12 months in these patients.

There have been reports of late events with the bioresorbable stents after discontinuation of the ADP receptor antagonist.[36] This might be related to the mechanical disintegration or breakdown of the stent. Some people are advocating a longer duration of DAPT with fully bioresorbable stents maybe out to 24 months. The European guidelines recommend 6 months[37] for conventional DES. There is now harmonization with the update of the American guidelines,[38] and they are also moving towards 6 months for standard DES, but with bioabsorbable stents I think it’s 12 months minimum at the current time point.

I don’t think that we Europeans have been poorly served by the CE mark approval process. | Medscape: Finally, a recent study[39] found that devices (cardiovascular, neurologic, orthopedic) that received approval in Europe before FDA approval were more likely to be subsequently removed from the market than devices that got FDA approval first. Do you think the bar is too low for CE mark approval?

Dr Byrne: Each regulatory agency has to decide whether it wants a more permissive regulation for devices with perhaps earlier access for unmet clinical need, and then rigorous postmarketing surveillance which might lead to the withdrawal of the device, or whether it wants to set a higher bar for approval in the first place. With the latter, a smaller number of devices make it through and take a longer time to do so, but, of course, are less likely to run into issues that might lead to their withdrawal.

There are pros and cons to both approaches. I don’t think that we Europeans have been poorly served by the CE mark approval process. It has had benefits in areas like structural heart disease, where patients have had relatively early access to important improvements in technology like transcatheter aortic valve implanting (TAVI), or TAVR, as you say.


Google Duo jumps ahead of Pokemon Go and Facebook Messenger in app rankings

Although it has only been around since the start of the week, it looks like Google’s new video calling app is already a smash hit in the US. Google Duo, the video chat app that the Android makerlaunched earlier this week, is now the most downloaded free app in the Google Play Store.

Open up Google Play on your Android device, go the ‘Top Free’ section, and you’ll find that Google Duo is the #1 app in this category. Facebook Messenger and Pokemon Go complete the podium. Facebook, Snapchat, and YouTube Music complete the first page of the section.
Given the strength of its competitors, it looks like Google Duo has managed to raise a significant amount of interest among Android users.
It’s also worth pointing out that Google Duo has an average rating of 4.5, which is much better than the rating of Facebook (4.0), Facebook Messenger (3.9), and Snapchat (3.9).
In the past week, many were quick to point out that Google Duo has little chance of actually competing against the likes of WhatsApp, Facebook Messenger, and FaceTime in terms of users. As it turns out, however, Google Duo is already a smash hit with Android users.
google duo knock knock
After a limited initial launch in a number of countries around the world. Google Duo is now available globally.
Getting off to a very good start is one thing, but maintaining this initial inertia is another story altogether. It remains to be seen if Google Duo will be able to convert this wave of initial users into daily active users. This Google Play chart tells us for sure is that many Android users gave the app a chance, but Google’s real challenge is to convince users that Google Duo is their best option for video chats looking forward.

Ketamine for Depression Treatment

The experimental drug esketamine (also known as ketamine) has been placed on the fast track for U.S. Food and Drug Administration approval for treating major depression, according to Janssen Pharmaceutical.

Ketamine — perhaps best known as a street drug — is listed by the World Health Organization as an important anesthetic and has been used off-label for pain, anxiety, depression and post-traumatic stress disorder, CNN reported.

In 1970, the drug received FDA approval for use in people and was used on American soldiers in Vietnam as an analgesic and sedative. However, doctors became reluctant to use it because it caused minor hallucinogenic side effects.

If the new use gets the go-ahead from the FDA, it would be the first new treatment for major depression approved in about half a century, according to CNN.

World’s Smartest Physicist Thinks Science Can’t Crack Consciousnes.

String theorist Edward Witten says consciousness “will remain a mystery”.

Physicist Edward Witten: “I think consciousness will remain a mystery… I have a much easier time imagining how we understand the Big Bang than I have imagining how we can understand consciousness.” 

I’ve been writing a lot lately about consciousness, the ultimate enigma. I used to think why there is something rather than nothing is the ultimate enigma. But without mind, there might as well be nothing.

Some mind-ponderers, notably philosopher Colin McGinn, argue that consciousness is unsolvable. Philosopher Owen Flanagan calls these pessimists “mysterians,” after the 60’s-era rock group “Question Mark and the Mysterians.”

Recently, physicist Edward Witten came out as a mysterian. Witten is regarded with awe by his fellow physicists, some of whom have compared him to Einstein and Newton. He is largely responsible for the popularity of string theory over the past several decades. String theory holds that all of nature’s forces stem from infinitesimal particles wriggling in a hyperspace consisting of many extra dimensions.

Witten is optimistic about science’s power to solve mysteries, such as why there is something rather than nothing. In a 2014 Q&A with me he said: “The modern scientific endeavor has been going on for hundreds of years by now, and we’ve gotten way farther than our predecessors probably imagined.” He also reaffirmed his belief that string theory will turn out to be “right.”

But in a fascinating video interview with journalist Wim Kayzer, Witten is pessimistic about the prospects for a scientific explanation of consciousness. The chemist Ash Jogalekar, who blogs as “The Curious Wavefunction,” wrote about Witten’s speech and transcribed the relevant section. (Thanks, Ash.) Here is an excerpt:

I think consciousness will remain a mystery. Yes, that’s what I tend to believe. I tend to think that the workings of the conscious brain will be elucidated to a large extent. Biologists and perhaps physicists will understand much better how the brain works. But why something that we call consciousness goes with those workings, I think that will remain mysterious. I have a much easier time imagining how we understand the Big Bang than I have imagining how we can understand consciousness… 

Just because Witten is a genius does not mean he is infallible. He is wrong, I believe, that string theory will eventually be validated, and he could be wrong that consciousness will never be explained. I nonetheless find it newsworthy—and refreshing–that a scientist of his caliber is talking so candidly about the limits of science. For reasons that are perhaps too obvious, I like Ash Jogalekar’s take on Witten’s comments. An excerpt:

It’s interesting to contrast Witten’s thoughts with John Horgan’s End of Science thesis… The end of science really is the end of the search for final causation. In that sense not just consciousness but many aspects of the world may always remain a mystery. Whether that is emotionally pleasing or disconcerting is an individual choice that each one of us has to make.

The Next World and the Next

Award-winning sci-fi writer Alice Sola Kim imagines a beautiful and dark future world.

Lena Dunham on Alice Sola Kim’s Story and Women Innovators

Sugar-Sweet Lennys,

My father is a sci-fi nerd of the highest order. Before the Internet, that meant a closet full of dusty 25-cent paperbacks, their covers crawling with cyborgs and barren lunar landscapes and microwaves that could commence time travel. Every Saturday we would walk across then-barren Soho to the now-defunct Science Fiction Bookstore, where, desperate to be every inch his daughter, I would search for my own reading material. But even at age seven I already knew what I liked: stories about girls. And it soon became apparent I wasn’t going to find any of those here. The young-adult series, like My Teacher Is an Alien and Johnny Swift, had scrappy male protagonists traveling through space on glorified skateboards. As for the adult books, the only women I found were nude blue aliens with jaunty antennae, ready to sexually satisfy lonely space captains. I didn’t yet know about Ursula K. Le Guin or the other grand dames of sci-fi, but then again, it didn’t occur to anyone to tell me.

Science fiction is notable as a genre not just because of its escapism, but because of the way it grapples with our current reality: what are science, technology, and innovation doing to the human mind and spirit, and when they reach their inevitable full-on collision, where will that leave us humans? These are the big questions that were being contemplated in my father’s 25-cent paperbacks. But never by women. Not as writers nor as heroes.

Science, technology, engineering, and mathematics (fun and easy acronym: STEM!) are not worlds we associate with women, yet they are full of female pioneers whose stories demand to be told. GE and Lenny have partnered on a program that doesn’t just tell you that women should be at the forefront of science and technology, but shows that they already are.

So it seems only natural that GE would also share our goal of supporting an emerging female sci-fi author as she herself wrestles with questions of science and human consciousness and whether the twain shall meet. Alice Sola Kim is a writer of uncommon philosophical depth and also great imagination. Her story envisions a world in which sick people don’t die — they enter a state of cryogenic stasis instead — but the question remains: what’s in their heads when they’ve been placed on pause? In a series of vignettes, our (gal!) protagonist slowly realizes she may not be among the living anymore, but, because of the advancements in medicine and technology, she is also not dead.

We’ve been excited about our partnership with GE from the jump — we have the chance to profile industry leaders like Beth Comstock and an all-female robotics team, and to show our Lennys just how hard women in science and tech are showing up to play. But I’m especially thrilled that my child self now has some sci-fi she can get behind. No horny three-boobed alien princesses here, just an often hilarious and sometimes painful look at a future where technology enriches our lives and yet we still can’t quite escape being human.

The Next World and the Next

By Alice Sola Kim

Franny went to college, graduated with honors. After that, she got her masters and a Ph.D, and then another Ph.D, for which she completed a thesis on the hermeneutics of online bodybuilding forums. She got tired of the humanities and went back to undergrad so she could do med school. It took a lot of time, but she had the time. She made the time.

After med school, Franny decided to get an MFA. She wrote a story about catching squid with her dad, applied, got in — it all seemed to happen so fast! Franny sat in a small conference room, waiting for the other students to arrive. She hoped at least one or five of them would be cute. A cute girl walked in and sat down across the table from Franny. Franny smiled at her, the girl smiled back, and time passed in a weird way. Franny looked at the clock, which she couldn’t see very well. Her eyes were probably blurry from all the studying. “Where’s everyone else?” she said.

The girl smiled. All she had done, this whole time, was smile. It was getting a little old. “I ate them,” she said, and opened her mouth teasingly. A drop of blood trickled out, then a spurt, then more and more and faster until the blood was gushing from her mouth. The girl was still composed, now laughing, as blood covered the floor. Franny thought, I should have never gotten an MFA, then all thought left her as she paddled frantically, the blood rising to her chest, her chin, her nose, filling her eyes—

Maria had come here through a portal in her hallway closet, and now she was on the road. She was journeying toward a mountain filled with lava in order to destroy a dangerous magical ring. There were many who would attempt to stop her, but she was stalwart, and she was with friends. There was a hot short guy, another hot short guy, a hot tall guy, a hot sociopathic detective and his hot doctor friend, and these two brothers who killed demons together (also hot), who had traveled here from the future.

One day, she awoke to find them all slain. “Run,” someone screamed into her ear, and before she could think, there was a tugging at her belt and she was run-run-running, she was running and being run so fast her feet left the ground and she fluttered like a pennant in the wind—

Jim was a good boy! He couldn’t see red or green, but what he could smell was better than any color. Pebbles, soccer balls, cats, Italian hoagies, car seats, pennies, perms. Jim had no future and was happy all the time. He lived with some friends who were tall and had very long wiggly legs with flat faces balanced on top.

One day, a friend was walking Jim through his neighborhood when, suddenly, the leash went slack. Jim looked up. His friend had disappeared. In his friend’s place was a large, dark, buzzing cloud collecting itself directly above him, thickening by the second. Jim whined.

Everyone is dreaming very busily

When Aya visited her sister, she didn’t try to talk to her.

Other visitors did talk to their stacies, leaning close to the cryocases, resting their hands on top until the cold became unbearable. As you passed, you could hear their murmurs over the unending exhalation of the machines. But there was no point in Aya talking to her sister when her sister couldn’t even talk back. It would feel very bad. It would feel like every worst fight they’d ever had, her sister so nonchalantly sullen that it didn’t even seem like she was angry — more like, Aya had just suddenly never been born, so of course her sister wouldn’t think to speak to her or acknowledge her existence. Which was when Aya would freak out and apologize, saying absolutely anything her sister wanted to hear, because she couldn’t stand glimpsing that dark, lonely universe where her sister would nothear and understand every thought Aya wanted to share with her.

Which were honestly a lot of them.

Aya’s sister was wide and long and flat like Gumby, or an Olympic swimmer. Her shoulders filled the cryocase like she could rip it out of its mooring if she turned over even once during stasis. She had the most sweetly soft look on her face, as if she was about to wake up and ask a question.

But Aya knew better. She was a materials scientist, and so were her best friends. It wasn’t like that TV show with the group of best friends where one was a chef and one was a fashion designer and one was the president and one was a ghost that lived on the Internet. Aya and her closest friends had met and banded together at school, at work, at work-related conferences. Her friend Min worked in cryostasis. She had helped to develop the plasma complex that replaced the stacies’ blood. Min told Aya that what looked like a window on the cryocase was actually a screen. “Stacies aren’t cute,” she said. “Dead is dead.” Min was not unaware of people’s feelings and sensitivities; rather, she considered them and then decided it was best to be blunt anyway, which Aya usually appreciated.

It had bothered people that they couldn’t look at the faces of their loved ones in stasis. It felt abstract and chilly and stupid to visit, like, a giant silver pill. Anything could be in there. Bad for morale, bad for funding, but it would all be even worse if the visitors saw how the stacies really looked, so instead the cryocenter had screens put into the cryocases, displaying cute, cleaned-up, highest-fidelity 3-D images of the stacies resting within.

Aya thought that it was hard to know so much.

Unlike the other stacies, Aya’s sister had a private room at the cryocenter. Aya had paid for it, and for a higher quality of care. She had a lot of money, but she spent all her time hanging out with her dead-not-dead sister and working. She loved work, but she could definitely be having more fun. Going to Belize, watching the coral rebuild. Partying in a Manhattan watermanse. She had the invitations and everything; her work had helped make it all possible.

Her sister’s room was not a nice room. There was a cot in case Aya wanted a nap alongside her sister, no window, and, despite her complaints, there were always persistent dust flurries caught around the bottom of her sister’s cryocase, the same way dust and hair collected around every crevice of Aya’s free weights. But she knew that everything was as expensive as it didn’t look. It cost a lot of money to thwart death. It was hard work to keep a body ready to be alive when all it wanted was the other thing. You had to make the body so cold that entropy would ignore it, tricked into thinking that it was out of the game and thus beyond entropy’s notice. But also, this frozen body had to be a place where life could possibly return in the future, where shoots might come up and blood would rush in.

The last time Aya spoke to her sister was right before she went into stasis. The more Aya thought about it, which was a lot, the more firmly she decided that maybe this was one of those opportunities that no one should have. Her sister had been inconsolable about the prospect of dreaming for so long. During stasis, you were meant to have a kind of brain activity that was sort of like dreaming, but more consistent. The first generation of stacies had been lost because no one had known that they needed a bunch of interesting, distracting stuff going on in their brains; like, stasis was supposed to be stasis, so who knew? But what happened to the first generation was creepy and undeniable, even though everything else had gone as it should.

“What if it’s a bad dream,” her sister sobbed. “I don’t want a bad dream. I don’t want to have anything.”

“It’s not,” Aya had said. “It won’t be. It’s not.” She said it over and over again as if quantity could compensate for quality, for actual factual information, because who even did know? There was no second generation yet.

She was so tired. She had come to visit her sister from work, where the current project was a new kind of membrane for a third round of desalination machines, through which seawater sieved and came out fresh. The old ones worked OK, but they weren’t as energy-efficient as they could be, and California was still thirsty. People were moving back in droves — she really should visit. Aya knew she been born to a dirty world. A tired world. Her mother and father had waded through it, and Aya had been born miraculously, seemingly fine despite all that, but not her sister.

And it was seeing this little sister of hers in pain, in trouble after trouble after trouble, that made Aya vow to not worship a god that was a man or a deity but instead become her own god, to study and learn so that she could grow up to remake and unmake Earth how she thought best — and it was working, wasn’t it? Aya and the women she knew were creating a better world, whether they were harvesting giant beds of genetically engineered kelp or staying the hand of death.

She loved work and she loved her sister and she could not tell which of these things was making her feel tired. It should have been neither, right? Aya lay on the cot, leaving a foot on the floor like she was drunk, and dozed off for a moment.

She heard people talking. Their voices loomed over her, pleasantly stretchy and smooth. She was still sleeping and couldn’t move.

“I’m worried about her.”

“What’s to worry about?”

“This readout.”

“It’s within normal. These variations happen. It’s a long time. Just chill. Haha, get it?”

“Ugh, please stop. I guess you’re right.”

“Look, it’s not like she’s the only one—”

Their voices kept going but now they were quieting, dwindling, as if they were getting sucked out into space. But suddenly there was a new voice.

“Do you think we should eat her?” it said, right by her ear.

Aya awoke, freezing cold. She had just had a dream, possibly the most boring dream ever, about a conversation she had had a few days ago with Min about her sister. Except in the dream, she wasn’t herself, she was her sister, unable to see or move or do anything. She could hear, even though stacies couldn’t hear anything. The dream had ended weirdly — Aya couldn’t remember how, but she felt terrible. That was the thing about dreams: They could make you feel so mad or sexy or scared even when you couldn’t remember a thing about the dream. All that remained was the animal part of your brain that was convinced something had happened.

She left her sister’s room and walked down the hallway. Sometimes people worked late at the cryolab, but tonight everyone had gone home. In the bathroom, it was so dark for a moment that the darkness had heft and texture, a goopiness, but then the lights flickered on. Aya would have preferred for the lights to have been on already. Motion-sensor lights, but ones that could predict the future and would turn on right before they detected your motion so you’d never have to be scared of the dark! She yawned so hugely her mouth threatened to eat her face.

She peed, washed her hands, tried to be kind and generous about the droopy, unpromising image reflected back at her. As she left, Aya heard a sound and turned. In the stall closest to the door, she saw a pair of bare feet drop down daintily and pivot to face her. The lights flickered off. This time the dark was definitely a thing with intention (bad) and movement (swift, in her direction).

Aya dashed toward her sister’s room and slammed the door behind her. She looked out of the little window inset in the door. There was nothing in the hallway. However, there was something in the room with her. Two women and a dog were huddled in the corner. One woman was covered in blood, one woman in dirt. The dog seemed normal, happy, even. They all looked familiar.

The dirty woman stood. “Halt,” she said, “Do not go out there. You are in grave danger.”

The three of them had been fighting for days, they said. The bloody woman, whose name was Franny, had been attacked first. She had kicked a window out and spilled into the dirty woman’s world. The dirty woman, whose name was Maria, had fought off the creature with Franny’s help, and they had been moving from world to world together, but were too late or weak to save the others from being devoured. They had just rescued the dog, whose nametag read “Jim.”

Franny and Maria did not agree on what the thing was, if it was an alien or if it was bad people or if it was a manifestation of their own minds. They just called it a thought-creature. What was clear was that at some point, they would need to fight it. But not here, not yet, not when they were cornered.

Maria said, “What you must do is find the weak point into the next world.”

“Hold on,” said Aya. There was a knock at the door.

“It’s the demon,” said Maria.

“It’s the serial killer!” said Franny.

Jim barked.

Franny said, “Open that thing.”

“No!” said Aya.

Franny glared at her and kicked the cryocase. When Aya went to stop her, she saw that the cryocase had changed. Instead of her sister, it was Aya who was lying inside, sleeping, looking like she was about to wake up and ask the question. Oh. She wondered what the question might be.

The knocking grew louder, booming against the door.

Aya was nothing if not pragmatic. She was adaptable, not a dumb person or a pushover, but someone who was fully aware of all the beautiful and dark possibilities of the world. She knew she had a very short time to mourn everything. “Wait,” Aya said. “What was it like, where you came from?”

“Adventures available to brave men and women alike. Friends banding together against evil. Many hotties,” said Maria. “I want to go back.”

“Time enough for everything,” said Franny. “Me too.”

“And yours?” they asked.

Aya told them about jets the size of mansions. Mansions floating on water in Manhattan, coral reefs corseted and bolstered back to life, skyscrapers in earthquake zones that jiggled instead of cracked. “Sure,” they said. “OK.”

She told them that the world had become harder to live in. But that it was their fault, they knew that, and they were fixing it. They were learning from their mistakes. She told them about Cassandra, her friend who loved flesh so much she could think of ways to create and shape it that had never been seen before. Cassandra had developed a comfortable polymer that protected and supported the skin. It didn’t feel like you were wearing anything, and it even flattened your eye bags. She was the most beautiful woman Aya had ever known in person, and she had a different face tattoo every week. Vain Cassandra with her sumptuous kindness, who had been burned on over half her body as a child and would have no one know what it felt like to be in such suffering.

Franny and Maria looked at each other and shrugged.

“Truly, a world of miracles,” said Maria.

“I wish I could stay,” said Aya.

“For our sakes, I hope that some of this world is real,” said Franny. “It sounds like a beautiful place. I’d take a piece of it. But we really do have to go right now.”

“I love my world,” said Aya. “I will fight for it.”

“We’ll all fight for it,” Maria said.

The door began to crack. They opened the cryocase onto a narrow gray void and each jumped in, Aya last, giving one final lingering look at her world, a world made and fixed by her and her friends and people she would never meet now, her gorgeous world which she was either dreaming up or dreaming in.

Monsanto has known for over 35 years that its glyphosate-soaked ‘food’ causes cancer

Image: Monsanto has known for over 35 years that its glyphosate-soaked ‘food’ causes cancer

Most folks who comprehend the GMO fraud know this basic fact. In 1992, FDA scientists’ thought there could be unknown toxins and other dangers in these foods. There comments were ignored. For the uninitiated, Steven Druker’s book, “Altered Genes, Twisted Truth,” is a dynamic expose of the con job forced upon American’s digestive systems. Yet Monsanto, who ruled the White House in 1992, had already known a decade earlier about Round Up’s carcinogenic ingredient. But this killer herbicide was Monsanto’s key economic engine. So they hid the facts. But they knew that glyphosate, Roundup’s main ingredient, caused cancer way before 1992. Natural News has the story:

“Both Monsanto and the EPA knew full well, at least as early as 1981, that glyphosate, the active ingredient in Roundup herbicide, causes cancer in mammals. Earlier studies conducted during the late 1970s and early 1980s appear to have documented cancer-causing effects from glyphosate in rats, mice and dogs, though this information was buried by Monsanto with the blessing of the EPA…

“‘The evidence shows that by 1981 both Monsanto and the EPA were aware of malignant tumours and pre-cancerous conditions in the test animals which were fed small doses of glyphosate in the secret feeding experiments,’ said Dr. Brian John for GM-Free Cymru, about the facts.”

Although concerns were expressed at the time by EPA committees, these concerns were later suppressed under the weight of conflicting evidence brought forward by Monsanto, some of it involving the inappropriate use of historical control data of dubious quality. None of these studies are available for independent examination.”

Even now, the evidence to force feed GMO seed in African nations includes that same 1992 guarantee from the USDA, the EPA and the FDA. They’re just plain “safe.”  Gee, so is plutonium, if you’re not standing anywhere near it.

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