Posted by: leigh | March 14, 2014

the farewell academia stories

i’m gonna get all hipster on you all and say that i left academia before it was the big new thing on the internet.

yeah, i’m glad to see that we’re suddenly paying more of our collective attention to the majority of people with a great scientific education background who don’t become professors at elite universities running multiple-research-grant labs and setting the pace of our fields. because let’s face it. it takes a lot of finding one’s inner strength to get through graduate school and this makes us prone to thinking we are the exception to the job market/principles of national economics/other non-favorable situations. but reality dictates that we are not *all* special flowers. there isn’t room for many people to do the above career track because academia is a limited enterprise. and if everyone did this stuff for a living, we’d all be falling over our own feet trying to get any other kind of scientific work done, or implement science in society, anyway.

alright, though i am out of academia myself, i’m not here trying to tell you that i am no longer in research. because i am, i actually do some pretty badass stuff and i’ll be there at the same conferences that academics frequent. i’ll be the outlier everyone looks at funny. no, seriously, i kinda stand out. i went to a pretty specialized research sector, and no i don’t care to describe what that is. some jobs you just can’t talk about on a blog, so that’s where this bit of the conversation ends.

it’s just that there are a lot of things to do outside the academy. it’s great if you get the opportunity to do one of these many and varied jobs. society is gonna benefit. i know we’ve got a shitload of disgruntled postdocs out there who envisioned their ideal career track since the age of whatever years. i know it totally sucks that not everyone hits that target. but if you have a PhD that means that you’ve learned to THINK, above all the other skills you’ve acquired. (or, we could assume so, though i will say i have run across exceptions.) this matters, and critical thinkers are needed in far more places than the ivory tower. it is no tragedy for someone to bow out of the academic rat race if they make great waves in a different arena.

Posted by: leigh | September 23, 2013

revisiting and talk of jobs that aren’t found in academia

i recently went back to my graduate school lab for a few days. after that visit, i can never go “home” again because the lab is moving. the histology room where epic hilarity happened as we all pored through absurd numbers of slides in various stages of staining, where Eldest Grad Student sliced a thumb open and Second Eldest followed suit shortly after making a big mockery of people who slice thumbs open on the cryostat. the office, my old desk, the binders full of data going back decades. the ancient copies of goodman and gilman’s (7th edition, nearly as old as i am) on the shelves across from mine. my old lab bench, where i used to terrify younger graduate students and do badass science. i inadvertently arrived just in time to say my goodbyes to places from my history.

more importantly, i had a short but great conversation with my mentor. my no-bullshit, straight-shooter, opinion-never-understated grad mentor likely had no idea just how meaningful the talk we had was for me at that moment. while i unhesitatingly left academia some years back (and have yet to regret it, thanks), it still irritates me that the prevailing attitude in academia is that non-academic jobs are for those who couldn’t cut it. in fact, most most graduate students in my department used the “couldn’t cut it” or “won’t cut it” or the like anytime they didn’t agree with a competitor’s decisionmaking process and i got pretty stabby over that bullshit even then. so these days i’m in the process of applying for a new job that, well, let’s say is atypical and has a very high bar for shit that you need to do to get the job. grad mentor wrote me an enthusiastic letter of support, and in this conversation enlightened me with how much fun it was to write this letter and the thought process that went into her support.

i wasn’t sure what i was getting into, hearing this start to the talk. but it was so. damn. refreshing.

grad mentor acknowledges the significant socioeconomic barriers i’ve had to overcome just to get admitted to the stadium, much less play the game. and compares me to herself, someone who was not so much burdened by that type of socioeconomic disadvantage. (i would have countered that her generation had plenty of barriers and she’s told me about some, but i was shutting the hell up right here.) goes on to tell me that academia is not a true meritocracy, and i will excel in the system i aim to get myself into because i won’t have to rely on privileges i never had just to get ahead.

this is quite possibly the most important thing grad mentor has ever told me. back when i was a student and we swapped some life stories, it was acknowledged that i had put much more effort into reaching that level compared to my peers in the program. but these more nuanced things, the reliance on unearned privileges as standard currency in the high-end academic game, i didn’t hear about these things directly. i just assumed them given the people who surrounded me, but this fresh-faced acknowledgment just validated me in so many ways. it validated my entire graduate school experience. and then the conversation drifted off to something else and i was left with that breathless feeling of revelation to myself. as is typical…

Posted by: leigh | June 11, 2013

lilacs

we took him to the homestead, back to the patch of earth that now anchors five generations of us. we took him to the big lilac stand, fragrant purple in bursting bloom, fresh after the rainstorms roared through, clear reflective droplets lingering on the leaves.

the lilac that used to shade the old metal chair where my grandmother used to sit and enjoy the evening air as the sun drooped low in the sky, where i tethered calves and left my children’s gardening tools laying out in the grass.

he loved it instantly. as if i had somehow passed the warmth of these memories to him, he was drawn to it. pointed out the flowers, breathed in the scent.

we walked the fields beyond the hill, the places i spent time digging in the rock piles and finding suitable sticks, the occasional bug or snake, and collecting frogs. we called the killdeer and the whipporwhills.

so this, this is what life means.

Some months back, there was a publication that ended up being highly hyped by the press. Controversy and science by press release ensued. Public relations people had field days hitting all the target demographic periodical outlets. There was a convenient lack of PR for a concurrently published paper with results that could not be more negative. Great situation for people who like to get all fired up about things, useless hype in terms of evidence-based discovery efforts.

The publication in question? A follow-up study by Mithoefer et al describing the long term effects of their MDMA therapy for PTSD, based upon which the press releases make the bold* claim that MDMA augmented therapy has an 89% success rate in treating PTSD.

Herein, I describe the reasons this is an ostentatious conclusion at best.

First, we go back a couple of years

The contested claim is from a story that really gets going in the first phase of their study, which was published back in 2011. So to understand the recent publication, we must start at the beginning.

Briefly, this study used a double-blind design to investigate the effects of MDMA as a psychotherapy adjunct. They recruited 20 subjects, and decided to complicate their study off the bat by using an unbalanced design (unequal sample sizes). Their active drug group was 12 subjects, while the inactive placebo group was 8 subjects. They used common evaluation tools such as the CAPS (clinician-adminstered PTSD scale).

They set out to compare MDMA vs placebo. For the active drug, they administered 125 mg of MDMA at the start of the therapy session, and offered an optional supplemental dose of 62.5 mg MDMA 2-2.5 hours later. (I assume they also offered a supplemental placebo “dose” to the inactive group.) Not all subjects took them up on this, which complicates things further. Pharmacologically speaking, it gets even harder to interpret when you also consider that patients were asked to discontinue use of any psychotherapeutics for the duration of the study. (Withdrawal effects? Rebound effects? How long were they off the meds? We don’t know.) And some patients were given one or two medications to assist recovery after some MDMA+therapy sessions. (What are the effects of these sporadic and inconsistent treatments on consolidating progress made in therapy?)

When you wish to make a big claim, yes, your work is under a level of scrutiny that directly correlates with the size of the claim you intend to make. Their entire study design seems to treat subjects and groups inconsistently, which is a big problem when you want to harp on the strengths of the prospective, double-blind design of the study. Well folks, you have to treat all subjects the same way, too. To the greatest extent possible.

They found plenty of effects, which may or may not be directly related to the primary finding: that people are pretty effin’ good at determining whether or not you gave them MDMA. (As are the study observers.) So much for placebo, so much for the double-blind study.

So, in what reads like a grand gesture of shoulder-shrugging, they offered MDMA +therapy to their placebo group members in an open-label “crossover” phase. Except one placebo subject, whose CAPS score had decreased from 67 to 15, felt satisfied with his or her experience and declined further participation in the study. (The authors note that a second placebo subject experienced a decrease in CAPS score from 54 to 15 after therapy, which later increased to 64. This makes me ponder the effect of the therapy protocol as well as the drug treatment.) They present the data from the crossover phase in a table, arguing this data further demonstrates that MDMA+ therapy improves PTSD symptoms. We can’t tell this claim from a simple effect of more time passing after placebo+therapy sessions, since there is no control group anymore! Also, the way they say these things makes me wonder how exactly they ran their statistics. Well, the way they say things and their inconsistent use of descriptive statistics. (Yes, I lean toward the stats douchery. One kinda has to, in my field.)

These results, as presented, must be considered with a deluge of caveats. Here are a few important ones:

  1. Unbalanced design compromises a lot of things, particularly your ability to evaluate the effects of the therapy protocol alone. They seemed much more interested in comparing MDMA vs placebo, not placebo+therapy vs MDMA+therapy. This is one way to look at the problem, but I argue it is the less valid way to look at it.
  2. It’s pretty hard to argue for an effect when your control group is not functioning as a control, and your blinding is nonexistent.
  3. The non-standardized dosing (the optional additional dose) presents a big confound.
  4. The variability of therapy sessions and post-therapy-session drug treatment (with sleep drugs and benzodiazepines, which I view as a considerable blunder) again reduces the validity of the results. We now have a number of confounding factors that distract from the main effect they attempt to demonstrate.
  5. This is a tiny study, including just 20 people (12 MDMA, 8 placebo followed by crossover MDMA). Their population was primarily female and primarily survivors of child abuse or sexual trauma, so it’s also a big jump to assume that all populations and all causes of PTSD are going to apply.

That said, with all the limitations and caveats and skepticism, at the end of my first reading of this paper I still thought the data were interesting. Overall, I had the impression that it was worth a further look if they could improve the study design to clear up as many of these initial flaws as possible.

And then the follow-up

So the follow-up is where Science By Press Release took place just recently. Recall, at the end of the study we just analyzed, all participating subjects had received MDMA+therapy. The only acknowledged difference between groups at this point is whether or not the group received placebo+therapy a few months earlier. (Of course, there are many un-acknowledged differences within groups and between groups due to the inconsistent treatment design.)

Now the authors conduct a long term follow-up on their subjects. They received responses from all but three subjects. This gives them a total of 16 subjects (20 to start – 1 declined the open label second phase in the original study – 3 did not complete follow up). They take the data from these 16 individuals and see what can be learned from a more distant timepoint.

Some subjects appear to maintain similar CAPS scores, others seem to show further improvement between the last study timepoint and the long-term follow up, and still others seem to relapse. We see that some subjects completed a third MDMA+therapy session, as well. Importantly, the study authors reveal the full dataset in table format (rather than the graphs presented in the first paper, which were really uninformative without error bars). There is a far wider range of CAPS scores at study entry in the MDMA+therapy group (compared to the group that was originally assigned placebo+therapy and then put into a crossover study).

The authors boast that 8/19 subjects are in psychotherapy at follow-up (a 50% decrease from the 16/19 at study entry). However, they downplay the fact that of the three subjects NOT in therapy, one is in therapy at follow-up. (Though unbalanced, if they wish to compare these things, one could argue this is more than a 50% increase.)

The changes in medication prescriptions seems to be a wash. Some started new prescriptions, some went off prescriptions. I don’t see anything outstanding, and neither did the authors.

Still, they become so bold as to assume that the three subjects who did not complete the CAPS assessment showed improvement without the hard data to back it up and conclude, “Therefore, it may be the case that up to 89% (17/19) of those who received MDMA had long-term improvement in their PTSD symptoms.”

Wow. They quickly get their heads on straight and go back to the data, but that’s really amazing. Even so, they really have shifted to treating these subjects as a set of case studies rather than a treatment group to analyze. They kind of had to, given the lack of control group and not much else to go on. Still, when you shift from a prospective study to a series of case reports, you’re looking at far less powerful results. The press releases certainly don’t reflect that.

Again, it’s an interesting result, but at this point the power of the data is severely reduced- and quite a few of the losses of potential information gained are due to blunders on the part of the authors. That said- do we really need to go around selling early (VERY early) results in a civilian cohort (primarily women, primarily survivors of sexual violence) as the answer to a warfighter/combat trauma audience? That’s cheap and awful.

But lest we forget the conveniently ignored study…

One of the conclusions of this long-term study is clear: people know when you’ve given them MDMA. The subjective effects of the drug create a major problem in doing any kind of blinded study. So the authors of this study used a low dose of MDMA (25 mg + 12.5 mg) as an active placebo, and the same dose of MDMA that was used in the previous study (125 mg + 62.5 mg) as their therapeutic dose. Again they had a low number of subjects split into uneven groups (4 active placebo, 8 full dose MDMA). They claim it was to test safety of the full dose (didn’t the last study do this well enough?) and to enhance recruiting efforts. Huh. They added a third therapy session to their regimen, which differed from the first study.

They effectively solved the blinding problem. Subject and investigator guesses didn’t look a lot better than a random (50/50) chance of being right. So, that’s a plus to the active placebo!

However, there is a massive downside here. Magically, when your subjects can’t tell which experimental group they’re in… your clinical effect disappears. Placebo effect for the win!

Where were the press releases for this study? It was published in the very same issue of J Psychopharmacol as the Science By Press Release (long-term follow-up) study- in fact, it’s the next article in that issue- yet it’s ignored. I only stumbled upon the paper by accident, and was stunned to find the exact opposite of what all the press releases were screaming about.

This is why Science By Press Release sucks. It’s also why double-blind studies are useful, why holding extraordinary claims to high standards is important, and why replicability (especially for small sample size studies) can make or break a finding.

It’s whether you choose to incorporate that new knowledge in your worldview that makes you a Scientist rather than a True Believer in a romanticized idea that sounds great but might just not be right.

 

Notes:

* this is a politically correct term for “overreaching” or “not really correct”

I really don’t intend to sound as uncharitable as I come off. However, I think that if you’re going to invest the time and effort, it really should be done right and not halfassed. I see many lost opportunities to learn things here and it’s disappointing. It’s my opinion that, at this time, there’s really not much more to go after on this therapeutic front.

 

Further reading:

Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. (2011) The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol 25(4):439-52.

Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Martin SF, Yazar-Klosinski B, Michel Y, Brewerton TD, Doblin R. (2013) Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. J Psychopharmacol 27(1):28-39.

Oehen P, Traber R, Widmer V, Schnyder U. (2013) A randomized, controlled pilot study of MDMA (± 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). J Psychopharmacol 27(1):40-52.

Posted by: leigh | February 22, 2013

on running

my nemesis, open pavement. it’s been a long, long time. shoes tied tight, check. sense of dread, double check.

i’ve been running for a while now. it will take me a while longer before i decide whether i like it. but i have decided i can *do* it. and this is a start. the first few weeks were tough as my body adjusted again, the newly learned mechanics of just standing upright, of just taking steps, challenged as i added new motion. and hell yes, it hurt. my neglected running muscles were sore, my knees ached. my lungs never did like the cold air, but they will protest longer than my legs ever did. even as i re-implement the breathing patterns that got me through those seemingly endless training runs in the soccer pre-seasons.

in, two, three, out, out, in, two, three, out out…

the knees have decided to get with the program, they don’t bother me anymore. my legs don’t hurt much anymore, my lower body is loosening up. i found a comfortable cadence.

i slow down to a walk occasionally. my lungs aren’t fabulous yet. but my run time comes down a bit every time i go out, proving that i’m getting stronger with every run. so i just keep going.

Posted by: leigh | January 21, 2013

from below baseline back up to zero

amazingly, it took about four months for my evil awesome physical therapist to get the pain out of my life. there was a period where there was more pain- a LOT more pain. continuing on seemed like it would be worse than just settling for what i had been dealing with for so many years. but i kept on, 6-7 days a week at home and 2-3 hours a week in the PT office.

apparently my dedication to getting through this is unique among PT patients, but here we are. i am holding my own and don’t need much intervention from evil awesome PT anymore.

it has been years since i have felt even “okay” – much less good. a good week was one in which i had little to complain about. but this. this is not something i even remember. it’s entirely different, and i’m still not used to it. but from here i have to keep building up on my own.

i haven’t been able to run without debilitating pain since the late 90s. just typing that kind of blows my mind. so now i have to reclaim the running, for real this time. it’s time to get the strength back, no limitations.

most of my online presence is on twitter these days, since that format seems to suit my current wavelength of internetting behavior better than the blog setting.

writing this paper while dealing with the random stressful events that life tends to throw at a person from time to time had me blowing off a bit of steam. and i got to thinking about this- often we scientists write papers as small stories of data- “we did A, and that was interesting, so then we did B, which led us to C, and ta-da now we have new knowledge!” but really, it’s bullshit. chances are we did B first and asked wtf that result meant, then we did A, and C was something that the lab had been sitting on for a year since it wasn’t related to anything that was actually going out for publication at the time.

regardless, we’re compelled by convention to make it out like every step of everything was thoroughly justified and went just as planned.

#overlyhonestmethods started as being about revealing the “between the lines” in our methods sections. nobody states that procedures are scheduled around things like lunch breaks or other human elements of our day. but we all know when we read “behavioral assessments were collected at 0900 and 1300″ that the authors wanted to sit the fuck down and eat something in the middle of their day. we may report that “we” did some tedious video scoring, but you know it was the editorial “we” – aka, some undergrad did it. sometimes we set out to run ten replicates, and we fuck one up. or something else crazy happened in the middle, like an earthquake or a fire drill. well, now we’re reporting nine. but nowhere in the methods will you read “so we kinda blew that first attempt and had to try again” because that’s the lab lore, not the scientific literature. because in the scientific literature we’re professional, we Totally Meant To Do It That Way.

it’s been a ton of fun to see the outpouring of lab lore behind what’s in our methods sections. i’ve seen some snark and sarcasm and written my own, especially regarding statistics (who has reviewed more than a few papers and hasn’t run across ONE where the authors were clearly looking for p<0.05, come on). someone somewhere is going to take that literally, and won’t that be fun. meanwhile i don’t think you’ll see a published mention of how the reported incubation time was defined by how long the author spent drinking a cup of afternoon tea, but i think #overlyhonestmethods gets it out there that there are real people doing the science. for the most part we’re not as stiff and sterile as our publications (the measure of our careers) make us out to be.

Posted by: leigh | October 22, 2012

physical therapy. aka hell

i’ve made a number of failed attempts to take back some aspects of my life that i lost a long time ago.

once upon a time, i was a pretty epic halfback on the soccer field. i ran like the wind. once upon a time, a little bit later than this, i had a lot stolen from me without apology. and despite having all manner of medical practitioners’ opinions, alternative treatment modalities, and shovels full of drugs thrown my way, i never got it back. all the king’s horses and all the king’s men, and what have you. the false hope (oh and working my ass off in a shitty retail job to afford the medical treatment, so i could physically tolerate the work i had to do to pay for said medical treatment) assailed my spirit and the conveniently prescribed drugs were probably the wrong way to cope with it. the “passage of time” – aka wait it out- method wasn’t particularly helpful either.

and so on several occasions in the last however many years, i said fuck this, i’m going to try running again. on the same number of occasions, i finally admitted defeat because it sucks to try to go about life in that kind of pain and quite simply, i don’t wanna do it again. i had also carefully tracked down my medical records and discovered that most of my practitioners effectively washed their hands of me very early on, citing that i did not want to improve. (alright, i was an angry and headstrong young person but to think i preferred to live in that hell is mystifying.) highly discouraging.

but then there is the physical therapist i met a few months ago. and she was great so i thought i’d give it another shot. i have some additional pressure, the job i want to have next is contingent on me meeting some physical requirements.

let me tell you. reversing almost half a lifetime worth of structural problems is difficult. and it involves a lot of new pains when i had already figured out the workarounds to keep the comfort level acceptably high. but my PT tells me we can do this if i can work through the temporary soreness. and she doesn’t wash her hands of me because i have a bad week or don’t make as much progress as i’d hoped.

don’t call me optimistic, but i’ll give it a try.

Posted by: leigh | October 7, 2012

ramblings on a changing sense of self…

with the passage of time, life just keeps on happening whether you’re ready for it or not. some things change and some stay the same, but these life experiences never stop rolling in.

as the sum of my own experiences, i can’t help but change as i go through my days. i was on a pretty straight trajectory toward increased cynicism for a long damn time. i wasn’t one of those optimistic, fresh faced naive kids for long. life wasn’t too kind to me in my early years, but i kept on going. i discovered sarcasm, i learned how to fight, i grew my claws and i used them. i felt i needed all of these things to protect myself.

now my 30th birthday is coming up (geez. really?) and i am so different. i’m amazed i’ve made it this far. when i was younger, i felt it wasn’t worthwhile to plan anything because i didn’t hold the expectation that i would be alive for much longer at any given time. and looking back, i see that i lived my life accordingly and had to make big adjustments as my expectations turned out to be wrong. every couple of years i can see events in my life changing my outlook, my approach to life, my outward behavior, everything.

yeah, i’ve still gotten more cynical as the years go by. but perhaps more slowly than the alarming rate of my earlier years. and i’ve run a wide range of operating parameters, from a cold and calculating “get the fuck out of my way or i’ll run your ass over” persona to being someone’s everything when he can’t do much for himself.

you’ve got it: the biggest change, by far, was when my son was born. because now it isn’t about me anymore. he needs me to be there for him, to introduce the world to him. i worried about my ability to face some terrible memories that i was sure would come flooding back. instead, he has given me strength. and to be brutally honest, for the very first time in my life i have stopped questioning whether it was was truly worth fighting to survive those early years.

i welcome the challenges and changes the world has for me- and i know that 30 years from now, if i’m still alive, i’ll look back and again i’ll see such contrast. life offers few guarantees other than constant change.

I received a very polite and well-thought out question that I would be remiss in not answering. Sorry it’s taken a while, micycle, life has taken several sharp left turns on me this week.

As a principle, I don’t give medical advice or anything that might sound like medical advice. I actually skirt the whole giving any kind of advice on the internet thing when it comes to the things people do with their bodies, in favor of informing them what the effects may be. So in response to such a question, I am going to just put some discussion out there about what happens when one is exposed to a fat-soluble molecule and then loses or gains a bunch of weight.

Now, say I’ve got a friend Joe who has some substantial fat stores and a friend Tim who has lesser fat stores. Joe and Tim happen to be hanging out together in the wrong place at the wrong time, and they are both exposed to the same weight-adjusted dose of a fat-soluble drug, let’s call it X.

What is the first thing that X does? It gets into the bloodstream and circulates around the body. As soon as it encounters some fatty tissue, it will preferentially move to the fat and hang out there. The rest is sent around the body, causes whatever effect it may cause on various body systems, is broken down by the liver, and eventually gets sent out of the body.

Who has a greater initial exposure effect- Joe or Tim? Joe has more fat to sequester the X molecules, so the rest of his body is exposed to a lower effective dose immediately. Tim has less fat and more of the X affects his organ systems acutely.

What about in the longer run? Who is worse off? The stored X equilibrates out of the fat over time to provide Joe with a longer duration, lower-level exposure. If X has toxic effects, Joe will likely need continued treatment to counter the effects of X over several weeks. Tim, on the other hand, is much more likely to recover fairly quickly with prompt treatment.

What if Joe loses weight? What will happen? Will he get rid of the X more quickly? If Joe substantially decreases his body fat (not just a pound or two), his fat cells will become smaller. The X will become more concentrated, and the concentration gradient between the blood and fat will become greater. This will favor more X equilibrating from the fat to the bloodstream so that it can be metabolized and cleared. It will also cause an acute toxic syndrome, if X has toxic effects, as the drug once again affects his organ systems. Eventually the blood concentration of drug will drop below the threshold that causes systemic effects/can be detected but this is not going to be immediate. It’s worth noting that we’re talking a pretty substantial weight loss, and a couple lbs here or there for your average 175-lb adult male would not have such dramatic effects.

What if Joe gains weight? Will he extend the amount of time required to clear the drug? A substantial weight gain would decrease the concentration of X in the fat cell as the fat volume increases inside the cell, but there would still be more X in the fat than in the blood. So the concentration gradient would still favor release of X into the bloodstream. Whether or not the concentration of X in the blood would be below the lowest adverse affect exposure level- or detectable- depends on the amount of X that was stored in the fat to begin with.

How about if Joe just eats a lot of fatty foods- will that slow the release of X into the bloodstream? The factor of interest here is the difference in concentration between X stored in the fat cells and X circulating in the bloodstream. Adding fatty acids to the bloodstream does not change this factor. So, no, eating a lot of fatty foods will not help except in the case of preventing weight loss.

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