Holiday Cheer

One of the most hilarious things on the blogs recently is, as Isis the Scientist put it, PhysioProf vs. iPad.

It took an Apple product to do it but I do believe PhysioProffe is breaking down at last.

Confession

I much prefer, in these multi-victim random shooter events, when the perpetrator ends up dead by his own hand.

More for the co-equal contribution authorship dealiobob fans

First, let’s all enjoy the bliss of, count ’em, EIGHT authors who….

¹D.S., A.B., M. Maroteaux, T.J., C.P.M., R.S., J.-A.G., and G.S. contributed equally to this work.

To make it extra hilarious please note that the first four are listed first authors and the last four are…listed last authors.

This is ridiculous. Going by the affiliations of the first four and the last four (and knowing a little something about the careers status of several of the last four) it looks very much like typical trainee-PI pairings in a multi-group collaboration. Consequently it would make considerably more sense to identify the four trainees and the four PIs as contributing equally compared with each other…but not across the trainee/PI divide.

But really, the discussion of the day is raised by a troll communication to the blog.

As you know there are style guides for journals as to how previous studies are to be cited and how they are to be referred to in the text. One typical style guide might suggest that you use “As shown by Gun et al (2009), the PhysioWhimple nucleus is critical in…“. You might also resort to the more conversational “Gun and colleagues demonstrated…“.

Very good, right?

Now what about when the paper in question indicates co-equal contribution, eh? Then you should say “Genedog, Tideliar and colleagues showed….“. Right? You should absolutely insist on including the name of the co-equal authors, should you not?

Especially if you are one of those who insists that this designation is meaningful…

h/t: a certain troll

Ok, NRA nutjobs, I'm on board with your plan for more guns

I get it. I do.

You think the 2nd Amendment to the US Constitution lets you own guns in the event of a need for armed insurrection against a tyrannical government. Frankly, given what happened under Dubya Bush, I’m kinda surprised more of my libbie-leftie friends didn’t join me in this understanding. But whatever.

Most of you, even on the rightwing, tend to reject my argument for equal force- nobody seems to be fond of Michigan Militia wingnuts getting their hands on tanks and F16s and Stinger missiles…so we’re stuck with lack of parity. I mean, I don’t get it…if you think this is what the 2nd means (and I do) then why you are not trying to pick up one of these modest multi-billion dollar weapons systems on the blackmarket is a mystery to me. but….ok. something less than parity with the US armed forces. That’s a first principle.

Second, hunting. Now true, the 2nd Amendment does not seem to guarantee your right to blast small woodland creatures into oblivion but what the heck. Sure. By all means let us justify the sort of weapon that is necessary to bring down a deer or something. And leaves it….well, edible. As opposed to, say, riddled with heavy metal projectiles of a 0.223 calibre.

Third, you seem to think that the solution to gun violence is that we have more guns. More people with more access to guns at any moment in the event we need to put down a mad dog, I mean, defend a movie theatre against a disgruntled neuroscience graduate student, er, nutter. Fine. I agree. If someone is actively shooting up the place, if we could have some calm, cool, collected return fire….well it looks fine on paper to me.

So how can we have more guns, available for hunting, best for accurate shooting and with some inherent features that exert a calming effect on the rate of fire?

The bolt-action rifle. Preferably with the magazine limited to 3 or 5 cartridges.

So here’s what I propose. We ban, and I mean BAN, these stupid penile replacement firearms. Period. No handguns, no AR15 military bullshit. No magazine/clips bigger than 5 in capacity. No goddamn cammo stocks. No. Muppet. Hugging. Grandfather. Clause.

And in exchange you nutjobs can have as many bolt-action rifles as you want and as many long barrel shotguns as you want. You can hunt, grab them out of the rack on your pick ’em up truck in case you happen by a Sikh temple when some shit is going down from a white supremicist and have them under your bed come the armed insurrection.

Good?

In a rare moment of clarity, NRA flack LaPierre makes huge Freudian slip

From this transcript of his remarks:

Isn’t fantasizing about killing people as a way to get your kicks really the filthiest form of pornography?

And there we have it. The full reveal.

For the slower members of the audience, or those reading after too many eggnogs…an explainer from Comradde Physioproffe.

all these delusional right-wing microdicke Republican gun fetishists … we all know that their real goal has nothing to with preventing the slaughter of kindergartners, and everything to do with delusional phallic power fantasies to compensate for their real-world angry white d00d ineffectual dicklessness.

So yeah, LaPierre was talking about videogame fans…but dude. Fruedian slip much? Who the hell would compare GrandTheftAuto to porn unless he was popping a chubbie thinking about blowing people away in a hail of semiautomatic fire from his M-16 imitating AR-15 “sporting rifle”? And you know who those people are?

for Sporting Purposes only.

Honestly. Tell me there isn’t something wrong with these folks.

social media helpful suggestions…-ism busting or too damn stupid as yet

in this case it is the gmailz suggesting I add a couple of more email addresses to my group message…

Some data on simple possession raps for three of my Readers

This is from a bit by David Frum:

NIH small business awards per capita by State

hmm. looks just like the political Red State / Blue State division, doesn’t it?

Only in this case the government largesse is going preferentially to the Blue, instead of the Red. (Also see this).

The Blue states are getting more government investment in Small Business, the Red ones more government investment in, well, the dole. Interesting, isn’t it?

via Rock Talk blog.

Why are postdocs so dismal at simple mathematics?

on the perennial topic of underpaid postdocs who want more money.

per usual, PhysioProf:

The only possible end-game to this continued simultaneous slashing of RPG budgets and inflation of the NRSA pay scale is (1) more layoffs of RPG-supported post-docs and (2) the few post-docs still supported on R01s sitting in front of computers playing Angry Birds because there is no money left after paying their salaries to pay any other research expenses.

To which some bonehead replies:

Quit viewing us as cheap labor and recognize that we are desperately scrambling for security. We’re getting older, forced to constantly move, write grants -and- do the actual research, all without job security, and you think a salary less than half of yours is fair? Well I guess you got yours so the rest of us can suffer.

Later on in the thread there is another comment suggesting that any PI who can’t just pay their postdocs $3,000 more is incompetent.

The mind boggles.

There is a fixed pool of NIH money here supporting science. Actually it is shrinking. But whatever. If all the postdocs are paid more per year, there are going to be fewer post docs supported. Or, as PP points out, no money to do research. Perhaps these disgruntledocs are okay with the latter but they sure as hell aren’t going to be okay with the former when it is them that is out of a job.

What gives these morons the idea that they would be magically exempt from the axe?

Twelve Months of Drug Monkey (2012)

As I’ve noted in past editions…

The rules for this blog meme are quite simple.
-Post the link and first sentence from the first blog entry for each month of the past year.
I originally did this meme, after seeing similar posted by Janet Stemwedel and John Lynch. Prior editions include 2011, 2010, 2009 and 2008.

If you blog, I encourage you to do your own year-end wrap up post.

---

2012

Jan: ah, a tragic conundrum emerges from the thickets.

Feb: It’s been awhile since I last talked about MDMA, aka 3,4-methylenedioxymethamphetamine, the canonical ingredient in Ecstasy.

Mar: Perusing the ‘pedia on the 19th Amendment to the US Constitution I found what I was looking for.

Apr: This is my understanding, anyway.

May: This is huge. Previously the only IC that, to my knowledge, made their funding data available was the NIGMS.

Jun: Dude. I realize you are white and male and think you are quite a smart scientist.

Jul: I received a kind email from Elsevier this morning, updating me on the amazing improvement in 2011 Impact Factor (versus 2010) for several journals in their stable of “Behavioral & Cognitive Neuroscience Journals”.

Aug: What a fucking summer.

Sept: Phew. We’re okay. For now.

Oct: Obviously it is an academic career credit to be selected as the Editor in Chief of a journal, no matter how humble that journal may be.

Nov: We have touched on the Investigator criterion of NIH grant review in the past.

Dec: I’m attending a meeting that is enriched in the older and established luminary type of scientist.

UUSA

We need a University of the United States of America.

It would be set up much like the service academies (USAFA, Annapolis, West Point)…admission for undergraduates via Congressional nomination. Tuition room and board for free. Well..”free”. There would be a service payback of some sort. Generally less dangerous than the military, so there’s that. And presumably the post-service skills would be marketable.

On the Professor side, I imagine the research and scholarship to be like intramural NIH. For every discipline. Arts, Humanities and the Sciences. Professors will do great things without having to grub for extra grant support.

The flagship campus has to be in Detroit. No ifs, ands or buts about it. Real Estate will be cheap….and not just for the UUSA proper but also for the rapidly emerging spinoff businesses. Housing relatively affordable.

And lord knows Detroit needs the rejuvenation. Heck, most of the Rust Belt could use this kind of kick forward.

There will be no B-school. I can’t think of a possible “service” role for that nonsense. But the Medical School will provide the finest in evidence based, scientific, modern medical practice possible.

And the J-school….oh my lights. The tarnished Fourth Estate will be restored my friends. Just you watch. Every journalism student will be put through the science wringer so they know how to deal with facts and not the logic of the pull quote.

First Aid for Mental Health

Almost by definition there is something wrong with the mental health of mass shooters like the Aurora cinema guy, the Sikh Temple shooter and the one who just killed 20 elementary school children, 6 staff members, his own mother and ultimately himself.

In parallel with the calls for better gun control in the US we experience calls for improved health care for the brain. But the failing is not the provision of care so much as it is the detection of mental health problems that might lead to mass shootings.

We will never get to a one to one prediction of who is about to become the next news cycle. But then, we don’t know who will heal eventually from a given infection, who will recover from stroke without a given intervention…or who will get heart attack save for the cholesterol meds, statins and what not.

So we go with the odds.

And we detect problems with broad screening (annual checkups), acute responses (minor cardiac event perhaps)…and crowdsourcing.

If someone were bleeding in front of you, chances are decent that you would know whether to get a bandaid (even a 5 year old knows to add the antibiotic cream) or stick a finger on the vein while yelling for help. In a crowd? Someone would know CPR if a person stops breathing…in a pinch you’d have a go based only on what you remember from teevee shows.

What about when someone shows signs of a mental health problem? How does the crowd and pre-FirstResponse do with those situations?

I have only recently been made aware of Mental Health First Aid.

It intrigues me.

You know what starts academics a-blogging?

Mind bogglingly out of touch statements from people at the higher echelons of the NIH, that’s what.

Ahh, reviewers

One thing that cracks me up about manuscript review is the reviewer who imagines that there is something really cool in your data that you are just hiding from the light of day.

This is usually expressed as a demand that you “consider” a particular analysis of your data. In my work, behavioral pharmacology, it can run to the extent of wanting to parse individual subjects’ responses. It may be a desire that you approach your statistical analysis differently, changing the number of factors included in your ANOVA, a suggestion you should group your data differently (sometimes if you have extended timecourses such as sequential drug self-administration sessions, etc, you might summarize the timecourse in some way) or perhaps a desire to see a bunch of training, baseline or validation behavior that…

….well, what?

Many of these cases that I’ve seen show the reviewer failing to explain exactly what s/he suspects would be revealed by this new analysis or data presentation. Sometimes you can infer that they are predicting that something surely must be there in your data and for some reason you are too stupid to see it. Or are pursuing some agenda and (again, this is usually only a hint) suspected of covering up the “real” effect.

Dudes! Don’t you think that we work our data over with a fine toothed comb, looking for cool stuff that it is telling us? Really? Like we didn’t already think of that brilliant analysis you’ve come up with?

Didya ever think we’ve failed to say anything about it because 1) the design just wasn’t up to the task of properly evaluating some random sub-group hypothesis or 2) the data just don’t support it, sorry. or 3) yeah man, I know how to validate a damn behavioral assay and you know what? nobody else wants to read that boring stuff.

and finally..my friends, the stats rules bind you just as much as they do us. You know? I mean think about it. If there is some part of a subanalysis or series of different inferential techniques that you want to see deployed you need to think about whether this particular design is powered to do it. Right? I mean if we reported “well, we just did this ANOVA, then that ANOVA…then we transformed the data and did some other thing…well maybe a series of one-ways is the way to go….hmm. say how about t-tests? wait, wait, here’s this individual subject analysis!” like your comments seem to be implying we should now do…yeah that’s not going to go over well with most reviewers.

So why do some reviewers seem to forget all of this when they are wildly speculating that there must be some effect in our data that we’ve not reported?

Should NIMH be funding Me-Too drug development?

Hard on the heels of something I just learned about at a recent conference, the NIMH issued a Press Release for a new clinical trial they funded.

A drug that works through the same brain mechanism as the fast-acting antidepressant ketamine briefly improved treatment-resistant patients’ depression symptoms in minutes, with minimal untoward side effects, in a clinical trial conducted by the National Institutes of Health. The experimental agent, called AZD6765, acts through the brain’s glutamate chemical messenger system.

Interesting. The background is that prior studies* have shown that the dissociative anesthetic ketamine is capable of the rapid (within hours) amelioration of depressive symptoms. Yes, ketamine. The recreational drug known as Special K and the veterinary anesthetic they’ve used on your pet cat or dog. Same ketamine that is approved for human use in pediatric anesthesia, emergency medicine in some cases and for tricky clinical situations.

The same ketamine that has been widely used for decades in humans and nonhuman animals. It has established efficacy, mechanism of action and a huge therapeutic index. A big distance between effective doses and the dose that will kill you. Whether effect is recreational, medical or veterinary. Meaning it is safe.

So why are the studies (cited below*) of effect in depression so exciting? Because traditional drug therapy for depression takes weeks to have effect. Weeks of daily dosing. Selective Serotonin Reuptake Inhibitors (SSRIs) like Prozac are broadly familiar to most of my Readers, I would assume. Efficacy with these front-line meds takes up to three weeks to see effect on depressive symptoms. Trouble is, some cases of depression are acutely suicidal–they may just kill themselves before any SSRI has a chance to make them feel better. And hell, who wants to wait three weeks if another med could make you feel better by tomorrow? Prior to the ketamine work, the only other thing that seemed to have such a rapid effect was ECT. Yeah, ElectroConvulsive Therapy. Which has come a loooooong way from the One Flew Over the Cuckoo’s Nest era….but still. A single ketamine dosing seems quite preferable.

So…..on to the me-too drug development! Woot!
Zarate CA Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA, Luckenbaugh DA. A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression. Biol Psychiatry. 2012 Nov 30. pii: S0006-3223(12)00941-9. doi: 10.1016/j.biopsych.2012.10.019. [Epub ahead of print][Publisher, PubMed]

This AZD6765 compound is, as you might deduce from the letters, property of AstraZeneca Pharmaceuticals and indeed one of the authors lists this as his affiliation. The rest of the folks are from the NIMH intramural program which, presumably, provided the majority of the funding for the study.

The conclusions appear to be that this novel compounds, with a similar mechanism of action as ketamine worked but less well. From the Presser:

About 32 percent of 22 treatment-resistant depressed patients infused with ASD6765 showed a clinically meaningful antidepressant response at 80 minutes after infusion that lasted for about half an hour – with residual antidepressant effects lasting two days for some. By contrast, 52 percent of patients receiving ketamine show a comparable response, with effects still detectable at seven days. So a single infusion of ketamine produces more robust and sustained improvement, but most patients continue to experience some symptoms with both drugs.

However, depression rating scores were significantly better among patients who received AZD6765 than in those who received placebos. The researchers deemed this noteworthy, since, on average, these patients had failed to improve in seven past antidepressant trials, and nearly half failed to respond to electroconvulsive therapy (ECT).

So this is good. Anything that shows promise as a rapid-alleviator of depression is good by my lights.

But why is NIMH spending taxpayer dollars to develop me-too drugs? Look, I recognize that drugs within a class of pharmacological mechanism, like the SSRIs, may be differentially effective for different patients. And it is a good thing if we have more options to tailor medication to the individual patient. ADHD is another situation where an array of monoamine transporter inhibitors, including methylphenidate and amphetamine, are used with success and failure. One drug works for one patient, another works for a different patient….and they might describe the other medication as even worse than not being treated. So…great.

But make no mistake. The central feature driving me-too drug development is profit. Drug companies decide they can take a big enough slice of the market away from the market-leader to make it worth their while. Perhaps they had development in parallel and had sunk enough cost in by the time their competitor gained FDA approval that there was no turning back. Whatever. Point being that they are in it for the money and not for some noble cause of serving that subset of patients that do not gain relief from their competitor’s drug.

Over the past few years the side-chatter about the ketamine effect on depression has frequently been a lament about the lack of financial motive for companies to push forward with ketamine. Push forward with specific clinical trials to gain on-label approval for the indication of depression. Push forward with marketing campaigns. Push forward with physician education and stroking like they do with their proprietary stuff.

The Zarate paper took a stab at claiming the reason for developing something else was an attempt to avoid the adverse effects of ketamine. The dissociative type effects can be unpleasant and recovery doesn’t look fun. So there’s some toehold there to claim one is motivated to find a “perfect” drug which somehow produces the therapeutic effect with nothing else. Color me skeptical, given what I know about existing NMDA channel blockers like ketamine (and PCP, did I mention that? Yeah, angel dust might work for depression….).

So I smell profit motive in this effort.

What I don’t understand is why NIMH is involved with this. Why not just pursue the evidence body for ketamine?
___
*References pulled out of the paper
R.M. Berman, A. Cappiello, A. Anand, D.A. Oren, G.R. Heninger, D.S. Charney et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry, 47 (2000), pp. 351–354

N. Diazgranados, L. Ibrahim, N.E. Brutsche, A. Newberg, P. Kronstein, S. Khalife et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry, 67 (2010), pp. 793–802

C.A. Zarate Jr, N.E. Brutsche, L. Ibrahim, J. Franco-Chaves, N. Diazgranados, A. Cravchik et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: A randomized controlled add-on trial Biol Psychiatry, 71 (2012), pp. 939–946

G.W. Valentine, G.F. Mason, R. Gomez, M. Fasula, J. Watzl, B. Pittman et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS Psychiatry Res, 191 (2011), pp. 122–127

M. aan het Rot, K.A. Collins, J.W. Murrough, A.M. Perez, D.L. Reich, D.S. Charney et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression Biol Psychiatry, 67 (2010), pp. 139–145