DrugMonkey

UK bans Mephedrone

Thu, 08 Apr 2010 14:34:13 -0500

The UK House of Lords has followed the riff-raff MPs in voting for a ban of the previously uncontrolled recreational drug 4-methymethcathinone (4-MMC, mephedrone, meow-meow, plant-food, etc). Prior observations from me are here and here.

This is a good opportunity to point to the report on the cathinones [ pdf ] that was created by the Advisory Council on the Misuse of Drugs. This more or less echos my points in my prior posts that while we may know a bit about cathinones the available scientific knowledge is pretty pathetic compared to the amphetamine-class drugs. And essentially nothing has been published on 4-MMC/mephedrone.

Second annual rally in support of biomedical science at UCLA

Thu, 08 Apr 2010 01:59:59 -0500

Wow, has it really been a year? Time for the second annual rally in support of biomedical research. I'll quote liberally from the UCLA Pro-Test for Science bit hosted at Speaking of Research:

In 2009, Pro-Test for Science held an historic rally on the UCLA campus; bringing over 700 people onto the streets in support of the scientists and researchers who carry out lifesaving medical research using laboratory animals. Such research continues to advance scientific knowledge and plays a vital role in the development of innovative treatments for human disease. However, animal rights extremists have continued to escalate their threats against researchers and their families.

On Thursday April 8th Pro-Test for Science will respond by rallying students, scientists and members of the public to support the cause of medical science. We call on the community to stand together against the recent tide of animal rights activism which has worked to misrepresent research and coerce those that carry it out.

A video from the rally held last year.

If you cannot attend perhaps you might want to take a look around Janet Stemwedel's blog. She has a number of thoughtful entries on topic of Research with Animals that are fantastic starting points for your own discussions that you will be having with your friends, family and colleagues. My own posts on the topic are perhaps less fulfilling but you may find a nugget or two. I would point you specifically to the Lie of the Truncated Distribution, an introduction to the heavily regulated activity of animal research, a description of additional guidelines that carry the weight of law and regulation and why the use of mice and rats is well regulated despite the Helms amendment.

You might also read a computer guy demolishing the myth that animal research can be replaced with computer simulations and an extensive and link-heavy discussion of typical animal rights' extremist tropes from Orac.

Happy reading.

Scienceblogs.com Press Release on Traffic

Tue, 06 Apr 2010 17:33:38 -0500

The Seed Media Group media center has a press release out [ pdf ] bragging on how awesomez we in the Scienceblogs.com stable are. Key stats include:

• Visits for the quarter ending March 31 grew by 41% year-over-year to approximately 13 million, and page views topped 25 million. Monthly unique visitors grew to 2.4 million worldwide and in the US surpassed 2 million for the first time this March.
• Total visits for 2009 grew by 55% year-over-year to 45 million and average monthly unique visitors climbed 49% to 1.9 million.
• ScienceBlogs.com has achieved high double-digit traffic growth (at least 50%) every year since its launch in 2006.

Nice job sciblings!!

I bother to highlight this for a number of reasons, including bragging on the performance of my fellow bloggers here under the Sb umbrella.

More importantly, however, I return to one of my occasional themes that if you think that science and science-related online activities are useful, you should also be interested in extending this usefulness to your colleagues. Whether it be your professional topic domain, mentoring, grant seeking, a rekindled interest in SuperCharismaticExtinctTetrapods doesn't really matter. If you want to see greater integration with your professional life you have to demonstrate efficacy to a skeptical audience.

Scienceblogs.com has not been in lockdown, precisely, about their traffic numbers but they have considered it privileged and proprietary information. So it has been hard to use this network to show others exactly what potential audiences exist. This is a nice step forward in openness.

source

Repost: NIH Basics: The Study Section

Tue, 06 Apr 2010 14:11:00 -0500

A recent comment revisits a perennial issue for those new to the NIH grant game. It is initially not clear to all grant writers that you do not need to pitch your grant to an audience of all biomedicine or even to your subfield at large. You need to pitch it to a set of about 15-30 people, most of whom you know specifically because they are serving 4 (*or 6!) years terms of service on the panel. The rest you can easily phenotype by reviewing the types of individuals who have served recently in an ad hoc capacity on the panel in question. This post originally appeared July 30, 2008.

A comment from drieken on a previous post asks:

Can anyone provide some context (eg, what's a study section that's not in the library?) for us not-yet-researchers?

This was echoed by a recent comment over at Evil Monkey's pad.

is there an online resource that explains the entire grant review process (NIH, NSF, whatever)?

There was also an email I received some time ago asking for an overview of the NIH system (sorry for the delay on that!).

Let's start with the NIH study section and how you should go about educating yourself with the information that you need to guide your own grant writing.

The study section is the panel of scientists who review a group of similarly-themed grant applications for the NIH. This is the initial (and some might say most important) level of review of the merit of a proposal. A typical study section might be 20-30 scientists who meet in person, traditionally in Washington DC or Bethesda (but now elsewhere), for 2-3 days to discuss applications. There are variants, however, including larger panels, longer meetings and even very small focused panels of ~3-8 reviewers who only discuss applications by conference call.

The Center for Scientific Review of the NIH administers the workings of the majority of panels. A list is here: http://www.csr.nih.gov/Roster_proto/sectionI.asp. This is the place to start your research into how your grant applications are likely to be reviewed and therefore how you should write them!

If you click on a specific study section you will first find a description of the areas of focus for that panel. Click on the "roster" link and you will find additional links to the appointed member rosters as well as the rosters for three of the most-recent meetings.

[Of course this is not news to my Readers. You already have been thinking about the typical study sections to which you might submit, familiarizing yourself with the types of reviewers that are on those panels, etc. Right? If not, you have homework. Yes, even you graduate students! ]

The appointed members are scientists who have accepted an invitation to serve on each meeting of the panel for a four year period. It is permissible to skip one of the meetings here and there but generally these individuals are committing to reviewing grants three times a year for four years. Intervals of service overlap such that there are always individuals rotating off after the June/July meetings and other individuals rotating into service during the October/November meetings. These individuals form the core of the study section culture and have the greatest overall impact on review behavior. It would be a very good idea for you to know what these people work on, where their scientific interests lie, etc. If you are new to the field (or even just don't know these scientists and their work) perhaps it would also be a very good idea to make sure they are on your schmooze list at scientific meetings. What could it possibly hurt that they can connect a face (and your witty convivial personality) with your name on the application? And what the heck? You might even ask them to have a coffee to discuss the nitty gritty of grant review since you are "a young scientist anticipating submitting grants to that study section and wish to educate myself on grant review which is a giant and frightening mystery". Trust me, people will eat that up and regale you with all kinds of interesting stuff.

The dated panels include the appointed members who were actually reviewing grants that round as well as an additional number of ad hoc reviewers generally indicated with an asterix. (The relevant dated roster, btw, is appended to the summary statement you receive for your grant application.) The ad hoc reviewers serve to enhance the breadth of the panel based upon the grants that have been assigned for that particular round (one of the key SRO jobs is to round up the ad hoc reviewers). These individuals may receive a relatively full load of applications or only contribute a single review (generally by phone in that case). They may be new to grant reviewing (this is one way the SRO can check out someone for potential appointment to the panel at a later time), be a frequent ad hoc reviewer (for this or a diversity of panels) or be a person who used to be appointed on the panel in the past. Obviously the individuals in question will not give you the most specific information because s/he may never review again for that panel. Keep in mind, however, that you can start to suss out a certain type of reviewer that is likely to be selected by the SRO. Similarly, the ad hoc reviewers frequently do come back and frequently make the rounds of a small group of study sections. A small group of study sections with similar interests to which you might conceivably be assigned for various of your applications. Remember, you are in this for the long haul so think beyond a single study section.

Beyond this, the study section is entirely simple.

1) Your grant gets assigned to 3 reviewers who receive your grant about 6 weeks prior to the study section meeting.

2) They carefully and thoughtfully read each proposal, assigning both a narrative critique and a preliminary score to each application. ~~Eventual scores range from 100 (excellent) to 500 (not so). Reviewers use single unit with one decimal point scores- 1.2, 2.4, etc which will eventually translate into the familiar 120, 240 scores.~~ [N.b. for repost: The scoring has been revised to range from 1 to 9 in integer increments, eventual priority scores are multiplied by 10.]

3) Preliminary scores and critiques are submitted one week prior to the meeting in the electronic reviewer system which is hosted at eRA Commons. All the reviewers assigned to a given grant can then review the critiques and scores and decide to modify their positioning on an application if so persuaded.

4) A triage line is drawn. Currently about 60% of applications are not scheduled for discussion at the meeting and will (generally) not receive a score. The remaining 40% will be further discussed.

5) Grants are discussed with each reviewer presenting his or her review. There can then be a bit of discussion between the reviewers to argue out differences of opinion. The other members of the panel frequently chime in as well.

6) The three reviewers then issue their "post-discussion" scores which, hopefully, describe a range with even better agreement than the initial scores.

7) The entire panel votes within the range of post-discussion scores.

Simple, eh?

HAH! This is where things get interesting and we'll have to discuss the devilish details in subsequent posts.

*Remarkably I have started to see the first people selecting this 6 yr term thing--you can tell because the termination year is listed in parenthesis next to the listings on the permanent roster for the panels. Insanity.

breadcrumbs...

Mon, 05 Apr 2010 18:27:08 -0500

in case you were wondering where I've been lately, I'm talking about those ballot-happy Californicans and their upcoming attempt to legalize recreational dope smoking over at A Vote for Science.

Your academic society is working for (or against?) you under the NIH Grant waterline

Fri, 02 Apr 2010 14:25:42 -0500

A recent blog entry from Pascale H. Lane discusses her reasons for belonging to academic societies. Our good blog friend Dr. Isis is frequently found to be going all fangrrl about the APS (no, not the real APS, these Physiological pretenders who are well down the GoogJuice list). Pascale touched on one Golden Thought about what academic societies can do that is, or should be, of general interest to my readership:

The society maintains several grant programs for research funding, and it leads advocacy efforts to maintain adequate federal funding for kidney disease research and treatment.

Grant $$$! Wooot!

Quite some time back on the original incarnation of DrugMonkey we started talking about the bunny hopper phenomenon. This was long-time commenter whimple's coinage of the term:

Say I work on the mechanics of bunny-hopping. My papers get sent for review to colleague bunny-hoppers, my grants are reviewed by the bunny-hopping study section, and there is never really an opportunity (ESPECIALLY with the study section) for a non-bunny-hopper to stand up and say, "look, other than the bunny-hoppers, nobody really cares about bunny-hopping, and I think we already know all we need to know about bunny-hopping for now," and close down the field.

Academic societies, of course, are bunny-hopper advocates. That's the whole point. To enhance, support and promulgate science in a relatively specific domain of interest. It could be disease related, basic science theory-related, biological sub-system associatedor technique-dependent. It can involve a specific research species or human subpopulation. Perhaps the bigger societies seem very broad ("Neuroscience") but that is only because you are not considering all of biology, health/medical science and/or all Federally supported research. Even these big ones are bunny hoppers by some accounting.

One of the things that academic societies are doing, or should be doing, on the behalf of the bunny-hopper scientists in their domain is to manipulate the NIH grant system. To work to ensure that as large a share of the NIH pie goes into their preferred topic domain as possible. We have seen some of this in the current (albeit waning) battle to merge the Alcohol-focused NIH Institute with the Drug-Abuse focused one. The Research Society on Alcoholism has been battling mightily to keep NIAAA intact and un-assimilated. Another way academic societies battle is by sticking their noses into the grant review process.

IFBH represent!Today's topic comes from a long-term reader who sent me something that ties back to our prior discussion (original here) of what NIH terms "clustering" and "captive study sections". The most extreme version of a captive CSR study section would be one that exclusively reviews grant proposals that would be assigned to a given NIH IC, say, NIAAA. But study sections might also be captive to a given topic domain. Conceptually we might think of this as captive to a specific academic society such as the International Fellowship of Bunny Hoppers. If we harken back to whimple's original critique, this sort of topic insularity of a study section risks continued NIH funding of decreasingly relevant science which has long since passed it's "drink by" date. Naturally, this is the concern of those who are not in the IFBH but are rather in the Society of Badger Diggers which, as we all know, work on much more relevant topics and publish more impactful research in journals of significantly higher prestige.

For the IFBH scientists, however, it is absolutely Right and Good that the relevant domain-captive NIH study section stay just like it is and has always been. The situation passed along by a reader, however, suggests otherwise. The NIH is apparently discussing the re-organization of a study section that is highly important to the IFBH scientists because many grants are reviewed there. The communication points out something you may not initially appreciate. Competition for funding, as we know, is tight. If you have 100 applications in a study section within a given round, then only about 10 of them (for argument's sake) are going to get funded. If that study section is captive to Bunny Hopping scientists, then they are competing against each other for an essentially fixed pool allocated to that study section (this is not the way it works exactly but it is a decent way to think about it). If, however, those 100 applications are spread out across four study sections with a more general mission and the Bunny Hopper proposals are highly competitive against say the Badger Digger, Otter Slider and Squirrel Hoarder applications then the IFBH might end up with 20-30 proposals being scored within the top tenth percentile.

So while the line PIs who have been successful might fear study section re-organization, perhaps the academic society is saying "Stop panicking, we've got plenty of more broadly competitive proposals, so let's go get some of that NIH $$ away from those other societies".

The trick is, of course, that only some subset of the IFBH membership is going to benefit. Some other subset is going to lose out. The question for any society, or any kvetching PI, is whether these shifts are a good or bad thing.

Back to the individual PI level I advise, as always, that devising research proposals which span the interests of a range of study sections (and ICs) is absolutely essential. Sometimes you are going to have Bunny Hopper wheelhouse proposals that would get eaten up in a broader section- so it's nice to have that internecine section available. Other times, you are going to bring new techniques and approaches to the Bunny Hopper field and it is easier to convince fans of those techniques/approaches of the importance of Bunny Hopping than it is to get the Bunny Hoppers on board with the HawtNewTechnique.

Clustering under the new NIH scoring system, just as predicted.

Thu, 01 Apr 2010 20:39:27 -0500

Score clustering, that is.

From the recent NIAID Funding bulletin (h/t: writedit), we have confirmation of what everyone expected when the new scoring system was announced for NIH grant review.

As a brief reminder, scores used by NIH grant reviewers ranged from 1.0 to 5.0 in decimal increments. The average of scores assigned by the panel members (or any applications that were discussed at the meeting-roughly the top 40-50%) was multiplied by ten to give the old application priority score range of 100 (the best) to ~250 (assuming about half were scored). The new system changed to an integer assignment system of 1 to 9.

Prior experience affirms that when the three assigned reviewers were in fairly tight agreement about a score under the prior system, the range might be from 1.2 to 1.5. A more typically ambivalent (but still "pretty good app" range) might have been from 1.3 to 1.8. Add on the effect of ~20 other panel members and you are looking at score outcomes that are reasonably distributed between, say 120-150 or 130-180. Lots of chances for numerical differences between closely-scored applications.

The new system poses the chance that a lot of "ranges" for the application are going to be 1-2 or 2-3 and, in some emerging experiences, a whole lot more applications where the three assigned reviewers agree on a single number. Now, if that is the case and nobody from the panel votes outside the range (which they do not frequently do), you are going to end up with a lot of tied 20 and 30 priority scores. That was the prediction anyway.

NIAID has data from one study section that verifies the prediction.

The bulletin points out the obvious:

In one study section, overall impact scores are clustered at 20, which translates to the 9 percentile. That study section has 8 ties, all of which get a percentile of 9. Because of that clustering, 21, the next score, skips a point to a percentile of 11, which is above the payline. Hence the distortion.
In contrast, when few applications score at a given level, several scores can get the same percentile. For example in the same study section, overall impact scores of 13 to 15 all translate to the 2 percentile.

Lately, we have seen a disproportionate number of overall impact scores at 10, 20, and 30. In the first two review cycles of this fiscal year, approximately 3 percent of applications reviewed by CSR received a score of 20.

I love the tone of that NIAID bulletin. "blur the payline picture". "distortion". "the uncertainty we face". HAHAHAHAAHA. Why, you might almost get the idea that they are as mystified as the applicant. And on our side, don't you see? What a joke. It cannot be repeated frequently enough.

This is a feature, not a bug.

The NIH knew this going in.

The new scoring system may produce more applications with identical scores ("tie" scores). Thus, other important factors, such as mission relevance and portfolio balance, will be considered in making funding decisions when grant applications are considered essentially equivalent on overall impact, based on reviewer ratings.

More importantly, read this 1996 report on NIH grant scoring. Page 2 of the document proper (page 9 of the pdf) has this bullet point which I find highly illustrative.

Scores are generated (by reviewers), calculated (by computer algorithms) and used (by program staff) as if they represented a higher degree of reliability and precision than they actually have.... Program staff are then put in a position of and held hostage to making and defending funding decisions based on these small and likely meaningless mathematical differences.

Emphasis added.

The NIH wanted and expected a lot more identical scores. Which inevitably come with massive percentile jumps across single allowable priority score increments. It was built in. The natural result is a lot of kvetching from applicants who see a 1-pt difference in priority score and a big-ol, and highly funding-relevant, jump in percentile between their application and that of their colleague down the hall (I think their 1-pt to 2%ile example here is optimistic, personally).

Beyond this general discontent effect on my fellow PIs who are not thinking this whole thing through, I have to say I'm in favor of this approach and the outcome. I feel that in the past POs were all too willing to act as if they believed, and likely did actually believe, that "small and likely meaningless mathematical differences" in score were producing bedrock quality distinctions. I felt that this allowed them to take the easy way out when it came to sorting through applications for funding. Easy to ignore bunny hopper bias which resulted in 10X of the same-ol, same-ol projects being funded. Easy to ignore career-stage bias. Easy to think that if HawtNewStuff really was all that great, of course it would get good scores. Etc.

I like that the POs are going to have to look at the tied applications and really think about them. It doesn't guarantee a given PO will come to the decision that you or I would, but at least they have to make a decision based on something related to the content of the application.

Nobody likes the Yankees, Disco Mag!

Thu, 01 Apr 2010 10:38:48 -0500

Look, it was bad enough that you poached off Not Exactly Rocket Science and Gene Expression in the span of two days. Now this [Update: links removed, further commentary deleted]

CongressCritters, can you please get the left hand talking to the right hand?

Thu, 25 Mar 2010 14:35:29 -0500

From this Op-Ed.

The Institute of Medicine has recently released a report outlining the ominous public-health threat of chronic hepatitis C, much of which is the result of unwitting infection through medically-necessary blood transfusions, leading to 350,000 deaths worldwide each year and infecting more than three to five times as many people in the United States as HIV.

Narsty isn't it? We should get right on that, don't you think? Any decent models for research?

Currently, chimpanzees are the only experimental animal, except for humans themselves, susceptible to infection with hepatitis C. The Great Ape Protection Act would end the use of chimpanzees in biomedical research, grinding promising studies to a halt and unconscionably delaying the release of anti-viral therapies and a vaccine for chronic hepatitis C.

Whoops.

Of course this isn't really any different than any other debate over whether the medical / health problem in humans is sufficient justification for a given type of animal research. Sure, we're talking Great Apes here and this is a very special species indeed when it comes to considering costs and benefits.

Nevertheless what I really focused on here was the Congressional idiocy.

You may have heard there is a bill afoot which will ban all research on Great Apes. ( Or, I should say "may". It is just a bill at this point, after all, and as we've just seen in the Health Care Reform debate, bills in the US Congress can be significantly modified prior to passage.)

The Institute of Medicine report did not go unnoticed by Congress: its release stimulated a press release from the Congressional Tri-Caucus promoting the Viral Hepatitis and Liver Cancer Control and Prevention Act (H.R. 3974) which, among other provisions, calls for additional research on a chronic hepatitis C vaccine. Ironically, nearly every sponsor of this legislation is also a co-sponsor of the Great Ape Protection Act, including Rep. Mike Honda (D-Calif.), who introduced the bill and has been a strong advocate for hepatitis research.

Now this is the real and actionable problem. Congressional decisionmaking that selects each bill for support/opposition based on how it looks in isolation. Great Ape Protection! Who can't get behind that? Cure Hep C? Big w00tangs all around! Congress is working for you, American people.

So who is going to point out that support for the one goal seriously undermines the success of the other goal?

[h/t: @harlequinclrty]

IACUC 101: Satisfying the erroneous inference by eyeball technique

Thu, 25 Mar 2010 09:11:29 -0500

I stumbled back onto something I've been meaning to get to. It touches on both the ethical use of animals in research, the oversight process for animal research and the way we think about scientific inference.

Now, as has been discussed here and there in the animal use discussions, one of the central tenets of the review process is that scientists attempt to reduce the number of animals wherever possible. Meaning without compromising the scientific outcome, the minimum number of subjects required should be used. No more.

run more subjects..

We accept as more or less a bedrock that if a result meets the appropriate statistical test to the standard p < 0.05. Meaning that sampling the set of numbers that you have sampled 100 times from the same underlying population, fewer than five times will you get the result you did by chance. From which you conclude it is likely that the populations are in fact different.

There is an unfortunate tendency in science, however, to believe that if your statistical test returns p < 0.01 that this result is better. Somehow more significant, more reliable or more..real. On the part of the experimenter, on the part of his supervising lab head, on the part of paper reviewers and on the part of readers. Particularly the journal club variety.

False.

p < eleventy dude!

I think this is intellectually dishonest. I mean, fine, there may be some assays and data types (or experiments) that essentially require that you adopt a different criterion to accept a result as resulting from other than chance. But you should have consistent standards and in the vast majority of cases that standard is going to be p < 0.05. Meaning that if pressed, you are willing to publish that result and willing to act as if you believe that result as firmly as you believe any other result. Trumpeting your p < 0.001 result as if it is somehow more real, however, is trying to say that you had a more stringent criterion in the first place. Which you most certainly did not. So it is dishonest. Within scientist, within fields and across science as a whole.

If p < 0.05 is the standard, than all else is gravy.

As anyone who has done any work with animals knows, in a whole bunch of cases you can lower that p-value simply by running more subjects. In fact it is not unheard of for PIs to tell their trainees to run a few more subjects to make the p-values (or error bars, same principle) "look better".

"Look better" means, "we don't actually make our inferences by statistics at all, what we actually believe in is the significant-by-error-bar-eyeball technique".

So imagine yourself on an Institutional Animal Care and Use Committee. One of the things you are supposed to evaluate is if the number of rats proposed to study, say, mephedrone is excessive. Roughly speaking let us stipulate that N=6 gives us the minimum power required to get a significant p-value; N=12 is robust. A decent chance of p < 0.01. But the PI is asking for N=18 per group so that the error bars look super tight and that notorious Reviewer #3 won't complain that the p < 0.05 doesn't seem real to him.

What group size are you going to approve? On what basis? How do you reconcile Reduction with the eyeball inference technique?

__
By all means take a stab at interpreting the graphical results derived from a repeated-measures study involving two timepoints. Which one is the significant result? [Update: I initially forgot to mention the bars are SEM]

Scientific Research 101: Results!

Wed, 24 Mar 2010 02:33:25 -0500

So you've just completed your last assays on physioprofitin signaling in the Namnezian complex. Lo and behold it is qaz-mediated, just like you suspected and the beccans are off the freaking chart. woot! PiT/PlS ratios are within relevant physiological ranges and still this work of art, your labor of love, came through with the experimental goods.

With a hope and a prayer you run your stats....and YES! p < 0.01!!!!!!!!!!!!!!!

What is the correct way to report your big Result?

doin it right

Sat, 20 Mar 2010 11:49:33 -0500

[ Please welcome our guest blogger, who identifies as robin, just your average everyday neuropharmacologist. -DM ]

One of the most important yet overlooked tasks of the average pharmacologist is dissolving drugs into solution. Those of you who work with things that don't have to cross the blood-brain barrier probably have a generally easier time dissolving shit than those of us who prefer to study CNS-active compounds. For those of us who play with compounds that are hydrophobic enough to cross the blood-brain barrier, I can testify that those range from fairly easy to major suck to put into an aqueous solution.

The principal reason this is important is pharmacokinetics. I almost said simple pharmacokinetics, but those two words really only belong together when the intent is sarcastic. In the in vivo model, one has to contend with the processes of absorption and distribution before the drug can go to work. Absorption, being the first step, is crucial.

In order for a drug to do its thing, it first has to be absorbed into the bloodstream. A typical experimental route of administration is through the peritoneal cavity, or i.p. This is not injecting directly into the bloodstream, but there is quite a bit of blood circulating in the general vicinity. The drug has to pass through all of the membranes standing between it and the blood in order to begin to circulate to its site of action. And once we've got this batch of drug molecules running around in the bloodstream, presuming they got there in the first place? They're hanging out in the fat cells, or not. They're slowly (or quickly) making their way to the site of action. And that's not even considering the metabolism and excretion parts of pharmacokinetics! You see there are many variables to in vivo pharmacology, even under the most optimal conditions.

So what happens when things go wrong? Say the drug is not dissolved. It's decided it hates you (ok, probably too much anthropomorphizing, but at this point I might as well go for it) and when you add anything the least bit aqueous, it crashes out of solution into crystallized form. Convenient way to isolate a drug, perhaps- shitty way to prepare one for use. If this happens and you try to gather some of this shit up and inject anyway, well, you're doin it wrong. The drug needs to be in some kind of homogeneous solution.

Why do we care? Pharmacologists like to see a drug concentration-response effect when looking for drug effects. Drug concentration is a measure of how much drug is dissolved in solution. Using an incompletely dissolved drug will not reflect the drug concentration, but instead how many crystals comprised of how many milligrams (or fractions thereof) that you randomly collected for that particular syringe draw- if you collected any at all. Dissociation of molecules from the crystallized form into the body compartment is a major rate-limiting step in absorption. This is a crucial step in the oral dosage format, but injection of solutions is intended to bypass some of the common problems of oral dosing. In this case, the intended, effective drug concentration might never be reached.

But there are more reasons than just the theoretical science here. The crystal might not fit through an appropriately sized needle, for one. And pushing a crystallized drug can cause undue pain to the subject, which is to be avoided at all costs. These are not secondary concerns; they are non-negotiable from an ethical standpoint.

So what do you do? There are ways around it- rain dances that we do. Some dissolve hydrophobic drugs straight up in some kind of oil and inject as an oil depot. This is a slower pharmacokinetic situation, because the drug equilibrating between the oil and the body is a huge rate-limiting step. Hydrophobic interactions between drug molecules can slow absorption considerably. But it's useful for some types of studies. In general, aqueous solution is preferred. Why? Most simply, we want the drug solution to be miscible with the aqueous body compartment that receives the injection. But we don't like to add pure water into biological systems. Pure water screws with the delicate ionic balance maintained by cells, and causes major trouble. Saline is the default water-based injection vehicle. Creating an aqueous solution sometimes requires one to fuck around for ages (in bench-science time) finding the lowest percent of [choose your oil-based substance] that will keep the drug in solution. And in some cases, you can dilute a hydrophobic drug in a non-aqueous solvent far enough that adding aqueous liquid slowly and carefully will not cause it to crash out of solution. It all depends on the drug and the concentration you're looking for, but it's usually a task.

What about emulsions? Consider propofol, a short-acting intravenous anesthetic and recent headline-maker in the death of Michael Jackson. Propofol is totally fucking hydrophobic. You will not for the life of you get that shit into a water-based solution. In this case, in order to prepare the drug sufficiently for use in people, it is dissolved in oil first. The drug dissolved in oil is mixed with aqueous solution and surfactants, and processed to a uniform oil droplet size and dispersion in the aqueous solution. The surfactants keep the oil droplets suspended in the water-based solution, whereas oil droplets would typically merge and separate from solution without surfactants. The small size of the oil droplets increases drug surface area, improving drug-blood equilibration time. (note that i.v. means the drug goes straight into the bloodstream.) This is the next-best thing because the amount of drug is evenly distributed through the solution. If it was not properly distributed, physicians would not know whether they were giving a proper dose to maintain sedation and anesthesia. With any drug concentration unknown or outside a certain error margin, major problems arise. With propofol, patients might wake up during surgery without sufficient drug administration- or conversely, they might overdose with too much. Both are very much undesirable, and this potential source of error is considerably reduced due to proper procedure in dissolving drug.

While we experimental pharmacologists may work in very different settings and conditions than, say, your average anesthesiologist- the principles of drug dissolution remain the same. In order for the drug to work for us, we have to work with the drug to get it into solution. Taking the time and trouble to do it right matters.

Scientific Research 101: Meow-Meow, "plant food", 4-MMC, mephedrone...

Fri, 19 Mar 2010 13:55:29 -0500

sourceI recently introduced a paper on the discriminative stimulus properties of cathinone analog drugs with reference to the recent emergence in the popular media of an analog called 4-methylmethcathinone (4-MMC), mephedrone (2-methylamino-1-p-tolylpropan-1-one), Meow-Meow, MMCAT. The name "plant food" is what 4-MMC is apparently being marketed under in the UK, given that the compound itself is not controlled but it is illegal (I surmise) to sell things as "legal ecstasy" or "legal methamphetamine" or similar. There has been one fatality attributed* to 4-MMC that I can find and a few bits of seized-drug analysis confirming that the stuff is indeed being used.

An early report of a fatality associated with consumption of the drug in Sweden resulted in placement of mephedrone on the controlled list. The followup in the Swedish press shows that the woman was reported to have consumed mephedrone (confirmed post-mortem) and smoked cannabis (no apparent confirmation; alcohol and other narcotics excluded postmortem) and then collapsed. Emergency services were unable to revive her and she died a day and a half later; symptoms of brain swelling, stroke, hyponatremia and hypokalemia were mentioned, as well as a low body temperature of 33 degrees C.

The story has heated up recently in the UK press after the death of two individuals who are, at present, suspected of taking 4-MMC/mephedrone, reportedly in combination with methadone (an opiate) and alcohol. As I mentioned before, a quick scan of PubMed finds little reported on the effects of this compound in animal models or in humans.

So the question is, scientists, what next?

Let's play virtual science, shall we?

[ Before we start, let me remind you that my usual disclaimers apply. I may or may not have a variety of dogs in this hunt but I would suggest that if issues of potential conflict of interest concern you, you simply assume that I am conflicted up the wazzoo and read my thoughts accordingly. ]

In this exercise, feel free to inhabit any of a number of players so long as you keep focused on the science. Perhaps you want to approach this as a Principal Investigator or maybe a funding agency's Program Official. Perhaps as a member of a policy advisory panel or governmental advisory division (such as the US DEA which contains people whose job it is to make reports on whether a drug should be scheduled or not). Even as a member of tax paying public or recreational user groups- if you are in this latter I would appreciate you keeping it as brief and on-topic (e.g., you might make an argument for why existing information on cathinone class drugs is enough knowledge).

The answers I am looking for are varied. We start with a pretty low baseline of scientific knowledge about this specific compound, but some decent knowledge of related cathinones and slightly-more-distantly related amphetamine class drugs. Do we need to know more? What? What should we throw money into and in what order?

I'd like to first play Program Official (and probably IC Director because she's the one that gets to really make things happen by fiat).

The scope of the problem: First off, I'd like to lean on my drug epidemiology folks and those running clinical research programs to start asking where mephedrone is being used, how popularity is growing and how many people are calling Poison Hotlines to ask about toxicity. I'd think I can pull this off first by making a request of existing grantees, maybe bring a few to Bethesda (or wherever your local apparatus may meet) for a one-day brainstormer. If pressed, maybe we could cut loose a few supplements, maybe 10 or so, to the tune of about $50K to do some additional surveying.

Pharmacology: Yes, we have a general idea of what cathinone derivatives do but I'd want to see some pharm workup in bench models right away. This would have the benefit of helping to guide any animal work we'd want to do later. What are the affinities for dopamine, serotonin and norepinephrine signalling components such as pre- and post-synaptic receptors and transporter mechanisms? How effective is mephedrone at activating, inhibiting of being a substrate for these? How does it compare to the various amphetamine analog drugs? I can probably task someone in the Intramural Research Program of the NIH for this, if not I expect to have to cough up at least $100K in directs to an extramural laboratory. Definitely worth it.

Animal studies: Even on the strength of the UK popular reports, I think we have enough to justify some initial work in animals. Rodent lab stuff, done to the tune, again, of R03 money. I'd want to immediately generate the standard LD₅₀ estimates. This a research design in which groups of animal subjects are dosed with a range of doses until you can get an estimate of at which dose half of them die. (You can start thinking about the ethical implications now a little bit but I'm planning to have another virtual-Animal Care and Use Committee post tied into this later.) I'd also want to see some self-administration data, here I think mephedrone substitution in amphetamine and cocaine trained rats would probably do for starters. Then I'd want some drug-discrimination data, preferably in animals trained to discriminate amphetamine and MDMA. Maybe some data from one of the hyperlocomotion / stereotypy laboratories as well. So maybe four $50K awards to run off some quick and dirty data.

A question for me (again, as a Program Official) is whether to issue an RFA on this topic. It is tempting. Why? Because rumoring and then putting out an RFA on mephedrone has a damn good chance of getting the bigger laboratories with the major models to whip out some quick studies as Preliminary Data within their existing funding. I.e., I can get all of the above data generated, and into the NIH system where I can see it, at no additional cost (save the opportunity cost of a bunch of PIs diverting their ongoing work for this purpose). Trouble is, we may not be at the point where we're ready to actually justify funding bigger / longer term projects yet. (Hmm, I suppose we could just troll the investigators and then not actually fund anything out of the RFA but that seems kind of mean.)

So, DearReader, what would you do? As a scientist do you have some studies to put the grad student on? Are you taking a pass for affirmative reasons? Do we need to know anything more about mephedrone or not? If we do, where do we start?

Scholars and Teachers on Divergent Paths

Thu, 18 Mar 2010 13:29:32 -0500

Research (source)via Female Science Professor. A recent news bit in the Chronicle of Higher Education details another case in which the alleged three legged stool of Professorial careerdom (teaching, research, service) is revealed to stand only on the one leg- research.

his department's tenure-and-promotion guidelines.. were revised in 2000, shortly after he had received the university's Distinguished Teaching Award and a similar prize from a statewide association of governing boards.

Under the revised criteria, faculty members are given many more points for supervising graduate students than for teaching undergraduate courses. "I can teach an undergraduate course with 44 students and get only three points," Mr. Vable says. "But a faculty member who supervises a graduate student gets 19 points and can be released from course duty. So that totally skewed the algorithm."

Well, at least they are up front about it.

Look, this is no surprise to me and it shouldn't be to you either. Even in primarily teaching-focused colleges you can have evidence of "scholarship" raising its head as being more-equal than teaching excellence. Research University? Forgeddaboutit. I've never yet heard of a professor with high research productivity and grant acquisition being held back in any serious way because of crappy teaching. It may happen somewhere but it sure isn't common. OTOH, reports of faculty with teaching accolades being denied tenure because of a failure to generate a sufficiently active or awesomez! research program are easy to find.

I'm not so concerned about the specifics of this case. About whether the University changed promotion criteria mid-stream, whether a faculty member was a fool or not to believe the three-legged-stool lie when originally hired, what this dude's publication rate was relative to colleagues, etc.

The question is whether this is a good thing to be doing in our higher education / academic research institutions. What does it mean to be a faculty member of a research university? Are we right to be encouraging a sort of dual-track separation between researchers and teachers?

Mr. Vable, for his part, believes Michigan Tech is still far out of balance. Last month students in Michigan Tech's College of Engineering named him one the college's best three instructors. He used the occasion to write an open letter to students. "We are creating a system where teachers and scholars are on divergent paths," he wrote.

Whether or not this is the case at that University, at least Professor* Vable's provost argues that this is not the intent.

"I firmly believe in the unity of teaching and research at a doctoral university," Mr. Seel says. "And hopefully discussions about how to achieve that balance will never end. Those discussions are healthy for all of us."

I don't know that I agree with this and I certainly believe that our business has been actively dissolving this relationship for a long time. The reasons for tenure-denial and failure to make full professor are one area in which this is apparent. Also the relative number of teaching hours covered by temporary vs. tenure track staff. The way research grant awards can be used to "buy-out" of teaching duties.

I am just not convinced that undergraduate education, as education, is superior at a research institution. Teaching is.....a thing. An art, a craft, a profession, a vocation...call it what you will, not everyone can do it. Not everyone can excel at it. And it takes work. Real work. Focus. I just don't see how anyone can argue that the teaching / learning part of undergraduate studies is not superior when the instructor has but the single job- of teaching undergraduates.

Now, there may be other benefits to being around research or cutting edge humanities scholarship, particularly for those who will eventually continue into academic-type careers. I am not sure these benefits outweigh the cost of inferior education for the vast majority of college students who will not go on to graduate studies.

The conversation over at FSP's place seems to be focused a little bit on the cost angle. Are undergrads being forced to pay for research activities of doctoral students and faculty from which they do not benefit?

I'd ask the other question- are NIH funds being used to underwrite general undergraduate education? Do those grants keep the University infrastructure rocking, thereby lowering tuition costs? How much of that grant/University time allocation edges over to the professor engaging (reluctantly) in his or her teaching responsibilities on the NIH grant dime? If those alleged educational benefits of active research laboratories are accruing to the student (see this comment), what fraction should be charged to the tuition bill and what fraction to the NIH dime?

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*Anyone know why the Chronicle doesn't use "Dr." or "Professor" and opts for "Mr./Ms."?

A survey on "science blogs"

Tue, 16 Mar 2010 14:12:49 -0500

After I read the now-infamous paper by I. Kouper, entitled "Science blogs and public engagement with science: practices, challenges, and opportunities", I was left in some confusion as to how the author selected 11 blogs to study. I was also curious about what my readers thought of when asked to generate a list of "science blogs" so I asked them. I left the request as general as possible because I was interested in what "science blog" meant as much as in specific examples.

For your entertainment and edification, I tabulated* the results from the 31 answers supplied as of this writing.

I sorted the 101 mentioned blogs by the number of mentions and then alphabetically for ties. As you can readily see, there would appear to be effects obviously attributable to my specific audience. Namely those who are interested in the conduct of science, the Tribe of Science (as Janet Stemwedel coined it) and academic careerism. I was sort of fascinated to see that my personal take / approach in thinking of just-the-papers-ma'am type of blogs was not how my readers were reacting. It was also pretty cool to see some blogs mentions that I'm not familiar with, some new reading if nothing else. Ok, on to...

The Results.

DrugMonkey	20
Female Science Professor	13
On Becoming a Domestic and Laboratory Goddess	13
Pharyngula	11
Not Exactly Rocket Science	10
Neurotopia	9
Adventures in Ethics and Science	8
Respectful Insolence	7
White Coat Underground	7
Effect Measure	6
Bad Astronomy	5
In the Pipeline	5
Terra Sigillata	5
The Loom	5
Thus Spake Zuska	5
Blue Lab Coats	4
Obesity Panacea	4
Professor in Training	4
Uncertain Principles	4
Chemical BiLOLogy	3
Comrade PhysioProf	3
Cosmic Variance	3
Gene Expression	3
Laelaps	3
Medical Writing Editing & Grantsmanship	3
Neurologica	3
Prof-like Substance	3
Young Female Scientist	3
A blog around the clock	2
Ambivalent Academic	2
Applied Statistics	2
Candid Engineer in Academia	2
Cocktail Party Physics	2
Deep Sea News	2
Exponential Book	2
Flowing Data	2
Living the Scientific Life (Scientist, Interrupted)	2
Mike the Mad Biologist	2
Real Climate	2
Scientific Misconduct Blog	2
Tetrapod Zoology	2
The Frontal Cortex	2
The Science Insider	2
Aardvarchology	1
Adolescent Risk Behavior	1
Aetiology	1
Backreaction	1
Bench Marks	1
biocurious	1
Bitesizebio	1
Cognitive Daily	1
Confessions of a Science Librarian	1
DamnGoodTechnician	1
Depleted Cranium	1
Dispatches from the Culture Wars	1
Dot Physics	1
Dr. Jekyll & Mrs. Hyde	1
Ecce Medicus	1
Eruptions	1
erv	1
Fat Nutritionist	1
Flying Flux	1
Genomics, Evolution and Pseudoscience	1
Greg Laden's Blog	1
Highly Allochthonous	1
Incoherently Scattered Ponderings	1
Insigulo	1
Inverse Square	1
Janus Professor	1
John Hawks Anthropology	1
Language Log	1
Learning Curves	1
Marginal Revolution	1
Mommy / Prof	1
Neoformix	1
Neurocritic	1
Neurophilosophy	1
Neuroskeptic	1
Not Even Wrong	1
Now, what was I doing?	1
Open Mind	1
Pharmagossip	1
Revolutions	1
ScienceNOW	1
Skeptical Science	1
Slacker Astronomy	1
Some Lies	1
Statistical Modeling, Causal Inference and Social Science	1
Swans on Tea	1
Tales of a Genomic Repairman	1
The Clade	1
The Great Beyond	1
The Intersection	1
The Mind of Dr. Pion	1
The Primate Diaries	1
The Pump Handle	1
The Science of Sport	1
The Tree of Life	1
Thoughtful Animal	1
Urban Science Adventures	1

I also had left the door open for mention of blog collectives or aggregators because the Kouper paper seemed to mix-n-match. The number of mentions of a group of blogs are ranked in this table.

Collectives and Aggregators

scienceblogs.com	7
Science Based Medicine	4
Nature Networks	3
researchblogging.org	2
The Panda's Thumb	2
scienceblogs.de	1
Psychology Today	1
Discovery Blogs	1

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*I did one quick run-through. It is possible that I missed a blog mention or miscounted here or there. If anyone spots an error try to be as specific as you can and I'll correct it.

Note: In case any of you are HTML idiots like me, I found a neat hint to turn Excel columns into HTML table entries here.