TL neuro

April 13, 2017

Pre-Prints

Filed under: Careerism, NIH — mtaffe @ 10:11 am

In 2017 the NIH issued NOT-OD-17-050 Reporting Preprints and Other Interim Research Products to encourage funded investigators to speed the dissemination of tax-payer funded research by citing and claiming pre-prints as products of NIH funding.

The NIH encourages investigators to use interim research products, such as preprints, to speed the dissemination and enhance the rigor of their work. This notice clarifies reporting instructions to allow investigators to cite their interim research products and claim them as products of NIH funding.

Pre-prints are manuscripts (and other interim research products) which have not undergone peer-review and formal acceptance for publication.

The most critical implication of this new policy is for grant preparation.

Interim research products can be cited anywhere other research products are cited.  These sections include the following:

The benefits should be clear. Instead of having to describe work as being “in preparation” or “submitted” one can now point to a link and any interested reviewers can see it for themselves. This will be critical on the CV or Biosketch of junior scientists in transition. The publishing timeline is slow compared to their needs with respect to finding a postdoc appointment after graduate school, winning a fellowship as a postdoc or getting a job offer after postdoctoral training.

This will potentially help all PIs with their grant applications as well. Productivity can be a major point of review for new applicants, for renewal applications and indeed for any application if a PI is perceived to have too much funding. Productivity as reflected in peer reviewed published papers is not always under the direct control of the research team- the publication racket can induce significant unexpected delays. This pre-print policy allows the grant applicant to post pretty much anything that they want. It will potentially function as a hybrid of Preliminary Data and Publications. “Potentially” because there is no obligation for any reviewer to consider these documents.

I have decided to respond to this new initiative, for now, by submitting manuscripts to bioRχiv (http://biorxiv.org). I have found the submission process to be relatively easy on the scale of the usual manuscript submission for publication or to the PMC repository. The first two I submitted were available online within 24 h of my upload.

The critical question for most of us will be to try to determine what our threshold should be for publicizing any pre-print or interim research product. I have come to the conclusion that a manuscript that we have already submitted for publication somewhere clearly fits the bill as a sufficiently complete work to put on a pre-print server. A manuscript that we plan to submit for peer review essentially concurrently is also very clearly sufficient and the only difference here, to my view, is whether we are really, really at a submittable-draft stage or maybe jumping the gun with the pre-print.

The following three manuscripts had already been reviewed by the time I put them up on bioRχiv. I would characterize two of the reviews as being concerned about interpretation of the data in a way that would require a LOT more data to satisfy. This appears to me to satisfy one potential goal of posting pre-prints. I.e., that people can interpret the quality and meaning of the data for themselves before the authors manage to satisfy all theoretical concerns, sidelines or unlikely possibilities that might be required for publication acceptance. The third one is awaiting one more figure of data for the resubmission. We thought we had a decent rebuttal without it, one that would possibly fly with the editor. But we are also generating new data that is relevant. This has been slower to emerge than I had hoped and we have noticed some recent publication activity in this area. Posting this manuscript as a pre-print is essentially putting down a priority marker at this time.

Javadi-Paydar, M., Nguyen, J.D., Grant, Y., Vandewater, S.A., Cole, M., and Taffe, M.A. Effects Of Δ9-THC And Cannabidiol Vapor Inhalation In Male And Female Rats.  bioRχiv, 2017, Posted April 18, 2017 doi:

Taffe, M.A. Wheel running increases hyperthermia and mortality rate following 3,4-methylenedioxymethamphetamine (MDMA) in rats. bioRχiv, 2017, Posted April 11, 2017 doi:

Aarde, S.M., Huang, P-K  and Taffe, M.A. High Ambient Temperature Facilitates The Acquisition Of 3,4-Methylenedioxymethamphetamine (MDMA) Self-Administration. bioRχiv, 2017, Posted April 4, 2017 doi:

 

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September 20, 2016

Just. Keep. Swimming.

Filed under: 4-MMC/Mephedrone, Cathinones, MDPV, NIH — mtaffe @ 1:07 pm

In the prior post I tried to give some flavor of the sort of grant submission effort that it has taken for me to keep my lab afloat to this point in time. That description gave an overview of my rough success rates which hovers somewhere in the high teens, not too far away from the aggregate NIH success rate over a similar interval of time.

As I point out to trainees now and again, there is no reason for any of us to think we are somehow special in securing grant funding. The NIH system of extramural funding has been under high stress in the past 10-15 years and there are far more deserving proposals being submitted than can be funded.

In this post, I want to outline the course of a particular research program of mine.

In early 2010 I became aware of a new recreational drug called mephedrone, (aka meow-meow or plant-food) which was very popular in the UK. It was not legally controlled and it seemed to emerge in a bit of a MDMA drought in that country. I soon found that 4-methylmethcathinone was the drug of interest, that the core molecule of cathinone was very similar to amphetamine and that it appeared to be only one of several substituted cathinones which were circulating. I did a bit of searching on PubMed and rapidly concluded that very little science had been published with any of the cathinones after a brief interest in methcathinone and cathinone in the 80s. From what little pharmacological evidence was available, combined with human subjective trip reports I could find online, it was pretty clear that we were facing a reboot of the substituted amphetamine era of the 1980s.

Mephedrone had first come to media attention around 2008 with an overdose in Sweden and had gradually grown in popularity through 2009 and into 2010. The UK government was alerted, trying to complete legal controls and had to rely on very imprecise reviews of the available knowledge.

I found this professionally embarrassing that so little was known. We spent so much effort on methamphetamine and MDMA and here, one to two years into a novel drug phenomenon we knew nothing. Nobody was presenting data at the scientific meetings I was attending, either.

I was also very interested scientifically precisely because of my interest in that prior episode of substituted amphetamine popularity and in the clear “winner”, i.e., MDMA or Ecstasy. This highly popular new drug, mephedrone, was being used by MDMA type populations in the MDMA type environment with many of them explicitly saying they were looking for a MDMA substitute. This drew my attention. There was also a very clear under-current that this mephedrone stuff was like a poor echo of MDMA but watch out for the compulsive use risk. Users were suggesting that this compound was perhaps more like a traditional psychostimulant than MDMA is.

This realization came as I was working on a final revision of an R01 proposal I was submitting on the topic of the abuse liability of MDMA, why it differs from a traditional psychostimulant like methamphetamine and how various situational or experiential factors may make MDMA more compulsively abused. The A1 had received a 21 %ile with pretty minor criticisms so of course there was no way I was going to start dragging in new drugs for the A2 (which I submitted in April of 2010).

Instead I started plotting an assault on specific funding for these novel cathinone drugs. I contacted my Program Officer who, having driven some funding opportunities for MDMA back in the day, was of course interested. But this was 2010. And there was about zero enthusiasm down in the NIDA trenches for anything that wasn’t already on NIDA Director Volkow’s current priority list. In emails and eventually in person at CPDD that year, I bounced around from one NIDA person to another and came up with a similar story. Nobody was enthusiastic about generating any special interest. “Get a fundable score and we’ll talk” was the size of it. There was even a hilarious (not really) standoff between DEA who were demanding data from NIDA (for their intent to Schedule some of these drugs) and the latter’s demand that DEA pay for it and sure, they’d see what they could do.

I got friendly with some DEA scientists to find out what was being seen in the US since law enforcement detection usually runs far ahead of any epidemiology in the peer reviewed literature. From this I deduced that mephedrone was actually pretty rare in the US but that MDPV was going to be a thing.

As we all know, Preliminary Data was going to be required to get a grant funded. But that requires….the drugs!

NIDA drug supply wouldn’t provide any of these new drugs. The usual commercial suppliers didn’t have them either.

Luckily, I was working with a couple of investigators in the department of Chemistry. One of them, Tobin Dickerson, took a look at what I needed and said “Looks pretty simple, how’s next Thursday?”. Boom! We were in business.

Our first grant proposal on this topic was submitted in October of 2010 and focused on mephedrone/4-MMC. It included self-administration data, thermoregulation and activity data, metabolism and PK data from Karen Houseknecht at UNE, microdialysis data on dopamine and serotonin responses generated with Larry Parsons’ lab and receptor/transporter screening from Bryan Roth’s Psychoactive Drug Screening Program at UNC. We proposed self-administration investigations, physiological endpoints and PK. In recognition that there were going to be many other substituted cathinone derivatives of interest we proposed a bit of structure-activity manipulation to start looking at whether specific chemical alterations conferred enhanced/decreased risk for adverse outcomes. In retrospect, putting all this together in the early days of this drug trend was probably one of the best things I’ve ever done in terms of a scientific program.

It was triaged. The app went to MNPS study section instead of BRLE (which we had requested) or even NMB, probably because of all the PK and the structure/activity content. Even though the focus was really on the novelty and the abuse liability/risks. We got 4-6s on the Innovation and 5s on the approach. But really, reading on and between the lines of the critiques it was all about “Problem? What problem?“. This could have occurred at any study section.

One has to be a bit sanguine about the inherent conservatism of the NIH grant process. It was absolutely true that there was not as yet overwhelming evidence of broad use of substituted cathinones, no evidence of large numbers of addicted people in serious life crisis and no evidence of weird/unique dangers akin to the serotonergic neurotoxicity that attends high-dose repeated MDMA exposure to drive enthusiasm.

But still. We weren’t the only ones who could see the importance of this. And as I started to present our data at meetings, I would run into colleagues who were also interested in studying these drugs. And their efforts at grant funding were to sound very familiar over the coming years.

The A1 for this initial proposal was submitted July of 2011 and likewise triaged by MNPS. There was still a lot of kvetching about “Problem? What problem?” but also some typical grant stuff. “Too descriptive”. “What’s the hypothesis”. Etc. This is always a problem for how I look at science, of course, but in this case it was kind of annoying since very little was known about any of these drugs yet, and we did have a clear hypothesis under investigation. [Related papers: Huang et al, 2012; Wright, Angrish et al, 2012; Miller et al, 2013; Aarde, Angrish et al, 2013]

I next incorporated cathinone studies on a competing continuation application for a prior MDMA-focused project that admittedly had issues with its chance of being renewed, even before I added cathinones. The first one went in July 2011 and was triaged by BRLE. The A1 went in March 2012 and got a 42 %ile. As far as the inclusion of substituted cathiones goes, it was mixed. Some reviewers saw this as a positive but some also made comments to the effect of “Problem? What problem?” and “Why don’t you have clearer hypotheses?”. Seeing a pattern? [Related paper: Wright, Vandewater et al, 2012]

I had been doing some work on methamphetamine vaccines with the Janda lab, where my collaborator on the cathinones had done his doctoral studies. As a newish PI, he’d been trying to get away from that area of work (successfully) but here I was dragging him back into work on drug abuse. So it seemed natural for us to put in a vaccine proposal in October, 2012. This time we were focused on MDPV because it was becoming clear in our ongoing studies that this was much more like a traditional psychostimulant with a high potential for addiction in humans. Triaged. With reviewers throwing 6s and a 7 and an 8! Ouch. Well, it certainly wasn’t my strongest proposal but, more to the point, there wasn’t much complaint about the drug choice. Maybe because the rest of it drew so much fire, I couldn’t say. [Related paper: Aarde, Huang et al, 2013]

[Updated: I forgot about this one] I tried a slightly different strategy at this point, submitting a new proposal in October 2012 that wasn’t focused on the cathinones, per se. Instead, this was a proposal about another topic in substance abuse research (one which had background, we’d been working a little bit on it, had a pub, etc, etc) where we just used MDPV self-administration as the drug model. Our most recent Preliminary Data were from this so why not, right? The PMDA study section triaged it- one reviewer threw a 9 for approach and a 7 for significance but the other three reviewers were throwing 3s and 4s mostly. Leaving aside the hater reviewer who went off hilariously on ad hominem attacks and thoroughly unjustified complaints (going by my rather considerable collection of grant reviews testifying to my minimal competence level), the remaining three reviewers ranged from slightly skeptical (insufficient justification for selecting MDPV as the model) to out and out objecting (“…should be examined using a drug that has well characterized patterns of self-administration in the laboratory“). Needless to say when I put the revision in it did not include a cathinone as the model. [Related papers: Aarde, Huang et al, 2015; Aarde, Miller et al, 2015]

In Feb 2013 we submitted a new approach to the cathinones, now with the take on Hypothesis B, as opposed to the Hypothesis A that underlay most of our arguments up to this point. Triaged by NMB. Things were improving slightly, however. A little bit of kvetching over methodology but for the most part no complaining about the relevance of studying these emerging drugs. A fascinating new all-reviewers complaint was included about our structure-activity studies somehow informing clandestine chemists how to make better (or worse from another point of view) drugs. [Related paper: Aarde, Creehan et al, 2015]

Of course by this point we had started publishing papers on cathinone-related topics. Our first ones must have appeared online in early 2012 with print versions issued in fall of 2012. I think we had 6 papers published by the end of 2013. I’ve added citations to the above to indicate the approximate stage of Preliminary Data that were available and relevant at each grant submission- obviously the papers appeared later in most cases.

I’m not entirely sure I remember why but we submitted a different take to the question in November 2013. This one backed off of Hypothesis B and struck out on a tack that tried to address what was now a diverse set of substituted cathinones on the open market. This was promptly triaged by BRLE. One reviewer was convinced that we’d never publish many papers. Most of the rest was the usual ticky tack stuff about “why didn’t you do it this way?” and questions that really can only be resolved by getting in there and doing the work. In a word, empirical. By this point, reviewers were viewing the attention to these novel drugs as a strength, no more comments about demonstrating the scope of the real world problem.

In February of 2014, NIDA posted a new funding opportunity announcement on synthetic drugs, the R01 version was PAR-14-106. Actually, it was initially posted as a PA, withdrawn and reposted as a PAR “to allow a Special Emphasis Panel to provide peer review of the applications”. Why? Who knows. But as soon as the original PA was posted I sent an email to the Program Officer in charge that included my summary statements to that point in time and an observation that throwing these apps into regular study sections was unlikely to produce fundable scores. If you are keeping track, nearly everything I had submitted was triaged, except the A1 for my competing continuation (which you might view as a sympathy scoring/discussion).

Up to that point in time, if you search RePORTER for funded grant projects on “mdpv, methylone, mephedrone or cathinone” for fiscal years 2010-2014 you would first find 2 pre-doc fellowships and one post-doc fellowship. Next you would notice that one R01 was funded in FY2012 via a conflict special emphasis panel for a study section chair, one R01 was funded in FY2014 on human epidemiology through a regular standing study section and one R21 was funded through BRLE for FY2012. In addition, five NIDA intramural labs started mentioning these key words and are located by this search.

The point here is that clearly my colleagues who were also submitting grants on cathinone-related topics were having a similar lack of success. We talk at meetings so, trust me, there were several quite accomplished PIs who were applying during this interval of time as well.

We submitted a new version of the Hypothesis B proposal in June 2014 for this new PAR. It got a 25%ile so we resubmitted it in March 2015 again to the PAR. It got a 24%ile. No movement. The resume of discussion for the first version complained about minor technical issues, interdependence of Aims (this is grantsmithing stuff) and “sloppy constructed, lacking clarity and consistency”. This latter bit was interesting since one of the prior reviews of this Hypothesis B lauded it for clarity and fantastic grantsmithing. It happens. Oh, and by now we were trying to get out ahead of the looming SABV initiative and mentioned including female and male rats. Got killed for “design concerns”. The resume of discussion for the second one was a classic case of “we don’t have any real complaints but there are one or more grants better than yours in the list so we have to find something”. Very frustrating. Oh, and we were offered the opportunity to propose a R56 Bridge on the last version of this (yay!) to focus on the sex-differences and improve our hypotheses…..but it wasn’t selected for funding. Another half-submission in late 2015.

In between these submission we put in an R21 on vapor inhalation of cathinones in Jun of 2015 to be reviewed by the SEP. It received a 39 impact score with concerns mostly focused on the novel inhalation model. So no real issues with the cathinone topic itself, after all it was a synthetic drugs SEP! [Related paper: Nguyen, Aarde et al, 2016]

By this time, the MDMA-related grant I mentioned at the top was due for a competing continuation application, which went in November 2015. You may be wondering by now how we were able to sustain the effort to generate new preliminary data and such for all of these applications and, ultimately, papers. Well, our MDMA grant was funded pretty soon after we got really interested in the cathinones. There was a lot of dovetailing of the topic domains, as I mentioned, the mephedrone compound was originally reported as being sort of MDMA-like, but with enhanced abuse liability. Methylone eventually emerged as the direct cathinone cousin of MDMA. So it actually made a lot of sense to draw these together for the competing continuation. It got a 27%ile from BRLE and the reviewers were totally on board with the inclusion of new cathinone experiments as well as the harmony of what we’ve been doing over the past 4 years with the original MDMA proposal (which was originally designed before these designer cathinones appeared in user groups). This put us up to something like 4 straight applications discussed after our initial run of 6 7 triages interrupted only by one kiss-your-sister score of a -06A1 application. Progress! [Related papers: Creehan et al, 2015; Vandewater et al, 2015; Nguyen, Grant et al, 2016]

The stalling of the Hypothesis B proposal at an unfundable 24-25/%ile was frustrating, but what can you do? The ideas seemed to have legs and the complaints were not substantial. We put it back in as new application in October 2015, for the SEP once more. It got an 18%ile. Definitely outside the likely payline for the year*. So I revised and resubmitted it in August 2016. Sixth time (honestly I’m losing track at this point) is the charm for Hypothesis B?

So here we are in September of 2016. We’ve been working on this topic for over 5 years and submitting grants for almost 5 years. We’ve had thirteen papers and I’ve submitted thirteen fourteen grant applications (my collaborator has put in a few more during this interval as well).

NIDA eventually created a FOA for synthetic drugs (not just cathinones, includes cannabinoids and opioids as well). The degree to which this was influenced by our advocacy and publications, I don’t know but it had to have helped. Certainly our early triaged summary statement results were key to getting a SEP convened for this purpose. They’ve funded, by my count, two R15s, one R21 and one R03 via regular study sections and one R21 via SEP for a more general funding opportunity announcement. The PAR on synthetic drugs resulted in the funding of an R21 and four R01s on synthetic cathinones since being issued, that is 6 possible funding rounds to this date*.

We recently received word that the aforementioned October 2015 submission of the Hypothesis B proposal will be funded.

Time to REALLY get to work!

 

__

Addendum: We never work alone on these projects and it has been a large team effort. Deepshikha Angrish synthesized compounds in the Dickerson lab in the early days. Deborah Barlow in the Houseknecht lab was essential for the PK work. Matt Buczynski jumped right on a key early neuropharmacology experiment in the Parsons laboratory. Jerry Wright, Shawn Aarde (in particular), Michelle Miller and Jacques Nguyen are postdocs that did heavy lifting on this topic in my group. My laboratory’s incredible technicians Sophia Vandewater, Kevin Creehan and former technician PK Huang (now a graduate student elsewhere) likewise did great work.

 

*There is an interesting vignette in here about the effectiveness of convening SEPs for PARs. My three scores for Hypothesis B in this SEP (which doesn’t have standing members but is convened per-round) ranged from 31-36. At one point the PO seemed to let slip that my 31 was the top score in that round for the SEP. Going from the PO’s general demeanor in discussing how the FOA was going, and the rather thin list of funded grants (not many cannabinoid or opioid ones emerged either), I conclude that reviewers are not issuing clearly-fundable scores in every round. And not many fundable scores all together over 6 rounds. This is somewhat puzzling**.

 

**In FY2014 alone, NIDA funded 37 new R01s that included cocaine as a keyword and 13 with heroin. Eighteen competing continuation R01s with either heroin or cocaine referenced. Of course there would be far more that were in the middle of non-competing intervals of funding.

June 28, 2013

RFAs for Tobacco Control “Regulatory Science”

Filed under: NIH, Tobacco/Nicotine — Tags: , — mtaffe @ 10:33 am

One of the more interesting symposia at the recent CPDD meeting focused on a new drive by the FDA and NIH to respond to the 2009 Family Smoking Prevention and Tobacco Control Act.

In short, the FDA is seeking to generate scientific information to guide and justify any steps they take to regulate tobacco products in the future. The money is apparently coming from taxes on said products so this will not involve any new appropriates to the NIH…from what I understood the NIH will simply be administering the research process.

There are now a flurry of RFAs:

are the standard R-mechanism ones.

For the R01s, due dates are January 15, 2014; June 17, 2014, January 16, 2015 and they anticipate devoting $11 Million to 20 awards.

It gets even better since they’ve thrown up some RFAs for K mechanisms

including the K99/R00. Serious stuff.

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