On 2016 Oct 11, David Keller commented:

Frequent ejaculation is associated with lower incidence of prostate cancer: how frequent is frequent enough?

Kotb and colleagues conclude in this review that "frequent" ejaculation is associated with reduced incidence of prostate cancer.[1] This finding begs the question: how frequent is "frequent"? Two of the reviewed studies provided relevant answers.

A study of 2,338 men found that men who averaged 5 or more ejaculations per week in their 20's had only 2/3 the risk of later developing prostate cancer, compared with men who ejaculated less frequently.[2]

Another study, of 29,342 men, found the lifetime relative risk of prostate cancer for men reporting 21 or more ejaculations per month (about 5 ejaculations per week) was 33% lower compared to men reporting 4 to 7 ejaculations per month (about 1 to 2 ejaculations per week).[3]

Kotb and colleagues do not present any data on whether ejaculation rates significantly higher than 5 times per week are associated with even lower risk of prostate cancer, or whether the benefit maxes out at a certain rate.

References

1: Kotb AF, Beltagy A, Ismail AM, Hashad MM. Sexual activity and the risk of prostate cancer: Review article. Arch Ital Urol Androl. 2015 Sep 30;87(3):214-5. doi:10.4081/aiua.2015.3.214. PubMed PMID: 26428643.

2: Giles GG, Severi G, English DR, et al. Sexual factors and prostate cancer. BJU Int 2003; 92:211-6.

3: Leitzmann MF, Platz EA, Stampfer MJ, Willett WC,Giovannucci E. Ejaculation frequency and subsequent risk of prostate cancer. JAMA. 2004; 291:1578- 86.

On 2015 Nov 08, Lydia Maniatis commented:

As was the case with the authors' previous article this year (Testing the role of luminance edges..), this article should be read starting with the last section of the discussion (pp. 14-15). It is here that readers are filled in on methodological problems so severe that they (almost) render any theoretical criticism of the study moot.

We learn that pilot experiments showed that there was a “high variability in responses even between experienced observers.” In some conditions the “test patch” was so “hard to detect” that “some observers looked at the stimulus for a very long time trying to detect the test patch, while others simply matched the lightness of the grating bar.” In other words, in some conditions the “test patch” was for some viewers a purely theoretical construct of the authors.

The authors then attempted to make the task “more objective” (meaning the tried to make the data appear less messy) by imposing a forced-choice paradigm, but this couldn't solve the problem of the unseen target. On further testing, the authors found that “reducing presentation time...led to more similar behavior across subjects, so [they] opted for a lightness-matching paradigm with short presentation times.” Does “similar behavior” translate into comparable and/or interpretable behavior, or are subjects using an unknown strategy to achieve a common solution to an awkward task? What are they perceiving? Are they all perceiving the same thing? The authors don't know and don't seem to care, as long as the data seem consistent.

Unfortunately, despite all these manipulations, the data remained messy: “...two of our 11 observers showed behavior very different from the others, and the magnitude of both White's illusion and the effect of noise differed widely across observers...”

The authors understand that “One possible explanation for these difficulties is that the noise may make the matching task perceptually ill-defined.” In addition to ambiguity, it appears that “the noise can appear as a layer of clouds or haze in front of a homogeneous grating...At very high noise frequencies, the noise is so fine-grained that it is not difficult to get an impression of the average lightness of the test patch, which...may appear textured...At intermediate noise frequencies...it can be difficult even to detect the test patch as a separate region, which makes the matching most difficult.” Most difficult, indeed.

Three related facts should be very clear from the above description.

1) The data are uninterpretable and thus have no theoretical significance.

2) The descriptor “noise frequency” is wholly inadequate to describe a manipulation that produces qualitatively different effects, ranging from haze/clouds to textured surfaces to invisibility. It is theoretically and practically meaningless.

It is something like adding lines to a square to produce a cube percept, and describing the manipulation simply as “adding an intermediate number of lines;” or adding various chemical substances to a solution and describing them on the basis of their color. Such theoretically blind (a term that in perception science has a literal as well as metaphorical meaning) manipulations are antithetical to scientific investigation.

3) The first of the effects in (2) – transparent layers - cannot, to my knowledge (and please correct me if I'm wrong), currently be accounted for by any of the ad hoc spatial filtering models being tested, all of which are “successful” for a narrow set of stimulus types, but cannot begin to handle most perceptual lightness effects. Thus, they are already extensively falsified. The fact that contemporary perception science seems to give standing to failed models incapable of rationalizing their failures - even in principle - should not be allowed to obscure this fact.

In sum, this study contains no usable data and has no necessary theoretical purpose.

On 2015 Oct 03, Friedrich Thinnes commented:

miR-29 and VDAC-1

According to a recent paper of Reema Roshane et al. (2014) the expression of miR-29a is reduced in patients and animal models of several neurodegenerative disorders, including Alzheimer’s disease, Huntington’s disease, and spinocerebellar ataxias. Furthermore, the authors reported on cellular and behavioral effects of in vivo, brain-specific knockdown of miR-29. Large regions of the hippocampus and cerebellum showed massive cell death, reiterating the role of miR-29 in neuronal survival.

Interestingly, the apoptotic targets of miR-29, such as Puma, Bim, Bak, or Bace1, failed to show expected levels of up-regulation in mice, following knockdown of miR-29 while another miR-29 target, voltage dependent anion channel (VDAC-1), was found to be induced several fold in the hippocampus, cerebellum, and cortex of mice following miRNA knockdown.

Partial restoration of apoptosis was achieved by down-regulation of VDAC1 in miR-29 knockdown cells.

Anyway, it may pay to keep this observation on the schedule.

References

Roshan R, Shridhar S, Sarangdhar MA, Banik A, Chawla M, Garg M, Singh VP, Pillai B. (2014) Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice. RNA. 20:1287-1297. doi: 10.1261/rna.044008.113. Epub 2014 Jun 23. PMID: 24958907 Free PMC Article

Thinnes FP (2015) Plasmalemmal VDAC-1 corroborated as amyloid Aß-receptor. Front. Aging Neurosci., 30 September 2015 | http://dx.doi.org/10.3389/fnagi.2015.00188 OPINION ARTICLE

On 2015 Oct 05, Klaus Okkenhaug commented:

In their discussion, Louie and colleagues suggest that mesenteric B cells may inhibit Treg and that idelalisib dysregulates Treg by inhibiting B cell differentiation. Not only is this argument internally inconsistent, but also ignores the potential direct effect of idelalisib on Treg. PI3Kδ-deficient mice develop colitis Okkenhaug K, 2002, PI3Kδ-deficient Treg fail to prevent colitis Patton DT, 2006, and there is a T cell-intrinsic role for PI3Kδ required for effective suppression of CD8⁺ T cells Ali K, 2014. It is therefore reasonable and more parsimonious to sugest that idelalisib causes enterocolitis through a direct effect on Treg. In addition, if depletion of B cells were the main mechanism behind idelalisib-induced colitis, then surely rituximab would have a similar or greater effect as this is a more effective way of depleting B cells.

On 2015 Oct 03, Seyed Moayed Alavian commented:

Today the improatnce of occult HCV infection is more obvious and I think detection of HCV RNA in PBMC is critical for this issue. Yours Alavian SM

On 2015 Nov 03, Martine Crasnier-Mednansky commented:

Figure 7 is improperly done and rife with error. One of the characteristic of the PTS is that its substrates are transported and phosphorylated concomitantly. Therefore glucose phosphorylation does not occur inside the cell as depicted in the figure. Representation of the phosphorylation state of the PTS proteins is misleading (a pale P for Enzyme IIA^Glc does not lead to a dark P for Enzyme IICB^Glc).

The figure legend wrongly indicates excess glucose increases the level of 2-oxoglutarate thereby inhibiting the phosphorylation cascade. In fact 2-oxoglutarate, which accumulates in nitrogen limitation, inhibits the PTS phosphorylation cascade Doucette CD, 2011. On the other hand, an increase in nitrogen availability (figure 7C) causes an increase in glucose uptake, which cannot possibly activate adenylate cyclase to allow for transport of alternative carbon sources (in these conditions, glucose transport also prevents utilization of alternative carbon sources due to inducer exclusion). Thus, in the presence of glucose, a decrease in 2-oxoglutarate upon sudden nitrogen availability is unlikely to 'partially activate adenylate cyclase' and 'activate carbon catabolite pathways', as stated in the figure legend.

A direct inhibition of adenylate cyclase by 2-oxoglutarate, as depicted in Figure 7B, relies on questionable studies (see PubMed Commons comment attached to You C, 2013), and is not supported by data from Yang JK, 1983 (Table VII, caption a) indicating 10 mM 2-oxoglutarate (α-ketoglutarate) did not inhibit adenylate cyclase activity.

On 2015 Oct 13, Francesco Buonocore commented:

As you can see from: Bioessays. 2015 Aug;37(8):877-87. "Evolution of vertebrate adaptive immunity: immune cells and tissues, and AID/APOBEC cytidine deaminases." from Hirano M., one of the theory is that: "Around 500 million years ago, a common ancestor of jawed and jawless vertebrates evolved a genetic program for the development of prototypic lymphoid cells as a foundation for an adaptive immune system. This acquisition preceded the convergent evolution of alternative types of clonally diverse receptors for antigens in all vertebrates"

On 2015 Oct 02, Jens Staal commented:

Cool! Personally I am very curious about the adaptive immune system development between the lampreys and the sharks - especially since homologs of my "pet protein" MALT1 underwent a double duplication event from PCASP3 in lampreys to PCASP1(MALT1), PCASP2 and PCASP3 in sharks (and the rest of the vertebrates except mammals). My "gut feeling" says that this has something to do with the evolution of the adaptive immune system found in jawed vertebrates, since MALT1 is a critical signaling protein in T- and B-cell antigen receptor signaling.

On 2018 Jan 24, Erick H Turner commented:

As the last author on this paper, I must say that Dr Berger has a point. There do seem to be systematic differences in the degree of blinding. Can anyone be blind to the fact that he or she is receiving psychotherapy? And can an investigator be blind to whether he or she is administering psychotherapy (or which kind)? Perhaps we are comparing apples and oranges.

On 2018 Jan 21, Doug Berger commented:

It is hard to understand why the authors state that both psychological interventions and pharmacotherapy for depression are both "efficacious". While medications for depression have been studied and approved by the FDA based on clinical trials that are double-blinded and have a blind-placebo control groups, no psychotherapy has ever been studied with either a single-(patient blind) nor double-blind (patient and therapist blind), and neither has there ever been a blind-placebo control. It is impossible to weed-out the effects of hope and expectation that can bias results in psychiatric conditions such as depression that have subjective endpoints and large random error. "Blind raters" are not part of a double-blind and these raters only record the reports of unblinded subjects. Non-blind outcome research is only acceptable in conditions with objectively measurable endpoints such as bone fracture rates, myocardial infarction, stroke, tumor size etc.Thus, psychotherapy has never been actually shown to be "efficacious" in a clinical trial with robust control on bias (and never can be as the subject and treaters must be ublind to the treatment given).

These and other points are discussed in more detail and are referenced in this article: https://www.ncbi.nlm.nih.gov/pubmed/26870318.2

On 2016 Dec 18, Laura Williams commented:

Our online journal club discussed this paper on January 25, 2016. https://www.youtube.com/watch?v=YGA3Pn8dz7c

On 2016 Mar 06, Boris Barbour commented:

The debate continues under Blatt's follow up editorial Blatt MR, 2016.

On 2015 Dec 24, Michael R Blatt commented:

Dear Gerhard,

Thank you for your comment. Setting aside the issues of fraud and whistleblowing, I agree that there is no place for anonymous commenting in scientific debate.

Open debate is the cornerstone of scientific progress, especially in the "massively cooperative exercise" (to quote one of the PubPeer commenters) that is scientific research. Publication is only the beginning of scientific debate. Furthermore, contrary to arguments commonly raised about the flood of supposedly 'ultimately unreliable publications', history has shown time and again that progress often arises from what, in hindsight, is ultimately unreliable.

The SCIENCE article from 2011 that I referred to is a classic example. There was nothing fraudlent about the data presented at the time. It proved unreliable only in the hyperbole of its interpretation and it stimulated research leading to important insights about a transporter that scavenges phosphate in the presence of exceptionally high levels of the structurally similar arsenate anion.

Let us hope that this next generation of internet-literate scientists take the time to think through, and rectify, the conflated reasoning that has been promoted by certain elements behind PPPR.

Best regards,

Mike

On 2017 Jun 17, Misha Koksharov commented:

"Is what we do really science or a glorified marketing exercise?"

This is indeed a very interesting and controversial question. Opinions vary from "problems are minor" to "iceberg dead ahead, sir".

Yuri Lazebnik wrote a really interesting and thoughtful paper (Lazebnik Y, 2015) trying to dissect this problem.

At this time it may be even more important than his famous piece ('Can a biologist fix a radio?' Lazebnik Y, 2002) on still current challenges of comprehensive understanding of biological systems.

Regarding the marketing topic, the entertaining and educative paper by Dan Graur (Graur D, 2013) is too good not to mention here. He is also sometimes depicted as a 'vigilante scientist' (Bhattacharjee Y, 2014).

On 2015 Dec 15, Gerhard Nebe-von-Caron commented:

a thought provoking editorial indeed. Do we want to foster an environment were people hide in anonymity or do we want to promote openness and honesty. To turn into anonymity is only showing that one has no faith in openness and honesty as one is not prepared to take a personal risk for its value. If they are however not the foundation of ones science, is what we do really science or a glorified marketing exercise?

On 2015 Nov 01, Brandon Stell commented:

PubPeer has responded to this editorial in a post titled "Vigilant Scientists" http://blog.pubpeer.com/?p=200

On 2015 Oct 14, Jaime A. Teixeira da Silva commented:

I think we need to give time to all parties to evaluate the need, or not, for anonymity. I personally believe that anonymous opinions are important, even if sometimes there are risks involved, simply because a large segment of scientists might be feeling afraid to comment openly by name, not because they are trying to hide, or to be malicous in any way, but simply because they are afraid. The fear of whistle-blowers, vigilantes and vigilant scientists who prefer to comment anonymously needs to be respected.

A few things: 1) A disclaimer. I have never met, or communicated with Lydia, below. 2) Prof. Blatt has given his personal assurances to enact reform and improve the system at Plant Physiology. This is an extremely positive thing, and an example we would pray for in so many other plant science journals. So, to be fair, Prof. Blatt should be given some space, and time, to fulfill his promises. The only aspect I am concerned that he might not consider, is to act upon the anonymous voice. 3) Given the real risks, as Lydia has pointed out, of abuse by publishers to silence the voices of critics, I have opened up a question at ResearchGate, namely: When should scientists be banned by journals and publishers?

http://www.researchgate.net/post/When_should_scientists_be_banned_by_journals_and_publishers

On 2015 Oct 12, Lydia Maniatis commented:

Mike, T&S and Elsevier evidently have the de facto right to ban any author they want from their journals, for whatever reason they see fit, without warning, without appeal, making up the rules as they go along, picking off critics who annoy them. It doesn't matter whether you or I agree or disagree with their decision (should you choose to take a position); as you said in an earlier comment, it wouldn't make much difference. Given that these journals are conduits for scientific communication, this is an extraordinary power for the scientific (and any democratic) community – including the editorial boards of all the journals involved - to tacitly grant them. At a minimum, I would expect some verbal protest, some minor effort to push back on this worrying state of affairs.

Anonymity on PubPeer is here to stay, for all the excellent reasons its editors laid out in their blog post. It's clear that it has enabled more information to emerge, much in the public interest - and more information is better than less. From now on, scientists who publish their work should expect it to be gone over with a fine-tooth comb, and problems publicly aired, by Peers, Unregistereds, and people with names. You express faith in the majority of your colleagues – among these are the Peers commenting on PP.

In case there's a misunderstanding, I have no connection to, nor have I ever communicated with, Dr. T. da Silva. T&S's side of the story was laid out in the email they sent him, which was published in the article in Retraction Watch.

On 2015 Oct 12, Michael R Blatt commented:

Dear Lydia,

I did not unmask you; one of your PubPeer ‘Unreg’ colleagues did. However, that you should choose to hide in this way does not lend credence to your stance nor, as Moriarty notes, does it command respect.

Your desire to see the world in black and white also does not do Jaime’s cause justice. Let’s just say that it is presumptuous to suggest that I believe T&S acted properly. I did not declare my support for T&S. What I did say was that I reserve the right to withold comment until I can know the full details, or at least hear the other side of the argument. I would certainly welcome what further correspondence you (or Jaime) might have. However, you need to have the courtesy to allow me to think for myself.

On one matter we can agree, however: this conversation is probably over.

Regards,

Mike

On 2015 Oct 09, Lydia Maniatis commented:

Dear Mike,

Take your time. I think our conversation has run its course. You believe that Taylor and Francis may have acted properly, that it is sometimes OK for a publisher to ban an author. I believe the opposite, to the point that I find it difficult to believe they were within their legal rights. If and when you find the time to inform yourself to your satisfaction about this particular case, we can continue the conversation.

If I had been particularly concerned with guarding my anonymity on PubPeer, you would have needed to be far more clever to unmask me. Your attempt to make this conversation about me (to label me as "highly emotional" - another evasive tactic on your part) and your triumph in "unmasking" me as Peer 14, as though this mattered (did I make any comments there I should be ashamed of?) is one of the reasons I support anonymity. Fortunately, my participation in future PubPeer discussions, when I choose to remain anonymous, won't be subject to such unworthy, ad hominem tactics.

Regards, Lydia

On 2015 Oct 08, Michael R Blatt commented:

Dear Lydia:-

I can see that this is a highly emotionally-charged issue for you, whereas it appears less so for Jaime (though I can fully imagine why it might be otherwise). So, I do think it important to step back for a moment.

Let me relate another matter to you. This pertains to a case that goes back more than a quarter of a century and took place in a university in the mid-West of the United States. I was peripherally associated with the case, primarily because of my knowledge of the professor involved (a good friend, as it happens, and we remain so still). The professor, let’s call him Fred for now, became embroiled in an argument with his head of institute. The details of the argument are less important than the consequences. Fred was so aggrieved by the way he felt he had been treated, that he became disruptive, aggressive and threatening to other academic staff and students alike. In the end, following disciplinary proceedings, Fred was barred from the institute and took ‘early retirement.’ From my own perspective, I could understand why Fred was aggrieved – I, too, felt that the initial handling of the argument was problematic – but I could also see that his reaction was inappropriate and disproportionate, and that the institute had no choice but to bar him. In effect, Fred was within his rights, but was unwilling to accept responsibility for his actions and their consequences.

I am not suggesting that there is a parallel here, but I recall the story to point out that there are always two sides to an argument. In Fred’s case, I was close enough to the events that it was easy to see what was going on, from both sides. In Jaime’s case, I have gathered what information I can from RetractionWatch, but I note that the information is presented almost entirely from his perspective. In your insistence that I choose a side, do you really mean to deny me the right to hear both sides of the argument?

Bests,

Mike

p.s. I’ll need to attend to my own day job now, so it may be a few days before I respond to any more comments.

On 2015 Oct 08, Lydia Maniatis commented:

Are there circumstances that, in your opinion, would justify banning an individual from the literature in order to stifle and punish legally protected speech?

If not, then it's not much of a stretch to say that you oppose, not only the "idea that a scientist could be unjustly banned", but the real-life act itself, as inflicted, for example by Taylor and Francis, on TdS. Do you still feel uncomfortable making such a statement, and if so, what type of information do you feel you would need in order to make a decision, one way or the other - to be able to say, in other words, either: "I think what Taylor and Francis did was proper or justifiable;" or "I think TdS was banned unjustly as the consequence of signed critiques."

As discussed in my earlier comments, I think it's important that you take a position on this. It's hollow to say, well, I oppose injustice/censorship in theory, but I won't take a position on any particular case. You might as well be for it.

On 2015 Oct 08, Michael R Blatt commented:

Dear Lydia, My apologies for misinterpreting your question. Let me also rephrase my answer then. Of course I am dismayed at the idea that a scientist could be banned unjustly from publishing as the consequence of signed critiques. Bests, Mike

On 2015 Oct 07, Lydia Maniatis commented:

Dear Dr. Blatt: Please allow me to rephrase my question: Do you oppose, as a matter of principle, the banning of scientists from the scientific literature by corporations in retaliation for their speech? If not, then I can only surmise that you endorse the right of your own journal, and any journal, to ban troublesome critics. Is this correct? Ethically speaking, do you believe scientific publishers have the right to punish their critics in this way?

As he himself points out, the Texeira da Silva case is extremely pertinent to what we are discussing here. It shows that the system can effectively silence critics (that he stubbornly persists is to his credit, but he has been gravely disadvantaged). So as an ardent opponent of anonymous post-publication peer review, the choice you are proposing is this: a. Don't criticize the scientific establishment; b. Criticize by name, but don't expect members in good standing of said establishment to stand up for you - even when your scientific speech is censored in retaliation (what worse can happen to a scientist?). You will simply be neutralized if your criticism hits too close to the bone, and that will be OK with, for example, Dr. Michael Blatt. This isn't a case where an institution can fudge an excuse about irreconcilable differences – this is banning from the literature because a corporation wants to silence a critic! The situation could not be more clearcut, nor your reply more evasive.

In short, and with all due respect, you cannot play the innocent bystander in all this and still be a credible voice in the conversation. Anyone could be next. What if you were banned by PubPeer, for your opposition to anonymity? I suspect you would have something to say about that. I am not asking you to “speak out without knowledge,” but to inform yourself about, and take the proper action with regard to -at a minimum, express an opinion - facts that are, again, highly pertinent to the present conversation.

On 2015 Oct 12, Michael R Blatt commented:

Dear Jaime,

There are a lot of threads in your comment above. However, I suspect that your stance in ‘vigilance’ is not that different from the Anglo-Saxon definition. Certainly, you will understand the commonality of the two.

I guess where we part ways is that I do not see academia as somehow deeply tainted. Of course, as with any human endeavor, there are always a small number of individuals who will misuse the system. However, I am cautious to apply generalizations (I think Oscar Wilde had something to say about this!). The majority of the colleagues I have come to know in my career are firmly committed to improving society through knowledge and understanding, and they are open to criticism and debate. They certainly do not fall in the category of self-serving hypocrits.

With best regards,

Mike

On 2015 Oct 08, Jaime A. Teixeira da Silva commented:

Mike, once again, thank you for taking the time to respond. I guess you never imagined what a response your editorial would bring. Again, you should be praised for bringing the topics of anonymity and post-publication peer review or PPPR to the table among more respectable plant scientists. As you now know well, I have been struggling for years to convince plant scientists (and I have been in contact with several tens of thousands already) that there are very serious problems with the publishing process like traditional peer review, with what I perceive to be pseudo-ethics by some of the mainstream STM publishers, or at least double standards, and problems that range from small to serious in a wide range of plant science journals. I have even seen some comments critiquing Plant Physiology papers. This then tells me, as you have already confirmed, that there are some very fundamental problems. And one of the reasons why some of the most basic problems do not appear to be resolved is because of what I call an "editorial firewall". In other words, editors and publishers who are actively resisting correcting the literature for sometimes some very valid reasons, such as no pay, no time, or too much stress. Their excuses are sometimes valid, but the truth of the matter is that the problems remain and the issues don't get resolved. And this is ultimately their responsibility. Editors benefit from the glory of their positions, journals benefit from gambling the impact factor, which brings with it tremendous economic benefits since the IF is literally used as a form of currency in some countries. That is why individuals like me stand up against what we perceive to be hypocrisy, failure in leadership, double standards, lack of editorial ethics, common sense and professionalism, and cronyism.

I know, like you, that those who hold a position in academia have much to lose, including their position, salary, benefits, travel funding and of course research funding and grants. So, the vast majority most likely do not see any benefit in getting involved with PPPR, because it does not benefit them. This is the true sad part about the plant science community: it’s ultimately selfish. Indeed, some will argue ferociously about this claim, but think about it, for whose good exactly are you serving when you are serving as the EIC of Plant Physiology? What is the end game and final objective? Actually, I suspect that in your particular case, the objective is noble and the means to achieve it are thorough. So, it is not individuals like you whose integrity I am questioning. I am questioning the integrity of editors who have abused their power and positions, as I have documented abundantly about Elsevier’s Scientia Horticulturae and some editors in Taylor and Francis journals. Revelations about other editors in other publishers’ journals are likely going to surface as this “ban Jaime” trend expands.

But we will expand on these issues in more detail later on because they are intricately linked with your editorial.

To answer your question: yes, I am a science vigilante. When searching for the term vigilante online, it tends to result in a definition that is associated with anti-governance, anti-law, anti-establishment and, most importantly, using criminal methods. At least that is the predominant definition in the Anglo-Saxonic literature, and thus based upon which your editorial’s title has been based. Yet, in Latino cultures, the term “vigilante” means to be vigilant, or aware, or conscious. And it is within this framework that I would like to consider myself as a vigilante, as one who is aware of the issues, is concerned with them, and who is taking a pro-active stance to resolve them. Yet, I use no illegal methods or weapons, even though I have often described the state we are in in science and science publishing as a war. So, those who criticize my methods of criticism, who emphasize tone over facts and who prefer to point out politically-insensitive language over academically unsound literature are, very unfortunately, those who are in power. In editor boards, serving as the front-line of academic defense (actually farce) for publishers, and serving as PR managers for the publishers’ share-holders. I get it know. They really don’t like my voice. But they do lke to make profit from my intellect… do you understand what I’m getting at, Mike?

If in fact you did manage to see the move I pointed to, you will see a common thread between the grass-roots struggle. That is why I believe that the anonymous voice must never be removed, despite its darker side, because it serves to balance the scales of excessive and abusive power and injustice. It is this powerful elite that is hoping to expand, as Pope Francis so eloquently describes as the “globalization of indifference”. Have a good day Mike. Hope to continue this conversation at PMC.

On 2015 Oct 08, Michael R Blatt commented:

Dear Jaime:-

Okay. I’ve just checked my OED and Wikipedia. Here’s the latter’s summary:

"Vigilante justice" is often rationalized by the idea that adequate legal mechanisms for criminal punishment are either nonexistent, insufficient, or inefficient. Vigilantes typically see the government as ineffective in enforcing the law; such individuals often claim to justify their actions as a fulfillment of the wishes of the community.

Now, to answer your questions, perhaps obliquely, would you not agree that PubPeer has effectively (if inadvertently) associated itself with vigilantism? And is it not possible for such activities to include some identified individuals, even if the larger number are faceless? Finally, do you consider yourself a vigilante?

I suspect that you are coming back to the questions of anonymity, scientific commentary, and whistleblowing. Could I point you to the post on PubPeer (below)?

Unreg from 5th October: Whistleblowers need protection.

Scientists do too. For all its good intentions, PubPeer has become the Reddit of the sciences, full of bullies and harassers. Blatt’s editorial says in a nutshell “Don’t feed the trolls”.

Vigilante justice assumes guilt and is associated with murder by mob. Fortunately in science as in society at large we have agreed-upon systems to protect the rights of both the innocent and the guilty (yes, even those who err or worse should be treated with due process).

It takes little investment to pull up a figure, adjust the contrast, and slap it onto FigShare. Then the “guilty until proven innocent” army chimes in. How many times have you read words to the effect of “If you have nothing to hide than show us the blots”, and threatening statements to the effect of “hiring committees need to be informed of this”. (Yes, I realize a few criticisms are meticulously documented on PubPeer, but the majority involve little intellectual investment – I assume that this is the intention of Blatt’s widely disparaged comments about “minor issues with blots”).

Can you imagine a world where we interacted by shouting at each other “Your top button’s unbuttoned” “Your socks don’t match” – valid statements yes, but ultimately pointless. Is this really PubPeer’s vision for post-publication peer review? I don’t see where Blatt says there is no place for criticism, just an appeal for that criticism to be meaningful. Whether or not anonymity has a place in PPPR is an interesting question, but Blatt has a right to express his opinion.

A massively cooperative function like science requires a level of courtesy that goes beyond even those we afford to individual citizens. I applaud PubPeer for its efforts to initiate PPPR, but appeal for the implementation of policies that remove the witch-hunt element.

As I noted in my response to you before, anonymity embeds inequality in any debate and, from my perspective, is the cause of more problems than it solves. I noted too, in my response to Leonid Schneider, that I would be one of the first to jump onboard with PubPeer if they found a way to address the problems associated with anonymous posting.

I hope this helps.

Bests,

Mike

On 2015 Oct 07, Jaime A. Teixeira da Silva commented:

Prof. Blatt, I have tremendous respect for you, as a plant scientist, particularly your work on SNAREs. I also have great respect for Plant Physiology, which has resisted thus far the temptations of being enveloped by the larger commercial STM publishers to turn intellect into profit rather than seeking the greater good of science. And that is why some parts of your editorial disappointed me. Beginning with the title. I have much to share and explain, ask and show, but before I get there, I'd like to take a step back, right to the beginning of your editorial, namely the title. I’d like to keep the conversation public.

And I would like to home in on one word "vigilante".

I am not quite convinced yet that you understand the full implications of what you have written. I am not even sure how such a respectable scientist seems to have lost his touch with the base. In order for me to explain my concerns, I would like to ask you, and those who will be reading this, to take a precious 100 minutes of their time to view the following 2015 movie. It is called Cartel Land. You can view it for free at viooz if you do not have access. In particular, I would like you to home-in on three sound-bites in that movie: 51 minutes, 87.5 minutes and 93.45-95.00 minutes.

After you have watched this movie, I would like to ask 2 questions: 1) Do you associate the anonymous science movement with vigilantism? 2) Does a vigilante scientist have to be anonymous?

Then, if possible, please read my own editorial and special issue: http://www.globalsciencebooks.info/JournalsSup/13AAJPSB_7_SI1.html In particular: http://www.globalsciencebooks.info/JournalsSup/images/2013/AAJPSB_7(SI1)/AAJPSB_7(SI1)5o.pdf

Now my 3rd question: Would you, Prof. Blatt, consider me, based on the title of your editorial, to be a science vigilante? When you reflect on this response, please keep in mind the following: http://retractionwatch.com/2014/04/10/following-personal-attacks-and-threats-elsevier-plant-journal-makes-author-persona-non-grata/ http://retractionwatch.com/2014/11/20/journal-retracts-paper-when-authors-refuse-to-pay-page-charges/ http://retractionwatch.com/2015/09/24/biologist-banned-by-second-publisher/

I look forward to your frank responses to my three questions so that we can continue this dialogue that affects the entire plant science community.

On 2015 Oct 06, Michael R Blatt commented:

Dear Lydia:- Please consider what you are asking. First, I run a small society journal (however prestigeous) that has no connection to the publishers of which you speak. My influence woulld be pretty close to zero. Second, I am not familiar with the details of Teixeira da Silva case. If you are asking me to speak out without knowledge, I don't believe is the correct thing to do. I'm sorry. Bests, Mike

On 2015 Oct 05, Lydia Maniatis commented:

Dr. Blatt, I have one simple question. Dr. Texeira da Silva has been banned by scientific publishers because he openly, transparently, and honestly criticised them. Are you as angered by this as you are by the anonymity of PubPeer? Have you raised your voice against this unmitigated outrage, this clear and present danger to the open debate you say you advocate?

You ask: "how do we encourage thoughtful debate? How do we enable quality control and at the same time protect whistleblowers [and critics, I would add]?" Since you're against anonymity, I suggest that a good first step would be for people in your position - and you, specifically - to speak out in support of your courageous and banned colleague.

On 2015 Oct 12, Michael R Blatt commented:

Leonid:-

I am, of course, open to suggestions. I do think your reference to university 'research integrity' offices is a bit of a red herring - a bit like counting the the American Civil Liberties Union as an offshoot of the US government (which it isn't, at least it was not the last time I looked). Your opening statement is that the model doesn't work, but you conclude that it "does not work very well", so I suspect you recognise that your argument is on shaky ground.

I agree that there are a few high-profile cases (specifically the one you noted in Italy) that show the worst of political mishandling. However, I'm not convinced that anecdotal evidence of this kind is useful as a basis for discounting an independent watchdog altogether.

Perhaps we can discuss further either here or directly by email? I have great respect for your experience as a science journalist and will welcome your further thoughts.

Best regards,

Mike

On 2015 Oct 06, Leonid Schneider commented:

Dear Mike, I would happily support your model of cross-discipline body, but the thing is: it already exists and it doesn't work. Every serious university has its office of research integrity, most states have some kind of central investigative bodies, run by central public funders or independent officials. Yet what we get instead most of the times is Realpolitik, otherwise nobody would go and post anonymously all these accusations of data irregularities on PubPeer. Sometimes the investigations are orchestrated in a way the scientist must come out exonerated, there was recently such a case in Spain involving a prominent Italian cell cycle scientist (uncovered on PubPeer, actually). Sometimes more junior scientists shoulder entire blame so someone important may get away with a stern admonishment. Sometimes rules of scientific conduct are simply redefined to fit a certain case to protect an influential scientist. You as plant biologist surely know who I am talking about. I am not an idealist and I know there can never be a perfect system. But what you suggest is already in place and it does not work very well. What we need are more honest and integer scientists in senior positions than there are obviously now.

On 2015 Oct 06, Michael R Blatt commented:

Leonid:- I believe my response to Jaime Teixteira da Silva might help clarify my position. I apologise if my nuancing has perhaps clouded matters. So let me dispense with it and put the matter to you this way: if PubPeer were to address the issues of anonymity and moderating that I posed in my challenges (in my editorial and reiterated in the letter), then I guaranteee you that I would be one of the very first to jump on board as a supporter of the site. What am not prepared to do is to support the scientific vigilantism (and, again, I use the term advisedly) that is inevitable and demonstrable with the unmoderated anonymity of PubPeer as it operates now.

I think we agree that the current publishing system is not perfect and is under much strain. I also think that there are ways to address the most difficult problems you, and others, have identified without resorting to the current PubPeer model. For example -- and here I am thinking out loud, so you will please excuse me -- consider the idea to set up a cross-discipline body (or bodies) to deal with issues of fraud, etc., independent of the journals and recognised by the community. Such a body (or bodies) might be tasked with moderating and reviewing complaints, communicating with journals, and given teeth to drive their handling. The identity of its members would need to be open, and the charge would be not to hunt out instances of fraud, but to make the initial adjudication on community-initiated referrals and issue recommendations to the corresponding journals. Referrals to the body would be made in confidence, ie. non-anonymous (to prevent malicious referrals), but could be anonymized at the stage of communication to the journal to protect the referrer if need be. The board could also publish statistics on the broad-sense quality of journal handling (e.g. no response, in-processes, resolved) and some timeliness metric. N.B.: Here I am paraphrasing from recent discussions with some of my opposite numbers. So, yes, I have been thinking about how to deal with the problems of perception, transparency, protection of those who have not committed fraud/misconduct, community responsibility, etc.

In the end, we come down to the age-old problem: how to ensure due process that will give rigor to the way we deal with those who carry out fraud while protecting those who have not. I am simply not prepared to give support to a scheme that creates many more problems than it solves.

I hope this helps.

Best regards,

Mike

On 2015 Oct 05, Leonid Schneider commented:

Dear Dr. Blatt, reading your editorial again and again, I have the feeling that your primary issue is with the anonymous commenting on image/data irregularities, and less so about leading general academic discussions in the open. You have applied some interesting euphemisms for what some might consider as evidence of possible scientific misconduct. Thus, if you really think that whistle-blowing of potential data manipulations should go exclusively through "proper channels" and happen confidentially, you would be defending a broken system. You see, this approach has been tried for decades, with unsatisfactory results. But then again, what some perceive as potential data manipulations, you appear to see as utterly excusable. Thus I would appreciate if you were to clarify your position accordingly, maybe in a correction or an addendum to your editorial.

On 2015 Oct 04, Michael R Blatt commented:

Dear Dr. da Silva,

Thank you for your comments. I am happy to discuss thoughtfully on the open forum of PubMed Commons. Like you, I reflected long and hard before writing my piece for precisely the reasons we are entering into this discussion: anonymity, fear, and scientific debate. Several of my closest colleagues expressed their anxieties that putting my head ‘above the social media parapet’ could have negative consequences for them. I, too, had my doubts but felt it important to raise concerns expressed to me by colleagues, young and old, which I share. I am therefore writing both in response to your invitation and generally to some of the comments posted to my editorial. I want to thank Philip Moriarty who I have come to know over the past week and who is much more eloquent than I could ever be, and Leonid Schneider who has shown true grace in stepping back from his initial cynicism to participate in the discussion.

I agree with your point that we should not fear to associate our names with critical opinion and, like Moriarty, I am dismayed by the lack of appetite to engage in open debate (note my emphasis on names and open). I am also deeply disturbed by the attitude of those who think that scientific critique is a license to ride roughshod into any discussion without once considering the possibility of a wider context or background to the questions at hand. At the most trivial level, it is easy – and cheap – to extract a few lines and twist them to the ridiculous; at the most fundamental, it shows an ignorance of social norms that make constructive debate possible. It’s no wonder that my colleagues were anxious and that there is fear within the community. They fear to engage because they do not want to become targets of the vitriol that pervades anonymous social media. To my mind, this is a sign that the “patient is not well” and I agree fully with the assessments of Moriarty, Schneider and others that our current approach to scientific exchange is deeply flawed in many ways.

So we come to your concerns: journal publication, PPPR, and anonymity. Here I must respectfully disagree with you on several points. Consider your starting premise, that “the final product, i.e. the published paper [is] the product of a failsafe process that is not meant to be challenged.” Surely, this flies in the face of scientific enquiry and one of the first lessons we all learn as students: to challenge ideas in order to progress understanding. Nor is publication a final product; it’s just the most visible at times. The real product of a body of work lies in its capacity to guide subsequent studies and predict their outcomes. As scientists, we subject our own work, and that of others, to scrutiny that either validates, discounts, or refines their outputs. The scientific literature is riddled with misconceptions, false conclusions, and ideas that failed this so-called ‘test of time’. And so it should be. As scientists, we put our work and ideas out into the community and, as a community, we improve and expand on each body of work. In short, publication is only one small step in the scientific process and always has been.

Second, let me stress that the purpose of editorial review is to assess a body of research, its scientific soundness, and whether it is of sufficient interest to the community – and, most important to the journal readership – to justify publication. Maintaining ethical standards is, of course, part of this task, but only one part of it. Nor is is the editorial process failsafe. No journal editor is able to catch all errors, innocent or otherwise, although on the whole editors are usually pretty good at identifying problems. I agree that there is a place for post-publication critique, including an element of quality control. I stated as much in my editorial.

What I cannot abide is PubPeer’s stance on anonymity, and I am angered by their efforts to masquerade as a site for open discussion that reflects the opinions of the scientific community. Both I consider to be fundamentally deceitful. I outlined my reasons in the editorial and these have been reiterated in several posts in response. Anonymity does not ‘level the playing field’; quite the contrary, it embeds inequality in any debate simply because one side is hidden. Furthermore, anonymity opens the door to all kinds of antisocial and nefarious behaviour. You need only read many of the comments posted in response to my editorial to see the innuendo and vitriol that was unleashed towards me as well as towards others posting on the site. Such verbal abuse belongs … well, let’s just say it does not belong in the public domain outside the schoolyard. Call me old-fashioned if you will, but in my book this is unnecessary, grubby and, what’s worse, counterproductive. For most people, the mob mentality behind this kind of behaviour is quite frightening. And like it or not, mob mentality is the framework of vigilantism. Is it any wonder, then, that so many of my colleagues, young and old, are fearful? Is this the kind of ‘scientific debate’, indeed the kind of society, we want to support? I don’t. It seems to me that anonymity in these circumstances is not the solution, but the problem. It is at the root of much that has gone terribly wrong in scientific exchange today.

I agree that there are some circumstances in which confidentiality (not anonymity!) is necessary to protect the identities of individuals, especially of whistleblowers (I’ll come to this point in a moment). However, the vast majority of posts on PubPeer do not fall in this category, even those which highlight one or more errors in a figure. I maintain that it is possible for a PhD student or postdoc to approach a colleague, even a senior scientist, in order to point out an error, and to do so in a way that is constructive and non-threatening. This is a vital social skill to learn. I shudder to think that, through ‘social’ media, this skill could be lost to the sound bite of a tweet. Like Julian Stirling (cited on PubPeer in several posts), I have no patience with lazy or conflicted thinking, and I welcome critical analysis when presented thoughtfully. I encourage my students and postdocs to question me, and others, all the time and, no surprise, the ones who have done so have also proven most successful when they leave my lab. I think you and others have vastly overstated the dangers of retribution, in part perhaps by conflating scientific debate and error correction with whistleblowing. They are not the same.

As for misconduct, of course whistleblowers need protection through confidentiality, but not through anonymity. Again, I have set out my reasoning in the editorial and will not reiterate here. Mechanisms are in place to provide confidentiality, in the first instance through the established channels of most journals. I agree, too, that if these fail, then there must be alternative mechanisms that allow legitimate concerns to be addressed effectively. I, for one, support efforts to ensure such alternatives. However, I do not agree that the answer is through a culture of secrecy and hearsay.

So how do we encourage thoughtful debate? How do we enable quality control and at the same time protect whistleblowers? I don’t pretend to have all the answers, but it is patently clear to me and many others that the answer is not through a so-called post-publication peer review process that is anonymous and, for all intents and purposes, unmoderated. Again, I point you to my editorial and the three challenges I have laid before PubPeer. I believe Stell and his colleagues have a real opportunity to lead the way in raising the tenor of science in this social media age, but they must address these challenges to do so.

Finally, to your personal critique, I appreciate that you have included reference to your own pieces, as I am sure other readers will too.

Thank you.

Mike Blatt

On 2015 Oct 02, Paul Brookes commented:

I wrote a blog post response to this rather inflammatory editorial. http://www.psblab.org/?p=445 The gist of it is, this article is an exercise in punching down.

On 2015 Sep 30, Jaime A. Teixeira da Silva commented:

As a plant scientist, I consider this editorial to be very important since the topic affects us all. It is also important because it is one of the few open attempts to address post-publication peer review (PPPR) in plant science at the editorial level, which is precisely where the issue of failed traditional peer review [1] needs to be reformed. So, in that sense, Prof. Michael R. Blatt must be applauded for bringing the issue to the discussion table. However, I have read some very valid concerns and criticisms [2, 3] in the public debate, one being on PubPeer. PubPeer is the PPPR commenting platform that Prof. Blatt is precisely being mostly critical of in his editorial. I personally am a supporter of the anonymous movement in science simply because I have seen such widely egregious failure, at many levels (manuscript processing, editing, peer review, publisher-induced errors, etc.), in a wide range of plant science journals in my short career. I am aware that there are a lot of very powerful individuals in the editorial boards of plant science journals whose best interests do not seem to be to serve science itself, or its integrity, but rather to be self-serving (NOTE: I am not in any way implying this about Prof. Blatt, about his editors or his journal, with which I have had no, or limited, experience). And I have also seen how anonymity has been able to point out errors and misconduct in the plant science literature, allowing it to be finally corrected.

In a publishing system that has documented failure in the editorial system, and where publisher retribution can take place for calling out editorial failure [4, for my most recent personal experience], I am of the opinion that the voice of the critic needs protection. As much as the protection offered the blind peer reviewer in traditional publishing. This is because the critic’s voice needs to be heard and not suppressed. And one form is through the anonymous voice. Unfortunately, I am also of the belief that the plant science community is still vastly conservative and that the image associated with anonymity is still very negative, as implied by the title of this editorial, namely vigilantism, also synonymously used with witch-hunting, snitching, etc. So, very broadly, those who complain, or point out errors, or who are critical of authors, published papers, editors or publishers, tend to be demonized, and their opinions shot down. This can, very practically speaking, have very negative consequences on a scientist’s career, because conventional wisdom in science publishing is that the traditional peer review and the final product, i.e., the published paper, are the product of a fail-safe process that is not meant to be challenged. Because this also implies a challenge on the publishing status quo. Yet, in practical terms, how does one criticize the work of an individual, face to face, in an email, for example, without facing negative consequences (personal and professional), even if the claims or concerns are valid? Thus, the purpose of me making this comment at PubMed Commons (which I should add was not easy for me to decide to do) is to indicate to the plant science community that they should not fear their own voices, or to associate their names with a critical opinion. They should also not fear the anonymous voices of critique or discontent. There should be the liberty by all plant scientists, irrespective of their rank, to comment freely, either by name or anonymously, even if the opinions vary widely. However, I caution, especially in public, to maintain a respectful tone always, and always leave open the option that there are widely different views.

I think that the impact of this editorial needs to sink in a bit more, to allow the plant science pool to absorb the central message, but also the possible flaws and short-falls associated with Prof. Blatt’s image of PPPR and the central importance of anonymity in PPPR.

In closing this commentary, I do have one personal critique of this editorial which I will personally relay to Prof. Blatt and the Plant Physiology editor board once my PubMed Commons comment has been published. If one enters the terms “post-publication peer review plant science” into Yahoo, Google, or some of the widely used scientific data-bases, several of my own papers will appear addressing this topic [e.g., 5, 6]. I find it very disturbing, and disconcerting, as a fellow plant scientist, that Prof Blatt has not referenced any one of these papers (even if they are mostly letters or opinion pieces) that I have written, because they are the de facto birth of the PPPR movement in plant science. This to me indicates that Prof. Blatt (and/or Plant Physiology editors) did not reference the literature fairly, correctly, or in a balanced way, in this editorial. This would then imply that the editorial may reflect professional or literature bias and that the editorial process may thus be flawed. One could then question if all editors at Plant Physiology were aware of this editorial, and if they approved of its content, before it was published. Even though editorials are not usually peer reviewed in a traditional sense of the word, I am concerned, given my own side-lined literature, as well as the very critical opinions stated at PubPeer and by Paul S. Brookes, that this editorial was not sufficiently vetted, or revised, before publication.

I sincerely hope that the wider plant science community may offer more comments at PubMed Commons or at PubPeer, by name or anonymously, because, in my opinion, this editorial highlights the cross-road in plant science, and science itself, where the future of academic integrity, accountability and transparency are meeting, i.e., with PPPR and the anonymous movement. I have been trying to bring this issue to the attention of plant scientists for some years now, and have been heavily criticized by some and silently praised by others. I am hopeful that perhaps, with Prof. Blatt’s editorial, that more awareness and pro-active discussion, can now take place, in the public arena. I look forward to seeing a spirited and passionate discussion, with the purpose of hammering out some positive proposals to “fix” the plant science literature which is, in my opinion, currently full of flaws (small and large) that have resulted from the failure of the traditional publishing system. I also welcome critiques to my views expressed herein (by name or anonymously).

References

[1] Teixeira da Silva, J.A., Dobránszki, J. (2015) Problems with traditional science publishing and finding a wider niche for post-publication peer review. Accountability in Research: Policies and Quality Assurance 22(1): 22-40.

http://www.tandfonline.com/doi/full/10.1080/08989621.2014.899909#.VJXPV0oBg

DOI: 10.1080/08989621.2014.899909

[2] https://pubpeer.com/publications/209CA2DF493322A5B5470F3B8EEDA0

[3] http://www.psblab.org/?p=445

[4] http://retractionwatch.com/2015/09/24/biologist-banned-by-second-publisher/

[5] Teixeira da Silva, J.A. (2013) The need for post-publication peer review in plant science publishing. Frontiers in Plant Science 4: Article 485, 3 pp.

http://journal.frontiersin.org/Journal/10.3389/fpls.2013.00485/full

DOI: 10.3389/fpls.2013.00485

[6] Teixeira da Silva, J.A. (2015) A PPPR road-map for the plant sciences: cementing a road-worthy action plan. Journal of Educational and Social Research 5(2): 15-21. (and references therein)

http://www.mcser.org/journal/index.php/jesr/article/view/6551

DOI: 10.5901/jesr.2015.v5n2p15

On 2016 Aug 02, Anthony Jorm commented:

There is an error in a statement made in this article. Where it states "This initiative involved the setting up of an initial 10 enhanced primary care services for young people aged 12-15 years...", the age range should be 12-25 years rather than 12-15 years.

On 2015 Dec 09, Cicely Saunders Institute Journal Club commented:

The Cicely Saunders Institute journal club reviewed this paper on Wednesday 4th November 2015. We enjoyed discussing this paper and appreciated that the authors had tackled an important question about the efficacy of nutritional interventions, which are widely used in the NHS and associated with substantial costs, but with little evidence for improving function in this population. The paper reports an interesting example of a feasibility trial. We agreed with the authors that the participating care homes are unlikely to be representative due to their prior involvement in a dietetic intervention, which limits the conclusion regarding the feasibility of a future trial beyond these care homes. The authors recognised that using weight and BMI as outcomes is problematic; despite being widely used clinical markers they are not directly measuring or necessarily indicative of function. Therefore, we wondered if this feasibility trial might have included alternative outcomes more aligned with the aim of the study. One suggestion is to look at incidence of pressure ulcers or infections which would be available in routinely recorded clinical notes. In addition, we were interested that consent was not sought from most participants and felt this warranted further attention and justification – consenting adults who lack capacity presents challenges but is not impossible. However, we were pleased to see this study contributing to the growing body of work in the care home population.

Commentary by Joanna Davies (@JoannaDavies58), Research Assistant at the Cicely Saunders Institute, KCL.

On date unavailable, commented:

None

On 2016 May 25, Hans-Rudolf Weiss commented:

The subject was: Physical therapy for idiopathic scoliosis! The relevant articles were not cited and personal opinion and 'experience' are not relevant as these do not provide any evidence. Therefore the paper simply is pointless. In evidence based medicine colleagues are guided by evidence based guidelines (1-3) as these are available for long and not by a personal opinion of someone who has never presented or published a relevant paper on this topic so far.

Evidence based 'Best Practice' (the synergy of evidence and Best Practice) is described in a textbook (4).

1. http://www.ncbi.nlm.nih.gov/pubmed/16759357
2. http://www.awmf.org/uploads/tx_szleitlinien/033-045l_S1_Wirbensäulendeformitäten_Rehabilitation_2012-03.pdf
3. http://www.ncbi.nlm.nih.gov/pubmed/22264320
4. http://www.amazon.com/Schroth-Therapy-Weiss-Hans-Rudolf/dp/3659667951/ref=sr_1_2?s=books&ie=UTF8&qid=1428388771&sr=1-2&keywords=schroth+Therapy

On 2016 Apr 18, Kay Steffan commented:

In his statement my colleague Mr. Weiss reduces the quality of the article to current scientific publications on the subject of scoliosis therapy. However, this was not the subject of the article. A collection of current scientific publications does not reflect the common treatment of scoliosis, nor does it serve to guide and inform established colleagues who ask for support concerning the therapy of scoliosis. In the article currently relevant and commonly used physiotherapy treatments are presented. Furthermore their effectiveness is proved by existing scientific work. Thereby, the reference should be based not only on the topicality of the publications, but consists above all of longstanding practice and the experience of the author. The ratio of evidence based and best practice is decisive for a successful therapy, especially in a border area like scoliosis therapy. There is a variety of current work on scoliosis therapy in more or less relevant journals, however the practicality and relevance are lacking in most cases. Common therapy methods have been clearly shown and listed, though surely it would be worded too general for established colleagues if we only talked of "specific corrective physiotherapy". In Germany or at least in German-speaking countries, Schroth’s, Vojta’s and Bobath’s therapeutic methods are currently the most common and best known. Therefore constantly reoccurring therapies were neglected although they were supposed to proof their effectiveness over a longer period of time and should be especially applied by established therapists and stationary facilities.

On 2016 Apr 05, Hans-Rudolf Weiss commented:

I was asking myself how a paper containing ‘experiences’ and the 'personal opinion' only can be published in a Pub Med listed journal...

This paper not at all relates to the actual knowledge of this topic as published in Pub Med listed literature. Meanwhile there is highest evidence for the application of physiotherapy in the treatment of scoliosis [1-8]. As early as 2003 a prospective controlled paper was published providing evidence on Level II [1], followed by a Cochrane review 2012 [3]. Since 2014 there are now 4 randomized controlled studies and one metaanalysis published supporting physiotherapy for scoliosis on level I!

Therefore the paper of K. Steffan is misleading. Even an expert opinion would usually not be published when there is evidences on level I already available.

The latest news on this topic has been published in a special edition:

http://www.ncbi.nlm.nih.gov/pubmed/26769612

http://www.ncbi.nlm.nih.gov/pubmed/26573167

http://www.ncbi.nlm.nih.gov/pubmed/26573166

1. Weiss H, Weiss G, Petermann F. Incidence of curvature progression in idiopathic scoliosis patients treated with scoliosis in-patient rehabilitation (SIR): an age- and sex-matched controlled study. Pediatric rehabilitation. 2003;6(1):23 - 30.
2. Weiss H, Negrini S, Hawes M, Rigo M, Kotwicki T, Grivas T, et al. Physical exercises in the treatment of idiopathic scoliosis at risk of brace treatment -- SOSORT consensus paper 2005. Scoliosis. 2006;1:06.
3. Romano M, Minozzi S, Bettany-Saltikov J, Zaina F, Chockalingam N, Kotwicki T, et al. Exercises for adolescent idiopathic scoliosis. Cochrane Database Syst Rev. 2012;8.
4. Monticone M, Ambrosini E, Cazzaniga D, Rocca B, Ferrante S. Active self-correction and task-oriented exercises reduce spinal deformity and improve quality of life in subjects with mild adolescent idiopathic scoliosis. Results of a randomised controlled trial. European spine journal. 2014;23(6):1204-14.
5. Kuru T, Yeldan I, Dereli EE, Ozdincler AR, Dikici F, Colak I. The efficacy of three-dimensional Schroth exercises in adolescent idiopathic scoliosis: A randomised controlled clinical trial. Clinical rehabilitation. 2015.
6. Schreiber S, Parent EC, Moez EK, Hedden DM, Hill D, Moreau MJ, et al. The effect of Schroth exercises added to the standard of care on the quality of life and muscle endurance in adolescents with idiopathic scoliosis-an assessor and statistician blinded randomized controlled trial: "SOSORT 2015 Award Winner". Scoliosis. 2015;10:24.
7. Anwer S, Alghadir A, Abu Shaphe M, Anwar D. Effects of Exercise on Spinal Deformities and Quality of Life in Patients with Adolescent Idiopathic Scoliosis. BioMed research international. 2015;2015:123848.
8. Weiss H, Lehnert-Schroth, C, Moramarco, M, Moramarco, K. Schroth Therapy - Advancements in Conservative Scoliosis Treatment. 2015.

On 2016 Apr 05, Hans-Rudolf Weiss commented:

None

On 2015 Nov 18, Alvaro Alonso commented:

Just a couple of comments. 1. I am somewhat surprised that this is described as a 'case-control study' since it seems to be a cohort study with an exposed group (children from mothers who received a diagnosed of cancer during pregnancy) matched to an unexposed group (children from mothers without a cancer diagnosis), and followed up for outcomes. 2. The results show that, even if the differences were not significant, exposed children had >40% increased risk of low birth weight and higher risk of other outcomes. Based on these data, I do not think the authors have enough evidence to conclude that maternal cancer did not lead to worse outcomes in children.

On 2016 Feb 23, NephJC - Nephrology Journal Club commented:

This trial was discussed on Oct 27th and 28th in the open online nephrology journal club, #NephJC, on twitter. Introductory comments by Paul Phelan are available at the NephJC website, along with a primer on spironolactone by Joel Topf on the NephJC blog. The discussion was quite detailed, with more than 70 participants, including nephrologists, fellows, residents and patients. A transcript and a curated (Storify) version of the tweetchat are available from the NephJC website. The highlights of the tweetchat were:

• The authors should be commended for designing and conducting and the british Heart Foundation and National Institute for Health Research for funding this trial.

• This was a very well designed and conducted trial, with good selection of population (hypertension not at target despite three frontline agents (ACE-inhibitors or ARB, calcium channel blockers and a thiazide diuretic) and meticulous assessment of non-adherence, including direct observed therapy. Minor weaknesses brought up included the use of office and home blood pressure measurement rather than ambulatory monitoring, and the lack of washout between the crossover phases.

• This trial does establish spironolactone as the drug of choice for reducing blood pressure patients with uncontrolled hypertension despite the three frontline agents. However, the discussion did raise the cautionary tale of a rise in hyperkalemia admissions after the RALES trial. There is a need to be careful with generalizability as spironolactone gets used less judiciously and with less monitoring than would happen in a clinical trial.

Interested individuals can track and join in the conversation by following @NephJC, #NephJC, signing up for the mailing list, or visit the webpage at NephJC.com.

On 2016 Mar 03, thomas samaras commented:

A contrary report is available from the Indian Heart Journal l2013: Shorter height is related to lower cardiovascular disease risk--a narrative review, Samaras TT 65: 66-71.

On 2016 Jan 09, thomas samaras commented:

Shorter height is certainly an indirect marker for CAD. However, this relationship is not causal and virtually all studies showing shorter height is related to CAD are confounded by various risk factors. Actually, within population and ecological studies indicate that shorter height is related to substantially lower CAD. A few examples follow:

1. US CAD/CHD mortality by ethnic group showed the Asians had almost 80% lower rates than taller Whites and Blacks. Latinos and Native Americans had in-between rates and were in-between in height. These findings are based on the years 1985 to 2000 and involved roughly 8 million deaths.

2. The preceding findings are not due genetic superiority of the Asians. For example, when I compared the CAD/CHD of the Japanese in different areas, I found the shortest group. the Okinawans, had the lowest CAD. The taller mainland Japanese came next. The taller Hawaiian Japanese and tallest California Japanese saw CAD increase progressively with height.

3. I only know of relatively short populations that are totally free of CAD and stroke. These include the Solomon Islands, Papua New Guinea, Kalahari Bushmen, Congo Pygmies, and Kitavans. Males are all roughly 5'4" or less in height. No tall European population can match these results (based on research conducted around the mid 1900s).

4. US Native Americans also were found to increase in CAD with increasing height.

5. US males have 17 times the death rate from CAD as shorter rural Chinese males. In addition, within China, shorter rural males have lower rates than taller Chinese rural males.

6. In 1900, CAD was rare compared to today. However, the average person in 1900 was much shorter than we are today.

7. The 2007 WCRF Report stated that as a result of industrialization, we have seen increases in height, weight and chronic disease, including CAD. From 1100 to 1700 European height was declining but CAD did not start increasing until after the start of the industrial revolution.

8. Women are shorter than men and have less CAD.

9. Around the end of the 20th century, the countries with the lowest CAD were Japan, Hong Kong, France, Portugal, Spain and Italy. All relatively short populations. In regard to France, the taller Northern French have much higher CAD compared to the shorter Southern French.

10. In the later part of the 20th C, taller Nothern Europe had 40% higher CAD compared to Southern Europe.

11. In the US, taller WWI military recruits had more heart problems than shorter ones. (Based on about 1 million men.)

12. A US study found that when tall poor people were compared to short poor people, the tall people had almost 40% higher risk of a heart attack.

13. Bonnett studied about 350,000 dogs and found that a Great Dane is 60 times the risk of heart failure as a miniature Dachshund. A standard size Dachshund had seven times the risk compared to the miniature breed. Therefore, small body size does not appear to be a problem when it comes to heart failure.

The problem with most research is that it is very difficult to eliminate risk factors related to shorter height. For example, if short height is due to childhood disease or health problems, these problems will increase the risk of adult CAD and other chronic diseases. However, it is difficult to identify this confounder. Shorter people also tend to smoke more and are more likely to be obese and of lower socioeconomic status. Even if a short person who was born poor reaches higher SES as an adult, he or she will be at risk for higher CAD and all-cause mortality than taller people who were higher SES all their lives.

Research over the last 30 years provide many other examples of why shorter height, combined with healthy nutrition and a good life style and environment, tends to promote less CAD.

On 2015 Oct 01, Friedrich Thinnes commented:

Plasmalemmal VDAC-1 discussed as amyloid Aß-receptor

In 2010 I referred to a cell outside located GxxxG motif on the N-terminal helical stretch of plasmalemmal VDAC-1 (voltage dependent anion channel) and to a series of those inside the amyloid Aß peptide. The motifs are known to work as membrane perturbation motifs.

The hint included a first rational on an interaction of the molecules, VDAC-1 suddenly appearing to figure as a receptor of toxic Aß molecules. Another link to Alzheimer´s Dementia research arose from data pointing to amyloid Aß as an apoptotic opener of cell membrane-integrated VDAC-1 and to counteracting polyphenol preparations from several plants. Together, a revised version of the amyloid cascade hypothesis came up (F.P. Thinnes, 2015; www.futhin.de).

Accordingly, Alzheimer's disease – downstream of APP processing – can bee seen as resting on some form of extrinsic induced cell death, this via opening cell membrane-standing VDAC-1 (= receptor) and accumulating over time. The process is boosted by excessive amyloid Aß (= agonist) production via increased processing of the amyloid precursor protein (APP) of weakening cells of critical and redundant brain regions.

Recent data on the slow down of progress of Alzheimer Disease of proven Alzheimer patients in early states by monoclonal anti-amyloid antibodies that neutralize amyloid mono- or oligomers, from my point of view, corroborate plasmalemmal VDAC-1 as a receptor of those (E.R. Siemers et al., 2015)

However, a study presented by Y.H. Liu et al. (2015) reports on three monoclonal antibody preparations elaborated against different epitopes inside the amyloid Aß peptide. One of those called 6E10 a) in vitro disaggregates artificial amyloid fibrils and thus increases the number of Aß oligomers while b) injection of co-incubates into the lateral ventricle of 6-month-old C57 mice increased the neurotoxicity in vivo. Anyway, to raise amyloid Aß oligomers increases the risk of their docking to plasmalemmal VDAC-1 finally resulting in the induction of accumulating neuronal cell deaths. From here: To raise amyloid Aß oligomers accelerates AD progress.

The authors call the phenomenon dust-raising. It is tempting to think Alzheimer plaques formation as a salutary form of wipe-the-dust procedure that may even protect from Alzheimer Dementia. In other words: does plaque formation work as a buckler?

References

Thinnes, F.P. (2015) Phosphorylation, nitrosation and plasminogen K3 modulation make VDAC-1 lucid as part of the extrinsic apoptotic pathway-Resulting thesis: Native VDAC-1 indispensible for finalisation of its 3D structure. Biochim Biophys Acta. 1848:1410-1416. doi: 10.1016/j.bbamem.2015.02.031. Epub 2015 Mar 11. Review. PMID: 25771449

Siemers, E. R., Sundella, K. L., Carlson, C., Case, M., Sethuraman, G., Liu-Seifert, H., Dowsett, S. A., Pontecorvo, M. J., Dean, R.A., Demattos, R. (2015) Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients. Alzheimer’s & Dement. Aug 1. pii: S1552-5260(15)02148-2. doi: 10.1016/j.jalz.2015.06.1893. [Epub ahead of print].

Liu, Y. H., Bu, X. L., Liang, C. R., Wang, Y. R., Zhang, T., Jiao, S. S., Zeng, F., Yao, X. Q., Zhou, H. D., Deng, J., Wang, Y. J. (2015) An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect. J Neuroinflammation. 12:153. doi: 10.1186/s12974-015-0379-4.

On 2016 Apr 11, thomas samaras commented:

A large body of research also indicates that lower height and body weight promote greater longevity. A sampling of the findings follow:

1. A large Hawaiian study by He et al. found shorter elderly men had lower mortality and increased longevity.

2. A study by Mueller and Mazur found that shorter West Point graduates tracked into their 60s, 70s and 80s had lower mortality starting after 60 years of age.

3. A Harvard study (Polednak) of elderly graduates who were formerly athletes found shorter men had longer lifespans.

4. A large study by Shapiro found shorter men and women had lower mortality from all-causes, cancer and CVD.

5. A Spanish study (Holzenberger) based on 1.3 million men found that shorter men lived longer.

6. A Sardinian study (Salaris) found that shorter men lived longer.

7. A study of San Diego veterans found shorter men lived longer.

8. The 1959 Build and Blood Pressure Study found that men in the age range of 60 to 70 years had an overall increase in mortality with increasing height. Except for very short women, the same pattern was followed.

9. A Swedish study found that when 67 year olds were tracked into their 90s, shorter men were more likely reach 90 years of age. Other studies found similar results.

10. Chan, Suzuki and Yamamoto found that being short and lean increased chances for reaching 100 years of age.

11. Animal studies show that within a species, smaller individuals live longer. Dogs are an example.

12. Many biological parameters support the preceding findings.

On 2016 Mar 06, Jonathan Eisen commented:

Interesting paper. Given that the authors made extensive discussion of the Coprothermobacter genome that we sequenced I wish they would have cited the "Data Report" paper we published on the genome in 2014. See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022818/.

On 2016 Jun 17, Luis Quadros commented:

Conflicting conclusions.

In abstract: "Bleeding disturbances, the most frequent reason for method discontinuation, were significantly more common in the ENG group [16.7 (95% CI 14.4-19.3)] than in the LNG group [12.5 (95% CI 10.5-14.9)] (P 0.019)."

(A P value can be < 0.05 with overlapping 95% Confidence Intervals.)

In the paper results it is written: "The frequency of symptoms and signs reported in the course of the study by ENG- or LNG-implant users is shown in Table II together with diagnoses of PID. Apart from more reports from ENG-implant users about amenorrhoea, therewere no significant differences recorded between the two implant groups."

And in discussion: "In conclusion, this RCT showed that the ENGand LNG implants have the same contraceptive effectiveness and similar reasons for implant removal for all combined medical reasons in the 3 years after insertion, continuation rates for the two implants were similar up to the middle of the third year of use and had, during this time period, higher continuation rates than the TCu380A IUD."

On 2016 May 19, Lydia Maniatis commented:

Below is my reply to the author. My polemic tone notwithstanding, I appreciate his taking the time to respond. I've interspersed my responses with his text.

Author: A researcher I highly respect once told me that a good review paper is one that engages and stimulates the reader to think critically and broadly about a particular phenomenon. In this sense I appreciate the commentary by Prof. Maniatis, which suggests the review at least succeeded in stimulating critical thought in at least one distinguished reader. And I will add that, though my initial reaction was that Prof. Maniatis' commentary is a polemic, it is clear that my critic takes the issues very seriously and raises some important research questions suggesting future experimental work.

Me: My commentary is a polemic, if by that you mean it raises serious objections. I'm not recommending future work along the same lines; I'm saying the rationale for such work is vague to non-existent, not least because it conflicts with known facts. (My (ongoing) comments on Ariely (2001), which this article and many others treat as as “seminal,” as well as the other comments I've cited here, may make this clearer. Disagreement with the facts is supposed to be disqualifying in science, unless and until theoretical alignment can be achieved. Avoiding the (easy) possibility of falsification by choosing the route that Runeson describes (quoted in my second comment on Dube and Sekuler) is not the same thing as subjecting a hypotheses to serious tests. Inconclusive tests and an avoidance of critical discussion to point out logical inconsistencies/inconsistencies with the phenomena ensures that more work is always needed.

Author: Nonetheless, the response, roughly a third of which seems to revolve around a passing reference to work by Koffka that has little to no bearing on the main points and conclusions of the review (and which misses the point of the reference to Koffka)...

Me: If I've missed the point, then please let me know what I've missed. I consider the mistake that I flagged serious because it implies that the work of the Gestaltists supports the work being discussed here, when in fact the opposite is true.

Author:...contains a number of misintepretations of the points made in the review. I take responsibility for any lack of clarity that may have produced this. I will detail a couple of examples that seem most directly related to the review (discussion of modeling methods, which don't fit algorithms as Prof. Maniatis stated but use algorithms to fit models, has to do with standard practice in the field itself and not the review).

Me: Standard practice isn't necessarily good practice.

Author: Encoding and retrieval of statistical information about stimuli, such as the average diameter of circles in a set of circles with different diameters, may or may not involve direct "perception" of the average in the sense used by Prof. Maniatis. The relevant experiments, I suspect, have yet to be conducted.

Me: Encoding and retrieval of statistical information about stimuli, such as the average diameter of circles, may or may not actually happen. Scientific hypotheses are indeed guesses, but to be worthy of testing there needs to be a rationale and a clear articulation of associated assumptions. Relevant experiments pre-suppose that the idea has been developed enough to specify, for the purpose of testing, what these assumptions are. If investigators, after decades, haven't even decided whether direct perception is involved (which it clearly isn't – it's the nature of direct perception to be self-evident), then what have they been doing?

Author: For this reason, "perceptual" may not be the best term and several different terms for the effects we have described are in in use (ensemble representation, statistical summary representation, etc). In my prior work (Dubé et al., 2014) I have discussed conceptual difficulties related to this term, and in my current work I favor "statistical summary representation" for this reason. However, the findings detailed in the review are indisputable.

Me: I dispute them, partly along the lines of Runeson. I think when we look on a case by case basis, we find serious problems of method and/or misrepresentations in the interpretation.

Author: There is a clear consensus in the literature that participants can accurately recall the average.

Me: It's interesting that experimenters jump to the recall stage but skip the (presumably less challenging) perception stage. Why are observers being forced to recall what they are supposed to be perceiving?

Author: If they can accurately recall it, they must have encoded and stored it. There is no question as to whether such memories exist. I just returned from VSS at which there were around 50 presentations on the topic of summary statistical representation, according to one talk, and the special issue of JoV in which our review appeared was devoted entirely to summary statistical representation. Clearly a decent number of scientists remains convinced that the effects exist!

Me: Numbers of proponents is not an argument. I've criticized some of these authors' work, and when there's a response its not very convincing.

Author: The final comment in the review, which Prof. Maniatis takes as our own admission that the existence of statistical representation is questionable, was meant to be somewhat tongue-in-cheek. How can the effects that have been attributed to remembered averages be due to memory for fine details of individual items when several studies, including the seminal one by Ariely (2001), demonstrate memory for the average despite chance performance on memory tests of the individual items from which the average was computed?

Me: I'm in the process of commenting on Ariely (2001). His methods and interpretations are questionable and his arguments are full of inaccuracies and inconsistencies. It is an extremely casual, not a seminal, study.

Author: It is in no way a statement that the effects don't exist (or even that we suspect they don't), even if taken at face value, and as I have detailed there is a quite large amount of empirical evidence to contradict the philosophical position of Prof. Maniatis. I will not detail all of these studies here, since a review detailing them already exists: Dubé and Sekuler (2015).

Me: There are often other ways to interpret performances that have been attributed to some kind of mental calculation. The brain can use rules of thumb, as Gigerenzer has discussed. One example is how baseball players can catch a ball without subconsciously doing the complex math that some thought was required. When you a. ignore falsifying facts and b. don't consider alternative interpretations, then you have no doubts.

Author: In my view, the conceptual nuances involved in discussion of summary statistical representation are suggestive of a need for more concrete, computational modeling, less verbal theorizing, and more neural data in this area."

Me: If by verbal theorizing you mean critical discussion and exchange of ideas, I would say that more is desperately needed. The conceptual problems aren't “nuances,” they're huge. Useful data collection presupposes clear theories; otherwise its a waste of time, money and people. (As Darwin said, if you don't have a hypothesis, you might as well count the stones on Brighton Beach). The normalized view (espoused by journal editors) that critical discussion is the enemy of progress is convenient, but unscientific and wasteful.

On 2016 May 18, Chad Dube commented:

A researcher I highly respect once told me that a good review paper is one that engages and stimulates the reader to think critically and broadly about a particular phenomenon. In this sense I appreciate the commentary by Prof. Maniatis, which suggests the review at least succeeded in stimulating critical thought in at least one distinguished reader. And I will add that, though my initial reaction was that Prof. Maniatis' commentary is a polemic, it is clear that my critic takes the issues very seriously and raises some important research questions suggesting future experimental work. Nonetheless, the response, roughly a third of which seems to revolve around a passing reference to work by Koffka that has little to no bearing on the main points and conclusions of the review (and which misses the point of the reference to Koffka), contains a number of misintepretations of the points made in the review. I take responsibility for any lack of clarity that may have produced this.

I will detail a couple of examples that seem most directly related to the review (discussion of modeling methods, which don't fit algorithms as Prof. Maniatis stated but use algorithms to fit models, has to do with standard practice in the field itself and not the review).

Encoding and retrieval of statistical information about stimuli, such as the average diameter of circles in a set of circles with different diameters, may or may not involve direct "perception" of the average in the sense used by Prof. Maniatis. The relevant experiments, I suspect, have yet to be conducted. For this reason, "perceptual" may not be the best term and several different terms for the effects we have described are in in use (ensemble representation, statistical summary representation, etc). In my prior work (Dubé et al., 2014) I have discussed conceptual difficulties related to this term, and in my current work I favor "statistical summary representation" for this reason. However, the findings detailed in the review are indisputable. There is a clear consensus in the literature that participants can accurately recall the average. If they can accurately recall it, they must have encoded and stored it. There is no question as to whether such memories exist. I just returned from VSS at which there were around 50 presentations on the topic of summary statistical representation, according to one talk, and the special issue of JoV in which our review appeared was devoted entirely to summary statistical representation. Clearly a decent number of scientists remains convinced that the effects exist!

The final comment in the review, which Prof. Maniatis takes as our own admission that the existence of statistical representation is questionable, was meant to be somewhat tongue-in-cheek. How can the effects that have been attributed to remembered averages be due to memory for fine details of individual items when several studies, including the seminal one by Ariely (2001), demonstrate memory for the average despite chance performance on memory tests of the individual items from which the average was computed? It is in no way a statement that the effects don't exist (or even that we suspect they don't), even if taken at face value, and as I have detailed there is a quite large amount of empirical evidence to contradict the philosophical position of Prof. Maniatis. I will not detail all of these studies here, since a review detailing them already exists: Dubé and Sekuler (2015).

In my view, the conceptual nuances involved in discussion of summary statistical representation are suggestive of a need for more concrete, computational modeling, less verbal theorizing, and more neural data in this area.

On 2016 May 17, Lydia Maniatis commented:

(For some reason the system's not allowing me to edit at the moment: The following is the edited version of the earlier comment). I have a number of issues with this paper, among them that it refers to "perceptual averaging" as though it actually exists, before admitting, at the very end, that it might not. It's an odd situation; can an experience be perceptual in the absence of something being actually perceived? (Who are you going to believe, the investigators or your lying eyes?) Apparently, the authors and others they cite have never personally perceived perceptual averages (if they had there would be little doubt of their perceptual existence), but they have purportedly generated a great deal of evidence that other humans do experience such percepts. If, on the other hand, they mean to refer to some type of blindsight, then it is still the case that the term perceptual is not quite right, since the striking thing about blindsight is precisely the lack of a percept.

I've addressed the averaging issue and its existence in other comments, including a comment here on Bauer (2015) and Solomon, May and Tyler (2016).

Another problem I have is that the authors refer to perception in terms of "signal detection," in which the main problem is what to discard, as though "features" were an intrinsic part of the proximal stimulus pre-organization, and we just have to decide what to get rid of or to "summarise." I've criticised the signal detection model in various comments including one on Allard and Faubert (2014). Such descriptions completely miss the point, which is that "features" such as shape and even color are not simply given in the stimulus, which consists of disconnected photons striking the retina. The failure of contemporary "signal detection" and "statistical summary" proponents to understand the fundamental problems of perception, and the tendency to essentially oversimplify the problems, puts them in the same boat with the structuralists, behaviourists and psychophysicists of yore. Of course, what is not simple are the fussy algorithms that are constantly being fitted and adjusted to the data, but this is just a technical not a conceptual complexity. If these activities had heuristic value, rather than being exercises in post hoc data-fitting, then we wouldn't be in a position where Bauer (2015), in a review of related research up to 2000, can state that some people continue to doubt the very existence of the assumed processes, or where the present authors could say pretty much the same thing: "Future work will be required to evaluate such claims fully, determining whether what appear to be the effects of perceptual averages might in the end reduce to the effects of memory for fine details of individual stimuli." Even though he's gotten a lot of flack for it, Helmholtz's "unconscious inferences" are basically a description of unconscious processes. Unperceived percepts, on the other hand, are simply paradoxical.

To the failure of the authors to appreciate the subtle but fundamental problems that the Gestaltists were addressing is added the misrepresentation of the latter, who are described as an early version of the former: "As Haberman and Whitney (2012) have noted, the idea that the visual system extracts summary statistics at the expense of individual features is far from a new one, going back at least as far as the writings of first-generation Gestalt psychologists (e.g., Koffka, 1935, pp. 270, 273). Despite the idea's long history and the recent increase in efforts to understand the statistical representations generated by the visual system, the basic structural mechanisms and functional significance of such summary statistics remain unclear." The reference to Koffka is completely off, as in the relevant passages he's discussing binocular vision and the matching or "summarising" of two retinal images to produce the perception of a single one in depth. The Gestaltists would have been acutely sensitive to the failure of visual statisticians to understand that the problem is not extraction and reaction but construction. They have extensively argued against past incarnations of these fallacies.

On 2016 May 17, Lydia Maniatis commented:

I have a number of issues with this paper, among them that it refers to "perceptual averaging" as though it actually exists, before admitting, at the very end, that it might not. It's an odd situation, since "perceptual;" can an experience be perceptual in the absence of something being actually perceived. (Who are you going to believe, the investigators or your lying eyes?) Apparently, the authors and others they cite have never personally perceived perceptual averages (if they had there would be little doubt of their perceptual existence), but they have purportedly generated a great deal of evidence that other humans do. If, on the other hand, they mean to refer to some type of blindsight, then it is still the case that the term perceptual is not quite right, since the striking thing about blindsight is precisely the lack of a percept.

I've addressed the averaging issue and its existence in other comments, including a comment here on Bauer (2015) and Solomon, May and Tyler (2016).

Another problem I have is that the authors refer to perception in terms of "signal detection," in which the main problem is what to discard, as though "features" were an intrinsic part of the proximal stimulus pre-organization, and we just have to decide what to get rid of or to "summarise." I've criticised the signal detection model in various comments including one on Allard and Faubert (2014). Such descriptions completely miss the point, which is that "features" such as shape and even color are not simply given in the stimulus, which consists of disconnected photons striking the retina. The failure of contemporary "signal detection" and "statistical summary" proponents to understand the fundamental problems of perception, and the tendency to essentially oversimplify the problems, puts them in the same boat with the structuralists, behaviourists and psychophysicists of yore. Of course, what is not simple are the fussy algorithms that are constantly being fitted and adjusted to the data, but this is just a technical not a conceptual complexity. If these activities had heuristic value, rather than being exercises in post hoc data-fitting, then we wouldn't be in a position where, as Bauer (2015) in a review of related research up to 2000, can state that some people continue to doubt the very existence of the assumed processes, or where the present authors could say pretty much the same thing: "Future work will be required to evaluate such claims fully, determining whether what appear to be the effects of perceptual averages might in the end reduce to the effects of memory for fine details of individual stimuli." Even though he's gotten a lot of flack for it, Helmholtz's "unconscious inferences" are basically a description of unconscious processes. Unperceived percepts, on the other hand, are simply paradoxical.

To the failure of the authors to appreciate the subtle but fundamental problems that the Gestaltists were addressing is added the misrepresentation of the latter, who are described as an early version of the former: "As Haberman and Whitney (2012) have noted, the idea that the visual system extracts summary statistics at the expense of individual features is far from a new one, going back at least as far as the writings of first-generation Gestalt psychologists (e.g., Koffka, 1935, pp. 270, 273). Despite the idea's long history and the recent increase in efforts to understand the statistical representations generated by the visual system, the basic structural mechanisms and functional significance of such summary statistics remain unclear." The reference to Koffka is completely off, as in the relevant passages he's discussing binocular vision and the matching or "summarising" of two retinal images to produce the perception of a single one in depth. The Gestaltists would have been acutely sensitive to the inadequacies and contradictions in the arguments in the current literature. They have extensively argued against past incarnations of the same fallacies.

On 2015 Oct 02, Robert Groom commented:

Thank you for your scholarship and insights related to Gibbon’s first successful open heart procedure with cardiopulmonary bypass. There are many lessons to be learned from this amazing “story behind the story.” Do you think that as a scientific community, we have improved in our ability to accurately characterize medical advances in the peer reviewed published literature? On another note, I admire your humility and your call to clinicians to strive to make scholarly contributions.

On 2015 Oct 06, Tom Kindlon commented:

No objective outcome measures were used

This trial just used subjective outcome measures. Objective outcome measures are important as subjective outcome measures may not translate into objective improvements with graded activity-oriented interventions in Chronic Fatigue Syndrome (CFS) (1-3). Examples of more objective outcome measures that have been used in CFS interventional studies include actigraphy, employment data, disability payments data and exercise testing.

References:

1 Kewley AJ. Does Cognitive Behavioral Therapy or Graded Exercise Therapy Reduce Disability in Chronic Fatigue Syndrome Patients? Objective Measures Are Necessary. Clinical Psychology: Science and Practice 2013:20;321-322.

2 Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010:40;1281-7.

3 Kindlon T. Comment on: Exercise therapy for chronic fatigue syndrome. http://www.ncbi.nlm.nih.gov/pubmed/25674924#cm25674924_11779

On 2015 Sep 30, Hiskias Keizer commented:

More studies studying CLA induced fat loss in humans have been published than referred to in this study. The large majority of high quality studies among these(meeting EFSA guidelines)do report fat-loss. However, the minimum time required to find such an effect in group sizes as most often used (10-20)is 12 weeks of daily exposure to CLA. This study had a duration of 8 weeks, and was therefore probably too short for finding a fat-loss effect of CLA in a study with this limited size.

On 2015 Sep 26, Eric Fauman commented:

I applaud the authors for identifying novel genetic associations with metabolites but I disagree with their interpretations and conclusions in several regards.

As tempting as it is to use eQTL data to assign causal genes to SNPs it is frequently seen that SNPs tag expression of unrelated genes as often as they tag the true causal gene for the given trait.

In this study the most obvious example is at rs2066938 where the authors report eQTL associations with 5 egenes (RNF10, MLEC, UNC1198B, CAMKK and COQ5), but not ACADS which is almost certainly the true causal gene, as the authors acknowledge in the text.

At the ARG1 and CRAT loci, other genes have stronger eQTL signals so here too the eQTL data is incomplete.

The ALMS1/NAT8 locus is less clear, but previous authors have assigned this locus to NAT8 given the association with N-acetylornithine and NAT8's presumed acetylation function. The biochemical linkage of N-acetylornithine and arginine in the urea cycle suggests that NAT8 is also the causal gene for this paper. If NAT8 is truly the causal gene, the eQTL data missed it at this locus.

A striking example of the over-reliance on eQTL data in this paper is at the "PPP1R16A" locus which associates with the ratio of aspartic acid to alanine. This SNP is in fact just upstream of GPT which encodes glutamic-pyruvic transaminase, also known as alanine transaminase. GPT is a far more plausible causal gene even though it is not one of the 10 egenes listed for this SNP. Interestingly, there is a coding variant in GPT in reasonable LD with the lead SNP (rs1063739, r2=0.77).

In fact 6 of the loci are linked to coding variants in the most probable causal gene (NAT8, GPT, ACADS, SLC22A16, MCCC1 and CPS1).

Again, it's great to see new SNP-metabolite associations still emerging. However any GWAS interpretation must make use of all biological lines of evidence and not rely only on one or two types of data or analysis.

On 2015 Nov 03, John Tucker commented:

The authors find evidence in support of the unsurprising conclusion that pharmaceutical employees are loathe to criticize their own company's products. I don't think anyone will contest that. They also find that academic authors who have accepted research funding from industry currently or in the past are less likely than those who have not to make critical remarks in the paper abstract, and conclude that this represents the influence of conflict-of-interest.

While the first conclusion is both clear and expected, the second involves an implicit and unproven assumption that those who eschew all contact with industry represent an absolute standard of objectivity against which others can be measured. While one can readily point a finger at research support as a conflict, the same reasoning requires that we ask why others have turned research money down. Is it purely a desire for both the actuality and appearance of complete objectivity? Does it stem from a pre-existing distrust and dislike of for-profit drug development? All we really know is that there are likely systematic differences between those who work with industry to develop drugs and those who keep industry at arms length.

One way to address this question might be to take the list of authors of meta analyses included in this study and assess the extent to which positive/negative assessments of individual drugs correlates with public expressions of positive/negative opinion about the pharmaceutical industry as a whole. I suspect that the observed correlation is high, and that when reading any meta analysis, one should be aware that the subjective and non-transparent processes of study selection and data reduction makes most meta analyses little more than detailed editorials.

On 2015 Sep 25, Jacob H. Hanna commented:

The Hanna group congratulates our friends, colleagues and collaborators on their elaborate, timely and elegant review. We wish to alert the readers to four minor constructive comments and points, which may be useful for future discussions:

1) On page 473 the authors state: “Direct derivation of ground state ES cells from human embryos would be a landmark”

We fully agree with the authors that for any newly established stem cell growth conditions, it is important to show technical feasibility for such conditions to obtain newly derive human ESCs from pre-implantation blastocysts. However, it should be kept in mind that the pluripotent state identity is going to be dictated by the derivation growth conditions and not by whether their source was from the human inner cell mass (ICM). The fact that human ICM cells explanted in conventional/primed FGF2/TGFB1 containing conditions, undergo a dramatic in vitro adaptation process and have yielded only primed human ESCs for the last 20 years (Thomson et al. Science 1998), certainly does not prove that conventional human ESCs are in an ICM-like/naïve state. Similarly, mouse ICM derived cells yield naïve stem cells when derived in mouse stem cell naïve conditions in vitro, or give rise to primed Epiblast Stem Cell (EpiSCs) when explanted and derived under mouse primed pluripotency growth conditions (Hanna et al. Cell Stem Cell 2009, Najm et al. Cell Stem Cell 2011). http://www.cell.com/cell-stem-cell/abstract/S1934-5909(11)00049-X http://www.cell.com/cell-stem-cell/abstract/S1934-5909(09)00169-6

The latter examples constitute a clear cautionary note against using ability for ESC derivation from human ICMs in itself as a validation criterion for endowing naïve-like pluripotent state characteristics in any in vitro expanded stem cell type or condition. In fact, we modestly believe that applying such a criterion to annotate the state of an in vitro captured pluripotent cell would be wrong. ESC derivations from human ICM are only technical validations for new growth condition capabilities and applications, and can yield naive or primed pluripotent cells depending on the conditions applied.

2) Less importantly, on page 473 the authors indicate: “Nonetheless, a recent study described altered primate PS cells that can incorporate into host embryos and develop into chimaeric fetuses with low-grade contribution to all three germ layers and early germ cell progenitors57. As in mice, high-grade contribution and germline transmission remain as more stringent tests to demonstrate naive pluripotency in primate ES cells“

We find it unfortunate that this review fails to clearly indicate that the “altered” primate PS cells used in Reference 57 and capable of generating monkey chimeric fetuses for the first time ever, were expanded in negligibly “altered” NHSM conditions previously described by our group in Gafni et al. Nature 2013 (Reference 52). For clarification, the latter fact is clearly indicated by the author in Chen et al. Cell Stem Cell 2015 (Reference 57). http://www.cell.com/cell-stem-cell/abstract/S1934-5909(15)00264-7

3) On Page 473 the authors indicate: “More compelling evidence for cross-species blastocyst chimaerism has been reported following injection of primate naive iPS cells into mouse blastocysts, leading to clonal contribution to solid tissues56.”

We find it unfortunate that this review fails again to indicate that the naïve monkey iPSCs used in Reference 56, and capable of generating cross-species chimerism after micro-injection in mouse blastocysts, were also expanded in presumably “altered” NHSM conditions previously described by our group in Gafni et al. Nature 2013 (Reference 52). Instead of providing exogenous low-dose TGFB1 as devised in NHSM conditions, Fang et al. Cell Stem Cell 2014 (Reference 52) simply used mouse embryonic feeder cells that are known to secrete other TGF family members ligands (including Activin A), and similarly substitute for TGFβ1 in supporting pluripotent stem cell expansion. http://www.cell.com/cell-stem-cell/abstract/S1934-5909(14)00395-6

4) At the end of Page 471 the authors indicate: “The observation that naive cells tolerate depletion of epigenetic regulators supports the concept of naive pluripotency as a configuration with a reduced requirement for epigenetic repression compared to primed PS cells and somatic cells.”

The authors did not provide a citation for the the first and only study thus far conducting side by side comparison on mouse naive and primed cells and showing for the first time opposing tolerance of epigenetic repressor depletion in naive and primed cells from the same species, which was conduced by our group (Geula et al. Science. 2015 Feb 27;347(6225):1002-6. doi: 10.1126/science.1261417).

We had indicated in the discussion by Geula et al Science 2015: “The fact that murine naïve cells, rather than primed cells, are tolerant to depletion of epigenetic and transcriptional repressors supports the concept of naïve pluripotency as a configuration with a relatively minimal requirement for epigenetic repression (in comparison to primed pluripotent and somatic cells)”.

Relevant data and discussion backing these original conclusions are presented in Figure 1 http://www.sciencemag.org/content/347/6225/1002.long, Supplementary Page 17 and Figure S1 http://www.sciencemag.org/content/suppl/2014/12/30/science.1261417.DC1/1261417.Guela.SM.revision1.pdf of Geula et al Science 2015.

With great appreciation,

Jacob (Yaqub) Hanna M.D. Ph.D.

Department of Molecular Genetics

Weizmann Institute of Science

Email: jacob.hanna@weizmann.ac.il

Lab website: http://hannalabweb.weizmann.ac.il/

Twitter: @Jacob_Hanna

On 2017 May 03, Andrea Messori commented:

Please refer to the Letters' section of the Journal.

Presenting the results of a pharmacoeconomic study: incremental cost-effectiveness ratio vs net monetary benefit

Andrea Messori and Sabrina Trippoli

HTA Unit, ESTAR Regional Health Service, 50135 Firenze (Italy)

The article by Wouters and colleagues (1) presents an exhaustive overview on how QALYs can be used in cost-effectiveness analysis. In this framework, the authors also mention the incremental cost-effectiveness ratio (ICER), which is the parameter typically employed to express the results of a cost-effectiveness study. The article, however, does not discuss the net monetary benefit (NMB), which is another parameter employed to express the results of a cost-effectiveness study.

The incremental cost (deltaC) and the incremental effectiveness (deltaE) are the two main parameters of pharmacoeconomics and cost-effectiveness analysis, along with the willingness-to-pay threshold (lambda). The decision rule (e.g. in the case of a favourable pharmacoeconomic result) is (deltaC/deltaE)<lambda (Equation 1), if based on the ICER, or (deltaE x lambda - deltaC) > 0 (Equation 2), if based on the NMB. Likewise, an unfavourable pharmacoeconomic result is when (deltaC/deltaE)>lambda or when (deltaE x lambda - deltaC) < 0; NMB is defined as deltaE x lambda - deltaC, while ICER is defined as deltaC/deltaE. Despite its apparent complexity, most part of pharmacoeconomic methodology is described by the two simple equations reported above (i.e. Equations 1 and 2), but whether the ICER or the NMB is the best parameter for the purposes of pharmacoeconomic decision-making remains on open question.

The study by Cowper et al evaluating new versus old oral anticoagulants in patients with atrial fibrillation (2) is a typical ICER-based cost-effectiveness analysis in which the ICER of apixaban versus warfarin is compared against a willingness-to-pay threshold. This analysis can be taken as an example for comparing ICER vs NMB.

In one of the base-case analyses of the study by Cowper et al, QALYs per patient were 7.94 for apixaban and 7.54 for warfarin, while pharmacological costs per patient were $22,934 and $4,392, respectively. These data yielded, for apixaban versus warfarin, an ICER of $46,355 per QALY gained, a value that remains within the willingness-to-pay threshold of $50,000 per QALY gained and is therefore considered favourable (or “high value care”). As pointed our by Hlatky (3), in interpreting a specific ICER value, more than a single willingness-to-pay threshold is frequently considered (e.g. the threshold between $50,000 and $150,000 or the threshold above $150,000), and this allows us to better understand a pharmacoeconomic result expressed on the basis of an ICER.

In the methodology of pharmacoeconomics, the net monetary benefit (NMB) plays a role similar to that of ICER, but some differences are important.

Firstly, the ICER –by definition- has always an incremental nature and consequently the absolute cost-effectiveness ratio (calculated for a single treatment in the absence of any comparison) makes little sense and, for this reason, is rarely employed. In contrast, the NMB can be calculated for a single treatment in the absence of any comparison (absolute NMB) or can conversely be calculated as an incremental parameter [according to the equation: (incremental NMB) = (incremental QALYs per patient) x (willingness-to-pay threshold) – (incremental cost per patient)]. Another feature of NMB is that the incremental NMB for the comparison of A vs B can be estimated as the absolute NMB calculated for A minus the absolute NMB calculated for B. In this sequence of calculations, calculating the absolute NMB makes sense because the absolute NMB (separately calculated for the experimental treatment and for the control treatment) represents an intermediate step in the calculation of the incremental NMB (Table 1)

The values of absolute NMB for apixaban and warfarin (Table 1) are, respectively, 374,066 and $372,608 per patient (calculated according to Equation 2). Hence, the incremental NMB for apixaban vs warfarin is simply the difference of the above two values, i.e. $1,458 per patient.

References

[1] Wouters OJ, Naci H, Samani NJ. QALYs in cost-effectiveness analysis: an overview for cardiologists. Heart. 2015 Dec;101(23):1868-73.

[2] Cowper PA, Sheng S, Lopes RD, Anstrom KJ, Stafford JA, Davidson-Ray L, Al-Khatib SM, Ansell J, Dorian P, Husted S, McMurray JJ, Steg PG, Alexander JH, Wallentin L, Granger CB, Mark DB. Economic Analysis of Apixaban Therapy for Patients With Atrial Fibrillation From a US Perspective: Results From the ARISTOTLE Randomized Clinical Trial. JAMA Cardiol. 2017 Mar 29. doi:10.1001/jamacardio.2017.0065. [Epub ahead of print]

[3] Hlatky MA. Are Novel Anticoagulants Worth Their Cost? JAMA Cardiol. 2017 Mar 29. doi: 10.1001/jamacardio.2017.0126. [Epub ahead of print]

Table 1. Cost-effectiveness of apixaban vs warfarin in atrial fibrillation: basecase analysis reported by Cowper et al.(2)

a) STARTING VALUES

apixaban: QALYs per patient = 7.94, cost per patient = $22,934

warfarin: QALYs per patient = 7.54, cost per patient = $4,392

willingness-to-pay threshold = $50,000/QALY

b) PHARMACOECONOMIC PARAMETERS

ICER = ($22,934 - $ 4,392) / (7.94 – 7.54) = 18,542 / 0.40 = $46,355/QALY

absolute NMB for apixaban = 7.94 x $50,000 – $22,934 = $374,066

absolute NMB for warfarin = 7.54 x $50,000 – $4,392 = $372,608

incremental NMB = absolute NMB for apixaban - absolute NMB for warfarin = $374,066 - $372,608 = $1,458

c) INTERPRETATION

ICER (equal to $46,355/QALY): favourable because <$50,000/QALY

incremental NMB (equal to $1,458 per patient): favourable because >0

On 2016 Mar 24, Jan Tunér commented:

The 20 J stated here rather appears to be 20 J/cm2, as this fluence has been used in two previous studies by these authors.

On 2017 Jul 04, Randi Pechacek commented:

Alex Alexiev mentioned this article on microBEnet while describing the urban microbiome.

On 2016 Oct 18, Erick H Turner commented:

The ClinicalTrials.gov entry for this study (https://www.clinicaltrials.gov/ct2/show/record/NCT01584440?term=NCT01584440&rank=1) contains the original registration information, but as of October 2016, study results have still not been posted. Credibility of the published results would be enhanced by doing so.

On 2015 Nov 30, Geriatric Medicine Journal Club commented:

This article was critically appraised at the November 2015 Geriatric Medicine Journal Club (follow #GeriMedJC on Twitter). Concerns discussed included that the trial was funded by pharma, last-observation carried forward is not a recommended method for imputing missing data in dementia trials, biases introduced by the choice of rescue medication (Lorazepam), agitation in this trial lumped together several different behaviours (verbal aggression, physical aggression, and non-aggressive activity), and mode of action of the medications. Nevertheless, the findings are interesting but perhaps not quite ready for wide adoption. A transcript of the full discussion can be found at: http://gerimedjc.blogspot.com/2015/11/dextromethorphan-quinidine-not-quite.html?spref=tw

On 2017 Apr 27, Randi Pechacek commented:

Trent Northen, one of the authors of this paper, wrote an interesting blog post on microBEnet giving some background behind this research.

On 2015 Oct 03, Robert Groom commented:

The author raises an important question about use of candidate demographic data and exam results to identify opportunities to improve the education of perfusionists. Clearly there is a moral obligation to use information to inform and refine perfusion education.

On 2015 Sep 28, Bill Cayley commented:

A good piece of research suggesting that sometimes "less" is "more": https://lessismoreebm.wordpress.com/2015/09/28/comparative-effectiveness-of-generic-versus-brand-name-antiepileptic-medications/

On 2015 Sep 26, Lydia Maniatis commented:

None

On 2015 Sep 25, James Hadfield commented:

This appears to be a carbon copy of http://www.ncbi.nlm.nih.gov/pubmed/25278450 and may need investigating

On 2016 Jun 12, John Duffy commented:

Kari Poikolainen and I sent a letter to the Lancet about this paper. It was not published. The content is as follows

The authors report no association between level of alcohol intake and a composite health measure. They write that "In summary, our study shows that current drinking is not associated with a net health benefit." What they fail to mention is that their study also "shows" that current drinking is not associated with net health harm. The interpretation, "sufficient commonalities to support global health strategies and national initiatives to reduce harmful alcohol use" does not follow from their study, which taken on its own suggests that there is no need for such initiatives. However there are a number of methodological problems with their data and analysis. The follow-up time (median 4.3 yrs) was short and the proportion of alcohol consumers (33%) small. There is a strong implication of overfitting, and in the stratified analyses in particular a shortage of degrees of freedom. Since a large body of earlier well-conducted studies shows evidence of both benefits and harms it would be inappropriate to base conclusions on this work.

On 2015 Sep 26, David Keller commented:

Dose-response relationship observed between concentration of ingested alcohol and cancer rate

This study reported that "the risk for cancer was 38% higher in wine drinkers than in never drinkers (HR, 1.38; 95% CI, 1.05 - 1.81), 69% higher in spirit drinkers (HR, 1.69; 95% CI, 1.26 - 2.26), and 20% higher in beer drinkers (HR, 1.20; 95% CI, 0.91 - 1.57)." These 3 data points demonstrate a dose-response curve relating the concentration of ingested alcohol with increased risk of cancer. For cardiovascular (CV) disease, it is the amount of alcohol consumed per day, not its concentration, which is known to be the relevant modifiable risk factor. The maximum CV benefits are associated with consumption of around 2 standard servings per day of alcohol of any concentration.

Note that the 95 percent confidence interval for the Harm Ratio due to drinking beer spanned 1.0, and thus beer did not raise the risk for cancer to a statistically significant degree.

5 percent Beer.....HR = 1.2 non-significant

12 percent Wine.....HR = 1.38

40 percent Spirits..HR = 1.69

Dose-Response Between Alcohol Concentration and Harm Ratio for Cancers

Thus, drinking beer, which, in moderation, is associated with significant cardiovascular (CV) benefits, is not associated with any statistically significant increase in cancers, as are wine and spirits, presumably due to beer's lower alcohol concentration.

This study did not report separate findings for high-volume and low-volume beer drinkers for its risk-benefit analyses. If beer drinkers who limited themselves to 2 servings per day had been analyzed separately, might the harm ratio for incident cancers have been even lower? Might a reduction in cancer incidence perhaps have been observed? At what volume of daily alcohol ingestion in the form of beer (the least carcinogenic alcoholic beverage) was the greatest improvement seen in the composite outcome of cancer and CV disease? Does the optimum amount of beer per day differ for the composite outcome versus the optimal 2 servings per day associated purely with optimal CV outcomes?

The main purpose of studies such as this should be to result in actionable information. Telling us that low economic level countries exhibit different outcomes associated with the consumption of alcohol does little good unless we are given clues as to what alcohol consumers in poor countries might be doing differently than their counterparts in richer nations. Are they drinking higher concentrations of alcohol, greater volumes, both, or is their nutritional status or some other factor implicated?

On 2016 Mar 10, Lydia Maniatis commented:

I'm interleaving my comments to Hoffman's last reply below:

Hoffman: The interface theory predicts that realism is false, and thus that Bell correlations exist. Were experiments to demonstrate that Bell correlations do not exist, then the interface theory would be falsified. Thus the interface theory is an empirical theory, and its prediction is experimentally testable.

LMM: There's a difference between constructing a theory and simply making a loosely argued assertion. Your “theory” doesn't have the logical consistency, respect for facts and specificity to actually predict Bell's correlations. Many people have said the real world doesn't exist, but that doesn't make them physicists, it doesn't make sense to say that they had in effect predicted Bell's correlations. The variables you use are much too vague to justify predictions at any level of specificity, let alone that required at the level of quantum physics.

Hoffman: The remaining experimental loopholes in tests of Bell correlations that Howard Wiseman cites in his paper “Physics: Bell’s theorem still reverberates” are the following: “… they lacked large separations and fast switching of the settings, opening the ‘separation loophole’: information about the detector setting for one photon could have propagated, at light speed, to the other detector, and affected its outcome.” These loopholes are now closed. Bell correlation is confirmed. See Hensen et al., 2015, “Loophole-free Bell inequality violation using electron spins separated by 1.3 kilometres”, Nature, 526, 682-686.

LMM: And there's an even more recent one. However, as I reread Wiseman's article, it is those who (unlike you) don't agree with the Bell's notion of hidden variables (b/c they are empirically inaccessible) need to forgo realism. They (according to Wiseman) must either conclude that some events are correlated for no reason or accept Bell's metaphysical hidden variables. So it's not even clear that Bell's supporters are not realists.

At this point, it seems that physicists are in a very difficult place, caught between two paradoxical options. This is the point at which ground-breaking new theories sometimes emerge. I don't think vision science has a lot to say here.

The fact remains that there are principles of visual perception (and of mechanics, to take an example from physics) that are close enough to the truth in our environment to make useful predictions, lead to useful applications, and to lead to ever more useful theories. That's the world that science lives in. You say this world doesn't exist, yet your story is full of assumptions about that world (natural selection, etc). All I'm saying is, you can't have it both ways.

On 2016 Mar 05, Donald D Hoffman commented:

The interface theory predicts that realism is false, and thus that Bell correlations exist. Were experiments to demonstrate that Bell correlations do not exist, then the interface theory would be falsified. Thus the interface theory is an empirical theory, and its prediction is experimentally testable.

The remaining experimental loopholes in tests of Bell correlations that Howard Wiseman cites in his paper “Physics: Bell’s theorem still reverberates” are the following: “… they lacked large separations and fast switching of the settings, opening the ‘separation loophole’: information about the detector setting for one photon could have propagated, at light speed, to the other detector, and affected its outcome.”

These loopholes are now closed. Bell correlation is confirmed. See Hensen et al., 2015, “Loophole-free Bell inequality violation using electron spins separated by 1.3 kilometres”, Nature, 526, 682-686.

When Wiseman states that “Most physicists are localists” that means that most physicists give up realism. You simply misunderstood him.

On 2016 Feb 17, Lydia Maniatis commented:

This is the status of Bell's theorem in the physics community:

Physics: Bell’s theorem still reverberates Howard Wiseman 19 June 2014

"...But 50 years on, the experimental verifications of these quantum correlations still have ‘loopholes’, and scientists and philosophers still dispute exactly what the theorem states.

...As of now, there are no loophole-free Bell experiments.

...Most physicists are localists: they recognize the two options but choose the first, because hidden variables are, by definition, empirically inaccessible [i.e. outside the realm of empirical science]. Quantum information scientists embrace irreducible randomness as a resource for secure cryptography3. Other physicists and philosophers (the ‘non-localist camp’) dispute that there are two options, and insist that Bell’s theorem mandates non-locality4."

Apparently perception scientists are supposed to side with the minority opinion in physics on an issue of extraordinary complexity, and in turn to figure out what this implies for their discipline. Meanwhile, physics goes on as usual.

Btw, the online descriptions of Bell's theorem often include the term "metaphysics." Again, we are not dealing with empirical science, i.e. testable claims.

The only apparent relevance of the metaphysical claims being put forth as the "interface theory" is that the fundamental assumptions that enable empirical science are false. Yet persistent and irresolvable metaphysical problems with "reality" haven't stopped scientific progress before.

With respect to "H1 and H2," the framing of the questions is paradoxical. What is "it" and what is doing the perceiving? How does the perceiver come into existence? What if no one perceives the perceiver? What if there were no perceivers?

In general, science can never prove that the world exists beyond perception, but it acts as though it could, and that seems to lead to some practical benefits.

On 2015 Dec 10, Donald D Hoffman commented:

Consider two hypotheses.

H1: When it is not perceived, an object has a definite value for each of its dynamical physical properties.

H2: When it is not perceived, an object does not have a definite value for each of its dynamical physical properties.

H1 is widely accepted by vision researchers. Is H1 falsifiable?

If yes: There is an experiment that can support H1 or its negation, viz., H2. Thus H1 is falsifiable iff H2 is falsifiable.

If no: H1 and H2 are both outside empirical science.

In fact H1 and H2 are both falsifiable, and within empirical science. Understanding this nontrivial fact was an intellectual achievement of John Stewart Bell, published in 1964.

Below are published papers presenting empirical tests of the falsifiable hypothesis H2. The results in each case support H2, and thus support the interface theory of perception. A gentle introduction to this literature, and to the remarkable theorem on which it relies, is the paper by Mermin. These experiments, and the theory behind them, are among the greatest achievements of modern science.

Ansmann, M., Wang, H., Bialczak, R. C., Hofheinz, M., Lucero, E., Neeley, M., . . . Martinis, J. M. (2009). Violation of Bell’s inequality in Josephson phase qubits. Nature, 461, 504–506. doi:10.1038/ nature08363

Bell, J. S. (1964). On the Einstein Podolsky Rosen Paradox. Physics 1 (3): 195–200.

Cabello, A., Estebaranz, J. M., & García-Alcaine, G. (1996). Bell– Kochen–Specker theorem: A proof with 18 vectors. Physics Letters A, 212, 183. doi:10.1016/0375-9601(96)00134-X

Giustina, M., Mech, A., Ramelow, S., Wittmann, B., Kofler, J., Beyer, J., . . . Zeilinger, A. (2013). Bell violation using entangled photons with- out the fair-sampling assumption. Nature, 497, 227–230. doi:10.1038/nature12012

Mermin, N. D. (1985). Is the moon there when nobody looks? Reality and the quantum theory. Physics Today, 38(4), 38–47. doi:10.1063/1. 880968

Pan, J.-W., Bouwmeester, D., Daniell, M., Weinfurter, H., & Zeilinger, A. (2000). Experimental test of quantum nonlocality in three-photon GHZ entanglement. Nature, 403, 515–519.

Rowe, M. A., Kielpinski, D., Meyer, V., Sackett, C. A., Itano, W. M., Monroe, C., & Wineland, D. J. (2001). Experimental violation of a Bell’s inequality with efficient detection. Nature, 409, 791–794.

Salart, D., Baas, A., van Houwelingen, J. A. W., Gisin, N., & Zbinden, H. (2008). Spacelike separation in a Bell test assuming gravitationally induced collapses. Physical Review Letters, 100, 220404.

Weihs, G., Jennewein, T., Simon, C., Weinfurter, H., & Zeilinger, A. (1998). Violation of Bell’s inequality under strict Einstein locality conditions. Physical Review Letters, 81, 5039.

On 2015 Dec 02, Lydia Maniatis commented:

Very brief summary: The "falsifiable prediction" that “No object has a position, or any other physical property, when it is not perceived” cannot be tested except by perceiving some objective property of a part of the world (e.g. the absence of an object)...while we are not perceiving it.

It's like turning around really quickly to check if the world behind you disappears when you're not looking at it. Whimsical, but not very scientific.

On 2015 Nov 24, Lydia Maniatis commented:

The authors' proposal NOT FALSIFIABLE (i.e. it is not testable, i.e. it does not belong to empirical science), for a number of reasons.

In addressing the falsifiability question explicitly, Hoffman et al say that “if either [of two predictions – see below] is false, then the interface theory is false” (p. 1501).

The “predictions” being referred to are the following: 1) “No object has a position, or any other physical property, when it is not perceived.” 2) “No object has any causal powers.

The problem should already be obvious. The “interface theory” says that we cannot perceive the state of the objective world, no way, no how – that even space-time is not a property of the physical world. Therefore, on what basis can we ever corroborate any claims regarding position/physical properties of objects? The same goes for “prediction” number 2. We would have to be able to say "Look, this here object HAS a position and physical properties x, y, z EVEN WHEN NOT PERCEIVED! I can't perceive it or any other object, but I can somehow access this information!" With no access to the physical world, we can provide no proof possible about claims regarding the physical world. The assumptions of the “theory,” in other words mean that PROVING IT WOULD BE TANTAMOUNT TO DISPROVING IT.

Another reason that the theory is unfalsifiable is that its computations are based on statements such as: W = a set of world states. How can we ever substitute any kind of numerical value here? I suggest that the “precision” the authors claim for their proposal collapses with this impossibility. (Perhaps as a non-mathematician I'm missing something...).

Also, as an analogy, the interface theory fails to make the case (and the analogy is pretty much the whole case). The claim is that, just as the e.g. square, blue file icon on the desktop doesn't correspond in its properties to the underlying electronics, so percepts don't correspond in any way to physical objects. But our perception of the blue square presumably corresponds to the spectral properties of the light, and the luminance relationships, of the surface of the computer. Hoffman et al can claim that our perception of the properties of the icon are not veridical, but not using the lack of correspondence between icon and electronics as evidence. No one claims that because we can't accurately perceive the shape of a tree because we can't also see the interior, back, atoms that compose it...

Basing broad, unfalsifiable statements such as those being made in this article on a particular, crude similation is not credible. The “non-linearity” assumptions are said to be frequent but not universal, and even the examples given don't hold up. We are told that “not enough water and one dies of thirst; too much and one drowns; somewhere in between is just right” (p. 1506). This is no argument against the accurate (linear) perception of quantity – seeing a lot of water doesn't mean we actually have to drink it all. We might want to decide to swim in it.

There's just no reason to claim that the refined optical structures and responses of organisms have no purpose in using reflected light to infer and represent the world veridically. It's absurd, and leads to absurdity and, again, unfalsifiable claims. There is absolutely no special relationship between this “theory” and the theory of evolution by natural selection; the implication that a fitness criterion is opposite to a veridical (as veridical as possible and necessary) outcome is unfounded (and, again, unfalsifiable). In fact, the normal assumptions about structure and function (based on perceived structures) are more consistent with evolutionary discussions (they are actually required to make such discussions rational).

The claim, in his comment on the article, by the Editor-in-Chief of this journal that “Our measurements...are species-specific and we should worry if they form the starting point for physical theories” (Hickok (2015, p. 1478) just recycles an old philosophical conundrum that is irrelevant to scientific progress. The “worry” cannot be resolved by science but also cannot, in principle and in practice, affect, let alone “be the future of the science of the mind” (p. 1479) - or of any science (otherwise physicists would also have a problem). It just takes us round in circles for the millionth time. The focus on quantum physics is silly, implying as it does that progress in perception depends on an understanding of the unsolved mysteries of that discipline.

On 2015 Nov 11, Lydia Maniatis commented:

Feldman seems unaware of a fundamental principle of perception. His error (can you spot it?) is contained in the following statements:

“What we can say, often, is whether estimates from distinct perceptual systems “agree.” When I reach out and grasp the banana, I may find that it feels the same size as it looked. This is extremely useful, because it means that the perceptual system is coherent: estimates drawn from different sorts of evidence agree.”

In fact, there is a fundamental asymmetry between our visual sense and our body senses. The body senses defer to vision – what vision says, goes. With respect to haptics, this is described as “visual capture.” In the relevant experiment, a subject observes a straight rod through a distorting lens that makes it appear curved. It feels curved.

In the tilted room, our eyes tell us we're tilted, even though our body senses tell us (or should tell us) that we're upright. We feel tilted.

In the rubber hand illusion, our eyes tell us that the rubber hand is being tickled in the same rhythm as we are experiencing tickling on our real hand. The experience is percieved as originating in the hand that we see, not the hand that is actually doing the feeling.

Thus, when this false argument is used to promote the “Bayesian inference” brand, it is moot:

“Not incidentally, this is the central principle underlying Bayesian inference, which Dennis Lindley (2006) paraphrased as (his emphasis) “BE COHERENT.”

In the case of perception, the “central principle' seems to be resting on a false assumption.

Coherence is also a central principle of scientific argument. It is impossible, in this brief report, for a reader to evaluate Feldman's remaining claims for “B'ian inference.” For a critical analysis of very sloppy arguments, please see my PubPeer comment on Feldman's (2015) “Bayesian models of perceptual organization.”

On 2015 Nov 17, Lydia Maniatis commented:

Anderson concludes his critical commentary on Hoffman, Singh and Prakash's (2015) "Interface theory of perception" with the following remark:

"But remarkable theories require remarkable evidence, and there is currently insufficient evidence to take the metaphysical leap proposed by interface theory."

In fact, as I observe in a recent editorial (http://pec.sagepub.com/content/44/10/1149.full) critical of the "anti-realism" of Hoffman and others, the position is not amenable to evidence; any appeal to evidence in favour of the anti-realist position is paradoxical.

If you say that the features of the perceived world bear no correlation, no connection to the real world, then you cannot EVER produce evidence in support of this position. You cannot prove such a position, because you can't compare the "real world" with your (supposed) wholly inaccessible-to-perception-world. As it is impossible, Hoffman cannot be not doing it, even when he is claiming that he is. He is free to believe anything he wants, but the issue is outside of empirical science.

(I will follow this up with a critique of Hoffman, Singh and Prakash (2105) but wanted to make this quick point.)

On 2015 Oct 29, Dmitri Graifer commented:

I have read with great interest this excellent paper. Regretfully, I found that the authors cite earlier studies in somewhat careless way. First, when mentioning biochemical data on eRF1 motifs involved in stop codon recognition, they ignore data obtained by site-directed cross-linking, which for the first time directly demonstrated that one of the mentioned motifs, GTS, is actually located close to the purines of the A site bound stop codon in the mammalian ribosomal termination complexes (Bulygin et al., 2010, RNA). In this regard, the authors cite only the later paper by Wong et al. (Nucleic Acids Res., 2012) as ref. 25, where a suggestion on implication of this motif in stop codon recognition has been made based on the application of a model ribosome-free system but this paper does not contain any original evidence for the proximity of GTS motif to the stop codon bound at the ribosomal A site. Besides, I have found an “empty” reference 52 (Blanchet et al., Nucleic Acids Res., 2015), which does not contain information on contacts of Arg residues in eRF1 positions 65 and 68 with rRNA as one could expect from the phrase “…and the following Arg65 and Arg68 interact with ribosomal RNA (52)”. In particular, in the paper by Blanchet et al., 2015 (ref. 52) Arg68 is not mentioned at all, and interaction of Arg65 with the rRNA is only hypothesized in the middle part of the penultimate paragraph of the Discussion but it is not shown. I guess that inappropriate referencing corrupts really existing priority in the field and gives distorted ideas on the actually obtained scientific results.

On 2015 Nov 13, Lydia Maniatis commented:

Brainard and colleagues have apparently been using the practical-definition-free term "naturalistic" for at least 18 years, as indicated by the article titled: "Color constancy in the nearly natural image. 1. Asymmetric matches. (Brainard, D. H., Brunt, W. A, & Speigle, J. M. (1997), Journal of the Optical Society of America. A, Optics, Image Science, and l'ision, 14, 2091-2110.)

Without stimulus/variable control, questions cannot be framed in a meaningful, clear way. To say that we are controlling for "degree of naturalism" is clearly not a viable option. Not to mention that, as noted above, proving that color constancy is pretty good in "natural" conditions is not interesting - if it weren't, we wouldn't even be asking the question. The question for scientists is, how is it achieved? Refining the answers to this question requires that we posit the role of specific factors, and this means clarifying what features of our stimulus are being manipulated. Again, "degree of naturalness" is a non-starter, and if investigators want to use it, they need to be clear about what they mean by it, and what features are under their control, and what features are NOT under their control, and might affect their results.

In the present study, not even the factor supposedly being manipulated - illumination - was under the investigators' control (see above). They are taking a graphics package's assumptions about what will be perceived as the color of the illumination at face value.

On 2015 Nov 03, Lydia Maniatis commented:

What is the purpose of the data collected in this study? Assuming there is a purpose, are its methods consistent with achieving it?

The title, “Color constancy in a naturalistic, goal-directed task,” is no guide. The ability of humans to achieve color constancy evolved in the natural environment, on the basis of interaction with that environment. Only goal-directed action could lead to selection for a functional perceptual process. “Natural” conditions are where the process enabling color constancy is expected to be most reliable. A plausible question, then, might be “how accurate can color constancy be at its best (assuming we were interested and could measure this.)” However, this is not what the authors are asking.

The abstract suggests two possible motives. First, we are told that “whether and to what degree constancy supports accurate cross-illumination object selection is not well understood.” It is not clear why we would not expect reliable surface perception under variable lighting to “support object selection.” At any rate, this framing of the question seems to assume good color constancy as the independent variable and “object selection” as the dependent variable. A few sentences later, however, the question seems to change; the authors tell us that they “were able to infer and quantify the degree of color constancy that mediated subjects performance.” Now, what seems to have been under investigation is the degree of subjects' color constancy.

However, the question “How good is a subject's color constancy” is meaningless unless we specify conditions. Under some conditions, it is very good, under others, it fails completely. Much is known about these conditions. Artists, for example, are expert at causing radical failures of color constancy via pictorial impressions of inhomogeneous illumination. Perception scientists sometimes have an inkling of this as well. So what specific conditions did the authors aim to test, and why?

The term used is “naturalistic.” What does this mean? The authors apparently can't say. We are told that they manipulated “complexity” by increasing (relative to a previous experiment) the number of distinct surfaces, but that they “do not have at present a precise technical definition of complexity nor precise ways of relating the concepts of scene complexity and scene naturalness” (p. 19). Evidently, “naturalistic” is being defined as “containing more surfaces than stimuli used in a previous experiment.”

At any rate, the stimuli used are clearly not “naturalistic” in any intuitive sense of the word. The authors themselves describe stimuli in one condition as having “a visually jarring appearance – somewhat reminiscent of an image of an early 1970's discotheque...” (p. 17).

So are the authors at least testing color constancy in a randomly selected stimulus? They are not doing even that. This is because their definition of a color constant selection is not based on subjects selecting an e.g. actually red surface under different illuminations, but on subjects matching a red surface with a surface that, in many cases, is not red (i.e. does not have the same chromaticity as the sample.) The stimuli are images on a computer screen, and the changes of illumination are manipulations that the authors hope, or expect, will correspond to the impression of a change in illumination, e.g. the impression of orange lighting. The theoretical assumptions underlying this expectation are part of the graphics package and are never made explicit. They might need reassessment, as subjects did not always make the predicted “color constant” selections. There was, for example, a deviation from the authors' definition/prediction of veridical choices, which based on deviation from their assumptions, they call a “blue bias.” In other words, subjects sometimes matched a sample surface with one that projected more in the blue part of the spectrum than what the authors defined as a “color constant” match. They “do not have an explanation for this bias” (p. 18). However, whether we are dealing with a bias on the part of subjects' perceptual system (unlikely) or a failed prediction of the authors' prepackaged, implicit color constancy/illumination perception model is impossible to say in this hopelessly confounded study.

I would note, finally, that defining the effect of simultaneous contrast as a “failure of color constancy” constitutes a failure to distinguish between figure/ground contrast and adjustments of color contingent on perceived illumination variation.

On 2015 Sep 22, ANDRES TIRADO-SANCHEZ commented:

Are we near to our Krypton?. World paranoia about future experiments at CERN…again. There is growing concern among world's population about the next experiments of the Large Hadron Collider at CERN related to smash subatomic particles at nearly the speed of light, looming next months (interestingly, if we add one of the most mentioned dates on Google maps ©, it redirects us to CERN). This conCERN has invaded the World Wide Web (both created by CERN) through social networking, news, search engines and very descriptive and witty videos that clearly may misinform, in addition to alarm people about the impending destruction of our planet. Detailed information on what lies ahead the CERN experiments is unknown to most of the population, similar to other “end of the world” events, who have gone without fulfilling what they promised however, such events left a feeling of uncertainty that affected people more susceptible, a feeling of fear of an upcoming uncontrollable black hole, that will lead to our extinction. The dark side of the (I must say, exciting) experiments at CERN, are a source of curiosity, fear and uncertainty. Many renowned physicists are concerned and believe that, at some point, both the amount of energy and the black hole generated will get out of control ending in disaster. In order to calm this (still) small outbreak of paranoia, more information is needed; CERN must open doors to the public, reduce mysticism and establish clear rules and communicate the details of the experiments performed there, the real scope, the real risks and the usefulness for mankind; to the extent that the above mentioned aspects are clarified, the population will not create speculation and feel better knowing that what is currently done at CERN will be for our benefit and not our extinction.

On 2017 Jul 04, Randi Pechacek commented:

Elisabeth Bik examines this paper on a microBEnet blog post.

On 2015 Dec 04, Siddharudha Shivalli commented:

I read the article by Gebre M et al, with a great interest. Authors’ efforts are commendable. In their community based study, authors highlight the lower birth preparedness practice in the study area.

Introduction part of the manuscript should delineate the health problem, research question or the hypothesis in such a way that even reader without subject expertise should be able to understand the present situation and need of the study. Keeping the international readers in the mind, authors should have given a brief explanation of existing programs to address maternal and child health issues, with a special emphasis on birth preparedness, in the introduction. Role of healthcare extension worker in the same should have been delineated. In addition, how the study findings could be useful in streamlining of ongoing strategies to foresee the impact should have been discussed.

The level of birth preparedness should have been reported with 95% confidence intervals (i.e. n=104, 18.3%, 95% CI: 15.3-21.7). Authors used the ‘knowledge of danger signs’ during pregnancy, delivery, and postnatal period as a predictor of birth preparedness. However, in methodology, they should have explicitly mentioned the various danger signs asked to assess the same. In Table 4, authors should have reported row wise percentages to make it clearer. Regression analysis is an excellent way of adjusting the effect of con-founders. However, it is always recommended to assess and report the adequacy of applied regression model. Failure to do so may lead to misleading or incorrect inferences. Although the study sample was relatively large (n=569), a word about R2 (explaining the variance in birth preparedness) of the applied regression model would have been more affirmative.

Nonetheless, I must congratulate the authors for exploring an important public health problem in the study area. No competing interests declared.

On 2017 Apr 25, Jeffrey Ross-Ibarra commented:

In my 2007 paper I find a positive correlation between the number of crossovers per bivalent and genome size. I note that this correlation is weaker than linear, such that genome size increases faster than the number of crossovers per bivalent. This means that measures of recombination that include genome size (e.g. cM/Mb) will decrease with increasing genome size (because the denominator increases faster than the numerator). The findings reported here of a negative correlation between cM/Mb and genome size are thus consistent with those reported in my 2007 paper.

On 2015 Oct 07, Bill Cayley commented:

For adolescents with depression, "less" appears to be "more": https://lessismoreebm.wordpress.com/2015/09/17/restoring-study-329-efficacy-and-harms-of-paroxetine-and-imipramine-in-treatment-of-major-depression-in-adolescence/

On 2015 Sep 29, Carlos Maia commented:

http://www.ncbi.nlm.nih.gov/pubmed/25806553

On 2015 Sep 17, Tom Kindlon commented:

(contd.)

11 National Institute for Health and Clinical Excellence. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management of CFS/ME in adults and children, 2007. http://www.nice.org.uk/guidance/CG53 Accessed September 6, 2015. London: National Institute for Health and Clinical Excellence.

12 White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 2011;377:823-36.

13 Kindlon T. PACE Trial - 97% of the participants who didn't have a psychiatric disorder satisfied the definition of M.E. used. https://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind1106A&L=CO-CURE&P=R2764 Accessed: September 6, 2015

14 Ellen Goudsmit on PubMed Commons: http://www.ncbi.nlm.nih.gov/myncbi/ellen m.goudsmit.1/comments/

15 Green CR, Cowan P, Elk R, O'Neil KM, Rasmussen AL. National Institutes of Health Pathways to Prevention Workshop: advancing the research on myalgic encephalomyelitis/chronic fatigue syndrome. Ann Intern Med. 2015; 162:860-5.

16 Haney E, Smith MEB, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Diagnostic methods for myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015; 162:834-40.

17 Smith MEB, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015; 162:841-50.

On 2015 Sep 17, Tom Kindlon commented:

Comment 2 of 2 formally submitted on September 9, 2015 on the full Cochrane review using instructions here: http://www.cochranelibrary.com/help/submitting-comments-on-cochrane-reviews.html

(This is available in one piece at: http://forums.phoenixrising.me/index.php?threads/my-two-detailed-comments-on-the-cochrane-exercise-therapy-for-cfs-review-2015.39801/ )

Second comment:

I have decided to split my comment into two as it was getting very long. This is part two.

Variation in interventions

It would have been useful to have some more information on the “exercise with pacing” intervention tested in the Wallman et al. (2004) trial and how it was distinct from some other exercise interventions tested. The authors say (1): “On days when symptoms are worse, patients should either shorten the session to a time they consider manageable or, if feeling particularly unwell, abandon the session altogether” (p. 143). I don't believe the description given in the review conveys this. In the review, this approach is described as "Exercise with pacing: exercise in which the incremental increase in exercise was personally set." But Wallman et al.’s approach allows patients to decrease as well as increase how much exercise they do on the day. This approach also contrasts with how White (an investigator in two of the trials) has described graded exercise therapy: "if [after increasing the intensity or duration of exercise] there has been an increase in symptoms, or any other adverse effects, they should stay at their current level of exercise for a further week or two, until the symptoms are back to their previous levels" (2). In the PACE Trial manual White co-wrote (3), the GET intervention was guided by the principle that “planned physical activity and not symptoms are used to determine what the participant does” (p. 21); similarly, “it is their planned physical activity, and not their symptoms, that determine what they are asked to do” (p. 20). Compliance data would help us examine which approach patients are actually using: I suspect many patients are in fact doing exercise with pacing even in trials such as the PACE Trial (i.e. when they have increased symptoms, often reducing levels of exercise and sometimes doing no exercise activities at all on that day).

Bimodal versus Likert scoring in Wearden et al. (2010)

I find it odd that the fatigue scores for the Wearden et al. (2010) trial (4) are given in the 0-33 format rather than the 0-11 scoring method. The 0-11 scoring system is what is mentioned as a primary outcome measure in the protocol and is what is reported in the main paper reporting the results (4, 5). It is even what your own report says on p. 44 is the scoring method (“Fatigue Scale, FS; 11 items; each item was scored dichotomously on a 4-point scale [0, 0, 1 or 1]”). This is important because using the scoring method for which you don't report data (0-11), there is no statistically significant difference at the primary outcome point of 70 weeks (5).

Diagnostic criteria

One problem with using these trials as an evidence base, which I don't believe was mentioned, is that all the trials used the Oxford and Fukuda diagnostic criteria (6, 7). Neither of these criteria require patients to have post-exertional malaise (or something similar). Many consider this to be a core symptom of ME/CFS and it is mandatory in most of the other major criteria (8-11). [Aside: The London criteria were assessed in the PACE Trial (12) but they seem to have been operationalised in an unusual way. Ninety seven per cent of the participants who satisfied the (broad) Oxford criteria who didn't have a psychiatric disorder satisfied the definition of M.E. used (13). Ellen Goudsmit, one of the authors of the London criteria, has rejected the way they were used in the PACE Trial (14)]. So this lack of requirement for patients to have post-exertional malaise (or a similar description) means we cannot be sure that the evidence can be generalised to such patients. An independent National Institutes of Health committee this year concluded "continuing to use the Oxford definition may impair progress and cause harm. Therefore, for progress to occur, we recommend that this definition be retired" (15). An Agency for Healthcare Research and Quality review of diagnostic methods this year reached a similar conclusion: "Consensus groups and researchers should consider retiring the Oxford case definition because it differs from the other case definitions and is the least restrictive, probably including individuals with other overlapping conditions” (16). An Agency for Healthcare Research and Quality review of ME/CFS treatments said: "The Oxford CFS case definition is the least restrictive, and its use as entry criteria could have resulted in selection of participants with other fatiguing illnesses or illnesses that resolve spontaneously with time" (17).

Exclusion of some data from analyses due to baseline differences

It seems unfortunate that some data cannot be used due to baseline differences e.g. "Four trials (669 participants) contributed data for evaluation of physical functioning at follow-up (Jason 2007; Powell 2001; Wearden 2010; White 2011). Jason 2007 observed better results among participants in the relaxation group (MD 21.48, 95% CI 5.81 to 37.15). However, results were distorted by large baseline differences in physical functioning between the exercise and relaxation groups (39/100 vs 54/100); therefore we decided not to include these results in the meta-analysis". It would be good if other methods could be investigated (e.g. using baseline levels as covariates) to analyse such data.

Thank you for taking the time to read my comments.

Tom Kindlon

Conflict of Interest statement:

I am a committee member of the Irish ME/CFS Association and do a variety of unpaid work for the Association.

References

1 Wallman KE, Morton AR, Goodman C, Grove R. Exercise prescription for individuals with chronic fatigue syndrome. Med J Aust. 2005;183:142-3.

2 White P. How exercise can help chronic fatigue syndrome. Pulse: 1998. June 20:86-87.

3 Bavinton J, Darbishire L, White PD -on behalf of the PACE trial management group. Graded Exercise Therapy for CFS/ME (Therapist Manual) http://www.pacetrial.org/docs/get-therapist-manual.pdf

4 Wearden AJ, Riste L, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S, Dunn G, Richardson G, Lovell K, Powell P. Fatigue Intervention by Nurses Evaluation--the FINE Trial. A randomised controlled trial of nurse led self-help treatment for patients in primary care with chronic fatigue syndrome: study protocol. [ISRCTN74156610]. BMC Med. 2006 Apr 7;4:9.

5 Wearden AJ, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S, Riste L, Richardson G, Lovell K, Dunn G; Fatigue Intervention by Nurses Evaluation (FINE) trial writing group and the FINE trial group. Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial. BMJ. 2010 Apr 23;340:c1777. doi: 10.1136/bmj.c1777.

6 Sharpe M, Archard L, Banatvala J, Borysiewicz LK, Clare AW, David A, et al. Chronic fatigue syndrome: guidelines for research. Journal of the Royal Society of Medicine 1991;84 (2):118–21.

7 Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Intern Med. 1994; 121: 953‑959.

8 Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic Encephalomyelitis/chronic fatigue syndrome: Clinical working case definition, diagnostic and treatments protocols. Journal of Chronic Fatigue Syndrome. 2003; 11: 7-115.

9 Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011; 270: 327-338.

10 IOM (Institute of Medicine). Beyond myalgic encephalomyelitis/chronic fatigue syndrome: Redefining an illness. Washington, DC: The National Academies; 2015.

(continues)

On 2015 Sep 17, Tom Kindlon commented:

(continues)

References:

1 Turner L, Boutron I, Hróbjartsson A, Altman DG, Moher D: The evolution of assessing bias in Cochrane systematic reviews of interventions: celebrating methodological contributions of the Cochrane Collaboration. Syst Rev 2013, 2:79.

2 Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry. 2015;2:141-152.

3 White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 2011;377:823-36.

4 Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bull IACFS ME. 2011;19:59-111. http://iacfsme.org/ME-CFS-Primer-Education/Bulletins/BulletinRelatedPages5/Reporting-of-Harms-Associated-with-Graded-Exercise.aspx

5 Lipkin DP, Scriven AJ, Crake T, Poole-Wilson PA (1986). Six minute walking test for assessing exercise capacity in chronic heart failure. British Medical Journal 292, 653-5.

6 Kadikar A, Maurer J, Kesten S. The six-minute walk test: a guide to assessment for lung transplantation. J Heart Lung Transplant. 1997 Mar;16(3):313-9.

7 Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

8 Friedberg F. Does graded activity increase activity? A case study of chronic fatigue syndrome. Journal of Behavior Therapy and Experimental Psychiatry, 2002, 33, 3-4, 203-215

9 Results and In-depth Analysis of the 2012 ME Association Patient Survey Examining the Acceptability, Efficacy and Safety of Cognitive Behavioural Therapy, Graded Exercise Therapy and Pacing, as Interventions used as Management Strategies for ME/CFS. Gawcott, England. http://www.meassociation.org.uk/2015/05/23959/ Accessed: September 3, 2015

10 Critical Illness - A Dreadful Experience with Scottish Provident. http://forums.moneysavingexpert.com/showthread.php?t=2356683 Accessed: September 4, 2015

11 McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD. Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis. PLoS One. 2012;7(8):e40808.

12 Rapport d’évaluation (2002-2004) portant sur l’exécution des conventions de rééducation entre le Comité de l’assurance soins de santé (INAMI) et les Centres de référence pour le Syndrome de fatigue chronique (SFC). 2006. http://health.belgium.be/internet2Prd/groups/public/@public/@shc/documents/ie2divers/14926531_fr.pdf (Starts on page 223.) Accessed September 4, 2015 (French language edition)

13 Evaluatierapport (2002-2004) met betrekking tot de uitvoering van de revalidatieovereenkomsten tussen het Comité van de verzekering voor geneeskundige verzorging (ingesteld bij het Rijksinstituut voor Ziekte- en invaliditeitsverzekering) en de Referentiecentra voor het Chronisch vermoeidheidssyndroom (CVS). 2006. http://health.belgium.be/internet2Prd/groups/public/@public/@shc/documents/ie2divers/14926531.pdf (Starts on page 227.) Accessed September 4, 2015 (Dutch language version)

14 Stordeur S, Thiry N, Eyssen M. Chronisch Vermoeidheidssyndroom: diagnose, behandeling en zorgorganisatie. Health Services Research (HSR). Brussel: Federaal Kenniscentrum voor de Gezondheidszorg (KCE); 2008. KCE reports 88A (D/2008/10.273/58) https://kce.fgov.be/sites/default/files/page_documents/d20081027358.pdf Accessed September 4, 2015

15 Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010; 40:1281-1287.

16 Van Kessel K, Moss-Morris R, Willoughby, Chalder T, Johnson MH, Robinson E, A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue, Psychosom. Med. 2008; 70:205–213.

17 Powell P. FINE Trial Patient Booklet http://www.fine-trial.net/downloads/Patient PR Manual ver9 Apr05.pdf Accessed September 7, 2015

18 Twisk FNM, Maes M. A review on Cognitive Behavorial Therapy (CBT) and Graded Exercise Therapy (GET) in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett. 2009;30:284-299.

19 Carruthers BM et al. Myalgic Encephalomyelitis – Adult & Paediatric: International Consensus Primer for Medical Practitioners. ISBN 978-0-9739335-3-6 http://www.investinme.org/Documents/Guidelines/Myalgic Encephalomyelitis International Consensus Primer -2012-11-26.pdf Accessed September 5, 2015

20 Twisk FN. Objective Evidence of Post-exertional “Malaise” in Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. J Sports Med Doping Stud 2015. 5:159. doi: 10.4172/2161-0673.1000159

21 Higgins JPT, Green S: Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. Table 8.5.d. The Cochrane Collaboration; 2011. http://handbook.cochrane.org/chapter_8/table_8_5_d_criteria_for_judging_risk_of_bias_in_the_risk_of.htm Accessed: September 5, 2015

22 White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; on behalf of the PACE trial group. Protocol for the PACE trial: A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurology 2007, 7:6 http://www.biomedcentral.com/1471-2377/7/6 Accessed: September 5, 2015

On 2015 Sep 17, Tom Kindlon commented:

(contd.)

Compliance

The review doesn't include any information on compliance. I'm not sure that there is much published information on this but I know there was a measure based on attendance at therapy sessions (which could be conducted over the phone) given for the PACE Trial (3). Ideally, it would be interesting if you could obtain some unpublished data from activity logs, records from heart-rate monitors, and other records to help build up a picture of what exercise was actually performed and the level of compliance. Information on adherence and what exercise was actually done is important in terms of helping clinicians, and indeed patients, to interpret and use the data. I mention patients because patients' own decisions about their behaviour is likely to be affected by the medical information available to them, both within and outside of a supervised programme of graded exercise; unlike with an intervention like a drug, patients can undertake exercise without professional supervision.

"Selective reporting (outcome bias)" and White et al. (2011)

I don't believe that White et al. (2011) (the PACE Trial) (3) should be classed as having a low risk of bias under "Selective reporting (outcome bias)" (Figure 2, page 15). According to the Cochrane Collaboration's tool for assessing risk of bias (21), the category of low risk of bias is for: "The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way". This is not the case in the PACE Trial. The three primary efficacy outcomes can be seen in the published protocol (22). None have been reported in the pre-specified way. The Cochrane Collaboration's tool for assessing risk of bias states that a “high risk” of bias applies if any one of several criteria are met, including that “not all of the study’s pre-specified primary outcomes have been reported” or “one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified”. In the PACE Trial, the third primary outcome measure (the number of "overall improvers") was never published. Also, the other two primary outcome measures were reported using analysis methods that were not pre-specified (including switching from the bimodal to the Likert scoring method for The Chalder Fatigue Scale, one of the primary outcomes in your review). These facts mean that the “high risk of bias” category should apply.

Thank you for taking the time to read my comments.

Tom Kindlon

Conflict of Interest statement:

I am a committee member of the Irish ME/CFS Association and do a variety of unpaid work for the Association. (continues)

On 2015 Sep 17, Tom Kindlon commented:

Comment 1 of 2 formally submitted on September 9, 2015 on the full Cochrane review using instructions here: http://www.cochranelibrary.com/help/submitting-comments-on-cochrane-reviews.html

(This is available in one piece at: http://forums.phoenixrising.me/index.php?threads/my-two-detailed-comments-on-the-cochrane-exercise-therapy-for-cfs-review-2015.39801/ )

I would first like to thank those involved for their work in preparing this document. Even for those of us who have read the individual Chronic Fatigue Syndrome (CFS) papers it is useful to have the results collated, as well as details regarding the interventions. Also it is interesting to see the results of sensitivity analyses, subgroup analyses, standardised mean differences, etc.

I would like to make a few comments. I’m splitting them into two submissions as the piece had become very long. I’ve added some loose headings to hopefully make it more readable.

Objective measures

The review assessed the studies as having a high risk of bias regarding blinding, since neither participants nor assessors were blinded. Evidence suggests that subjective outcomes are more prone to bias than objective outcomes when there is no blinding (1). It is thus unfortunate that the review concentrated almost exclusively on subjective measures, failing to include results from nearly all the objective outcome measures that have been published with trials. (The exception was health resource use for which you presented follow-up data from one trial).

I hope objective outcome data can be included in a future revision or edition of this review.

Examples of objective outcomes include: exercise testing (work capacity by oxygen consumption); fitness test/step test; the six minute walking test; employment status; and disability payments.

Adding in these results would allow a more rigorous assessment of the effectiveness and relevance of the therapies, their causal mechanisms, therapeutic compliance, and safety.

On exercise testing, for example, in the PACE Trial (the largest trial in the review) there was no improvement in fitness levels as measured by a step test (2). The fitness data contrasts sharply with the many positive results from subjective self-report measures in the trial, so one is left wondering how much the subjective measures reflect reality.

On another exercise test used in the PACE Trial, the 6 minute walk test, there was a small (mean) increase from 312 metres at baseline to 379 metres at 12 months: this was 35.3 metres more than the "passive" control group when adjustments were made. However, the final result of 379 metres remains very poor compared to the more than 600 metres one would expect from healthy people of a similar age and gender make-up (3,4). By comparison, a group with Class III heart failure walked an average of 402 metres (5). A score of less than 400 metres has been suggested as the level at which somebody should be put on a lung transplant list (6). Such information from objective measures helps to add important context to the subjective measures and restraint to the conclusions that can be drawn from them.

Objective data is also needed to check compliance with a therapy. If patients diligently exercised for 12 months one would expect much better results on fitness and exercise testing than the aforementioned results in the PACE Trial. This is important when considering adverse events and safety: such trials may not give us good information on the safety of complying with such interventions if patients haven't actually complied.

Employment and receipt of disability payments are practical objective measures of general functional capacity so data on them would help establish whether patients can actually do more overall or whether they may just be doing, for example, a little more exercise but have substituted that for doing less in other areas (7,8). Also, CFS patients are sometimes pressured by insurance companies into doing graded exercise therapy (GET) programs so it would be useful to have data collated on employment outcomes to see whether pressure can in any way be justified (9,10). In the PACE Trial, there was no significant improvement in employment measures and receipt of disability payments in the GET group (11). Outside the realm of clinical trials, the quantitative and qualitative data in a major (UK) ME Association survey also found that GET didn't lead to higher levels of employment and lower levels of receipt of disability payments on average (9). Also, extensive external audits were performed of Belgian CFS rehabilitation clinics that treated using cognitive behavioural therapy (CBT) and GET. The main reports are in French and Dutch (12,13), with an English summary available (14) that says, "Employment status decreased at the end of the therapy, from an average of 18.3% of a 38h working week, to 14.9% [...] The percentage of patients living from a sickness allowance increased slightly from 54 to 57%." This contrasts with the average improvements reported in the audit for some symptoms like fatigue.

While data on (self-reported) symptoms like fatigue (one of your two primary outcomes) is interesting, arguably more important to patients is improving their overall level of functioning (and again, objective measures are needed here). Being able to work, for example, despite experiencing a certain level of fatigue would likely be more important for many than being unable to work but having slightly lower levels of fatigue.

An example of how reductions in the reported levels of fatigue may not lead to improvements in functioning can be seen in an analysis of three graded activity-oriented CBT therapy interventions for CFS (15). The analysis showed, compared to controls, there were no improvements in overall activity levels as measured by actometers despite improvements in self-reported fatigue (15). Activity in these trials was assessed using actometers. Another study that exemplifies the problem of focusing too much on fatigue scores after behavioural interventions is a study of CBT in multiple sclerosis (MS) patients with “MS fatigue”(16). The study found that following the intervention, patients with MS reported significantly lower (i.e. better) scores on the Chalder Fatigue Scale (0-33 scoring) than those in a healthy, nonfatigued comparison group! This significant difference was maintained at 3 and 6 months’ follow-up. It is difficult to believe that patients with MS fatigue (at baseline) truly subsequently had less fatigue than healthy nonfatigued controls: a much more likely scenario is that undertaking the intervention had led to response biases.

You mention that "many patient charities are opposed to exercise therapy for chronic fatigue syndrome (CFS)". One reason for concern about the way in which exercise programmes are promoted to patients is that they are often based upon models which assume that there is no abnormal physiological response to exercise in the condition, and make unsupported claims to patients. For example, in the FINE trial (Wearden et al., 2010) patient booklet (17), it is boldly asserted that: "Activity or exercise cannot harm you" (p. 49). However, a large number of studies have found abnormal responses to exercise, and the possibility of harm being done simply cannot be excluded on the basis of current evidence (discussed in 4, 18-20)."

(continues)

On 2016 Feb 08, Theo Sanderson commented:

"Briefly, PMA stock solution (20 mM in 20 % dimethyl sulfoxide; Biotium Inc., Hayward, CA) was added at a concentration of 200 mM." It seems likely that the working concentration was in fact 200 μM?

On 2015 Sep 30, Anders von Heijne commented:

This is an important analysis. The only thing missing is the temporal relationship between the debut of the PML-IRIS related encephalitic symptoms and the imaging findings. Do they occur at the same time or are there cases when the imaging findings precede the clinical worsening?

On 2017 Oct 12, Sander Houten commented:

This paper focuses on the role of KLF14 in the regulation of hepatic ApoA-I expression. The authors show that hepatic KLF14 expression is reduced in dyslipidemia mouse models. They show that overexpression of human KLF14 in liver of mice that were fed a high fat diet, increased HDL-cholesterol, cholesterol efflux and ApoA-I expression. Conversely, they show that liver-specific deletion of Klf14 decreased HDL-cholesterol and ApoA-I expression. The authors offer a mechanistic explanation by demonstrating that the ApoA-I promoter contains one KLF14-binding site. Moreover, perhexiline was identified as a KLF14 activator that raised HDL-cholesterol, ApoA-I and cholesterol efflux in vivo and reduced atherosclerosis development in Apoe^−/− mice (Guo Y, 2015). I would like to point out that there is little evidence to support the hypothesis that KLF14 plays an important role in adult mouse liver biology. We found no evidence for expression of KLF14 in adult mouse liver as we were unable to amplify Klf14 cDNA, did not find Klf14 mapped reads in liver RNA sequencing data and found no specific signal upon immunoblotting (Argmann CA, 2017). Our data on the absence of Klf14 expression in liver are consistent with previously published work by others (Parker-Katiraee L, 2007) and publicly available data sources. We also investigated the physiological functions of KLF14 by studying a whole body KO mouse model and focused on the metabolic role of this transcription factor in mice on chow and high fat diet. Our results do not support a major role of hepatic KLF14 in the regulation of ApoA-I and HDL-cholesterol levels (Argmann CA, 2017).

On 2016 Apr 16, Miguel Lopez-Lazaro commented:

Important flaws in the identification of the cells of origin in cancer

This is an extension of this Editorial (Cancer arises from stem cells: opportunities for anticancer drug discovery) and a commentary on the article http://www.ncbi.nlm.nih.gov/pubmed/27044116

Abstract: The cells of origin in cancer are the cells in which carcinogenesis starts, i.e., the normal cells that acquire the first cancer-related hit. These cells should not be confused with the cancer stem cells or tumor-initiating cells, which are malignant cells with the ability to initiate and maintain tumor growth. Recently, many articles published in leading journals claim that they have experimentally demonstrated the cellular origin of several types of cancer. These articles, however, have important flaws that may have led to wrong conclusions. Here I briefly discuss one of the many articles in this field of research to draw attention to these flaws. In addition, I analyze the striking differences in prostate cancer incidence by age to examine the article’s conclusion and to propose that prostate cancer originates in stem cells. The striking variations in cancer risk among tissues also indicate that stem cells are the cells of origin in cancer.

Full text at: Lopez-Lazaro, M. Important flaws in the identification of the cells of origin in cancer. ResearchGate: DOI: 10.13140/RG.2.1.4321.5769; http://dx.doi.org/10.13140/RG.2.1.4321.5769

On 2015 Dec 10, Kenneth Witwer commented:

As a co-author of this meeting report on an RNAi session at the 40th meeting of The Toxicology Forum, I summarized a talk I gave on human health considerations related to environmental RNA molecules. During my talk, I also reflected briefly on a 2014 US Environmental Protection Agency panel and a European Food Safety Authority (EFSA) workshop I had recently taken part in. During the preparation and revision process of this manuscript, EFSA published a workshop report on the EFSA website. I inadvertently did not include a link to this report in the manuscript, so I would like to note that the pdf can be downloaded here. "Selected key outcomes of the workshop" were also described by Ramon M, 2014.

On 2014 Dec 23, Akshaya shetti commented:

can i get the full text of this article?

On 2017 Apr 01, Misha Koksharov commented:

It's interesting whether LREs have a gluconolactonase function. Or whether gluconolactonases have the LRE activity

On 2017 Mar 26, Misha Koksharov commented:

None

On 2017 Jul 04, Randi Pechacek commented:

Matt Perisin, first author of this paper, wrote a "Behind the Paper" blog on microBEnet.

On 2016 Feb 16, Robert Courtney commented:

A study that uses questionable assumptions rather than empirical evidence leads to conclusions that stretch credibility.

Chalder et al. [1] used the “single mediation model” for their methodology, which is explained in detail in a book by MacKinnon [2]. Explaining the methodology MacKinnon says a temporal separation between variables must be observed (i.e. changes in mediating variable must occur before changes in the mediated variable) for a mediation effect to be empirically and robustly established.

Chalder et al. were working to this model and acknowledged that they failed to establish a clear temporal separation between variables, and therefore did not empirically establish a causal mediation effect: “Given the pattern of change in the mediators was similar to the pattern of change in the outcomes it is possible that the variables were affecting each other reciprocally”.

However, despite the lack of robust empirical evidence to support a mediation effect, the investigators concluded that they had established mediation effects, e.g: “Our main finding was that fear avoidance beliefs were the strongest mediator for both CBT and GET.”

The study’s conclusion relied upon an assumption that the investigators’ favoured hypothetical model of illness for ME/CFS has a robust empirical evidence base and is applicable to this study. The hypothesis is based upon the idea that symptoms and disability in ME/CFS are perpetuated by unhelpful or maladaptive illness beliefs, fear, and an avoidance of activity.

However, the prestigious National Academy of Medicine (formerly known as the Institute of Medicine) recently released a comprehensive report [3] into ME/CFS that rejected such a hypothetical model of illness, and unambiguously concluded that ME/CFS does not have a psychological or cognitive-behavioural basis, but is an organic illness that requires biomedical research.

Chalder et al. discussed the possibility that more frequent measurements may have potentially demonstrated a temporal separation between the variables, and therefore a mediation effect. However, this raises the possibility of whether changes in the primary outcome variables (self-report physical function and fatigue) may, in fact, have occurred before changes in the presumed mediator variables. Such an outcome would entirely contradict the investigators’ premature conclusions. According to MacKinnon [2] and Wiedermann et al. [4], unexpected outcomes should not be ruled out.

Chalder et al. concluded that symptoms and physical impairment, in ME/CFS patients, are mediated by activity avoidance and other factors. (e.g. This would mean that a decrease in activity would cause an increase in symptoms.) However, from a common sense point of view, this seems like rather a convoluted conclusion, and it seems more likely that increased symptoms would be the direct cause of activity avoidance in any illness, rather than vice versa. To conclude that activity avoidance causes fatigue (rather than fatigue being a direct cause of activity avoidance), is similar to concluding that a person has flu because they’ve taken a day off work, rather than the obvious conclusion that they’ve taken a day off work because they have flu.

In the case of fatigue, flu-like malaise and other symptoms of ME/CFS, it seems reasonable to consider the possibility that, as the symptoms fluctuate, patients may intuitively or rationally adapt their activity levels according to what is comfortable and safe. i.e. patients reduce activity levels because they are fatigued. The investigators have concluded that patients are fatigued because they have reduced activity levels.

Perhaps patients’ perspectives and insights would help clarify the issues but, unfortunately, patients were not consulted for this study.

References:

1. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry 2015; 2: 141–52.

2. MacKinnon DP. Introduction to Statistical Mediation Analysis. Taylor and Francis: New York 2008.

3. IOM (Institute of Medicine). 2015. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: Redefining an illness. Washington, DC: The National Academies Press. http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx

4. Wiedermann W, von Eye A. Direction of Effects in Mediation Analysis. Psychol Methods 2015; 20: 221-44.

On 2015 Sep 15, Tom Kindlon commented:

(Contd.)

References:

1 Torjesen I. Tackling fears about exercise is important for ME treatment, analysis indicates. BMJ 2015;350:h227 http://www.bmj.com/content/350/bmj.h227

2 Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry 14 Jan 2015, doi:10.1016/S2215-0366(14)00069-8.

3 Burgess M, Chalder T. Manual for Participants. Cognitive behaviour therapy for CFS/ME.http://www.pacetrial.org/docs/cbt-participant-manual.pdf (accessed: January 17, 2015)

4 Bavinton J, Darbishire L, White PD -on behalf of the PACE trial management group. Graded Exercise Therapy for CFS/ME. Information for Participants http://www.pacetrial.org/docs/get-participant-manual.pdf (accessed: January 17, 2015)

5 Wechsler ME, Kelley JM, Boyd IO, Dutile S, Marigowda G, Kirsch I, Israel E, Kaptchuk TJ. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Engl J Med. 2011;365(2):119-26.

6 Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow CD, Ramírez G. Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. JAMA. 2001 Sep 19;286(11):1360-8.

7 Burgess M, Chalder T. PACE manual for therapists. Cognitive behaviour therapy for CFS/ME.http://www.pacetrial.org/docs/cbt-therapist-manual.pdf (accessed: January 17, 2015)

8 White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al, for the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011;377:823-36.

9 McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD. Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis. PLoS One. 2012;7(8):e40808. doi: 10.1371/journal.pone.0040808

10 Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Aug;40(8):1281-7. doi: 10.1017/S0033291709992212. Epub 2010 Jan 5.

11 Heins MJ, Knoop H, Burk WJ, Bleijenberg G. The process of cognitive behaviour therapy for chronic fatigue syndrome: which changes in perpetuating cognitions and behaviour are related to a reduction in fatigue? J Psychosom Res. 2013 Sep;75(3):235-41. doi: 10.1016/j.jpsychores.2013.06.034. Epub 2013 Jul 19.

12 Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Apr;65(4):423-42. doi: 10.1002/jclp.20551.

13 Knoop H, Prins JB, Stulemeijer M, van der Meer JW, Bleijenberg G. The effect of cognitive behaviour therapy for chronic fatigue syndrome on self-reported cognitive impairments and neuropsychological test performance. Journal of Neurology and Neurosurgery Psychiatry. 2007 Apr;78(4):434-6.

14 Bavinton J, Darbishire L, White PD -on behalf of the PACE trial management group. Graded Exercise Therapy for CFS/ME (Therapist manual): http://www.pacetrial.org/docs/get-therapist-manual.pdf (accessed: January 17, 2015)

15 O'Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technology Assessment, 2006, 10, 37, 1-140.

16 Knoop H, Wiborg JF. What makes a difference in chronic fatigue syndrome? Lancet Psychiatry 13 Jan 2015 DOI: http://dx.doi.org/10.1016/S2215-0366(14)00145-X

17 Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME. 2011;19(2):59-111http://iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/ta...

18 Lipkin DP, Scriven AJ, Crake T, Poole-Wilson PA. Six minute walking test for assessing exercise capacity in chronic heart failure. Br Med J (Clin Res Ed) 1986. 292:653–655. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1339640/pdf/bmjcred00224-001...

19 Marin JM, Carrizo SJ, Gascon M, Sanchez A, Gallego B, Celli BR. Inspiratory Capacity, Dynamic Hyperinflation, Breathlessness, and Exercise Performance during the 6-Minute-Walk Test in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2001 63(6):1395-1399.http://171.66.122.149/content/163/6/1395.full

20 Goldman MD, Marrie RA, Cohen JA. Evaluation of the six-minute walk in multiple sclerosis subjects and healthy controls. Multiple Sclerosis 2008. 14(3):383-390. http://pocketknowledge.tc.columbia.edu/home.php/viewfile/download/65399/The six-minute walk test.pdf

21 Ross RM, Murthy JN, Wollak ID, Jackson AS. The six minute walk test accurately estimates mean peak oxygen uptake. BMC Pulm Med. 2010 May 26;10:31. PMID 20504351.http://www.biomedcentral.com/1471-2466/10/31

22 Camarri B, Eastwood PR, Cecins NM, Thompson PJ, Jenkins S. Six minute walk distance in healthy subjects aged 55–75 years. Respir Med. 2006. 100:658-65 http://www.resmedjournal.com/article/S0954-6111(05)00326-4/abstract

23 Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J. 1999. 14:270-4. http://www.ersj.org.uk/content/14/2/270.full.pdf

24 Rapport d'évaluation (2002-2004) portant sur l'exécution des conventions de rééducation entre le Comité de l'assurance soins de santé (institué auprès de l'Institut national d'assurance maladie invalidité) et les Centres de référence pour le Syndrome de fatigue chronique (SFC), Bruxelles, juillet 2006. (French language edition)

25 Evaluatierapport (2002-2004) met betrekking tot de uitvoering van de revalidatieovereenkomsten tussen het Comité van de verzekering voor geneeskundige verzorging (ingesteld bij het Rijksinstituut voor Ziekte- en invaliditeitsverzekering) en de Referentiecentra voor het Chronisch vermoeidheidssyndroom (CVS). 2006. Available online:https://drive.google.com/file/d/0BxnVj9ZqRgk0QTVsU2NNLWJSblU/edit (accessed: January 17, 2015) (Dutch language version)

26 Stordeur S, Thiry N, Eyssen M. Chronisch Vermoeidheidssyndroom: diagnose, behandeling en zorgorganisatie. Health Services Research (HSR). Brussel: Federaal Kenniscentrum voor de Gezondheidszorg (KCE); 2008. KCE reports 88A (D/2008/10.273/58)https://kce.fgov.be/sites/default/files/page_documents/d20081027358.pdf (accessed: January 17, 2015)

On 2015 Sep 15, Tom Kindlon commented:

Objective measures found a lack of improvement for CBT & GET in the PACE Trial: subjective improvements may simply represent response biases or placebo effects in this non-blinded trial

[Originally posted here: http://www.bmj.com/content/350/bmj.h227/rr-10]

This BMJ article and a flurry of articles in the lay media this week followed the publication in Lancet Psychiatry of an analysis of the mediators of change in the important PACE Trial, a chronic fatigue syndrome (CFS) trial which cost UK taxpayers £5 million[1,2]. What seems to have been lost in the coverage is that, although there were some modest improvements in the self-report measures, there was an almost complete absence of improvements in objectively measured outcomes for cognitive behavioural therapy (CBT) and graded exercise therapy (GET) compared to the control group (specialist medical care only (SMC)).

This is a non-blinded trial, where participants were told CBT and GET had previously been found to be effective in CFS and other conditions[3,4]: one way to look at the mediation results for subjective measures when there was a lack of objective improvements is that they may merely tell us how response biases and/or placebo effects are mediated[5].

The focus on subjective measures in some CFS studies was previously criticised in a systematic review published back in 2001 (long before the PACE Trial started)[6]. They suggested instead "a more objective measure of the effect of any intervention would be whether participants have increased their working hours, returned to work or school, or increased their physical activities."

The model presented for cognitive behaviour therapy (CBT) in the PACE Trial manuals posits that the impairments and symptoms are reversible with the therapy[3,7]. However, the latest paper shows that fitness, as measured by a step test, didn't improve following CBT[2]. An earlier PACE Trial publication reported that the addition of CBT to SMC did not result in an improvement in 6-minute walking test scores compared to SMC alone[8].

The PACE Trial was part funded by the UK Department of Work and Pensions, a rare move for them, presumably done due to an expectation that the therapies would improve measures of employment and levels of benefit receipt. However, again CBT brought about no improvement using objective measures, such as days of employment lost, levels of disability benefits received and levels of receipt of insurance payments[9].

These results are in line with earlier studies of CBT. For example, an analysis of three randomized controlled trials of CBT interventions for CFS found no improvement in objectively measured activity, despite participants reporting a reduction in (self-reported) fatigue and (sometimes) functional impairments[10]. Similar results were found in another uncontrolled trial where changes in objectively measured activity did not predict fatigue levels, and objectively measured activity on completion remained low compared to population norms[11]. An uncontrolled study found improvements in self-reported physical functioning and fatigue were reported despite a numerical decrease in (objectively measured) activity[12]. In another study, the level of self-reported cognitive impairment in CFS patients decreased significantly after CBT, however, cognition had not improved when it was measured objectively using neuropsychological test performance[13].

It is unsurprising that 15 sessions of CBT (and the associated homework exercises and management program) might alter how participants respond to self-report questionnaires. A PACE Trial manual itself says "the essence of CBT is helping the participant to change their interpretation of symptoms": this could lead to altered or biased fatigue scores, one of the two primary outcome measures[14]. Also, one of the aims of CBT (for CFS) has been said to be "increased confidence in exercise and physical activity"[15]. The possible responses for the other primary outcome measure, the SF-36 physical functioning subscale, are "yes, limited a lot", "yes, limited a little" and "no, not limited at all" to questions on a range of physical activities. Such responses could be easily be artificially altered following a therapy like CBT for CFS.

The results were not that different with the GET cohort in the PACE Trial. Again the manuals predicted that the impairments and symptoms are reversible using the intervention[4,15]. The model said there was no reason participants should not be able to get back to full functioning. Deconditioning was posited to be an important maintaining factor. However, GET did not result in an improvement in fitness, as measured by the step test. GET did result in a small improvement on the six minute walking test to a final distance of 379 metres, or 35 metres more than the SMC-only group[7]. However, as Knoop and Wiborg commented in an accompanying editorial in Lancet Psychiatry: "an increase in distance walked during a test situation without an increased fitness suggests that patients walk more because of a change in cognitive processes (eg, daring to do more or an increased self-efficacy with respect to activity), not because of a change in physiological capacity”[16]. The result remained very poor given that normative data would suggest a group of similar age and gender should walk an average of 644 or so metres[17]. The distance walked remained comparable to people with many serious conditions[18-21], and considerably worse than the distance walked by healthy elderly adults[22,23], despite the PACE trial cohort having a mean age of only 40[8]. Also, to be allowed entry into CFS research studies such as the PACE Trial one can not have a range of chronic illnesses so with genuine recovery one would expect results comparable to healthy people[8].

As with CBT, measures relating to employment showed no improvement following GET in days of work missed, which remained very high, nor a reduction in levels of benefits (financial support from the state) or payments from insurance companies[9].

These results are in line with an audit of Belgian rehabilitation centres for CFS offering CBT and GET[24-26]. Some improvements in subjective measures were found, but there was no improvement in the results of the exercise test and hours in employment actually decreased.

Probably the main contribution of the PACE Trial has been to add to a growing body of evidence that while CBT and GET for CFS have resulted in some changes on subjective measures, they haven't lead to improvements on objective measures.

Competing interests: I am a committee member of the Irish ME/CFS Association and perform various types of voluntary work for the Association.

(continues)

On 2015 Oct 15, Radboudumc Psycho-Oncology Journal Club commented:

This interesting commentary, which has important implications for the field of psycho-oncology, was discussed by our Journal Club members on 14th of October, 2015 and generated a lively discussion and the following comments and questions:

• 1) After reading your commentary, we concluded that it would be worthwhile to incorporate lifestyle variables in psychosocial intervention programmes on tertiary prevention, to further explore the relationship between psychological outcomes and health behaviours. Our group is based within an academic medical centre and there was debate within our group about the role of psycho-oncologists should take. Some members of our journal club believed that psycho-oncology as a discipline should focus more on collaboration with public health, health psychology and other disciplines working in the area of primary and secondary cancer prevention.. However, other members believed health behaviour change is the area of expertise of health psychologists not psycho-oncologists. Furthermore, in light of resource constraints, psycho-oncology professionals should focus on the core business of providing care to those affected by disease and ill-health in medical settings.<br>
• 2) We welcomed the proposal of The Expanded Model of Research in Psycho-Oncology and congratulate the authors for stimulating debate over the role of psycho-oncology. As for a suggestion, we would have liked it if the new conceptional model had an additional box with factors relevant to secondary prevention after cancer diagnosis. For example, psycho-oncologists are well placed to conduct activities that focus on the secondary prevention of psychological problems (e.g. depression, anxiety) or which might prevent a new disease recurrence following a diagnosis of cancer (e.g via lifestyle change programmes for cancer survivors). We also believed that psychological screening within oncology settings can be conceptualised as a secondary prevention activity.
• 3) We believe that psycho-oncology as a discipline, if it is to be involved with primary and secondary prevention at all, might focus on the three non-tumor specific health behavior changes with the biggest impact smoking, diet and exercise.
• 4) When it comes to medical psychologists working in psycho-oncology, essentially it comes down to the question whether a hospital is a “health valley” or a place in which we treat those affected by disease. Primary and secondary prevention implies the “health valley” model, which needs a much larger paradigm shift of medicine in general rather than in psycho-oncology alone. It will also require increased funding for hospitals to enable this to occur.<br>
• 5) We identified systemic barriers such as the organisational separation of hospitals and public health programmes in many jurisdictions. We concur with the authors that further investment is needed in the training of psycho-oncologists to ensure they learn how to apply their skills to preventive health and have more opportunities to gain work experience in preventive health care settings.

On 2015 Oct 02, Robert Groom commented:

Thank you to the authors for this tribute to an outstanding perfusionist that invested herself in improving her field. The commentary from her friends and contemporaries exemplifies the importance of our relationships with colleagues in professional societies and how through those relationships we are able to make the World a better place.

On 2015 Dec 06, Gwinyai Masukume commented:

Unacknowledged important limitation - the effective sample size of 229 was insufficient to detect a statistically significant association.

Dean and colleagues find that there was a deficit of 229 pregnancies among women who were in the first trimester when the mass shooting at Port Arthur occurred and that by sex there was no statistically significant differential loss. They estimate that for every 100 females, 107 males were lost.

Although Dean and colleagues did not find a statistically significant difference by sex, their sample size of 229 was insufficient to detect the difference given the small effect size Austad SN, 2015.

A rigorous study Orzack SH, 2015 demonstrated that normally, in the absence of exogenous stressors such as that caused by the Port Arthur calamity, more female embryos/fetuses are lost during the first trimester, approximately 100 females for every 97 males.

In conclusion, the results presented by Dean and colleagues show excess male loss during a period when more female loss is expected. Thus, the small sample size of 229 should have been mentioned as an important limitation of the paper and a formal power calculation was apt.

On 2015 Sep 17, Daniel Himmelstein commented:

Thanks Dr. Levine for your thoughtful response. As you mention, the practices I criticize in your discovery phase are not unique to your study. Your study caught my attention because of its remarkable finding that such a small sample yielded a highly predictive and robust classifier for such a complex phenotype. Hopefully, others will benefit from our discussion here.

Additionally, I agree that replication grants researchers the freedom to discover as they wish. Suboptimal model training should not cause "type I" replication error, if the replication dataset is independent.

However, a replication p-value alone is insufficient to identify the probability of a model being true. This probability depends on the plausibility of the model. Since I think that the odds are low that your study design could produce a true model, I require extraordinary evidence before accepting the proposed PRS model. I think your replication provides good evidence but not extraordinary.

Follow-up studies on different populations will be important for establishing extraordinary evidence. I think it would be helpful to specify which allele is minor for each PRS SNP: my impression is that minor alleles are sample not population specific.

On 2015 Sep 16, Morgan E Levine commented:

Daniel Himmelstein, thank you for your comments. I will try to address them to the best of my ability.

We acknowledge that the sample size is very small, which we mention in our limitations section of the paper. Because we are studying such a rare phenotype, there is not much that can be done about this. “Long-lived smokers” is a phenotype that has been the subject of a number of our papers, and that we think has strong genetic underpinnings. Despite the small sample size, we decided to go ahead and see if we could detect a signal, since there is evidence to suggest that the genetic influence may be larger for this phenotype compared to many others—something we discuss at length in our introduction section.

To the best of our knowledge the finding that highly connected genes contain more SNPs, has not been published in a peer-reviewed journal. Therefore, we had no way of knowing or evaluating the importance of this for our study. Similarly, we used commonly used networks and do acknowledge the limitations of these networks in our discussion section. The network you link to was not available at the time this manuscript was accepted.

We acknowledge the likelihood of over-fitting in our PRS, which is probably due to our sample size. This score did validate in two independent samples. Therefore, while it is likely not perfect, we feel that it may still capture some of the true underlying signal. We followed standard protocol for calculating our score (which we reference). In the literature there are many examples of scores that have been generated by linearly combining information from SNPs that are below a given p-value threshold in a GWAS. While, not all of these replicate, many do. Our study used very similar methods, but just introduced one additional SNP selection criteria—SNPs had to also be in genes that were part of an FI network. I don't think this last criteria would introduce additional bias that would cause a type I error in the replication analysis. However, we still recognize and mention some of the limitations of our PRS. We make no claim that the score is free from error/noise or that it should be used in a clinical setting. In fact, in the paper we suggest future methods that can be used to generate better scores.

We feel we have provided sufficient information for replication of our study. The minor alleles we used are consistent with those reported for CEU populations, which is information that is readily available. Thus, the only information we provide in Table S2 pertain to things specific to our study, that can't be found elsewhere. Lastly, the binning of ages is not 'bizarre' from a biogerontology and longevity research perspective. A number of leaders in the filed have hypothesized that the association between genes and lifespan is not linear (variants that influence survival to age 100+ are not the same as variants that influence survival to age 80+). Thus, using a linear model would not be appropriate in this case and instead we selected to look at survival by age group.

On 2015 Sep 15, Daniel Himmelstein commented:

I have several concerns with the discovery phase of this study. Specifically:

Underpowered: The sample size (90 cases) is insufficient for a complex phenotype where effect sizes are small. My own research, Himmelstein DS, 2015, does not consider GWAS with under 1000 samples because any findings are likely to be false (Sawcer S, 2008). The pathway-based prioritization attempts to alleviate the underpowered study design but suffers from the following two criticisms.

SNP abundance confounding: Genes were selected for the network analysis if they contained any SNPs with p < 5×10^-3. Therefore, genes containing more SNPs were more likely to get selected by chance. Since genes with more SNPs appear more frequently in curated pathway databases, the enrichment analysis is confounded. A permutation test that shuffles case-control status and recomputes SNP p-values would prevent SNP abundance confounding. However, this does not appear to be the permutation test that was performed.

Limited network relevance: The network analysis uses only curated pathway databases. These databases are heavily biased towards well-studied genes as well as being incomplete. In our recent network that includes more curated pathways than Reactome FI, only 9,511 genes are in any curated pathway. In other words, the majority of genes aren't curated to a single pathway and hence cannot contribute to this study's prioritization approach.

Overfitting: The polygenic risk score (PRS) was ruthlessly overfit. The PRS perfectly discriminated the 90 long-lived smokers from the younger smokers. The authors don't appear to appreciate that the performance is due to overfitting and write:

Results showed that the score completely accounted for group membership, with no overlap between the two groups.

Not only were scores significantly higher for the long-lived group, but scores also appeared to be more homogeneous.

Egregious overfitting is guaranteed by their PRS approach since 215 logistic regressions are fit, each with only 90 positives and without regularization or cross-validation. When a model is overfit on training data, its perfomance on novel data diminishes.

Unreplicable: Table S2 of the supplement does not specify which allele is minor for each SNP. Therefore, the PRS computation cannot be replicated by others.

Given these issues, I find it unlikely that the study found a reliable genotype of longevity. Rather, I suspect the successful validation resulted from confounding, p-value selection bias, or an implementation error.

Finally, the binning of continuous outcomes, primarily age, is bizarre. The binning serves only to reduce the study's power, while providing much room for unintended p-value selection bias.

Update 2015-09-15: I am not suggesting any misconduct, negligence, or intentional bad practices. Rather the methods are clearly described and the validation quite impressive and seemingly honest. I believe the study makes a valuable contribution by proposing a genotype of longevity, which future studies can confirm or deny.

Update 2015-09-19: I replaced "p-hacking" with "p-value selection bias". My intended meaning is the greater investigation and preferential publication granted to more significant findings.

On 2017 Oct 21, Anju Anand commented:

This article was discussed at our #rsjc. This captures the summary: http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(15)00523-8/fulltext

On 2016 Jun 13, Stuart Phillips commented:

Please see a letter to the editor regarding the results from this paper: http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=10353765&fileId=S000711451600221X

On 2016 Apr 30, Stuart Phillips commented:

None

On 2016 Apr 30, Stuart Phillips commented:

None

On 2015 Sep 18, Alejandro Diaz commented:

Prepubertal gynecomastia is a very rare condition and there have been an unexpected number of cases reported in the Miami area. This case report highlighted three cases. However, we have seen many other children in our practices with prepubertal gynecomastia or thelarche who were similarly exposed to the lavender-containing cologne described in our report. Unfortunately, the evaluation and follow up for these children was not as in-depth as in the cases that we presented in the article, which included chemical analysis of the cologne product.

In Politano VT, 2013 article, uterotrophic assay, performed in immature female rats, was used to evaluate estrogenic activity in vivo. However, these rats were only treated with lavender oil for a period of 3 days, whereas the children we reported on were exposed to the lavender-containing cologne for several years. As described by Henley DV, 2007, the estrogenic activity of lavender is weak, which may explain why there was not uterotrophic effects on these rats.

You mentioned that the reason Henley found that lavender and tea tree oil activated the estrogen receptor was due to the use of polystyrene in their test system as opposed to the use of glass. Both Ohno K, 2003 and Fail PA, 1998 could not demonstrate estrogenic response from polystyrene. Therefore, this explanation is not substantiated. Moreover, there was an estrogenic response to the lavender and tea tree oils, but not to the control substance, despite having used the same test system containers in both conditions.

While it is true that there are additional components in many lavender preparations, we have not found prepubertal gynecomastia to be associated with other non-lavender-containing colognes or topical products. Thus, lavender itself is a logical and well-founded explanation for the physical findings in our patients.

Regarding tea tree oil, I previously evaluated a patient who was exposed over a period of several years to numerous products containing tea tree oil, including shampoos, toothpaste, detergents, home cleaning products, and melaleuca essential oil for minor cuts, burns, and other skin issues. He developed severe prepubertal gynecomastia that improved upon discontinuation of the exposure to these products. As I did in the cases of lavender exposure, I conducted a complete endocrine evaluation and his hormone levels were all within normal ranges. I did not publish this case at the request of his parents, who were in the tea tree oil industry. As clinicians, if we find patients with prepubertal gynecomastia who have been exposed for prolonged periods of time to substances known to activate the estrogen receptor, it provides substantial evidence of causality.

The possibility exists that there are contaminants that have estrogenic activity in these preparations. However, it is the responsibility of the industry that the products as sold are safe for human exposure.

It is, however, of utmost importance to publish these case reports to offer the balance you refer to, and to deepen the scientific knowledge base and protect consumers from unnecessary harm. Clinicians must be informed and use their clinical judgment to determine what is best for their individual patients.

Alejandro Diaz, M.D. and Marco Danon, M.D. Pediatric Endocrinologists

On 2015 Sep 14, Tony Larkman commented:

It is disappointing that the authors didn’t include or at least refer to the following two articles in this paper: 1. Politano VT et al (2013), Uterotrophic Assay of Percutaneous Lavender Oil in Immature Female Rats; International Journal of Toxicology; 32(2): 123-9 (http://www.ncbi.nlm.nih.gov/pubmed/23358464) 2. Carson CF et al. (2014), Lack of evidence that essential oils affect puberty; Reproductive Toxicology; 44:50-1 (http://www.ncbi.nlm.nih.gov/pubmed/24556344)

The first paper largely exonerates lavender oil through the ’gold standard’ uterotrophic assay while the second hypothesizes a mechanism that may be causal in incidences of both gynecomastia and premature thelarche as well as the ‘in vitro’ findings of Henley et al (2007) where they in fact used polystyrene in their test system and not glass. Based on these it is not impossible to conceive that other endocrine disruptors may have been inadvertently present in the material tested.

A further, as yet untested, hypothesis for these manifestations is the high incidence of adulteration in essential oils. The incidence of adulteration in TTO is remarkably high as reported in Wong YF et al. (2014) Enantiomeric distribution of selected terpenes for authenticity assessment of Australian Melaleuca alternifolia oil; Industrial Crops & Products; 67: 475-83 (http://ijt.sagepub.com/content/early/2013/01/24/1091581812472209) where more than 50% of 43 commercial samples tested failed to comply with the proposed chiral ratios. Of 15 commercially sourced samples in the European Union 73% of these showed significant differences in chiral abundances while TTO from both North America and Asia also displayed similar results where ≥50% of the tested samples did not match the expected results. In material of Chinese origin the incidence rises to 100%. An extraordinary range of compounds never found in pure TTO has been coincidentally detected so it has been further hypothesized that this, along with the likelihood that the material used is heavily oxidized, may be significant source of problems such as allergic contact dermatitis attributed to the use of TTO as well as conditions related to endocrine disruption.

It is disappointing for the tea tree oil industry as a whole that TTO continues to be mentioned as a potential endocrine disruptor without a more balanced view being presented when there are clear indications available in the literature that the original proposal by Henley et al in 2007 may be flawed. The fact that TTO was not present at all in any of the material tested is also disappointing as TTO can in no way be implicated yet its mention continues to promulgate the link and implicate TTO unfairly.

On 2018 Jan 07, Mark Milton commented:

In defense of the authors, their article was first published online on September 8, 2015 and appeared in the Issue published on April 1, 2016. The BIAL incident occurred in Jan 2016, i.e. after this article was published and hence there couldn't have been any discussion of the BIAL incident in this article.

On 2016 Jun 08, Christopher Southan commented:

Some discussion of the BIA-10-2474 fatality and AEs would have been pertinant, even though it was more recent than the cut-off date https://cdsouthan.blogspot.se/2016/01/the-unfortunate-case-of-bia-10-2474.html

On 2015 Dec 07, Sanjay Kumar commented:

We appreciate the interest in our work. While we are unable to comment on the internalization mechanisms of the SmartFlare reagents based on our data, our independent RT-PCR measurements (Fig. 3) are consistent with the SmartFlare data and confirm that matrix stiffness and ligand density regulate miR18a levels in this system.

On 2015 Nov 18, Raphael Levy commented:

This article uses the SmartFlare technology to detect miR18a. I would be most interested in the authors' opinion on how these probes escape endosomes to report on miR18a level. In our experience, they do not and fluorescence increase is most likely correlated with degradation in endosomes. It might be quite plausible that endocytosis "is non-linearly regulated by matrix stiffness and fibronectin density in glioma cells."

On 2015 Nov 12, Christopher Sampson commented:

It seems that personalised screening for breast cancer is a sheep in wolves' clothing (rather than the author's suggestion of the reverse).

The purpose of risk-based screening is to redirect resources to those at the greatest risk of disease; those in the greatest need. I have argued elsewhere that it is possible to prioritise screening in this way, in order to maximise the benefits of screening within a given budget.

Feig's commentary suggests that the terms "risk-based screening" and "personalized screening" are being misappropriated. That may well be true. However, the criticisms therein relate to very specific uses of these terms and to particular guidelines (I do not see these claims holding true more broadly). It does not then follow that 'risk-based screening' and 'personalisation' are wolves, and indeed the way they have been clothed does not appear desirable. They are sheep in wolves' clothing!

We should not -- as I hope Feig would agree -- allow the unsavoury dressing-up of these ambitious developments waylay further research into risk-based screening.

On 2017 Feb 18, Clive Bates commented:

Erroneous interpretations have been placed on these results and overly confident conclusions drawn from very small numbers of imperfectly characterised teenagers. The headline recommendations were based on the behaviour of six out of 16 baseline e-cigarette users in a sample of 694 adolescents deemed not to be susceptible to smoking. Large conclusions drawn from small numbers should always be a cause for caution, as discussed in this article about this study by Five Thirty-Eight:

Ignore The Headlines: We Don’t Know If E-Cigs Lead Kids To Real Cigs by Christie Ashwandan, 11 September 2015

One should expect the inclination to use e-cigarettes to be caused by the same things that cause an inclination to smoke - they are similar habits (the former much less risky) and it is quite likely that those who used e-cigarettes first would have become smokers first in the absence of e-cigarettes - a concept known as shared liability. A range of independent factors that create a common propensity to smoke or vape, such as parental smoking, rebellious nature, delinquency etc. explain the association between vaping and smoking incidence but without this relationship being causal.

The authors try to address this by characterising teenagers non-susceptible to smoking if they answer “definitely no” when asked the following: “If one of your friends offered you a cigarette, would you try it?” and “Do you think you will smoke a cigarette sometime in the next year?”. The study concentrates on this group.

This is not a foolproof way of characterising susceptibility to smoking, which in any case is not a binary construct but a probability distribution. Nor is susceptibility a permanent condition for any young person - for example, if a teenage girl starts seeing a new boyfriend who smokes that will materially changes her susceptibility to smoking. The fact that some were deemed unsusceptible to smoking but were already e-cigarette users is grounds for further unease - these would be more likely to be the teens where the crude characterisation failed.

It is a near-universal feature of tobacco control research that the study presented is a wholly inadequate basis for any policy recommendation drawn in the conclusion, and this study is no exception:

These findings support regulations to limit sales and decrease the appeal of e-cigarettes to adolescents and young adults.

The findings do not support this recommendation, not least because the paper is concerned exclusively with the behaviour of young people deemed not susceptible to smoking and, within that group, a tiny fraction who progressed from vaping to smoking. Even for this group (6 of 16) the authors cannot be sure this isn't a result of mischaracterisation and that they would not have smoked in the absence of e-cigarettes. The approach to characterising non-susceptibility is far too crude and the numbers involved far too small to draw any policy-relevant conclusions.

But this isn't the main limitation. Much more troubling is that the authors made this policy recommendation without considering the transitions among young people who are susceptible to smoking - i.e. those more likely to smoke, and also those much more likely to use e-cigarettes as well as or instead of smoking. This group is much more likely to benefit from using e-cigarettes as an alternative to smoking initiation, to quit smoking or cut down or as a later transition as they approach adult life.

There are already findings (Friedman AS, 2015, Pesko MF, 2016, Pesko MF, Currie JM, 2016) that regulation of the type proposed by the authors designed to reduce access to e-cigarettes by young people has had unintended consequences in the form of increased smoking - something that should not be a surprise given these products are substitutes. While one may debate these findings, the current study makes no assessment of such effects and does not even cover the population that would be harmed by them. With these limitations, it cannot underpin its own over-confident and sweeping policy recommendation.

On 2015 Sep 15, Aadil Inamdar commented:

The very aim of a systematic review is to provide a critical summary of the available evidence. The authors of a systematic review may draw conclusions based on the collected studies on a particular topic. It is equally important to present to their readers an unbiased quality assessment of the included studies in the review, which is an integral part of a systematic review process. This process is what differentiates a systematic review from the rest and a missing quality assessment of included studies section brings it as par with the common narrative or a literature review. The risk of bias and quality assessment of studies included in this review is missing. The onus is on the researchers to provide clear, simple conclusions of studies that has been meticulously checked and rechecked for their validity. Otherwise, on the contrary, it only helps to pollute the current evidence.

It is important to note that;

• Systematic reviews are one of the highest levels of information in the hierarchy of evidence LINK
• Steps involved in a systematic review have been laid down by the Cochrane collaboration STEPS
• A major section involves assessment of quality and risk of bias, of the included studies
• Assessment not only helps in ascertaining validity of a particular study, but also gives a true estimate (over/under) of the intervention (or exposure) Assessment of quality and risk of bias

On 2015 Nov 14, Arnaud Chiolero MD PhD commented:

An enlightening review revealing the issues of universal lipid screening in children. Similar issues with the screening of other CVD risk factors in children (see www.publichealthreviews.net/content/36/1/9)

On 2015 Sep 10, David Keller commented:

Did droxidopa increase dyskinesias, blood pressure, heart rate & adrenergic side-effects?