On 2015 Oct 21, GEANNCARLO LUGO commented:

Should you not have access to this publication, please feel free to contact me at lugo@ipbs.fr

On 2015 Oct 21, Jan Egger commented:

A video demonstrating the interactive RFA Volumetry can be found here: https://www.youtube.com/watch?v=GcEwwY2rG-c

For further information please visit: http://www.clinicimppact.eu/

On 2015 Dec 03, Benedict Nwomeh commented:

In pediatric surgery, as in all aspects of medicine, teamwork is critical to achieving the best results for kids and their families. I'm excited to be a part of #IGSJC and I invite everyone - surgeons, non-surgeons, non-physicians - to join the tweetchat on Dec 14 & 15 at 5-9pm EST.

On 2015 Dec 03, Benedict Nwomeh commented:

None

On 2015 Dec 03, Christian Jones commented:

Dr. Gusani (@nirajgusani on Twitter) is certain to be an outstanding moderator, and I'm really excited about this IGSJC session. We're only starting to realize how teamwork matters in surgery, and it's great to see such concepts being formally studied. Kudos to Dr. Greenberg and her entire team.

On 2015 Dec 03, Niraj Gusani commented:

I am delighted to moderate the International General Surgery Journal Club (#IGSJC) Twitter discussion of this manuscript. We hope to have a robust discussion about the effect of surgeon leadership styles and their effects. We are honored to be joined during the chats by several of the authors, including Drs. Sarah Parker, Caprice Greenberg, and Steven Yule. Join us by following the hashtag #IGSJC during the discussion - Dec 14th & 15th, 5-9pmET for live discussion with the paper open for comments/discussion throughout both days.

On 2015 Dec 03, IGSJC - The International General Surgery Journal Club commented:

In addition, a lay article about this paper is available at http://www.reuters.com/article/2015/10/29/us-health-surgeons-leadership-skills-idUSKCN0SN26L20151029#Al3U1ELlyhGcZiq0.97

On 2015 Dec 03, IGSJC - The International General Surgery Journal Club commented:

We're proud to announce that this article will be discussed online in a session of the International General Surgery Journal Club. The conversation will happen on Twitter with the hashtag #IGSJC on December 14 & 15, 2015, from 5-9pm EST each evening. For more information about IGSJC and how to use Twitter to participate in the conversation, visit https://igsjc.wordpress.com/guide-for-new-twitter-users/. Join us!

On 2017 Nov 14, Egon Willighagen commented:

There is a new paper on recent updates for WikiPathways: http://dx.doi.org/10.1093/nar/gkx1064

On 2016 May 22, Egon Willighagen commented:

Read about the integration of Reactome pathways into WikiPathways is this new paper: http://dx.doi.org/10.1371/journal.pcbi.1004941

On 2016 Mar 24, Egon Willighagen commented:

FYI, there is an R package to interact with the WikiPathways API: http://chem-bla-ics.blogspot.nl/2015/12/using-wikipathways-api-in-r.html and https://github.com/wikipathways/rwikipathways

I appreciate feedback!

On 2017 Feb 07, Michelle Fiander commented:

Systematic Reviews (SRs) are a common publication format, but manuscripts frequently do not follow national or international guidance in the conduct or reporting of these reviews. This is not entirely surprising considering the time it takes to become fully (or moderately?!) conversant SR methodologies. With that said, journal editors and authors should engage methodologists to assess SR manuscripts in light of conduct standards (e.g. Cochrane, AHRQ or other) and reporting standards (PRISMA) to ensure systematic reviews fulfill their role of providing reliable, synthesized evidence to inform practice, policy and further research in health care.

This manuscript addresses an interesting and important topic--the impact of state regulations on nurse practitioners' contribution to health care in the US. Unfortunately, it is not clear what systematic review methodology was followed for the conduct or reporting of the review. Conduct standards include Cochrane Handbook; Finding What Works in Health Care (National Academy of Science, etc), among others. Reporting standards include PRISMA, and Cochrane MECIR. Below are 4 areas where this manuscript does not seem to adhere to standards.

1. Risk of Bias: Tool not described or referenced; data of RoB assessment for each study is not provided; seven (7) studies were excluded from the review based on risk of bias--which is not common practice.

Examples of RoB Tools: Cochrane RoB tool-- https://sites.google.com/site/riskofbiastool/ ROBINS (RoB for non-randomized studies)-- https://sites.google.com/site/riskofbiastool/

About RoB: http://methods.cochrane.org/bias/assessing-risk-bias-included-studies. Reporting RoB: http://prisma-statement.org

1. Search Methods: incomplete; not reproducible. A search strategy is described, but is not presented; thus there is no way for readers or methodologists to verify how the evidence base was identified, or if the searches identified the included studies. PRISMA and Cochrane MECIR Standards suggest including at least 1 search strategy "as run", e.g. showing number of results per line as well as total results of the combined concepts within the strategy.

2. No evidence of an a priori protocol.

3. Inclusion criteria are folded into a paragraph on search methods. While inclusion criteria can impact a search strategy--e.g. study design (an inclusion criteria) will determine the type of methodological filter or hedge employed--they are distinct from methods used to identify the evidence base.

On 2016 Feb 01, Lu Wang commented:

Thanks for Cattoretti’s comment, including the literatures presented. Certainly, we agree with the information that specificity of any antibodies used in research should be standardized to ensure the accuracy of research (Bradbury A and Plückthun A). We also agree with the opinion that commercial antibody producers should test their antibodies more rigorously before selling them to scientists who often lack the resources and expertise to evaluate acquired antibodies (Holmseth S, et al). For example, no matter how to explain the result of a preadsorption test, it needs the enough free antigen to perform the test (Holmseth S, et al), hence PRDM1 antibody is also the case. As to the detection system of PRDM1 antibody in our study, please notice that both the final dilution and the secondary antibody were clearly stated in the paper. Meanwhile, cytoplasmic staining of PRDM1 is a question really puzzling us, because this expression pattern was different from all the previous reports. As you said that while cytoplasmic localization of PRDM1 needs to be proven and founded by some methods (for instance, preadsorption test, etc), however, our research design is scientific and rigorous. Firstly, we have established strict controls during beginning of IHC assay, including blank control. When the detecting system excluded PRDM1 antibody, no any signals were found in both cytoplasmic and nuclear of normal follicular epithelial cells. Secondly, we got same results in immunofluorescence detection. There is no exogenous or endogenous biotin participated in the response as everyone knows. Thirdly, we detected PRDM1 mRNA in whole cell mRNA, it exists in cytoplasms, too. So, we trust that there must be some unclear mechanisms to make this nuclear transcription factor expressed in cytoplasms. According the reasons mentioned above, we trust our results and decided to submit our research paper at last. Thanks again and best regards.

On 2015 Dec 04, Giorgio Cattoretti commented:

The claim that the cytoplasmic PRDM1 staining (a nuclear transcription factor) is indeed specific relies on the sole evidence of staining with an antibody known to produce non-specific cytoplasmic staining, whose concentration in the final dilution is not stated, counterstained with an unknown secondary antibody in a tissue known to be rich in endogenous biotin. As the sole first evidence of cytoplasmic localization of PRDM1, this is unproven, unfounded and false until proven otherwise with tools nowadays accepted for showing antibody specific staining in situ (see Bradbury A, Plückthun A (2015). Reproducibility: Standardize antibodies used in research. Nature 518:27-29. and Holmseth Set al (2012). Specificity controls for immunocytochemistry: the antigen preadsorption test can lead to inaccurate assessment of antibody specificity. J Histochem Cytochem 60:174-187.). Respectable Journals are increasingly called to enforce strict quality controls for these type of often flawed results. Best regards Cattoretti (see PMID:11232338, 12204275 and 15772984)

On 2015 Oct 27, Bastian Fromm commented:

the affiliations look little odd...

On 2016 Apr 09, Lydia Maniatis commented:

"This result suggests that the effect of pattern masking is not the integration of mask and target (Breitmeyer, 1984), but instead the complete suppression of the target at threshold."

As always, it depends on the structure of the mask/stimulus, something these authors don't seem to appreciate.

On 2015 Nov 18, Yuri Lazebnik commented:

Editorial or Advertorial?

An apparently objective article that is sponsored by a manufacturer to promote its products is known in the advertisement business as an advertorial, a portmanteau of ‘advertisement’ and ‘editorial’. We are concerned that this editorial has too many similarities with an advertorial, giving an impression that this genre of advertisement has found home in a venerated scientific journal.

Indeed, the editorial, which introduces the Nature Insight on precision medicine, is sponsored by AstraZeneca, a company whose financial interest depends on implementing the concept of precision medicine. As the company explains: “[AZ] is proud to support a new Insight by Nature on precision medicine. Currently, 80% of our pipeline takes a precision medicine, or personalized healthcare approach.” https://www.astrazeneca.com/our-company/media-centre/articles/astrazeneca-is-proud-to-support-a-new-insight-by-nature-on-precision-medicine-14102015.html. In other words, promoting precision medicine would promote AstraZeneca’s future products. As would also be expected from an advertorial, the editorial overlooks the voices of skeptics (1,2). Likewise, the papers commissioned by the Editor for the Insight are overwhelmingly optimistic. Although each acknowledges the enormous changes in health care that would be required for implementing precision medicine, none considers that these changes may be infeasible, unaffordable, and distract us from finding inexpensive practical alternatives. The appearance of bias is not helped by finding that three of the four articles declare competing financial interests.

Although the Nature editorial has acknowledged AstraZeneca sponsorship, this disclaimer fails to dispel the impression that the editorial promotes the products of its sponsor and can lead one to suggest that one of the most revered of scientific journals has abandoned its role as an unbiased moderator. Even a hint of advertorial practices would hardly be beneficial to anyone at a time when the influence of industry on the integrity of research and clinical practices is increasingly becoming a public concern.

Michael J. Joyner, MD, Caywood Professor of Anesthesiology,Distinguished Mayo Investigator, Mayo Clinic

Nigel Paneth, MD, MPH, University Distinguished Professor, Departments of Epidemiology & Biostatistics and Pediatrics & Human Development, College of Human Medicine, Michigan State University

Yuri Lazebnik, PhD, Lerna Consulting, LLC

The authors thank Professors Ana Soto, Carlos Sonnenschein, Sandro Galea, Richard Cooper, and Arturo Casadevall for their helpful comments

REFERENCES

1. Bayer, R. & Galea, S. Public Health in the Precision-Medicine Era. The New England Journal of Medicine 373, 499-501 (2015), doi:10.1056/NEJMp1506241.

2. Joyner, M. J. & Paneth, N. Seven Questions for Personalized Medicine. JAMA 314, 999-1000, (2015) doi:10.1001/jama.2015.7725 .

On 2017 Mar 02, Prajak Barde commented:

A study by Kaul U successfully concluded that paclitaxel-eluting stents failed to demonstrate non-inferiority against everolimus-eluting Stents that in diabetic patients undergoing PCI.

The trial was powered to detect non-inferiority on the basis of Spirit IV trait assuming that 1 year rate of target vessel failure of 8.4% with each stent, with non-inferiority margin of 4 %. However, documented failure rate in Spirit IV was 4.2 % in CAD patients and 6.4% in diabetic patients. Author did not explain the reason for these differences which potentially may lead to under powering of trial.

Author choose the margin (4%) based on Absolute risk difference that can result in under powering of the trial due to lower than expected event rates. Author might have foreseen the differences in the event rate however this was not justified why the sample size adjustment was made.

In the current the relative risk was inflated substantially increasing the risk of accepting the hypothesis of non-inferiority, which was not demonstrated due to clear differentiation of the effect.

On 2015 Nov 12, Sameer Al-Abdi commented:

Result of this outstanding trial can be summarized metaphorically as “The operation (Budesonide) was successful, but the patient died”

On 2017 Nov 18, Christopher Southan commented:

This publication is now updated in our 2018 version https://www.ncbi.nlm.nih.gov/pubmed/29149325

On 2015 Dec 22, Christopher Southan commented:

The new Concise Guide to PHARMACOLOGY (Dec 2015) has been compiled from this database content http://www.ncbi.nlm.nih.gov/pubmed/26650438

On 2015 Oct 15, Christopher Southan commented:

While this supercedes the 2014 equivalent (http://www.ncbi.nlm.nih.gov/pubmed/24234439) the information in both papers is complementary

On 2017 Jan 14, Boris Barbour commented:

I have tried to clear up my confusion about the simulation conditions and more specifically the boundary conditions, which must often represent the physical context of the sphere. The Perspective seems to offer several versions, none of which is entirely satisfactory.

1) The images in Fig. 3 might be taken to suggest that the spheres are surrounded by nothing. In consequence, my calculation in the previous comment assumed a vacuum. However, one should of course read the equations and not put one's faith in Nature illustrations. I apologise to the authors and readers for initially jumping to this probably wrong conclusion.

2) Box 1 states that there is "no flux of the electric field" at the spine boundary. I think this would imply no net charge within and no net charge outside the spine, which would appear to be inconsistent with the case where the spine contains ions. (There are other logical possibilities: a grounded boundary or some exotic distributions with very specific inside-outside symmetries. But these are implausible in the present context). I therefore believe this statement refers to some special case or is an error. Or maybe it represents that well known and remarkably accurate approximation of strict electroneutrality?

3) Box 2 equation 5 gives a different boundary condition, this time with a non-zero electric field

E = Q/(4 * pi * er * e0)

However, I believe this contains an error. If the denominator also included a factor of R² , the equation would be dimensionally correct and also compatible with an infinite aqueous medium. The physical model would then be water everywhere, with a thin, "electrically invisible" barrier enclosing the ions. There would be no ions outside the spine. (It should be understood that we are dealing with "idealised" water that contains no ions, not even from the spontaneous dissociation of water molecules that occurs in reality.)

The corrected option 3) and therefore the infinite aqueous milieu seems the most plausible to me. In this case the arguments in the previous comment about the large potentials required in the "vacuum" case are still relevant, except that the values would be attenuated 80-fold by the relative permittivity of water. Voltages would range from about 20mV for 1000 ions to about 20V for 1000000. Figs. 3b and 3c would still require clearly unphysiological voltages.

In Fig. 4, the authors argue that the model spine has a "logarithmic capacitance" (i.e. V is proportional to log(Q)). However, they define V as the voltage difference between the centre and the rim of the spine. I see two problems with this definition.

1) A minor issue is that, in the model, most ions added to the spine distribute to radii other than zero (the centre), attaining a different potential in the process. An alternative might be the potential averaged over all charges.

2) A more significant issue is that the reference voltage is taken at the rim of the spine, which is well within the potential field of the spine, thereby excluding some if not most of that potential. All practical measurements and most neuronal current loops involve much larger distances outside the spine, and for these a reference at infinity is a reasonable approximation. This alternative of an external reference would require inclusion of the large voltages mentioned above. These are proportional to the charge and are likely to dominate the small intra-spine nonlinearities highlighted by the authors.

In the end, however, spines exist neither in a vacuum nor even in distilled water. As discussed in my earlier comments, most if not all of the electrical behaviour in insulators (dielectrics) described by the authors is likely a poor guide for what happens in conductors. The phenomena could thus be radically altered by the inclusion of a conducting external solution, ions of opposite charges at realistic (near equal) concentrations and a membrane.

On 2017 Jan 07, Boris Barbour commented:

[This comment has been edited as a result of uncertainty about the exact conditions for the simulations. Follow up in next comment.]

A simple calculation shows how unrealistic assumptions of significant deviations from electroneutrality are.

Imagine the sphere is in a vacuum, such that there is no external solution and the membrane capacitance is therefore absent. Then from Gauss' Law and symmetry it can be shown that the potential at the rim of the sphere with respect to infinity (i.e. a distant reference) will be:

V = Q/(4 * pi * e_0 * r),

where V is the potential, Q the charge, r the radius of the sphere and e_0 the vacuum permittivity. (This is equivalent to the classical isolated spherical conductor.)

Taking e_0 = 8.85E-12F/m, r = 0.5E-6m and an electronic charge of 1.6E-19C, we can calculate that just a single ion produces a potential of about 2.8mV. The 1000 ions in the simulation of Fig. 3a will therefore create a voltage of 2.8V (in my slightly smaller sphere), while the 1E6 charges of Fig. 3c would generate a whopping 2.8kV. Thus, the largest physiological potential could not generate a deviation from electroneutrality greater than the equivalent of a few tens of ions in the spine.

In practice a few thousand ions of the same sign can be accumulated (calculated in my first comment), but this is only possible because the charge-compensating mechanisms of the membrane capacitance and polarisation of the medium are present, which largely preserve electroneutrality.

On 2016 Dec 26, Boris Barbour commented:

Despite this article appearing in a journal dedicated to reviews, I appreciate it is tagged as a "Perspective", which presumably indicates that it contains some speculation. However, I still think it is worth pointing out to readers that electrostatic screening has in effect been omitted from the modelling, which could have an extremely strong influence on the phenomena illustrated, particularly as this is not made clear in the article.

This problem will only be addressed by analytical or numerical approaches that include at least two oppositely charged species at approximately physiological concentrations. I insist on this point because the cited preprint (like this Perspective) models the charge alone, which means only a single charged species is considered. Additional manuscripts treating this non-biological situation do not help address the biologically relevant questions. The standard approach to simulating the two-species system would be to include distinct electrodiffusion equations for the concentrations of cations and anions, whose difference yields the net charge distribution.

In the spirit of not jumping to conclusions or trusting to intuition in a complex situation, I would equally encourage readers (and the authors) to exercise due care before extrapolating from simulations with low concentrations of a single charged species to the situation with high concentrations of oppositely charged species.

EDIT: The effective omission of the membrane capacitance should also be rectified in any realistic modelling. This is because most if not all of the net charge in the spine will accumulate below the membrane, where it is quasi-neutralised by a symmetrical accumulation of opposite net charge the other side of the membrane. Without this mechanism, the actual capacitance of the spine/membrane will presumably be lower than observed in situ. In other words, biologically relevant voltages could not drive many charges into a spine without a membrane capacitance. The present modelling ignores the membrane capacitance because there is no extracellular saline in which an oppositely charged accumulation of ions can occur.

On 2016 Dec 26, Rafael Yuste commented:

We appreciate the concerns of Dr. Barbour and thank him for his frankness. But we alert the reader that this publication is not a proper experimental study but an opinion piece with a very limited set of data, which were added strictly to illustrate the point, and did not represent a comprehensive analysis of electrodiffusion in spines. Our review should be viewed precisely as what it is, a "Perspective", highlighting new and potentially controversial topics. The role of electrodiffusion in nanophysiology has been traditionally ignored by cable theory because of the difficulty to analytically solve the corresponding joint equations. Moreover, the interaction between electric fields and diffusion and geometry are not easy to dissect because they are highly nonlinear and sometimes counter intuitive and consequently difficult to discuss without adequate computational simulations. We, and others, are exploring this potentially important phenomenon with simulations and theoretical studies, some of which have already been published (https://arxiv.org/pdf/1612.07941.pdf), and which will hopefully address all the concerns of Dr. Barbour. We encourage the reader not to jump to quick dismissive conclusions but to be patient and wait for further work.

On 2016 Dec 26, Boris Barbour commented:

In this "perspective", the authors build up the importance of using full electrodiffusion simulations without an electroneutrality constraint to describe current flow and ion distributions within dendritic spines, rather than treating the cytoplasm as an Ohmic conductor. Although an electrodiffusion model is in principle more accurate and may in some cases be necessary, the authors do little to make their case here, because their illustrative model in Fig. 3 is quite divorced from physiological conditions.

They illustrate the equilibrium spatial distribution of ions within a small and isolated sphere of water, a situation loosely representing the head of a dendritic spine. When electrical interactions between the ions are considered at high concentrations, a highly nonuniform spatial distribution emerges. However, there are both trivial and fundamental problems with this apparently dramatic illustration.

It is worth fixing some numbers. Empirical measurements of membrane capacitance typically yield values of ~1microF/cm^2. So the capacitance of a typical spine head with diameter 0.5 microns will be about 10fF. Charging this capacitance to the most extreme membrane potentials observed in neurones (of the order of 100mV) will therefore require about 1fC, a charge that represents about 5000 ions. The volume of such a spine head would be about 70aL (attoLitres) and, assuming a 150mM saline of monovalents, would contain about 600000 each of cations and anions. The authors use a rather oversized spine head compared to this, but the numerical differences will be unimportant to what follows.

The authors simulate 1000, 100000 and 1000000 charges, but already the second number exceeds the largest net concentration of charges that will occur physiologically.

The concentrations they report are numerically incorrect at least in Fig. 3b (where the mean concentration should be 40 microM) and in Fig. 3c (where the mean concentration should be 400 microM).

A true representation of these gradients would include the existing 150mM saline. Thus, for Fig. 3a, the ~100nM gradient would be superimposed upon 150mM, about one part in a million, which may not be that significant.

Another important problem arises from the fact that the authors only include charges of one sign in their model, while physiological saline contains both cations and anions, in roughly if not exactly equivalent concentrations (we calculated above that the net charge represents of the order of 1% of ions present, and even this number is only made possible by the membrane capacitance). This unrealistic situation is likely to have a very strong influence on the behaviour illustrated, because the existence of ions of the opposite sign would allow electrostatic screening, which the authors have in effect banished from their model by only including a single ionic species.

The ionic gradients illustrated by the authors arise from collective mutual Coulombic repulsion (note that the submembrane ionic concentration shown is unrelated to the concentrations of charges normally occurring on either side of the membrane capacitance, because the external saline is absent in this model). Such Coulombic forces are usually annihilated over all but the shortest distances and times by electrostatic screening. The habitual approximation considers electrostatic shielding to cause an exponential attenuation of Coulombic interactions with a length constant of the Debye length. In 150mM monovalent saline the Debye length is about 0.6nm (using an approximate formula given on wikipedia), so, even over a fraction of a micron, Coulombic interactions should be attenuated to a cosmic degree and the forces generating the interesting concentration gradients of Fig. 3 are unlikely to operate.

In conclusion, although I'm not in a position to describe exactly the distribution of net charges in the spine head under physiological conditions in the absence of strict electroneutrality, neither are the authors. However, ignoring electrostatic screening seems to be an extremely unrealistic approximation.

On 2015 Nov 19, Cecile Janssens commented:

It is important to distinguish the method from how it was investigated. We applied the method to an unselected sample of meta-analyses rather than limiting to high-quality meta-analyses, because we wanted to show when the method works and when it doesn’t. Our results show that the method does not work that well when the topic of the meta-analysis is heterogeneous, and when there is a need to include grey literature or articles from non-English languages, which is no surprise. The poor performance of the method for these meta-analyses should not be interpreted as a shortcoming of the method, but as guidance for when and when not to use the method.

We did not suggest that the method should be used standalone. We mention in the first paragraph of page 8 that “additional strategies like these can be used to complement our search method–either to find more eligible studies or to increase confidence in the results of the search method when no other studies are found.”

Regarding the specific meta-analyses: The method does not improve the efficiency of meta-analyses that were already efficient. We screened more than 100% of the articles in the studies of Kumar, Stevens and Shan because they screened 573, 400 and 243 articles, compared to 1013, 536 and 289 using our method. More than half of the studies in the meta-analysis of Kumar were case studies, which often have no or a limited number of citations, and several of the other studies were published in non-English language. The topics of both other studies were quite heterogeneous. Shan investigated quality of life, covering quality of life instruments and assessments of functional status, and Stevens summarized six studies on a post-operative drug interaction, which investigated six entirely different surgeries. As said, the method does not work well when topics are heterogeneous.

Finally, this is the first paper on this method, describing two pilot studies. More work is certainly needed. Given the high efficiency of the method and the impressive accuracy, we are most interested in a direct comparison of the method with keyword searching in Pubmed as a first search. The method may well be a more efficient start of literature searching than keyword searching.

On 2015 Nov 10, Wichor Bramer commented:

This article investagates the effectiveness of citation based searching for systematic reviews, because the gold standard keyword-based searching is inefficient. The authors propose a new method of co-citation and bibliographic coupling. Their conclusion is that Citation searching is a reasonably accurate method. But what is reasonably accurate? One should not look at the median or mean or overall recall, but at the minimum recall. A researcher is not performing 20 reviews for which the median recall is accurate enough, researchers decide on which method they want to use for their single review. They want to minimize the chances of missing relevant articles in their N=1 case.

What was the question that the authors tried to answer? Can it be used as a standalone method for indetifying included references in systematic reviews? The answer has te be 'No!'. The most complete method in study 1 (screening all co-citations) retrieves and appropriate median of 94% of all included references, but the minimum of 75% is unacceptable. And that method is only occasionally more efficient than the traditional method. The method that is more efficient than traditional (all co-cited > 1) retrieves sometimes only 50% of all included references. In study 2 the best method (indirect and direct citations) retrieves a minimum of 10% of all included references. In seven out of 42 studies 50% or less of all included references were retrieved, and sometimes not even by reducing the number of hits needed to screen, such as Kumar, where screening 177% of the traditional method resulted in a recall of only 31% of the originally included studies. In their discussion the authors give reasons why their method does not work for the 5 lowest scoring articles, concluding that if these are not taken into account 89% of all references is found. But that still does not explain Stevens [68] in which 138% of hits have to be screened to find 50% of all includes, and Shan [65], where 142% is needed to find 58%.

An interesting question would be whether the described method can add additional references that were not found with the traditional keyword-based approach or traditional citation screening? This cannot be concluded from these results, as the investigators only tried to find the articles that were already included (and thus had been found by the traditional methods).

The conclusion of the authors that: "Researchers … [have] … the advantage of being able to screen only half of the number of articles compared to keyword-base literature search …[which]… is an efficient strategy for finding key articles related to one or more “known” articles" might be correct, but it cannot replace traditional keyword based searching, but only complement it, but that was not investigated.

On 2016 Jun 10, Ali Poormohammadi commented:

If it is possible please mention the experimental conditions in each step.

On 2016 Jun 09, Ali Poormohammadi commented:

None

On 2016 May 10, Morten Oksvold commented:

Please pay attention to the following report from ORI (Office of Research Integrity) before reading this article:

https://ori.hhs.gov/content/case-summary-pastorino-john-g

On 2017 Jun 28, Randi Pechacek commented:

Alex Alexiev briefly described this paper for the public on microBEnet.

On 2016 Mar 01, Ram Dessau commented:

Residual symptoms after Lyme neuroborreliosis. The prevalence is unknown? Comment by Ram B. Dessau

Department clinical microbiology Slagelse Hospital, Region Zealand Ingemannsvej 46, DK4200, Slagelse, Denmark ramd@regionsjaelland.dk

Dersch et al. have performed a systematic review and meta-analysis on the prevalence and spectrum of residual symptoms in patients after treatment for Lyme neuroborreliosis (LNB)[1]. 5579 bibliographic records were screened and 38 studies were included. An overview of treatment studies reporting residual symptoms is given. The follow up time is about one year concerning most of the studies. The conclusion is that 28% of LNB patients may experience symptoms after treatment. This conclusion may be misinterpreted as associated to LNB or caused by LNB. The 38 treatment studies were not designed to elucidate the association of LNB with residual symptoms, as control groups without LNB were not included.

Many of the cited symptoms like sensory disturbances, cognitive disturbances, pain and headache are non-specific and even common in the population at large. Thus, it would be of paramount importance to compare the prevalence of events to a control group using the same methods. Only a higher frequency of residual symptoms in the LNB group may indicate association with LNB. Due to the design of the included studies the residual symptoms could as well be due to other causes such as adverse effects of treatment [2].

Reporting the gross proportion of events may be misleading for other reasons. The load of residual symptoms will depend on not only the number of events for each symptom, but also the number of recorded items and the length of time, where symptoms may occur. The more questions you ask and the higher the gross rate of symptoms will become and eventually the rate of symptoms may approach 100%. Especially if there is also a long time span for the observations.

Along this line of reasoning Dersch et al. also misinterpreted the studies including a control group[1]. The results of these studies do not “remain inconclusive”, but show comparable results, even if there are differences. These differences are not very large and a substantial proportion of the controls also have a similar level of problems. For example the mean physical component FS36 score in LNB was 44(9) compared to 51(6) in controls[3]. A significant difference in mean score was found, but the size of the standard deviation show that the distribution of scores in the two groups have a large overlap. Given that the 95% interval is about 2 SD then FS36 score in LNB is 26-62 and in controls 39-63. Even if LNB patients have “significantly” lower FS36 score than controls, this is not a large difference. Thus a weak or absent association alone could explain that some studies do not report statistical differences and some do due to random variation. Thus, residual symptoms associated with LNB are probably quite rare, if at all.

Grouping together any symptoms without considering a variable relevance to LNB is problematic. For example, it was found in Swedish children that residual symptoms were persistent nerve defects such as facial palsy, but not nonspecific subjective symptoms [4]. Thus, it would be important to distinguish different types of symptoms and their severity. The study by Dersch et al. adds to a large volume of uncontrolled case reports and case series overstating the possible risk of symptoms associated with Lyme borreliosis[5]. This may contribute to unnecessary anxiety about Lyme borreliosis.

It is acknowledged that Dersch et al [1] do state important reservations about especially the "possible" case definitions, as patients with other conditions could contribute to the high load of reported symptomps.

Conclusion The prevalence of residual symptoms associated with LNB after treatment may not be concluded from the study by Dersch et al [1] because control groups are missing. A meaningfull interpretation is not possible. The authors should have focused on the available controlled studies instead.

Conflict of interests: None to declare.

References

1.Dersch R, Sommer H, Rauer S, Meerpohl JJ. Prevalence and spectrum of residual symptoms in Lyme neuroborreliosis after pharmacological treatment: a systematic review. J Neurol 2015 Oct 12.

2.Dersch R, Freitag MH, Schmidt S, Sommer H, Rauer S, Meerpohl JJ. Efficacy and safety of pharmacological treatments for acute Lyme neuroborreliosis - a systematic review. Eur J Neurol 2015 Sep;22:1249-59.

3.Eikeland R, Mygland A, Herlofson K, Ljostad U. European neuroborreliosis: quality of life 30 months after treatment. Acta Neurol Scand 2011 Nov;124:349-54.

4.Skogman BH, Glimaker K, Nordwall M, Vrethem M, Odkvist L, Forsberg P. Long-term clinical outcome after Lyme neuroborreliosis in childhood. Pediatrics 2012 Aug;130:262-9.

5.Baker CJ, et al. Final report of the Lyme disease review panel of the infectious diseases society of America (http://www.idsociety.org).2010.

On 2015 Oct 17, David Keller commented:

Wine should be diluted to reduce epithelial carcinogenic effects in the upper aerodigestive tract

Epidemiologic evidence suggests that people with diabetes are at significantly higher risk for many forms of cancer [1]. It has also been observed that cancer patients with pre-existing diabetes experience higher mortality than cancer patients without diabetes [2]. The randomized controlled trial by Gepner and colleagues confirmed prior observations that moderate ethanol consumption is associated with improved cardiometabolic risk in diabetics and in other groups [3].

A large observational study reported data on cancer and other harms among drinkers whose usual alcoholic beverage was wine, beer or spirits [4]. A dose-response relationship was identified between the concentration of ethanol in the beverage of choice, and the incidence of cancers among those who consumed it [5]. The risk of cancer for drinkers of beer (which contains about 5% ethanol), wine (12% ethanol) and distilled spirits (40% ethanol) were each divided by the cancer risk for teetotalers to yield respective cancer harm ratios (HRs) of 1.2, 1.38 and 1.69; note the dose-response relationship between the ethanol concentration in a beverage, and cancer rates for those who drink that beverage. The cancer HR for beer drinkers was not statistically significantly elevated above that for teetotalers, but its trend is consistent with the proposed dose-response relationship.

Given the elevated risk of cancer in diabetics, and a risk of cancer in drinkers of alcoholic beverages which increases monotonically with the concentration of ethanol in the beverage, it seems prudent for diabetics who consume ethanol to dilute their beverage of choice to a concentration of 5% or less. Wine can be diluted to 4% ethanol by combining one part wine with two parts water or juice.

References:

1: Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. Diabetes Care. 2010 Jul;33(7):1674-85. doi: 10.2337/dc10-0666. PubMed PMID: 20587728; PubMed Central PMCID: PMC2890380.

2: Ranc K, Jørgensen ME, Friis S, Carstensen B. Mortality after cancer among patients with diabetes mellitus: effect of diabetes duration and treatment. Diabetologia. 2014 May;57(5):927-34. doi: 10.1007/s00125-014-3186-z. Epub 2014 Mar 15. PubMed PMID: 24633676.

3: Gepner Y, Golan R, Harman-Boehm I, Henkin Y, Schwarzfuchs D, Shelef I, et al. Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Controlled Trial. Ann Intern Med. [Epub ahead of print 13 October 2015] doi:10.7326/M14-1650

4: Smyth A, Teo KK, and the PURE Investigators. Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study. Lancet. 2015 Sep 17. doi:10.1016/S0140-6736(15)00235-4. PubMed PMID: 26386538.

5: Keller DL. Dose-response relationship observed between concentration of ingested alcohol and cancer rate. Comment on PMID 26386538. In: PubMed Commons [Internet]. National Library of Medicine; 2015 Sept 26 [cited 2015 Oct 12]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26386538#cm26386538_11980

The above comment is also posted on the following Annals of Internal Medicine web page:

http://annals.org/article.aspx?articleid=2456121

On 2015 Oct 15, Andrea Messori commented:

Producing evidence in support of disinvestment: the experience of the Tuscany region in Italy

HTA Unit, ESTAV, 50100 Firenze (Italy)

In June 2013, the regional institution (ESTAV) responsible for drug acquisition in Tuscany (Italy) started a project aimed at identifying a series of pharmacological treatments suitable for disinvestment (i.e. suitable to be replaced by an equi-effective and less costly alternative). One criterion for this initiative was to write a full scientific report focused on comparative effectiveness for each therapeutic issue.<br> Table 1 shows the bibliografic details of the main 10 analyses of disinvestment conducted within this project.

Table 1. Information shown in this table: (a) therapeutic issue; (b) more costly treatment; (c) less costly tretament; (d) references

[1] -----------------------------------------------------------------------

(a) First line treatment of previously untreated patients with genotype-1 HCV infection ; (b) Sofosbuvir + ledipasvir (12 weeks) ; (c) Ritonavir-boosted dual therapy (12 weeks) ; (d) Trippoli S, Fadda V, Maratea D, Messori A. Bayesian network meta-analysis to evaluate interferon-free treatments in naive patients with genotype 1 hepatitis C virus infection. Eur J Gastroenterol Hepatol. 2015 Aug;27(8):983-4.

[2] -----------------------------------------------------------------------

(a) First line treatment of previously untreated patients with multiple sclerosis ; (b) Beta-Interferon ; (c) Azathoprine ; (d) Messori A, Fadda V, Maratea D, Trippoli S. Indirect meta-analytical comparison of azathioprine and of beta interferon effectiveness in all forms of multiple sclerosis pooled together. J Neurol Sci. 2014 Dec 15;347(1-2):408-10.

[3] -----------------------------------------------------------------------

(a) Prevention of Venous Thromboembolism in Major Orthopedic Surgery ; (b) Enoxaparin ; (c) Dalteparin ; (d) Messori A, Trippoli S, Maratea D, Fadda V, Marinai C. Prevention of venous thromboembolism in major orthopedic surgery: Bayesian network meta-analysis of 21 randomized trials evaluating unfractionated heparins, low-molecular weight heparins, and new oral anticoagulants. Int Cardiovasc Res J.2015;9(4):238-242

[4]------------------------------------------------------------------------

(a) Targeted Treatments for Pulmonary Arterial Hypertension: ; (b) Various agents of recent approval ; (c) Sildenafil ; (d) Badiani B, Messori A. Targeted Treatments for Pulmonary Arterial Hypertension: Interpreting Outcomes by Network Meta-analysis. Heart Lung Circ. 2015 Jul 6. pii:S1443-9506(15)01248-2. doi: 10.1016/j.hlc.2015.05.020. [Epub ahead of print]

[5]------------------------------------------------------------------------

(a) Thromboprophylaxis in orthopedic surgery ; (b) Rivaroxaban ; (c) Apixaban ; (d) Messori A, Fadda V, Maratea D, Trippoli S, Marinai C. Testing the therapeutic equivalence of novel oral anticoagulants for thromboprophylaxis in orthopaedic surgery and for prevention of stroke in atrial fibrillation. Int J Clin Pharmacol Ther. 2015 Mar;53(3):211-9. doi: 10.5414/CP202183.

[6]------------------------------------------------------------------------

(a) Treatment of Moderate-to-Severe Psoriasis by Subcutaneous Route ; (b) Ustekinumab 45mg ; (c) Adalimumab ; (d) Messori A, Fadda V, Maratea D, Trippoli S, Gatto R, De Rosa M, Marinai C. Biological drugs for the treatment of moderate-to-severe psoriasis by subcutaneous route: determining statistical equivalence according to evidence-based methods. Clin Drug Investig. 2014 Aug;34(8):593-8.

[7]------------------------------------------------------------------------

(a) Anti-reabsorptive treatment in women with osteoporosis ; (b) Risedronate or ibandronate or denosumab ; (c) Alendronate ; (d) Messori A, Fadda V, Maratea D, Trippoli S, Marinai C. Anti-reabsorptive agents in women with osteoporosis: determining statistical equivalence according to evidence-based methods. J Endocrinol Invest. 2014 Aug;37(8):769-73.

[8]------------------------------------------------------------------------

(a) Intravenous proton pump inhibitors for stress ulcer prophylaxis in critically ill patients ; (b) Omeprazole ; (c) Pantoprazole ; (d) Messori A, Fadda V, Maratea D, Gatto R, Trippoli S, De Rosa M, Marinai C. Intravenous proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: determining statistical equivalence according to evidence-based methods. Int J Clin Pharmacol Ther. 2014 Oct;52(10):825-9.

[9]------------------------------------------------------------------------

(a) Stroke prevention in atrial fibrillation: ; (b) Novel oral anticoagulants ; (c) Devices for closure of appendage (Watchman) ; (d) Messori A, Trippoli S. Left atrial appendage occlusion devices vs pharmacological agents for stroke prevention in atrial fibrillation: testing non-inferiority. Journal of the American College of Cardiology 2015 (in press) http://www.osservatorioinnovazione.net/papers/jacc2015.pdf

[10]-----------------------------------------------------------------------

(a) Biological drugs for inducing remission in patients with Crohn’s disease ; (b) Certolizumab ; (c) Adalimumab ; (d) Messori A, Maratea D, Fadda V, Trippoli S, Marinai C. Biological drugs for inducing remission in patients with Crohn's disease: determining statistical equivalence according to evidence-based methods. Arch Med Sci 2014 in press http://www.osservatorioinnovazione.net/papers/arch-med-sci-2014.pdf

On 2015 Nov 17, Suomeng Dong commented:

Erratum: The repeat content (%) of Magnaporthe oryzae is 10% instead of 52% (Table1). We are sorry for any confusion we brought by this mistake. Authors: Suomeng Dong, Sylvain Raffaele, and Sophien Kamoun.

On 2015 Nov 30, Chandan Kumar commented:

Actually, author is listed at the bottom of the article as Robert P. Kruger

On 2017 Dec 15, Franz Schelling commented:

Is it allowed to remind this fact: An improved lesion detection cannot make do for a clear lesion identification: T2 hyperintense ovoid areas can hardly be regarded as a hallmark of a particular pathology. It is quite sobering besides if brain loss and (a growth in) T2 lesion volume and counts must be viewed to as the clinical MS trials' typical imaging endpoints.

On 2016 Jan 30, Johannes M Dijkstra commented:

Dear Rachel Wolfson,

Thank you for your extensive answer, and my compliments for your work and attitude.

Johannes Dijkstra

On 2016 Jan 28, Rachel Wolfson commented:

My name is Rachel Wolfson and I am one of the co-first authors on this paper. I am submitting these comments on behalf of all the authors.

1) Yes, we have noticed the shift in the Sestrin2 band. The modification on Sestrin2 is phosphorylation. This phosphorylation seems to be induced by binding to GATOR2, as overexpression of GATOR2 is sufficient to drive the phosphorylation of Sestrin2. We have created mutants of Sestrin2 that are either phospho-mimetic or that do not get phosphorylated. In either case, these mutants bind leucine to similar degrees as wild-type Sestrin2, still bind to GATOR2, and have leucine-regulated interactions with GATOR2. Thus, the phosphorylation of Sestrin2 does not seem to be important for any of the conclusions made in our papers. Furthermore, the leucine binding data and crystal structure were obtained from Sestrin2 purified from bacterial cells, which is not phosphorylated. Future work will be needed to understand the function of Sestrin2 phosphorylation.

2) We agree that understanding how leucine can have such a profound effect on the Sestrin2-GATOR2 interaction is a fascinating question, and this was indeed a major motivation for us to solve the crystal structure of leucine-bound Sestrin2. Below are some points to consider:

A) Due to the highly specific and closed nature of the pocket (observed in Fig. 2A of Saxton et. al), leucine is able to make numerous direct contacts with Sestrin2, including 2 salt bridges and 6 hydrogen bonds, in addition to the hydrophobic van der waals contacts, which all together could contribute several kcal/mol of free energy. This is a non-trivial amount in the context of protein-protein interactions (which are also noncovalent). For an intuitive comparison, consider that the mutation of just two acidic residues (DD406-407AA in Fig. 5 of Saxton et. al) likely corresponding the elimination of 2 salt bridges at the Sestrin2-GATOR2 interface, is sufficient to completely abolish the Sestrin2-GATOR2 interaction.

B) In addition, our model actually suggests that the leucine signal is amplified: not by external factors, but rather by its ability to facilitate a conformational change in Sestrin2 that allows for the formation of additional stabilizing contacts. For example, the closing of the lid and formation of the latch contacts, observed in Fig. 3 of Saxton et. al.

With these considerations it becomes easy to imagine how leucine binding could contribute enough free energy to overcome the Sestrin2-GATOR2 interaction. Importantly, the ability of small molecule mediators to have profound effects on protein-protein interactions is not specific to Sestrin, but is actually a common theme found throughout biological signaling systems and forms the basis for many drug discovery efforts.

3) Thank you for catching the mix up in the blots. Both control blots look nearly identical and while our mistake does not affect any of our conclusions we have asked Science to have the correct panel inserted. Here is an image of the published and corrected figure: http://i.imgur.com/aHT8PV0.png

Rachel Wolfson, Lynne Chantranupong, Robert Saxton, and David Sabatini

On 2016 Jan 28, Rachel Wolfson commented:

None

On 2016 Jan 26, Johannes M Dijkstra commented:

The Sabatini group published two related articles, Wolfson et al. and Saxton et al. Saxton RA, 2016, in the January 1^st edition of Science. They convincingly showed that the interaction between Sestrin2 and GATOR2, which affects mTORC1 activity, is leucine-dependent, and that the Sestrin2 molecule has a specific pocket for binding leucine. I think that overall their study is an important and solid contribution to science. However, I have a few issues/questions in regard to their discussion/presentation of the data.

1. The authors did not discuss that their Western blot analyses suggest that Sestrin2 is represented by multiple differently modified forms, the largest of which is increased by leucine starvation and has the highest affinity for GATOR2 (or FLAG-WDR24). I couldn’t find any mentioning in the two articles by the Sabatini group of the fact that Sestrin2 is represented by multiple, probably differently covalently modified, forms. However, Wolfson Fig. 1A cell lysate anti-Sestrin2 shows that absence of leucine in the cell medium enhances the presence of a larger band, and playing with the contrast of the Fig. 1A IP-FLAG anti-Sestrin2 picture suggests that it is this larger band which efficiently binds to FLAG-WDR24 or its associated proteins (the GATOR2 complex). Once one is aware of this, once can find this phenomenon in many figures of the two papers, of which I will only give a few examples. In Wolfson Fig. 3B cell lysate anti-Sestrin2 picture, the larger Sestrin2 band disappears with larger concentrations of leucine, and this larger band seems to represent the form that is most efficiently precipitated with anti-FLAG-WDR. In Wolfson Fig. 4B cell lysate anti-HA-Sestrin2 picture the relative amount of the larger Sestrin2 band increases when the binding site for leucine was mutated, and similar effects might be present in Saxton Figs. 2D, 3D and 4C; admittedly, in those Saxton figures the cell lysates were not directly analyzed prohibiting a distinction between differences in presence and efficiencies of co-precipitation. Actually, this leucine-dependent (probably covalent) modification of Sestrin2 into a form which is more efficiently bound by the GATOR2 complex, fits beautifully with the major conclusion of the authors that Sestrin2 is a leucine-dependent regulator of GATOR2 activity. However, strangely, the authors did not discuss this phenomenon at all, leave alone that they investigated the nature of the modification(s). The only model that they postulated was an effect of leucine on Sestrin2 conformation (and not on covalent modification).

2. I wonder how non-covalent binding of a single leucine can provide enough energy to directly break the specific interaction between two (much larger) proteins. By showing that leucine can interfere with the interaction between Sestrin2 and GATOR2 when added to cell lysates for 2h at 4°C, Wolfson et al. claim to provide evidence that enzymatic activity is not necessary for explanation of the leucine effect. Within the in vitro experimental setting they are probably right in this, and the in vivo effect on apparent Sestrin2 size (see item 1) is not observed. However, I am not a biochemist, but wonder how non-covalent binding of a single amino acid can provide enough energy for disrupting a specific bond between two proteins. Shouldn’t the leucine signal somehow be amplified? I guess that in vivo it may be amplified by stimulation of some covalent change (see item 1), and that in vitro it may be amplified by the binding of Sestrin2 to additional cellular factors or by the immunoprecipitation procedure. I know that the authors do not particularly exclude the possibility of such amplification, and that their Saxton Fig. 5D model may be a simplified depiction of the core principle. Nevertheless, especially since I don’t know enough about these matters and would like to learn, I would appreciate if the authors and others could discuss this matter. Hence, this item 2 is more a question than a criticism.

3. The pictures portraying anti-FLAG-metap2 in Fig. 1B IP:FLAG and cell lysate seem to be identical. From checking the rest of the papers and because of the nature of the duplication, I deem it an unintentional honest mistake.

In summary, the Sabatini group made very important and believable contributions to elucidation of the mTORC1 pathway system in regard to Sestrin2 structure and its leucine sensitivity. However, they failed to note a very important observation, and their explanation model needs discussion. I would very much appreciate if the Sabatini group, but also other experts on the energy of protein interactions, could discuss the above items 1 and 2.

On 2015 Oct 20, Gaetano Santulli commented:

"G-protein-coupled receptor kinase 2 and hypertension: molecular insights and pathophysiological mechanisms".

Santulli G, Trimarco B, Iaccarino G. High Blood Press Cardiovasc Prev. 2013 Mar;20(1):5-12. doi: 10.1007/s40292-013-0001-8.

PMID: 23532739 http://www.ncbi.nlm.nih.gov/pubmed/23532739

Full text: http://www.researchgate.net/publication/235747571_G-Protein-Coupled_Receptor_Kinase_2_and_Hypertension

On 2016 Jan 25, Robert Eibl commented:

The publication could have included a reference on the first specific measurements of beta(1) integrins on living cells: IEE Proc Nanobiotechnol. 2004 Jun;151(3):128-32. Molecular resolution of cell adhesion forces. Eibl RH1, Benoit M. PMID: 16475855

On 2015 Oct 11, Donald Forsdyke commented:

GC% – A COLLECTIVE VARIATION THAT FOSTERS SPECIATION

Among members of a species there is generally a mean genomic GC% value with a bell-curve distribution about this mean. The small group to the left of the mean are biased towards low GC%. The small group to the right of the mean are biased towards high GC%. These fringe groups can be said to have collectively varied away from the mean.

In keeping with the proposal that the reproductive isolation needed for speciation would be fostered by a collective variation (1), it has been shown how differences in GC% would impair recombination between a group on the fringe of the bell-curve and the main species group at the centre of the bell-curve (2). Other conditions being propitious (e.g. further rein is given to natural selection), a fringe group could then become a separate species with its own bell-curve GC% distribution.

Thus, if through reproductive isolation the low GC% group departed the main species, the population mean value would move slightly to the right (higher GC%). While Mugal and her colleagues (3) provide a valuable review of the literature on genomic base composition, the implications for speciation are not mentioned. For more please see my speciation text (4) and my bioinformatics textbook (5). There are also recent PubMed comments (6, 7).

(1) Romanes GJ (1886) Physiological selection: An additional suggestion on the origin of species. Journal of the Linnaean Society, Zoology 19, 337-411.

(2) Forsdyke DR (1996) Different biological species "broadcast" their DNAs at different (G+C)% "wavelengths". J. Theoret. Biol. 178, 405-417. Forsdyke DR, 1996% "wavelengths".")

(3) Mugal CF, Weber DD, Ellegren H (2015) GC-biased gene conversion links the recombination landscape and demography to genomic base composition. BioEssays 35: (in press) doi:10.1002/bies.201500058 Mugal CF, 2015

(4) Forsdyke DR (2001) The Origin of Species Revisited. McGill-Queen’s University Press, Montreal.

(5) Forsdyke DR (2011) Evolutionary Bioinformatics. 2nd edition. Springer, New York.

(6) Clément Y, Fustier M-A, Nabholz B, Glémin S. (2014) The bimodal distribution of genic GC content is ancestral to monocot species. Genome Biology and Evolution 7, 336-348. Clément Y, 2014

(7) Turner LM, Harr B (2014) Genome-wide mapping in a house mouse hybrid zone reveals hybrid sterility loci and Dobzhansky-Muller interactions. Elife Dec 9;3 doi: 10.7554/eLife.02504 Turner LM, 2014

On 2017 Oct 03, Morten Oksvold commented:

I am puzzled how the authors can be sure they are stuyding exosomes, referring to the TEM data in figure 6 and 7. The presented micrographs could be everything from artefacts in the grid to dust or other rubbish.

On 2015 Oct 25, Brendan Everett commented:

We appreciate and agree with Dr. Gortler’s comments about the long-term benefits and safety of statin therapy in preventing important clinical cardiovascular events. We expressed concern in our Perspective that PCSK9 inhibitors might be broadly substituted for statins, when statins have a substantial body of evidence supporting their role in cardiovascular event reduction, as well as an excellent safety profile. This is of particular concern among patients with statin intolerance, which remains a difficult condition to define. For example, approximately 70% of patients who were considered unable to take statins prior to enrolling in a blinded alirocumab study who were randomized to the statin arm were able to tolerate atorvastatin 20 mg for 24 weeks. Nonetheless, many patients cannot tolerate the intensity of statin therapy that would be indicated based on their own specific clinical situation, even after switching statins or trying alternate-day dosing, as suggested by Dr. Gortler. While many non-statin treatments for hyperlipidemia have demonstrated safety, very few of these medications have shown evidence for cardiovascular event reduction when added to ongoing statin therapy, even when those statins are not at goal intensity. For patients and physicians caught in this clinical bind, PCSK9 inhibitors may represent a reasonable adjunctive therapy, particularly if the ongoing studies show evidence of cardiovascular event reduction with a tolerable safety profile. - Brendan M. Everett, Robert J. Smith, and William R. Hiatt

On 2015 Oct 11, David Gortler commented:

Unlike PCSK9 inhibitors alirocumab and evolocumab, long term findings from statins show that statins are unquestionably beneficial and safe for lowering LDL-cholesterol in hypercholesterolemic and hyperlipidemic patients. Prescribers are far too hasty to label their statin patients as intolerant, often grossly misdiagnosing and/or not differentiating between myopathy, myalgia and rhabdomyolysis due to a lack of established critera. True statin intolerance is very rare -- and there are clear pharmacologic options in those cases. Most obvious: if a patient experiences statin intolerance with one particular statin, he may be eligible for dosing of any one of the six other FDA approved statins available on the market.

Statin intolerance may be attributed directly to drug levels in the body and good data in multiple clinical pharmacy publications have shown that QOD dosing of the Type 2 statins cuts down true and legitimate cases to about half. For those that are still statin intolerant, there are non-statin drug treatment options for hyperlipidemia, all of which have more long-term safety data as compared to PCSK9 inhibitors alirocumab and evolocumab.

There is a “niche” need for PCSK9 inhibitors alirocumab and evolocumab for patients who fail all statin and all other pharmacology treatments, or who are unable to meet their goals with all available pharmacological treatment options. This residual population represents a very small percentage of hyperlipidemic patients eligible for the PCSK9 class.

On 2016 Aug 23, Ben Goldacre commented:

This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0161323. We believe the correct ID, which we have found by hand searching, is NCT01613235.

This comment is being posted as part of the OpenTrials.net project^[1] , an open database threading together all publicly accessible documents and data on each trial, globally. In the course of creating the database, and matching documents and data sources about trials from different locations, we have identified various anomalies in datasets such as PubMed, and in published papers. Alongside documenting the prevalence of problems, we are also attempting to correct these errors and anomalies wherever possible, by feeding back to the originators. We have corrected this data in the OpenTrials.net database; we hope that this trial’s text and metadata can also be corrected at source, in PubMed and in the accompanying paper.

Many thanks,

Jessica Fleminger, Ben Goldacre*

[1] Goldacre, B., Gray, J., 2016. OpenTrials: towards a collaborative open database of all available information on all clinical trials. Trials 17. doi:10.1186/s13063-016-1290-8 PMID: 27056367

* Dr Ben Goldacre BA MA MSc MBBS MRCPsych<br> Senior Clinical Research Fellow<br> ben.goldacre@phc.ox.ac.uk<br> www.ebmDataLab.net<br> Centre for Evidence Based Medicine<br> Department of Primary Care Health Sciences<br> University of Oxford<br> Radcliffe Observatory Quarter<br> Woodstock Road<br> Oxford OX2 6GG

On 2017 Jul 07, Wei Wang commented:

Several issues has been raised about this paper on PubPeer below I highlight a few of the comments:

Comment #1: "This review focuses on highlighting two research papers coauthored by Maria Barna. Peers have raised questions about both papers and the questions remain unanswered: 1) https://pubpeer.com/publications/A77C7AE5A8AEF8F5E36C4FC7139B03 2) https://pubpeer.com/publications/25409156

The review omits many of the seminal papers, including:

1) The the ribosome filter hypothesis that introduced the idea of specialized ribosomes in the post-genomic era: Mauro, V.P., and Edelman, G.M. (2002). The ribosome filter hypothesis. PNAS 99, 12031–36

2) Earlier demonstrations of translation initiation dependent on the interaction between IRESs and ribosomal proteins: Landry, D.M., Hertz, M.I., and Thompson, S.R. (2009). RPS25 is essential for translation initiation by the Dicistroviridae and hepatitis C viral IRESs. Genes Dev. 23, 2753–64".

Comment #3: "This review offers two line of evidence for heterogeneous ribosomes:

1) Levels of mRNAs encoding ribosomal proteins. -- Inferring protein levels from mRNA levels is generally precarious, especially for ribosomal proteins that correlate very poorly (or even negatively) to their transcript levels. For example see Figure 2c in Zhang et al., 2014: doi:10.1038/nature13438. Why are these data not mentioned ? -- There is wealth of transcript data, and the data included in this review are among the least convincing.

2) Protein separated on 1-D gels and stained with coomassie blue -- How do the authors know that the spots correspond to ribosomal proteins, as apposed to translation factors ? -- How do the authors know that the spots do not correspond mostly to immature ribosomes ? -- How do the authors know that the spots staining is quantitative ? -- I did not find these papers convincing decades ago when they were first published, and they did not convince the community. Are they more convincing now? What am I missing?

Many of the references are incorrect. Examples include asserting a change in the ribosomal composition, while the referenced article actually reported change in the total cytoplasmic levels of ribosomal proteins or change in their rate of protein synthesis."

On 2017 Jul 04, Randi Pechacek commented:

Jennifer Glass, first author of this paper, wrote a blog on microBEnet that chronicles her journey from first falling in love with marine science as a college freshman, to the first original research paper out of her own lab.

On 2015 Sep 30, Bill Cayley commented:

A good example (even if low-quality evidence) of when "Less" is "More" in fracture care. Other similar evidence is at: https://lessismoreebm.wordpress.com/?s=fractur

On 2015 Oct 19, David Keller commented:

Actual patient wait times were not measured directly, and the estimation method was flawed

In their editorial comments about a study on patient waiting times in medical clinics, Ross and Katz state "on average, Americans spend 80 minutes at a clinic to receive care, during which approximately only 20 minutes are spent face-to-face with the physician" [1]. They implicitly attribute the remaining 60 minutes of clinic time to excessive waiting and call for "effective interventions to shorten the time patients spend waiting."

However, the "other activities" patients engaged in during their 60 minutes in the clinic when they were not face-to-face with the physician included "completing paperwork, paying bills, interacting with non-physician staff and/or waiting", as noted in the study's Discussion section [2]. One important way in which patients interact with non-physician staff is having their blood drawn for tests ordered by the physician. An electrocardiogram, if indicated, would be obtained during this time, usually without the doctor's face anywhere in sight. Other tests, such as spirometry, audiometry, visual testing, even the measurement of height, weight and vital signs are performed by non-physician staff, while the ordering physician might be examining another patient altogether.

The bottom line is that the data sources used in this study only ascertained 2 time intervals in the doctor's office: the total time patients spent in the doctor's office, from arrival to departure, and the duration of facetime with the doctor. Subtracting the facetime from the total time spent in the office does not provide accurate information about the amount of time the patients spent waiting. They may have been undergoing diagnostic or therapeutic interventions during this interval rather than just waiting.

References:

1: Ross JS, Katz MH. No Time to Wait. JAMA Intern Med. 2015 Oct 5:1. doi: 10.1001/jamainternmed.2015.5393. [Epub ahead of print] PubMed PMID: 26437319.

2: Ray KN, Chari AV, Engberg J, Bertolet M, Mehrotra A. Disparities in Time Spent Seeking Medical Care in the United States.JAMA Intern Med. Published online October 05, 2015. doi:10.1001/jamainternmed.2015.4468.

On 2015 Oct 11, David Keller commented:

Time is Money - the cost of reducing outpatient waits for medical care

The editorial "No Time to Wait" argues that when a patient is made to wait a long time to receive care from a physician "the implicit message is clear: the patient’s time is less important than the clinician’s", adding that "if a patient must wait a long time every time he or she sees the doctor, there is a problem in the system" and concludes that doctors "need additional work" to "shorten the time spent waiting." I reply below:

First, physicians who intentionally keep patients waiting to send a message about the importance of their time should have their licenses revoked before they can do any real harm. All zero of them.

However, in the clinic, the doctor's time is clearly a scarce and valuable commodity which must be allocated efficiently among many patients. This task is complicated by the fact that each patient requires an unpredictable amount of physician time to diagnose and treat. In addition, it is common for a doctor to allow a number of patients with urgent problems to be added onto an already full schedule, and for patients who do have appointments to simply not show up, without notice. It is rare for these no-shows and added-on appointments to occur with the timing required to cancel out each other's effects.

The underlying reason doctors run late is overbooking, which is the practice of scheduling more patients to be treated than there is time on the schedule for their treatment. The opposite of overbooked time is downtime, when there are no patients for an available physician to treat during office hours, when there are high fixed overhead expenses. Overbooking reduces physician downtime caused by no-shows, but it increases the number of patients waiting to be treated, reducing physician downtime at the cost of increased patient waiting times.

In order to heed the call to reduce patient waiting times, overbooking could be reduced or eliminated. However, less overbooking would also increase physician downtime, because fewer patients would be waiting and ready to fill in for no-shows, which often occur in clusters. Overbooking increases waiting times for patients, but it reduces costly physician downtime. Are patients willing to pay extra for the convenience of reduced wait times?

Low physician payments and marginally profitable practices increase the need for overbooking to ensure that patients are waiting for the physician, and not the other way around. Actions taken to reduce patient waiting times may have the unintended effect of increasing physician downtime, and thereby jacking up the cost of medical care. Lastly, requiring "additional work" of already overworked physicians to reduce patient waiting time could cause unintended side-effects far more deleterious than spending an hour or twelve in a waitinig room.

On 2016 Aug 26, Brandon Horn commented:

The phagocytic function of neutrophils is decreased significantly with the addition of glucose (PMID:4748178). Dextrose (the "placebo") is simply D-glucose. This would compromise patients' immunological function: a highly relevant effect given the outcome measure of this study. Therefore, dextrose is an inappropriate "placebo" and essentially invalidates the conclusions of the study. See PMC:3137704 for a discussion of the improper use of sham control groups.

On 2015 Oct 07, Bill Cayley commented:

Suggestive evidence that when it comes to beta-blockers and non-cardiac surgery, "Less" is better": https://lessismoreebm.wordpress.com/?s=beta

On 2015 Dec 12, Yuwei Fan commented:

Figure 3 doesn't make any sense. How could they compare materials with curves? Release should always be expressed by either accumulative release amount or release rate.

On 2015 Nov 04, Jeffrey Beall commented:

I am commenting here to express a concern about this article, "Clinical significance of microRNA-130b in osteosarcoma and in cell growth and invasion." My concern is that the article contains unattributed text that matches or nearly matches the text of the article "miR-218 expression in osteosarcoma tissues and its effect on cell growth in osteosarcoma cells": Wang HT, 2014. Both articles appear in the same journal. The earlier article was published in late 2014. The later article was published at the end of July, 2015 and does not cite the earlier article, despite the abundance of similarities.

On 2015 Oct 08, David A Coil commented:

This comment is cross-posted from the original article.

This is the first time I’ve commented on an article using this system, but this paper was so riddled with problems I felt that I had to start. “Respiratory” is mis-spelled in the title and the rest of the paper is in a similar vein. I understand that it is difficult to write in a foreign language, and that seeing “have your paper read by a native English speaker” is annoying. However, in this case the writing is so confusing as to be nonsensical in places. For example, I’ve read this sentence a dozen times and I still don’t know what it means “This reminder the potential network monitor of this method due to the lower detection limit of which VS culture based technology and the easy handling of the system.”

But what I really can’t understand how the spelling mistakes made it through editorial and peer review (starting with the title). Just a few examples easily found by any spell checker include “postion”, “microorgnisms”, “maliganant”, “leathal”, and “noncosomicol”. Not to mention random capitalization such as “Petri dish” and “petridish” in the same paragraph.

I won’t get into the lack of stats, the total lack of references to much of the related work in the field, and the fact that demonstrating the increase in taxa seen by metagenomics versus culturing is not exactly news.

On 2017 Mar 05, thomas samaras commented:

This results of this study are consistent with a similar study by Shapiro, et al. This study is also consistent with many longevity and mortality studies published over the last 40 years. For example, a short list is presented next.

He, et al. Japanese-Hawaiian: shorter elderly have lower mortality and live longer Chmeilewski: Based on 800,000 deceased Polish men and women, shorter people live longer Samaras: Eight difference types of studies support the greater longevity of smaller people Samaras: shorter men lived longer based on a study of deceased San Diego veterans Mueller: shorter elderly West Point graduates had a lower mortality after 60 years of age Salaris: shorter deceased men in Sardinia lived longer Miller: shorter men and women who died in Ohio lived longer Willcox: short Okinawans have highest percentage of centenarians Wilhelmsen: men who were shorter at 67 years of age were more likely to reach 90 years of age Bartke: smaller body size promotes greater longevity

On 2016 Jan 25, Dimitrios Tzalis commented:

The European Public Compound Collection (PCC) is a very unique collection of compounds that are already synthesized and available for screening within ELF Screening Campaign. The goal of the paper was to compare PCC with other compounds that are available for biological screening or that were actually screened. That is why, with a full awareness, we have analyzed it against part of the PubChem collection called MLP of NIH, commercially available Maybridge and already tested compounds represented by ChEMBL. It might be interesting to collate the PCC and the 15 millions of patent-extracted compounds, in respect to broadly understood novelty, but we wanted to avoid the contamination of our comparison with theoretical compounds. In such a way the work is much more consistent. Nevertheless, thank you for your valuable comment and we can think of extending our novelty check also in respect to theoretical compounds in the future analysis since our collection is still growing. We believe that by focusing on exploring underrepresented chemical space of spiro-compounds and saturated, fused hetero rings we are offering a very competitive and unprecedented collection.

On 2016 Jan 14, Christopher Southan commented:

Interesting paper but it would have been more rigourous to define uniqueness against PubChem, especially since the recent patent-extracted chemistry expansion (see http://www.ncbi.nlm.nih.gov/pubmed/26194581)

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