14,839 Matching Annotations
  1. Feb 2018
    1. On 2014 Apr 24, B Hidalgo commented:

      Thanks for your comment. Yes, predictors/risk factors, etc. Hope this helps.


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    1. On 2014 Mar 05, Christopher Southan commented:

      A full-text version can be found at: http://figshare.com/articles/Challenges_and_recommendations_for_obtaining_chemical_structures_of_industry_provided_repurposing_candidates/978680

      The link below is to a March 2014 version of molecular structures and patent mappings for 58 structures from the 77 code names, but note many of these still do not have a name match in PubChem. http://figshare.com/articles/NCats_Compounds_with_identifications/92850


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    2. On 2016 Jan 31, Christopher Southan commented:

      Aspects described are relevant to the Jan 2016 BIA-10-2474 clinical trial disaster where the structure was initialy blinded http://cdsouthan.blogspot.se/2016/01/the-unfortunate-case-of-bia-10-2474.html


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    1. On 2014 Jan 21, Ellen M Goudsmit commented:

      This paper describes some of the political issues that have undermined the study of CFS and its subsets during the past ten years. I too have felt the pressure to promote one intervention rather than another, or to support the use of criteria which were clearly flawed. However, the non-scientific influences that have distorted the view of fatigue syndromes are various and often rather surprising. For example, a number of highly regarded journals have for years refused to publish any article which challenges the CBT model of CFS [1]. The last time that the BMJ published a report alluding to a pathological cause was in 1995 (Lane, cited in 1). Alternative views are relegated to the correspondence page. And the one journal that deals with fatigue has just rejected a paper describing criteria which in the past, have shown to select a homogeneous group. The latest issue (2014, 2, 1,) includes two studies that recommend the formulation of new criteria focusing on core symptoms but when these were offered, the editor decided the subject was contentious. We can identify problems but not try and resolve them. Ergo, we are using different terms for different symptom complexes. ME/CFS could refer to CFS or to ME or a hybrid. Is it any surprise that patients and doctors are confused?

      Perhaps it is useful to recall that fatigue is a symptom and not an illness. However, the Oxford criteria for CFS used in the PACE trial require only the presence of fatigue to some degree, at sometime, during six months. A number of referees seem to miss that point. Fatigue is a symptom of many illnesses, and of chronic stress. Five minutes on PubMed would lead one to the conclusion that CBT might well help tiredness but there's no evidence to support its value to deal with dizziness and muscle weakness. If trials only measure fatigue and sleep, and define recovery in terms of a lower score on one or two measures and report that a person feels better, it's easy to argue that it's effective. It's not effective for the majority. It helps with tiredness but as any clinician will admit, there's more to CFS than fatigue.

      There's a lack of balance in scientific publications and some serious spin re CBT and GET, which patients and independent scientists are well aware of. But this journal, like others, doesn't invite commentaries from people who aren't enthusiastic about the CBT protocol as evaluated in RCTs. Readers therefore don't get a range of opinions. It helps no one and undermines the scientific process. Most of all, it's very, very sad.

      [1] Goudsmit, E and Stouten, B. Chronic fatigue syndrome: editorial bias in the British Medical Journal. Journal of Chronic Fatigue Syndrome, 2004, 12, 4, 47-59.<br> http://freespace.virgin.net/david.axford/JCFS.pdf


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    1. On 2014 Jul 05, David Keller commented:

      An important factual error in this paper was corrected by JAMA on their website, as of 7/10/2014. A copy of this paper which is posted on the PubMed Central website was corrected, as of 7/31/2014.

      For readers of the paper edition of JAMA, here is the incorrect statement, from the end of paragraph #5 of this paper's "Comment" section (1):

      "In addition, the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) primary prevention trial (2) of 13,017 participants randomized to a low-dose combination of vitamin C, vitamin E, beta carotene, selenium, and zinc found no overall effect on total cancer, but there was a significant interaction with sex with a reduction in risk of total cancer in women only...."

      The above sentence should read "...a reduction in risk of total cancer in men only". To confirm this, I copied the following sentences from the Conclusions section of the abstract of the above-cited Su.Vi.Max study:

      "Conclusions After 7.5 years, low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. Supplementation may be effective in men only because of their lower baseline status of certain antioxidants, especially of beta carotene."

      I wish to thank PubMed Central and JAMA for correcting this important error on their websites.

      References

      1: Gaziano JM, Sesso HD, Christen WG, Bubes V, Smith JP, MacFadyen J, Schvartz M, Manson JE, Glynn RJ, Buring JE. Multivitamins in the prevention of cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA. 2012 Nov 14;308(18):1871-80. PubMed PMID: 23162860; PubMed Central PMCID: PMC3517179.

      Below is the link to the JAMA website page which contains the corrected version:

      http://jama.jamanetwork.com/article.aspx?articleid=1380451

      Below is the link to the PubMed Central version, which has been corrected, as of 7/31/2014:

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517179/

      2: Hercberg S, Galan P, Preziosi P, Bertrais S, Mennen L, Malvy D, Roussel AM, Favier A, Briançon S. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004 Nov 22;164(21):2335-42. Erratum in: Arch Intern Med. 2005 Feb 14;165(3):286. PubMed PMID: 15557412.


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    1. On 2016 Jan 30, Gary Goldman commented:

      The Goldman and King review did not contain an exhaustive summary of varicella vaccine trends. The editor, Dr. Gregory Poland, while not allowing a 500-word rebuttal response letter from Goldman and King, suggested that their material "may be suitable for other peer-reviewed journals."

      In response to Myers' Vaccination to prevent varicella, additional statistically significant trends and supporting documentation derived from annual summary reports to the CDC were published by a different journal editor in Vaccination to prevent varicella: Goldman and King's response to Myers' interpretation of Varicella Active Surveillance Project data. Goldman GS, King PG. Hum Exp Toxicol. 2014 Aug;33(8):886-93. doi: 10.1177/0960327113512340. Epub 2013 Nov 25. Goldman GS, 2014


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    1. On 2014 Aug 13, Amanda Capes-Davis commented:

      Much of the work done here is performed using the KB cell line. Please be aware that KB is not an appropriate model for oral squamous cell carcinoma. KB cells are cross-contaminated with HeLa, from cervical adenocarcinoma. For a list of known cross-contaminated cell lines, see http://iclac.org/databases/cross-contaminations/.


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    1. On 2017 Dec 12, Peter Rogan commented:

      Regarding GABRQ:c.306G>C: Whereas none of the splicing analysis programs tested predict outcomes shown in the mini-gene construct shown in Figure 2A, information theory-based exon definition analyses using ASSEDA (Mucaki EJ, 2013) was completely concordant. A novel band 116nt longer than the product expected from the wild type exon is observed. The mutation reduces the strength of the natural donor splice site of exon 3 from 9.5 -> 4.5 bits (32 fold). The pre-existing intronic cryptic site 116 nt downstream (8.6 bits) is 17 fold stronger than the mutated splice site. ASSEDA indicates that the total exon information (Ri,total) of wildtype exon is reduced (19.8 -> 14.8 bits) and the corresponding strength of the gap-surprisal adjusted cryptic exon significantly exceeds this (17.7 bits). The wildtype exon is predicted to be ~5-6 fold more abundant than the cryptic exon BEFORE mutation, and the cryptic exon is predicted to be ~8 fold more abundant AFTER mutation.


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    1. On 2014 Jan 08, Brett Snodgrass commented:

      Dear Authors,

      Thank you for the excellent report.

      Please provide your kind consideration to the distinction between the vessels of Wearn and the Thebesian veins.

      http://bit.ly/JTWearn

      http://bit.ly/Thebesius

      Morphological and Functional Alterations of the Coronary Circulation. Harvey Lecture, 1940 - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933738

      http://www.ncbi.nlm.nih.gov/pubmed/22704295

      For examples of Thebesian veins, please see:

      1. http://www.ncbi.nlm.nih.gov/pubmed/18703466

      2. http://www.ncbi.nlm.nih.gov/pubmed/23428022

      3. http://bit.ly/Thebesius

      4. http://bit.ly/ThebesianByPratt

      For additional commentary, please see

      https://twitter.com/BrettSnodgrass1/status/418890181509263360

      https://twitter.com/BrettSnodgrass1/status/406332234073792512

      https://twitter.com/BrettSnodgrass1/status/417945453498335232

      Comments and feedback are welcome.

      Thank you very much.


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    1. On 2015 Dec 11, Mark Johnston commented:

      An interactive protocol from this article is freely available at protocols.io.


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    1. On 2014 Aug 12, Miguel Lopez-Lazaro commented:

      In this article, my team assessed the in vitro cancer therapeutic potential of the compounds using a colorectal cancer cell line (HT29). We observed that several compounds improved the cytotoxic potency of the anticancer drug 5-fluorouracil; the IC50 value of the five most cytotoxic compounds was between 0.36 and 1.48 micromolar, and the IC50 value of 5-Fluroracil was 4.32 micromolar. Because our compounds killed cancer cells at lower concentrations that those of this commonly used anticancer drug, we discussed that they could have therapeutic potential.

      More recently, we assessed the cytotoxic potency of these five compounds against lung cancer cells (A549) and lung nonmalignant cells (MRC5). Their IC50 values were between 0.96 and 4.31 micromolar in the cancer cell line and between 1.24 and 3.11 micromolar in the nonmalignant cell line. Some of the compounds were in fact more cytotoxic against the nonmalignant cell line.

      Considering these new results, I think that the potential of these compounds for the treatment of colorectal cancer and lung cancer is low. I also think that my experimental design was unable to reveal their cancer therapeutic potential. To properly assess therapeutic potential using in vitro experiments one should use the most suitable experimental conditions to answer the following question:

      Can my compounds improve the ability of the standard drugs to kill cancer cells without significantly affecting nonmalignant cells from a variety of appropriate tissues? (1)

      Unfortunately, we did not address this question in our article.

      Dr. Lopez-Lazaro

      (1) Lopez-Lazaro, M. Experimental Cancer Pharmacology for Researchers: At What Concentration Should my Drug Kill Cancer Cells so that it has Potential for Cancer Therapy? 2014, ASIN: B00MMO25NM http://www.amazon.com/Experimental-Cancer-Pharmacology-Researchers-Concentration-ebook/dp/B00MMO25NM/ref=sr_1_1?ie=UTF8&qid=1407829198&sr=8-1&keywords="at+what+concentrations+should"


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    1. On 2014 Mar 09, Gyanshankar Mishra commented:

      We have also done a study on Tuberculosis management In India: Mishra G, Mulani J. Tuberculosis Prescription Practices In Private And Public Sector In India. NJIRM. 2013; 4(2): 71-78. Available online at http://www.scopemed.org/?mno=36915

      Our other study highlights the fact of how drug resistant TB is created under programmatic management of TB in India: Gyanshankar Mishra, S V Ghorpade, Jasmin Mulani (2014) XDR-TB: An outcome of programmatic management of TB in India. Indian Journal of Medical Ethics 11: 1. 47-52 Jan-Mar.Available online at http://216.12.194.36/~ijmein/index.php/ijme/article/download/932/2179

      Full text article Available online at http://www.ijme.in/index.php/ijme/article/view/932


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    1. On 2014 Dec 10, Kath Wright commented:

      Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home


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    1. On 2013 Dec 23, Gregory Francis commented:

      A longer version of the following text was submitted to JPSP as a comment. The editor agreed with three reviewers who felt that even if the analysis was valid, it was not useful to publish such a critique.

      Based on six experiments, Wiltermuth and Gino (2012), henceforth WG, concluded that separating rewards into categories increased people’s motivation to complete reward-earning tasks. An analysis of the reported findings suggests that the experiments do not properly support the conclusion.

      The primary variable for experiments 3, 4, and 5 was analyzed with a two-sample t-test, and post-hoc power was estimated with standard calculations. The analyses of the primary variable for experiments 1, 2, and 6 involved a logistic regression analysis, and the post-hoc power for each analysis was estimated with 10,000 simulated data sets that were drawn from populations having parameters matching the sample statistics from the experiments. The simulated data sets were then analyzed in the same way as the original experiments and the proportion of times they reported statistical significance was computed as an estimate of power. For experiment 6, the conclusion of a successful experimental outcome involved two different comparisons being statistically significant, and this requirement was also imposed on the estimate of experimental power. In every case, power was measured as the probability of rejecting the null hypothesis in the direction consistent with the findings reported in WG.

      When re-computing the p-values for the data presented in the paper, experiments 2, 3, and 4 produced p-values slightly above the standard significance criterion (.0546, .0516, .0544). The deviations are large enough that they cannot be due to rounding of the reported sample proportions or t-statistics. It appears that WG rounded down some p-values to .05 and then indicated statistical significance. In practice, this means that for these experiments WG used a significance criterion of .055 rather than the typical .05. Experimental power increases with the p-criterion, so the value .055 was used to estimate power, as this properly reflects the criterion used by WG.

      Since most of the experiments just barely rejected the null hypothesis, the post hoc power values tend to be close to one half. For the six experiments, the estimated power values are: .618, .507, .509, .499, .677, .561, respectively. Since each experiment is independent, the expected number of experiments that would reject the null hypothesis is the sum of the power values, which is 3.37. The probability that six experiments like these would all reject the null hypothesis is the product of the power values, which is .030. This probability is so low (an often used criterion is .1) that it renders the reported experimental results “too good to be true.”

      The analysis does not specify how such unusual results could have been produced, but there are three broad possibilities. First, the reported experiments might be a subset of a larger experiment set that included unreported null results. Second, the reported experiments may have been subject to a verification bias that utilized improper sampling methods. Third, the reported statistical analyses may have been one of several different methods (e.g., using different criteria to indicate significance) that were used to find one that produced statistically significant results. All of these approaches misrepresent the properties of the populations or the experimental outcomes. Thus, readers should be skeptical about the theoretical conclusions derived from the data reported in WG.

      R code for the simulated experiments is available at http://www1.psych.purdue.edu/~gfrancis/Publications/WiltermuthGino/


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    1. On 2013 Jun 22, Martin Fenner commented:

      This editorial provides a good overview of the important open questions in the treatment of Hodgkin lymphoma:

      • Is radiation therapy needed and if so, who should receive it?
      • Is there a role for midcycle PET scanning in treatment planning and if so, what is it?
      • What about escalated BEACOPP?
      • Is there any prospect for new effective therapies that might actually be an improvement over ABVD?

      This editorial accompanies the report Gordon LI, 2013 of a randomized phase III trial showing no improvement of the response rate with Stanford V chemotherapy compared to standard ABVD. This report comfirms the results of an earlier phase III trial Hoskin PJ, 2009, clearly demonstrating that Stanford V is no improvement over ABVD, and that ABVD remains the standard of care.

      The discussion of the role of escalated BEACOPP in advanced Hodgkin lymphoma is of particular importance, because it is the standard of care for patients up to 60 years old in Germany, but not in the US and other countries. The author follows the logic of the study Viviani et al. Viviani S, 2011 that showed higher progression-free survival for BEACOPP vs. ABVD, but similar overall survival because of salvage high-dose chemotherapy. The paper by Viviani et al. has been critizised in three comments published in the same journal (see link from PubMed page), for example because progression free survival at 5 years was the primary endpoint and no power calculation was made for the secondary endpoint overall survival.

      It is positive to see a discussion of important studies on journal pages (and to make the comments available to readers without a journal subscription), but we are in the unfortunate situation that standard treatment practices for patients with advanced Hodgkin lymphoma vary between countries. If the scientific community can't agree on a standard treatment strategy (the first randomized phase III trial with BEACOPP was published in 1998 Diehl V, 1998), then the different options should at least be clearly stated in treatment guidelines, editorials, and in particular in discussions with patients about to undergo treatment.


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    1. On 2015 Dec 02, Christopher Southan commented:

      Queries (Dec 2015) return the quote "Due to technical difficulties, this service has been disabled for online analysis" So is this transient or permenant?


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    1. On 2016 Apr 20, Lydia Maniatis commented:

      The authors of this study have constructed an experimental setup that has generated data that are “consistent with a stochastic process that degrades memory for each individual item and plays out independently across them.” On the basis of this, they conclude that “visual working memory is stochastic both at the level of a memory's content and at the level of its quality.”

      A few objections to this assertion are in order. I want to preface them by noting that it has long been understood that it is always possible to generate data “consistent” with any point of view: “A nice adaptation of conditions will make almost any hypothesis agree with the phenomena” (J. Black (1803, Lectures on the Elements of Chemistry, quoted by Popper in Popper Selections, Miller, Ed, 1985). In order for “consistency” to carry weight, investigators must have really tried to look for “inconsistency” or falsification, wherever it seems most likely to be found.

      As it happens, there is a preponderance of evidence that memory in general and visual memory in particular is not stochastic either in its content or its quality. With respect to visual memory, the organizing principles that influence the percept itself also influence the memory of those percepts, as is shown, for example, by Goldmeier (1981, The Memory Trace, its Formation and its Fate). Other investigators who have shown that memory changes are not random include Bartlett and Loftus.

      If the authors want to challenge the legitimacy of the view that “degradation” and random change is not the proper account of memory, then they should do it. It would be fine if they validly challenged the results of studies that falsify their position. They could, for example, claim the methods of the falsifying experiments were flawed. What is not OK, however, is for scientists to ignore contradictory evidence, and set up experiments that produces “consistency” with their preferred view.

      Significantly, the task used by Fougnie, Suchow and Alvarez' (2012) involves a structure-less feature – color - thus ensuring that the known effects on memory of structural principles will not interfere with their preferred outcome. As they note in their introduction, this is a task that is commonly used for such studies. Unfortunately, as here, many studies today rationalize their methodological choices not on theoretical grounds, but on the grounds that they are widespread, popular, common, even "traditional" (!). As here, a method may have become normalised for the wrong reason, i.e. because it doesn't complicate the perpetuation of preferred paradigms uncritically accepted.

      In my discussion above I have not distinguished between “working memory” and other types of memory. The authors, while using the term “working memory” have not provided a working definition, i.e. a description of how they circumscribe the term and distinguish it from other types of memory. Once they do this, they might try and check the literature for examples that falsify their account, and construct experiments that, on the basis of what has already demonstrated, make a credible effort to falsify it, rather than simply to “confirm” it.


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    1. On 2014 Jan 08, Brett Snodgrass commented:

      Dear Authors,

      Thank you for the excellent article. Please provide your kind consideration to the vascular nomenclature and the distinction between the Thebesian veins and the vessels of Wearn.

      The text highlights at the following website may illustrate the difference.

      https://twitter.com/BrettSnodgrass1/status/417888788346462209

      Comments and suggestions are welcome.

      Thank you kindly.


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    1. On 2013 Jul 17, Jessie Tenenbaum commented:

      A nice paper that raises some important points. I wonder about the composition of the readership of BB- seems like it's preaching to the choir in informatics- many known points. I wonder what % of readers are more on the biology side of things?

      For that matter, for scientific literature more generally- in the pubmed era, where fewer journals are being read as bound paper versons, how do people come upon papers they decide to read? Scanning TOCs (how I came upon this one), references from other papers, pubmed searches for keywords or authors... Of those 3, only the middle option- bibliography from another paper- would seem likely to bring this paper to the attention of a non-informaticist.


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    1. On 2016 Jun 03, Ian Fingerman commented:

      The Epigenomics database, a public repository that was developed to archive genome-wide maps of DNA and histone modifications, will be retired on June 1, 2016.

      All epigenomics data are available in our GEO resource. If you are specifically interested in the NIH Roadmap Epigenomics Project, we will maintain a page for this project's data.


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    1. On 2013 Dec 23, Yannick Pouliot commented:

      It would be nice if the gene expression data described in this paper were deposited into GEO...


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    1. On 2014 Dec 10, Kath Wright commented:

      Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home


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    1. On 2014 Feb 23, ossama mansour commented:

      it is an interesting topic in endovascular treatment of aneurysms. where actually we do not have such evidence based medicine regarding the optimum option for treatment of such aneurysm . we need to design a RCT for studying such notion.


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    1. On 2013 Oct 28, Steven Salzberg commented:

      I heard a rumor very recently that the contamination problem, discussed cogently after the first Neanderthal papers (see http://www.ncbi.nlm.nih.gov/pubmed/17937503), has arisen again, and that the authors are now aware of the very real likelihood that modern human DNA is contaminating these samples. If true, this would invalidate the analysis of FOXP2 and the multiple other papers about this genome. What do the authors have to say?


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    1. On 2013 Dec 09, Gregory Francis commented:

      I submitted the following text to J. Neuroscience a few months ago. The editor evaluated the critique but decided against publishing it.

      Zhou, Zhang, Chen, Wang, and Chen (2012) reported experimental findings that perfectly matched their theory that olfaction influences early visual perception. Calculations of experimental power suggest that such perfection is contrary to the uncertainty that exists from random sampling.

      Three results showed significant nostril-specific effects of odor on vision: experiments 1 (two results) and 2 had powers of 0.501, 0.513, and 0.529, respectively. Experiment 3 showed a significant effect of odor on visual perception (power 0.547) but, consistent with the theory, no nostril-specific effect.

      Seventeen null results also provided evidence for the theory by ruling out alternative explanations. If the theory is valid, the true effects are similar to what was reported, and the null findings are accurate, then the probability of an entire set of findings being perfectly aligned with the theory is the product of the power values times the probability of the null findings: 0.075 x (0.95)<sup>17</sup> = 0.031.

      One hundred thousand simulated replications, using the observed significant statistics as population parameters, checked the possibility of a chance pattern. Applying the same power analysis, only two of the simulated experiment sets produced a probability below the observed 0.075. On average, a simulated experiment set produced 2.1 significant findings out of four experiments.

      The too perfect data undermine the theoretical interpretation. Perhaps experiments were run improperly, the analysis was done improperly, or publication bias filtered out inconsistent experimental findings. Seemingly trivial choices in experimental design or analysis can bias findings that depend on complex patterns of experimental outcomes.


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    1. On 2016 Sep 12, Morten Oksvold commented:

      Please note that this article has been retracted and should therefore not be cited.


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    1. On 2015 Apr 08, Jason Stajich commented:

      The genome sequence accession is AMRR00000000 but not linked to this pubmed record or vice-versa.


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    1. On 2014 Dec 01, Cosmin Saveanu commented:

      Affinity purification of pre-60S complexes associated with tagged Ssf1, Rix1, Arx1 and Lsg1 (alias Kre35) coupled with quantitative mass spectrometry were used to obtain a picture of pre-60S dynamics in yeast. Overexpression of a dominant negative form of Drg1, as well as deletion of BUD20 were also used to perturb 60S assembly and test the changes in levels of various pre-60S factors.

      The quantitations presented in this paper correlate well with our published results that were based on affinity purification of Rlp24, Nog1 and Mak11 associated particles under various mutant conditions and quantitative mass-spectrometry based on stable isotope labeling (Lebreton A, 2008).

      The major caveat of these methods is the uncertainity in the faith of blocked pre-60S particle that accumulate under mutant conditions - are these "dead-end" or real intermediates in the pathway ?


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    1. On 2014 Jan 17, Amanda Capes-Davis commented:

      What's in a name? A great deal, when it comes to cell lines. KB, one of the tumor cell lines used in this paper, is cross-contaminated and is actually HeLa. It is not a nasopharyngeal epidermoid cell line. For a database of cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.


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    1. On 2014 Jun 30, Torsten Seemann commented:

      For those who not have access to the paywalled article, the web portal is accessible at http://www.proteomebrowser.org/


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    1. On 2013 Nov 01, Stephen Turner commented:

      RNA-seq enables transcript-level resolution of gene expression, but there is no appropriate methodology for simultaneously accounting for biological variability across replicates and uncertainty in mapping fragments to isoforms. Figure 1 in this paper illustrates the problem with existing approaches, which only count the number of fragments originating from either the entire gene or constitutive exons only. The method presented here addresses both of these problems simultaneously by modeling variability in the number of fragments generated by each transcript across biological replicates. Compared to existing methods, the procedure described here has equivalent sensitivity with a much lower false-positive rate when there is substantial isoform-level variability in gene expression between conditions. The manuscript also addresses and points out weaknesses in several undocumented 'alternative' workflows that are highly discussed in the field, where transcript counts from tools like Cufflinks and RSEM (RNA-Seq by expectation maximization) are used in downstream negative-binomial-based differential expression analyses.


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    1. On 2015 Nov 13, University of Kansas School of Nursing Journal Club commented:

      Reviewer (Team 11): April Urie, Caitlin Colston, Elizabeth Diaz, Bethany Macchi, Lauren Meyers, Madison Steele, & Huntre Graham (Senior Nursing Students - Class of 2016)

      Background Introduction:

      The purpose of this study is to investigate the perceptions of new graduate nurses on the influence of authentic leadership and empowerment on the quality of interprofessional collaboration in healthcare work environments (Laschinger & Smith, 2013). Many work environments have little to no interprofessional collaboration, especially new graduate nurses in feeling comfortable with being contributing members. Our team chose this article because we feel that through this study researchers will be able to define what best exemplifies authentic leadership and empowerment and how these two aspects influence interprofessional collaboration through healthcare practice as seen appearing in the lens of new graduate nurses. The article states that, in a previous study lack of communication and collaboration between healthcare team members showed to have dramatic effects and is responsible for approximately 70% of adverse events (Laschinger & Smith, 2013, p. 24). The study presents substantial text and statistics displaying the validity of authentic leadership, empowerment, and interprofessional collaboration within healthcare settings.

      Methods:

      Our group used CINAHL database engine to find opportune related articles. We searched “(Authentic AND Transformational) Leadership” and “Meaningful Recognition”. After sifting through the vast amount of articles we found that this article portrayed many key aspects relating to authentic and transformational leadership, creating a motivational climate, meaningful recognition, and staffing considerations. A correlational survey design and a secondary analysis from a larger longitudinal study of newly graduated nurses were used (Laschinger & Smith, 2013, p. 26). “The original sample was obtained from College of Nurses of Ontario registry list (n = 342). The 2nd wave of the study (2010) contained several items to capture new graduate nurses’ experiences of interprofessional collaboration on their units. 194 of new graduates form the 2nd wave constituted the sample” (Laschinger & Smith, 2013, p. 26). The method to collect data initially was mailed surveys and then reminder letters were sent out at 3 and 6 weeks after. The instrument that was used in this study consists of The Authentic Leadership Questionnaire to measure new graduates’ perspectives of their current leader’s leadership behaviors. The data was then plotted in Supplemental Digital Context 1 (Table) to measure psychometrics. A researcher- constructed Interprofessional Collaboration Scale was also used based on previous research identifying important characteristics of interprofessional collaboration (IPC) in health care setting (Laschinger & Smith, 2013). To analyze the data “The Statistical Package for Social Sciences” was used (Laschinger & Smith, 2013). The target population of this study is new graduate nurses and the impacts on interprofessional collaboration in the workplace if authentic leadership and empowerment is being used. This is important in healthcare settings in order to maximize patient care, outcomes, safety, success, decrease burnout, and the provide the opportunity for advancement and acknowledgement in healthcare environments. Laschinger & Smith (2013) suggests because authentic leaders are inclined toward values such as empathy, respect, trust and human connection they are more likely to create environments that empower employees to work with colleagues to accomplish their work in meaningful ways.

      Findings:

      Key findings and outcome of this study overall include, new graduates perceiving their leaders to display a moderate amount of authentic leadership where relational transparency was highest and self-awareness was lowest (Laschinger & Smith, 2013, p. 28). Overall perceptions of IPC on work units were high and personal beliefs that interprofessional teamwork improves patient care rated highest (Laschinger & Smith, 2013, p.28). However, what rated lowest by new graduates was the fact that healthcare professionals on their unit understood each other’s role in providing holistic patient care (Laschinger & Smith, 2013). When testing the hypothesis it was found that higher levels of supervisor authentic leadership and structural empowerment were significantly associated with a higher perceived quality of interprofessional collaboration (Laschinger & Smith, 2013, p. 28). This study has shown that new graduates views of the quality of interprofessional collaboration on their units were related to authentic leadership and structural empowerment. “In addition, new graduates perceptions’ of their manager’s authentic leadership behaviors and their own structural empowerment were significantly related to their feelings that their knowledge was respected by other health professionals, that health professionals on the team understood their roles in providing care, and that other healthcare professionals believed that IPC improves patient care” (Laschinger & Smith, 2013, p. 27). The article also spoke of the possibility of new graduates being exposed to interprofessional collaboration before graduating which would also reflect in today’s interactions and within the survey, for example, Team STEPPS. To compare and contrast how this study would be different if done in different parts of the U.S. We would make the assumption that the results would be approximately the same but could vary depending on what college is surveyed. For instance, University of Kansas has had the opportunity to have interprofessional collaboration before graduating nursing school while others have not. If this study was completed outside the US we could see how the results would be different because healthcare settings vary around the world. The cross-sectional, exploratory nature of the design limited their ability to draw strong casual inferences (Laschinger & Smith, 2013). The only other limitations include the possibility of bias from the responders and a low response rate due to mailing out the surveys (Laschinger & Smith, 2013, p. 28).

      Implications:

      This article is important to nursing and nursing practice because it depicts the differences in authentic leadership and structural empowerment in healthcare work environments. While also displaying how this type of leadership can affect interprofessional collaboration whilst influencing less fragmented patient care and positive outcomes. This aids persons’ of charge in knowing the perceptions of new graduates in authenticity and empowerment and how to improve these perceptions and the work environment. “Authentic Leaders are well positioned to ensure that new graduates are integrated into interprofessional teams and are seen as valued contributors in the delivery of care” (Laschinger & Smith, 2013, p. 28). In nursing it is crucial to have this collaboration and for all healthcare caregivers to be in congruence with each other when treating patients. This not only improves the work environment setting but this also improves the care being given. When working in a microsystem it is important to remember that a team is meant to work together, provide each member with the specialty knowledge that the other individual has, and to ultimately treat the patient with the best care possible.

      References

      Laschinger, H. S., & Smith, L. M. (2013). The Influence of Authentic Leadership and Empowerment on New-Graduate Nurses' Perceptions of Interprofessional Collaboration. Journal Of Nursing Administration, 43(1), 24-29 6p. doi:10.1097/NNA.0b013e318278606-


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    1. On 2014 Jan 08, Brett Snodgrass commented:

      Dear Authors,

      Thank you for the excellent article.

      Is it possible that three of the connections are consistent with the normal connections reported by Wearn in 1933? http://bit.ly/JTWearn

      Wearn identified the vessels of Wearn connecting to both atria and both ventricles. The above report by Sohrabi et al. document a connection between the LAD and LA, and two VCACs connecting to the LV. Wearn reported coronary-cameral connections to each of the four heart chambers and noted that they are were distinct from those described by Thebesius.

      For further references please visit the following link. https://twitter.com/BrettSnodgrass1/status/418780318682738689

      Comments, disagreements, concerns, and feedback are encouraged in the interest of accuracy and clarity.

      Thank you kindly.


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    1. On 2014 Jun 02, Claudio Gil Araújo commented:

      For those interested in knowing more about the sitting-rising test (SRT), please access the Youtube link https://www.youtube.com/watch?v=MCQ2WA2T2oA


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    1. On 2013 Jun 29, Rahul Bakshi commented:

      The association of 'delayed parasite clearance' in response to artemisinin with a general mechanism like DNA repair suggests that Cambodian parasites of interest may simply be 'fitter'in terms of dealing with the DNA damage that accompanies any drug-induced death pathway. This gives rise to a couple of questions: 1) Would these parasites demonstrate delayed clearance when challenged with other drug classes? 2)Why is the parasite population structure in Cambodia still so heterogenous? One would (perhaps naively) expect the fitter population to take over. Is there a cost associated with these SNPs in other stages of the lifecycle? 3)Would the parasite population structure in Cambodia change if artemisinin pressure was withdrawn? Thoughts, anyone?


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    1. On 2014 Jan 01, Qian Liu commented:

      This is an official government file for Chinese oncologists. It would be updated in 2014.


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    1. On 2014 Mar 18, Gwinyai Masukume commented:

      Nejad and colleagues present a case of a man with alcohol withdrawal delirium and multifactorial delirium. This patient had thrombocytopenia and part of his work-up included testing for antibodies against heparin-platelet factor 4 complexes to elucidate the cause of the thrombocytopenia - the test was negative (1). Thrombocytopenia in early alcohol withdrawal is associated with development of delirium tremens or seizures (2). In patients who develop severe alcohol withdrawal syndrome (like the one presented) thrombocytopenia is more frequent (2).

      Additionally, from the provided laboratory data, this patient has a De Ritis (aspartate aminotransferase/alanine aminotransferase) ratio greater than 2. His albumin/globulin ratio of less than 1.6 is low. Given his history of alcoholism, a De Ritis ratio greater then 2, and a decreased albumin/globulin ratio a diagnosis of alcoholic liver disease is made (3,4). Liver disease is briefly mentioned in the article; however it is important to highlight the role of laboratory data in diagnosing alcoholic liver disease.

      References

      (1) Nejad SH, Schaefer PW, Bajwa EK, Smith FA. Case records of the Massachusetts General Hospital. Case 39-2012. A 55-year-old man with alcoholism, recurrent seizures, and agitation. N Engl J Med 2012, 367(25):2428-34.

      (2) Berggren U, Fahlke C, Berglund KJ, Blennow K, Zetterberg H, Balldin J. Thrombocytopenia in early alcohol withdrawal is associatedwith development of delirium tremens or seizures. Alcohol Alcohol 2009, 44(4):382-6. Berggren U, 2009

      (3) Majhi S, Baral N, Lamsal M, Mehta KD. De Ritis ratio as diagnostic marker of alcoholic liver disease. Nepal Med Coll J 2006, 8(1):40-2. Majhi S, 2006

      (4) Das SK, Vasudevan DM. Biochemical diagnosis of alcoholism. Indian J Clin Biochem 2005, 20(1):35-42. Das SK, 2005


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    1. On 2016 Oct 03, Morten Oksvold commented:

      Please note that after an investigation at the University of Cologne, six articles where T. Wenz figures as first or senior author were found to contain questionable data due to scientific misconduct. This article is one of these six articles.

      The conclusion from the report was ready June 28, 2016, please see the link (in German):

      http://www.portal.uni-koeln.de/9015.html?&tx_news_pi1[news]=4335&tx_news_pi1[controller]=News&tx_news_pi1[action]=detail&cHash=1deb8399d7f796d65ca9f6ae4764a1ce


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    1. On 2013 Dec 11, Gary Ward commented:

      This paper presents a clever new way to generate gene knockouts in T. gondii, using a conditional dimerizable Cre recombinase (DiCre) system. Because the knockouts are experimentally induced with rapamycin, even essential genes can be disrupted for phenotypic characterization. In a first application of the technique, the authors show that two genes encoding proteins previously believed to be essential for parasite invasion, myosin A and the secreted adhesin MIC2, are in fact dispensable. In the case of the myoA knockout parasites, it would be interesting to see whether or not another parasite myosin is upregulated or now associates with the myosin motor complex (e.g., as assessed by a GAP45 IP) in the absence of myosin A.

      In contrast, parasites could not tolerate disruption of act1 (actin). Evidence is presented to suggest that the actin knockouts remain capable of invasion and the authors suggest that the most important defect is instead in apicoplast segregation. Have the authors attempted to isolate and maintain an act1 knockout clone in the presence of isopentenyl pyrophosphate (IPP)? Blood-stage Plasmodium falciparum can survive independently of the apicoplast as long as this isoprenoid precursor is provided (Yeh et al. PLOS Biol [2011] 9(8): e1001138). It would be interesting to look at the T. gondii act1 knockout’s ability (or perhaps inability) to glide and invade under similar conditions.

      The picture that emerges from these ground-breaking studies is that myosin A, MIC2 and actin are involved in host cell invasion, as the current model would posit, but that there is another previously unrecognized way for the parasites to invade independent of these proteins.

      Posted by Gary Ward on behalf of the University of Vermont Toxoplasma Journal Club (UVM ToxoJC); members include Jenna Foderaro, Anne Kelsen, Shruthi Krishnamurthy, Jacqueline Leung, Pramod Rompikuntal, Luke Tilley & Gary Ward


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    2. On 2016 Jan 21, Sebastian Lourido commented:

      The conditional dimerizable Cre recombinase (DiCre) has been a powerful technique for conditional genome engineering in Toxoplasma, as first established in this article, and elaborated later (see Pieperhoff, et al. 2015. PLoS One). It has worked well in our hands for a variety of applications. Recently, we discovered that the reporter construct used in this study was cloned down stream and in frame of a Ty-tag (EVHTNQDPLD), such that the KillerRed expressed prior to recombination contains and N-terminal Ty-tag. This observation does not affect any of the experiments presented in the article. However, it might be important to note for future investigators planning further manipulations of the existing DiCre strains or reporter constructs.


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    1. On 2016 Aug 24, 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 NCT88597077. We believe the correct ID, which we have found by hand searching, is NCT00597077.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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


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    1. 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 NCT0000473. We believe the correct ID, which we have found by hand searching, is NCT00004732.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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

      * 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


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    1. On 2015 Feb 03, Ivan Oransky commented:

      The first author of this retracted paper has published a rebuttal of this retraction, 25 years later: http://retractionwatch.com/2015/02/03/25-years-aids-fraud-comes-back-swinging/


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    1. On 2016 Apr 19, Lydia Maniatis commented:

      I would like to pose a few questions to the authors of this paper.

      First, with respect to the meaning of the term “feature”

      In paragraph 1, the authors state that: “Identifying a letter requires two steps of visual processing: the observer first detects the letter's features and then combines them to recognize the letter (Pelli, Burns, Farrell & Moore-Page, 2006).”

      The insertion of the reference to Pelli et al (2006) seems to imply that this assertion has been corroborated by those authors, but it turns out that in fact, the study in question does not even clarify what it means by the term “features” nor does it employ “features” as independent variables.

      Specifically, Pelli et al, (2006) define features “as an image, or image component...” So they have merely equated “feature” with “image” or “part of an image.” (That this is pretty useless is confirmed by them when they say that “Rather than start with a given list of features (e.g., Gibson, 1969), we left the features unspecified).” Substituting “image” for "feature" in Suchow and Pelli's (2013) title results in the somewhat nonsensical “Learning to detect and combine images (or parts of images) of an object.”

      In their second paragraph Suchow and Pelli (2013) decide to tackle the question themselves, asking “However, what is a feature?” They “narrowly define features as discrete components of an image that are detected independently of each other (Pelli et al 2006).” (It's not clear what the significance of the Pelli et al (2006) reference is here, given the vagueness described above.) The term “component” is wholly uninformative – and there is no indication of which “components of an image” tend to be “detected independently of each other.” So the authors don't seem to have answered their own question. There is nothing in their definition of the term "feature" to help the reader understand what they mean by it. Claims built on terms without an intelligible working definition are not testable in principle, and therefore are not scientific.

      In fact, the authors admit they don't know what they mean by the term “feature:” “To separate the [arbitrarily hypothesized] steps, we need to know the letters features; they are uncertain for traditional letters, so we use Gabor letters instead.” So now “feature” is equivalent to "Gabor". The title should read: “Learning to detect and combine the Gabors of an object.”

      The authors “suppose that our Gabors are features, detected independently (Watson (1979) Robson, Graham (1981).” So we're not even stating on principle that our Gabors are features, merely "supposing" that they are. Neither of the two references provided to support this “supposing” seem to refer to features.

      On what rationale are Gabors to be referred to as “features” rather than as “objects”?

      It seems as though the authors just want something they can label a “feature” without worrying what they mean by it. They state that the “juxtaposition of n Gabors creates an n-feature letter” but this claim is not supported by the two citations they provide; one deals with peripheral vision and the other uses structures made from Gabors and calls them features but offers no definitions or rationale.

      So I would ask the authors a. What is the basis for your claim, quoted above, that “Identifying a letter requires two steps of visual processing...” b. How do you (or do you) distinguish a “feature” from an image or an arbitrary part of an image, or from an “object”? c. What do you mean when you say that an (undefined) feature is “detected independently”?

      With respect to the phrase “learning to detect.”

      In normal circumstances, we don't need to learn to see the world around us. In your experiments, you're making it so difficult that people have to guess, and practice discerning particular forms when they are very faint or lack the homogeneous surface structure that our visual system relies on to segregate figure from ground. Even if it is possible to learn to harness expectation to achieve better quasi-guesses, why do you consider these difficult and unnatural conditions conducive to learning about the normal functioning of our visual system?

      Is the 75% cut-off point used to define contrast threshold derived from studies of the visual system? On what basis is it chosen? If it is arbitrary, then how can calculations based on it illuminate visual function?

      With respect to the use of “Gabors”

      You say that: “Gabors are fairly well matched to the receptive fields of simple cells in the primary visual cortex” though you offer no references to support this statement. Do you mean to imply that different figures, e.g. drawings of puppies, might be poorly-matched to V1 receptive fields? Would this impair our perception of them? Given that V1 neurons are presumably involved in all of our visual percepts, on what basis do you infer a “well-matched” vs “poorly-matched” dichotomy? Are you aware of Teller's (1984) arguments that the notion that particular stimuli tap into particular neurons or groups of neurons is highly problematic on logical and empirical grounds?


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    2. On 2016 Apr 19, Lydia Maniatis commented:

      You refer to “detection” and “identification.” In vision science, people often refer to “perception.” Where does perception come in, in your scheme? It would seem that identification of any percept presupposes perceiving it in the first place. In addition, we are capable of seeing things that we cannot “identify.” A random blob, for instance. Given that you refer (however invalidly) to the primary visual areas (V1), it would seem that you are interested in the way percepts arise, i.e. perception. Perceiving an object obviously doesn't correspond to detection, which you describe, in effect, as perceiving any inhomogeneity in the surface on which the stimulus is presented, and again, identification is post-perception. So where in your model does object perception come in?

      Relatedly, your equations are founded on terms for contrast, but it seems inappropriate to model identification or recognition on contrast, since this is a post-perception act of comparison. You might say, in response, that your viewing conditions are so poor that observers need to guess, but what does guessing have to do with basic visual processes? And since the reliability of their guesses depends on an arbitrary selection of “letters” and their in particular their frequencies, of what relevance is such reliability to understanding perception?

      Finally, are you aware that the perceptual emergence of parts of a stimulus are contingent on its structure? This was ascertained in experiments performed by Gottschaldt (1929) (in Ellis, A Source Book of Gestalt Psychology) using line drawings (and you state that you consider lines - “bars” - to be “features.”) He showed that for particular figures, the order of emergence of parts with increasing illumination (analogous to increasing contrast here), was repeatable and structure-dependent. You take for granted that all of the parts of your individual Gabors are “detected” (or identified, I'm not sure which) simultaneously, but if this is the case it is because of their structure, which you don't consider.


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    3. On 2016 Apr 19, Lydia Maniatis commented:

      The authors state that "the conclusions of this paper do not depend on our claim that Gabor "letters" are letters; it is enough that they are objects." This seems to imply some kind of generality of the conclusions, extending to "objects" generally. But later they seem unsure if the method can be extended beyond collections of Gabor patches: "It may be possible to extend our approach beyond Gabor letters to other stimuli, such as words, faces and scenes, whose features are unknown. If one assumes the separability found here, then it may be easy to factor out the efficiency of detecting."

      If the "features" of these other entities are unknown, then what is to be separated, and how? How might the "features" come to be known?

      What is clear is that the authors have not considered and do not seem obliged to consider whether in principle (and on the basis of what principle), their specific experimental conditions and results have any generality - i.e. theoretical significance for perception - at all. In this case, they have simply collected some data and crunched the numbers in some arbitrary (because theoretically ambiguous) fashion. Yet this is supposed to be a top journal, whose editors, one might assume would take such factors into consideration.

      The fact is that the whole conversation is moot because perception demonstrably does not and cannot consist of an arbitrarily asserted "two-step process of feature detection and combination" even if the authors could explain what they mean by "feature."


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    4. On 2016 Apr 19, Lydia Maniatis commented:

      I don't think it is ever explained why "noise" is added to the stimuli.


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    1. On 2014 Nov 17, Raphael Levy commented:

      The evidence behind the structure and special properties of “striped” nanoparticles has been challenged by Cesbron Y, 2012. The publication in 2012 of Cesbron Y, 2012 took three years and has been followed by post-publication peer review of the various existing and new stripy articles on my blog, PubPeer, etc.

      A detailed analysis of this body of work is published today in PloS One by Stirling et al; from the abstract: “through a combination of an exhaustive re-analysis of the original data with new experimental measurements of a simple control sample comprising entirely unfunctionalised particles, we conclusively show that all of the STM evidence for striped nanoparticles published to date can instead be explained by a combination of well-known instrumental artefacts, strong observer bias, and/or improper data acquisition/analysis protocols.


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    1. On 2013 Oct 28, Mick Watson commented:

      We have now published the software behind many of the analyses in this paper:

      Watson M, Schnettler E, Kohl A. (2013) viRome: an R package for the visualization and analysis of viral small RNA sequence datasets. Bioinformatics. 29(15):1902-3

      http://www.ncbi.nlm.nih.gov/pubmed/23709497

      The website for the software is here: http://www.ark-genomics.org/bioinformatics/virome


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    1. On 2014 Aug 10, Raha Pazoki commented:

      "GPRC6A in Myocardial Infarction"

      The article by Rossol and co-workers demonstrated the role of GPRC6A in activation of inflammatory response in the necrotic area. This topic could be interesting in cardiovascular genetics specifically in understanding the mechanisms involved in cardioprotection during myocardial infarction (MI).

      Depending on the size of infarction, tissue injury and necrosis of cardiomyocytes occurs during MI. GPRC6A may activate inflammatory response in the infarct area and may have a function in cardioprotectivity and healing of the damaged tissue. Experimental investigations are necessary to give insight on this topic.


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    1. On 2014 Dec 10, Kath Wright commented:

      Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home


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    1. On 2014 Apr 13, Tom Kindlon commented:

      When one looks at all the transfers (i.e. unemployment, etc.) the differences between the groups effectively disappear:

      The abstract only gives the percentages who received disability pension. However, there are other transfers and most people in both groups got transfers.

      "Transfer payments were divided into five categories: 1: disability pension; 2: flexible work (jobs created for persons with limited working capacity); 3: sickness benefit; 4: unemployed; and 5: self-supporting. Which of these five categories each patient fit into was determined at two time points: a 12-week period immediately before baseline and a 12-week period 15 months after baseline. We chose a 12-week period over a one-week period to obtain an estimate as precise as possible of the transfer payments received during the two time periods.

      "We used the transfer payment categories proposed by Hjollund et al. [18] and Carstensen [19]. Carstensen [19] grouped sickness benefit and vocational rehabilitation as temporary health-related benefits, whereas flexible work and disability pension were grouped as permanent health-related benefits."

      "Flexible work and disability pension are permanent health-related benefits"

      Here are the results (I haven't tried to calculate the percentages but the sample sizes in both groups are virtually the same so one can see the similarities by inspection).

      Mindfulness therapy (n=59):

      Baseline: Self-support: 19 Unemployed: 6 Sickness benefit: 21 Flexible work: 9 Disability pension: 4

      Follow-up: Self-support: 17 Unemployed: 9 Sickness benefit: 2 Flexible work: 16 Disability pension: 15


      "Enhanced treatment as usual"

      Baseline: Self-support: 17 Unemployed: 6 Sickness benefit: 23 Flexible work: 7 Disability pension: 7

      Follow-up: Self-support: 13 Unemployed: 4 Sickness benefit: 3 Flexible work: 13 Disability pension: 27

      So if one just looks at self-support, the only one that doesn't involve transfers, there is little difference (as well as there being a (small) deterioration in both groups):

      Mindfulness therapy (n=59): Baseline: 19 Follow-up: 17

      "Enhanced treatment as usual" (n=60) Baseline: 17 Follow-up: 13


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    2. On 2014 Apr 13, Tom Kindlon commented:

      There are quite big differences between the two groups in terms of changes in healthcare costs:

      In the abstract have collapsed the healthcare costs from the two groups, one of which is "enhanced treatment as usual" which would usually be seen as more like a control group.

      Mindfulness therapy: One year prior to baseline: $4643 Baseline and one year ahead: $3937

      "Enhanced treatment as usual" One year prior to baseline: $5996 Baseline and one year ahead: $3355

      Also, the baseline figures may not be average figures for a typical year: this figure was in the year in the lead up to be referred to the clinic so these were likely in the period when the patients, and indeed health professionals, were looking for answers to do with their health problems.


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    1. On 2016 Aug 24, 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 NCT700732472. We believe the correct ID, which we have found by hand searching, is NCT00732472.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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


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    1. On 2015 Apr 10, Martine Crasnier-Mednansky commented:

      According to Bledig SA, 1996, deletion of FruR (Cra) resulted in an appreciable increase of pykF-encoded pyruvate kinase synthesis on gluconeogenic carbon sources as compared to glycolytic carbon sources (casamino-acids were added to the culture medium to allow gluconeogenic growth). In addition, overexpressed FruR repressed the transcription of the pykF gene significantly on gluconeogenic carbon sources but not on glycolytic carbon sources. Thus the FruR (Cra) effect on pykF transcription significantly takes place under conditions of gluconeogenic growth. Therefore using pykF as a reporter gene for analyzing, under glycolytic growth conditions, a transcriptional regulation by FBP/Cra appears inappropriate. In addition, the concentration of FBP is dependent on the concentration of PEP because phosphofructokinase is subject to allosteric control by PEP Blangy D, 1968. Therefore decreasing pyruvate kinase synthesis below physiological level also decreases the FBP concentration which is in conflict with the present data (see Fig. S1 and Fig. 2B).

      As shown in Fig. 1C, concentrations of FBP controlling the glycolytic flux are below 1 mM. This concentration range has been reported to be insufficient for FBP to displace FruR from its operator sites. In addition, cAMP-dependent carbon catabolite repression was reported by Nanchen A, 2008 to be the dominant control mechanism of metabolic fluxes under glucose limitation condition (used in Fig. 1B, black squares).


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    1. On 2017 Oct 05, ROBERT HURST commented:

      Unfortunately, KU-7 is not bladder cancer but is, instead, HeLa cells. PMC3805942


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    1. On 2015 Apr 02, Marcus Munafò commented:

      Flegal and colleagues suggest that being overweight may decrease risk of all-cause mortality, and being slightly obese confers no increased risk compared to being of normal weight [1]. We think these conclusions are misleading and may give a detrimental public health message, particularly given the publicity they attracted.

      Despite the authors’ suggestion that there is “little support for the suggestion that smoking and pre-existing illness are important causes of bias”, these factors are not consistently controlled for within the contributing studies [1]. It has been demonstrated in two large prospective studies that the increased risk of death from being overweight or obese can be masked when smoking is not adequately controlled for, and when sufficient initial years of follow up are not excluded [2]. Smoking is associated with both lower body mass index (BMI) and increased risk of death, while underlying illness can lower BMI prior to death. Furthermore, it is widely appreciated that conventional statistical approaches to “control” for such factors are inadequate. Support for a positive causal effect of BMI on mortality comes from studies less subject to the biases associated with BMI measured in later life because they used BMI in adolescence or offspring BMI as the exposure [3, 4]. These measures are suitable proxies since they are strongly associated with an individual’s BMI in middle age but are not substantially affected by reverse causality and are less confounded by smoking. Higher BMI in adolescence was associated with greater risk of all-cause mortality in middle age in a study of over 200,000 individuals [3]. Stronger inferred associations were observed with offspring BMI and all-cause and cardiovascular mortality than with own BMI, suggesting that positive associations of BMI and mortality may in fact be underestimated in conventional observational studies [4]. In addition, this study demonstrated that the commonly observed inverse association between BMI and death from respiratory and other diseases may also be due to such biases.

      Given the importance of the public health messages regarding “healthy” weight, we feel that further research is needed in this area using innovative research methods to overcome potential biases; further conventional observational studies will simply recapitulate the biases inherent in all such investigations. One such approach would be Mendelian randomisation, using obesity-related genetic variants, such as those in FTO. Mendelian randomisation methods, when applied correctly, are free from confounding by environmental factors and are not affected by reverse causality [5].

      Marcus Munafò, Amy Taylor and George Davey Smith

      1. Flegal, K.M., et al., Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA, 2013. 309(1): p. 71-82.
      2. Lawlor, D.A., et al., Reverse causality and confounding and the associations of overweight and obesity with mortality. Obesity (Silver Spring), 2006. 14(12): p. 2294-304.
      3. Bjorge, T., et al., Body mass index in adolescence in relation to cause-specific mortality: a follow-up of 230,000 Norwegian adolescents. Am J Epidemiol, 2008. 168(1): p. 30-7.
      4. Davey Smith, G., et al., The association between BMI and mortality using offspring BMI as an indicator of own BMI: large intergenerational mortality study. BMJ, 2009. 339: p. b5043.
      5. Davey Smith, G. and S. Ebrahim, 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol, 2003. 32(1): p. 1-22.


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    2. On 2015 Apr 18, John Spitzer commented:

      The article in JAMA by Flegal et al is a summary of the literature. It includes 97 articles with 2.88 million individuals and more than 270,000 deaths. The conclusions described as "misleading" by Munafò et al (below) are simply a summary of the results that arise from the data and the statistical methods. Munafò et al do not present any specific criticisms of the methods of the Flegal et al article nor do they assert that the summary of the literature is incorrect. The single study by Lawlor, described by Munafò et al as "large," based its results on 5,337 never-smoking participants, and it was one of the articles included in the review by Flegal et al. The majority of those articles do not show smoking and pre-existing illness as important causes of bias. Opinions about "detrimental" public health messages arising from scientific findings should be distinguished from scientific criticisms of those findings. In a commentary on reactions to the Flegal et al article the editors of Nature stated: "It is risky to oversimplify science for the sake of a clear public-health message." http://www.ncbi.nlm.nih.gov/pubmed/23936910


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    3. On 2015 Apr 25, Arnaud Chiolero MD PhD commented:

      Probably the best and more exhaustive review addressing the issue of overweight and mortality. Many health scientists have difficulties to accept the idea that a BMI in the overweight category is not associated with a higher mortality. To move beyond this controversy, studies assessing the effect of interventions to reduce BMI will be needed (see e.g. Chiolero Epidemiology 2015). Meanwhile, it seems difficult to deny these observations.


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    1. On 2014 Apr 30, Jason Stajich commented:

      Unfortunately the web server URL referenced in this manuscript is no long available (as of April 2014).


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    2. On 2014 May 31, Torsten Seemann commented:

      There is now a HTTP redirect to the new version: http://cge.cbs.dtu.dk/services/snpTree-1.1/


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    1. On 2016 Apr 06, Lydia Maniatis commented:

      The authors' approach has serious problems, similar to those discussed by Teller (1984), as commented on by me here: https://pubpeer.com/publications/23283693


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    1. On 2014 Dec 15, Chinmoy Saha commented:

      I think there is a printing mistake in the abstract (line 3). Wrong: 13 to 8% in K562 cells? Right: 3 to 8% in K562 cells?


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    1. On 2013 Jun 17, John Overington commented:

      Reviews and discusses two important concepts - firstly - ligand-based clustering of biological receptors on the basis of ensembles of ligands that bind to them, and then the development of an organisational framework based on these similarities; and secondly - the concept of a time domain in biological signalling and response to a given small molecule ligand - reflecting the limited repertoire of small molecule ligands and the response systems with radically different time constants.


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    1. On 2014 Feb 14, Daniel J Simons commented:

      I just wrote a post-publication review of this paper on my blog: http://blog.dansimons.com/2014/02/hi-bar-10-questions-about-inattentional.html

      If the method proves robust, this approach could have large theoretical and practical implications for our understanding of attention sets in inattentional blindness. I do have some concerns about how robust this effect is. And, as my blog post highlights, I have a number of questions about the methods and analyses. It would be great if the authors could provide additional information here or as supplemental material for their paper.


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    1. On 2016 Apr 09, Arnaud Chiolero MD PhD commented:

      An easy-to-read review to better understand what brings modern approach of causal inference in epidemiology and public health.


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    1. On 2013 Nov 15, Gaétan Kerdelhué commented:

      Two later studies confirmed a high recall of Google Scholar but argued it could not be used in realistic settings for systematic reviews. See Giustini D, 2013 and Boeker M, 2013.


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    2. On 2013 Dec 27, Wichor Bramer commented:

      More recently another article was published that revisited the conclusions from Gehanno: Bramer WM, 2013.

      In this article we conclude that, though the coverage of Google Scholar is near 100%, the retrieval is far from that. Because Google Scholar is only able to show the first 1000 hits, we investigated whether the authors of 21 reviews that used google scholar would have identified every included reference if they had used only google scholar.

      Only 72% of all references would have been found, which is almost equal to the recall of PubMed (68%).

      Therefor Google Scholar should not be used alone in searching for Systematic Reviews.

      Not even with improved precision, because the factual precision (the number of hits found in the first 1000, divided by 1000) is not as problematic as when precision is calculated based on the (estimated) total number of hits, which very often is exeptionally high when searching Google Scholar.


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    3. On 2014 Mar 28, Farhad Shokraneh commented:

      I think the conclusion of the paper is not supported by the data. This study just shows that "If you KNOW that a paper ALREADY exist, you can find it in Google Scholar". So the authors have NOT used Google Scholar for searching for systematic review but just for re-finding the list of the papers have ALREADY found by other resources and included in the systematic reviews. The conclusion could be right just when the authors use GS for systematic searching and finding the relevant studies among search results. Also, the next time I think 'Google' gives the same coverage!


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    4. On 2014 Mar 31, M Felix Freshwater commented:

      The AMSTAR standard http://amstar.ca/Amstar_Checklist.php is 2 electronic sources. According to the Cochrane Handbook http://handbook.cochrane.org/ 6.2.1.3 Database overlap

      Of the 4,800 journals indexed in EMBASE, 1,800 are not indexed in MEDLINE. Similarly, of the 5,200 journals indexed in MEDLINE, 1,800 are not indexed in EMBASE. o www.info.embase.com/embase_suite/about/brochures/embase_fs.pdf


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    5. On 2014 May 21, Francesc Roig commented:

      From my point of view, according to the methodology of the study of Gehanno et col, and according to the results presented, they cannot affirm that "If the authors of the 29 systematic reviews had used only GS, no reference would have been missed". The only conclusion we could maintain would be something like "all references in the 29 systematic reviews selected were accessible through GS", but not that these references would be retrieved in a search with the objective to conduct the systematic reviews. As far as the study doesn’t compare search results in both engines (as other studies posted here actually do), it seems clear that you cannot maintain that results would be the same and then, you cannot maintain that using GS for the systematic reviews would produce the same results.


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    6. On 2014 May 27, Chris Hafner-Eaton commented:

      This study should be viewed as one "data pull" of 29 systematic reviews. In order to support the conclusions, the study must be replicated many times. It will be through repeated true positives (the sensitivity) with minimal false positives/maximizing the specificity or true negatives that we will come closER (although never declarative) to saying that Google Scholar "could be use alone for systematic reviews." As others have noted, PubMed doesn't capture all and yet it is entirely possible to pick up too much erroneous material--particularly in the grey literature and for certain review topics such as Comparative Effectiveness Reserach. However, one must always weigh the costs of being wrong versus being late with the results!


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    1. On 2013 Nov 09, Jonathan Moore commented:

      Very nice job to the team who made this. The prospects for integration of automated learning and literature-based curation of ontologies are great, and it looks like a useful tool for discovery - I'd like to try it in discovery mode with some other species with 'thin' ontology annotations.

      One thing I wondered about is the need for the hierarchical tree imposed at step one, and its effects on the final result. I wonder whether the tree-like requirement leads to the possibility of falling into a local optimum final graph, ending up with more of the initial tree-like structure than the data really suggest, rather than finding the optimum final graph from the true shape of the input data. The computational requirements for learning an arbitrary graph at step one seem daunting though.

      Maybe this could be part of the reason for the better match to GO for cellular components, which maybe tend to be more inherently hierarchical in comparison to molecular functions or biological processes.


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    1. On 2013 Oct 25, Stephen Turner commented:

      Two of the most common questions at the beginning of an RNA-seq experiments are "how many reads do I need?" and "how many replicates do I need?". This paper describes a web application for designing RNA-seq applications that calculates an appropriate sample size and read depth to satisfy user-defined criteria such as cost, maximum number of reads or replicates attainable, etc. The power and sample size estimations are based on a t-test that the authors claim performs no worse than the negative binomial models implemented by popular RNA-seq methods, such as DESeq {1}, when there are three or more replicates present. Empirical distributions are taken from either (1) pilot data that the user can upload; or (2) built-in publicly available data. The authors find that there is substantial heterogeneity between experiments (technical variation is larger than biological variation in many cases), and that power and sample size estimation will be more accurate when the user provides their own pilot data.


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    1. On 2015 Aug 27, Zhicheng Lin commented:

      The evidence that unconscious response inhibition emerges when subliminal stimuli are mixed with supraliminal stimuli (mixed session), but disappears when they are presented alone (single session) is unwarranted because the two types of session differ in a critical aspect: level of awareness (Lin and Murray, 2014). Indeed, when the level of awareness is comparable between sessions, there is no difference in unconscious response inhibition between the mixed and single sessions (Lin and Murray, 2015).

      Refs: Lin, Z., Murray, S. O. (2014). Priming of awareness or how not to measure visual awareness. Journal of Vision, 14(1), 1–17. Lin, Z., Murray, S. O. (2015). Automaticity of unconscious response inhibition: Comment on Chiu and Aron (2014). Journal of Experimental Psychology: General, 144(1), 244–254.

      Direct links to the refs: http://jov.arvojournals.org/article.aspx?articleid=2295565 http://psycnet.apa.org/journals/xge/144/1/244


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    1. On 2014 Dec 05, Dina Danso-Abeam commented:

      The discussion part of this article mentions 3 proposed modes of inheritance for Olmsted syndrome (OS). However, via exome sequencing, it is now known that the X-linked inheritance form of the disease has MBTPS2 (Membrane-bound transcription factor protease, site 2) as the pathogenic gene. The autosomal dominant form of OS has TRPV3 (transient receptor potential cation channel, subfamily V, member 3) as the pathogenic gene Lin Z, 2012. Recent study from Wang et al, actually challenges the existence of the X-linked form to be a true OS instead of being a severe form of IFAP (Itchyosis follicularis, alopecia, and photophobia) syndrome Wang HJ, 2014.

      References:

      1. Lin, Z. et al. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. American journal of human genetics 90, 558-564 (2012).

      2. Wang, H.J. et al. Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient. Clinical and experimental dermatology 39, 158-161 (2014).


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    1. On 2013 Jul 01, lu tian commented:

      The authors have made the timely call for moving beyond the traditional statistical analysis plan that “within the tried and true comfort zone for clinical acceptance and regulatory approval” in the setting of survival analysis with re-current events. In this case, the “comfort zone” is the so-called time to the first event analysis which is not only often underpowered but also completely fails to characterize the treatment effect beyond the first event. The true difficulty to go beyond the “comfort” zone is in summarizing the whole patient experiences during or after the treatment in an objective clinically meaningful way. For example, how to weigh the relative importance of non-fatal events compared with death? This is a difficult task and probably we will never be able to come up with a perfect consensus.

      However, the authors convincingly conveyed the message that albeit those difficulties, clinicians and statisticians need to be bold to go beyond the simple “time to the first event analysis” to address the clinical meaningful question which is to understand the treatment effects on entire disease burden characterized by both non-fatal and fatal events in this case. The initial solution may not be perfect but at least we should answer the right question.


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    1. On 2017 Feb 17, Donald Forsdyke commented:

      EPONYMS: "DM" FOR GENIC AND "WCB" FOR CHROMOSOMAL SPECIATION THEORIES

      The remarkable observations made in this outstanding paper have been well supported by subsequent studies (e.g. Moehring 2011; Forsdyke 2016). However, encompassing both genic and non-genic incompatibilities under the Dobzhansky-Muller rubric is regrettable. As described elsewhere (Forsdyke 2011), while William Bateson's term "epistasis" is used to describe interactions between genes, he himself espoused a non-genic "chromosomal" model for the initiation of the divergence of one species into two species. Thus, Bhattacharyya et al. (2013) correctly employ the eponymous acronym "DM" rather than the widely employed "BDM."

      Yet, they write that "several pieces of indirect evidence are in favor of D-M incompatibilities based on non-genic sequence divergence." This implies that Dobzhansky and Muller had non-genic viewpoints (which they did not). For those who like eponymous acronyms, some new form, relating to the history of the chromosomal viewpoint, would seem appropriate.

      Clear articulations of the chromosomal viewpoint trace back to the Danish "father of yeast genetics" Ojvind Winge, and were elaborated in the 1920s by Crowther and Bateson. Thus, it would seem appropriate that, while retaining "DM incompatibilities" for appropriate genic speciation theories, we introduce "WCB incompatibilities" for appropriate chromosomal theories. For further background please see Bateson Webpage.

      Bhattacharyya T, Gregorova S, Mihola O, Anger M, Sebestova J, Denny P, et al., (2013) Mechanistic basis of infertility of mouse intersubspecific hybrids. Proc Nat Acad Sci USA 110: E468–E477.Bhattacharyya T, 2013

      Forsdyke DR (2011) The B in BDM. William Bateson did not advocate a genic speciation theory. Heredity 106: 202.Forsdyke DR, 2011

      Forsdyke DR (2016) Evolutionary Bioinformatics, 3rd edn. Springer: New York.

      Forsdyke DR (2017) Speciation: Goldschmidt's chromosomal heresy, once supported by Gould and Dawkins, is again reinstated. Biol Theor (in press) doi: 10.1007/s13752-016-0257-z

      Moehring AJ (2011). Heterozygosity and its unexpected correlations with hybrid sterility. Evolution 65: 2621–2630.Moehring AJ, 2011


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    1. On 2014 Aug 09, Michael Cianfrocco commented:

      To view the UCSF Chimera session associated with this paper, you can download the .zip Chimera session from figshare

      If you use this Chimera session, please cite figshare!


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    1. On 2014 Jan 13, Brett Snodgrass commented:

      Grant described the vessels of Wearn in 1926.

      In 1929 Grant and Viko assessed hearts for the presence of the vessels of Wearn, but noted they were identified. The reason for this negative study is not entirely clear. It may be explained that some of the vessels of Wearn are greater than 10um but less than 40 um. 40um was the smallest lumen diameter of a vessel which the specific dye would enter.

      Vessels of Wearn identified by Grant in 1926:

      1. https://twitter.com/BrettSnodgrass1/status/420281076070637568

      For additional commentary and reference to Grant's 1929 study, please see:

      1. http://bit.ly/1929Grant

      2. http://scholar.google.com/scholar?cluster=5189678684113164458&hl=en&as_sdt=0,26&sciodt=0,26

      3. https://twitter.com/BrettSnodgrass1/status/410929217170206721

      4. http://bit.ly/ThebesianVeins

      5. http://bit.ly/vasaThebesii

      Comments and suggestions are welcome. If this comment is not helpful, please consider adding a comment about how it may be improved.

      Thank you kindly.


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    1. On 2013 Oct 31, John Cannell commented:

      The authors reported that immune system dysregulation is common in autism spectrum disorder (ASD”. Vitamin D deficiency produces very similar immune dysregulation.

      Prietl B, 2013

      < PMID:20119827>

      < PMID:23359064>

      < PMID:20427238>

      Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

      Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

      Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

      Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

      There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

      Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

      DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

      Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

      Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

      Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

      Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

      70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day and few toddlers or pregnant women get any sunshine due to the sun scare. As vitamin D fortified milk consumption and sun exposure has declined, so have toddlers and pregnant women’s vitamin D levels. The dramatic increase in the incidence of ASD occurred during the same time vitamin D levels were falling in toddlers and pregnant women.

      Cannell JJ. Autism, will vitamin D treat core symptoms? Medical Hypotheses. 2013 Aug;81(2):195-8. Cannell JJ, 2013

      Some autism researchers seem cognizant of the entire body of autism research. For example, a group of well-known European ASD researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into the vitamin D deficiency theory of ASD.

      Kočovská E, Fernell E, Billstedt E, Minnis H, Gillberg C. Vitamin D and autism: clinical review. Res Dev Disabil. 2012 Sep-Oct;33(5):1541-50. doi: 10.1016/j.ridd.2012.02.015. Epub 2012 Apr 21.Kočovská E, 2012

      Until all autism researchers become cognizant of the wider body of scientific research, we will continue to wonder how to prevent - and perhaps even treat - this modern day plague.

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


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    1. On 2013 Oct 31, John Cannell commented:

      The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

      Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

      Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

      Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

      Also, supplemental vitamin D significantly reduces oxidative stress in humans.

      Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

      Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

      Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

      Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

      Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

      Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

      There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

      Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

      DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

      Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

      Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

      Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

      Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

      70% of American toddlers do not take


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    1. On 2015 May 04, Peter Rogan commented:

      The Logic and Formulation of Exon Definition for Splice and Splicing Regulatory Sites with Negative Information Content. PK Rogan, EJ Mucaki

      Update on: Mucaki EJ, 2013 and the Automated Splice Site and Exon Definition Analysis server (ASSEDA).

      In Mucaki EJ, 2013, we described a method of predicting the overall strength of an exon by calculating its total information content (Ri,total) from the sum of the Ri values of its donor and acceptor splice sites, adjusted for their gap surprisal (the self-information of the distance between the two sites). Differences between ΔRi,total values are predictive of the relative abundance of these exons in distinct processed mRNAs.

      Splice sites altered by mutations that prevent stable interaction with splicesomes are said to be abolished. Information theory predicts abolition of binding below their minimum binding affinity, Ri,minimum, which is empirically derived. This value is slightly above zero bits, the theoretical minimum for binding at equilibrium (ΔG = 0; Schneider TD, 1997). Sites with Ri < 0 are not bound, forming stable interactions would be endergonic (ΔG > 0). This raises the question, when predicting the change in exon strength (ΔRi,total) due to a mutation that inactivates binding, whether mutant sites with varying degrees of negative information content are energetically distinguishable from one another.

      The computation of Ri,total contains the sum of the the Ri values of component binding sites, irrespective of their initial or final strengths. Thus, a mutated site with Ri << 0 would result in greater ΔRi,total compared to a site with Ri ~ 0. To assess whether the degree of unfavorable binding should be applied to the exon definition calculation, or if values below 0 bits should be computed similarly to a binding site at equilibrium (Ri ~ 0), we reevaluated experimentally validated natural and regulatory splicing mutations in our paper with both approaches. Ri,total was calculated for 10 variants from Supplementary Table 2, both including and excluding the negative information (ie. Ri < 0 vs. Ri = 0) of inactivated splice sites. Mutation #2 of Supplementary Table 2 [ADA:g.43249658G>A] abolishes a natural donor site, from 8.8 to -9.9 bits. In applying the full decrease in strength (ΔRi,total: -18.7 bits), the natural exon strength decreases from 21.0 to 2.3 bits. When the negative information content is set to zero bits, the change is significantly smaller (21.0 -> 12.2 bits; ΔRi,total = -8.8 bits). When a weak natural splice site is abolished, the difference as expressed as ΔRi,total can be quite small (Mutation #9; -14.8 vs -3.1 bits). In the case of Mutation #38, the reduction in ΔRi,total leads to a partially discordant prediction where the abolished natural exon is weaker than the experimentally confirmed activated cryptic exon. Results for this mutation were concordant with the published version when the negative bit value of the mutated natural site was included in the calculation.

      The impact of mutations in splicing regulatory (SR) factors can also be predicted on ASSEDA, where the Ri of the SR binding site is added to the R_i,total, as well as a secondary gap surprisal value for the particular SR protein. These sites can also be abolished. But when a SR protein binding site is no longer active, should the SR gap surprisal still be applied, or is the SR gap surprisal no longer applicable?

      We tested mutations from Mucaki EJ, 2013 (Supplementary Table 4), which abolish the splicing enhancer SF2/ASF with and without the SR protein gap surprisal when Ri of the SR site is < 0 bits. The removal of the gap surprisal term for Mutation #2 of Supplementary Table 4 leads to a discordant prediction, where the ΔRi is less than the SR gap surprisal at that distance and therefore the ΔRi,total is positive. As experimental evidence shows an increase in skipping, it is a discordant prediction. Therefore, the gap surprisal is still applied in the computation of both initial and final Ri,total values when the SR protein of interest is abolished as the site is naturally present and therefore expected for binding. Conversely, when we apply the gap surprisal to the initial Ri,total for a splicing factor that is being created, we are essentially applying a penalty for a site that does not normally exist. Therefore, we no longer apply the SR gap surprisal value to the initial Ri,total in these cases.

      The revised Ri,total values of SR binding site mutations slightly differ from those reported in Mucaki EJ, 2013 (Supplementary Table 4). This is because the gap surprisal distributions were recomputed for the following factors: SF2/ASF, SC35 and SRp40, with updated versions of these models based on CLIP Seq data (Blin K, 2015, Khorshid M, 2011). This resulted in small changes to the distributions for SF2/ASF and SC35, however changes for SRp40 were significant, and now more closely resembles the other gap surprisal functions. The updated graphs of distance vs. gap surprisal are available at: http://splice.uwo.ca/gapsurprisals.html. While this should not significantly affect ΔRi,total values, it may affect the initial and final Ri,total values.


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    1. On 2014 May 06, Madhusudana Girija Sanal commented:

      Dr. Norman is picturing the great progress in education as a result of the information distribution revolution as if it is an ‘unavoidable evil’! Probably, many of his generation expresses high inertia, still consider, 'physical' universities, libraries, books, lecture halls etc. very much essential! I understand their nostalgia! You know what this means for humanity? Rich countries such as USA hold only a small fraction of the world’s population. Through virtual universities more and more people across the world, irrespective of rich and poor, would be able to attend the best schools and courses. They would be able to take the same exams and get ranked along with the most privileged, rich or intelligent. This would be great! This is 'new' justice! (Although I believe “Justice is ‘man made’ or artificial”). All we want is better tools to evaluate human intellectual qualities, online. I do not think face to face lectures will be better than online recorded, interactive lectures, may be multidimensional (3D-4D-5D) lectures by several professors of the learner’s choice. Lectures will be ranked and paid by based on their quality by student communities and not by bureaucrats or by administrators and politicians. This system is great especially when I consider the advantages! On demand, personalized lectures would be "ready-made" for commonly observed (student) personality traits -say there are 100 personality subtypes and intellectual levels! Custom lectures are available for them all because there are much more people to teach online-lectures need not be real time. You can learn from a "personality" who matches your rare personality, perhaps, one who lived 10 years back. His lectures had to wait for ten years for a student like you! Is not this a very exciting possibility? However, I do agree that face to face lectures can be more individualized and beneficial (for the rich, because they only have money to ‘buy’ good teachers!) Nevertheless, I do not think there is a huge benefit for extreme personalization except for exceptional children who are extremely out-of-the-box in a positive or negative way. It may be, however, noted that overall poor but brilliant students have a better opportunity to come out and stand before the world. This global free learning system will benefit specially those brilliant minds in less privileged countries. Do Dr. Norman has any evidence to support his statements in the editorial? I do not know what Dr. Norman will write if tomorrow we find a new technology which allows direct transmission of knowledge to brains! Then what will happen? Think! Everyone will have equal opportunity to accumulate the same amount of information if he or she wants. Now who will win this game? Those who have money? Probably not! Those fractions of the society who are blessed with right genome, epigenome and the best neural connections!


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    2. On 2014 May 09, Chandan Kumar commented:

      Is there a middle ground between Dystopia and Utopia?! May be the real, organic world, with or without the internet driven education system. Methinks, as well as the brick and mortar business has survived, nay thrived in an internet world, so the academic community has and will- if for no other reason, than that Education is Big Business!


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    1. On 2013 Nov 01, Casey M Bergman commented:

      In reviewing the location of P-element insertions in the human genome reported in Table 1 of Majumdar S, 2013, we noticed that the sequences of the P-element target site duplications reported in the paper did not correspond to the sequences observed in the GRCh37/hg19 version of the human genome sequence available at the UCSC Genome Browser.

      To resolve this discrepancy, we obtained the original data and methods used to generate the genomic coordinates reported in Table 1 from the authors. Sequence data for integration events catalyzed by the P-element transposase or THAP9 that were mapped from both the 5’ and 3’ end of the P-element insertions are as follows (target site duplication shown in capitals, posted with permission of the authors):

      Drosophila P-element Transposase

      ctacaaggatgccaagggctgtttcttcagcatggtggGTGGCCATatgtaagcaggtgtgcacacatgtgggcacatgtgctgcat cttgaatgagagctgtgattgttagtgatgtccaggtatgtGTCTGCCAtctcagagtgaccctgagaaaggcattcatttggaagctt tgtttcctgactttgctgtGTGTTCGAtcgtctgttttcaaagtgggatcattagttatgaaggaagatttttcatgaa tttctttccttgtctctgagacgccactttctcctggctctccttctttccgtcggTCTGCCTTttgctctccttttctggttccgtctcacca cgagccactggtggggctcctgccacctccacactgGTCGGCCTcggccacctccacgcctcagggatggggcgcgcgtgccc tctcagtagataatgaggatcactgcagatggcatgatatttagcagactacGGATCTCGagcagtcatccaggatctcaacagtgg

      Human THAP9

      gtggcgtgatcccagctcactgcaaccTCGGCCTGctcggcttaagtgatcctttcacctcagcttctcaagtagctgggactacag ccctgtccctgtgagtgatgttcccttgttgttccaGTCTCTCTtctctggtcaggaaggtaccactcaatccagggctttctcctggttt gaacttccccagtgagggcctGTGTCTGCattcaggagtgagagtttccccaggagaggagactgaaaagacctgggaaggcaa ccactggactccagcctgggcgacagagcgaTACGTCTCataaaaataaataaataaaacagaaacttaacacaattaaatgactg ataaagaggaatttgtttctccacaccacaaggcctttGTGCGAAGgtgactgtgtgtgtcaacgtcagacagtccctctttctgggag ttaaatgaggttgttagggtggtccatcattcaacatgactgcGGTCGTCCtaacgacaggaaatttgggccccagagacagacac

      Using these data, we were able to reproduce the majority of the authors’ results in Table 1 using the default settings of the BLAST service at NCBI for the GRCh37/hg19 version of the human genome in September 2013. However, the same sequence data yielded different coordinates when mapped to either the UCSC Genome Browser (using default BLAT settings) or the Ensembl Genome Browser (using default BLAST settings), with consistent genomic coordinates being reported by both UCSC and Ensembl.

      Based on empirical observation and through correspondence with Dr. Deanna Church at NCBI, we learned that results for the organism BLAST service at NCBI prior to mid-September 2013 defaulted to local (scaffold) not global chromosome ("top level") coordinates. Thus, the coordinates of the P-element insertions reported in Table 1 of Majumdar S, 2013 do not accurately reflect the exact location of integration on global chromosomal coordinates.

      Based on our re-analysis, the chromosomal location of target site duplications for P-element insertions in the human genome are as follows (GRCh37/hg19, 0-based coordinates):

      chrom start end strand

      chr17 5024087 5024095 +

      chr20 16619371 16619379 +

      chr21 17382446 17382454 +

      chr11 122102746 122102754 +

      chr3 61550440 61550448 +

      chr9 25178151 25178159 +

      chr14 87818626 87818634 +

      chr11 72875900 72875908 +

      chr11 79446804 79446812 -

      chr15 55619023 55619031 +

      chrX 17150535 17150543 +

      chr11 11291642 11291650 +

      As a consequence of this interchange, NCBI have now updated the default behavior of their organism BLAST service to report global (scaffold) chromosome coordinates, as reported in the 17 Oct 2013 BLASTFeed update.

      We thank the authors for making their raw data available and Deanna Church and others at NCBI to help resolve this issue, and thank the authors and Deanna Church for reviewing this comment before posting.

      Sincerely,

      Casey Bergman

      Raquel Linheiro


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    1. On 2016 Aug 23, Ben Goldacre commented:

      One of the trials in this article 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 NCT003766090. We believe the correct ID, which we have found by hand searching, is NCT00376090.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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


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    1. On 2013 Oct 23, Andrew R Kniss commented:

      Although this paper provides necessary toxicity data on some common pesticides, the extension of that data to causing global amphibian decline is quite a leap (pun intended). Toxicity alone does not equal risk, and this paper (and many they cite) provide little information on the exposure aspect of risk. The authors also fail to provide context about other risks amphibians may face in the absence of pesticide use. If pesticides are removed, pests would still need to be controlled in agricultural fields. Those other pest management practices may be equally likely to harm amphibians. More information about the proper context for this study here.


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    1. On 2014 May 27, Irving I. Gottesman commented:

      Scholars interested in a deep understanding of the complex etiology of ASD can find no better starting point than the perspective provided by Stein, Parikshak, & Geschwind and the citations they invoke to support their data-informed views.Uninformed pontifications in our field of inquiry are all too common. No one said it should be easy. Their perspective can be generalized to other complex psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, and even suicide.


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    1. On 2016 Feb 05, Kristina Hanspers commented:

      The pathway in Figure 3b is available in the "Open Access Publication" Collection at WikiPathways: http://wikipathways.org/index.php/Pathway:WP3300. This pathway can be used for network analysis in tools like Cytoscape and PathVisio.


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    1. On 2016 Feb 21, Torsten Skov commented:

      The main conclusions of the paper are not founded in the data but rather in the theory which the data was set to test. To show this, I have revisited the five studies which are being reported in the paper and pinpointed a number of methodological issues which limit the conclusions that can be drawn, please see the file

      https://dl.dropboxusercontent.com/u/2053425/Reviewofwhodeserveshelpv6.pdf

      In summary, the analysis and interpretation of the WVS data is flawed and strongly biased towards the authors’ preconceived theory. Study 2 does not address the effect of instincts on welfare opinion but this does not prevent the authors from drawing conclusions from it about this relation. Study 1 is invalidated by the findings of Study 2. The limitations of cross-sectional designs are either unknown to the authors or are being ignored. Causal direction is assumed rather than demonstrated. Basic theoretical concepts are used inconsistently. In the end, no empirical evidence relating to the political psychology aspects of the article, the translation of the instinctive reactions to political welfare opinion, holds up.


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    1. On 2016 Apr 30, Morten Oksvold commented:

      Please be aware that this article represents one of eleven publications which were found to contain false data, after an investigation lead by ORI in 2015:

      https://ori.hhs.gov/content/case-summary-dasmahapatra-girija


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    1. On 2014 Aug 27, Ryan Radecki commented:

      Post-publication commentary:

      "The Latest Myth: Contrast-Induced Nephropathy?"

      Here’s the simple explanation for why none of our observed treatments to prevent contrast-induced nephropathy – acetylcysteine, hydration, sodium bicarbonate – reliably work: CIN is a myth.

      There’s a lot of observational literature evaluating the incidence of mild acute-kidney injury after iodinated contrast exposure – either CT scans or vascular procedures – and every study shows some increase in serum creatinine in a small, but significant, proportion of patients. But, as this study suggests, is this just random effects, a confounder from co-occurring medical illness, or true dose-dependent renal injury?

      http://www.emlitofnote.com/2013/12/the-latest-myth-contrast-induced.html


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    1. On 2013 Oct 29, Tom Kindlon commented:

      Changes to the recovery criteria have not improved their validity

      When one publishes a protocol for a trial, as the PACE Trial investigators have done (White et al. 2007), there needs to be compelling reasons to deviate from it (Evans, 2007). White et al. (2013) claim that the revised recovery definition is conservative, with the changes being made to "more accurately reflect recovery". Is this true with regard to the Chalder Fatigue Questionnaire (CFQ) and SF-36 physical functioning (SF36 PF) criteria?

      The new CFQ criterion, a score of 18 or less (Likert scoring), was chosen because it represented the mean plus 1 standard deviation in a community sample (Cella & Chalder, 2010). The CFQ scores were not normally distributed but we know that only 13.6% of the sample scored higher than 18. However, it does not follow that this threshold represents a reliable cut-off for fatigue-caseness as fatigue problems are common in the general population. For example, in the paper the authors referenced when discussing symptoms in the general population (McAteer et al. 2011), 41.3% reported “feeling tired/run down” while 23.1% of a representative sample of the Norwegian population had high levels of fatigue (Lerdal et al. 2005). That is to say, it is quite possible that more than 13.6% of the sample in Cella & Chalder (2010) were experiencing significant fatigue problems.

      The recovery criteria described in the protocol require a score of 3 or less (bimodal scoring) which is a validated definition for the absence of fatigue (Chalder et al. 1993). Although exact translation between Likert and bimodal scores is not possible, it can be shown that such a score is stricter than the new criteria because it translates to a Likert score between 6 and 17. Therefore, when compared against the established definition of fatigue-caseness, a Likert score of 18 always indicates the presence of abnormal levels of fatigue.

      Furthermore, the trial's entry criterion for fatigue, a CFQ bimodal score of 6 or higher, translates to a Likert score between 12 and 23 meaning that participants could have baseline scores which were already 18 or less so that no improvement was required for them to recover according to the new criteria. Indeed, 17.6% of patients diagnosed with CFS at the Chronic Fatigue Unit at the South London and Maudsley NHS Trust had scores of 18 or less on the CFQ before treatment for their fatigue.

      For SF-36 PF scores, the protocol required a score of ≥85 for recovery, whilst the newer criteria require a score of ≥60. Again, participants could score 60 or more at baseline which suggests the new criterion is neither conservative nor "more accurately reflects recovery".

      Also, while I have not undertaken an exhaustive search, in all the other trials that I am aware of that used the SF36 PF to operationalize CFS criteria, a score of 60 would have been sufficiently low to meet each trial's requirements for a diagnosis of CFS (e.g. Stulemeijer et al. 2005; Tummers et al. 2012; van't Leven et al. 2010; Wearden et al. 2010).

      White et al. (2013) used the formula of mean minus one standard deviation (sd) from data on the UK general population from Bowling et al. (1999) to derive the threshold of SF-36 PF ≥60. However, CFS is not unique in causing reductions in this domain, with Bowling et al. noting that 22% in the same survey reported a long-term health problem while 16% reported having an acute illness. Moreover 28.6% were aged 65 or more; population norms from these age groups are of questionable relevance to the PACE Trial cohort (mean (sd) age at baseline: 38 (12)).

      In summary, the CFQ and SF-36 PF criteria that constitute White and colleagues' new definition of recovery have been revised such that they are less strict than those contained in the published protocol. These changes suggest that it is not safe to conclude that the new criteria are either conservative or more accurately reflect recovery than those published in the trial's protocol.


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    2. On 2014 Apr 28, Tom Kindlon commented:

      Easy-to-understand video criticising the (adjusted) recovery definition:

      A former mathematics teacher has made an easy-to-understand video explaining and criticising the PACE Trial's recovery criteria:

      http://youtu.be/d_7J5ELjArU


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    3. On 2014 Sep 20, Tom Kindlon commented:

      Letter published criticising aspects of the PACE Trial recovery paper and criteria:

      Kindlon T, Baldwin A. Response to: reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evid Based Mental Health doi:10.1136/eb-2014-101961 http://ebmh.bmj.com/content/early/2014/09/19/eb-2014-101961.extract


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    4. On 2015 Oct 23, Lily Chu commented:

      For a critique of the PACE trial and papers related to it, see:

      http://www.virology.ws/2015/10/21/trial-by-error-i/


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    5. On 2016 Feb 15, Sam Carter commented:

      Exploring changes to PACE trial outcome measures using anonymised data from the FINE trial.

      When the results of the PACE trial were published (1, 2) it was noted that the primary outcome measures and the definition of "recovery" described in the trial's published protocol (3) had been abandoned and replaced with markedly less stringent criteria.

      The fully anonymised data set from the FINE trial(4), considered to be the PACE trial's "sister" study, makes it possible to explore how these changes may have affected the reported efficacy of the PACE trial's interventions.

      At week 20 (assessment 2), 18 FINE trial participants met PACE trial post-hoc recovery thresholds (SF36 PF ≥ 60 and CFQ Likert ≤ 18) compared to only 3 participants who met the stricter, protocol-defined recovery thresholds (SF36 PF ≥ 85 and CFQ bimodal ≤ 3). Therefore, at assessment 2, the post-hoc changes increased the "recovery" rate by a factor of 6.

      By week 70 (assessment 3), between 10 and 12 of the original 18 had relapsed so that they no longer met the post-hoc recovery thresholds (data are missing for two participants). Such a high rate of relapse within a year shows that the post-hoc recovery thresholds, said to represent a "strict criterion for recovery" in a Comment (5) which accompanied the original publication of PACE trial results, are neither strict nor reliable indicators of sustained wellbeing.

      Regarding the Chalder fatigue questionnaire, White et al wrote that "we changed the original bimodal scoring of the Chalder fatigue questionnaire (range 0–11) to Likert scoring to more sensitively test our hypotheses of effectiveness" (1). However, data from the FINE trial show that Likert and bimodal scores are often contradictory and thus call into question White et al's assumption that Likert scoring is necessarily more sensitive than bimodal scoring.

      For example, of the 33 FINE trial participants who met the post-hoc PACE trial recovery threshold for fatigue at week 20 (Likert CFQ score ≤ 18), 10 had a bimodal CFQ score ≥ 6 so would still be fatigued enough to enter the PACE trial and 16 had a bimodal CFQ score ≥ 4 which is the accepted definition of abnormal fatigue.

      Therefore, for this cohort, if a person met the PACE trial post-hoc recovery threshold for fatigue at week 20 they had approximately a 50% chance of still having abnormal levels of fatigue and a 30% chance of being fatigued enough to enter the PACE trial.

      A further problem with the Chalder fatigue questionnaire is illustrated by the observation that the bimodal score and Likert score of 10 participants moved in opposite directions at consecutive assessments i.e. one scoring system showed improvement whilst the other showed deterioration.

      Moreover, it can be seen that some FINE trial participants were confused by the wording of the questionnaire itself. For example, a healthy person should have a Likert score of 11 out of 33, yet 17 participants recorded a Likert CFQ score of 10 or less at some point (i.e. they reported less fatigue than a healthy person), and 5 participants recorded a Likert CFQ score of 0.

      The discordance between Likert and bimodal scores and the marked increase in those meeting post-hoc recovery thresholds suggest that White et al's deviation from their protocol-specified analysis is likely to have profoundly affected the reported efficacy of the PACE trial interventions.

      An independent re-analysis of anonymised PACE trial data as described in its published protocol is urgently required to quantify the effects of the revised outcome and recovery criteria.

      References

      (1) White PD et al (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet Mar 5;377(9768):823-36.<br> (2) White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M (2013) Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. Oct;43(10):2227-35.<br> (3) White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R (2007) Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol Mar 8;7:6.<br> (4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685991/bin/pone.0144623.s002.dta<br> (5) Bleijenberg G, Knoop H. (2011) Chronic fatigue syndrome: where to PACE from here? Lancet. Mar 5;377(9768):786-8.


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    6. On 2016 Mar 31, Lily Chu commented:

      Dr. Rebecca Goldin of STATS.org, connected to the American Statistical Association, recently published a critique of this paper at the link below:

      http://www.stats.org/pace-research-sparked-patient-rebellion-challenged-medicine/


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    7. On 2016 Sep 27, Alem Matthees commented:

      A preliminary re-analysis of ‘recovery’ in the PACE trial based on the published protocol

      Much has been written about the problems with the revised recovery criteria in the PACE trial and the poorly or erroneously justified deviations from the published protocol after the trial was over. There have been calls for a re-analysis of recovery using the protocol-specified recovery criteria. While a formal publication is still pending, a preliminary re-analysis of 'recovery' using individual participant data has recently been released on Virology Blog [1].

      http://www.virology.ws/2016/09/21/no-recovery-in-pace-trial-new-analysis-finds/

      Summary: The PACE trial tested interventions for chronic fatigue syndrome, but the published ‘recovery’ rates were based on thresholds that deviated substantially from the published trial protocol. Individual participant data on a selection of measures has recently been released under the Freedom of Information Act, enabling the re-analysis of recovery rates in accordance with the thresholds specified in the published trial protocol. The recovery rate using these thresholds is 3.1% for specialist medical care alone; for the adjunctive therapies it is 6.8% for cognitive behavioural therapy, 4.4% for graded exercise therapy, and 1.9% for adaptive pacing therapy. This re-analysis demonstrates that the previously reported recovery rates were inflated by an average of four-fold. Furthermore, in contrast with the published paper by the trial investigators, the recovery rates in the cognitive behavioural therapy and graded exercise therapy groups are not significantly higher than with specialist medical care alone. The implications of these findings are discussed.

      Update 1:

      When asked about the re-analysis for an article in The Times, Professor Peter White (lead PACE trial investigator) did not dispute the methodology of the re-analysis, but added that the argument was about the definition of recovery. He stated: "We thought people who rated their health as 'much better' or 'very much better' should be included. They used 'very much better'." [2]

      We used the recovery criteria as established by Prof. White and colleagues in the published PACE trial protocol. However, including those who rated themselves "much better" makes little difference to the number of participants classified as recovered when using the other protocol-specified recovery criteria, even when imputing the missing participant-rated CGI scores with doctor-rated scores, which tend to be more optimistic than the participant-rated scores: SMC, 5 to 6; APT, 3 (unchanged); CBT, 11 to 13; GET, 7 to 9. Our conclusion remains the same, no therapy group has a (statistically) significantly higher rate of recovery than for SMC alone, for either intention-to-treat or available-case. Almost all the participants who rated themselves "much better" failed to meet the remaining protocol-specified recovery criteria.

      The comment from Prof. White does not address the major changes to other criteria. The revised "normal range" for fatigue and physical function overlaps with trial eligibility criteria for severe disabling fatigue, whereas previously there was a significant gap. Not meeting Oxford CFS criteria in the revised recovery criteria is not what it sounds: participants were counted as not meeting Oxford CFS criteria if they had a CFQ (bimodal) fatigue score of less than 6 or a SF-36 physical function score of more than 65, irrespective of whether they still met Oxford CFS criteria or not. Approximately half of those who 'no longer met Oxford CFS criteria' according to the revised recovery criteria still actually met Oxford CFS criteria. Feeling "much better" is not necessarily the same as recovered and can be a result of changes not relating to fatigue or physical function. None of the revised recovery criteria, alone or combined, convincingly reflect being recovered. Over one-third meeting all the revised recovery criteria still met Oxford CFS criteria.

      Contrary to the impression given by Professor George Lewith's statement for The Times [2], we did not "torture the data until it proves what they believe", we followed the published PACE trial protocol before it was changed after the trial was over, and we made this clear in our article. While the article in The Times states that Prof. Lewith was not involved in the original research, perhaps it should be noted that he has co-authored a paper with the co-principal PACE trial investigators using PACE trial data [3].

      Individuals who defended the revised PACE trial recovery criteria, including in the UK House of Lords [4], argued that the results were impressive or meaningful because it means no longer having CFS. Unfortunately, the PACE trial data shows or confirms that these people have been misled.

      Update 2:

      In an article in The Guardian, Prof. White asserts that "The authors got their figures by tweaks such as increasing the pass-grade for what counted as recovery, and excluding patients who had reported themselves as 'much better'." [5]

      This implies that we fiddled with the recovery criteria to get the results we wanted. That is false and misleading; again, we simply used the thresholds established by Prof. White himself (and colleagues) in their own published trial protocol, before they changed it after the trial was over. Furthermore, counting "much better" towards recovery makes no significant difference to the results; CBT and GET still do not significantly increase recovery rates.

      References

      1) Matthees A, Kindlon T, Maryhew C, Stark P, Levin B. A preliminary analysis of ‘recovery’ from chronic fatigue syndrome in the PACE trial using individual participant data. Virology Blog. 21 September 2016. http://www.virology.ws/wp-content/uploads/2016/09/preliminary-analysis.pdf

      2) Whipple T. Exercise and therapy cure for ME is 'seriously flawed'. The Times. 28 September 2016. http://www.thetimes.co.uk/article/b0c9d588-84d8-11e6-9270-cf26736cb244

      3) Lewith G, Stuart B, Chalder T, McDermott C, White PD. Complementary and alternative healthcare use by participants in the PACE trial of treatments for chronic fatigue syndrome. J Psychosom Res. 2016 Aug;87:37-42. doi: 10.1016/j.jpsychores.2016.06.005. Epub 2016 Jun 10. PMID: 27411750.

      4) PACE Trial: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. House of Lords Hansard. Volume 743. 06 February 2013. https://hansard.parliament.uk/Lords/2013-02-06/debates/130206114000195/PACETrialChronicFatigueSyndromeMyalgicEncephalomyelitis

      5) White P. If my team’s research on ME is rejected, the patients will suffer. The Guardian. 30 September 2016. https://www.theguardian.com/commentisfree/2016/sep/30/me-chronic-fatigue-syndrome-patients-suffer-put-off-treatments-our-research


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    8. On 2017 Nov 25, Tom Kindlon commented:

      More data demonstrating why the SF-36 physical functioning threshold of 60+ is problematic

      The PACE trial's principal investigators (PIs) argue that scores of 60 or higher on the SF-36 physical function subscale (SF-36 PF) fall within the "normal range" and use this threshold as one component of their revised definition of recovery from Chronic Fatigue Syndrome (CFS), as well as a post hoc measure in the main PACE trial paper[1,2].

      Referring to the normal ranges for physical function and fatigue used in the PACE trial, one of the trial's PIs, Trudie Chalder, stated that “twice as many people on graded exercise therapy and cognitive behaviour therapy got back to normal”[3]. This same terminology, "back to normal", was also used by the PIs in a patient information leaflet[4].

      The use of this phrase, which implies full restoration of health, merits closer scrutiny following publication of a new paper containing data from CFS patients assessed at one of the PACE trial's treatment centres, the Chronic Fatigue Research and Treatment Unit in London, UK, between November 2007 and January 2014[5].

      The paper, whose corresponding author is Trudie Chalder, reports that 39.6% of the patients diagnosed with CFS (228/576) had SF-36 PF scores of more than 60; i.e, despite having a score within the normal range, they were judged as sufficiently disabled to be diagnosed with CFS. Note that the data given were for more than 60 on the SF-36 PF so the figure for 60 or more would likely be higher again.

      Moreover, Dutch researchers recently reported that 39% of patients with CFS had SF-36 PF scores of 65 or higher[6], and in the PACE trial itself patients could start with a SF-36 PF score of 65 at baseline[7]. Also, as we reported in a reanalysis of the PACE Trial data, in a large British community sample 90% of people aged 18–59 without a long-term illness or disability actually score 90 or higher[8].

      Taken together, these data suggest that the derived normal range threshold for physical function is too low to serve as a meaningful indicator of recovery and does not, in fact, represent getting "back to normal".

      References:

      1 White PD1, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011; 377: 611–690

      2 White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013;43(10):2227–2235.

      3 Boseley, S. Study finds therapy and exercise best for ME. The Guardian. Feb 18, 2011 https://www.theguardian.com/society/2011/feb/18/study-exercise-therapy-me-treatment

      4 PACE participants newsletter 4. February 2011. http://www.wolfson.qmul.ac.uk/images/pdfs/participantsnewsletter4.pdf

      5 Ryan EG, Vitoratou S, Goldsmith KA, Chalder T. Psychometric properties and factor structure of a shortened version of the Cognitive Behavioural Responses Questionnaire (CBRQ). Psychosom Med. 2017 Oct 10. doi: 10.1097/PSY.0000000000000536. [Epub ahead of print]

      6 Janse A, Nikolaus S, Wiborg JF, Heins M, van der Meer JWM, Bleijenberg G, Tummers M, Twisk J, Knoop H. Long-term follow-up after cognitive behaviour therapy for chronic fatigue syndrome. J Psychosom Res, 2017. doi: 10.1016/j.jpsychores.2017.03.016.

      7 White, PD, Sharpe, MC, Chalder, T et al. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007; 7: 6

      8 Wilshire CE, Kindlon T, Matthees A, et al. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue. 2017;5:1–4.


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    1. On 2014 Aug 11, Dr. Priyanka. M Jadhav commented:

      Ayurveda: science beyond scepticism and snake oil

      Priyanka M. Jadhav, Research Scientist

      Maharashtra University of Health Sciences

      Comment on: Ayurvedic medicine offers a good alternative to glucosamine and celecoxib in the treatment of symptomatic knee osteoarthritis: a randomized, double-blind, controlled equivalence drug trial

      Sir, This is the age when the concept of remote surgery does not surprise us, but we are not prepared to accept a concept that has existed and survived for centuries—the science of Ayurveda. I read with great interest the study published by Chopra et al. and am excited that the New Millennium Indian Technology Leadership Initiative (NIMTLI) project set up with an interdisciplinary approach is evaluating traditional and Ayurvedic drugs in clinical trials for treatment of osteoarthritis[1]. It is interesting to see how modern medicine approach is being used to study the effect of an Ayurvedic medicine assessed by a series of experiments [2–4]. The acceptance of Ayurveda or any other traditional system of medicine in western medicine is low; however, what causes frustration are the allegations and misinformation being promoted.

      Recently, a a letter was published in which the author termed Ayurveda as quackery.[5] Patients and the next generation who aspire to find a cure and career in this age-old science find such information as very misleading and confusing. On the other hand, many other journals are documenting the reports on the study of these drugs.

      The National Center for Complementary and Alternative Medicine clearly states the lack of randomized controlled clinical trial for complementary and alternative medicines and a need to build evidence-based datab to assess the plausibility of claims[6].

      As an Ayurvedic practitioner, I welcome such suggestions and efforts, which are more than mere dismissal of age-old science. Although the current research and published papers concentrate on the extracts of plants, the point of holistic treatment is lost. As many scientists use extracts, the pressure of using purified extracts in studies is very high. Any researcher who proposes to work on a whole medicinal plant not only faces technical difficulties but also pressure from the scientific community, which again steers them to use purified extracts. Negative results of many experiments are not even published.

      NMITLI arthritis project is one such attempt to translate the language of traditional medicine in a way that the western world can understand. In doing so, the scientists involved are those who are experts in their field and have done their best to generate data from in vitro and human studies. Moreover, one can also argue that Ayurveda treats a patient not only by medicine but also by other methods such as application of oil, hot fermentation, purgation, etc., which varies for each patient depending on their prakruti or constitution.[7] If one aims to study these medicines, a novel and innovative approach or a fresh perspective is needed when designing a suitable trial. [8]

      More such studies as the one done by Chopra et al. should be done. Such studies will focus on chronic and infectious diseases, which are of grave concern not only for the developing or resource-poor countries but also for the developed world too. These medicines may form a good alternative, if not a substitute, for modern medicine that has mild to severe adverse effects particularly for chronic diseases. In a way, this study may be a base to prove to the funding agencies and other organizations that natural products can be just as effective as modern ones.

      Some very important issues to be addressed are whether we are prepared to accept a concept riddled with prejudice or embrace one used by billions for their good for centuries.

      References

      1 Chopra A, Saluja M, Tillu G et al. Ayurvedic medicine offers a good alternative to glucosamine and celecoxib in the treatment of symptomatic knee osteoarthritis: a randomized, double-blind, controlled equivalence drug trial. Rheumatology 2013. doi: 10.1093/rheumatology/kes414. First published online: January 30, 2013.

      2 Chopra A, Saluja M, Tillu G et al. Evaluating higher doses of Shunthi - Guduchi formulations for safety in treatment of osteoarthritis knees: a Government of India NMITLI arthritis project. J Ayurveda Integr Med 2012;3:38-44.

      3 Chopra A, Saluja M, Tillu G et al. A randomized controlled exploratory evaluation of standardized ayurvedic formulations in symptomatic osteoarthritis knees: a government of India NMITLI project. eCAM 2011;2011:724291.

      4 Sumantran VN, Kulkarni A, Chandwaskar R et al. Chondroprotective potential of fruit extracts of Phyllanthus emblica in osteoarthritis. Evidence-based complementary and alternative medicine : eCAM 2008;5:329-35.

      5 O'Cathail S, Stebbing J. Ayurveda: alternative or complementary? Lancet Oncol 2012;13:865.

      6 Briggs JP. NIH. Turning discovery into health? Available from: http://nccam.nih.gov/about/offices/od/2011-06.htm (17 April 2013, date last accessed).

      7 Dieppe P, Marsden D. Managing arthritis: the need to think about whole systems. Rheumatology 2013.doi: 10.1093/rheumatology/ket127 First published online: March 7, 2013.

      8 Patwardhan B. Ayurveda GCP guidelines: need for freedom from RCT ascendancy in favor of whole system approach. J Ayurveda Integr Med 2011;2:1-4.

      Conflict of Interest: None declared

      Published July 9, 2013 http://rheumatology.oxfordjournals.org/content/52/8/1408.long/reply#rheumatology_el_105


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    1. On 2014 Jun 09, Jake Chen commented:

      This is the first article that showed how to use multi-scale network models to classify breast cancer subtypes using noisy proteomics data. The method can be applicable to other disease classification applications.


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    1. On 2016 Dec 15, M Mangan commented:

      This paper is being used by nonsense peddlers to suggest that GMO insulin is harmful to people, and to scare people away from proper treatment for diabetes. Please see this piece for some guidance on this issue: http://kfolta.blogspot.com/2014/06/when-liars-cross-line-gmo-insulin.html

      Edit to add: another science blogger has taken this on now as well. http://theness.com/neurologicablog/index.php/abusing-science-you-dont-understand/


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    1. On 2014 Jan 12, Om Prakash commented:

      This CBT model appears useful in patients with Dhat syndrome.


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    1. On 2014 Jan 31, George W Hinkal commented:

      The National Cancer Institute has been investing in the development of an online webportal of curated cancer nanotechnology data called caNanoLab. The numerical data and additional nanomaterial characterizations related to this publication have been added to the database and can be found at:

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39649280&page=0&tab=ALL

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39649281&page=0&tab=ALL

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39649282&page=0&tab=ALL

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39649283&page=0&tab=ALL

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39649284&page=0&tab=ALL

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39649285&page=0&tab=ALL

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39649286&page=0&tab=ALL

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39649287&page=0&tab=ALL

      The left navigation links on these pages provide information about each sample (under Navigation Tree).

      For general information on how to use caNanoLab, please visit https://cananolab.nci.nih.gov/caNanoLab/home.jsp


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    1. 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 NCT00167000. We believe the correct ID, which we have found by hand searching, is NCT00167700.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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


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    1. On 2015 Jun 26, Donald Forsdyke commented:

      In the light of new reviews (Zhang J, 2015 and Forsdyke DR, 2015), the following email to the senior author (Feb 6 2013) may be of interest:

      'I was delighted to see a new paper from your laboratory in this week’s PNAS Early Edition Park C, 2013 and, as expected, it did not disappoint me. The convergence of our thinking can be seen in the earlier emails and the attached articles on "Functional Constraint" (ELS where I squeezed in a last-minute reference to your work) and on "Collective Gene Functions" (BioEssays). Since I differ from you and your coauthors in some current interpretations, I hope you will not mind my again offering comments, which I hope will be helpful.

      1. I think you would agree that your statement "Amino acid substitutions are slower as the mRNA folding strength increases" could be restated as "Amino acid substitutions are faster as the mRNA folding strength decreases". The latter was the main observation of my paper in Molecular Biology and Evolution (1995 12, 1157-1165, http://post.queensu.ca/~forsdyke/introns.htm). In other words, under strong Darwinian positive selection (high dN), amino acid substitutions (codon changes) primarily serve the needs of protein function, rather than of nucleic acid structure. When the protein is conserved (evolving slowly) then the needs of nucleic acid structure are more readily accommodated. This approach can even be used to assay positive Darwinian selection (see Immunogenetics 1996 43, 182-189, http://post.queensu.ca/~forsdyke/introns.htm). The point was recently reiterated (see J. Biol. Systems 2007 15, 95-108, http://post.queensu.ca/~forsdyke/speciat3.htm).

      2. While your Introduction implies the possibility of "a selective pressure at any level (DNA, mRNA, or protein)," you assume that there is "a major role of natural selection at the mRNA level in constraining protein evolution." You do not mention the possibility that mRNA structure is by default, because the encoding DNA needs structure (i.e. DNA has the potential to extrude single strands as stem-loops). Since such structure is pervasive in DNA (in exons and introns and in extragenic locations), it appears that DNA needs structure, whether it encodes proteins or not. I have considered the rationale for this elsewhere.

      3. You note that "most of the correlations reported in this study are strong" when using enzymic (Fig. 1a) rather than computational (Fig. 1b) RNA structure determination. And you point out that mRNA folding strength may be impacted by "different amino acid, nucleotide, and synonymous codon frequencies." Here it might have been better first to look at the nucleotide component by comparing folding energies with randomly shuffled sequences. Your use of "pseudo-mRNAs" as a basis for comparison was useful for eliminating the possibilities of roles for "specific protein sequences or synonymous codon usages," but would have greatly reduced the statistical significance of your results.

      4. You call for "further improvement of the computational prediction." Base composition tends to be a genome-wide, or segment-wide, characteristic; it tends not to be a local characteristic. On the other hand, base order is a local characteristic. Nucleic acid structure depends on both base composition and order, but for many purposes, base order provides a more sensitive measure. If you follow my method for dissecting out the base order-dependent component of the folding energy, I believe you will obtain more satisfactory results with the computational method of structure determination.

      5. Compared with low expressed proteins, highly expressed proteins are more likely to have both specific and collective functions. Thus, there are two sources of negative selective pressure on genes with highly expressed protein products, and only one source of negative selection pressure on genes with low expressed protein products. So the former genes tend to evolve more slowly, and are less likely to be affected by deletion mutations since their contributions to collective functions are shared with other highly expressed proteins, which can compensate. Since they evolve slowly, they are better able to accommodate structure at the nucleic acid level. I consider this more extensively elsewhere.

      6. Genes under positive Darwinian selection pressure may be of various expression levels, so "amino acid substitution rate is negatively correlated with mRNA folding strength, with or without the control of expression level." Furthermore, there is "a significant [negative] correlation between mRNA folding strength and dN/dS, even when gene expression level is controlled."

      All this comes with no guarantee. I may be wrong. If you have any problem with these comments please get back to me. Having crossed this territory in the 1990s I feel some obligation to warn later explorers of possible pitfalls!'

      The ELS and BioEssays papers referred to in the above email were:

      Nature Encyclopedia of Life Sciences 7, 396-403 (2002). Functional constraint and molecular evolution. This was updated for Wiley Online Library in 2005 and 2012.

      BioEssays (2012) 34, 930-933 Forsdyke DR, 2012.


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    1. On 2014 Nov 19, Helen E Benson commented:

      The complement receptor family page on the IUPHAR/BPS Guide to PHARMACOLOGY can be found here.


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    1. On 2013 Nov 24, John Sotos commented:

      JAMA’s laudable effort to upgrade medical abstracts [1] represents only a syntactic improvement in communicating quantitative results. It was proposed by editors faced with reviewing multitudes of abstracts submitted to research meetings.

      Of greater use to JAMA’s general medical readership, and especially to the innumerable members of the public who read JAMA abstracts online via the Pubmed system, would be a graphical flow chart describing each study’s design. Instead of syntactic sugar, this would provide at-a-glance understanding of what is often the most innovative part of a study.

      Such charts are now familiar to readers, having been part of JAMA’s instructions to authors since at least 1998 [2]. However, because they are often laden with details [3], they are themselves candidates for abstraction.

      Although Pubmed already supports graphics in its abstract pages, authors would be better specifying these proposed abstract-flow-charts declaratively, e.g. with an XML data description language. Pubmed could then, someday, support searches based on details of study design, thereby fulfilling the hope expressed during JAMA’s introduction of structured abstracts in 1991: to “allow more precise computerized literature searches” [4].

      [1] Bauchner H, Henry R, Golub RM. The restructuring of structured abstracts: adding a table in the results section. JAMA. 2013; 309: 491-492.

      [2] Anonymous. JAMA instructions for authors. JAMA. 1998; 279: 69-72.

      [3] Paradise JL, Bluestone CD, Colborn DK, Bernard BS, Smith CG, Rockette HE, Kurs-Lasky M. Adenoidectomy and adenotonsillectomy for recurrent acute otitis media: parallel randomized clinical trials in children not previously treated with tympanostomy tubes. JAMA. 1999; 282: 945-53.

      [4] Anonymous. Structuring abstracts to make them more informative. JAMA. 1991; 266: 116-117.


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    1. 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 body of the text of the article. The ID given is NCT0151529. We believe the correct ID, which we have found by hand searching, is NCT01515293.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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

      * 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


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    1. On 2013 Oct 23, Stephen Turner commented:

      This study set out to compare shotgun metagenomic sequencing to 16S rRNA amplicon sequencing to determine the taxonomic and abundance profiles of mixed community metagenomic samples. Thus far, benchmarking metagenomic methodology has been difficult due to the lack of datasets where the underlying ground truth is known. In this study, the researchers constructed synthetic metagenomic communities consisting of 64 laboratory mixed genome DNAs of known sequence and polymerase chain reaction (PCR)-validated abundance. The researchers then compared metagenomic and 16S amplicon sequencing, using both 454 and Illumina technology, and found that metagenomic sequencing outperformed 16S sequencing in quantifying community composition. The synthetic metagenomes constructed here are publicly available (Gene Expression Omnibus [GEO] accession numbers are given in the manuscript), which represent a great asset to other researchers developing methods for amplicon-based or metagenomic approaches to sequence classification, diversity analysis, and abundance estimation.


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    1. On 2017 Jan 20, Claudiu Bandea commented:

      To be productive translational research must be driven by scientifically sound working hypotheses

      (This is an abbreviated version of a comment originally posted in Nature in 2013: http://www.nature.com/news/translational-research-medicine-man-1.12380)

      Many effective therapies and drugs have been discovered fortuitously or with little science backup. This door for discovery is still open. However, for some diseases, the development of prevention and therapeutic approaches requires deep scientific understanding of their etiology and pathogenic mechanisms. Take, for example, neurodegenerative diseases. Despite decades of research, continuous effort by thousands of scientists and clinicians, and huge investments in the order of billions of US dollars per year, there are no successful preventive or therapeutic approaches.

      Incidentally, it was the dramatic experience of ‘Losing a life’ to amyotrophic lateral sclerosis (ALS) that drove Christopher Austin, the director of the National Center for Advancing Translational Sciences (NCATS), to biomedical research and his quest for drug discovery almost three decades ago (1). Since then, millions of people have dies of ALS, Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD), Creutzfeldt-Jacob disease (JCD) and other neurodegenerative diseases.

      In light of the extraordinary public health and economic burden associated with neurodegenerative diseases, including tens of millions of affected patients and their families and economic losses estimated at over two hundred billion dollars per year in the Unites States alone, it is imperative to ask: (i) why there are no successful prevention and therapeutic approaches, and (ii) how can this unfortunate situation be resolved in a matter of years, not decades?

      Unfortunately, these uncomfortable questions are often marginalized or obscured by empty optimism or deceiving ambiguity. Articulating these questions, though, would not only establish a high sense of urgency and concern for people’s life, but might also help with the science. By emphasizing that despite decades of research the etiology of these diseases and the physiological function of the primary proteins implicated in these diseases are not known, these questions point to the possibility that the current working hypotheses might be wrong.

      Indeed, I recently proposed (2) that the protein misfolding theory and the prion hypothesis, which have directed most of the thinking and research on neurodegenerative diseases, are scientifically flawed, and that, by misdirecting the research and strategies for developing prevention and therapeutic approaches, these working hypotheses have been responsible for the lack of progress. According to the protein misfolding theory, AD, PD, HD, ALS and CJD are caused by the misfolding of the primary proteins implicated in these diseases: amyloid-beta and tau in AD, alpha-synuclein in PD, huntingtin in HD, TDP-43 in ALS, and prion protein in CJD (3). And, the prion hypothesis posits that protein misfolding is caused by prions (i.e. self-replicating proteins) or prion-like pathogens (4). In summary, according to these two working hypotheses, the isomeric conformation changes of amyloid-beta, tau, alpha-synuclein, huntingtin, TDP-43 and prion protein and their assembly into various protein complexes, including oligomers, plaques and tangles, are protein misfolding or prion replication activities.

      In a radical departure from the current paradigms, I proposed that:

      (i) A-beta/APP, tau, alpha-synuclein, huntingtin, TDP-43, and prion protein are members of the innate immune system;

      (ii) The isomeric conformational changes of these proteins and their assembly into various oligomers, plaques, and tangles are not protein misfolding events or prion-replication activities, but part of their normal, evolutionarily selected innate immune activities;

      (iii) The immune reactions associated with the function of these proteins in innate immunity lead to AD, PD, ALS, HD, CJD and other neurodegenerative diseases, which are innate immunity disorders.

      If correct as the current evidence indicate, these new paradigms will be eventually embraced, as science always corrects itself. However, this is a slow process that usually takes many years or even decades, and for the millions of people affected by these diseases time is everything. Therefore, when it comes to scientific issues that affect people’s life, the life of tens of millions of people in this case, the conventional approach of letting science takes its (usually lengthy) course is not acceptable.

      The solution is rather straightforward: all new data, observations, ideas and hypotheses need to be immediately, openly and systematically evaluated. This is where NCATS and other agencies, institutions and associations could have the opportunity to make a life-or-death difference for millions of people. How can this be accomplished in a field, such as neurodegenerative diseases, in which the existing primary working hypotheses, the protein misfolding theory and prion hypothesis, have directed the work and the careers of an entire generation of researchers?

      It is unrealistic to expect researchers in the field to systematically and specifically search for data and observations that challenge their current and previous work. It is reasonable, however, for the funding agencies to establish an open and comprehensive Peer-Review Platform (PRP) for critical and timely evaluation of all the research and publications. The PRP would be supported by a small percentage (e.g. 5%) of the biomedical funds, which would be awarded as ‘peer-review grants’ to qualified scientists (surprisingly, the funding agencies and the philanthropists invest billions of dollars in scientific projects but very little in the systematic evaluation of the results and publications, which undermines the entire process). Additionally, the scientists receiving research grants would be encouraged to contribute to PRP by providing critical evaluations of the research projects and scientific publications in their field of expertise. The PRP would be open to all scientists, including the authors of the research and publications under review. Generating data and observations is only half of the scientific process, the other half is their evaluation, interpretation, and integration into useful knowledge and productive working hypotheses.

      References

      1.Wadman M. 2013. Translational research: Medicine man. Nature. 494:24-6; Wadman M, 2013

      2.Bandea CI. 2013. Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders. bioRxiv. doi: 10.1101/000604; http://biorxiv.org/content/biorxiv/early/2013/11/18/000604.full.pdf

      3.Dobson, C. M. 2003. Protein folding and misfolding. Nature 426:884-90. Dobson CM, 2003

      4.Prusiner SB. 2012. A unifying role for prions in neurodegenerative diseases. Science. 336:1511-3; Prusiner SB, 2012


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    1. On 2014 Jun 16, Dave Hayes commented:

      Erratum: Note that the final three columns of Table 3 should be titled "Regional BP x vmPFC % signal change" and NOT "Regional vmPFC...", i.e. the GABA(A) receptor binding potentials of each region from the first column were correlated with BOLD signal changes in the vmPFC.


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    1. On 2014 Jan 15, Satoko Hattori commented:

      "ImageLD" and "ImageEP", image analysis application softwares used in this article, are now freely available from http://www.mouse-phenotype.org/software.html.


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    1. On 2015 Feb 14, Satyanarayan Hegde commented:

      Interesting observation. Authors do not mention the patient's FEV1 at other time points prior to starting HFCWO which they probably did not have access to. How do we know the modest increase in FEV1 (~400ml) after starting HFCWO is not because of resolution of an exacerbation? If the patient were to have neutrophillic inflammation, he would not respond to systemic steroids. Patient reported symptoms as a measure of disease severity can be notoriously unreliable. Authors should have attempted in obtaining more objective data such as frequency of systemic steroid use, unscheduled physician office visits, ED/hospitalization rates, missed work days and medication refill history. Nevertheless, they describe another mode of potential therapy for a select group of patients.


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    1. On 2013 Oct 31, John Cannell commented:

      I congratulate the authors on a fine study. I wonder if they are aware that Mostafa et al found that an anti neural antibody found in autism had a -.86 correlation coefficient with 25(OH)D levels? If not it goes to show that scientists become experts in their own niche but apparently do not keep up with relevant science in other fields.

      Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

      Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

      Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

      Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

      Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

      There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

      DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

      Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

      Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

      Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

      Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

      70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day. As milk consumption has fallen, so have toddler’s vitamin D levels.

      Cannell JJ. Autism, will vitamin D treat core symptoms? Medical Hypotheses. 2013 Aug;81(2):195-8. Cannell JJ, 2013

      Some autism researchers seem cognizant of the entire body of autism research. For example, a group of well-known European autism researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into the vitamin D deficiency theory of ASD.

      Kočovská E, Fernell E, Billstedt E, Minnis H, Gillberg C. Vitamin D and autism: clinical review. Res Dev Disabil. 2012 Sep-Oct;33(5):1541-50. doi: 10.1016/j.ridd.2012.02.015. Epub 2012 Apr 21.Kočovská E, 2012

      However, these scientists appear to be in the minority. Until all autism researchers become cognizant of the wider body of autism research, we will continue to wonder how to prevent - and perhaps even treat - this modern day plague.

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


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    1. On 2015 Oct 23, Vojtech Huser commented:

      This is a comment from the first author of the article:

      Several months after publication, the journal changed publishers (from BMJ group to Oxfort University Press) and as a result, the appendix data for the article are not available via the current journal site.

      To obtain the online supplemental data, use the following ResearchGate links:


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    1. On 2013 Dec 30, Gregory Francis commented:

      In response to my critique of their original article, Elliot & Maier (E&M) raised three points. I respond in reverse order, because the first point is the most interesting.

      3) E&M propose that the discussion about bias should be at the field level rather than at the level of individual articles. I strongly disagree. A discussion at the field level dilutes responsibility, so researchers can simultaneously believe that the field is biased and believe that their own effects are sound. One gets a hint of such an attitude in E&M, where they describe the problems of bias in the field, but insist that their findings related to the red-attractiveness effect are valid. Scientists fundamentally care about individual effects, so that is the appropriate place to consider the influence of bias.

      2) E&M suggest that my article was incautious because it considered several different analyses of effects. Perhaps the text in Francis (2013) did not make clear that different bias tests were applied in order to see if there might be some way to interpret the experiments so that they did not indicate bias. This exploratory search was unsuccessful; every combination of effects and measures lead to a conclusion of bias for at least some of the effects.

      E&M also suggest that my use of the test is inappropriate because the analytical approach was originally developed by Ioannidis & Trikalinos (2007) to detect bias in large sets of experiments. This claim is entirely without justification. If E&M want to argue that my analysis is flawed, then they should demonstrate an error in the calculations or reasoning.

      1) E&M claim that there is independent evidence that the red-attractiveness effect is real. They cite additional studies (including some from other labs) that report the presence of the effect. These studies may indeed demonstrate the validity of the effect, but their properties do nothing to remove the appearance of bias in the study by Elliot et al. In fact, if E&M intend to use these additional studies as evidence for their theoretical claim, then the success of these experiments only makes the bias problem worse. The probability of success for all the experiments in Elliot et al., low as it is, must be larger than the probability of success for those experiments and the additional studies.

      E&M also reported a new experiment designed to check on the validity of the red-attractiveness effect. In the original study, this experiment produce a standardized effect size of 0.83 (n1=16, n2=17). The new study found a smaller effect size of 0.25 (n1=75, n2=69), which did not produce a significant effect (p=.13). E&M concluded that the red-attractiveness effect is in the small to medium range rather than the large range. Most research psychologists would go further and suggest that there is insufficient evidence to interpret the red-attractiveness effect as being different from zero (for many researchers the null hypothesis is the default position, until proven otherwise).

      Given that Francis (2013) argued that the original experiments were too successful, one might wonder if the new (non-significant) experiment diffuses that critique. A new version of the analysis using the original five experiments in Elliot et al. and the new experiment produces a pooled effect size of 0.53. This value is substantially smaller than the pooled effect for the original studies (0.78) because the new experiment has a small effect size and carries substantial weight in the pooling due to its larger sample size.

      With the new pooled effect size, the estimated power of each of the experiments (in order of publication) is 0.21, 0.30, 0.316, 0.49, 0.26, and 0.89. It is rather odd that the experiment with the largest power estimate is the only experiment to not reject the null hypothesis. Moreover, the probability of rejecting (any) five (or six) out of six experiments like these is 0.03, which is so low that it indicates bias.

      Since it presumably is not biased, the new experiment arguably gives the best estimate of the red-attractiveness effect. The estimated power derived from an effect size of 0.25 for the original experiments is 0.08, 0.10, 0.11, 0.15, and 0.10. The probability that all five such experiments would reject the null is the product of the power values, which is 0.000013. So, if the new experiment provides a valid estimate of the effect, readers should be very skeptical about the validity of the original experiments in Elliot et al.

      Finally, it is worth noting that E&M never explicitly discussed the presence of bias in their reported experiment set. They did not disclose whether there were unreported null findings or whether some experiments used sampling methods that inflate the Type I error rate. It is possible that bias occurred without their awareness, but the absence of a clear statement highlights that readers should be skeptical about the reported experiments.

      Ultimately, the new experiment in E&M only strengthens the argument for some form of publication bias in Elliot et al. The other points deserve a frank and creative exchange of ideas, but they do nothing to alter the unbelievability of their original findings.


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    1. On 2014 Sep 16, Christopher Southan commented:

      Unfortunately Google has now become capricious in matching either part of the Key and thus producing false positives from just the second half. It is therfore more effective to try the inner 14-characters of the Key (the connectivity layer) first. The overall utility still stands and the better news is that, even though the full InChI strings are truncated to 32 caracters in a search, they can give useful partial matches.

      In reply (Oct 2015) to Egons Q above. As we know, rankings move so its difficult to know what (legitimate) SEO steps are making the difference (exepting traffic per se). Yes, databases could do more, in particular PubChem has a backlog problem (i.e. new entries not indexed). It would also be geat if UniChem and SureChEMBL contrived to get fully crawled. Then we really could check the global 100+ million in a ~0.3 sec pop


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    2. On 2015 Oct 01, Egon Willighagen commented:

      Dear Christopher, when you studied the indexing of IKs by Google, did you also look at the effect of SEO tricks? That is, Google suggests that writing a good page title and description will help them correctly index pages. For example, I can imagine you had looked at one of the lists, e.g. for atorvastatin, and determined if the IK was used in the page title and/or description. Would you expect that if chemical databases adopted this SEO technologies for the IK, it would further improve the situation? Or would the effect be minor? Could it help overcome the problem with partly matching IKs, as you noted here about a year ago?


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    1. On 2014 Jun 27, David Keller commented:

      H2-water therapy improved Parkinson disease in this pilot study - can it be replicated?

      The results of this small but apparently well-designed pilot study were very encouraging, and seemed to demonstrate in humans with Parkinson disease [PD] significant benefits from drinking water saturated with dissolved hydrogen gas (also called "H2-water"). H2-water is hypothesized to be an effective antioxidant in vivo, and has demonstrated benefits in animal models of PD (1,2,3). More than a year has elapsed since the publication of the provocative findings of this pilot study. We need a large clinical trial to either confirm or refute the benefits of H2-water in humans with PD.

      References

      1) Fu Y, Ito M, Fujita Y, Ito M, Ichihara M, Masuda A, Suzuki Y, Maesawa S, Kajita Y, Hirayama M, Ohsawa I, Ohta S, Ohno K. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease. Neurosci Lett. 2009 Apr 3;453(2):81-5. doi: 10.1016/j.neulet.2009.02.016. Epub 2009 Feb 12.PubMed [citation] PMID: 19356598

      2) Fujita K, Seike T, Yutsudo N, Ohno M, Yamada H, Yamaguchi H, Sakumi K, Yamakawa Y, Kido MA, Takaki A, Katafuchi T, Tanaka Y, Nakabeppu Y, Noda M. Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. PLoS One. 2009 Sep 30;4(9):e7247. doi: 10.1371/journal.pone.0007247.PubMed [citation] PMID: 19789628, PMCID: PMC2747267

      3) Matsumoto A, Yamafuji M, Tachibana T, Nakabeppu Y, Noda M, Nakaya H. Oral 'hydrogen water' induces neuroprotective ghrelin secretion in mice. Sci Rep. 2013 Nov 20;3:3273. doi: 10.1038/srep03273.PubMed [citation] PMID: 24253616, PMCID: PMC4070541


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    1. On 2014 Jan 31, George W Hinkal commented:

      Lee GY The National Cancer Institute has been investing in the development of an online webportal of curated cancer nanotechnology data called caNanoLab. The numerical data and additional nanomaterial characterizations related to this publication have been added to the database and can be found at:

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=40566787&page=0&tab=ALL

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=40566788&page=0&tab=ALL

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=40566789&page=0&tab=ALL

      https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=41418754&page=0&tab=ALL

      The left navigation links on these pages provide information about each sample (under Navigation Tree).

      For general information on how to use caNanoLab, please visit https://cananolab.nci.nih.gov/caNanoLab/home.jsp


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    1. On 2015 Nov 13, University of Kansas School of Nursing Journal Club commented:

      Reviewers: (Team 10) Sydney Jourdan, Lucy Bush, Elijah Penny, Cassidy Playter, Brittany Winter, Alex Noller, Parwana Noori (Senior Nursing Students – Class of 2016)

      Background:

      Many of our class discussions in our microsystem leadership course focused on methods currently available to accurately measure nurse job satisfaction and the elements needed to contribute to a healthy work environment, such as nursing leadership. Our selected article attests to how there is an increasingly high number of nursing turnover due to a lack of managerial leadership and support. This study found that nurse leaders who practiced authentic leadership created an environment of nurse empowerment regardless of their experience level - this ultimately promotes nurse health and retention. . We believe leadership training for nurse managers should be a requirement in today’s health-care organizations as it will aid in the development of an empowering work environment and attract and retain nurses (Laschinger, Wong & Grau, 2013). Laschinger, Wong, & Grau (2013), examined the impact of authentic leadership, autonomous practice and continuous support on the nursing work environment. Our group felt this article directly correlated to recent class discussions, further exemplifying the impact of authentic leadership on nurse job satisfaction, performance and safety.

      Methods:

      Our group located this article using the CINAHL database from the Dykes Library Resource Center. The literature was discovered using the search terms “authentic leadership” AND “healthy work environment.” The design of this study included a secondary analysis of data obtained via questionnaire of two study groups from Ontario in an acute care setting. The pattern of relationships regarding emotional exhaustion and cynicism versus authentic leadership and structural empowerment were examined in a group of 342 new graduate nurses with less than two years of nursing experience and in another group of 273 nurses with over two years of work experience (Laschinger et al., 2013). This study targeted both new graduate nurses and experienced nurses in order to examine how each group was affected by a work environment in the acute care setting containing structural empowerment and authentic leadership and how such practices related to group cynicism and burnout.. The acute care patient population has a lower socioeconomic status and higher rate of drug addiction and drug seeking than other healthcare settings, rendering a higher rate of cynicism and burnout amongst its nurses. Not only does this study impact acute care nurses, but their patients as well - the empowered and contented nurse will provide better patient-centered care. Data was obtained via questionnaire. 907 questionnaire packages were sent out to a sample population with a follow-up questionnaire sent three weeks later. Of the 907 questionnaires sent, 342 responded and met the criteria of less than two years nursing experience. 280 responded for the “experienced” portion of the study however, seven cases were removed from the later analysis as these respondents did not have over two years of nursing experience, leaving a sample size of 273 experienced nurse subjects (Laschinger et al., 2013). The questionnaires utilized included the Conditions of Work Effectiveness Questionnaire-II, which examines the four components of structural empowerment and has been previously discussed in our class, the Authentic Leadership Questionnaire, which measures the four components of nurses’ perceptions of their managers’ authentic leadership qualities and the Maslach Burnout Inventory-General Survey, which measures the emotional exhaustion and cynicism of nursing burnout (Laschinger et al., 2013).

      Findings:

      The results of this study supported a model linking authentic leadership and structural empowerment to nursing burnout (Laschinger et al., 2013). This study is the first to investigate the relationship between authentic leadership and structural empowerment to nursing burnout and cynicism and concluded authentic leadership had both direct and indirect effects on cynicism, a phenomena that is found to be linked to emotional exhaustion related to poor work environments (Laschinger, et al., 2013). Self-awareness and balanced processing are two characteristics of authentic leadership found to be critical to the creation of an empowered work environment. Leaders who were perceived to support employees and provide both positive and negative feedback rendered nurses who reportedly felt empowered to perform quality patient care in a meaningful way. The results of this study support the validity of both structural empowerment and the authentic leadership theory. This contributes to knowledge leaders can utilize to make positive changes in nursing work environments and promote nurses’ health and retention (Laschinger et al., 2013). Health care work environments are extremely stressful - however, the results of this study show relationship-driven leadership strategies have the ability to transform current nursing environments positively and ensure all nurses are empowered to provide optimal patient-centered care. This study is important because it examines methods such as structural empowerment and authentic leadership and how these practices may lead to less emotional strain, turnover and burnout for the acute care nurse. The study also explores how a healthy work environment may render less cynicism amongst nurses - leading to happier patients, effective communication and better health outcomes.

      Implications:

      This article is important to nursing practice because it examines how healthy work environments are essential to effective and optimal patient-centered care. Nursing burnout and emotional strain is a very real dilemma the acute care setting faces and leads to job dissatisfaction, poorer health outcomes and turnover. In a field already facing vast nursing shortages, studies such as this one are pertinent to finding the best practice environment. This study provides evidence to implement across the healthcare setting in order to promote happier, healthier and safer work environments. As medicine and technology advance, leadership tactics and qualities must also in order to compete with a constantly evolving environment. This article resonated personally with group members who work and/or aspire to work in the acute care setting and have witnessed the reality of nurse burnout and cynicism. The nurse is already given the difficult task of treating and caring for the patient’s mind, body and spirit. Having to provide such care in a strained and/or unsupportive environment sets the nurse up for failure. As our class faces graduation, we want to feel confidently that all of our study and practice efforts will be rewarded in an environment that promotes support, empowerment and authenticity. As a result of reading and discussing this article, our group has learned preventing emotional exhaustion is key to preventing advanced burnout and can be accomplished through structural empowerment and authentic leadership practices (Laschinger et al., 2013). Moving forward as professional nurses, we will aim to act authentically, seek support when needed and ensure our work environments are those that promote empowerment in order to prevent emotional exhaustion and provide the best patient care possible.

      Reference:

      Laschinger, Heather K. Spence, Carol A. Wong, and Ashley L. Grau. Authentic leadership, empowerment and burnout: A comparison in new graduates and experienced nurses. Journal of Nursing Management 21, no. 3 (April 2013): 541–52 12p. doi:10.1111/j.1365-2834.2012.01375.x.


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    1. On 2014 Jan 03, RICHARD NIEDERMAN commented:

      This report is both intriguing and vexing.

      It is intriguing because it addresses a central issue in oral health care - what is the relative value of prevention. This is of central importance as the global community begins to seriously consider prevention vis-a-vis traditional surgical treatment of caries.

      It is vexing because nowhere in the article is there an explicit listing of the 17 reviews or 71 included articles identified in Figure 2, nor is there an appendix or link to the identified publications.

      Perhaps the authors might make this information available here?


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    1. On 2017 May 10, Marko Premzl commented:

      The comment "Response to Caiati and coauthors' article" was published on The Journal of Neuroscience article's internet site: http://www.jneurosci.org/content/33/7/2973#response-to-caiati-and-coauthors-article (10 May 2013).

      Project leader: Marko Premzl PhD, ANU Alumni, 4 Kninski trg Sq., Zagreb, Croatia

      E-mail address: Marko.Premzl@alumni.anu.edu.au

      Internet: https://www.ncbi.nlm.nih.gov/myncbi/mpremzl/cv/130205/


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    1. On 2016 May 10, Morten Oksvold commented:

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

      https://ori.hhs.gov/content/case-summary-walker-kenneth


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    1. On 2014 Mar 02, Joel Topf commented:

      I am disappointed that they did not provide a intention to treat analysis.


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    1. On 2013 Dec 23, Tom Kindlon commented:

      ME/CFS Patient Organisations should be free to not promote CBT and GET for ME/CFS and the models underlying them

      As somebody involved in running a myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patient organisation which might be seen to have been criticised by this paper, I would like to take the opportunity to respond.

      The paper seems to be largely based on an appeal to authority. However, the history of medicine is replete with examples of situations where views on the aetiology and pathophysiology of conditions, and how they should be treated, particularly those that were psychologised, have changed over time. Moreover, there is actually little consensus within the field on the aetiology or pathophysiology of ME/CFS; there are many competing theories (1). Patient organisations should not be compelled to support a particular model for the illness that is the basis for the use of cognitive behaviour therapy (CBT) and graded exercise therapy (GET), or indeed, the therapies themselves. The authors may claim such therapies are safe but this is in dispute, with large percentages of patients reporting deteriorations in their overall health in patient surveys (1,2). Moreover, claims for the efficacy of such therapies are mainly based on subjective outcome measures in non-blinded studies so there are plenty of reasons to be sceptical of such claims (1-3).

      The models underlying CBT and GET for ME/CFS may be described as "biopsychosocial" but are not equally "physical" and "psychological". They are based on the view that the symptoms and disability in the condition are reversible using these behavioural methods (4). This is distinctly different from many other conditions where these would be used as adjunctive therapies. I would venture that it is the proponents of such models (i.e. those underlying CBT and GET) who are out of step with the majority of the ME/CFS research community worldwide. For example, there are many studies which suggest the symptoms of the condition are not due to deconditioning (e.g. studies with sedentary controls) and I believe most would not accept the view that all the findings can simply be explained by deconditioning (1,2,5). In such circumstances, patient organisations should be entitled to make their own assessment of the evidence in its various forms rather than be compelled to follow any orthodoxy in a particular country.

      References:

      [1]. Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME. 2011;19:59-111.

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

      [3]. 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;3:321-322 DOI: 10.1111/cpsp.12042

      [4]. PACE manuals for Cognitive Behaviour Therapy and Graded Exercise Therapy for CFS/ME. http://www.pacetrial.org/trialinfo/ (last accessed: October 27, 2013)

      [5]. Snell CR, Stevens SR, Davenport TE, Van Ness JM. Discriminative Validity of Metabolic and Workload Measurements to Identify Individuals With Chronic Fatigue Syndrome. Phys Ther. 2013 Jun 27.

      Conflict of Interest: I am the Assistant Chairperson and Information Officer of the Irish ME/CFS Association. All my work for the Association is unpaid.


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    1. On 2014 Mar 14, Jonathan Eisen commented:

      The first author of the paper, Rachel Adams wrote a post about this paper for the "microbiology of the Built Environment network (microBEnet)" blog. See Dispersal in microbes: fungi in indoor air are dominated by outdoor air and show dispersal limitation at short distances


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    1. 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 NCT0027753. We believe the correct ID, which we have found by hand searching, is NCT00277537.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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


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    1. On 2013 Nov 25, Claudiu Bandea commented:

      None


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    2. On 2013 Nov 25, Claudiu Bandea commented:

      Junk DNA and the skewed perspective of Graur et al. on biological function and genome size evolution

      In their article “On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE” (1), Graur et al. dismantle ENCODE’s evidence and suggestion that 80% of the human genome is functional (2), which would render the traditional concept of junk DNA (jDNA) obsolete (3).

      I agree with many assertions made by Graur et al. about the poor rationale behind some of ENCODE’s experimental approaches and the overall interpretation of the results; indeed, it has been known for decades that, by its bare presence in the genome, so called junk DNA (jDNA) gets replicated and undergoes repair, recombination, non-specific transcription, transposition, etc., and that all these biochemical activities involve various DNA-binding proteins.

      However, the article by Graur et al. contains assumptions and statements that are questionable. For example, the authors limit their evaluation of genomic DNA’s biological functions to informational roles, which are based on sequence specificity. Although Graur et al. recognize, apparently as an afterthought, that: “It has been pointed to us that…some parts of the genome may be functional but not under constraint with respect to nucleotide composition”, the paper sidesteps the significance of non-informational roles for genomic DNA.

      In a recent paper (4), I discussed this and some the other weaknesses of Graur et al. and expanded on an old hypothesis (5) that might explain the evolution of genome size and jDNA, and solve the long-standing C-value enigma.

      References

      (1) Graur D, Zheng Y, Price N, Azevedo RB, Zufall RA, Elhaik E. 2013. On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE. Genome Biol Evol., 5(3):578-90. Graur D, 2013

      (2) ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. 2012. Nature, 489:57–74. ENCODE Project Consortium., 2012

      (3) Pennisi E. 2012. ENCODE project writes eulogy for junk DNA. Science, 337:1159–1161. Pennisi E, 2012

      (4) Bandea CI. 2013. On the concept of biological function, junk DNA and the gospels of ENCODE and Graur et al. bioRxiv doi: 10.1101/000588 (http://biorxiv.org/content/early/2013/11/18/000588)

      (5) Bandea CI. 1990. A protective function for noncoding, or secondary DNA. Med Hypotheses, 31(1):33-4. Bandea CI, 1990


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    1. On 2014 Oct 10, Fernando Castro-Chavez commented:

      Dear Researcher,

      I think that the PubMed comments are a good added feature for authors to comment and expand on their work, to answer and to get input from the readers, and to make personal comments related the human aspect of their research. For example, in my current work and in the upcoming ones, I aim at taking a computer programmer's perspective upon the genetic code. Here I was able to test its Defragging ability, and in a future article here to appear, I aim to test its File Compression ability.

      To develop programming algorithms and languages based on the genetic code, for me seems like a thrilling exercise.

      What do you think?

      With my best regards,

      Fernando Castro-Chavez, PhD.

      10/10/2014, 5:34 PM.

      Houston, TX.


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    1. On 2014 Dec 05, Andrea Messori commented:

      Treatments for naive patients with follicular non-Hodgkin lymphoma


      The study by Rummel et al. [1] is a potentially important advancement in the treatment of naïve patients with indolent non-Hodgkin’s lymphoma. Since, in this trial, the clinical results with bendamustine plus rituximb were very favourable in the subgroup of patients with follicular lymphoma, it can be worthwhile to compare these findings with those observed in other randomized trials aimed at naïve patients with this disease condition. According to the systematic review by Schulz and co-workers [2], two randomized trials [3,4] have previously been conducted in treatment-naive patients with follicular lymphoma. Another trial (the PRIMA trial[5]) has been published thereafter.

      If one employs the end-point of progression-free survival at 2 years, these randomized trials have reported the following results (n/N): a) Hiddeman et al. [3]: R-CHOP, 167/223 (74.9%) vs CHOP, 103/205 (50.2%); b) Marcus et al. [4]: R-CVP, 137/159 (86.2%) vs CVP, 81/162 (50%); c) Rummel et al [1] : bendamustine+ rituximab, 93/139 (66.9%) vs R-CHOP, 63/140 (45%); d) PRIMA trial [5] (subgroup of 1,019 patients who completed the induction treatment): i) First data set (unadjusted)= survival data determined from randomization until last date of the follow-up: induction+rituximab maintenance, 418/505 (82.8%) vs induction+no rituximab maintenance, 345/513 (67.3%); ii) Second data set with empirical adjustment (see FOOTNOTE) = survival data determined from registration until last date of the follow-up: induction+rituximab maintenance, 418/529 (79%) vs induction+no rituximab maintenance, 345/537 (64.2%). With the exception of the first data set of the PRIMA trial, these results selectively refer to treatment-naïve patients with follicular lymphoma. The numerators and denominators of the crude rates reported above were estimated from the Kaplan-Meier curves according to graphical methods [6,7]. In each trial, the following sources of information were used: Hiddeman et al. [3]: Figure 2, Panel A; Marcus et al. [4]: Figure 1; Rummel et al. [1]: Figure 3, Panel A; PRIMA trial [5]: Figure 2, Panel A.

      If one analyses the above pair-wise comparisons according to the end-point of achievement of progression-free survival at 2 years, the following values of odds-ratio (OR) can be obtained (random-effect model, Open Meta-analysts software): R-CHOP vs CHOP: 2.953 (95%CI: 1.964 to 4.442); R-CVP vs CVP, OR=6.227 (95%CI: 3.609 to 10.744); bendamustine+rituximab vs R-CHOP, OR=2.47 (95%CI: 1.521 to 4.015); R-CHOP+R-maintanance vs R-CHOP (adjusted data set): 2.303 (95%CI: 1.741 to 3.047).

      Interestingly enough, all of these comparisons show a significantly better effectiveness of the first treatment as compared to the second. In this framework, a Bayesian meta-analysis aimed at assessing these data could be useful to synthesise the comparative effectiveness of these treatments.


      FOOTNOTE: In the PRIMA trial [5], after a total of 1,202 treatment-naive patients were enrolled and registered, randomization to either rituximab maintenance or no maintenance was applied to the subgroup of 1,019 patients who completed the induction treatment. To make the PFS data of this trial (that refer to the randomised patients) comparable to those of the other trials reported above (that refer to treatment-naïve patients), the rates of progression (or, likewise, the rates of PFS) in the PRIMA trial need to be subjected to an empirical adjustment (increase in the numerator of the progression rate or increase in the denominator of the PFS rate applied to both the maintenance and the no-maintenance arms). This adjustment can be based on further information reported on the same patients in a more recent analysis [8].

      In their Figures 1 and 2, Ghesquières and co-workers [8] have provided useful details to compare the PFS data between the subgroup of registered patients (data shown in Figure 1, panels A and B) and the subgroups of randomised patients (data shown in Figure 2, panels AI, AII, BI, and BII). For this purpose, the two following comparisons can be made: i) Comparison A between Panel A of Figure 1 vs. Panels AI and AII of Figure 2; ii) Comparison B between Panel B of Figure 1 vs. Panels BI and BII of Figure 2. Comparison A uses the data of FCGR3A polymorphism, while Comparison B uses the data of FCGR2A polymorphism.

      In Comparison A, the crude rate of progression for registered patients (according to Figure 1, panel A) is 171/460 (37.17%) where 171=68+80+23 and 460=177+215+68 while the crude rate of progression for randomised patients (according to Figure 2, panels AI and AII) is 141/397 (35.52%) where 141= 35+45+11+17+26+7 and 397=76+93+27+ 72+98+31. The ratio of these two percent rates of progression (37.17% / 35.52%) is 1.0465; this indicates that, using an acceptable approximation, the rate of progression in registered patients can reasonably be estimated from the rate in randomized patients by applying a 4.65% increase in the number of events found in randomised patients (i.e. by increasing the numerator of the rate without changing the denominator). Likewise, in Comparison B, the crude rate of progression for registered patients (according to Figure 1, panel B) is 168/450 (37.33%) while the same rate for randomised patients (according to Figure 2, panels BI and BII) is 138/387 (35.66%). The ratio of these two percent rates of progression (37.33% / 35.66%) is 1.0468. which is very similar to that estimated from Comparison A.

      These two re-analyses (i.e. Comparisons A and B) consistently indicate that the rates of progression in registered patients can be estimated with a very good approximation from the rates found in randomized patients by applying a 4.7% adjustment to the survival data (i.e. an increase in the numerator of the progression rate or an increase in the denominator of the PFS rate).


      References

      1. Rummel et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10.

      2. Schulz et al. Chemotherapy plus Rituximab versus chemotherapy alone for B-cell non-Hodgkin's lymphoma. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003805.

      3. Hiddemann et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005;106(12):3725–3732.

      4. Marcus et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105(4):1417–1423.

      5. Salles et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. doi: 10.1016/S0140-6736(10)62175-7.

      6. Messori et aL. Survival meta-analysis of individual patient data and survival meta-analysis of published (aggregate) data. Clin Drug Invest 2000;20(5):309-316.

      7. Tierney et al. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007 Jun 7;8:16.

      8. Ghesquières et al. Clinical outcome of patients with follicular lymphoma receiving chemoimmunotherapy in the PRIMA study is not affected by FCGR3A and FCGR2A polymorphisms. Blood. 2012 Sep 27;120(13):2650-7.


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    1. On 2017 Jul 20, Alexander Kraev commented:

      Note that this is likely one of about 150 publications affected by the MHC-driven MerCreMer transgene, notoriously prone to induction of dilated cardiomyopathy in the absence of any induced target gene expression, in this case calreticulin. See PMID:27165291 for details. Erratum for this article in PLoS One. 2013;8(11) was made for a different reason.


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    2. On 2017 Jul 25, Marek Michalak commented:

      The full response to Alexander Kraev's comment can be viewed at the following URL: http://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0056387


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    1. On 2015 Jun 02, thomas samaras commented:

      None


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    2. On 2015 Jun 02, thomas samaras commented:

      Additional information on height, CHD, and longevity is available from these recent publications.

      Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

      Samaras TT. Human Scaling and Body Mass Index. In: Samaras TT (ed): Human Body Size and the Laws of Scaling: Physiological Performance, Growth, Longevity and Ecological Ramifications. New York: Nova Science Pub; 2007: pp 17-32.

      He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

      Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

      Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.


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    1. On 2017 Nov 29, Liz Dooley commented:

      This Cochrane Review has been superseded. A new author team has taken over and will expand the scope of the review to cover acute upper respiratory tract infections. Information provided by the Cochrane Acute Respiratory Infections Group.


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    1. On 2014 Aug 19, Qin-hong Zhang commented:

      Comment on "Interventions for treating persistent and intractable hiccups in adults"

      Zhang QH, Yue JH

      Department of Acupuncture and Moxibustion, College of Acupuncture and Moxibustion, Heilongjiang University of Chinese Medicine, Harbin 150040, China.

      I read with great interest the published article by Moretto et al., entitled “Interventions for treating persistent and intractable hiccups in adults”[1]. They evaluated the effectiveness of pharmacological and non-pharmacological interventions for treating persistent and intractable hiccups of any aetiology in adults. However, I had a few comments to make regarding the same. The authors only included four Chinese trials in acupuncture. However, they failed to search the Chinese databases, such as Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (which includes the database China Academic Journals) (CNKI), VIP Information (VIP), and Wanfang Data (WAN FANG). Thus, to our best knowledge, the authors far failed to include at least 18 eligible studies (including four randomized controlled trials (RCTs), and 14 quasi-randomized controlled trials (Q-RCTs)). In addition, three of 4 included studies used wrong comparator that means both groups used acupuncture, which could not evaluate the effect of acupuncture [2-4].

      References

      1.Moretto EN, Wee B, Wiffen PJ, Murchison AG. Interventions for treating persistent and Intractable hiccups in adults. Cochrane Database Syst Rev 2013; 1:CD008768.

      2.Bao F, Liang Z, Wang F. Clinical observation on treatment of stubborn hiccup by acupuncture with different needle retaining time. World Journal of Acupuncture-Moxibustion 2003;13(2):50–4.

      3.Jiang Feizhou.Stubborn hiccup treated with thumb-tack needles and needle-embedding on otopoint. Journal of Clinical Acupuncture and Moxibustion 2002;18(2):36.

      4.Wang B. 80 cases of intractable hiccup treated by acupuncture. Chinese Acupuncture and Moxibustion 2011; 31(2):181–2.


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    1. On 2017 Mar 23, University of Kansas School of Nursing Journal Club commented:

      Team Members: Cassie Caedo, Jessica Garcia, Jamie Radakovich, Olivia Kolar, Aaron Rutledge, Courtney Will, Sarah Stokes, Macy McKee. [Class of 2017)

      Background

      Shared governance is an increasingly prevalent leadership strategy in which nurses are an integral component of decision-making, both on the unit and institutional level. Shared governance gives nurses the power to influence their practice, which can positively affect both nurses’ job satisfaction and patient satisfaction. As we have learned in class, shared governance systems should integrate nursing professionals’ experiences and attitudes to shape nursing practice and improve nurses’ job satisfaction. Shared governance can also be viewed as a source of empowerment for nursing professionals. This literature helps fill the gap in perspectives that were not presented in class. In the presentations from staff nurses who participate in shared governance, they expressed the perspective of staff nurses’ participation in unit based councils and institutional councils. However, this article integrates viewpoints from both the staff nurses and nurse managers who participate in shared governance models. It was explained that shared governance models deviate from classic hierarchal structures of governance because nurses at the bedside can influence clinical practice across the entire institution. The success of shared governance can depend on the personal accountability of the nursing staff involved, and requires the institution to be receptive to the suggestions and ideas brought forth by nursing staff. By utilizing the perspectives of nurses who are directly impacted by institutional and unit policies, shared governance gives nursing staff more control over their practice.

      Methods

      This particular article was found on PubMed using the search terms “shared governance,” “nursing,” and “satisfaction.” We decided to select this particular article based on the insight that this qualitative study provided. In class, we explore the ways that shared governance can affect nursing staff and inadvertently affect patient outcomes. Nurse burnout, satisfaction, and retention can all be influenced by nursing leadership. The design of this study was a qualitative analysis via interview questions answered by 11 RNs. The study was designed for the purposes of assessing and documenting the attitudes and experiences of both staff RNs and nurse managers in shared governance structures. Specifically, nurses and nurse managers were asked for their opinion of the effect shared governance has on patient outcomes, their experiences with implementing a shared governance model, and describing their perceived roles in a shared governance system. The population of interest focused on staff nurses and nurse managers who implement shared governance models; in this study, this was implemented by utilizing unit practice councils. Evaluating attitudes about shared governance is important in assessing the efficacy of shared governance models and whether or not they have a positive impact on staff nurses’ experiences. Each verbal interview ranged from one minute to a minute and a half, and was recorded for data analysis later. Most nurses were interviewed in pairs by the unit practice councils.

      Findings

      The nurse managers cited shared decision-making and staff empowerment as integral components of succeeding in shared governance models. Nurses collaborated with clinical staff on the floor, including physicians and nursing administration, and nurse managers acted as facilitators between staff nurses and other professionals within the institution. Nurses who utilized shared governance models also integrated more evidence-based practice and quality improvement to improve processes on the unit. Empowerment by nurse managers fostered better job satisfaction and accountability for the staff nurses. Shared governance was viewed as a way to foster better communication between members of the care team, and encouraged a team-oriented mentality. Overall, shared governance was seen as an acceptable and effective avenue for improving patient outcomes, increasing nurses’ job satisfaction, and building stronger interprofessional relationships. Limitations of the study included small sample size (n=11), including five nurse managers and six staff RNs. Unit councils, as well as the individual participants, varied in shared governance experience but were all involved on their units’ practice councils. The generalizability of the study is limited because of the small sample size, the universal participation in practice councils, and the limited experiences with shared governance.

      Nursing Implications

      Implementing shared governance is important to nursing professionals because nurse burnout and job satisfaction can be affected based on the amount of influence nurses are able to have on their own practice. This is important on a personal level because nurses should be able to influence the policies and procedures that impact our daily practice. Not only would shared governance improve nursing professionals’ visibility, but it would also promote workplace satisfaction. The health care system stands to benefit from shared governance models because nurses are such a profound aspect of patient care, and their direct participation in how their unit provides care could lead to better patient outcomes and increased patient satisfaction. Nurses have a unique perspective that can identify more efficient procedures, more cost-effective utilization of resources, and promotion of a healing environment. This literature relates to future nursing practice because shared governance offers the promise of improved patient outcomes, higher rates of job satisfaction among nurses, and a method for collaborative improvement of entire institutions.

      References

      Ott, J., & Ross, C. (2014). The journey toward shared governance: the lived experience of nurse managers and staff nurses. Journal of nursing management, 22(6), 761-768.


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    1. On 2014 Mar 18, Willem Schaik commented:

      There is a typo in the abstract of our paper. The name of the gene which was deleted is ptsD (not pstD) to indicate that it encodes the IID subunit of the PTS. I apologize for this error.


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    1. On 2014 Jan 14, Hilmar Lapp commented:

      While I agree with the advantages the author advocates for Git, any distributed version control system (DVCS) can in principle have the same. There are several other mature and widely used DVCSs, in particular Mercurial (Hg) and Bazaar (Bzr), with similarly sophisticated repository hosting platforms and web interfaces available (Bitbucket and Launchpad, respectively). Thus, while Git does have great potential for facilitating reproducibility and transparency in science as the author argues, it is DVCSs in general that do, in contrast to client-server oriented VCSs, and Git is just one example of those, even if a particularly good one.

      This is indeed mentioned in the text, albeit only briefly, and is thus easily missed. In particular, I wish the title had a reference to distributed version control, rather than only to a single product that implements DVCS.


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    1. On 2013 Oct 23, Stephen Turner commented:

      This review lays out some of the challenges and recent advances in viral metagenomic sequencing. There is a good discussion of library preparation and how that affects downstream sequencing. Alarmingly, they reference another paper that showed that different amplification methods resulted in detection of a completely different set of viruses (dsDNA viruses with LASL, ssDNA with MDA). The review also discusses many of the data management, analysis, and bioinformatics challenges associated with viral metagenomics.


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    1. On 2017 Dec 01, Su-Fang Lin commented:

      Dear Authors:

      There are some discrepancies between Figure S7 legend (p9) and Table S8, could you please clarify those confusion for us? BTW, your work has paved the way for HNC stratification, thank you ALL very much! :-)

      1. SCC15 (predicted basal in Fig S7, noted as MS in Table S8)
      2. KYSE140 (predicted MS in Fig S7, noted as CL in Table S8)
      3. FADU (predicated MS in Fig S7, noted as AT in Table S8)


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    1. On 2014 Mar 21, Jacob Puliyel commented:

      Williams and colleagues have described assessment of AEFI employing the algorithm described by Halsey < PMID: 22507656>.

      I have posted two very detailed comments to an article by Tozzi Tozzi AE, 2013 which discusses the same subject of the revised WHO Classification of AEFI. I will not repeat the points I have made there but it may be viewed here.

      As this is a matter of patient safety I think it is important that the experts who understand the new scheme must explain why the revision was needed and that it will not miss opportunities of picking up new signals. The question is whether the new scheme would have picked up and flagged the signal of adverse-effects like the RotaShield-reactions, had the scheme been in use in 1999. The purpose of this posting is to invite the learned authors of this article on causality assessment to respond to the issues raised in the postings to the Tozzi article and I propose to flesh out those concerns a little further in the context of the article in Pediatrics by Williams and colleagues.

      1) Williams and colleagues Williams SE, 2013 suggest that the first step in the general approach to evaluating serious AEFI is to establish a clear diagnosis using Brighton Collaboration case definitions.

      The second step is to consider known biological mechanisms.

      Neither of these would have been evident when the intussusceptions signal was picked up by the old scheme (and the vaccine was withdrawn expeditiously preventing unnecessary distress to thousands of babies). Even today although a case definition has been developed for ‘intussusceptions’, the biological mechanism is not clearly defined and so the second step described by Williams et al cannot be completed.

      It was reported recently that Pentavalent vaccine (DPT co-administered with measles vaccine (MV) and yellow fever (YF) vaccine) is associated with increased mortality compared to MV + YF alone Fisker AB, 2014. It is pertinent to mention that the biological mechanisms involved are not understood.

      Neither is the biological mechanism for increased female mortality in recipients of the high-titer Edmonston-Zagreb vaccine known, although this was first noticed 2 decades ago. < PMID: 8237989>, Aaby P, 1993.

      2) It will be instructive to look at how the new algorithm has failed to flag up the deaths following Pentavalent vaccine used in Asia (DPT + Hib + Hepatitis B) and as a result, numerous children continue to be exposed to the risks of this vaccine.

      The glossary of the User Manual for the [Revised WHO classification]( who.int/vaccinesafety/publications/aevimanual.pdf) suggests ways and means to rule out a causal association. It defines causal association as a cause-and-effect relationship between the causative factor and a disease with no other factor intervening in the process.

      There have been many deaths following use of this Pentavalent vaccine in Sri Lanka. The committee WHO vaccine safety examined 19 deaths in Sri Lanka, 14 of them between 2010 and 2012. In six of the 19, a congenital heart disease was reported.

      Does preexisting congenital heart disease rule out a causal association between the vaccine and the deaths? Under this definition the 6 deaths in children with heart disease were not causally related to the vaccination.

      The older Advisory Committee on Causality Assessment Collet JP, 2000 looked at the problem more logically and holistically. For example it noted that elderly persons with concomitant or preceding chronic cardiac failure can develop cardiac decompensation after influenza vaccination due to a vaccine-caused elevation in temperature or from stress from a local reaction at the site of vaccinating. The vaccine is considered to have contributed to cardiac failure in this specific situation. It is obvious that with the older method of assessment of AEFI, caution would have been exercised when administering influenza vaccine to persons with preceding chronic cardiac failure, to avoid decompensation.

      The deaths in children with heart disease following administration of Pentavalent vaccine could well be due to decompensation. The Pentavalent vaccine must be used with caution in the presence of an underlying heart condition albeit asymptomatic. However detection of asymptomatic heart disease prior to vaccination in developing countries is impractical where the vaccine is administered by health workers who are barely literate. Is it prudent to use the vaccine under these circumstances given the findings of the Sri Lanka investigation? The new system disregards this real danger.

      3) Step 2 Checklist 4 of the revised [WHO classification for causality assessment]( who.int/vaccinesafety/publications/aevimanual.pdf) asks to check if the event can occur independently of vaccination (background rate). Thus it seems that until the deaths from vaccine AEFI are frequent enough as to increase the age specific mortality-rate in a statistically significant manner, they are to be ignored.

      The question of what background rate to use is not addressed specifically and this can further confound objective assessment of the AEFI. The Pentavalent vaccine in Asia is administered after 6 weeks of age. Would the local post-neonatal infant mortality rate (PN IMR) in the community before introduction of the vaccine be the comparator?

      Most of this post-neonatal IMR is made of babies who are very sick with pneumonia, diarrhea, sepsis, meningitis etc. The fact that the AEFI babies were brought by the mother for routine immunization suggests that the child was not sick and the mother did not consider the child was likely to die in the next day or two. The comparator must really be the SIDS rate in the locality for babies of a comparable age.

      Deaths in Bhutan were investigated and local newspapers reported on the various official explanations. It was argued that the deaths could have been due to encephalitis although there was little evidence for it. Officials explained that the encephalitis death rate in the years after the vaccine was introduced (even after adding AEFI deaths) had not increase significantly. This was sufficient grounds to accept the ‘coincidental encephalitis’ theory. One cheeky health official however pointed out that there were no cases of meningo-encephalitis reported among children below one year, in the eight months when Pentavalent vaccine was suspended in Bhutan.

      4) Another factor related to the deaths following Pentavalent vaccine is that the vast majority have occurred after the first dose and fewer after the second dose. A random event or coincidental SIDS cannot explain these deaths. However the new algorithm does not take this important factor into consideration.

      For all these reasons it would appear that the new algorithm is not a comprehensive means to assess serious adverse events. Its use will delay withdrawal of vaccines that result in serious AEFI and in the end it will erode confidence in the entire immunization programme and those who administer it.

      Can I suggest that we need to go back use older scheme namely Brighton Classification of AEFI till we find a better method to assess AEFI.


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    1. On 2014 Jul 29, David Keller commented:

      B vitamins for levodopa-associated peripheral neuropathy

      The problem: "Cases of symptomatic peripheral neuropathy [PN], sometimes severe, have been reported in patients receiving LCIG [levodopa/carbidopa intestinal gel]. Cases are generally a sensorimotor polyneuropathy with both subacute and chronic onsets, often associated with vitamin B12 and/or B6 deficiency."

      Observation: "Cases of LCIG-associated PN often have responded to vitamin supplementation"

      Advice: "It may be advisable to monitor vitamin B12/B6 status before and after patients start LCIG and be vigilant for signs of PN. Prospective, large-scale, long-term studies are needed."

      Administration of levodopa is associated with elevation of blood levels of homocysteine, a neurotoxic waste product which consumes vitamins B6, B12 and folic acid during its metabolism (1). Administration of these B-complex vitamins has been demonstrated to lower homocysteine levels, with postulated favorable effects on neurological degeneration (2). However, while I agree with the recommendation to monitor levels of B12 and B6 during levodopa therapy, I would add the suggestion that homocysteine levels be monitored directly as well, since homocysteine is the actual neurotoxin. Preventative addition of a vitamin B-complex supplement if taking levodopa is also reasonable, despite the lack of evidence from a clinical trial yet. By the time homocysteine-mediated peripheral neuropathy is symptomatic, it may be difficult or impossible to reverse.

      References

      1: Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett. 2006 May 29;580(13):2994-3005. Epub 2006 May 6. Review. PubMed PMID: 16697371.

      2: Cacciapuoti F. Lowering homocysteine levels with folic acid and B-vitamins do not reduce early atherosclerosis, but could interfere with cognitive decline and Alzheimer's disease. J Thromb Thrombolysis. 2013 Oct;36(3):258-62. doi: 10.1007/s11239-012-0856-x. Review. PubMed PMID: 23224755.


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    1. On 2014 Mar 08, Iffat Sumia commented:

      Love the paper ! I wonder, though, why the β-catenin-Venus fusion protein used has two point mutations in its Armadillo domain. I checked the von Kries et al., 2000 paper that's cited and it didn't help much. Is the reason for these mutations something trivial or purely technical that I missed?


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    1. On 2015 Oct 06, Jan Egger commented:

      A videos demonstrating the semi-automatic GBM segmentation can be found here: https://www.youtube.com/watch?v=z0f9RFRnC3g

      Best wishes, Jan


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    1. On 2015 Apr 06, Peter Good commented:

      To PubMed Commons: comment to Frye RE, 2013.<br> Frye et al. [2010] previously reported that sapropterin, a synthetic form of tetrahydrobiopterin (BH4), improved behavior in children with autism spectrum disorders (ASD) [Frye RE, 2010]. Their 2013 study [Frye RE, 2013] was intended to test whether sapropterin’s benefit was due to BH4’s role as cofactor for synthesis of the monoamine neurotransmitters dopamine and serotonin (as previous investigators suspected), or BH4’s role as cofactor for nitric oxide synthase (NOS), which produces the critical gaseous molecule nitric oxide (NO). Frye et al. concluded that improvements in communicative language in these children from sapropterin were due to restoration of NOS “coupling” disrupted by lack of BH4, which dysregulated nitric oxide metabolism. In support of their conclusion they cited evidence by Sweeten et al. [Sweeten TL, 2004] and others of high levels of nitric oxide metabolites nitrite and nitrate in blood of ASD children. In their previous study Frye et al. concluded: “[I]t is possible that BH4 in ASD could be depleted by the overactivation of the immune system and inflammatory processes during an excessive production of nitric oxide.” [Frye RE, 2010]

      There may, however, be more to this story. A few months after publication of Frye et al. 2013, Stanhewicz et al. reported sapropterin increased reflex vasodilation in aging human skin by increasing release of nitric oxide by endothelial and neuronal nitric oxide synthases [Stanhewicz AE, 2013]. Nitric oxide, the primary dilator of blood vessels in the body, is produced by three different forms of nitric oxide synthase – two constitutive forms present in blood vessel endothelial cells (eNOS) and neurons (nNOS), and a third form (iNOS) induced in brain microglia and other cells of the immune system in response to infections and other agencies. Endothelial nitric oxide maintains the vasodilator tone of blood vessels. Neuronal nitric oxide may be largely responsible for neurovascular coupling – dilation of nearby blood vessels when brain neurons fire. Faraci & Brian: “. . . NO appears to mediate cerebral vasodilatation in response to local neuronal activation.” [Faraci FM, 1994]. Koehler et al.: “. . . NO is required as a mediator of neurovascular coupling in the cerebellum, whereas NO acts as a modulator in the cerebral cortex.” [Koehler RC, 2009]. Inducible nitric oxide is released in large quantities to flush infective agents and toxins, and kill damaged cells.

      If nitric oxide is too high in autistic disorders, inducible nitric oxide is the form likely responsible, Frye et al. concluded. Sweeten et al. concluded likewise: “[I]t is reasonable to hypothesize that iNOS is involved in the elevated NO production in autism.” [Sweeten TL, 2004]. Yet inducible nitric oxide is often released to compensate deficiencies of constitutive nitric oxide [Hecker M, 1999;Kubes P, 2000]. One indication neuronal nitric oxide is deficient in children with autistic disorders is their failure of neurovascular coupling – their brains are often hyperexcitable, yet brain blood flow is consistently low [e.g. Ohnishi T, 2000]. Nitrite and nitrate also serve as reservoir forms to deliver nitric oxide elsewhere [Dejam A, 2005]. Lundberg & Weitzberg: “[N]itrate and nitrite should probably be viewed as storage pools for NO rather than inert waste products.” [Lundberg JO, 2005].

      Did sapropterin increase endothelial and neuronal nitric oxide in the brains of ASD children in Frye et al. 2013? Why would endothelial and neuronal nitric oxide be deficient in these children? One explanation is deficiency of BH4. Another is deficiency of the amino acid arginine – only substrate for nitric oxide [Wiesinger H, 2001]. Frye et al. found higher baseline levels of blood arginine in these children, and higher ratios of arginine to citrulline, were associated with greater improvements in language from sapropterin. They noted blood arginine and the arginine/citrulline ratio did not change significantly during sapropterin treatment – but also stated improvements in language were greater in children with “an attenuated increase in arginine.” [Frye RE, 2013]

      Considerable evidence argues that arginine is deficient in ASD children: (a) high levels of inducible nitric oxide; (b) consistently low brain creatine (arginine + glycine) [Friedman SD, 2003]; (c) frequent high blood ammonia [Filipek PA, 2004] which requires arginine to detoxify to urea; and (d) high levels of arginine vasopressin in autistic boys [Carter CS, 2007; Momeni N, 2005]. Furthermore, NOS produces harmful oxidants superoxide and peroxynitrite when NOS “uncouples” from lack of BH4 – or when arginine is deficient [Xia Y, 1996]. Because most supplemental arginine is taken up by the liver (thus unavailable to other tissues), citrulline (arginine’s precursor) or glutamine (citrulline’s precursor) may be better sources of arginine for NOS [Cynober L, 2010]. The evidence speaks for itself.

      Peter Good Autism Studies La Pine, OR www.autismstudies.net autismstudies1@gmail.com

      Carter CS. Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders? Behav Brain Res 2007;176:170–186.

      Cynober L, Moinard C, De Bandt J. The 2009 ESPEN Sir David Cuthbertson. Citrulline: A new major signaling molecule or just another player in the pharmaconutrition game? Clinical Nutrition 2010;29:545–551.

      Dejam A, Hunter CJ, Pelletier MM, et al. Erythrocytes are the major intravascular storage sites of nitrite in human blood. Blood 2005;106:734–739.

      Faraci FM, Brian Jr. JE. Nitric oxide and the cerebral circulation. Stroke 1994;25:692–703.

      Filipek PA, Juranek J, Nguyen MT, et al. Relative carnitine deficiency in autism. J Autism Dev Disord 2004;34:615–623.

      Friedman SD, Shaw DW, Artru AA, et al. Regional brain chemical alterations in young children with autism spectrum disorder. Neurology 2003;60:100–107.

      Frye RE, Huffman LC, Elliott GR. Tetrahydrobiopterin as a novel therapeutic intervention for autism. Neurotherapeutics. 2010;7(3):241–249.

      Hecker M, Cattaruzza M, Wagner AH. Regulation of inducible nitric oxide synthase gene expression in vascular smooth muscle cells. Gen Pharmacol 1999;32:9–16.

      Koehler RC, Roman RJ, Harder DR. Astrocytes and the regulation of cerebral blood flow. TINS 2009;32(3):160–169.

      Kubes P. Inducible nitric oxide synthase – a little bit of good in all of us. Glia 2000;47:6–9.

      Lundberg JO, Weitzberg E. NO generation from nitrite and its role in vascular control. Arterioscler Thromb Vasc Biol 2005;25:915–922.

      Momeni N, Nordström BM, Horstmann V, et al. Alterations of prolyl endopeptidase activity in the plasma of children with autistic spectrum disorders. BMC Psychiatry 2005;5:27–32.

      Ohnishi T, Matsuda H, Hashimoto T, et al. Abnormal regional cerebral blood flow in childhood autism. Brain 2000;123(Pt. 9):1838–1844.

      Stanhewicz AE, Alexander LM, Kenney WL. Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms. J Appl Physiol 2013:115:972–978.

      Sweeten TL, Posey DJ, Shankar S, McDougle CJ. High nitric oxide production in autistic disorder: a possible role for interferon-gamma. Biol Psychiatry 2004;55(4):434–437.

      Wiesinger H. Arginine metabolism and the synthesis of nitric oxide in the nervous system. Prog Neurobiol 2001;64(4):365–391.

      Xia Y, Dawson VL, Dawson TM, et al. Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc Natl Acad Sci USA 1996;93:6770–6774.


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    2. On 2015 Apr 30, Peter Good commented:

      None


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    3. On 2015 May 04, Peter Good commented:

      I asked Dr. Cynober whether oral arginine, citrulline, or glutamine would be the best source of arginine for brain nitric oxide and creatine in ASD children. He replied it was controversial whether oral arginine or glutamine produces more citrulline in the intestines. Citrulline enters the brain, he said, but whether it generates creatine there, and the balance between production of nitric oxide (NO) and creatine from citrulline-derived arginine, is unclear.[personal communication 2015]

      Their 2010 paper [Cynober L, 2010] presented much evidence critical to autistic disorders (ASD). Citrulline (CIT) is not normally present in protein; its usual sources are arginine (ARG) and glutamine in dietary proteins, which produce CIT in the intestines: “CIT is almost absent from natural foods, watermelon being a notable exception.” CIT bypasses the liver and forms ARG in the kidneys, which limits wasting of nitrogen as urea, and provides ARG to many other tissues, including the brain.

      “[D]irect supplementation of CIT should be more useful than ARG supplementation, leaving the kidney to convert CIT into ARG, so avoiding heavy first-pass splanchnic extraction of the ARG and the possible harmful effects of an excessive ARG [therefore NO] supply. . . . CIT is able to sustain NO production through eNOS but not iNOS. . . . CIT could also be a safe way to deliver ARG to endothelial and immune cells, and can certainly prevent excessive uncontrolled nitric oxide production. . . . [A]ntioxidant properties, together with the ability to generate NO, make CIT an excellent candidate for the treatment of pathological situations characterized by oxidative stress and decreased arginine availability . . . .”

      Because CIT stimulates protein synthesis when dietary proteins (i.e. ARG and glutamine) are low, it should be given in the postabsorptive state (3–5 hrs after meals) or fasted state (before breakfast). 10–15g/day of oral citrulline in healthy adults showed high bioavailability and no adverse effects. Because CIT is synthesized almost exclusively in the intestines, it may also be a useful biomarker of functional gut tissue.[Cynober L, 2010]

      In their 2005 paper [Curis E, 2005] Cynober and colleagues discussed other aspects of citrulline metabolism: “Citrulline presents the common reactivity of the α-amino acid family. In particular, it can form peptide bonds; hence it can therefore be present in proteins. However, since there is no known codon in the genetic table for this amino acid, its presence in a protein must always result from a post-translational modification of the protein. . . .

      “The main reason for this citrulline metabolism split between two organs [gut and kidney] is related to the efficacy of the capture of arginine by the liver. In fact, without metabolic adaptation, almost all the arginine coming from food supply would be withdrawn from the portal blood by the liver, leaving only very low amounts of available arginine for other organs. . . .

      “[M]any cell types which are able to metabolize arginine into NO are able to uptake circulating citrulline, which explains why citrulline induces certain of the NO effects . . . . The figure seems to be even more complex in the brain, since the recycling of citrulline into arginine is split between various cell types, defining a unique inter-cell-type cycle. Indeed, the brain neurones producing NO are not able to reconvert citrulline into arginine since they do not express the [necessary] enzymes. Hence, citrulline is released from the neurons and taken up by surrounding neural cells where return-conversion to arginine is performed.”[Curis E, 2005]

      Romero and colleagues presented other valuable information about citrulline [Romero MJ, 2006]: “With development, intestinal synthesis of L-arginine from glutamine decreases and the small intestine gradually becomes the major site of net L-citrulline production. . . . L-citrulline is largely taken up and metabolized by the kidney, which in turn releases arginine equivalent to ~75% of the L-citrulline taken up. Thus, much of the L-citrulline produced by enterocytes reaches the systemic circulation as L-arginine. This L-arginine/L-citrulline homeostasis allows a proper supply of L-arginine for the whole body. About 60% of dietary L-arginine makes it into the hepatic portal circulation, while the rest is metabolized in the intestine. . . . L-citrulline synthesis in many tissues also occurs as a byproduct of NOS activity. . . . Although NOS is widely distributed throughout the body, its activity does not contribute substantially to whole body L-citrulline flux under normal conditions. . . .

      “[A]cute oral administration of L-citrulline appears to be considerably more efficient raising plasma levels of L-arginine than L-arginine itself. Additionally, a recent study in children and young adults showed that five oral doses of L-citrulline every 12 hours (1.9 g/m2/dose) for a total dose of 9.5 g/m2 resulted in 57 and 85% increases in mean plasma levels of L-arginine and L-citrulline, respectively. . . . L-citrulline is generally recognized as safe for oral consumption. In fact, L-citrulline can prevent some of the untoward effects of L-arginine supplementation. . . . L-citrulline is a natural and apparently safe means of providing L-arginine for constitutive NOS production of NO.”[my emphasis] [Romero MJ, 2006]

      Deutz also presented important observations about plasma concentrations and interorgan transport of glutamine, citrulline, and arginine [Deutz NE, 2008]: “In daily practice, the plasma concentration is usually viewed as a parameter of production. This is not always correct as the plasma concentration can be high due to an increased production of the substrate and/or a reduced capacity of the body to dispose [of] this substrate. This means that the level of plasma concentration can be misleading and does not always give reliable information whether there is actually an intracellular deficiency of a certain substrate. . . .

      “The quantitative main production site [of glutamine] in the body is muscle and the main consumption sites are the gut, liver and the kidney. Liver plays a dual role as it can both produce and consume glutamine, depending on the metabolic state (fasting/fed). . . . [A]bout 80–90% of the citrulline is derived from the gut glutamine to citrulline conversion. Therefore, whole body citrulline production is related to the quantity of gut glutamine conversion to citrulline, and is most likely influenced by the amount of active gut tissue.”

      Most important conclusions for ASD: (1) oral citrulline bypasses the liver and becomes arginine in the kidneys, making arginine more available to other tissues, including the brain; (2) oral citrulline supports production of constitutive nitric oxide but not inducible nitric oxide; (3) in light of the benefit of casein-free/gluten-free diets in ASD children, citrulline’s stimulation of protein synthesis when dietary protein is low may be invaluable; (4) citrulline synthesis may be a useful marker of functional gut tissue in these children; (5) oral citrulline is safer than oral arginine. The evidence speaks for itself.

      Peter Good Autism Studies www.autismstudies.net autismstudies1@gmail.com

      Curis E, Nicolis I, Moinard C, et al. Almost all about citrulline in mammals. Amino Acids 2005;29:177–205.

      Cynober L, Moinard C, De Bandt J-P. The 2009 ESPEN Sir David Cuthbertson. Citrulline: A new major signaling molecule or just another player in the pharmaconutrition game? Clin Nutrit 2010;29:545–551.

      Deutz NEP. The 2007 ESPEN Sir David Cuthbertson Lecture: Amino acids between and within organs. The glutamate-glutamine-citrulline-arginine pathway. Clin Nutrit 2008;27:321–327.

      Romero MJ, Platt DH, Caldwell RB, Caldwell RW. Therapeutic use of citrulline in cardiovascular disease. Cardiovasc Drug Rev 2006;24:275–290.


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    1. On 2017 Jul 13, Robin P Clarke commented:

      This is an interesting finding but there is much danger of over-interpreting from it. Urine mercury has long been known to have little relationship to toxicity problems caused by mercury. The mercury causes harm not from being in the urine but from not being in the urine, due to instead getting bound up in the brain and other organs. There is abundant evidence elsewhere of the major harms being caused by mercury, and this study in no way counters that evidence.


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    1. On 2015 May 12, Gareth Pryce commented:

      There would appear to be a methodological flaw in this study which makes it's extrapolation to the human situation tenuous. Taken from this article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1397713 (Food & Drink intake of mouse)the food/fluid intake of a mouse (C57Bl/6 strain used in this study)is 4.4g/day and fluid = 6ml of fluid a day, this study used 1% salt in water = 1g in 100ml and 4% in food = 4g in 100g of food. I have calculated that on average the mice would ingest (before of course they got sick, when they wouldn't ingest any food or water) 236 mg/day for a 25g mouse = 236mg/25g = 9.44g/kg so 660g for a human ie over half a Kg of salt a day. The likelihood of any human ingesting this amount of salt is very unlikely.

      Even doing a factor of ten 60g of salt which is 8 times a recommended limit of 8g/day. and twice the 35g/day found in some papers.

      There was no dose response done in this paper, or repetition of the result reported. I am surprised that this was not picked up during the refereeing process.

      These results need to be taken with a pinch of salt!


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    1. On 2015 Apr 04, Arnaud Chiolero MD PhD commented:

      A fantastic and useful book to understand what is health risk. Highly recommended for all health scientists and especially epidemiologists lost in their odds ratios


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    1. On 2013 Oct 23, Paul Gardner commented:

      This is, in my totally unbiased opinion, a very exciting comparison of transposon mutagenesis libraries from two related species. This has fascinating consequences for pathogen evolution.


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    1. On 2013 Oct 18, James C Coyne commented:

      The authors had a responsibility to inform readers that patients assigned to the control group had to pay for any care related to diagnosis and treatment of depression. In contrast, patients assigned to the intervention group received free care. More care resulting from care being free might readily explain extraordinary differences between the two groups in receipt of care and in the primary outcome.

      For an extended discussion, see my PLOS blog post at Mind the Brain. Coordinating depression treatment from afar: Are results credible?

      http://blogs.plos.org/mindthebrain/2013/03/12/coordinating-depression-treatment-from-afar-are-results-credible/

      The letter posted below was rejected from JAMA Internal Medicine, eliminating the possibility for post publication correction of the limitations of peer review of this paper.

      Effect size in depression trial could be due to inadequacies of control treatment: Comment on Davidson and colleagues (2013) Davidson and colleagues [1] claimed benefits for a collaborative care (CC) intervention for depression that exceed not only previous CC trials, but also effect sizes for a variety of interventions for depression. Strong claims often later prove to be exaggerated or simply false [2] and deserve special scrutiny. We should keep in mind that effect sizes observed in trials are not attributes of interventions, but of comparisons between interventions and control groups. Large effect sizes can simply represent the exceptionally poor outcomes of control groups. Davison et al.’s underspecified “routine” care could simply have been inadequate care. The authors failed to acknowledge that patients in the control group had to pay for any depression treatment, whereas it was provided free to the patients in the intervention group. This might explain that the number of patients in the “routine” care group who received a new prescription of antidepressants increased by only two, versus ten in the intervention group. Similarly, the number of patients in the routine care group that received psychotherapy increased only by seven, versus an increase of 42 in the intervention group. The low rate of increased treatment occurred in the control group despite providers having been informed of patients’ depression scores. Patients were designated as “depressed” based on a self-report questionnaire. Thus, we cannot determine the extent to which patients with heightened depressive symptoms but failing to meet formal criteria for major depression were appropriately not having treatment initiated or inappropriately treated. Overall, we cannot determine whether active treatment or the mere attention and support and awareness of treatment being available free were associated with the greater improvement in the intervention group. Moreover, most patients identified as “depressed” in the intervention group were not in remission at follow up. Difficulty interpreting results could have been anticipated at the time of the study’s design. In short, results of this trial are insufficient to encourage a more ambitious trial with the same basic design, because of a lack of demonstration that any particular elements of centralized care management account for the group differences in improvement in depression that were observed, rather than inadequacies in the care provided to the control group.

      1. Davidson, KW, Bigger, JT, Burg, MM, Carney, RM, Chaplin, WF, Czajkowski, S, Dornelas, E, Duer-Hefele, J, Frasure-Smith, N, Freedland, KE; Haas, DC; Allan S. Jaffe, AS,, Ladapo, JA,; Lespe´rance, F, Medina, V, Newman, JD, Osorio, GA Parsons, F, Schwartz, JE, Shaffer, JA Shapiro, PA,. Sheps, DS, Vaccarino, V, Whang, W, Ye, S. Centralized, Stepped, Patient Preference–Based Treatment for Patients With Post–Acute Coronary Syndrome Depression CODIACS Vanguard Randomized Controlled TrialCODIACS Vanguard RCT. JAMA Internal Medicine, 2013, 1-8.

      2. Ioannidis, J. P. (2005). Why most published research findings are false. PLoS Medicine,


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    1. On 2017 Oct 31, Morten Oksvold commented:

      Please note that this article contains unreliable data, and should not be cited. The central ethical review board in Sweden found research misconduct in six articles by Macchiarini, including this one.

      Please see the report from the Central ethical review board in Sweden: http://www.epn.se/media/2516/pressmeddelande-o-12-2016eng.pdf https://drive.google.com/file/d/0By2HqPi4t2RbYzZweVRieVVMajhJQUM0cmFMekwyRVJTUFVr/view

      This information was provided by Leonid Schneider (forbetterscience.com).


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    1. On 2017 Sep 27, Seán Turner commented:

      According to the BCRC online catalog of strains, the type strain of Chiayiivirga flava is 80274, not 80273. Strain BCRC 80273 is assigned as the type strain of Azospirillum formosense Lin et al. 2012 (PubMed Id 21742820).


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    1. On 2013 Dec 08, Claudiu Bandea commented:

      Junk DNA is bunk, but not as suggested by ENCODE or Doolittle

      “Do data from the Encyclopedia Of DNA Elements (ENCODE) project render the notion of junk DNA obsolete?” (1). Echoing much of the response by evolutionary biologists to ENCODE’s suggestion that more than 80% of the human genome is functional (2), Ford Doolittle’s answer is clearly ‘No’ (1).

      However, Doolittle did not write 7 pages of small print text in PNAS (1) to discredit ENCODE’s questionable suggestion; many people only needed a paragraph or two (3; but see Ref 4). Instead, the author uses the ENCODE momentum to cover half of century of research and thinking on the evolution of genome size, junk DNA (jDNA) and the C-value enigma in search of solutions to these top remaining puzzles in genome biology. Doolittle navigates through deep conceptual gaps left open by decades of neglect in defining even the most basic notions, such as the meaning of biological function, and concludes his epic journey with a sensible prescription: “A larger theoretical framework, embracing informational and structural roles for DNA, neutral as well as adaptive causes of complexity, and selection as a multilevel phenomenon, is needed” and that, by building this theoretical framework, “Much that we now call junk could then become functional” (1).

      Like other scholars in the field of genome evolution (see, for example, Refs 3 and 4), Doolittle starts building his theoretical framework by outlining convincing data and arguments that exclude informational roles for most jDNA. Addressing non-informational roles for jDNA, however, is a much more complex and confusing issue, to the extent that the author’s narrative gets entangled as it navigates very close to a school of red herrings: “I submit that, up until now, junk has been used to denote DNA whose presence cannot reasonably be explained by natural selection at the level of the organism for encoded informational roles (bold added) (1).

      However, ever since the term ‘junk DNA’ was introduced a few decades ago (apparently, in the 1960’s, not in the 70’s as previously assumed; see Ref. 5) as jargon for presumably non-functional genomic DNA in species with high C-value, it denoted DNA whose presence could not be reasonably explained by natural selection at the level of the organism for both informational and non-informational roles, and implying otherwise is, well, fishy. Moreover, saying that “junk advocates have to date generally considered that even DNA fulfilling bulk structural roles remains, in terms of encoded information, just junk” (1) is also deceiving considering that the nucleo-skeletal and nucleotypic theories, which “describe genome size variation as the outcome of selection via intermediate of cell size” (6) have dominated the thinking in field of genome size evolution for decades; obviously, it would be equally nonsensical to state that from the perspective of non-informational functions of jDNA, the informational DNA is just junk.

      Nevertheless, it is admirable that Doolittle embraces the nucleo-skeletal and nucleotypic theories as pillars of his theoretical framework on genome size evolution and jDNA, because, as stated in the following excerpt, the nucleotypic theory was presented as a substitute for his previous ideas (7) about jDNA as ‘selfish DNA’: “Although some researchers continue to characterize much variation in genome size as a mere by-product of an intragenomic selfish DNA "free-for-all" there is increasing evidence for the primacy of selection in molding genome sizes via impacts on cell size and division rates” (8).

      So, is Doolittle’s suggestion valid? I don’t think so, not until the nucleo-skeletal and nucleotypic hypotheses or other hierarchical selection theories clearly explain the C-value enigma, and not before they pass the formidable ‘onion test’ (see Ref 4). As previously suggested (9,10), the data and observations interpreted as evidence for these theories can be explained simply as accommodating or adaptive responses by the hosts to the presence of large quantities of genomic jDNA sequences, which are there for other reasons.

      Is jDNA bunk? As proposed almost a quarter century ago (9) and re-emphasized more recently (10), there is strong evidence that jDNA serves as an adaptive defensive mechanism against insertional mutagenesis (in both germline and somatic cells) by endogenous and exogenous inserting elements, such as retroviruses, which in humans and other multicellular species can lead to a high incidence of uncontrolled cellular proliferation, or cancer. Expectedly, as an adaptive, genomic defense mechanism, the amount of protective jDNA varies from one species to another based on insertional mutagenesis activity and evolutionary constraints on genome size, which might explain the evolution of genome size and C-value enigma.

      References

      (1) Doolittle WF. 2013. Is junk DNA bunk? A critique of ENCODE. Proc Natl Acad Sci USA., 110:5294-300. Doolittle WF, 2013

      (2) ENCODE Project Consortium. 2012. An integrated encyclopedia of DNA elements in the human genome. Nature, 489:57–74. ENCODE Project Consortium., 2012

      (3) Eddy SR. 2012. The C-value paradox, junk DNA and ENCODE. Curr Biol. 6;22(21):R898-9; Eddy SR, 2012

      (4) Graur D, Zheng Y, Price N, Azevedo RB, Zufall RA, Elhaik E. 2013. On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE. Genome Biol Evol., 5(3):578-90.Graur D, 2013

      (5) Graur D. 2013. The Origin of Junk DNA: A Historical Whodunnit. Judge Starling; http://judgestarling.tumblr.com/post/64504735261/the-origin-of-junk-dna-a-historical-whodunnit

      (6) Gregory TR. 2004. Insertion-deletion biases and the evolution of genome size. Gene, 324:15-34). Gregory TR, 2004

      (7) Doolittle WF, Sapienza C. 1980. Selfish genes, the phenotype paradigm and genome evolution. Nature. 284(5757):601-3. Doolittle WF, 1980

      (8) Gregory TR, Hebert PD. 1999. The modulation of DNA content: proximate causes and ultimate consequences. Genome Res. 9(4):317-24. Gregory TR, 1999

      (9) Bandea CI. 1990. A protective function for noncoding, or secondary DNA. Med. Hypoth., 31:33-4. Bandea CI, 1990

      (10) Bandea CI. 2013. On the concept of biological function, junk DNA and the gospels of ENCODE and Graur et al. bioRxiv doi: 10.1101/000588; http://biorxiv.org/content/early/2013/11/18/000588


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    2. On 2014 Jul 16, Claudiu Bandea commented:

      Closing the gap between ‘words’ and ‘facts’ in evaluating genome biology and the ENCODE project

      When I referred to Ford Doolittle’s article (1) as “7 pages of small print text” (2), I meant it both, literary and figuratively. Indeed, Doolittle’s paper is a remarkable example of fine print, which is likely to induce heated arguments for a long time, just as the author concluded: “many of the most heated arguments in biology are not about facts at all but rather about the words that we use to describe what we think the facts might be.”

      Remarkably, more than 40 years ago, Susumu Ohno started his famous paper on junk DNA (3) with a related statement: “Over the years, I have learned that there is no such thing as a fact. What passes for a fact is in truth a set of observations and its interpretation. Therefore, the interpretation is just as important to a fact as the observation itself.”

      In my previous mini-essay (2) on Doolittle’s article (1), I made 3 main points:

      (i) Ever since the notion of ‘junk DNA’ (jDNA) was introduced as a metaphor for presumably non-functional genomic DNA in species with relatively high C-value, it has been clearly used by the scientists in the field of genome biology and evolution to denote genomic DNA that has no biological function at all, whether informational (iDNA) or non-informational (niDNA), and implying otherwise is nonsensical.

      (ii) The two main theories on putative non-informational functions for the so called jDNA, the nucleo-skeletal and the nucleotypic functions, which “describe genome size variation as the outcome of selection via the intermediate of cell size” (4), and which Doolittle uses as pillars for his theoretical framework on genome evolution and biology, do not explain the C-value paradox.

      (iii) Apparently, Doolittle is not aware of the theory that most genomic niDNA, redefined as symbiotic DNA (sDNA), functions as a protective mechanism (adaptive genomic immunity) against deleterious insertional mutagenesis by endogenous and exogenous inserting elements, such as retroviruses, and that this theory is fully supported by the current data and observations and it explains the C-value paradox (5, 6).

      Here, I attempt to further close the gap between 'words' and 'facts' in addressing the genome biology and in evaluating the ENCODE project.

      In the introductory section, Doolittle outlines the premise for his paper: “a flurry of articles and letters”, published in Nature in other journals under the umbrella of the ENCODE project, “collectively claim function for the majority of the 3.2 Gb human genome”, which, if true, would debunk the notion of jDNA (1). The problem with Doolittle’s premise, however, is that it is not based on facts; indeed, the “flurry of ENCODE publications” did not claim that the majority of the human genome is functional (7). On the contrary, in what seems to have been a concerted, but tacit ‘silence policy,’ the ENCODE authors went out of their way not to address the ‘functionally’ of the human genome in their publications. In light of this fact, Doolittle had no choice but to build the premise for his paper on secondary sources offered by various science writers (8-10), who were apparently caught into a publicity stunt orchestrated on the side by a few of ENCODE scientists. Whether Doolittle’s approach of using secondary sources, which is a strong departure from conventional academic standards, sets up a hasty precedent for the scientific literature remains to be seen.

      So, why wasn’t the ENCODE project designed in context of the fundamental issues and knowledge about genome biology and evolution, such as the C-value paradox, limited sequence conservation among closely related species, mutational load, and the evolutionary origin of most genomic sequences from transposable elements? And, why did the ENCODE researchers choose not to address these fundamental issues in their official publications? Obviously, this makes no sense considering that their massive and expensive project was funded specifically to annotate the ‘functional sequences’ of the human genome.

      Fully addressing these questions might take us deep into the science of human behavior, and might highlight deep deficiencies in our current system of funding science, which relies on a weak and closed peer review system (parenthetically, a sensible solution would be to replace this system, which is vulnerable to abuse, with a stronger and true peer review system that is open to all peers).

      Nevertheless, it is inconceivable that the ENCODE leaders, who represent some of the finest science institutions in the world, were scientifically incompetent, as suggested by some critics of ENCODE (10), and were not aware of these fundamental issues on genome biology and evolution. On the contrary, it was the appreciation for this fundamental knowledge that prompted them to be silent, as this knowledge is in conflict with some of their study objectives and raises inconvenient questions about the relevance of their study and results.

      However, as illustrated by Doolittle’s article, the full significance of this fundamental knowledge on genome biology and evolution is not clearly recognized in the field, which has led to tremendous confusion and has allowed projects such as ENCODE to flourish. Indeed, unfortunately, the knowledge on genome biology and evolution has yet to crystalize in clear facts. However, here is one (in large print): based on the C-value paradox, limited sequence conservation, mutational load, and the evolutionary origin of most genomic sequences from transposable elements, it is clear that MOST OF THE HUMAN GENOME CANNOT HAVE INFORMATIONAL FUNCTIONS, period.

      Now that we have cracked ENCODE’s ‘code of silence’, reset some of Doolittle’s small print, and crystalized the fact that only a small fraction of the human genome has informational functions, it is time to focus on the major question remaining in the field of genome evolution and biology:

      Does most of the genome in organisms with relatively high C-value have non-informational functions, or most of it is non-functional, metaphorically speaking junk?

      References

      (1) Doolittle WF. 2013. Is junk DNA bunk? A critique of ENCODE. Proc Natl Acad Sci USA., 110:5294-300. Doolittle WF, 2013

      (2) Bandea CI. 2013. Junk DNA is bunk, but not as suggested by ENCODE or Doolittle. PubMed Commons (National Library of Medicine; Bethesda, MD). Comment on: Doolittle WF, 2013

      (3) Ohno S. 1973. Evolutional reason for having so much junk DNA. In Modern Aspects of Cytogenetics: Constitutive Heterochromatin in Man (ed. R.A. Pfeiffer), pp. 169-173. F.K. Schattauer Verlag, Stuttgart, Germany.

      (4) Gregory TR. 2004. Insertion-deletion biases and the evolution of genome size. Gene, 324:15-34. Gregory TR, 2004

      (5) Bandea CI. 1990. A protective function for noncoding, or secondary DNA. Med. Hypoth., 31:33-4. Bandea CI, 1990

      (6) Bandea CI. 2013. On the concept of biological function, junk DNA and the gospels of ENCODE and Graur et al. bioRxiv doi: 10.1101/000588; http://biorxiv.org/content/early/2013/11/18/000588

      (7) ENCODE Project Consortium. 2012. An integrated encyclopedia of DNA elements in the human genome. Nature, 489:57–74. ENCODE Project Consortium., 2012

      (8) Kolata G. 2012 (September 5). Bits of mystery DNA, far from ‘junk’, play crucial role. The New York Times, Section A, p. 1.

      (9) Anonymous, 2012. Cracking ENCODE. Lancet, 380:950. Anonymous, 2012

      (10) Pennisi E. 2012. Genomics. ENCODE project writes eulogy for junk DNA. Science, 337:1159–1161. Pennisi E, 2012

      (11) Graur D et al., 2013. On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE. Genome Biol Evol., 5(3):578-90.Graur D, 2013


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    3. On 2014 Jul 25, Claudiu Bandea commented:

      Everlasting confusion on ‘functional DNA’ and ‘junk DNA’

      As discussed by Doolittle (1), addressing and defining the functionality of genomic DNA can be challenging. However, our common sense combined with our philosophical instinct - we know a function when we see one - should allow us to sensibly address the biology of our genome. After all, the ENCODE ‘function fiasco’ was not the result of misunderstanding the concept of biological function, nor was it due to scientific incompetence as suggested by others (2). On the contrary, because it conflicted with some of the project’s objectives and with its significance, there was a concerted effort not to bring this concept forward (3); indeed, as clearly shown in a recent ENCODE publication (4), at least some ENCODE members seem well aware of the scientific rationale and criteria for addressing putative biological functions for genomic DNA.

      Nevertheless, as concluded by Doolittle (1), poor use of words in communicating scientific observations, and lack of attention to detail have led to significant misrepresentations and confusion. Here are a few examples spanning more than four decades.

      In a recent study entitled “Multiple knockout mouse models reveal lncRNAs are required for life and brain,” which addressed putative biological functions of long noncoding RNAs (lncRNAs), it was concluded that “This study demonstrates that lncRNAs play critical roles in vivo…” (5). Unfortunately, both the title and the conclusion misrepresent the results; an accurate interpretation of the results is that “Multiple knockout mouse models reveal that some (or a few) lncRNAs are required for life and brain,” and that “This study demonstrates that some (or a few) lncRNAs play critical roles in vivo….” As a matter of fact, based on the results of the study, which showed that only 5 of the 18 lncRNAs, which have been selected from hundreds sequences as the best candidates for being functional, a more appropriate scientific interpretation would be: “This study demonstrates that most lncRNAs (i.e. 13 out of 18) do not appear to play critical roles in vivo….” Moreover, if the goal is to evaluate this study at the highest scientific standards (as presumably required by the journal eLife, where it was published), then, I would suggest that, due to lack of appropriate control experiments such as duplicated knockout experiments, we don’t know if the observed dysfunctions were associated with specific lncRNAs, or they were caused by untargeted genome modifications introduced accidentally during the procedure of generating knockout mice, which in fact questions the validly of the entire study. As previously noted (3), all these problems reflect the deficiencies of the current limited and closed peer review system; indeed, a document reviewed by a few peers (usually, 2 or 3) can hardly be considered peer-reviewed.

      The next three examples illustrate some of the confusion surrounding the concepts of biological function and junk DNA (jDNA), albeit in a more subtle way.

      In one of the first papers addressing the notion of jDNA (6), David Comings writes: “These considerations suggest that up to 20% of the genome is actively used and the remaining 80+% is junk. But being junk doesn’t mean it is entirely useless. Common sense suggests that anything that is completely useless would be discarded.”

      In their iconic paper “Selfish DNA: the ultimate parasite” (7), Leslie Orgel and Francis Crick, summarize their thoughts as follows: “The DNA of higher organisms usually falls into two classes, one specific and the other comparatively nonspecific. It seems plausible that most of the latter originated by the spreading of sequences which had little or no effect on the phenotype.”

      More recently, in a publication addressing the ENCODE project (8), Sean Eddy, remarked: “These data support a view that eukaryotic genomes contain a substantial fraction of DNA that serves little useful purpose for the organism, much of which has originated from the replication of transposable (selfish) elements.”

      Although seemingly innocent, these citations are relevant examples of poor use of words. Some of this confusion might dissipate by recognizing that: (i) if genomic sequences are not entirely useless, (ii) if they have little effect on the phenotype, or (iii) if they serve little useful purpose for the organism, then, these DNA sequences are functional, period.

      In the next example, the protagonists are Michael Eisen, the host of a popular blog suggestively named “it is NOT junk”, and Ryan Gregory, the host of another popular blog “Genomicron”. Interestingly, Eisen was the PNAS editor in charge of Doolittle’s article on jDNA (1), and, according to Doolittle, Gregory is “now the principal C-value theorist” (1). Undoubtedly, Eisen and Gregory are among the most knowledgeable and versed communicators on genome biology and jDNA and, therefore, their ‘words’ are representative of the thinking in the field.

      Immediately after the publication of ENCODE’s flurry of articles and the associated publicity stunt orchestrated by a few ENCODE scientists, both Eisen and Gregory reacted forcefully, but apparently from opposite perspectives. In a post in which he blasts ENCODE as “a carefully orchestrated spectacle” (9), Eisen writes: “nobody actually thinks that non-coding DNA is ‘junk’ any more. It’s an idea that pretty much only appears in the popular press… It is dishonest – nobody can credibly claim this to be a finding of ENCODE….”

      In a prompt response (10), entitled “Michael Eisen’s take on ENCODE — there’s no junk?”, Gregory goes into a detailed and cynical questioning of Eisen’s perspective. Fortunately, due to the open communication platform offered by these blogs, this scientific ‘drama’ ended within hours, when Eisen apparently clarified: “I was not saying that everybody knows that 100% of the genome is functional! I was saying that nobody thinks that 100% of non-coding DNA is non-functional” (10).

      Is there an end to this distressing confusion in the field of genome biology? Unlikely, if the funding system continues to focus primarily on generating data and observations, while neglecting their interpretation and integration into productive conceptual frameworks; in other words, you only get what you pay for.

      References

      (1) Doolittle WF. 2013. Is junk DNA bunk? A critique of ENCODE. Proc Natl Acad Sci USA., 110:5294-300. Doolittle WF, 2013

      (2) Graur D et al., 2013. On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE. Genome Biol Evol., 5:578-90. Graur D, 2013

      (3) Bandea CI. 2014. Closing the gap between ‘words’ and ‘facts’ in evaluating genome biology and the ENCODE project. PubMed Commons (National Library of Medicine; Bethesda, MD). Comment on: Doolittle WF, 2013

      (4) Kellis M. et al., 2014. Defining functional DNA elements in the human genome. Proc Natl Acad Sci USA., 111:6131-8. Kellis M, 2014

      (5) Sauvageau M. et al., 2014. Multiple knockout mouse models reveal lincRNAs are required for life and brain development. eLife (DOI: 10.7554/eLife.01749) Sauvageau M, 2013

      (6) Comings DE.1972. The structure and function of chromatin. Adv Hum Genet. 3:237-431. Comings DE, 1972

      (7) Orgel LE, Crick FH. 1980. Selfish DNA: the ultimate parasite. Nature. 284:604-7. Orgel LE, 1980

      (8) Eddy SR. 2012. The C-value paradox, junk DNA and ENCODE. Curr Biol. 22:898-9. Eddy SR, 2012

      (9) Eisen M. 2012. This 100,000 word post on the ENCODE media bonanza will cure cancer. Blog: it is NOT junk. http://www.michaeleisen.org/blog/?p=1167

      (10) Gregory TR. 2012. Michael Eisen’s take on ENCODE — there’s no junk? Blog: Genomicron. http://www.genomicron.evolverzone.com/2012/09/michael-eisens-take-on-encode-theres-no-junk/


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    1. On 2013 Oct 31, John Cannell commented:

      The authors reported that immune system dysregulation is common in autism spectrum disorder (ASD”. Vitamin D deficiency produces very similar immune dysregulation.

      Prietl B, 2013

      Kamen DL, 2010

      Yang CY, 2013

      Baeke F, 2010

      Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

      Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

      Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

      Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

      There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

      Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

      DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

      Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

      Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

      Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

      Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

      70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day and few toddlers or pregnant women get any sunshine due to the sun scare. As vitamin D fortified milk consumption and sun exposure has declined, so have toddlers and pregnant women’s vitamin D levels. The dramatic increase in the incidence of ASD occurred during the same time vitamin D levels were falling in toddlers and pregnant women.

      Cannell JJ. Autism, will vitamin D treat core symptoms? Medical Hypotheses. 2013 Aug;81(2):195-8. Cannell JJ, 2013

      Some autism researchers seem cognizant of the entire body of autism research. For example, a group of well-known European ASD researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into the vitamin D deficiency theory of ASD.

      Kočovská E, Fernell E, Billstedt E, Minnis H, Gillberg C. Vitamin D and autism: clinical review. Res Dev Disabil. 2012 Sep-Oct;33(5):1541-50. doi: 10.1016/j.ridd.2012.02.015. Epub 2012 Apr 21.Kočovská E, 2012

      Until all autism researchers become cognizant of the wider body of scientific research, we will continue to wonder how to prevent - and perhaps even treat - this modern day plague.

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


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    1. On 2013 Dec 23, guoan zhang commented:

      this study is very helpful to clarify the role of aspirin in cancer prevention because of its big sample and long follow-up time.


      This comment, imported by Hypothesis from PubMed Commons, is licensed under CC BY.

    1. On 2015 Oct 09, Simon Young commented:

      The authors of this study conclude “there was a statistically significant decrease on depression, stress, and mood disturbances scores among the intervention group”. They attribute this to the nutritional content of the Talbinah. However another explanation is more plausible. During the intervention period the participants received a single serving of Talbinah once a day, and during the control phase they received no nutritional supplement. Even if the participants were not aware of the belief that Talbinah improves mood before the study they would have been informed of this in description of the study in the consent form. Thus participants were fully aware of the fact that they were receiving a nutritional supplement thought to improve mood during one period and nothing in the other period. Given the lack of an active control group the expectations of the participants could have explained the changes seen when ingesting Talbinah. In this type of study a plausible placebo treatment is essential if the effect of an intervention is to be established. The authors discuss three potential mechanisms for the effect of Talbinah. The first is the effect of the carbohydrate in the Talbinah. The supplement contained 21.6g of carbohydrate per dose, which would obviously be a small percentage of the participants’ total daily carbohydrate intake and highly unlikely to alter mood significantly over the period of a day. While the paper includes information, on page 283, on nutrient intakes during intervention and control periods, results are given only for total calories (increased by 9.2% during the intervention period, although the Talbinah alone would have increased it by only 6.5%), zinc and magnesium. Although the authors must have had information on the increase in carbohydrate intake during the intervention, that information, surprisingly, is not included in the paper. The second potential mechanism is an increase in brain tryptophan and serotonin due to the tryptophan content of the Talbinah. The paper documents the fact that the ratio of trp:BCAA in Talbinah is much higher than in either milk or barley. However, the authors are not correct in stating on p.284 that “The amino acid composition of food is associated with brain serotonin levels, especially trp:BCAA and trp:LNCAA” and that “The ratio of trp:BCAA may have increased the tryptophan available to the brain”. As stated in the reference they cite in support of these statements (number 9 in the reference list) Wurtman RJ, 2003 “Brain tryptophan concentrations and the flux of tryptophan from blood to brain, depend, in turn, partly on plasma tryptophan and partly on plasma concentrations of ≥ 6 other large neutral amino acids (LNAAs): tyrosine, phenylalanine, leucine, isoleucine, valine, and methionine, which compete with tryptophan for blood-brain barrier transport”. The ratio of trp:BCAA is irrelevant as the brached chain amino acids are only some of the amino acids that compete with tryptophan for transport from blood to brain. The authors docment on page 284 of the manuscript that Talbinah has a low trp:LNAA ratio of 1:21. Given the low protein content of the Talbinah (1.2 g per dose, Table 1) and the low trp:LNAA ratio the Tablinah could not have increased brain tryptophan and serotonin to any appreciable extent. The third potential mechanism is an increase in zinc levels. Several studies have shown that zinc levels are often low in depressed patients. A recent review includes four studies on the effect of zinc on depressed mood Lai J, 2012. Two studies with a daily dose of 25 mg zinc showed an antidepressant effect in patients with major depression, while two other studies, one with a dose of 7 mg per day and the other with doses of 10.1 mg per day and 20.2 mg per day in different groups, did not reliably show an effect on mood in healthy people. In this paper the Tablinah increased mean zinc intake from 3.7 mg per day to 8.7 mg per day. There is no evidence that a supplemental dose of 5 mg per day of zinc can influence mood. In conclusion there is no plausible bioligcal mechanism for an effect of Talbinah, at the dose given, on mood. Given the way the study was designed the most plausible explanation for the effects on mood was a psychological mechanism, the expections of the participants.


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    1. On 2013 Jul 01, lu tian commented:

      It is a very interesting idea of using observable short-term event information such as PFS status up to a landmark time point to predict the long term survival status. Predicting the residual life based on most updated current information (including short-term event status) is THE real-life problem. The "baseline" used in traditional survival analysis is somewhat artificial and pertains to the study from which the data is collected.

      On the other hand, it will be interesting to study the proposed prediction performance measure such as AUC as a function of time t0, i.e., the landmark time. This can provide useful information on the choice of landmark time to evaluate the short-term event status such as tumor growth to maximize the performance boost in the predicting the long-term event outcome.


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    1. On 2013 Oct 31, John Cannell commented:

      The authors reported that immune system dysregulation is common in autism spectrum disorder (ASD”. Vitamin D deficiency produces very similar immune dysregulation.

      Prietl B, 2013

      Kamen DL, 2010

      Yang CY, 2013

      Baeke F, 2010

      Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

      Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

      Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

      Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

      There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

      Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

      DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

      Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

      Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

      Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

      Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

      70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day and few toddlers or pregnant women get any sunshine due to the sun scare. As vitamin D fortified milk consumption and sun exposure has declined, so have toddlers and pregnant women’s vitamin D levels. The dramatic increase in the incidence of ASD occurred during the same time vitamin D levels were falling in toddlers and pregnant women.

      Cannell JJ. Autism, will vitamin D treat core symptoms? Medical Hypotheses. 2013 Aug;81(2):195-8. Cannell JJ, 2013

      Some autism researchers seem cognizant of the entire body of autism research. For example, a group of well-known European ASD researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into the vitamin D deficiency theory of ASD.

      Kočovská E, Fernell E, Billstedt E, Minnis H, Gillberg C. Vitamin D and autism: clinical review. Res Dev Disabil. 2012 Sep-Oct;33(5):1541-50. doi: 10.1016/j.ridd.2012.02.015. Epub 2012 Apr 21.Kočovská E, 2012

      Until all autism researchers become cognizant of the wider body of scientific research, we will continue to wonder how to prevent - and perhaps even treat - this modern day plague.

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


      This comment, imported by Hypothesis from PubMed Commons, is licensed under CC BY.

    1. On 2014 Jan 15, Hirotaka Shoji commented:

      "ImageLD/EP/TM", image analysis application softwares used for behavioral analysis in this article, are now freely available from http://www.mouse-phenotype.org/software.html.


      This comment, imported by Hypothesis from PubMed Commons, is licensed under CC BY.

    1. On 2017 Aug 05, Fernando Castro-Chavez commented:

      Dear Reader, in this work I had the opportunity to use the novel technology of 3-D magnetic levitation to produce human Vascular Smooth Muscle Cells (VSMC) calcifying after the addition of Lyso Phosphatidyl Choline (LPC), it took me a couple of years to optimize every detail to obtain the most amazing images of those spherical clusters secreting the calcium Hydroxyl Apatite (HA) in an ordered and organized manner; so, we saw that the LPC (a traveler on the surface of the LDL) is the main culprit of Atherosclerosis, because it acts as detergent of the VSMC, so, actually their efforts at calcification, trans-differentiating into osteogenic cells is their strategy of survival to continue alive. The SHN3 slightly delayed the process. Att., Fernando Castro-Chavez.


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    1. On 2017 Jul 31, Boris Barbour commented:

      The restrictive journal correspondence format might allow the impression that there remains some uncertainty about these issues, but in my opinion there is none. I have added my viewpoint under the original commentary.

      https://www.ncbi.nlm.nih.gov/pubmed/22572946#cm22572946_73372


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