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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 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/

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?

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.

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."

On 2016 Apr 19, Lydia Maniatis commented:

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

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.”

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

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.

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

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

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.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 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).

On 2017 Oct 05, ROBERT HURST commented:

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

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.

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

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.

On 2014 Apr 30, Jason Stajich commented:

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

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/

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

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?

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.

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.

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.

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.

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.

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!

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

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.

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!

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.

On 2013 Nov 02, Matt Nolan commented:

Code for simulations in this study is available at: http://senselab.med.yale.edu/ModelDB/ShowModel.asp?model=150031

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.

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

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).

On 2014 Nov 08, Ivan Oransky commented:

This paper is being retracted: http://www.retractionwatch.com/2014/11/04/kidney-journal-to-retract-stem-cell-paper-for-duplicated-and-doctored-images/

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.

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

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!

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.

On 2014 Nov 25, Harri Hemila commented:

The paper has been commented on at the BMJ pages, see: http://www.bmj.com/content/346/bmj.f10/rr/629228.

On 2014 Oct 07, Murat Tunc commented:

Interesting study.

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

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

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.

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!

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!

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

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 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.

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.

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.

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.

On 2016 Aug 19, Lydia Maniatis commented:

Please find comments on this article on PubPeer.

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

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

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.

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

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

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/

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.

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/

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

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.

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

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.

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/

On 2014 Jan 12, Om Prakash commented:

This CBT model appears useful in patients with Dhat syndrome.

On 2014 Jan 31, George W Hinkal commented:

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2014 May 04, Ivan Oransky commented:

This paper has been retracted: http://retractionwatch.com/2014/04/28/university-of-queensland-investigation-leads-to-third-retraction/

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.

On 2014 Nov 19, Helen E Benson commented:

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

On 2015 Sep 15, Ivan Oransky commented:

This paper, along with a related article, has been retracted: http://retractionwatch.com/2015/09/14/fabricated-results-retract-jama-clinical-trial-plus-a-sub-analysis-of-the-data/

On 2015 Jun 29, Bill Cayley commented:

A good example of when "less" is "more" - https://lessismoreebm.wordpress.com/2015/06/29/effect-of-corticosteroid-injection-physiotherapy-or-both-on-clinical-outcomes-in-patients-with-unilateral-lateral-epicondylalgia-a-randomized-controlled-trial/

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.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 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.

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

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.

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.

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.

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

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:

• https://www.researchgate.net/publication/283089519_AppendixA_query_details_in_word_document
• https://www.researchgate.net/publication/283089520_AppendixB-v02_Counts_of_trials_in_ICMJE_approved_registries
• https://www.researchgate.net/publication/283089365_appendix_C_-_excel_file_-_journal-based-sample-trial-articles

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.

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

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?

On 2013 Nov 22, Attila Csordas commented:

data available via ProteomeXchange with identifier PXD000596 http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD000596

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

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

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.

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?

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/

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

On 2014 Mar 02, Joel Topf commented:

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

On 2015 Aug 18, Bill Cayley commented:

A good example of when "Less" is "More": https://lessismoreebm.wordpress.com/2015/07/31/health-outcomes-of-continuous-positive-airway-pressure-versus-oral-appliance-treatment-for-obstructive-sleep-apnea-a-randomized-controlled-trial/

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.

On 2015 Apr 20, Ivan Oransky commented:

This paper has become the focus of a lawsuit: http://retractionwatch.com/2015/04/20/former-postdoc-suing-lab-head-for-publishing-paper-he-wrote-without-his-name/

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

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2013 Nov 25, Claudiu Bandea commented:

None

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

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.

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.

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.

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