On 2017 Sep 12, Eric Vallabh Minikel commented:

A full text pre-print of this article is now available on Zenodo thanks to dissemin.

On 2013 Jul 01, Roger Peng commented:

This is a wonderful paper that introduces principal stratification for air pollution "accountability" analysis. Most studies in this area look for natural experiment type of analyses. The application of principal stratification has the potential for opening up a new methodological avenue for evaluating air pollution interventions.

On 2017 Apr 03, Jeruza Neyeloff commented:

The general suggestion raised by Holman is appropriate: when dealing with different data sets and adjusting the spreadsheets provided, we recommend seeking help from a statistician or someone experienced in meta-analyses.

Particularly, on the cited steps, the additional file indeed does not place a lower bound on I², and depends on the researcher to know that negative values are not possible. The paper should also have more clearly described to not use a recalculated I² statistic, since it should not change according to the model chosen (fixed or random).

As stated in the article, one of the main advantages of conducting the analysis with a step-by-step approach is a better understanding of the complete analysis process and of the formulas used. However, specific-purpose software or statistical packages will yield more stable results and usually require less data manipulation by the end user. In my research group, we tend to use the spreadsheet as a teaching tool (or to generate forest plots for presentations), and to use the R Meta and Metafor packages for more complex analyses.

We hope the article, by providing a view of how the calculations involved in these analyses work, continues to aid students and researchers interested in meta-analyses.

On 2015 Dec 29, Rebecca Holman commented:

A clinical researcher asked me for help in using the Additional file 1: Meta-analyses and forest plots in MS Excel provided by the authors of this paper. The file had produced a strange result for this researcher's meta analysis. My concern is around step 8 of "Steps in analyzing data and producing a forest plot". The authors definition of I² is slightly different to that presented previously (see for example Higgins JP, 2003). The authors of the current manuscript do not place a lower bound of 0% on the value of I² . Hence, in some meta-analysis data sets, the additional file can result in a value of I² of less than 0%. In addition, the authors have not placed a lower bound of 0 on the value of Q-(k-1) when calculating v in step 9B "Random effects model". In some meta-analysis data sets, this can lead to negative values of v (cell M16 in the additional file). This can lead to incorrect results for a random effects based meta-analysis. When viewed in conjunction with previous comments on this paper, I feel that researchers should exercise caution when using the formulas in or additional Excel file to this paper to perform calculations or obtain figures for a meta-analysis.

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 NCT00738170. We believe the correct ID, which we have found by hand searching, is NCT00738179.

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 Nov 18, Morten Oksvold commented:

An investigation committee at Wayne State University (WSU) recommends that 42 articles from Fazlul Sarkar to be retracted (report finished August 31, 2015). This article represents one of them.

This information was published by Retraction Watch (November 17, 2016) and you can find a link to the full report here:

http://retractionwatch.com/2016/11/17/details-of-investigative-report-into-sarkar-released-by-aclu/

This article should therefore no longer be cited.

On 2015 Sep 16, F Morceau commented:

Results concerning VPA-induced PU.1 and CD11b increased expression in K562 and HL60 cells notably, were previously reported (Chateauvieux et al., Biochemical Pharmacology, Volume 81, Issue 4, 15 February 2011, Pages 498–509). This reference has been forgotten here!

On 2017 Apr 11, Atanas G. Atanasov commented:

This research area is opening possibilities for some really interesting therapeutic interventions… I have featured the manuscript at: http://healthandscienceportal.blogspot.com/2017/04/inflammation-regulation-by-short-chain.html

On 2016 Jun 28, Andrey Fedorov commented:

The atlas produced as a result of this work is available here: http://www.nitrc.org/projects/vervet_atlas/

On 2013 Oct 28, Jamie Horder commented:

An excellent short paper in which the authors warn about the use of 'narrative' reviews of clinical evidence as a kind of poor-man's meta-analysis.

In reference to the novel antidepressant agomelatine, they point out that (at the time of writing) the PubMed search "agomelatine" + "depression", reveals 73 hits, of which no fewer than 34 were review papers. Of these reviews, 80% claimed efficacy for the drug.

Rigorous meta-analyses paint a much less positive picture of agomelatine's efficacy, they argue, and unsystematic reviews act as "a modern Trojan horse for reintroducing the brave old world of narrative-based medicine into medical journals."

On 2016 Mar 27, Bruno Ramalho Carvalho commented:

I would say that under a certain point of view, receiving a diagnosis of infertility is similar to being diagnosed with a terminal illness. Far from me to compare the severity of a cancer to infertility on the physical health of the individual, but both diagnoses break the ideal continuity of the human being. It may be the continuity of life itself. It may be the perpetuation of his memory, his legacy through their descendants. So, from the perspective of the end of the line, both diagnoses at least tangent each other, and hence the devastating impact that infertility can leave on the psyche of those who have to live with it.

On 2014 Jun 17, Serge Ahmed commented:

Imagine that a rat has come to expect a limited daily access time to a desired good and that it has no way to save it for future consumption. Intuitively, you might think that the shorter the expected access time to the good, the faster the rat will consume it. In other words, the rate of consumption should be inversely related to the daily access time to the good (at least within a certain range of time values).

In this elegant study, the authors report the opposite outcome in rats self-administering cocaine. Rats did not self-administer cocaine at a lower rate but instead at a higher rate when they expected a long (6h) versus short (1h) daily access time to the drug. Importantly, when rats had no way to predict whether access time to the drug will be short or long, they self-administered cocaine as if they were expecting a short access time!

How to make sense of these rather unexpected findings? To address this question, we will probably have to address first the following other questions: Is the positive relationship between rate of consumption and access time reported in this study TYPICALLY observed with other goods or is it specific to cocaine self-administration? What does this relationship tell us about how and what do rats exactly learn in this sort of differential access time setting? Does it imply that rats have a longer future time horizon than previously thought (i.e., hours instead of minutes)? I hope that future research will shed some light on these different questions.

On 2017 Nov 07, Victoria MacBean commented:

Plain English Summary

Cystic Fibrosis (CF) is a genetic disorder in which the genes that control the movement of salt and water in and out of cells are affected, this leads to a build up of mucus mostly in the lungs but also in the liver, pancreas and intestine. The aim of the study was to determine whether high intensity exercise tasks lead to fatigue (where the muscles become briefly less able to generate force) in the abdominal muscles or the diaphragm in patients with CF.

Two groups of people were tested, one group with 10 patients with CF and the other group with 10 healthy subjects. On two different occasions the test subjects went to the lab to carry out tests. On the first occasion the subjects performed an exercise test to characterise the subjects in terms of their exercise performance and to also calculate a work rate, which was used in the second test. The second occasion involved a cycling endurance test, lung function and respiratory muscle strength testing taken on all subjects. Before and after the exercise tests, subjects underwent magnetic stimulation of their diaphragm and abdominal muscles to assess how much force the muscles could generate.

Average exercise time was similar in the healthy subjects and those with cystic fibrosis, as was the intensity of exercise they performed during the test. The measurements taken show that there were not any significant changes in the responses to magnetic stimulation after exercise in both the healthy subjects and those with CF. A decrease the response to magnetic stimulation of greater than 15% is thought to be indicative of fatigue in respiratory muscles, however, none of the subjects saw a decrease larger than 15%, thus leading to the conclusion that fatigue did not occur in any of the subjects.

The fact that that fatigue did not occur in the diaphragm or abdominal muscles after exercise in the patients with CF suggests that feelings of breathlessness and weakness in leg muscles may be more important in limiting exercise performance in those with CF. Further studies are needed in order to exactly understand the factors that hinder exercise performance of those with CF such as muscle function in non-respiratory muscles.

This summary was produced by Amazing Grace Lawal, Year 13 student from Harris Academy South Norwood, London as part of the authors' departmental educational outreach programme.

On 2016 Sep 12, Morten Oksvold commented:

In this review article three references (ref. 12, 13 and 29) cite articles which have been retracted due to research misconduct;

1. Shafer-Weaver KA, Watkins SK, Anderson MJ, Draper LJ, Malyguine A, Alvord WG, Greenberg NM, Hurwitz AA (2009) Immunity to murine prostatic tumors: continuous provision of T-cell help prevents CD8 T-cell tolerance and activates tumor-infiltrating dendritic cells. Cancer Res 69:6256–6264
2. Watkins SK, Zhu Z, Riboldi E, Shafer-Weaver KA, Stagliano KE, Sklavos MM, Ambs S, Yagita H, Hurwitz AA (2011) FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer. J Clin Invest 121:1361–1372
3. Watkins SK, Zhu Z, Riboldi E, Shafer-Weaver KA, Stagliano KER, Sklavos MM, Ambs S, Yagita H, Hurwitz AA (2011) Foxo3a programs tumor associated dendritic cells to become tolerogenic in human and murine prostate cancer. J Clin Investig 121

Please note that reference no 29 is actually identical to reference no 13.

On 2014 Jan 07, Brett Snodgrass commented:

Dear Author,

Thank you for the excellent work. Unfortunately, the article does not illustrate the arteriosinusoidal vessels described by Wearn. In addition, the arterioluminal vessels do not connect to the myocardial sinusoids. Please see the following modified image.

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

Comments and suggestions are welcome.

Thank you kindly.

On 2014 Mar 17, Gaetano Santulli commented:

Healey et al. report that subclinical atrial fibrillation (AF) is associated with an increased risk of ischemic stroke or systemic embolism (1). This finding is really intriguing, but the interpretation is problematic in that the Authors did not mention in their analysis some widely recognized independent risk factors for ischemic stroke, such as smoking status and left atrial size (2, 3). These factors clearly partake in the pathophysiology of AF-associated stroke, which is indeed mainly due to embolism of thrombus formed during stasis of blood in the left atrial appendage (2). Furthermore, there is a well-known connection between atrial dimensions and new-onset AF (4). Thus, subclinical episodes of AF could be simply a marker of stroke risk, indicating another underlying disease (2). In this trial (1), the risk of stroke was improperly assessed using the CHADS2 score (5), which was instead specifically designed just for patients with overt AF. To better understand the prognostic clinical implications of asymptomatic AF, it would be of interest to validate the significancy of provided results after correction for the omitted risk factors.

Disclosures: None.

References 1. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012;366:120-9. 2. Sacco RL, Benjamin EJ, Broderick JP, et al. American Heart Association Prevention Conference. IV. Prevention and Rehabilitation of Stroke. Risk factors. Stroke 1997;28:1507-17. 3. Benjamin EJ, D’Agostino RB, Belanger AJ, Wolf PA, Levy D. Left atrial size and the risk of stroke and death. The Framingham Heart Study. Circulation 1995;92:835-41. 4. Tsang TS, Barnes ME, Bailey KR, et al. Left atrial volume: important risk marker of incident atrial fibrillation in 1655 older men and women. Mayo Clin Proc 2001;76:467-75. 5. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-70.

Gaetano Santulli, MD, PhD Columbia University Medical Center New York, NY - USA

On 2015 Oct 31, David Keller commented:

Marijuana smokers were compared with tobacco smokers who smoked 40 times more cigarettes per day

Pletcher and colleagues compare the long-term effects on pulmonary function of smoking marijuana versus smoking tobacco. They conclude that tobacco smokers suffer worse degrees of pulmonary function impairment, as measured by spirometry, than do marijuana smokers for comparable amounts of use of each substance. However, their formula for defining equivalent levels of tobacco versus marijuana smoking is heavily biased and seems designed to yield a comparison which is highly favorable to marijuana use.

In each defined level of use, the tobacco smokers at that level inhale far more hot smoke and combustion products per day than do the marijuana smokers to whom they are compared. For example, in Table 2, the heaviest category of tobacco smokers is defined as those with a lifetime smoking history exceeding 20 pack-years (146,000 cigarettes), while the highest category of marijuana smokers is defined as those with a history of greater than 10 joint-years (3650 marijuana joints). Thus, the tobacco user smokes 40 times as many cigarettes, over the same period of time, as a marijuana smoker with whom he is compared.

However, it seems far more reasonable to suppose that the damage due to smoking any dried plant is proportional to the amount of hot combustion products inhaled. Since each tobacco cigarette contains roughly the same weight (if not more) of combustible plant matter as each marijuana joint, it is completely unreasonable to compare the pulmonary effects of smoking 40 tobacco cigarettes per day with the effects of smoking just one marijuana joint (cigarette) per day. Further, it is dangerously misleading to imply, based on such a biased comparison, that smoking marijuana is in any way less damaging to the lungs than smoking tobacco. To convince me of that, the investigators should compare smokers of tobacco cigarettes with marijuana smokers who inhale the hot smoke and combustion products from an equal number of marijuana cigarettes per day.

The worst potential harm from smoking any burning dried plant matter is lung cancer, an outcome not reported or compared in this study. Furthermore, even if marijuana smokers do suffer less loss of pulmonary function than do tobacco smokers (at equal numbers of cigarettes per day), all smokers would be better off if they did not smoke at all, even if they continued to use tobacco or marijuana by some less harmful route of delivery; tobacco smokers should switch to the nicotine patch, gum or spray, and marijuana users can ingest it orally and obtain the same psychogenic effects.

On 2014 Dec 08, Alberto Halabe Bucay commented:

In this article the authors commented my work regarding treatment of cancer with citric acid (citrate).

On 2014 Mar 16, Alican Dalkilic commented:

Hoping to see more interdisciplinary research regarding psychiatric implications of medical and dermatological problems and also impact on quality of life in teh literature. Thanks, A. Dalkilic, MD, MPH

On 2015 Oct 05, Jan Egger commented:

Videos demonstrating the virtual stenting can be found here: https://www.youtube.com/c/JanEgger/videos

Best wishes, Jan

On 2016 Mar 18, ZHONGMING ZHAO commented:

My lab recently moved to the University of Texas Health Science Center at Houston. The software is now available at https://bioinfo.uth.edu/GenRev.html.

On 2016 Mar 15, Kristina Hanspers commented:

The schematic in Fig 3 is represented as a pathway in the Open Access Publication Collection at WikiPathways: http://wikipathways.org/index.php/Pathway:WP2406. These pathways are available for download in multiple formats and can be used for data analysis and visualization in tools like PathVisio and Cytoscape.

On 2017 Dec 07, Martine Crasnier-Mednansky commented:

In the discussion, the author questions whether Vibrio cholerae chitin-induced natural competence and transformation would ever occur in nature because of two seemingly irreconcilable posits: (1) transport of the PTS-sugar GlcNAc causes dephosphorylation of Enzyme IIAGlc thus preventing cAMP synthesis, and (2) chitin-induced natural competence and transformation requires cAMP for transcriptional activation of TfoX-regulated genes.

To solve this issue, the author claims "GlcNAc might not be abundant next to the chitin surface". This is probably the case as cells reaching the chitin surface are most likely limited in carbon sources, a condition in Escherichia coli leading to a marked increase in cAMP (Botsford JL, 1978). Under starving conditions, the cells are probably actively synthesizing chitinases and, in its natural chitin-rich habitat, chitin colonization and degradation are most likely not subject to catabolite repression, particularly at limiting concentrations of (GlcNAc)2 for growth.

As regards natural competence and transformation, the negative effect of GlcNAc transport is far from being established by the author’s data. According to figure 4, addition of 2 mM GlcNAc does not significantly affect transformation frequency with (GlcNAc)6 as inducer of natural transformation. Furthermore, it appears the effect of GlcNAc on transformation frequency is independent of GlcNAc transport (figure 2, third panel).

Meibom KL, 2005 proposed three controlling factors for natural transformation, "the presence of chitin; increasing cell density; and nutrient limitation, growth deceleration or stress". As regards cell density, the quorum-sensing master regulator HapR is essential for natural competence, and considering utilization of GlcNAc upon growth deceleration causes an increase in cAMP, GlcNAc may actually be a good carbon source in vitro for natural transformation in the presence of chitin.

On 2016 Apr 09, Morten Oksvold commented:

This article has been retracted due to numerous examples of unindicated splicing of gel lanes and of duplications and inversions of gel images, as described in the published retraction note:

http://www.jneurosci.org/content/36/14/4138?etoc

The problematic issues were known for the Editor of J Neurosci in fall 2012, but ignored. After massive correspondence by Paul Brookes (see link below), the journal has finally retracted the article.

http://www.psblab.org/?p=167

The article should not be cited in the future.

On 2016 Jun 25, James Tsung commented:

Link to case video: https://youtu.be/7FoNygMX__U?list=PLHg2xyua_Kjt2c69_3vGbciHwmlBIgI6R

On 2014 Feb 26, Preben Berthelsen commented:

NEJM: Not a First Born but a Worthy Sibling. In “A Reader’s guide to 200 Years of the New England Journal of Medicine” by Allan M. Brandt it is postulated that NEJM “remains the longest continuously published medical periodical in the world”. This is not accurate. The Danish journal - BIBLIOTEK for LÆGER (A Library for Physicians) - has been published continuously since the first issue in 1809. The Danish medical periodical thus antedates the Journal by three years. In science, priority has always been an issue of great interest. With this letter I do not claim priority for Bibliotek for Læger as the oldest still existing medical journal. It is, however, quite likely the case. Today, the main focus of the journal is on medical history, culture, philosophy and scientific methodology. Published papers are in Danish with summaries in English.

P.G.Berthelsen, MD. Charlottenlund, Denmark. Feb. 25, 2014

On 2016 May 23, Jonathan Heald commented:

Posted on behalf of the American Academy of Sleep Medicine:

The recommendations for the use of adaptive servo-ventilation for the treatment of congestive heart failure related central sleep apnea have been updated, and can be found in the following publication:

Aurora RN, 2016

On 2014 Mar 12, George W Hinkal commented:

None

On 2014 Feb 27, George W Hinkal commented:

The National Cancer Institute has been investing in the development of an online webportal of curated cancer nanotechnology data called caNanoLab. The numerical data, nanomaterial characterizations and composition information for the twelve nanoparticles 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=36601857&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=36601858&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=36601859&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=36601860&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=36601861&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=36601862&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=36601863&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=36601864&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=36601865&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=36601866&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=36601867&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=36601868&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 2014 Mar 10, Daniel Haft commented:

We noted in this paper that only some genomes with type II secretion systems (T2SS) have rhombosortase and a matching collection of GlyGly-CTERM proteins, but essentially all genomes with rhombosortase have T2SS. This comment discusses proteins from the cholera pathogen that are both T2SS targets and GlyGly-CTERM proteins. In Vibrio cholerae, cholera toxin and at least 20 other proteins depend on T2SS for export, including 16 found by Sikora, et al. (PMID:21385872) in 2011. Three targets found in that study, the related trypsin-like serine proteases VCA0803 (VesA), VC1200 (VesB), and VC1649 (VesC), are three of V. cholerae's six GlyGly-CTERM proteins (the others are VCA0065, VC2621, and VC1485). VesA, in particular, may be highly relevant to pathogenesis, since "...analysis of single, double, and triple protease knock-out strains indicated that VesA is the primary protease responsible for processing the A subunit of cholera toxin during in vitro growth of the V. cholerae strain N16961."

The GlyGly-CTERM domain appears only at a protein's C-terminus, and consists of a signature motif, a highly hydrophobic stretch likely to represent a transmembrane helix, and then a cluster of basic residues. Such a region could serve as a C-terminal transmembrane anchor, but perhaps only temporarily. In Gram-positive bacteria, sortases remove C-terminal regions from with similar structure, but with the signature motif LPXTG. In halophilic archaea, archaeosortases remove a similar region (PGF-CTERM) from the S-layer-forming major cell surface glycoprotein (see PMID:22037399 and PMID:23651326). But while archaeosortases (probably) and sortases both are transpeptidases, rhombosortase may be simply a hydrolase.

The reasons a bacterium would anchor multiple T2SS targets with a GlyGly-CTERM domain, then release them with rhombosortase, are unclear and would be interesting to know. Possibilities include delaying secretion until other steps in protein maturation have completed, apportioning proteins encoded by a single gene to two different destinations, and regulating protein destinations via signals that alter rhombosortase's expression or activity. It would also be interesting to know if every GlyGly-CTERM protein can be a T2SS target.

On 2016 May 02, Riccardo Polosa commented:

The assessment of pulmonary function and airway inflammation in healthy smokers before and after e-cigarette use by Vardavas and colleagues[1], is a perfect example of what clinical researchers should do to expand the current knowledge base of these products. Good quality research on e-cigarettes must be conducted in order to ensure that the decisions of regulators, healthcare providers and consumers are based on science. Unfortunately, the work illustrated by Vardavas and colleagues are not conclusive due to the small number of subjects studied, the choice of study outcomes of unclear clinical relevance, together with the lack of appropriate controls.

The authors state that the e-cigarettes tested in their study <have immediate adverse physiologic effects after short term use that are similar to some of the effects seen with tobacco smoking>. The reported 16% decrease in FeNO (i.e. 2.1ppb in absolute term!) and 11% increase in peripheral flow resistance (IOS) (i.e. 0.025kPa/L/s in absolute term!) after e-cigarette use from baseline are so small and well within tests variability[2,3] that it is highly unlikely to have meaningful adverse effects. Of note, no changes were detected by canonical pulmonary function testing after e-cigarette use. Toxicology characterization demonstrates that their primary components (i.e. water, propylene glycol, and nicotine) are not harmful, and this is in agreement with the detailed analysis of e-cigarette toxicology by Cahn and Siegel[4]. Moreover, clinical safety assessment of one such product showed only minor side effects (e.g. oral irritation and dry cough) in the initial few weeks of use[5] and switching to e-cigarette use led to a near-normalization of exhaled carbon monoxide levels[5]. Thus, authors’ conclusions are not fully supported by the data, and the accumulating evidence rather supports a good safety profile for these products.

The small changes in FeNO and IOS may be non specific. The mist generated by the e-cigarette per se might have contributed to these changes. In a series of pilot studies we have noted that nebulization of saline can reduce FeNO up to 25% from baseline (personal observation). Consequently, authors should have included a more pertinent control (e.g. saline mist generated by an ultrasonic nebulizer) in their study. Also, another reasonable comparator that should have been used as control could have been the participants’ own brand cigarette.

We agree that large and carefully conducted long-term prospective studies will be required before a definite answer about safety of these products can be formulated[6]. Nevertheless, it is not in the best interests of public health to halt marketing of e-cigarettes until these long-term studies are completed. Obviously, other valid options for tackling nicotine dependence in smokers exist, but it is still a personal choice how to reduce or eliminate his or her own smoking. Switching to an e-cigarette is a far better option than smoking.

References

1. Vardavas CI, Anagnostopoulos N, Kougias M, Evangelopoulou V, Connolly GN, Behrakis PK. Short-term pulmonary effects of using an electronic cigarette: impact on respiratory flow resistance, impedance, and exhaled nitric oxide. Chest. 2012 Jun;141(6):1400-6.
2. Oostveen E, MacLeod D, Lorino H, et al. The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J 2003; 22:1026-1041.
3. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin AC, Plummer AL, Taylor DR; American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical Applications. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184(5):602-15.
4. Cahn Z, Siegel M. Electronic cigarettes as a harm reduction strategy for tobacco control: A step forward or a repeat of past mistakes? J Public Health Policy. 2011;32(1):16-31.
5. Polosa R, Caponnetto P, Morjaria JB, Papale G, Campagna D, Russo C. Effect of an electronic nicotine delivery device (e-Cigarette) on smoking reduction and cessation: a prospective 6-month pilot study. BMC Public Health. 2011;11:786.
6. Caponnetto P, Campagna D, Papale G, Russo C, Polosa R. The emerging phenomenon of electronic cigarettes. Expert Rev Respir Med. 2012 Feb;6(1):63-74.

On 2013 Dec 07, Gary Ward commented:

This is a descriptive study of the ultrastructure of the residual body (RB) formed during T. gondii replication, highlighting the continuity between the parasite cytosol and RB as well as the intravacuolar connections between parasites. The authors argue that the dense granule protein GRA2 plays a role in maintaining these connections.

The EM images confirm the presence of previously observed structures and organelles within the RB, including portions of the nucleus. It is unclear what is meant by the author’s statement that “Antibodies against SAG1, the parasite major surface protein, labelled the plasma membrane of proliferating parasites but not the RB membrane; probably the availability of the RB membrane was limited by the binding of the tachyzoites”. We were left wondering why the RB doesn't stain for SAG1 even though there is clearly membrane present.

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

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 2017 Sep 18, Francisco Fernandez commented:

Hi, I've reached this article with interest due to an a priori similar case. Nevertheless, it doesn't seem correct to apply 'Sudden Death' diagnosis to a patient that was hospitalized with "severe toxicities"(sic) and "the condition of the patient quickly deteriorated with a fatal outcome on day 12"(sic). I believe that the selected title is misleading.

On 2016 Nov 02, Arturo Martí-Carvajal commented:

This abstract has omitted two very important issues: I-squared and quality of evidence.

On 2013 Jun 28, Robert Tibshirani commented:

None

On 2013 Jun 13, Robert Tibshirani commented:

Although this is an interesting proposal, its power can be very low compared to competing methods. Details can be found in our published comment in Science (web version), also available at

http://www-stat.stanford.edu/~tibs/reshef/comment.pdf

In my opinion, a better measure of non-linear dependence is "distance correlation":

https://en.wikipedia.org/wiki/Distance_correlation

Rob Tibshirani

On 2014 Feb 19, Paul Brookes commented:

This paper was the subject of a comment on the PLoS Biology website on July 23rd 2013, with concerns raised about the reliability of the western blot loading controls in Figures 6 and 8. In short, the control blots contained a different number of lanes than the protein-of-interest blots... something that should have been caught during peer review. In addition one of the control blots appeared to have been duplicated between two figures representing different experimental conditions and samples.

Recently I examined this paper (having been contacted by the person who posted the original comment). I prepared a series of images to illustrate the points raised, and posted them as follows: http://i.imgur.com/JvSuSn9.jpg http://i.imgur.com/bgOmUak.jpg http://i.imgur.com/nf60fQi.jpg http://i.imgur.com/F7PfovR.jpg

In addition, while examining the paper I came across three additional problems, in which western blot images appear to have been duplicated between pairs of figures representing different experimental conditions and samples: http://i.imgur.com/4DmR4it.jpg http://i.imgur.com/1Z42k5g.jpg http://i.imgur.com/wjEmuW0.jpg

It is rather troubling that the original concerns about this paper were raised over 7 months ago, but nothing appears to have been done about it. Perhaps the high level of publicity afforded the paper (it was picked up widely as a news story suggesting that obesity may be a contagious disease) has reduced the enthusiasm of the journal editors to act appropriately? In addition despite being asked for feedback in the original PLoS website comment, the authors have not yet offered any response.

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 NCT00412551. We believe the correct ID, which we have found by hand searching, is NCT00421551.

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 Dec 16, Gregory Francis commented:

A slightly longer version of the following text was submitted as a comment to the journal Psychological Research. The editor declined to publish the comment even though two reviewers agreed that the analysis was accurate.

Doerrfeld, Sebanz and Shiffrar (2012) tested whether anticipated effort alters perceptual experience by having individuals judge the weight of a filled basket when they intended to lift the basket either alone or with another person. Four experiments consistently rejected the null hypothesis that the weight judgments were the same across the two intention conditions. The experimental results were interpreted as strong evidence for the validity of the result and confirmation of a theoretical hypothesis that perception is shaped by what can be accomplished with other people.

However, experiments should only reject the null hypothesis at a rate that reflects the power of the experiments. When experiments have low or moderate experimental power, random sampling means that some experiments should not reject the null hypothesis even if the reported effect is true. The absence of expected null findings indicates publication bias, which makes it impossible to judge whether the reported experiments are valid. As shown below, such is the case for the findings in Doerrfeld et al. (2012).

The four experiments used very similar methods and measures, so it is appropriate to pool the effect sizes across the experiments. This produces a Hedges' g value of 0.865, which is the best estimate of the effect size for this phenomenon. Using that pooled effect size gives power values of 0.791, 0.364, 0.449 and 0.637 for the four experiments. The probability that four out of four experiments like these would reject the null hypothesis is the product of the power values, which is 0.082. If they were run properly and reported fully, the experimental outcomes in Doerrfeld et al. (2012) are quite unusual for the reported effect sizes and sample sizes. The low probability of the experiment set is below a 0.1 criterion commonly used to establish publication bias.

This observation is not intended as an accusation against Doerrfeld et al. (2012), who I suspect operated with the best of intentions in designing and reporting their studies. Seemingly minor decisions throughout a research project can lead to a biased experiment set. Ultimately, it does not much matter exactly how bias was introduced; the main observation is that the set of experimental results reported by Doerrfeld et al. (2012) as evidence for their thesis would be quite rare if they were generated without some form of bias. Since there is no way to know the extent of the bias, readers should be skeptical about the findings and conclusions of the study.

The full submitted text and an Excel file detailing the power analyses can be downloaded from:

http://www1.psych.purdue.edu/~gfrancis/Publications/DoerrfeldSebanzShiffrar2012.zip

On 2014 Mar 26, Tom Kindlon commented:

Uncontrolled study proves little about value of therapy received

I wrote an e-letter with the above title, in reply to this paper, which can be read here: http://bmjopen.bmj.com/content/1/2/e000252.abstract/reply#bmjopen_el_156

On 2017 Jun 04, Misha Koksharov commented:

For those interested to investigate this loop further, I suggest to also check the substitution D475P. More details are here: https://www.ncbi.nlm.nih.gov/pubmed/25448017#cm25448017_69289

On 2014 Jan 08, Brett Snodgrass commented:

Dear Authors,

Thank you for the excellent article.

Might Figure 1C depict an arteriosinusoidal vessel of Wearn? This particular vessel of Wearn is presumably unusually prominent and may be clinically classified as a fistula.

http://bit.ly/JTWearn

For an annotated image related to that particular aspect (figure 1c) of your more comprehensive paper, please see. https://twitter.com/BrettSnodgrass1/status/418011483524431872

Comments and suggestions are welcome.

Thank you kindly.

On 2013 Nov 10, Robert Tibshirani commented:

This paper studies serum mesothelin as a biomarker for pancreatic and biliary cancers. The teen prodigy Jack Andraka http://en.wikipedia.org/wiki/Jack_Andraka developed a cheap test for mesothelin that won him the Intel Science prize. From the abstract, this paper concludes that mesothelin is not useful for detecting pancreatic and biliary cancers.

Unfortunately I have not yet read this paper- it is not open access and costs $42. This is not right! The authors work at the NCI, clearly supported by our taxes. I hope that others knowledgeable in this area will comment on this work.

On 2015 Dec 18, David Reardon commented:

Oversight of Bipolar Disorder Link to Abortion Demonstrated by Subsequent 2015 Study

Munk-Olsen's failure to account for prior abortion history in this study is underscored by a new study in the Journal of Affective Disorders, in which researchers found that 42.4 percent of the women with bipolar disorders had a history of abortion compared to only 13.5 percent of the control group.¹

These findings are consistent with a 2003 record linkage study of 56,741 low income women in California that I conducted with my colleagues. In that study we found that the rate of first-time psychiatric admissions for bipolar disorders was three times higher after abortion compared to childbirth during the four years following the pregnancy.²

References

1. Marengo E, Martino DJ, Igoa A, Scápola M, Fassi G, Baamonde MU, Strejilevich SA.Unplanned pregnancies and reproductive health among women with bipolar disorder. J Affect Disord. 2015 Jun 1;178:201-5.

2. Reardon DC, Cougle JR, Rue VM, Shuping MW, Coleman PK, Ney PG. Psychiatric admissions of low income women following abortion and childbirth. Can Med Assoc J. 2003; 168(10):1253-7.

On 2014 Mar 05, David Reardon commented:

BiPolar Disorder Study Neglects Prior Research and Adequate Controls

The Munk-Olsen team’s study of elevated risk of bipolar affective disorder following psychiatric illness in the first month after a delivery is potentially important.¹ Unfortunately, the study neglected to control for the effects of prior pregnancy outcomes on bipolarity.

This omission is striking given the fact that Munk-Olsen has used the same data to publish two studies on abortion and subsequent psychiatric treatment.^2,3 She is also familiar with the three similar record linkage studies we have published in regard to a population of 56,751 low income women in California. ^4,5,6

One of these latter studies revealed that women with a history of abortion were three times more likely (OR 3.0, 95% CI 1.5-6.0) to be hospitalized for bipolar disorder than women who carried to term during the four years following pregnancy outcome.⁴ Our study also found that women who had abortions were 2.6 times more likely to be hospitalized for psychiatric treatment than were women delivered. ⁴ Similarly, Munk-Olsen has also found higher rates of psychiatric contact for each of the first 12 months following an abortion compared to delivery.² All of these facts have a direct bearing on the present study¹ and should have been addressed in the study design.

It is therefore tremendously baffling . . . if not suspicious . . . that the present study¹ did not include additional analyses relative to other pregnancy outcomes: abortion, miscarriage, and other pregnancy losses. Clearly, a history of pregnancy loss may impact the rates of postpartum depression following a live birth.^7,8 The failure to consider and control for pregnancy loss history is a major methodological weakness in this new study.

Both the American Psychological Task Force on Abortion and Mental Health and the Royal College of Psychiatry have called for more research regarding abortion and mental health. Yet studies such as this one continue to be published without information about the effects of pregnancy loss on the outcome, even when the researchers have access to complete reproductive histories. Whether investigation of these effects is being neglected due to lack of insight, or whether results are being redacted for ideological reasons, is unclear.

Journal editors and peer reviewers should heed the call for more research on associations between abortion and mental health by requesting that every study regarding reproductive outcomes and mental health should include segregated results allowing for comparisons relative to pregnancy outcome: live birth, miscarriage, abortion, and other losses.

While I communicated my hope that Munk-Olsen would correct this oversight in a reanalysis of the data shortly after this study was first published, no such results have yet been reported. To the contrary, the author has indicated there is no interest in addressing any of the issues I have raised. Despite this rebuff, it is important that reanalyses should be conducted to include segregated results allowing comparisons between delivering women with no history of pregnancy loss, women with a history of one abortion, women with a history of two or more abortions, and women with a history of one or more miscarriages.

References

(1) Munk-Olsen T, Laursen TM, Meltzer-Brody S, Mortensen PB, Jones I. Psychiatric disorders with postpartum onset: possible early manifestations of bipolar affective disorders. Arch Gen Psychiatry. 2011 Dec 5. [Epub ahead of print]

(2) Munk-Olsen T, Laursen TM, Pedersen CB, Lidegaard O, Mortensen PB. First-time first-trimester induced abortion and risk of readmission to a psychiatric hospital in women with a history of treated mental disorder. Arch Gen Psychiatry. 2012 Feb;69(2):159-65.

(3) Munk-Olsen T, Laursen TM, Pedersen CB, Lidegaard Ø, Mortensen PB. Induced first-trimester abortion and risk of mental disorder. N Engl J Med. 2011 Jan 27;364(4):332-9.

(4) Reardon DC, Cougle JR, Rue VM, Shuping MW, Coleman PK, Ney PG. Psychiatric admissions of low income women following abortion and childbirth. Can Med Assoc J. 2003; 168(10):1253-7.

(5) Coleman PK, Reardon DC, Rue VM, Cougle JR.State-funded abortions vs. deliveries: A comparison of outpatient mental health claims over five years. American Journal of Orthopsychiatry, 2002; 72(1):141–52.

(6) Reardon DC, Coleman PK. Relative treatment rates for sleep disorders and sleep disturbances following abortion and childbirth: a prospective record-based study. Sleep. 2006 Jan;29(1):105-6.

(7) Burke T, Reardon DC. Forbidden Grief. The Unspoken Pain of Abortion. Springfield, IL: Acorn Books; 2002.

(8) Stotland NL. Abortion: social context, psychodynamic implications. Am J Psychiatry. 1998 Jul;155(7):964-7.

On 2014 Sep 01, Graham Coop commented:

A blog post I wrote on Yaniv and my paper back in 2011: http://gcbias.org/2011/12/23/scrambing-eggs-toasts-meiotic-drive/

On 2013 Oct 31, John Cannell commented:

The authors found markers oxidative stress is 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 the Ameri

On 2013 Dec 19, Scott Federhen commented:

I am Scott Federhen, head of the GenBank taxonomy group, and author of his article. Since this article appeared, we have added a significant new feature to the taxonomy database - we have started to curate type material, and are using these data to flag sequence from type in Entrez. Sequence from type material is an important subset because the species identification is virtually certain to be correct (by definition) - but see Buddruhs N, 2013 for a rare cautionary example.

When a new species of prokaryote is described, the authors are required to designate a type strain and deposit it in at least two different culture collections. These are usually widely distributed between other culture collections and sold to researchers, so we have lots of sequence from type strains of prokaryotes, including many of our complete genomes.

When a new species of eukaryote is described, the authors are required to designate a type specimen and deposit it in a museum (or herbarium) where it is generally not available for subsequent sequence analysis (unless living cultures can be derived from the specimen, as with some of the fungi). We currently have very little sequence from type in the plants and animals, though it is becoming more common to include a little sequence with the description of new species - see Stoev P, 2013 for an extreme example.

See Salmonella enterica and Cercopithecus lomamiensis for examples of type material annotation in the taxonomy database.

The Entrez query sequence from type [filter] can be used to retrieve these sequence entries, and can be used in combination with other queries, e.g.: sequence from type [filter] AND metazoa[orgn].

sequence from type [filter] is also a very useful as an Entrez query to limit your BLAST searches to reliably identified sequences (particularly in the prokaryotes).

On 2016 Jan 17, M Felix Freshwater commented:

The author is William L. White

On 2013 Oct 31, John Cannell commented:

The authors found markers oxidative stress is 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 the Ameri

On 2013 Oct 24, Robert Tibshirani commented:

This paper presents a robust, nonparametric approach to inference from RNAseq data.

For a related paper and discussion of the nonparametric vs parametric approach, see

http://www.ncbi.nlm.nih.gov/pubmed/20979621/#cm20979621_226

On 2014 Jan 20, Dylmitr Rittoo commented:

A very important study. The mechanisms explaining the differences between cTnI and cTnT assays are getting clearer. I congratulate the authors on their excellent work.

On 2015 Dec 02, Benjamin Schuster-Boeckler commented:

Unfortunately it seems that this resource is now offline.

On 2017 Oct 31, Morten Oksvold commented:

Time is overdue to retract this article now. The central ethical review board in Sweden found research misconduct in six articles by Macchiarini, including this one. What more do you need Lancet?

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

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

On 2017 Jan 31, Morten Oksvold commented:

With an expression of concern since April 2016, concerns from the Royal Swedish Academy of Sciences regarding the patient handling, a declaration from the Swedish Research Council that the authors failed to apply for the legally required ethics permit to perform this operation, and three co-authors who no longer wish to be associated with this paper, and no further action, I am astonished by the editorial policy in Lancet.

On 2016 Sep 10, Md. Shahidul Islam commented:

The readers may wish to know information released by the Karolinska Instutute where the works reported in this paper were performed. Click here

On 2016 Mar 05, Andrey Alexeyenko commented:

None

On 2016 Feb 27, K Lee commented:

None

On 2014 Jul 06, David Reardon commented:

The Munk-Olsen team’s study of antidepressant use and psychological treatments before, during, and after childbirth¹ unfortunately omits any control for the effects of prior pregnancies and any comparison to other pregnancy outcomes.

A history of pregnancy loss (including induced abortion or miscarriage) can be a stressor that may arouse unresolved feelings during and following subsequent pregnancies.^2,3,4 This is also evidenced by findings that women with a history of abortion are significantly more likely to self-medicate with drugs or alcohol during a subsequent pregnancy than women without a history of this pregnancy loss.⁵

The Munk-Olsen study would have been much more informative if it had included (a) controls for prior pregnancy outcomes, and (b) parallel analyses showing the treatment rates a year before and after other pregnancy outcomes, including abortion, miscarriage, and other natural losses. The failure to provide this additional analysis is most striking given the fact that Munk-Olsen has used the same data to publish a much more nuanced comparison of psychiatric treatment rates among women who have abortions and women who carry to terms.

Both the American Psychological Task Force on Abortion and Mental Health and the Royal College of Psychiatry have called for more research regarding abortion and mental health.

In a broad sense, efforts to study the interactions between reproductive health and mental health will never be reliable as long as researchers ignore or suppress analyses which fail to encompass the full reproductive history of women, including both voluntary and involuntary pregnancy losses. Journal editors and peer reviewers should be alert to this problem and should heed the call for better research by demanding that every study regarding reproductive outcomes and mental health should include segregated results allowing for direct comparison of outcome variables relative to the entire range of pregnancy outcomes: live birth, abortion, miscarriage, and other natural losses. By pressing researchers to address and report on these related pregnancy issues, reviewers and editors will helping to advance more rigorous investigation of all of these issues. Without such requests for more detailed analyses, study designs can easily be fashioned to avoid or minimize the investigation of controversial issues.

It is my hope that Munk-Olsen will address the research imperatives raised herein by expanding the study design presented in the present paper.¹

Reanalysis should include segregated results allowing comparisons between: (a) delivering women with no history of pregnancy loss, (b) delivering women with a history of one abortion, (c) delivering women with a history of two or more abortions, (d) delivering women with a history of one miscarriages, (e) delivering women with a history of two or more miscarriages, and treatment rates for (f) women with no prior pregnancy whose first pregnancy is aborted, and (g) women with no prior live birth who have two or more abortions or other losses.

References

(1) Munk-Olsen T, Gasse C, Laursen TM. Prevalence of antidepressant use and contacts with psychiatrists and psychologists in pregnant and postpartum women. Acta Psychiatr Scand. 2011 Nov 25. doi: 10.1111/j.1600-0447.2011.01784.x. [Epub ahead of print]

(2) Reardon DC, Cougle JR, Rue VM, Shuping MW, Coleman PK, Ney PG. Psychiatric admissions of low income women following abortion and childbirth. Can Med Assoc J. 2003; 168(10):1253-7.

(3) Burke T, Reardon DC. Forbidden Grief. The Unspoken Pain of Abortion. Springfield, IL: Acorn Books; 2002.

(4) Stotland NL. Abortion: social context, psychodynamic implications. Am J Psychiatry. 1998 Jul;155(7):964-7.

(5) Coleman PK, Reardon DC, Cougle JR. Substance use among pregnant women in the context of previous reproductive loss and desire for current pregnancy. Br J Health Psychol. 2005 May;10(Pt 2):255-68.

On 2015 Jul 20, Bill Cayley commented:

A good example of when "less" is "more": https://lessismoreebm.wordpress.com/2015/07/20/perinatal-and-maternal-outcomes-by-planned-place-of-birth-for-healthy-women-with-low-risk-pregnancies-the-birthplace-in-england-national-prospective-cohort-study/

On 2014 Mar 09, Gyanshankar Mishra commented:

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

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

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

On 2014 Sep 29, Preben Berthelsen commented:

Before accepting the authors’ results it must be realized that the conclusions are based on a non-randomised, unplanned post hoc subgroup analysis of a larger study on remote ischaemic preconditioning in CABG surgery (ClinicalTrials NCT01406678). The results of the primary study were published in the Lancet (August 17, 2013). In the Lancet paper there is illuminating information on the present paper. The authors state that “After use in some patients, however, we became aware of apparent interference of propofol with remote ischaemic preconditioning and discontinued its use in the remainder of the study”. In my opinion this indicates that this is a case of betting after the race.

The authors have not statistically compared the difference in troponin release between the propofol and the isoflurane group. Their conclusions are instead solely based on within group statistical analyses. And as Bland & Altman lucidly put it “this approach is biased and invalid, producing conclusions which are potentially highly misleading” (Trials 2011,12:264).

Taken in all, I feel it justified to view the results of this paper with some scepticism. P.G.Berthelsen, Charlottenlund, Denmark.

On 2015 Jun 17, Pierre Lindenbaum commented:

http://nar.oxfordjournals.org/content/42/D1/D358 : "Recently, the MINT and IntAct databases decided to merge their separate efforts to make optimal use of limited developer resources and maximize the curation output. All data manually curated by the MINT curators have been moved into the IntAct database at EMBL-EBI and are merged with the existing IntAct dataset" http://www.ebi.ac.uk/intact

On 2014 Apr 11, Ivan Oransky commented:

This study has been subjected to an Expression of Concern: http://retractionwatch.com/2014/04/11/harvard-brigham-heart-researcher-under-investigation-earns-lancet-expression-of-concern/

On 2016 Jan 07, M Felix Freshwater commented:

A toll-free link to Goldschmidt's comment on the original research letter and my response is here.

On 2013 Sep 26, Pedro Beltrao commented:

In this paper the authors showed to what extent it is possible to predict growth phenotypes for different "individuals" (i.e. strains) of S. cerevisiae from their genome sequences.They used single knock-out fitness information under different conditions from the S. cerevisiae lab strain to interpret the consequences of likely deleterious mutations within open reading frames for the different strains. This study attacks the problem of genotype-to-phenotype predictions from a new angle as opposed to the GWAS field and marks a potentially interesting new research direction.

On 2015 Sep 10, Lydia Maniatis commented:

The authors claim that their data “characterize the luminance-to-lightness mapping in high-dynamic-range images that lack cues indicating the presence of multiple regions of illumination.” The assumption is that their checkerboards do not produce differential illumination or transparency effects, but a look at their stimuli proves otherwise. That checkerboards can produce impressions of differential illumination is acknowledged by Allred, Radonjic, Gilchrist & Brainard (2012) albeit non-commitally. The stimuli may lack known cues, but self-evidently they do not lack cues.

The authors conclusions are also complicated by the fact that in higher-range stimuli, the highest luminance was reported as glowing “on most trials.” They dismiss these results as being due to the presentation of stimuli on an “emissive display” but this doesn't explain why glow wasn't reported in the lower-range stimuli for targets of the same luminance.

On 2014 Mar 17, Gaetano Santulli commented:

Mega et al. report that in patients across the spectrum of acute coronary syndrome (ACS) low doses of the oral anticoagulant rivaroxaban reduced the risk of death from cardiovascular causes, myocardial infarction or stroke (1). Unfortunately, a large percentage of the enrolled patients was not at high cardiovascular risk. Thus, these results may be not applicable to subjects with an ACS who are commonly treated in routine practice (2). Moreover, patients with atrial fibrillation (AF), which represent up to 22% of subjects with ACS(3), were excluded from the study. Of interest, the Authors report that more than 1% of patients experienced AF, as ‘adverse event’, after rivaroxaban or placebo treatment. Although this is a small number of subjects, it would be of interest to see the data for this group presented separately. Indeed, this population represent the best category that may benefit from combined antiplatelet and anticoagulant therapy and these data could be noteworthy especially after the recent caveats stated by the Food and Drug Administration concerning this issue (4).

Disclosures: None.

References 1. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in Patients with a Recent Acute Coronary Syndrome. N Engl J Med 2011. 2. Roe MT, Messenger JC, Weintraub WS, et al. Treatments, trends, and outcomes of acute myocardial infarction and percutaneous coronary intervention. J Am Coll Cardiol 2010;56:254-63. 3. Jabre P, Roger VL, Murad MH, et al. Mortality associated with atrial fibrillation in patients with myocardial infarction: a systematic review and meta-analysis. Circulation 2011;123:1587-93. 4. Mitka M. FDA advisory decision highlights some problems inherent in pragmatic trials. JAMA 2011;306:1851-2.

Gaetano Santulli, MD, PhD Columbia University gs2620@columbia.edu

On 2013 Oct 11, Hilda Bastian commented:

This review could not take into account lifestyle factors that often accompany healthier diets and lower risk of cancer, such as not smoking. Studies like those analyzed here probably aren't enough to establish that a nutrient can prevent disease: Moorthy D, 2013. In the case of fiber and colorectal cancer, a systematic review of randomized trials (Asano T, 2002) did not find a reduction of colorectal cancer either from fiber supplements or dietary intake as in, for example, the large National Cancer Institute trial: Schatzkin A, 2000. This trial evidence is not discussed in this review by Aune and colleagues. Anyone interested in this subject would be better off starting with the systematic review of trials and trials on fiber and resistant starch published since then: Ishikawa H, 2005, Burn J, 2011. Further discussion here.

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 NCT0139171. We believe the correct ID, which we have found by hand searching, is NCT01393171.

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 Mar 20, Anders von Heijne commented:

Reviewing the MR images in this case report there is clearly an older lesion in the right medial temporal lobe with atrophy. This is not commented on by the authors. One might speculate that the patient has had an earlier episode of HSE. Additional information would be valuable.

On 2013 Nov 01, Gerard Ridgway commented:

There is new version of this work (somewhat confusingly with an unchanged abstract) "Updated April, 18, 2013", Weiner MW, 2013

On 2013 Oct 23, M Mangan commented:

Actually I found out about this new NCBI commenting system from BioStar. And I wanted to give it a try.

Here's the discussion at Biostar: http://www.biostars.org/p/84222/.

It will be interesting to see if this is much different than forum-style discussions and other sites with comments. I like the idea of a place that's not unique to one publisher. But I expect it could be difficult to build community in the same way forums and blogs do, and manage the comments.

On 2013 Jul 09, Joshua L Cherry commented:

This work develops metabolic models for six E. coli strains, performs relevant experiments with these strains, and compares model predictions to observations. The authors state that they have demonstrated that "quantitative models of different strains of E. coli can accurately predict strain-specific phenotypes." The results, however, do not support this conclusion. In fact, they point to the opposite conclusion: the models had little or no value for predicting differences between strains.

The authors predicted and experimentally determined the abilities of the strains to use various carbon sources under aerobic and anaerobic conditions. Most individual predictions agree with observations, but this fact alone means little; all strains were able to utilize the vast majority of substrates, so that simply "predicting" all positives would yield 95% agreement. For the data in Table 5, results are statistically significant under aerobic conditions for only one strain (Fisher's exact test). Under anaerobic conditions the predictions fare better: 5 of 6 cases are statistically significant. However, none of this tells us whether the predictions capture differences between strains. To address this question requires more information than counts of the sort found in Table 5.

Additional file 7 of the article provides the necessary kind of data: predicted and observed utilization capabilities for individual substrates. For reasons not clear to me, it contains predictions for only 68 substrates, rather than the 76 reported in Table 5. I have searched this data for correct predictions of differences between strains. These would be cases where one strain utilizes a substrate, another fails to do so under the same conditions, and this is correctly predicted. Across all 68 substrates and all pairings of the 6 strains, there is just one such case. This involves aerobic utilization of phenylethylamine. Even this cannot be considered a success because predictions for the other four strains are all incorrect, and all four possible combinations of predictions and observations occur. All the other differences between strains are missed, and there are several predicted differences that are shown to be false by experiment.

The authors also predict and measure growth rate and yield for growth on glucose (actually, the flux balance analysis itself predicts only yield; conversion to rate relies on measured rates of glucose uptake). When the aerobic and anaerobic data are combined, correlations between prediction and experiment are strong and significant. However, these high correlations have nothing to do with differences between strains. Rather, they reflect the difference between aerobic growth and anaerobic growth. Simply assuming that the growth rate (or yield) is higher under aerobic conditions than anaerobic conditions, and that there are no strain differences, results in similar high correlations. So does randomly permuting the predictions among strains. As the authors note, correlations disappear when strains are considered under a single condition, so there is no evidence for correct prediction of differences among strains.

Thus, it appears that the predictions contain little or no information about phenotypic differences between strains. Reconciling the models and experimental results may aid our understanding of metabolism and help improve future predictions.

On 2014 Jan 08, Tom Kindlon commented:

The SF-36 subscale scores in this paper are norm-based scores

The SF-36 subscale scores in this paper are norm-based scores. This was confirmed by the authors following a question by me on the PLoS one site: http://www.plosone.org/annotation/listThread.action?root=21433.

On 2015 Aug 08, Karl Broman commented:

The paper describing the JavaScript library D3.js, which has had an enormous impact toward popularizing web-based interactive data visualizations, because it's totally awesome.

On 2013 Jul 05, Richard Simon commented:

This is an interesting and important paper but some have misinterpreted it’s findings. The authors addressed the prognostic significance of published gene expression signatures for breast cancer (mostly for non-metastatic disease). They demonstrated that prognostic signatures can be developed over 90% of the time from random sets of >100 genes and that the signatures generated from sets of random genes are often as prognostic as published gene expression signatures. The reason is that there are an enormous number of genes that are correlated with cell proliferation and cell proliferation is strongly correlated with prognosis (estrogen receptor expression is strongly associated with outcome and prognosis and there are thousands of estrogen receptor target genes). Most published gene expression signatures are no longer prognostic after adjustment for the proliferation meta-gene. The take home message is that authors of biological mechanism papers should not claim that the genes they discovered in an experimental model system have relevance for the human breast cancer by showing that a signature based on their genes are prognostic in human breast cancer. That claim is common in cancer biology. The paper should not be misinterpreted to mean that claims of the prognostic accuracy of gene expression signatures are erroneous or that such signatures are not potentially useful for medical decision making. In fact, there are well documented pitfalls in the evaluation of predictive accuracy of prognostic signatures (e.g. using the same dataset to develop the signature and to evaluate it without using complete cross-validation). Predictive signatures which identify patients most likely to benefit from a specific treatment tend to be more useful than prognostic signatures derived based on a heterogeneous collection of cases. Nevertheless, prognostic signatures can be therapeutically relevant. This paper is well done however and it’s conclusions are carefully drawn.

On 2014 Nov 17, Raphael Levy commented:

The existence and cell penetrating properties of "striped" nanoparticles have been challenged by Cesbron Y, 2012.

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 2014 Nov 28, Juergen Borlak commented:

There has already been an extensive communication on this matter (see comments on the original manuscript in PLOS One at http://www.plosone.org/annotation/listThread.action?root=69409). Unfortunately, we note serious misconceptions that require clarification.

First, in our previous communications we already alluded to the methodology employed. Thus, all relevant information can be retrieved from the original paper. Furthermore, in our original study we alerted to the issue of underreporting and the difficulties in defining accurate incidences of ADRs. Apart from statistical issues, e.g. to determine an incidence of just 1 per 10,000 in the control group one would require 180,000 participants in the verum group, prospective studies are inevitably confounded by the study protocol inclusion and exclusion criteria that lead to additional bias. Second, in 2013 the pharmacovigilance risk assessment committee (PRAC) of the European Medical Agency (EMA) evaluated independently the evidence of flupirtine induced liver injury and concluded that the benefit still outweighs the risk for hepatotoxicity particularly when the treatment of acute pain with other analgesics (e.g. non-steroidal anti-inflammatory drugs, weak opioids) is contraindicated and the treatment duration is restricted to 14 days (http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Flupirtine-containing_medicines/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500146103.pdf). In our previous communication we referred to the deliberations of the PRAC, however, based on the comment provided we must assume that the commentator has no confidence in the capabilities of the PRAC and this would also imply that the EMA apparently is unaware of the issue of ADR underreporting which is a somewhat baffling assumption. Lastly, we do not believe that an estimate of incidences of ADR without causality assessment adds to the science of drug safety. Indeed, an incidence of less than 1 in 10,000 may be found acceptable; however, for an individual suffering from adverse drug reactions the incidence is intolerable. Therefore, we encourage the commentator to focus on the main thesis of our study, that is to improve pharmacovigilance through causality assessment and to identify individuals at risk for ADR prior to medication, as was recently reported by us for paracetamol (see Borlak et al., Genome Medicine 2013, 5(9):86).

On 2014 Nov 08, Dirk Wetzel commented:

Basic epidemiological terms should be used correctly

I respectfully disagree with the methods and conclusions of this publication. The article suggests that an incidence of flupirtine-related hepatobiliary adverse events of “1:100,000 …or 0.8 in 10,000” has been calculated. In fact, this "incidence" is based on reported cases only. The estimated number of unreported cases might be as high as 90 to 95%, because considerable under-reporting is a well-known phenomenon of spontaneous reporting. Incidence rate is clearly defined as the number of new cases of a certain condition in relation to the population at risk within a specified period of time. As the authors used the number of reported cases as numerator (“new cases”), this method probably leads to a dramatic under-estimation of the potential risks associated with flupirtine. This could be interpreted as downplaying the risks of flupirtine.

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 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 2016 Apr 05, Leigh Jackson commented:

The authors state (I have omitted text references):

"Four commonly held tenets among acupuncturists regarding electrodermal activity (EDA) at acupuncture points are: (1) acupuncture points have lower electrical resistance than surrounding skin; (2) pathology-related acupuncture points are distinguishable from non-pathology-related acupuncture points; (3) changes in electrical skin resistance or conductance at acupuncture points correlate with acupuncture treatments and with the persistence of, or recovery from, disease; and (4) changes in EDA at acupuncture points occur when substances that are either therapeutically beneficial or toxic to an individual are placed in the electrical circuit with that individual.For more than 50 years these widely-held assumptions have formed the basis for the use of electrodermal devices in clinical practice, yet scientific studies to support these beliefs are sparse and methodologically diverse. The first tenet was comprehensively evaluated by Ahn et al in a recent systematic review. This review found preliminary evidence to suggest that acupuncture points and meridians may be electrically distinguishable from non-acupuncture point and non-meridian tissue. The latter three tenets, however, have yet to be rigorously examined."

If (1) could be scientifically shown to be true, then the other tenets would become a credible prospect. Is (1) scientifically credible? What might explain such a state of affairs? The safest bet as regards the data examined by Colbert et al. is the null hypothesis. Without powerful evidence to support (1) and with no scientific explanation as to why (1) should be true, the other three tenets will require extraordinarily powerful evidence to convince sceptics.

The first tenet must be scientifically established before the others have a chance to run. Otherwise it is piling weak evidence on top of weak evidence, conjecture on top of conjecture. A house of cards is being built on a pre-scientific foundation.

On 2014 Mar 21, Pedro Reche commented:

In this manuscript, we predicted that the MHCI-like protein MR1 will have an empty groove.However, a recent report have shown that MR1 binds vitamin B metabolites (PUBMED: 23051753). Therefore, we have updated our models including that information and repeated the manuscript predictions. With the exception of MR1, all of the predictions remain the same. Prediction of the ligand-type specificity of classical and non-classical MCH I molecules with the updates models is available for free public use at http://imed.med.ucm.es/MHCLIG/

On 2016 Dec 02, Aurélie Névéol commented:

The annotated data sets are now available at https://perso.limsi.fr/neveol/DepositionDataSets.zip

On 2015 Jul 10, Egon Willighagen commented:

Because Google Code is closing down [0], the source code repository is now available from GitHub: https://github.com/semanticchemistry/semanticchemistry

0.http://google-opensource.blogspot.jp/2015/03/farewell-to-google-code.html

On 2013 Jun 15, Steven Salzberg commented:

A very important study looking at long-term use of supplements, which revealed the surprising finding that risk of death increases with regular use of vitamin supplements. Bad news for supplement manufacturers, but important news for anyone who has been taking multivitamins thinking it can't hurt.

On 2014 Sep 02, M Mangan commented:

I used this data to build a 3D-printable version of the structure: http://3dprint.nih.gov/discover/3dpx-000579 .

On 2014 Jan 31, Huiqi Qu commented:

Adiponectin/leptin ratio is suggested as a useful biomarker for metabolic syndrome by this study.

On 2014 Sep 30, Dale D O Martin commented:

Several of the proteins identified in this paper, including MACF and CD-IC2 have recently been confirmed endogenously in Thinon et al found here http://www.ncbi.nlm.nih.gov/pubmed/25255805

On 2014 Feb 07, Dale D O Martin commented:

We have since shown that caspase-cleavage of HTT releases an autophagy-inducing domain that requires its post-translational myristoylation. http://www.ncbi.nlm.nih.gov/pubmed/24459296

Videos can be seen here: http://hmg.oxfordjournals.org/content/early/2014/01/22/hmg.ddu027/suppl/DC1

On 2017 Jun 27, Andy Collings commented:

A subset of experimental results from this study were the focus of a replication attempt as part of the Reproducibility Project: Cancer Biology (https://osf.io/e81xl/wiki/home/). The experimental designs and protocols were reviewed and approved in a Registered Report (http://dx.doi.org/10.7554/eLife.08997) and the results of the experiments were published in a Replication Study (http://dx.doi.org/10.7554/eLife.25306).

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 NCT0016012. We believe the correct ID, which we have found by hand searching, is NCT00160121.

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 Oct 23, Toby Gibson commented:

LATS protein kinases function in the Hippo signalling system. They are basophilic kinases known to phosphorylate sites that match Hx[Rk]xx[ST] motifs. The requirement for a His residue marks out LATS from other AGC group basophilic kinases. LATS substrate proteins usually have multiple matches to these motifs, as for example YAP1 (human) and SSD1 (yeast). In these proteins the LATS P-sites are in regions of natively disordered polypeptide.

The LATS substrate reported here, Snail1 does have two matches to the LATS site as shown in Fig. 3

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252572/figure/f3/

But these lie within DNA-binding zinc finger domains. The His residues are part of the zinc coordinating residues that hold the domain in a folded conformation. So long as the zinc fingers are folded, these His sidechains are unavailable to access a kinase active site cleft. Indeed all the residues in the proposed site(s) are in alpha helices when the zinc fingers are folded. The H, R and T residues are conserved in many other zinc finger proteins. If Snail1 zinc fingers can be phosphorylated by LATS then many other zinc finger proteins should also be targets. Because of the restricted focus of the HIPPO signalling pathway and the limited number of known LATS substrates in fly, yeast and mammal systems, this might be unlikely.

In the absence of biophysical data showing that the Snail1 sites can become accessible under plausible phosphorylation conditions, they are considered to be false positive sites in our ELM resource entry for LATS kinases

http://elm.eu.org/elms/elmPages/MOD_LATS_1.html

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 2017 Aug 07, Randi Pechacek commented:

Jonathan Eisen used this paper as inspiration to write a blog post on microBEnet discussing the microbiomes of dishwashers.

On 2013 Dec 24, Kenneth Witwer commented:

As of April, 2014, published studies of dietary xenomiR transfer include the following (excluding reviews, in order of publication, and with public availability of high-throughput sequencing data noted if applicable):

This study: High-throughput sequencing (HTS) mapped up to tens of thousands of reads per million of specific plant microRNAs in human circulation; similar results in bovines; functional consequences for cholesterol metabolism in mice; public data availability not reported.

Zhang Y, 2012: analysis of >80 public HTS datasets; found uptake of few microRNAs; suggested contamination or other artifact(s) as explanation of miR168a detection; publicly available datasets identified in article.

Wang K, 2012: HTS, single digit reads per million of MIR168 in human circulation; public data availability not reported.

Wang K, 2013: HTS, fractional reads per million of MIR168 in murine circulation; public data availability not reported.

Snow JW, 2013: qPCR, little or no measurable uptake of dietary plant and/or animal microRNAs by humans, mice, and adult bees.

Witwer KW, 2013: qPCR, no response to dietary intake in a small primate feeding study; reportedly non-specific low-level amplification.

Dickinson B, 2013: HTS and qPCR; as mentioned by M Mangan, mouse replication study with negative results; data submitted to NCBI SRA as SRP028401.

Tosar JP, 2014: analysis of data and datasets; interpreted correlation between plant RNAs in original study findings and in a study of Amphioxus by the same group as evidence of contamination and "non-dietary" origin.

On 2013 Nov 16, M Mangan commented:

An attempt to replicate the claims in this paper has been published here: Dickinson B, 2013. The researchers were unable to make the same observations.

There's also an interesting backstory to the publication of the replication paper which you can find here: Anonymous, 2013.

On 2014 Mar 26, Wei-An (Andy) Lee commented:

In the safety-net clinic in Los Angeles, I find that premix insulin can be a great way to start patients. It reduces the initial burden of insulin initiation.

On 2014 Jan 08, Tom Kindlon commented:

References:

[1] Ross SD, Estok RP, Frame D, Stone LR, Ludensky V, Levine CB: Disability and chronic fatigue syndrome: a focus on function. Arch Intern Med 2004, 164:1098-1107.

[2] White P, Goldsmith K, Johnson A, Potts L, Walwyn R, Decesare J, Baber H, Burgess M, Clark L, Cox D, et al.: Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011, 377:823-836.

[3] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994, 121:953-959.

[4] NICE: Chronic fatigue syndrome/Myalgic encephalomyelitis (or encephalopathy); diagnosis and management. National Institute for Health and Clinical Excellence (NICE); 2007.

[5] Rapport d’évaluation (2002-2004) portant sur l’exécution des conventions de rééducation entre le Comité de l’assurance soins de santé (INAMI) et les Centres de référence pour le Syndrome de fatigue chronique (SFC). 2006. http://www.inami.fgov.be/care/fr/revalidatie/general-information/studies/study-sfc-cvs/pdf/rapport.pdf . Accessed September 16, 2011 (French language edition) [6] Evaluatierapport (2002-2004) met betrekking tot de uitvoering van de revalidatieovereenkomsten tussen het Comité van de verzekering voor geneeskundige verzorging (ingesteld bij het Rijksinstituut voor Ziekte- en invaliditeitsverzekering) en de Referentiecentra voor het Chronisch vermoeidheidssyndroom (CVS). 2006. Available online: http://www.inami.fgov.be/care/nl/revalidatie/general-information/studies/study-sfc-cvs/pdf/rapport.pdf Accessed September 16, 2011 (Dutch language version)

[7] Stordeur S, Thiry N, Eyssen M. Chronisch Vermoeidheidssyndroom: diagnose, behandeling en zorgorganisatie. Health Services Research (HSR). Brussel: Federaal Kenniscentrum voor de Gezondheidszorg (KCE); 2008. KCE reports 88A (D/2008/10.273/58) [The main link seems to (temporarily?) not to work on the Belgium government website; it can be seen combined with another file at: http://bit.ly/t6GxcN ; alternatively it is on its own at: http://sacfs.asn.au/download/ReportCFS-NL.pdf ]

[8] White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6.

[9] White PD, Goldsmith KA, Johnson AL, Walwyn R, Baber HL, Chalder T, Sharpe M, on behalf of the coauthors. The PACE trial in chronic fatigue syndrome - Authors' reply. The Lancet - 28 May 2011 ( Vol. 377, Issue 9780, Pages 1834-1835 ) DOI: 10.1016/S0140-6736(11)60651-X

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On 2014 Jan 08, Tom Kindlon commented:

Productivity costs may not drop dramatically when CFS patients avail of current services

The authors appear to do a reasonable job, given the limits of the data available to them, in calculating the productivity costs before Chronic Fatigue Syndrome (CFS) patients reach the services in the UK. However, the reader is left with the impression that the productivity costs will drop dramatically once the patient reaches the services: "We had no data with which to assess the rate at which people with CFS/ME recover and return to work, either with or without specialized treatment. According to a systematic review of the literature, the proportion of adults in employment increased following interventions for CFS/ME (individualised rehabilitation, cognitive behavioural therapy and exercise therapy) and decreased in observational studies with no intervention [1]. Evidence from a recent evidence trial of cognitive behavioural therapy and graded exercise therapy indicated a recovery rate of 30-40% one year after treatment [2]."

However it may not be the case that the therapy offered in UK clinics (or in similar clinics elsewhere) will reduce the productivity costs by much if anything.

It is interesting to consider what happened in Belgium where rehabilitation clinics for patients satisfying the same CFS criteria [3] were treated using cognitive behavioural therapy (CBT) and graded exercise therapy (GET), the same therapies recommended for use in the UK [4]. Extensive external audits were performed there on these (Belgian) clinics. The main reports are in French and Dutch [5,6]; however, for those who can't understand either of those languages, a five-page summary is available in English [7]. It says, "Employment status decreased at the end of the therapy, from an average of 18.3% of a 38h- working week, to 14.9% [...] The percentage of patients living from a sickness allowance increased slightly from 54 to 57%."

Collin and colleagues claim, "Evidence from a recent evidence trial of cognitive behavioural therapy and graded exercise therapy indicated a recovery rate of 30-40% one year after treatment [9]." However, although a recovery measure was included in the trial's protocol[8], the authors have made clear [10] that no recovery rate was reported in the Lancet paper [9]: "[i]t is important to clarify that our paper did not report on recovery; we will address this in a future publication."

Collin and colleagues also say, "[a]ccording to a systematic review of the literature, the proportion of adults in employment increased following interventions for CFS/ME (individualised rehabilitation, cognitive behavioural therapy and exercise therapy) and decreased in observational studies with no intervention [1]." This is indeed mentioned in the abstract of the review. However, when one reads the paper, the data on which this is based is very limited: 2 longitudinal studies reported employment at both times with no interventions[10,11], 2 rehabilitation programs [12,13], one trial of GET [14] and one trial of CBT[15].

The figures for the GET study are for everyone (n=66) who was in the trial so include the people who were in the other arm of the trial (flexibility exercises and relaxation therapy) who then chose to do GET. So not those who had GET alone. This trial used the Oxford criteria [16] to define CFS, criteria which only requires the symptom of fatigue rather than the other symptoms required in the Fukuda criteria [3]. A study of those with fatigue has shown that satisfying the Fukuda CFS criteria [3] was the most powerful predictor of poor response to either GET or CBT [17]. So one cannot be extrapolate from such studies that those satisfying the Fukuda criteria, who are the group that Collin studied (and the group who used the Belgian clinics), will have the same improvements in employment measures.

Similarly, the trial of CBT [15] didn't use the Fukuda criteria - patients either satisfied the Oxford criteria [16] or else criteria for F48.0 (Neurasthenia) [18] i.e. they didn't all satisfy CFS criteria at all. Employment data was only available for 51 of the 80 individuals who started CBT (64%).

Finally, in one of the rehabilitation trials quoted [12], only two individuals took part it (at baseline neither was in employment but at follow-up, one of the two was). All in all, the evidence that CBT, GET and similar interventions will increase productivity is not strong. If governments, and those involve in providing health services, want to decrease the costs associated with CFS, throwing more and more money at CBT/GET services may not be the answer; other methods of treating the condition should be investigated. As the authors have shown, costs associated with the condition per individual are substantial, so more expensive therapeutic strategies can be justified on cost grounds alone.

On 2017 Apr 02, Christine Carson commented:

There was a follow-up to this article. The full text of the response (in Swedish) is available free from Lakartidningen website http://www.lakartidningen.se/07engine.php?articleId=18503

The full text of the response (in English) is available free from ResearchGate website at https://www.researchgate.net/publication/315738411_Carson_et_al_2012_Lakartidningen_English_20130626