On 2017 Jul 10, Randi Pechacek commented:

Rachel Adams, first author of this paper, wrote a blog post on microBEnet to provide some background.

On 2016 Mar 13, Geir Bjørklund commented:

CORRECTION: My family name is Bjørklund, not BjΦrklund.

On 2015 Sep 27, Raechel Damarell commented:

The Dementia Search Filter is available on the Flinders Filters webpage at http://www.flinders.edu.au/clinical-change/research/flinders-filters/search-filters/. Other validated topic filters available include: heart failure, bereavement, residential aged care, glaucoma, contraception, and lung cancer.

On 2015 Jun 20, Matthias Kern commented:

The editorial title listed here in Medline is incorrect and contradicts the intention of the editorial. The correct title reads:

Editorial: On the scientific evidence that the sterilisation of customised implant abutments is required

The correct title of the editorial and the corresponding pdf-file can be found at: http://ejoi.quintessenz.de/index.php?doc=toc&year=2015&issue=2

On 2015 Jun 19, Christophe Dessimoz commented:

This paper is also available on Wikipedia: https://en.wikipedia.org/wiki/Inferring_horizontal_gene_transfer

Furthermore, I have written a blog post providing some background on the "Topic Page" format adopted in this article.

On 2015 Aug 20, Yoonsoo Hahn commented:

The second Comamonas bacterium (strain E6) containing the HSR1 sequence has been published (see the sequence at http://www.ncbi.nlm.nih.gov/nuccore/821590236 and the paper at http://www.ncbi.nlm.nih.gov/pubmed/26089421). Now there are two Comamonas bacteria with the HSR1 sequence. The first one JL14 was isolated in a mine in China and the second one in Niigata, Japan.

On 2015 Sep 09, Bill Cayley commented:

A good example of when less is more in cardiac care - a collection of related examples is at: https://lessismoreebm.wordpress.com/tag/cardiovascular/

On 2015 Jun 11, thomas samaras commented:

My research conflicts with the mainstream findings that short height is related to greater coronary heart disease. My conclusions are related to human studies based on worldwide research and various ethnic groups.

I have studied the relationship between height, chronic diseases, and longevity for almost 40 years. One of my papers in the Indian Heart Journal (2013) summarized worldwide findings showing shorter people have inherently lower heart disease. In 2014, I had a paper published in the Journal of Scientific Research & Reports that summarized key findings showing shorter people live longer. If tall people had inherently better hearts, then why do today's taller Americans have more coronary heart disease (CHD) compared to the early 1900s when we were a few inches shorter? Also women are shorter than men and have less CHD.

Studies from the 20th C found that many populations were free of CHD and stroke. Papua New Guineans, Kitavans, Kalahari Bushmen, Yanomami, and the Congo pygmies. Obviously, there was nothing wrong with their genes at the time they were studied. I know of no tall, western population that is free of CHD. Of course, the Japanese have had one of the lowest death rates from CHD in the developed world. When Japanese are compared in Japan, Hawaii and California, they see an increase in CHD mortality along with an increase in height.

In 2007, The World Cancer Research Fund reported that until recently, CHD was rare, even among the elderly. However, in parallel with industrial development, we have seen increases in height, weight and chronic disease (which includes CHD).

Many within population studies show that shorter people have lower CHD. These include findings from Hawaii, Sweden, Italy, UK and the US. For example, shorter elderly males were found to have lower CHD compared to taller males based on an over 40-year study of 8000 elderly Hawaiian Japanese males (He et al.). A Harvard study found that the tallest athletes had the highest rates of mortality from CHD compared to shorter athletes and non-athletes (the lowest CHD). Davenport reported that taller WWI military recruits had more heart problems than shorter ones based on 1 million men. In addition, US Asians have the lowest CHD and are the shortest ethnic group. Latinos and Native Americans are taller and have higher CHD. Whites and Blacks have the highest CHD and are the tallest.

Unfortunately, when it comes to human health and mortality, conflicting studies abound. However, confidence in a study's findings should be based on support from different types of studies (e.g., ecological, longitudinal, cross-sectional) that provide consistent results and include populations from different parts of the world and different ethnic groups.

Studies have shown that low income is a risk factor for CHD independent of other risk factors. Poor people tend to be shorter and fatter than higher income groups. A source of error in many studies is failure to compare short and tall people with the same degrees of overweight. Studies have found that shorter people tend to be more overweight than taller people. Thus, a substantial error in findings can be related to failure to compare tall and short people with the same body builds—this requires comparing taller people with higher BMIs vs. shorter people. A 10% taller person should have a 10% taller BMI for the same build type. The 1979 Build Study is the only study that I found which compared similarly overweight short and tall people. They found that the shorter cohort had a slightly lower mortality.

In 2014, a study also found that shorter people live longer (He, et al.) A 2012 study also found shorter men lived longer (Salaris, et al.)

I have reported scores of examples showing that non-Western shorter people have less CHD than taller Westerners. See www.humanbodysize.com for a listing of over 45 papers, book chapters and books expanding on what is discussed here. Some papers and a book related to height and CHD are listed below.

In conclusion, it worth noting Silventoinen's observation: CVD has increased in parallel with the Western diet and increased height.

References:

Samaras TT. Shorter height is related to lower cardiovascular disease risk—A narrative review. Indian Heart Journal 2013; 65: 66-71.

Samaras, TT. Is short height really a risk factor for coronary heart disease and stroke mortality? A review. Med Sci Monit 2004; 10(4): RA63-76.

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

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

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

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

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

On date unavailable, commented:

None

On 2015 Sep 23, Angelo Gaitas commented:

The entire response appears in the PLOS1 comment section under response: http://www.plosone.org/article/comments/info:doi/10.1371/journal.pone.0127219

In two recent articles [1, 2] two techniques for removing or inactivating blood borne pathogens were introduced. The initial experiments were performed in vitro under simplified conditions. First, the primary achievement of the PDT work deserves clarification [1]. PDT is a powerful therapeutic modality, but its clinical application has been hampered by the inability of light to penetrate deep layers of the tissue, which is mainly due to hemoglobins in the blood readily absorbing photons. Utilizing a millimeter- diameter transparent tube for extracorporeal blood circulation allows PDT to function well despite the presence of hemoglobins in blood. Another point that deserves clarification is that the tube capturing device is not a microfluidic device [2]. This technique can be adapted using existing medical tubing without the need for complicated microfluidics and micro-fabrication. The device is a medical tube that has been chemically modified using simple steps to adapt the internal surface for cell capturing. 

We would like to take this opportunity to respond to concerns brought up in [3]. We start off by addressing concern (1), which speculates about the possibility of overheating during the use of near IR light. Our control data (Fig.3 and Fig.4 of [3]), confirmed that controls illuminated without photosensitizer-antibody conjugates did not undergo cell death, whereas those with photosensitizer-antibody conjugates underwent significant cell death under identical conditions. Thus it is clear from our data that temperature did not affect the outcome. It has been shown that 660 nm irradiation is safe and effective [4-6]. 

Moving on to concern (2) part (a) that brings up the problem of using the CD-44 antigen as a target. Limitations of antibody specificity are common knowledge and not unique to CD-44, but to all antibodies. To our knowledge, a targeting method that exclusively binds only to cancer cells does not yet exist, making the use of such a compound an unreasonable standard for publication. We used CD-44 antibody to demonstrate feasibility. As targeting methodologies advance and better selectivity to target cells becomes available, this technique will have improved selectivity. Our experiments were designed to avoid non-specific damage to other cells by pre-staining pure cancer cells with the photosensitizer-antibody conjugates and subsequently removing extra free conjugates before spiking into blood (described in detail in [1]). This elimination of the possibility of side effects due to undesired binding to other blood cells and excess free photosensitizer-antibody conjugates precluded the need for a toxicity study, particularly because we were at the proof-of-principle stage.

Part (b) of concern (2) suggests that we may have caused non-specific damage to non-cancerous cells by ROS' convection in the blood stream. We believe that this is highly unlikely. One of the authors has been conducting research focusing on ROS and PDT for years, in collaboration with other researchers [7-15]. This research demonstrated that PDT is extremely selective to targeted cells [13]. 

 Part (c) of concern (2) states that we should have used additional cytotoxicity assays, such as Annexin V, TUNEL, and MTT. However, because none of these techniques are cell-type specific, they would be useless for the particular objective they were suggested. Once our line of investigation reaches a more mature stage, we plan to undertake more useful studies, such as applying separate fluorescent tags, or radio labels, in addition to a cell viability assay and analyzing cell death with a cell sorting technology, such as FACS, MACS, density gradient centrifugation, etc.  

Concern (3) is that the capturing work [2] lacked purity confirmation concerning non-specific capturing of blood cells. Though purity confirmation is critical in diagnostic testing, our work was strictly limited to in vitro conditions, using spiked pure PC-3 cells as a model. To visualize and quantify PC-3 cells in the presence of whole blood, PC-3 cells were pre-labeled using a fluorescence tag (Calcein AM) and the extra free dye was subsequently removed before spiking PC-3 cells into blood. Because only PC-3 cells can have fluorescence in the blood mixture, and because quantification was based on fluorescing cells, false-positive results from other blood cells can be reasonably excluded. Furthermore, if other blood cells were captured but not identified by our detection method our data would then indicate that the simple tube captured cancer cells despite being blocked by other blood cells. If our technique were applied to CTC diagnosis, independent isolation procedures could be used to ensure the purity of captured cells. In contrast, if used for therapy, the purity of captured cells would not be as critical, provided that CTCs are effectively removed. If, by chance, capturing is hampered by accumulation of non-specific binding in filtering the entire blood volume, this issue can be addressed with strategies such as scaling up the tube and carefully determining the tube dimensions, flow rate, frequency of tube replacements, etc. 

Finally, concern (4), points out that the experimental conditions were not translatable to clinical applications. Part (a) regards scaling up the system to show high throughput. The concept of extracorporeal cleansing of the entire blood volume has been used for years in cases such as hemodialysis. We already are working on optimizing the technique for larger blood volume processing. Part (b) of concern (4) discusses the static no-flow condition as being unrealistic. This issue was brought up during the review process, and we provided with our results showing data under constant flow conditions by peristaltic pump (to be published in future publication). The reviewers agreed that the use of a no-flow condition as a conservative approach during a proof-of-concept stage was appropriate.

Despite its preliminary nature, we believe that our work communicates novel ideas, an important objective of research and publication. Given the number of research articles dealing with diagnostics and microfluidics, perhaps a further point of confusion came about by thinking of our work in those terms. We want to clarify that diagnostics were not the primary objective in our work. Furthermore, as it becomes evident by this response our experimental design was carefully devised to minimized unnecessary interferences. We hope that this response mitigates any confusion and addresses the concerns raised. 

1. Kim G, Gaitas A. PloS One. 2014;10(5):e0127219-e.
2. Gaitas A, Kim G. PLoS One. 2015;10(7):e0133194. doi: 10.1371/journal.pone.0133194.
3. Marshall JR, King MR. DOI: 101007/s12195-015-0418-3. 2015;First online.
4. Ferraresi C, et al. Photonics and Lasers in Medicine. 2012;1(4):267-86.
5. Avci P, et al. Seminars in cutaneous medicine and surgery; 2013.
6. Jalian HR, Sakamoto FH. Lasers and Light Source Treatment for the Skin. 2014:43.
7. Ross B, et al. Biomedical Optics, 2004
8. Kim G, et al. Journal of biomedical optics. 2007;12(4):044020--8.
9. Kim G, et al Analytical chemistry. 2010;82(6):2165-9.
10. Hah HJ, et al. Macromolecular bioscience. 2011;11(1):90-9.
11. Qin M, et al. Photochemical & Photobiological Sciences. 2011;10(5):832-41.
12. Wang S, et al. et al. Lasers in surgery and medicine. 2011;43(7):686-95.
13. Avula UMR, et al.Heart Rhythm. 2012;9(9):1504-9.
14. Kim G, et al. R. Oxidative Stress and Nanotechnology, 2013. p. 101-14.
15. Lou X, et al. E. Lab on a Chip. 2014;14(5):892-901.
16. https://www.roswellpark.org/patients/treatment-services/innovative-treatments/photodynamic-therapy.
17. Yin H, et al. Artificial organs. 2014;38(6):510-5.
18. Yin H, et al. Journal of Photochemistry and Photobiology B: Biology. 2015.

On 2015 Aug 29, Michael King commented:

Our recent commentary discusses this paper:

http://link.springer.com/article/10.1007/s12195-015-0418-3

In cancer research, the discovery and study of circulating tumor cells (CTCs) have seemed to open a world of possibilities. We now have the potential to gain cellular and molecular understanding of individual cases of metastatic cancer without invasive procedures. This area of research is, however, not without some basic pitfalls. In this commentary, we address some of these pitfalls by considering two recent examples in the published literature and discuss ways to overcome their limitations with the hope of informing those who may be entering the growing field of CTC research. Careful research design should always be followed to prevent incomplete or misleading studies from entering the literature, and thereby avoid setting back this burgeoning field.

On 2015 Sep 10, Bill Cayley commented:

More evidence that for warfarin cessation, "less" is "more" - it seems better NOT to "bridge": https://lessismoreebm.wordpress.com/?s=bridg

On 2017 Mar 04, University of Kentucky Systems Biology and Omics Integration Journal Club commented:

The authors have tried to contact the journal at least a half-dozen times over the last few months to post an erratum for this article. At first the editor suggested waiting to fix the erratum until two other manuscripts submitted by the authors were fully reviewed. After both manuscripts were accepted, the authors started to inquire again about posting an erratum, but have not receiving any guidance on how to submit an erratum nor when it would be posted. Therefore, the authors of this manuscript are posting an impromptu erratum via the journal club onto PubMed Commons. We have a new version of Figure 6 that fixes a mistake in two of the images that have the wrong chirality due to the image being flipped. The corrected image can be found on a FigShare repo for the paper: https://figshare.com/articles/Zn_metalloprotein_paper/4229333

On 2015 May 27, Timothy Shakespeare commented:

Despite not being an expert in the field, I read this paper with interest. It seems that the definition of dyslexia is a difficult subject, and I wondered what the justification was for the definition of severe reading impairment including <level 4 KS2 in Science or English. Am I correct in thinking that this would put someone with very poor reading, but good science and English in the normally developing group? Is this the case, and if so, how many people are in that category and does that fit with other definitions of dyslexia? Also, in the online version there are typos in the inclusion criteria "Children who achieved scores <2 SD below the mean" should be >2SD below the mean (as it is in the abstract).

Finally, the discussion draws conclusions about the implications of this study for use of visual aids. This has been taken by some to mean this study provides evidence that coloured overlays don't work for people with dyslexia, but I am interested in whether 1) it leaves open the possibility that a subsection of people with dyslexia (e.g. those who describe words moving on page) could benefit whilst others don't and 2) coloured overlays could possibly have an effect on higher order visual processing that was not tested or shown to be normal in this study. There doesn't seem to be a strong evidence base for these interventions, but it's not clear whether that's absence of evidence or evidence of absence.

On 2016 Mar 04, Melissa Rethlefsen commented:

We attempted to replicate the authors’ Embase search strategy, as reported in the Appendix (pages 13-14). The authors, according to the PRISMA flow chart also located in the Appendix (page 37), retrieved 1,371 results for their Embase search strategy, prior to deduplication of records. The authors specifically mention that there was no language limit imposed on this search in the "search strategy and selection criteria" panel in the primary manuscript, but there are no other limits mentioned.

In case the phrase “for randomised controlled trials” in the "search strategy and selection criteria" panel indicated a limit to ‘randomized controlled trials’ as a study type (using the EMTREE term), we restricted to this term. There was also no indication of the dates of coverage of the version of Embase (via the Ovid platform) used. There are multiple possibilities of date ranges (1947-1979; 1980-1987; 1988-1995; 1947 to present; 1974 to present; 1980 to present; 1988 to present; 1989 to present; and 1996 to present). We attempted all of the different date ranges, until an entry date of February 1, 2014 to most closely mimic the published search. There was no exact search date mentioned, but the authors did note that the search went "up to January 2014"; we used a February 1, 2014 entry date to allow for a late January 2014 search, though it was not clear if the authors searched in January 2014, or limited to publications published prior to January 2014. Even with the assumed ‘randomized controlled trials’ EMTREE term applied, we could not replicate the search count for any year range available by default in any Embase via Ovid database option.

The search as presented by the authors retrieves over 50,000 records in Embase (up to an entry date of 2/1/14). With the ‘randomized controlled trials’ EMTREE term applied as a limit, it retrieves over 3,100 articles. Mimicking the smallest Embase database coverage at the time of the authors’ search (1996-present, limiting to an entry date before February 1, 2014), we still see nearly 3,000 articles. This is a 1,600 record difference between the authors’ published results and what their published search strategy retrieves, even with these assumptions applied.

This study highlights the need for more accurate and comprehensive reporting needed for search strategies in systematic reviews and other literature search-based research syntheses, and the need for better peer review of search strategies by information specialists/medical librarians. Though the searches in the Appendix are on face value replicable and high quality, on closer inspection, they do not in fact meet the reporting standards as outlined by PRISMA Statement items #7 and #8: “Describe all information sources in the search (e.g., databases with dates of coverage, contact with study authors to identify additional studies) and date last searched” and “Present the full electronic search strategy for at least one major database, including any limits used, such that it could be repeated.”

On 2015 May 29, Karl Herrup commented:

Shakespeare makes several good points. The tandem article was meant from the beginning as a strong 'counterpoint' to my own article. I find that it is a scholarly and well written piece and I encourage people to read both (especially students).

As for setting the age of onset where sporadic and familial AD diverge, I would have two responses. The first is to thank Dr. Shakespeare for raising the very real point that there is no bright line that separates the two. It is only a question of odds: AD that starts before age 65 is most likely fAD; AD after age 65 is most likely sAD. But "likely" is different from "is". The second response is to confess that I smiled when I saw the comment about how this was an 'unattributed' remark. I too complain about authors who assert that "it is commonly known that...." even when there is little or no primary source offered to back up the point. I have to admit that I was hoisted on my own petard here. I have glanced at the cited reference and am pleased to incorporate its findings in future writings...and to choose my words a bit more precisely.

Concerning my contention that there can be Alzheimer's without plaques. Here Shakespeare actually makes the exact point I was trying to make and I wish I had been clearer. Plaques may well contribute to the disease process and then disappear, which I assert is the message from the vaccine trials. The result is that mechanistically the plaques could have started the disease but then vanish. But given our current approaches, I assert that this is a serious problem. If this individual were to die and his brain come to autopsy, a trained neuropathologist would assure us that the individual's dementia could not possibly have been Alzheimer's, even though it was. I was trying to argue that the implications of this is that we may well distort our findings if we require the presence of plaques to reach a diagnosis of AD. My suggestion is that we should relax our dependence on them, detected through PET scans or neuropathologically, in our diagnostic regimens.

On 2015 May 27, Timothy Shakespeare commented:

This is an interesting article that I'm sure will stimulate much discussion. Readers may wish to see an alternative perspective published in tandem here: http://www.nature.com/neuro/journal/v18/n6/full/nn.4018.html

Working in the area of sporadic Alzheimer's disease with age at onset <65, I would disagree with the sentence "Sporadic AD first appears clinically after the age of 65." This sentence is uncited and incorrect. There is occasionally confusion between early onset or young onset Alzheimer's disease, and Dominantly Inherited Alzheimer's Disease (also known as Autosomal Dominant Alzheimer's Disease, familial Alzheimer's disease). An onset before 65 (early or young onset) should not be confused with a dominantly inherited genetic form of Alzheimer's disease. In fact sporadic AD is more common that familial AD even in people with an onset <61 http://dx.doi.org/10.1086/302553.

I would also make a point regarding the interpretation of vaccine trials that have not had great success in providing cognitive benefits. In this paper the interpretation is that this shows you can have Alzheimer's disease without plaques "The implication is that just as there can be plaques without AD, there can also be AD without plaques." The alternative interpretation, that the amyloid is being removed too late and has already had its effect, should be given consideration. I.e. you need to have plaques at some point, but perhaps only earlier in the disease process. Perhaps this would fit into the idea of rejecting the simple linear pathway tracing disease progression from Aβ to AD.

On 2015 Jun 10, Arthur Yin Fan commented:

The methodology flaws in Hinman's acupuncture clinical trial, part I: design and results interpretation. Fan AY. J Integr Med. 2015 Mar;13(2):65-8. doi: 10.1016/S2095-4964(15)60170-4. No abstract available. PMID: 25797635 Similar articles

On 2015 May 26, Wayne Butler commented:

There must be an error either by PubMed or the Brazilian journal in matching the proper abstract with the title and journal page numbers. The abstract above, pubmed/26005980, has nothing to do with the racial classification article by FR Romero, et al. in Int Braz J Urol, 2015;41(2):360-366. The abstract above is from the next article in the journal by A Billis et al. 2015;41(2):367-372, pubmed/26005981. 27 May 2015 – PubMed has corrected the error. What a fast 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 NCT00562293. We believe the correct ID, which we have found by hand searching, is NCT00562263.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2015 Sep 06, Martine Crasnier-Mednansky commented:

This review should have discussed transcription-coupled DNA supercoiling. Ma J, 2013 demonstrated that RNAP was fully capable of melting DNA at random, and indicated that RNAP-generated (-) supercoiling may facilitate initiation of transcription at adjacent promoters and binding of regulatory proteins. This agrees with the proposal CRP-cAMP has a preferential affinity for negatively supercoiled promoters. The same authors also indicated in vivo transcription-generated supercoiling may potentially dissociate DNA-bound proteins even at a distance. Thus current understanding suggests RNAP itself may have evolved to be a master regulator of gene expression. Simply said, transcriptional regulators do not recruit RNAP, they are recruited by RNAP.

On 2015 May 26, Christopher Southan commented:

Selected leads and targets resolved to molecular identities at http://cdsouthan.blogspot.se/2015/05/entity-resolution-for-antimalarial.html

On 2016 Apr 30, Robert Eibl commented:

The authors review many aspects of CD44 in the nervous system; they even discuss some findings in brain tumors, but lack to include the first paper on CD44v expression and functional assays of hyaluronan binding in primary astrocytomas and glioblastomas (GBM), as well as related tumor cell lines: PMID:8750182

J Neurooncol. 1995 Dec;26(3):165-70.

Expression of variant CD44 epitopes in human astrocytic brain tumors.

Eibl RH, Pietsch T, Moll J, Skroch-Angel P, Heider KH, von Ammon K, Wiestler OD, Ponta H, Kleihues P, Herrlich P.

On 2015 Dec 08, Patrick Schloss commented:

We have published a manuscript that is in part a response to this paper by He et al. https://peerj.com/articles/1487/

On 2015 Jun 10, David Keller commented:

Depression caused by early PD should respond to dopaminergic medication, not an SSRI or psychotherapy

Gustafsson and colleagues demonstrate an association between depression and a later diagnosis of Parkinson disease (PD). If a patient's depression is due to reduced brain dopamine levels caused by alpha-synucleinopathy involving the substantia nigra, then that patient's depression is probably a pre-motor symptom of their PD, rather than a psychological illness. Furthermore, any form of SSRI or psychotherapy should be futile to alleviate the depression caused by early PD; however, a therapeutic trial of levodopa or a dopamine agonist might be remarkably effective at relieving depression caused by low brain levels of dopamine. Dopaminergic therapy might also relieve a depressed patient's "psycho-motor retardation" if it is actually early Parkinsonian bradykinesia.

It might be difficult to reliably determine by clinical examination alone which depressed patients are actually exhibiting pre-motor PD, and a therapeutic trial of SSRI therapy should be avoided for these patients (since SSRI's can lower brain dopamine levels). Similarly, a therapeutic trial of dopaminergic medication in depressed patients who do not have early PD would be a waste of time if their psychiatric depression would respond better to SSRI therapy and / or psychotherapy.

What this all suggests is that scintigraphic dopamine transporter imaging of the brain (the "DaT scan") may be helpful when a depressed patient fails to respond to SSRI therapy and does not exhibit psychological depression. A DaT scan which diagnoses early pre-motor PD in such a patient could be useful if it discloses that the proper therapy for that patient's depression would be dopaminergic medication, rather than an SSRI and / or psychotherapy. If SPECT scanning lacks the spatial resolution to be helpful in identifying depression due to early PD, then perhaps PET imaging could be employed.

On 2016 Oct 24, Sean Ekins commented:

attached are some slides on this topic from an ACS in 2015 http://www.slideshare.net/ekinssean/mining-big-datasets-to-create-and-validate-machine-learning-models

On 2016 Oct 24, Sean Ekins commented:

Attached are some slides on this paper from an ACS given in 2015 http://www.slideshare.net/ekinssean/development-and-sharing-of-admetox-and-drug-discovery-machine-learning-models

On 2015 May 21, DOMINIQUE BERGMANN commented:

There is an error in the assignment of two Arabidopsis gene names in Fig S6. SPCH should be AtbHLH098 and FAMA should be AtbHLH097.

On 2015 Jun 16, Robert G Sawyer commented:

I hope it continues a trend to shorten routine antimicrobial courses.

On 2015 Jun 10, Bill Cayley commented:

A great example of when "Less" is "more": https://lessismoreebm.wordpress.com/about/less-is-more-database/

On 2016 Apr 11, Gustav van Niekerk commented:

We (van Niekerk G, 2016) have recently argued that sickness associated anorexia (SAA), evolutionary conserved across both vertebrates and invertebrates, my represent a strategy for upregulating autophagic flux systemically. As an example, patients with sepsis typically decrease a number of amino acids (AA), including branched chain AAs (see table 2 in Su L, 2015). Similar, bile acids returning into circulation (bile acid reabsorption in the gut is very efficient) inhibit hepatic autophagy by binding to FRX (Lee JM, 2014). Thus, SAA likely represents an evolutionary conserved strategy to maintain elevated levels of autophagic flux during an infection.

An upregulation of autophagy during an infection may be critical for a number of reasons:

• Serum and AA starvation induces autophagy in macrophages and protects against TB infection (Gutierrez MG, 2004).

• We speculate that hepatic autophagy may play a critical role in clearing LPS and bacteria from circulation.

• Pathogens entering a cell must quickly subvert host processes to prevent being degraded by autophagy. In this regard, upregulation of autophagic flux would confront pathogens with a narrower window of opportunity to modulate the host machinery. Thus, autophagy enhances cell autonomous defence.

• Autophagy processes ribosomal components into antimicrobial peptides (Ponpuak M, 2010). Note that all nucleated cells have ribosomes and are capable of autophagy, thus suggesting that autophagy may again enhance cell-autonomous defence.

• Autophagy is also involved in the non-canonical expression of epitopes on MHC II by non-professional antigen presenting cells such as adipocytes, muscle and endothelium cells.

Autophagy may also be important in cell survival. As an example, in tissue ischemia, the release of biocidal agents from immune cells as well as the increase in misfolded proteins resulting from a febrile response may lead to the generation of toxic protein aggregates. Here, autophagy may promote cell survival by processing ‘overflow’ of damaged protein aggregates when the proteasome pathway is overwhelmed.

Collectively, these observations suggest that autophagy probably plays an important role in both pathogen clearance and in promoting host survival. It also provides a rational basis for permissive underfeeding as a form of nutritional support. We suggest that the reason why studies present mixed results on the effect of nutritional support results from the heterogeneous context and timing. As an example, a patient in recovery might benefit from aggressive nutritional support after the body switches from a catabolic towards an anabolic state. Similarly, the kind of pathogen challenge would also impact on the efficacy of nutritional support, as derailing autophagy may render cells more susceptible towards infection by certain pathogens.

On 2017 Oct 28, thomas samaras commented:

The findings of this study are supported by about 70 studies showing that shorter people live longer. Some key facts from a few of these studies include:

1.A 2017 study (Lemez) of basketball players showed that the shorter players lived longer

2.A 2016 study (Chmielewski) of 800,000 deceased Polish men and women showed the shorter lived longer

3.A 2009 study (Mueller and Mazur) of about 8000 West Point graduates who retired showed shorter lived longer after 60 years of age.

4.Studies of centenarians generally show that they tend to be very short and lean

5.Animal studies show that smaller individuals within a species live longer

6.A recent study (2017) identified 36 biological factors that favor greater longevity in smaller individuals

A collection of articles, book chapters and books showing shorter or smaller individuals live longer are given in website: www.humanbodysize.com

On 2015 May 21, Peter Hajek commented:

A great study. Two important results are not in the abstract. Sustained quit rate at 6 months was 5% and 3%, so neither treatment led to smoking cessation; but at six months, 13% still used the gum and 27% continued to use snus (p=0.0006). It is likely that dual use of either product reduces smoke intake and thus reduces harm and it may also facilitate quitting in future. This also suggests that snus is more attractive to smokers despite the initial rating, and so even if the two products were to have the same effect (and the same cost and availability), snus would have better population impact.

On 2015 May 31, Robert Withers commented:

It is indeed difficult to tread the fine line between the need to insure client confidentiality and the need to present accurate clinical material. This is why I have restricted myself to describing and reflecting on a real critical incident,without disclosing any information that could identify 'John'.

On 2015 May 23, Andrew Kewley commented:

In the manuscript, the author states: "While Chris has kindly granted me permission to use his material in this article, I am not in a position to request similar permission from John. So I will create a composite case, within which to frame a real ‘critical incident’ to which I wish to give particular attention. In doing this, I will aim to remain as true as I can to the dynamics of the original case without compromising client confidentiality."

I'm not convinced that this is ethical. Basically, it means that either privacy/confidentially is violated, or that the case is basically fictional and thus has no place being published.

On 2015 May 29, Michal Kicinski commented:

I thank Dr. Hilda Bastian for her interest in our recent study (Kicinski M, 2015). I strongly believe that post-publication comments very often raise important issues and help the readers to better understand the merits of a study and its limitations. However, I was disappointed to see that the comments of dr. Hilda Bastian do not correspond with the content of our study. For this reason, I feel obliged to clarify a number of issues.

The study of Ioannidis JP, 2007 points out one of the limitations of a large part of publication bias methods based on the asymmetry of the funnel plot, namely that they do not take between-study heterogeneity into account. This is indeed an important limitation of these methods, as also discussed by other researchers (Song F, 2010). However, please note that we did not rely on the asymmetry of the funnel plot in our analysis. Additionally, please note that our model is just an extension of the standard random effects meta-analysis model, which is a valid approach when between-study variability is present. In fact, the study of Ioannidis JP, 2007 is one of the contributions that motivates our approach to model publication bias since our model takes heterogeneity into account.

Dr. Hilda Bastian correctly points out that our study is not the first study on publication bias. There are many valuable studies on this topic and we discussed those most relevant to our research questions in our article. The contribution of our study is that we analyzed a very large number of meta-analyses using a model with strong theoretical foundations. Our study is the largest study on publication bias in meta-analyses to date. Please note that previous studies, e.g., Ioannidis JP, 2007, which Dr. Hilda Bastian mentioned, considered small study effects, a phenomenon that may have many different causes, including publication bias (Song F, 2010, Sterne JA, 2011). Another merit of our study is that we estimated the association between the size of publication bias and the publication year of the studies included in the meta-analyses.

I completely agree that the best solution to the problem of publication bias is the complete reporting of study results. In fact, our findings showing that publication bias is smaller in the meta-analyses of more recent studies support the effectiveness of the measures used to reduce publication bias in clinical trials. I strongly advocate the introduction of new policies aimed to completely eliminate reporting biases from clinical trials and, as written in our article, the implementation of measures to reduce publication bias in research domains other than clinical trials, such as observational studies and preclinical research.

Although we did not investigate the use of publication bias methods in the meta-analyses from the Cochrane Library, it is clear from previous research that the potential presence of publication bias is often ignored by researchers performing meta-analyses and that the methods accounting for publication bias based on the statistical significance are hardly ever used (Song F, 2010, Onishi A, 2014). When publication bias is present in a meta-analysis, ignoring the problem leads to biased estimates of the effect size (Normand SL, 1999). Therefore, similar to others (Sterne JA, 2011), we argue that researchers should investigate the presence of publication bias and perform sensitivity analyses taking publication bias into account. One difficulty with the use of publication bias methods is that they require researchers to make certain assumptions about the nature of publication bias. For example, the trim and fill method defines publication bias as suppression of a certain number of most extreme negative studies (Duval S, 2000). The use of the Egger’s test (Egger M, 1997) as a publication bias detection tool requires researchers to make the assumption that publication bias leads to a negative association between effect size and precision. The performance of a certain publication bias method depends on whether or not the method’s assumptions are met. For example, it has been demonstrated that publication bias detection tests based on the funnel are characterized by a very low power when publication bias based on the statistical significance is present and the mean effect size equals zero (Kicinski M, 2014). Publication bias based on the statistical significance is the best-documented form of publication bias (Song F, 2009, Dwan K, 2013), The results of our study add to this body of evidence. Therefore, we argue that publication bias tools designed to handle publication bias based on the statistical significance should be used by researchers.

In the tweet with the link to her comment on PubMed, Dr. Hilda Bastian wrote on the 25th of May: ‘27% of cochranecollab reviews over-estimate effects cos of publication bias? Hmm.’ Please note that our study did not investigate the proportion of meta-analyses that overestimate effects. In fact, the objectives of our study were completely different. We estimated the ratio of the probability of including statistically significant outcomes favoring treatment to the probability of including other outcomes in the meta-analyses of efficacy and the ratio of the probability of including results showing no evidence of adverse effects to the probability of including results demonstrating the presence of adverse effects in the meta-analyses of safety.

On 2015 May 25, Hilda Bastian commented:

This is an interesting study. But it's a rather enthusiastic self-assessment of a method not validated by other researchers, and some perspective is useful in thinking about the conclusions.

Kicinski M, 2015 is neither the first, nor the largest study, of publication bias (PB) in meta-analyses, and the presence of publication bias in them is well-known. These authors used a scraper they have made available on Github to extract meta-analyses from Cochrane reviews. They looked at reviews with placebo or "no treatment" control groups and 10 or more included studies. Whether or not these results are applicable to interventions with active or usual care control groups is unknown.

For perspective here: Ioannidis JP, 2007 considered PB in 1,669 Cochrane reviews, ultimately analyzing 6,873 meta-analyses. A half of the meta-analyses had no statistically significant results in them, so the problem identified here could not have applied to them. Ioannidis JP, 2007 concluded that only 5% of the full set of Cochrane reviews would qualify for the use of asymmetry tests, and only 12% of those with a larger number of events and participants. They found very little concordance between different asymmetry tests - only around 3-4%. A more important problem according to Ioannidis JP, 2007 was the misapplication and misinterpretation of statistical tests, not under use. False-positives are a problem with tests for PB when there is clinical heterogeneity. Ioannidis JP, 2007 conclude that the only viable solution to the problem of PB is full reporting of results.

Kicinski M, 2015 conclude that statistical tools for PB are under-utilized, but the extent to which PB is assessed was not part of their study. Although PB itself may be decreasing over time, assessment of PB is increasing, even if the methods for exploring it are still problematic:

• Palma S, 2005 found that PB was assessed in 11% of trials between 1990 and 2002, increasing from 3% in 1998 to 19% in 2002 (less frequently in Cochrane reviews than others).
• Moher D, 2007 found that about 23% of systematic reviews in 2004 assessed PB (32% in Cochrane reviews, 18% in others).
• Riley RD, 2011 found that only 9% of reviews from one Cochrane group assessed PB.
• van Enst WA, 2014 found that most systematic reviews of diagnostic test accuracy in 2011/2012 mentioned the issue, with 41% measuring PB.

In assessing only the meta-analyses themselves, and not the reviews that included them, it's not possible to know, as the authors point out, to what extent other studies were included, but without data that could be pooled. An issue not raised by Kicinski M, 2015 are trials reported only in conference abstracts, and thus with minimal data. Cochrane reviews often include studies reported in conference abstracts only, and those are apparently more likely to have non-statistically significant results (Scherer RW, 2007) - as well as relatively little data for the multiple meta-analyses in a review.

It's important to consider the review, and not just the effect summaries within meta-analyses, because the conclusions of the systematic review should reflect the body of the evidence, not only the meta-analyses. Over-favorable results in a meta-analysis shouldn't be equated with over-favorable conclusions about effectiveness in a review (although unfortunately it often will). We shouldn't jump to conclusions about effect sizes from meta-analyses alone. They can be skewed by clinical heterogeneity and small study size as well as (or instead of) publication bias, and the devil may be more in the interpretation than the calculations.

Disclosure: I work on projects related to systematic reviews at the NCBI (National Center for Biotechnology Information, U.S. National Library of Medicine).

On 2015 May 26, Yanju Ma commented:

I am very interested in your study. In this study, you found no correlation between the numbers of CTC-clusters and that of single CTCs (Supplementary Fig. 9). But we could see that three patients with melanoma have higher CTC clusters. So is there any correlation between higher CTC clusters with poor prognosis? I will be glad to get your reply. Thank you.

On 2015 Jun 14, Preben Berthelsen commented:

In this editorial, Prof Matthay contents that the paper by Blodgett: The continuous inhalation of oxygen in cases of pneumonia otherwise fatal, and in other diseases. (Boston Med Surg J 1890;123:481-) is the first report on oxygen therapy. Blodgett’s case story is indeed interesting and heart-breaking but it is not a first – and Blodgett certainly does not claim priority in his paper.

Fifty years earlier, in “On Asphyxia, and on the Resuscitation of Stillborn Children”(a paper read at the Westminster Medical Society, London, October 16, 1841 and printed in Boston Med Surg J 1842;25:409-) John Snow states on page 414 “Oxygen gas is sometimes mixed with air to be thrown into the lungs of asphyxiated persons” And, “if it is deemed advisable, oxygen gas can be generated in great purity, in a few minutes, from chlorate of potash by means of a spirit-lamp and a small retort” Furthermore, “No harm can arise from thus using oxygen.”

I do not know if John Snow – the first academic anaesthetist in the world – was also the first to advocate oxygen treatment.

P.G.Berthelsen, MD. Charlottenlund, Denmark

On 2015 May 22, thomas samaras commented:

Researchers should be aware that two earlier reviews were published showing that shorter people are more likely to have lower coronary heart disease (CHD) (1,2). This apparent conflict with the Nuesch, et al. paper is no doubt due to various confounders and failure to recognize the biological mechanisms that underlie the inherently lower risk of CHD for shorter, lighter people. In addition, ecological studies showing short people often have little or no CHD are often ignored because of the belief that ethnic, racial, climatic and geographical factors make the results unreliable. However, Shaper (1) stated that these factors are completely irrelevant to the incidence of CHD unless they are related to social class and economic status.

In my opinion, the facts covered in the two papers cited below (1,2) provide overwhelming evidence that shorter people have the potential for very low CHD. (Unfortunately, Dr. Elrick and Professor Storms have passed away and cannot co-write this response.) A summary of some of our findings follows.

Before the early 1900s, Europeans and Americans were shorter but CHD was rare. As we got taller and heavier, CHD increased due to the Western diet.

Based on 1 million WWI military recruits in the US, Davenport and Love found that taller men had a much higher incidence of heart problems.

In the developed world, the Japanese have ranked within the top three countries in terms of low CHD for a number of decades. Japanese males average a little over 5’7”.

A number of populations that had very low or no CHD during the 20th C now have much higher rates along with their increased height. For example, S. Korea has seen a large jump in heart disease in recent years along with a substantial increase in height.

Western Sicilian centenarians are short and free of CHD risk factors.

Compared to men, shorter women have lower lifetime death rates from CHD.

A US study found that in a low-income cohort, taller people have almost a 40% higher risk of heart attacks. US mortality statistics based on ages ranging from youth to over 85 years of age show that shorter Asians have an almost 80% lower risk of CHD compared to taller Blacks and Whites. Latinos and Native Americans are taller than Asians but shorter than Whites and Blacks and fall between the shortest and tallest ethnic groups in mortality. (Findings based on a 15-year period and about 8 million deaths.)

A study of 350,000 dogs found that smaller dogs have much lower risk of heart failure compared to bigger dogs. For example, the Great Dane has 70 times the risk of heart failure compared to the miniature Dachshund. And the standard Dachshund has 3 times the rate of heart failure as the smaller miniature Dachshund.

I have also identified over 15 biological factors that would explain the advantages of smaller body size and low CHD. These include longer telomeres, smaller left ventricular mass, lower blood pressure, lower HDL, lower homocysteine, higher sex hormone binding globulin, lower C-reactive protein, higher adiponectin and FOXO3, and lower pulse wave velocity. These factors are based on the assumption that we are comparing shorter and taller people who have the same body type or proportions. (Otherwise, comparing a tall, thin person to a short stocky one would change these parameters.)

Many studies have also found that shorter people live longer. These include studies from the Hawaii, Ohio, San Diego, Spain, Sardinia, Okinawa, Bama (China), and Cuba (3). Many animal studies and experimental research support these human findings (4).

Recently, a 40-year longitudinal study based on over 8000 elderly Hawaiian Japanese males found that shorter men live longer (5). It is unlikely that they had more heart problems than the taller men who died younger.

Unfortunately, the findings discussed above have not received much attention because of the widespread belief that taller people are healthier and longer lived. Over 45 papers, books and book chapters on the ramifications of increasing body size are listed in www.humanbodysize.com

References

1 Samaras TT, Elrick H, Storms LH. Is short height really a risk factor for coronary heart disease and stroke mortality? A review. Med Sci Monit 2004; 10(4): RA63-76.

2 Samaras TT. Shorter height is related to lower cardiovascular disease risk—a narrative review. Indian Heart Journal 2013; 65: 66-71.

3 Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports 2014; 3 (16): 2150-2160.

4 Bartke A. Healthy aging: Is smaller better? –A mini review. Gerontology 2012; 58: 337-43

5 He Q, Morris BJ, Grove JS, Petrovitch H, Ross, Masaki KH, et al. Shorter men live longer: association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. PLOS One 2014; 9 (5) 1-8.

On 2015 Jun 22, Darko Lavrencic commented:

Your conclusions indicate that spinal extrathecal CSF collections are not the cause but direct consequence of intracranial hypotension/CSF hypovolemia, regardless of CSF leakage. For the most probable cause of intracranial hypotension/CSF hypovolemia see http://www.med-lavrencic.si/research/correspondence/

On 2015 May 29, Kim D Pruitt commented:

lncRNA-NR024118 is represented by NCBI Gene ID: 25602 and RefSeq accession NR_024118.1

On date unavailable, commented:

None

On 2015 Sep 23, Guangchuang Yu commented:

• 1. The so called Linux-like should be Unix-like.
• 2. you should also present runseq2pathway runnable example.
• 3. it seems you are not familiar with R

tmp <- sessionInfo() mySession <- ifelse(length(grep("Windows",tmp))==0, "L","W")

I recommend you use Sys.info() to extract platform information.

if (mySession=="W") sink(paste(tempdir(),"\",name,sep="")) else sink(file.path(tempdir(),name,fsep = .Platform$file.sep))

actually '/' works fine with Windows and Unix-like system in R. Why not just use:

name = tempfile()

and write your python script to that file?

On 2015 Sep 20, Xinan Holly Yang commented:

Thank you for pointing out. We have fixed the bug in the seq2pathway version >=1.1.6 as described below:

1) The new seq2pathway package runs on both Windows and Linux-like systems.

2) We activated a demon code:

data(ChipseqPeakdemo)

runseq2gene(inputfile=ChipseqPeakdemo)

3) We replaced the absolute path with Sys.which("python").

The significance of the package for the end-users could be:

1) It provides a detailed map and a flexible search of the human and mouse genome. Compared to other tools using the UCSC genome, we processed the newest GENCODE data thus can provide more information for the non-coding regions. Importantly, the runseq2gene() function is designed to find more target gene candidates for a given genomic locus using a customized search radius, which will help users to study trans-regulation. In fact, we have applied the method for the biological knowledge discovery (PLoS Genet. 2014 Oct; 10(10): e1004604, PLoS Genet. 2014 Oct; 10(10): e1004604.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214600/).

2) The se2pathway package implements a unique gene2pathway algorithm termed FAIME (PLoS Comput Biol. 2014 May;10(5):e1003609. http://www.ncbi.nlm.nih.gov/pubmed/22291585) and other three widely-used gene-set analysis (GSA) approaches. It also provides a way to include user-defined gene-sets, which is an adding to the current GSA tools and is important for the discovery of function. Unlike conventional GSA approaches, the package also calculates a corrected background for a more accurate Fisher's exact test (We have introduced the algorithm at BMC Medical Genomics 2015, 8(Suppl 2):S6 http://www.biomedcentral.com/1755-8794/8/S2/S6).

3) Furthermore, the package provides end-users a one-command option to find enriched pathways from 'omic' data.

Looking forwards to more users and comments and we will further improve the package.

-Holly

On 2015 Aug 21, Guangchuang Yu commented:

not runnable, see the post.

On 2016 May 11, Jonathan Heald commented:

Posted on behalf of the American Academy of Sleep Medicine.

Consensus Conference Panel., 2015

On 2016 May 05, Jonathan Heald commented:

None

On 2016 Mar 16, E M Sellers commented:

Nice - thanks for doing this ed

On 2016 Mar 13, Daniel Schwartz commented:

The CIWA-Ar scale can be used online or in a mobile application at http://qxmd.com/calculate/ciwa-ar

Conflict of interest: Medical Director, QxMD

On 2017 Jul 07, Morten Oksvold commented:

This article should have been retracted after an investigation by The University of Maryland found this article to contain "compromised" data (a total of 26 articles in 11 journals were affected). The journal Molecular Cancer Therapeutics was informed in August 2016, according to Retraction Watch.

http://retractionwatch.com/2017/04/26/university-asked-numerous-retractions-eight-months-later-three-journals-done-nothing/

On 2015 May 19, L Charles Murtaugh commented:

The basis of this paper will be somewhat confusing to those who adhere to the traditional definition of "transcription factor," as a DNA-binding protein that regulates gene transcription (http://www.nature.com/scitable/definition/general-transcription-factor-transcription-factor-167). Not one of the genes mentioned in the abstract is a transcription factor, by the conventional definition; instead, all of them are regulators of DNA synthesis or other aspects of cell cycle progression. In fact, only one of the 20 top "transcription factors" described as differentially-expressed in this study (Tables 3 and 4), Xbp1, is an actual transcription factor. I must question, therefore, the validity of the dense transcriptional regulatory networks presented in Figures 3-4 of this paper.

One culprit here seems to be the authors' uncritical acceptance of a previous study (http://www.ncbi.nlm.nih.gov/pubmed/18713790) that purported to establish a comprehensive database of mammalian transcription factors. Again, a cursory examination of this database (http://itfp.biosino.org/itfp/TFViewer/human_tf.jsp?table=human_tf&page=1) reveals that the majority of its members are not transcription factors at all. Indeed, the fact that this previous manuscript suggested the existence of >4000 human TFs, 2-3 times more than conventional estimates, should have raised red flags not only for its original peer reviewers, but also for authors of the current study.

On 2015 Jul 17, Andrea Messori commented:

Cumulative pairwise meta-analysis to evaluate the risk of infection in patients with rheumatoid arthritis treated with biological agents as compared with DMARDs: the difference is not significant using the random-effect frequentist model.

By Andrea Messori

HTA Unit, Regional Health Service, 50100 Firenze (Italy)

In the article by Singh and coworkers [1], biological agents were compared with traditional disease-modifying antirheumatic drugs (DMARDs). This comparison showed an increase in serious infections for patients treated with biological agents. To reach this conclusion, a frequentist cumulative meta-analysis (shown in Figure 4 of ref.1; 59 trials) was carried out in which the summary odds-ratio (calculated according to the Mantel-Haenszel fixed-effect [FE] model) was estimated to be 1.27 (95% confidence interval [CI]: 1.05 to 1.52).

Since Singh et al did not test one of the most commonly used meta-analytic models (i.e. the random-effect [RE] model according to Der Simonian and Laird[2]), we have re-analysed the data shown in Figure 4 of Singh’s article by running the above mentioned RE model as implemented in the Open Meta-Analyst software (version 4.16.12, Tufts University, url http://tuftscaes.org/open_meta/).

Our results are presented in the figure available at http://www.osservatorioinnovazione.net/papers/singhs-reanalysis.jpg

The odds-ratio that we obtained (1.25; 95%CI: 0.92 to 1.71; p=0.16; Figure) differs from the values reported by Singh et al. [1] mainly because “our” odds-ratio remained far from the threshold of statistical significance, whereas all the odds-ratios reported by Singh et al. satisfied this criterion.

References

[1] Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen R, Ghogomu ET, Coyle D, Clifford T, Tugwell P, Wells GA. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet. 2015 May 11. pii: S0140-6736(14)61704-9. doi:10.1016/S0140-6736(14)61704-9. [Epub ahead of print]

[2] DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–87.

On 2015 Nov 02, Christopher Southan commented:

Thanks to the authors for sending the 28 CID codes now mapped into PubChem http://cdsouthan.blogspot.se/2015/10/a-kinase-gift-horse.html

On 2015 Sep 08, Alexandra Alexiev commented:

This paper was featured in a microBEnet post here: http://microbe.net/2015/09/06/important-paper-on-how-biases-in-dna-extraction-can-shape-inferences-from-metagenomics-re-spore-formers/

MicroBEnet is a blog that writes about microbiology of the built environment and is funded by the Sloan Foundation to do outreach and science communication.

On 2016 Mar 22, Christopher Grefen commented:

FRET vector maps and sequences can be downloaded from my webpage.

I have prepared this little "How-to guide" for primer design of 2in1 Entry vectors; it can be accessed here.

For any other questions or vector requests, feel free to contact me via email: christopher.grefen@uni-tuebingen.de

On 2015 Aug 26, Donald Forsdyke commented:

DIMINISHED ROLE FOR CONVENTIONAL NATURAL SELECTION

This study decisively demonstrates both that nucleic acid level forces drive amino acid composition, rather than the converse, and that, in this respect, higher oligonucleotide frequencies are more powerful than mononucleotide frequencies (base composition). This is consistent with the case, made on different grounds, that oligonucleotide frequencies drive mononucleotide frequencies (summarized in Forsdyke 2011). Furthermore, there is now better support for Grantham’s “genome hypothesis” that natural selection by way of the conventional environment, may be secondary to some other form of selection that relates to speciation (see comment on Goncearenco A, 2014). Indeed, in some cases, amino acids in a protein may be mere “place holders” - there to serve the needs of the genome (Rayment JH, 2005).

Of course, some adaptation takes place at the protein level, but that the authors’ reading frame-specific analysis provides “contravening evidence” against the power of oligonucleotides is not readily apparent. In thermophiles the low frequency of TpA overlapping successive codons (e.g. NNT,ANN, …), and the depletion of ApT when positioned within a codon (e.g. NAT, NNN, … ), are easily explained by the pressure on thermophiles to purine-load their coding sequences (i.e. there is a nucleic acid level selective pressure). Thermophiles can best achieve this, without imposing excessively on amino acid composition, by incorporating purines in third codon positions. Thus, instead of the classical distribution of purines (R) and pyrimidines (Y) in codons (e.g. RNY, RNY, …), thermophiles tend to follow the RNR rule (e.g. RNR, RNR, … ) (see Lambros RJ, 2003).

Forsdyke DR: Evolutionary Bioinformatics. 2nd edition. New York: Springer, 2011.

On 2017 Jan 31, Robert Garry commented:

It is critical that the scientific literature provides an accurate account of the beginnings of the historic 2013–2016 epidemic of Ebola virus disease in West Africa. Wauquier and coauthors report incorrect information regarding the earliest known cases of Ebola in Sierra Leone. The timeline of the transmission chain that initiated the outbreak in Sierra Leone began earlier than described and the individual who performed the initial Ebola diagnosis in a Sierra Leonean is not properly acknowledged.

The date of death of a traditional healer from the village of Kpondu, Kailahun District in Sierra Leone differs from a timeline established by two independent highly credible investigations. Other publications that referred to the healer did not provide a date of her death, indicating that it occurred at an uncertain date before mid-May 2014 (1). Wauquier et al. state that, “On April 28, the healer became extremely ill and died two days later.” Investigations by the Awareness Times of Sierra Leone under the direction of Dr. Sylvia O. Blyden, who is currently Sierra Leone’s Honorable Minister of Social Welfare, Gender and Children Affairs, and separately by Dr. Sheri Fink and colleagues of the New York Times placed the date of death of the healer at or around April 8, 2014, three weeks earlier than April 30, 2014 (2, 3).

Wauquier and coauthors state that, “Ultimately, most of those who attended her [the healer’s] funeral ceremony became sick, each infected with the yet-to-be-identified Ebola virus.” This account is challenged by video taken at the funeral of the healer clearly documenting that hundreds of individuals were present (4). Only 14 confirmed Ebola cases are known to have attended the healer’s funeral. The scientific literature should reflect the fact that it is highly unlikely most individuals who attended the funeral of the healer become infected with Ebola virus.

While the first 14 cases of Ebola diagnosed in Sierra Leone are likely to have attended the healer’s funeral these individuals, all females, were diagnosed between May 25 and 31, 2014 (5). The latency period of Ebola from time of infection to symptoms is generally considered to be 2-21 days. The approximately 50 day delay to diagnosis from the actual date of the funeral circa April 8, 2014 indicates that these 14 individuals were unlikely to have been infected by contact with the healer’s corpse. Furthermore, Gire et al. (5) demonstrated that these 14 individuals were infected by Ebola virus of two genetically distinct lineages (Clade 1 and 2). This represents further strong evidence against direct infection of these individuals by pre- or post-mortem contact with the healer.

Conspicuously absent from Wauquier et al. are details of the early transmission in Sierra Leone documented in a March 19 memorandum from the World Health Organization [WHO], and emailed to a Tulane University co-author of Wacquier et al. on April 1, 2014 by a representative of Médecins Sans Frontières [MSF] (2, 3). The WHO memorandum described a probable case of Ebola who lived in or near the healer’s village. This probable early Sierra Leone Ebola case died approximately March 3, 2014. She is plausibly linked to the healer through a relative who was a close friend or assistant of the healer. Details of the March 3, 2014 death of a Sierra Leonean likely from Ebola were reported to have also been discussed in the field with the Wauquier et al. co-author by a MSF field operative.

Wauquier and coauthors state that, “On the afternoon of May 25th, the laboratory received the first blood sample from Koindu. Using reagents provided by the US Critical Reagents Program (CRP) in coordination with the US Army Medical Research Institute of Infectious Diseases (USAMRIID), the sample was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR), along with a batch of other routine samples received that same day.” The blood sample was received by Mr. Augustine Goba, Director of the Kenema Government Hospital [KGH] laboratory. Mr. Goba performed RT-PCR with detection by agarose gel electrophoresis showing that the sample sent from the Public Health Unit at Koindu was positive for Ebola virus (3). This sample was from a person living in the village of Sokoma, who attended the healer’s funeral. Confirmatory results using the USAMRIID RT-PCR were obtained only after Mr. Goba’s results had been obtained. Mr. Goba was awarded a Presidential Citation from His Excellency Ernest Bai Koroma for diagnosing this first case of Ebola in Sierra Leone.

Several co-authors of Wauquier et al. have been supported by grants and contracts on which I am the Principal Investigator. These grants and contracts contributed to the early epidemiological investigations of the Ebola outbreak in Sierra Leone. I was not informed about the submission of Wauquier et al. I also state that did not become aware of the March 19 WHO Memorandum until almost one year after April 1, 2014.

1. J. S. Schieffelin et al. (2014). Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone. N Engl J Med 371: 2092.
2. K. Sack, S. Fink, P. Belluck, A. Nossiter, “How Ebola roared back,” New York Times, December 29, 2014.
3. A. Goba et al. (2016). An Outbreak of Ebola Virus Disease in the Lassa Fever Zone. J Infect Dis 214 (supplement 3):S110.
4. D. Edge, S. Achilli. (2015). Outbreak, PBS.
5. S. K. Gire et al. (2014). Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. Science 345:1369.

On 2015 Jun 03, thomas samaras commented:

Body size is another factor related to differences in male vs. female longevity. For example, I found that American males were 9% taller than females and their life expectancy at birth was 9% less. Another researcher found that when he compared men and women of the same height, their longevity was nearly the same. Rollo found that differences in longevity between male and female mice was due to their differences in body mass. Smaller male dog breeds live longer than females in larger breeds. While women and men have the same length telomeres at birth, men have shorter telomeres at older ages due to higher telomere attrition rates promoted by the creation and maintenance of trillions of additional cells during their lifetimes.

Based on many species, Moore and Promislow also independently reported that while males generally have higher mortality, when the female of a species is larger, she has a higher mortality compared to the smaller male.

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

On 2015 Dec 28, Marco Weiergräber commented:

None

On 2015 Dec 07, Marco Weiergräber commented:

None

On 2015 Nov 10, Marco Weiergräber commented:

None

On 2015 Nov 10, Toni Schneider commented:

The comment of Marco Weiergräber is full of speculation. But scientific progress depends on careful control of novel hypotheses, especially when results of a similar research project are opposite. Scientific reports must mention opposite results, when new data are published. Siwek et al (Sleep 2014 May 1;37(5):881-92) did not refer to our results published a year earlier (Somnologie, September 2013, Volume 17, Issue 3, pp 185-192) but they speculate since then in an unscientific manner about our data, which were presented in our publication in an absolute transparent way (single data, in parallel to the resulting mean values). Our data are as reliable as the data from Siwek et al (2014). Taking this premise serious, one has to think about reasons for differences of results in an objective way. Two different mouse models were used in the two sleep studies mentioned. Logically, one must look for differences in these two mouse models, which we have discussed in an objective and fair way, without questioning the careful investigation done by Siwek et al (2014). To think about the different remnants left in the two different Cav2.3-knockout mouse lines should generate new hypotheses instead of condemning the results of a competing laboratory. We estimate the risk of an aminoterminal Cav2.3-peptide (resulting from the expression of exon 1) lower to contribute to calcium current disturbances as the risk of a "hemichannel".

The last chapter of Marco Weiergräber's comments also stays speculative, as long as he has not tested the transfer capacity of the transmitter device under discussion (a F20EET radiotransmitter from DSI). We tested the frequency bands under standardized conditions and can confirm that the bandwidth is broader than mentioned by him. Instead of repeating again and again the same critisism without mentioning e.g. a correction published by us (Schneider T. and Dibué M., 2015 in Somnologie 17, 307-308) and without presenting new proofing data, it seems to be a fight for something else but not for progress in Science.

On 2015 Oct 30, Marco Weiergräber commented:

This review article is dealing in major parts with a comparison of the work of Münch et al., "Cav2.3 E-/R-type voltage-gated calcium channels modulate sleep in mice" (Somnologie, September 2013, Volume 17, Issue 3, pp 185-192) and Siwek et al. "The Cav2.3 R-type voltage-gated Ca2+ channel in mouse sleep architecture" (Sleep. 2014 May 1;37(5):881-92. doi: 10.5665/sleep.3652). Following the publication of Münch et al. (2013), our group has raised substantial criticism to their work. For detailed information see: Weiergräber: "How do Cav2.3 voltage-gated Ca2+ channels affect sleep architecture?" (Somnologie, December 2013, Volume 17, Issue 4, pp 304-306) and Weiergräber: "Cav2.3 R-type Ca2+ channels in mouse sleep architecture—an update." (March 2015, Volume 19, Issue 1, pp 61-62) and Weiergräber: "A scientific assessment of Cav2.3 voltage-gated Ca2+ channels in rodent sleep architecture." (Sleep. 2015 Mar 1;38(3):501-2. doi: 10.5665/sleep.4520).

We had identified major experimental and analytical drawbacks in the study of Münch et al. (2013) that require -to our opinion- a total reperformance of the small sleep study performed by Münch et al. (2013). The numerous fundamental deficiencies in Münch et al. (2013) are not listet here again. We strongly advice reading our aformentioned commentaries.

However, instead of reperforming their study, Schneider and Dibue replied that the different mouse models might account for the differences in sleep study results between the groups (Schneider and Dibue, Somnologie, December 2013, Volume 17, Issue 4, pp 307-308 and Schneider and Dibue, Sleep. 2015 Mar 1;38(3):499. doi: 10.5665/sleep.4518). Although scientific reality tells a different story, Schneider and Dibue continue to suggest that the Schneider model of Cav2.3-/- might be superior to the Miller model of Cav2.3-/- which we used. In our response (Weiergräber: "A scientific assessment of Cav2.3 voltage-gated Ca2+ channels in rodent sleep architecture." Sleep. 2015 Mar 1;38(3):501-2. doi: 10.5665/sleep.4520) we have clearly elaborated that this explanation which is again repeated here in this review does not hold true and has no scientific basis. The suggestion that Cav2.3 fragments in the Miller model could form functional channels is not only speculative, indeed, publications by Annette Dolphins group (e.g. Raghib et al., 2001) has shown that it simply does not occur. Although we have communicated this fact to the authors repetitively, they again ignore it and they also did not cite our commentaries which might have helped to avoid their misleading argumentation again.

In order to comment or review their data it's mandatory for Münch et al. (2013) to first reperform their experiments to acquire valid sleep data, second to analyze for compensatory mechanisms in their model (which we did in the Miller model, but they did not in their model, at least they did not report) and finally, the Schneider model has to be evaluated for potential N-terminal peptide fragments and their influence on Ca2+ channel physiology. Finally, the authors cite Dibue et al. (2014, Epilepsia). We have explained to the authors in detail (Weiergräber and Papazoglou, Epilepsia. 2015 Jul;56(7):1180-1. doi: 10.1111/epi.13041.) that the gamma data presented there are not valid as the analysis of gamma up to 500Hz is not possible with the transmitter type they used (a F20EET from DSI with 1-50Hz bandwidth and 250 Hz nominal sampling rate). The Nyquist-Shannon-limit does not allow for analysis of such high gamma as Dibue et al. did. There is thus no justification to cite this publication. Given the misleading discussion here, a correction and clarification is requested for this part of the publication.

On 2015 May 14, Bernard Baars commented:

Jon Schooler and coworkers have conducted a wonderful series of studies on the stream of thought, distractibility, and the like. My remarks are not meant to diminish their great contribution.

Spontaneous mentation has a long and intellectually important history, including James, Freud, and Proust. I believe none of those people would believe that the spontaneous stream of thought is "mind wandering." That terminology suggests something that is dysfunctional. The alternative hypothesis is that the spontaneous stream of consciousness is indeed FUNCTIONAL, though its functions may be implicit. That is indeed the outcome of Jerome S. Singer's years of study, suggesting that "current concerns" are the focus of spontaneous thought. That includes recent difficulties in relationships, and possible solutions. It may include recurrences of traumatic memories or related cues. It may include inner complaints about the boring task, which people usually avoid if they get a chance to.

The competition between ASSIGNED tasks and spontaneous mentation may occur simply because the spontaneous stream is NEEDED and generally FUNCTIONAL. The mere fact that subjects sign a consent form does not mean they really consider the assigned task to have a higher priority compared to wondering about the attractive cabin attendant.

It is something of a scientific leap to label any preferred behavior to be dysfunctional. In clinical psychology and psychiatry such labeling only occurs after much debate, research, and review. Terms like "on-task" vs. "off-task" mentation are value neutral, and therefore preferable to "mind wandering". In one current literature on depression, sheer mind wandering is pathologized as "rumination," and taken to be a sign of depression. That would make Picasso's and Mozart's spontaneous thinking about painting and music to be dysfunctional and a sign of depression.

Not all task-independent thought is bad.

On 2015 Jul 06, Adrian Barnett commented:

I have used the random effects models on skewed exercise data with just 2 to 3 observations per person and the model converged and gave a meaningful answer. That may not always happen, but given the potential change in interpretation it is worth trying.

On 2015 May 29, Chris Wallace commented:

Thank you for your interest in our paper. We used the cosinor model because we wanted a parsimonious model for testing for seasonality. I completely agree, that to model and understand the specific seasonal patterns more precisely we will need to consider models with more parameters which do not enforce symmetry or a sinusoidal shape. Your point regarding individual random effects for the cosine and sine terms is interesting, but I wonder, does this require many repeated measures per individual to fit well? Typically the datasets we accessed, although longitudinal, had a limited number of observations per individual.

On 2015 May 16, Adrian Barnett commented:

This is an interesting and highly novel paper. The cosinor model uses only two parameters to create a seasonal pattern and is therefore parsimonious, however more complex seasonal models are likely to provide further understanding of the seasonal patterns shown.

Firstly the cosinor model used gives the seasonal pattern at a population level, but the seasonal pattern in individuals is likely to be stronger. As an extreme example, imagine half a study sample had a seasonal peak in early January and the other half in early July. At the population level these patterns would cancel out despite their being potentially strong individual seasonality. The strength of the individual seasonal pattern can be estimated by including random effects (at the individual level) for the cosine and sine terms. The greater the heterogeneity in individual seasonal patterns, the greater the difference between the individual and population seasonal pattern.

Secondly the cosinor model is symmetric in terms of both the peak and trough, and the rate of seasonal increase and decrease. More general models, such as splines or models that use a categorical variable for month, use more parameters but are able to show a wider variety of patterns, such as a steep increase during the autumn to winter transition and slower decrease during the winter to spring transition.

On 2017 May 26, Seán Turner commented:

Type strain of Sphaerisporangium corydalis is DSM 46723, not DSM 46732.

On 2015 May 18, Tony Larkman commented:

Recent advances in the detection of adulteration in tea tree oil (TTO) published by Wong et al in May 2015 (Enantiomeric distribution of selected terpenes for authenticity assessment of Australian Melaleuca alternifolia oil: http://www.sciencedirect.com/science/article/pii/S0926669015000680) show a significant number (>50%) of commercial samples varying markedly from the ∼68.5% expected value found for (+) terpinen-4-ol. It is notable that of the 15 commercially sourced samples from the European Union, 73% of these showed significant differences in chiral abundances indicating widespread incidence of this fraudulent practice.

In this article Santesteban Muruzábal et al state that the incidence of allergic contact dermatitis was "...until recently...infrequent in our setting" and "Further, three of the five patients also reacted to oxidized d-limonene". While limonene is present in pure TTO at ~1%, if the TTO is correctly stored the level of oxidation of not only the limonene but all other components remains low. More detail on this is available in a paper by Brophy et al: Gas chromatographic quality control for oil of Melaleuca terpinen-4-ol type (Australian tea tree) http://pubs.acs.org/doi/abs/10.1021/jf00089a027

In Australia, and other countries, when pure TTO steam distilled from Melaleuca alternifolia is correctly handled and stored to minimize degradation through oxidation the incidence of allergic contact dermatitis appears to be far less than that experienced in the European Union.

It is therefore not unreasonable to expect that the reactions noted may be caused by the use of adulterated material masquerading as TTO - this material is often manufactured using a poor quality (highly oxidized) product diluted with industrial waste sourced from 'normalising' other essential oils such as Pine and Eucalyptus. This industrial waste is uncontrolled and a diverse range of substances of unknown origin have also been detected when analyzed (personal observation: 2013 - 15).

It would be interesting to know if the enantiomeric ratios for the material used in this study conformed to the expected ratios as published by Wong et al.

On 2016 Aug 26, Diana Frame commented:

This article has been retracted because sections of its text are identical to another article (Afshar et al 2014, Obes Surg, PMID 25015708). The notice of retraction is featured on the publisher page, but should be shown more prominently in the PubMed record.

On 2017 Apr 12, Siegfried Hekimi commented:

We obtained very different results that suggest that CLK-1 functions exclusively in ubiquinone biosynthesis and not in the nucleus to affect the mtUPR. In a paper entitled: A single biochemical activity underlies the pleiotropy of the aging-related protein CLK-1. By Liu et al. http://www.nature.com/articles/s41598-017-00754-z?WT.feed_name=subjects_energy-metabolism

On 2015 May 15, Kausik Datta commented:

"P value of <0.1 was set as a meaningful difference with statistical significance."

I am curious, how exactly was the acceptable P-value set at a non-traditional, less robust/discriminatory value? How was this considered 'meaningful', based on... which consideration(s)? Did the peer reviewers for this article raise this question to the authors, and if so, what was the authors' response?

(Caveat: I don't have access to the full paper and, therefore, don't know if these questions have been answered in the discussion.)

On 2015 Sep 06, Lydia Maniatis commented:

The claims of Blakeslee and McCourt are flawed on logical, methodological, theoretical, and empirical grounds.

Perhaps the core error is the denial of perceptual facts, as described below (and as noted also by Gilchrist in his commentary on this article).

In the Adelson checker-shadow illusion (to take one example), a check in apparent shadow looks white, while an equiluminant check, apparently in plain view, looks black. Aside from the additional presence of the apparent shadow, the experience of the two surfaces is similar to looking at a white check and at a black check under homogeneous illumination. Kohler (1935), describes a “real-world” version wherein a white and a black paper appear white and black, respectively, even if the illumination is adjusted so that the two surfaces are actually equiluminant.

Imagine, now, what would happen if we asked a naive observer to report on “the intensity of the light coming from the surface of each of the two checks.” First, he or she would likely assume the question referred to the apparent illumination of the surfaces. In this case, the white, “shadowed” check should receive a lower rating than the black “plain-view” one. If we then tried to clarify that we want the observer to make matches based on “the amount of light each surface is sending to the eye,” (its luminance) I think the observer would have trouble a. understanding what we are asking and b. performing the required task. And I'm not sure anyone would be able to judge, with confidence, whether the two checks in the Adelson checkerboard are, or are not, in fact equiluminant. That's what makes the demo so impressive. Even if observers could estimate this value, the task would be difficult and the results unreliable. To achieve it, they would have to focus narrowly on each square, isolating it from the surround.

Yet, Blakeslee and McCourt maintain that the latter task, which requires viewers to overide their spontaneous, salient perceptual experience, is “strictly based on appearance,” while the former, effortless experience is “based on an inferential judgment.” If, however, we define “appearance” as “what something looks like,” then the authors' arguments are obviously false, as can be confirmed by any observer.

The authors' argue that the experience which is quite literally based on appearance, is actually a product of learning. This is a major claim (implying that learning can actually alter a percept from black to white), but the authors offer no evidence for it. All of the arguments and available evidence is against. As Gilchrist (2015) points out, even fish seem to naturally achieve this kind of learning. A child can see the Adelson checker-shadow effect as effortlessly as an adult. Our perceptions aren't affected by what we learn about the nature of light and the properties of surfaces, we don't have to learn how to judge when a surface is in shadow or merely darker than its neighbor, or when it is covered by various types of transparency, we don't even have to learn that at night things don't actually change color. Given the difficulty scientists have in analyzing and modelling percieved lightness, and given that massive, early exposure to artificial images mimicking illumination variation has no discernible effect on our perception of the “real” world, the claim that people go through a process of learning to make the inferences necessary to achieve veridical percepts in natural conditions does not seem credible. B and M have certainly not tested it.

The quality that the authors argue is “strictly based on appearance” is a quality that they term “brightness,” defined as the perceptual correlate of luminance. The view that there is a perceptual correlate of luminance seems to be uncontroversial among lightness researchers (e.g. Kingdom, 2011; Gilchrist, 1999)), although Anderson (2014) seems to define brightness (more properly, in my opinion) as apparent illumination. The claim seems easy to refute.

Suppose we observe a set of surfaces lacking cues to differential illumination, and that some appear white, some gray, some black. Suppose, then, that we observe the same set of surfaces, at a different time, under a different degree of illumination. Assume that have completely forgotten the previous experience with the surfaces, and are again asked to judge their white/gray/black character. Our responses will typically be similar to those we gave in the first (now forgotten) instance. In other words, even though the illumination (and consequently the luminance) of the surfaces will have changed, our responses will remain the same. If the range of luminances is complete enough, they will, in both cases, be correlated with reflectance and not with luminance. Thus, even under homogeneous illumination, we cannot say that we are perceiving luminance, or that perception is more direct than in other situations. As always, the percept is the product of a complex visual process based on luminance values and structural assumptions.

When it comes to the case of non-homogenous (apparent) illumination, the authors seem to be treating illumination boundaries as though they were directly-perceived facts serving to support “inferentially” perceived lightness judgments. They say, for example, that “when the illumination component is clearly visible” the observer can use “brightness contrast” at the boundary to infer the magnitude of the illumination. There are a number of problems with this description.

First, if a shadow is perceived – is “clearly visible” - as the cause of the luminance boundary, then viewers are perceiving a double-layer – a surface with lightness x and an apparent shadow of darkness y lying on top of it. They are not perceiving a single “brightness” value. The authors are using the term “brightness” when they actually mean luminance.

Relatedly, the illumination boundary only becomes “clearly visible” after the visual process has inferred its presence based on the luminance structure – including the relative luminances at luminance boundaries - of the image. Whether the darker side of an edge will be perceived as being similar in reflectance, but lower in illumination than its neighbor, or as darker than its neighbor due to a lower reflectance, or any other combination of possibilities, depends on the global structure of the image. Given certain conditions, even a non-existent luminance edge may produce an apparent lightness difference, as in the case of illusory surfaces. So the argument that perceiving a surface as continuing beneath a “shadow” boundary is more inferential than perceiving a particular surface as gray due to its luminance relative to other surfaces in an image is naive. If “appearance-based” means “based on luminances”, then all perception is appearance-based. If it means that surfaces are perceived based on local luminance conditions, then it never is. Local conditions do not even determine photoreceptor activity in the horseshoe crab.

As corroborating evidence, the authors point to a few references, including Blakeslee and McCourt (2008), which is supposed to prove the existence of “brightness” judgments. Their stimuli consist of the classic simultaneous contrast demo plus variations that create weak impressions of differential illumination. The “brightness” judgments are defined as those that arise when observers are instructed to focus narrowly on the targets. This is similar to applying a mask. Effectively, we are talking about the same visual process acting on a different stimulus, not about a different type of judgment. Due to the weakness of the structural cues to differential illumination in B and M's (2008) stimuli, the ability of observers to isolate the target in this way is very easy. The demand would be much more difficult, and the results surely very different, if the stimulus had been the Adelson checkerboard.

On 2015 Aug 10, Guangchuang Yu commented:

I have analyzed the data using my Bioconductor package clusterProfiler. The enriched term found by DAVID can be reproduced with more detail terms enriched. see https://github.com/GuangchuangYu/enrichment4GTEx_clusterProfiler.

On 2015 May 14, Jeff Kiefer commented:

The functional enrichment analysis performed in this paper was done with the DAVID resource Dennis G Jr, 2003, however, this resource has not been updated in nearly 5 years http://david.abcc.ncifcrf.gov/helps/update.html.

On 2015 May 27, DANIEL BROWN commented:

Unfortunately strain B2096 8B is actually Mycoplasma gallinaceum.

On 2014 Nov 25, Harri Hemila commented:

A secondary analysis of this study has been published in Hemilä H, 2013, DOI. The secondary analysis calculated that when the participants suffered from the common cold, vitamin C increased histamine PC20 level by 3.2 fold (95% CI 2.0 to 5.1). After the participants had recovered, the effect of vitamin C was smaller so that there was a significant interaction between vitamin C effect on PC20 and the presence of the common cold (P = 0.003).

On 2015 May 09, Christopher Southan commented:

Context and additional information http://cdsouthan.blogspot.se/2014/09/anti-ebola-medicinal-chemistry-time-for.html

On 2017 Jul 10, Randi Pechacek commented:

Elisabeth Bik discusses this paper in a microBEnet blog post about the microbiome of the built environment.

On 2015 Oct 06, M Felix Freshwater commented:

If other researchers obtain the same results then the quality of the data in the ACS-NSQIP database is suspect.

On 2016 Oct 11, UFRJ Neurobiology and Reproducibility Journal Club commented:

In this article, the authors demonstrate that the response to an aversively conditioned context is different between rats that have undergone conditioning individually or collectively, and suggest that this is mediated by olfaction.

Despite the interesting findings, we would like to point out that the statistical methods used for the results shown in Figures 2E and 4C do not support the conclusions made by the authors. In Figure 1B, the illustrated result was that the collectively conditioned group presented a significant decrease (p<0.01) in fear response 24 h after training when compared to animals conditioned individually. The same kind of comparison (collective vs. individual conditioning) was performed in Figure 2E, with the test performed 3.5 h after training; in this case, no statistical significance (p> 0.1) was found (even though a trend towards reduced freezing in the collectively conditioned group can be observed in the figure). Based on this, the authors conclude that “these data argue strongly that fear acquisition was similar in both groups and that neuronal mechanisms mediating fear memory consolidation and/or expression are involved in the markedly attenuated fear memory in Group animals.”

This conclusion, however, is based on a common statistical misconception: namely, to infer that, if a significant difference at a given threshold is found between two groups in one condition (i.e. collective conditioning) but not in another (i.e. individual condition), this implies that there is a significant difference between the two conditions. This statistical reasoning is erroneous, since the differences found in both conditions can be similar in magnitude (as they seem to be in this case), and the fact that one but not the other is found to be significant at an arbitrary significance threshold can be a consequence of statistical power, variability, or mere chance. As discussed by (Nieuwenhuis S, 2011) to argue in favor of a difference in magnitude between two differences found in individual comparisons, the correct statistical approach would be to test whether there is a significant interaction between the two independent variables (in this case, group and time of testing), and not simply report that an effect was statistically significant while the other it was not.

The same error occurs in Figure 4C, in which the collectively conditioned sham group presented a significant reduction compared to individually conditioned sham rats (p < 0.05) individually, while this difference between types of conditioning was not found (p > 0.1) in anosmic rats. Although the difference in this case indeed seems larger in the sham group, results for the interaction between type of conditioning and anosmia were not shown, and the post-hoc results presented cannot be used to conclude that the sense of smell is responsible for the difference between individual and collective conditioning. This does not mean that the sense of smell does not play a role, but to support this conclusion the authors should present a statistical analysis that actually tests this hypothesis.

On 2016 Oct 11, UFRJ Neurobiology and Reproducibility Journal Club commented:

None

On 2015 Jun 06, A Martinez-Arias commented:

This manuscript claims the discovery of a new kind of Embryonic Stem (ES) cell, so called ‘region specific Epiblast stem cells (rsEpiSC). A close look at the protocols, genetics and cell behaviours indicates that what is reported is likely to be an improved method for the maintenance of EpiSCs and the closely related human ES cells; it would be misleading to describe a more stable population as a new entity.

The main finding reported here is that inhibition of Wnt signalling in cultures of EpiSCs, and also human ES cells, leads to a stable pluripotent population. As briefly indicated below, this has been reported a number of times before, as has the ability of EpiSCs to integrate in postimplantation embryos, the other finding presented here as new. The observation that stabilized human ES cells can undergo a similar integration is, however, novel, though the degree to which this happens and its value will await further experiments.

It is well known that ES and EpiS cells are, for the most part, heterogeneous populations in dynamic equilibria. In the case of ES cells this can be biased towards a stable state, called ‘ground state’, by application of two inhibitors, one for MEK and another for GSK3 [1]. It is also well known that in contrast with ES cells, when EpiSCs and human ES cells are presented with high levels of Wnt signalling they differentiate [2, 3] and over the last few years a number of reports have shown that inhibition of Wnt secretion or Wnt/ß-catenin signalling increases the self renewal of EpiSCs populations [4-6]. Thus a cocktail of Activin, FGF2 together with Wnt/ß-catenin inhibitors leads to efficient derivation of EpiSCs as well as their stable culture. This is confirmed in this report without acknowledging the earlier studies –interestingly some of these studies are referred to but only as discussing Wnt signalling in pluripotency. Having repeated this observation, the authors now notice that removal of Activin from the cocktail –but not inhibition of Activin signalling, which is not tested- improved the stability of the culture; this tweak is novel and mechanistically intriguing, though it is not pursued further. Thus the main message of the work is that EpiSCs grown or derived in the presence of FGF2 and Wnt inhibitors are stable (this is no new kind of ES cell).

With regard to the ability of the cells to integrate in the posterior part of postimplantation embryos, there are also precedents showing that EpiSCs, which indeed are not able to integrate in preimplantation embryos under normal conditions, can and will integrate in postimplantation embryos [7, 8]. The point made here that ‘stable EpiSCs integrate preferentially in posterior regions of the embryo is not surprising as integration is likely to be easier in the region undergoing gastrulation, which is ongoing in the posterior region at the time of the injection. Furthermore, the conclusion that ‘rsEpiSCs’ are related to the posterior proximal epiblast of stage E6.5 is similar to that obtained by Kojima et al. that although it is possible to obtain EpiSCs from a range of stages during gastrulation, EpiSC lines tend to correspond to anterior primitive streak i.e. posterior proximal E6.5 [8]. The results presented here are compatible with the observation that EpiSCs derived from embryos at different stages of gastrulation can be different [8] i.e there might be many rsEpiSCs, which is probably not a helpful notion.

One of the arguments used by the authors to claim the identification of a new type of stem cell is their transcriptional profile. However, EpiSC lines derived from different stages around gastrulation have different properties and transcriptional profiled and much of these differences are likely to be down to signalling [8]. Thus it is not that surprising that a population of EpiSCs severely deprived of Wnt and Activin signalling exhibits a special transcriptional profile and maps, in a PCA plot, away from other cells in different states and notably from EpiSCs grown in Activin and FGF2, a very different cocktail. It is likely that under appropriate experimental conditions, rsEpiSCs will be shown to correspond to one of the EpiSCs derived by Kojima et al. [8], though the changes and adaptations associated with growth in specific signalling environments would make the comparison challenging.

In summary, this report is a protocol to obtain a state which is to EpiSCs what the ground state (2i) is to the ES cells. This is certainly useful but not enough to talk about a new kind of ES cells. Of course, this is an opinion. Nevertheless, the work provides further support to the importance of Wnt signalling in the control of the dynamics of stem cell populations.

References [1] Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, et al. The ground state of embryonic stem cell self-renewal. Nature 2008;453:519-23. [2] Singh AM, Reynolds D, Cliff T, Ohtsuka S, Mattheyses AL, Sun Y, et al. Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell 2012;10:312-26. [3] Davidson KC, Adams AM, Goodson JM, McDonald CE, Potter JC, Berndt JD, et al. Wnt/beta-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4. Proc Natl Acad Sci U S A 2012;109:4485-90. [4] Kurek D, Neagu A, Tastemel M, Tuysuz N, Lehmann J, van de Werken HJ, et al. Endogenous WNT signals mediate BMP-induced and spontaneous differentiation of epiblast stem cells and human embryonic stem cells. Stem cell reports 2015;4:114-28. [5] Kim H, Wu J, Ye S, Tai CI, Zhou X, Yan H, et al. Modulation of beta-catenin function maintains mouse epiblast stem cell and human embryonic stem cell self-renewal. Nat Commun 2013;4:2403. [6] Sumi T, Oki S, Kitajima K, Meno C. Epiblast ground state is controlled by canonical Wnt/beta-catenin signaling in the postimplantation mouse embryo and epiblast stem cells. PLoS One 2013;8:e63378. [7] Huang Y, Osorno R, Tsakiridis A, Wilson V. In Vivo differentiation potential of epiblast stem cells revealed by chimeric embryo formation. Cell Rep 2012;2:1571-8. [8] Kojima Y, Kaufman-Francis K, Studdert JB, Steiner KA, Power MD, Loebel DA, et al. The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak. Cell Stem Cell 2014;14:107-20.

On 2015 Jun 30, Prashant Sharma, MD, DM commented:

This paper basically addresses a cost-cutting issue that sometimes unfortunately still surfaces in resource-poor settings, wherein electrophoresis-derived hemoglobin fraction percentages are used for clinical decision making.

While electrophoresis followed by elution and chemical or photometric measurement is acceptable, electrophoresis followed by densitometry, we found, is simply too unreliable to be used in tests that establish genetic diagnoses or are used to screen antenatal women for fetal diseases.

We, the authors, would be happy to discuss the findings and our experiences with interested readers at the email provided at the publisher website.

On 2017 Mar 06, Atanas G. Atanasov commented:

Very interesting review dear Colleagues. I have used is as a base for writing a posting at: http://healthandscienceportal.blogspot.com/2017/03/the-health-promoting-potential-of.html

On 2016 Dec 18, Zvi Herzig commented:

The concerns for potential chronic toxicity in 2 of the 42 tested products refer to (1) terpene hydrocarbons in relation to Maximized Survey-Derived Intake (MSDI) levels and (2) diacetyl in relation to NIOSH-recommended safety limits.

MSDIs are the normal exposures considered when food safety standards are established. Exceeding them isn't necessarily hazardous, but it implies a level not considered in the assessment. Therefore, it's important to consider other available safety limits when possible.

The strictest 8 hr occupational exposure limit for terpenes is 20 ppm (111 mg/m3) Granström KM, 2010. Occupational safety limits consider a ~10 m3/workday respiration rate for active workers Kuempel ED, 2015. This corresponds to a safe terpenes inhalation limit of 1,110 mg/workday.

The highest concentration of terpenes in this study is 106.7 mg/g. A mean consumption of 3 g e-liquid daily among EC users is noted. This corresponds to terpene consumption of 320.1 mg/day for the highest terpene concentration e-liquid -- a fraction of the aforementioned safety limit.

Furthermore, with a high prevalence of switching between flavors Farsalinos KE, 2013, these quantities are further diluted in relation to chronic use. This study detected hydrocarbons at 2.5 mg/g on average, all hydrocarbons being terpenes. In contrast, a single cigarette delivers 4.9 mg of hydrocarbons, including 1.1 mg of terpenes Perfett TA, 2014. Despite the much higher exposure to terpenes in cigarette smoking, terpenes are not noted in any of the lists of cigarette smoke's notable toxicants.

With regards diacetyl estimated to result in 126 µg/day exposure in one case, it should be noted that tobacco smokers inhale 5700 µg diacetyl per day Farsalinos KE, 2015, 45 times greater than the exposure resulting from using the product with the highest diacetyl level among 42 liquids tested in this study.

On 2016 Apr 05, Marko Premzl commented:

The third party data gene data sets of eutherian adenohypophysis cystine-knot genes (128 complete coding sequences) and D-dopachrome tautomerase and macrophage migration inhibitory factor genes (30 complete coding sequences) HF564658-HF564815 were deposited in European Nucleotide Archive under research project "Comparative genomic analysis of eutherian genes" (https://www.ebi.ac.uk/ena/data/view/HF564658-HF564815). The 158 complete coding sequences were curated using tests of reliability of eutherian public genomic sequences included in eutherian comparative genomic analysis protocol including gene annotations, phylogenetic analysis and protein molecular evolution analysis (RRID:SCR_014401).

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

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

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

On 2018 Jan 19, Natalie Clairoux commented:

Free version of this article available at http://hdl.handle.net/1866/19737

On 2016 Sep 19, John Marshall commented:

None

On 2016 Sep 17, Christopher Southan commented:

The non-disclosure of the Genz-682452 molecular structure (even though it may have been exemplified in WO2012129084) renders this work irreproducible

On 2017 Mar 19, NLM Trainees’ Data Science Journal Club commented:

The NLM Trainees Data Science Journal Club for this discussion consisted of several NLM staff members, including one of the paper’s authors. In brief, the authors employed a visual and a computational method to explore the contribution of individual drugs to a drug class-level signal in the context of adverse events. The authors used both techniques to identify class effects caused by all members of a drug class individually, as well as class effects based on a subset of drug class members.

As background information regarding adverse events, one group member pointed out that there has to be enough evidence between a drug or class and an adverse event for it to be formally labeled an adverse event. As such, the type of comparison performed in this study has the potential to introduce false positives, where there is a co-occurrence between a drug and an event that is not to the level of a “label-able” event.

In terms of methodology, the group discussed that, while this study is biased towards using case reports, the strength of evidence would likely be higher if based on randomized controlled trials; however, RCT’s are generally more focused on drug efficacy than safety.

The question was raised as to whether study results might differ if the drugs or adverse events were mapped using different terminologies than ATC and MeSH, respectively. In response, the author pointed out that the FDA uses MEDRA to report events, but for the purposes of this study, it was more complicated to use than MeSH, as it would have required hand curation (beyond the automated curation the UMLS offers) to be useable. That said, the general methodology used by the authors is largely terminology agnostic and can be used with any terminology that is reasonably hierarchical.

One group member was curious whether this process could be used for clinical decision support. Discussion revealed that this methodology is not suited for CDS, as the evidence would need to be clearer. For CDS use, the process would need to be based on drug labels or drug information systems, which are usually expressed at the individual drug level. It might be interesting to know if a class was affecting adverse events at the class level or based on a subset of the class, but this would not be the primary concern in a primary care setting. However, the results of the study could be valuable to drug safety professionals and those building adverse event repositories to support their review or decisions in regard to adverse event relationships.

On 2016 May 18, Heidi Schulz commented:

The c.910_912delGAT mutation was already reported in Lotery et al. 2000 (PMID10798642), Kinnick et al. 2011 (PMID21273940) and Katagiri et al. 2015 (PMID26201355).

On 2017 Jul 01, L-T Jia commented:

the additional file (https://reproductive-health-journal.biomedcentral.com/articles/10.1186/s12978-015-0031-x) of the study seemed unrelative with morphokinetic illustration of the embryo development.

On 2016 Aug 01, Joaquim Radua commented:

Re: the first comment, I think there may be some unfortunate confusion. Raw p-values of current voxelwise meta-analyses have not the same meaning as usual p-values because they are not derived from the usual null hypothesis (“there are no differences between groups”), but from another null hypothesis (“all voxels show the same difference between groups”). Thus, up to the moment one of the only ways to "approximately" know if the results of a voxelwise meta-analysis are neither too liberal nor too conservative is to compare them with the results of a mega-analysis of the same data, and that's what it was done.

On 2016 Jul 14, Lars Schulze commented:

Dear Christopher Tench,

we agree that it is important to control the rate of false positives in meta-analyses. Please note, that our study did apply empirically validated thresholding procedures that have been shown to not only balance sensitivity and specificity, but also to be equivalent to a corrected P-value of 0.05 (Radua et al., 2012). To even further reduce the possibility of false positive results, we used an additional voxel-wise threshold with Z-values >1.

Thus, our meta-analysis applied validated and recommended methods to control the inflation of false positive results.

Sincerely, Lars Schulze

On 2016 Jun 19, Christopher Tench commented:

The methods employed do not constitute a meta analysis as uncorrected p-values offer no protection against false positive results. Consequently the study provides no evidence of significant consistency across studies. Uncorrected p-values are not useful in meta analysis of neuroimaging studies.

On 2015 May 04, Andrew Brown commented:

This is our letter about concerns with this paper Hernández-Cordero S, 2014; the authors' response is here http://jn.nutrition.org/content/145/5/1029 (not yet indexed in PubMed).

On 2015 May 05, James Tsung commented:

Link to Case Videos: https://youtu.be/vTyiofq-UsI?list=PLHg2xyua_KjtriEZcFW6tH0iIIPTwSQvT

On 2017 Jul 21, Horacio Rivera commented:

Are citations related to a faulty writing style or simply to content? The results got by Weinberger et al. (2015) in their analysis of >1,000,000 abstracts may not be so surprising. Taking into account the pervasiveness of an improper writing style (Woodford FP, ed. Scientific Writing for Graduate Students, CBE 1986; Gopen&Swan, Am Sci 1990, 78: 550; Knight J, Nature 2003, 423: 376; Editorial, Nat Struct Mol Biol 2010, 17: 139), I guess that the decreased citation rate associated with half of 15 well-known stylistic features can equally be ascribed to the papers’ content. Actually, the opposite pattern found for the remaining features suggests that style alone is not a consistent predictor of citation rates. A more reliable study would compare a sample of "well written" vs "poorly written" abstracts, classified according to conventional wisdom by expert colleagues, instead of analyzing all available abstracts in a given period. I do two additional comments: 1. Rule 4 of the authors "Use the present tense" is unsuitable when dealing only with abstracts. At least in biomedicine, the general advice is to use the past tense in the "M&M" and "Results" sections that account for half or more of an abstract. Obviously, the results would have been the opposite ones if the rule "Use the past tense" had been applied. 2. The assertion that in "writing a paper, the limiting step is the ability to find the right article" appears nonsense inasmuch it disregards the crucial intellectual input required for successful writing. In other words, "to find the right article" is a preparatory rather than limiting step. To conclude, I praise the effort of Weinberger et al. (2015) in summarizing ten simple rules aimed to improve our writing style.

On 2016 Oct 02, Atanas G. Atanasov commented:

Readers might also find of interest the study “Does a Graphical Abstract Bring More Visibility to Your Paper?”: https://www.ncbi.nlm.nih.gov/pubmed/27649137

On 2015 May 17, Egon Willighagen commented:

Like Open Access, "sharing" is a meaningless term if it is not linked to meaningful rights. The problems outlined in this paper result from the fact that their may be a wish to share data but only if it allows you to take back the data. Private, custom data licenses do just that. There is nothing wrong with this kind of sharing, but it must not be confused with Open Data. It must not be confounded with terms like "publicly available", because if it needs a signature, it's not publicly available. That makes the lead of this article quite misleading.

For public or open data, three basic rights are part of the social agreement between the data owner (yes, fact in many countries; database rights, etc) and data user. These rights are: 1. make a copy, 2. make modifications, and 3. reshare (under the same conditions). By using a license (or waiver) that gives this rights automatically to the receiver, then there is no need for signatures. It also allows for anyone to make the mappings that are required to convert one format into another.

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 NCT0033633. We believe the correct ID, which we have found by hand searching, is NCT00336336.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2015 May 01, David Mage commented:

"Close, but no cigar!" Human 5HT2A is autosomal. OMIM shows 182135 - 5-@HYDROXYTRYPTAMINE RECEPTOR 2A; HTR2A Cytogenetic locations: 13q14.2; SIDS and all respiratory deaths under 5 years of age have a 50% male excess suggesting an unidentified X-linked gene with a recessive non-protective allele with frequency q = 2/3 in Hardy-Weinberg Equilibrium may be involved (NB: 5HT2C is X-linked). See Mage DT, Donner EM. An explanation for the 25% male excess mortality for all children under 5. Scandinavian Journal of Forensic Science 2015;21(1) doi: 10.1515/sjfs-2015-0001

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 NCT0102455. We believe the correct ID, which we have found by hand searching, is NCT01024595.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2017 May 29, Rashmi Das commented:

We thank Harri for his comment. It is really sad to see that Harri is trying to disseminate his personal opinion (HANDLE) THOUGH A DETAILED PEER-REVIEWED REPORT IS AVAILABLE AT COCHRANE LIBRARY. We need to share the sequence of events here, so that, things can become more transparent. After our publication of the Cochrane review in 2011, Harri published another review on the same topic in Open Respiratory Medicine Journal in same year. He provided comment on our 2011 Cochrane review in 2012, which we incorporated in 2013 version of the Cochrane review. In 2015, Harri made a report on the Cochrane review 2013 version (not 2011 version, which is still available there) and complained to the Cochrane Editor (Whatever has been mentioned in the ABOVE HANDLE: http://hdl.handle.net/10138/153180, which is a PERSONAL OPINION AND NOT A PEER-REVIEWED CONTENT). The Cochrane editors made a detailed inquiry (INVOLVED AN INDEPENDENT STATISTICIAN) and made the recommendation to withdraw the review NOT BASED ON TEXT PLAGIARISM BUT BASED ON INCONCLUSIVE DATA ANALYSIS (Detail available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001364.pub5/abstract;jsessionid=FCA801377C71E663B0004B9BBB92A908.f02t03). This report also mentions that we have acknowledged and cited his review (Hemilla 2011). But the irony is that the ABOVE HANDLE (Which contains DIRECT COPY OF THREE IMAGES/FIGURES FROM OUR PUBLICATION) IS BEING DISSEMINATED AS A PUBLICATION/REFERENCE TO SENT THE MESSAGE THAT WHAT HE HAS MENTIONED IS ENTIRELY RIGHT (BUT THE COCHRANE REPORT DOES NOT FULLY AGREE TO THIS). MOREOVER THE HANDLE IS STILL ACTIVE AFTER THE COCHRANE LIBRARY PUBLISHED THE REPORT AND REACHED THE CONCLUSION.

On 2017 May 24, Harri Hemila commented:

Background of the withdrawal

Concerns were expressed about unattributed copying of text and data, and about numerous other problems in the Cochrane review “Zinc for the Common Cold” by Singh M, 2013.

Details of the concerns are available at: http://hdl.handle.net/10138/153180.

On 2015 Jul 14, Andrew Kewley commented:

The authors show that questionnaires and other diagnostic methods lead to statistical overlap (mush) and therefore conclude that this group of disorders can be re-branded as a spectrum called "ALPIM".

The sample group of this study is highly biased and cannot be generalised, so the question is, should this study be replicated with a community/population based study?

But in the big picture, what is there to gain from this?

Medicine demands specific criteria so that medical or psycho-social interventions can be targeted to those whom will benefit.

Yes, diagnostic measure and criteria for the underlying illnesses needs to become more specific to become more useful. But ALPIM does not offer specificity of diagnosis, nor specific treatments, therefore I don't really see this as a worthwhile direction.

On 2015 May 28, Peter Good commented:

Cochran et al. measured brain glutamate, glutamine, GABA, and other metabolites by MRS in the anterior cingulate cortex of ASD adolescents to test whether autistic behavior arises from imbalance of excitatory vs. inhibitory neurotransmitters. They found normal concentrations of excitatory transmitter glutamate, but significantly high non-transmitter glutamine and significantly low inhibitory GABA. They concluded high brain glutamine and/or low GABA might explain imbalance of excitatory vs. inhibitory transmission – i.e. autistic behavior.

True, low brain GABA could be responsible – but implicating high brain glutamine in autistic behavior is risky at best, and potentially dangerous. Not only do ASD children consistently have low plasma glutamine, high brain glutamine appears to protect against ASD. This is most obvious in children with high brain glutamine from inborn urea cycle disorders (UCD) or propionic acidemia (PA) [Good 2014]. In UCD, failure of the liver urea cycle to detoxify blood ammonia at first pass allows high levels into the brain, which astrocytes detoxify by combining with glutamate to form glutamine. Krivitzky et al.: “Children in this cohort [UCD] show other behavioral/emotional strengths, including a minimal percentage with previous diagnoses of Autism spectrum disorders, mood disorders, and other psychiatric disorders.”[Krivitzky L, 2009] Saul Brusilow (MD) never mentioned autism or autistic behavior in any paper on UCD or hepatic encephalopathy (HE) [personal communication 2013]. Gropman et al., however, noted patients with partial deficiencies of urea cycle enzymes and late-onset presentations may show signs of autism [Gropman AL, 2007]. Cochran et al. also found the osmolyte myoinositol normal in ASD brains; when astrocyte glutamine is high in urea cycle disorders or HE, myoinositol is consistently low. Gabis et al., however, found myoinositol high in ASD astrocytes [Gabis L, 2008].

Propionic acidemia is another inborn metabolic disorder where high blood ammonia becomes high brain glutamine. Al Owain et al.: “In the consensus conference about diagnosis and management of PA hosted in Washington, D.C. in January 2011, there was no reported association among the neurological sequelae of the disease between PA and autism.”[Al-Owain M, 2013] Other physicians who treat PA and UCD children also report they rarely show autistic behavior. Sabine Scholl-Bürgi (MD): “In our PA patient group none has an ASD.”[personal communication 2014]. Professor of pediatrics (MD): “I see lots of kids with PA and UCD but few (perhaps none) have ASD.”[personal communication 2013]

Moreover, plasma concentrations of glutamine and GABA in ASD children are consistently opposite brain concentrations detected by Cochran et al. Plasma glutamine is consistently low [e.g. Moreno-Fuenmayor H, 1996; Aldred S, 2003; Shimmura C, 2011] and plasma GABA high [Cohen 2000; Dhossche D, 2002]. Ghanizadeh concluded: “The low level of plasma glutamine . . . is suggested as a screening test for detecting autism in children especially those with normal IQ. The decreased level has been reported before in all children with autism.”[Ghanizadeh A, 2013] Dhossche et al. thought high plasma GABA explained mood disorders and stupor. Burrus concluded a reaction between ammonia and propionic acid could produce a molecule structurally very similar to GABA [Burrus CJ, 2012].

Glutamine is normally the most abundant amino acid in blood [Souba WW, 1991], a primary brain osmolyte, alternative fuel for brain neurons and astrocytes (especially during hypoglycemia) [Stelmashook EV, 2011], and primary fuel in rapidly replicating cells (e.g. blood vessel endothelial cells, intestinal enterocytes, liver cells, and lymphocytes) [Souba WW, 1987; Souba WW, 1991; Deutz NE, 2008]. Glutamine released from skeletal muscles for anabolic responses to infection may explain the dramatic ability of fever to relieve autistic behavior [Good P, 2013]. A new clue to this phenomenon was recently published at <www.autismstudies.net>.

Autism Research Institute practitioners commonly give ASD patients oral glutamine to heal their intestines, from 250mg–8g/day, with few side effects (some hyperactivity) [Good P, 2013] – although one neurologist reported seizures. Only two practitioners, however, reported improved behavior from glutamine. Franco Verzella (MD) in Bologna, Italy gives ASD children 5–7g/day of oral glutamine after cleansing their intestines of pathogens like bacteria and Candida: “Multifactorial and multisystemic is the condition, so that the improvement has different aspects in different children. Most common: sedation, less stereotypes, better sleep, more concentration.”[personal communication 2013]

Cochran and colleagues need to think twice about reducing brain glutamine in ASD children – whose plasma and brain glutamine are more likely TOO LOW than too high. Pangborn (2013) recommended the free amino acid taurine as a natural way to increase conversion of ammonia + glutamate to glutamine.

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

Aldred S, Moore KM, Fitzgerald M, Waring RH. Plasma amino acid levels in children with autism and their families. J Autism Dev Disord 2003;33:93–97.

Al-Owain M, Kaya N, Al-Shamrani H, et al. Autism spectrum disorder in a child with propionic acidemia. JIMD Rep 2013;7:63–66.

Burrus CJ. A biochemical rationale for the interaction between gastrointestinal yeast and autism. Med Hypotheses 2012;79:784–785.

Cohen BI. Infantile autism and the liver: a possible connection. Autism 2000;4:441–442.

Deutz NEP. The 2007 ESPEN Sir David Cuthbertson Lecture: amino acids between and within organs. The glutamate-glutamine-citrulline-arginine pathway. Clin Nutr 2008;27(3):321–327.

Dhossche D, Applegate H, Abraham A, et al. Elevated plasma gamma-aminobutyric acid (GABA) levels in autistic youngsters: stimulus for a GABA hypothesis of autism. Med Sci Monit 2002;8:PR1–PR6.

Gabis L, Wei Huang, Azizian A, et al. 1H-magnetic resonance spectroscopy markers of cognitive and language ability in clinical subtypes of autism spectrum disorders. J Child Neurol 2008;23(7):766–774.

Ghanizadeh A. Increased glutamate and homocysteine and decreased glutamine levels in autism: a review and strategies for future studies of amino acids in autism. Dis Markers 2013;35:281–286.

Good P. Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel? Med Hypotheses 2013;80:1–12.

Good P. Why do children with propionic acidemia or urea cycle disorders rarely show autistic behavior? Autism–Open Access 2014;4:3.

Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis 2007;30:865–879.

Krivitzky L, Babikian T, Lee HS, et al. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res 2009;66:96–101.

Moreno-Fuenmayor H, Borjas L, Arrieta A, et al. Plasma excitatory amino acids in autism. Invest Clin 1996;37:113–128.

Pangborn JB. Nutritional Supplement Use for Autism Spectrum Disorder. San Diego: Autism Research Institute; 2013.

Shimmura C, Suda S, Tsuchiya KJ, et al. Alteration of plasma glutamate and glutamine levels in children with high functioning autism. PLoS One 2011;6:e25340–e25346.

Souba WW. Interorgan ammonia metabolism in health and disease: a surgeon’s view. J Parenter Enteral Nutr 1987;11:569–579.

Souba WW. Glutamine: a key substrate for the splanchnic bed. Ann Rev Nutr 1991;11:285–308.

Stelmashook EV, Isaev NK, Lozier ER, et al. Role of glutamine in neuronal survival and death during brain ischemia and hypoglycemia. Int J Neurosci 2011;121:415–422.

On 2015 Nov 12, RUBEN ABAGYAN commented:

Additional disclosure. One of the co-authors, R.A., has an equity interest in Molsoft, LLC. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

On 2016 Feb 16, Rafa Carretero commented:

Why should I publish? I wonder that question again and again, and to be honest, I don't have any suitable answer yet. It's been a long time since I decided to make a PhD and to begin to publish scientific papers. I don't know if it's worth it. I've found this article useful because I firmly believe it's the librarian who encourages me constantly to catch up with my duties of publishing, although sometimes I cannot see the point of why I should invest as much effort in publishing, rather than procrastinating. The first aim of scientific publication is to build and share knowledge. Above this romantic, idealistic thinking, it must be clear to us our true motivations to publish, because over it, we have personal motivations. It's beneficial to us. Such a very good article made me to write more on this subject, so I eventually wrote a post to add a few thoughts to those mentioned in this paper: http://www.rafalinux.com/thesis/articles/25/why-should-i-publish Thank you.

On 2015 Sep 17, BSH Cancer Screening, Help-Seeking and Prevention Journal Club commented:

The HBRC Journal Club reviewed this paper, which investigates the effects of a decision aid administered in primary care on men’s intention to undergo prostate cancer screening. The authors conducted a randomised trial in a large number of general practices in France, in a mix of rural and urban areas. The topic intersects with several challenging and controversial areas of public health policy.

The authors report that the intervention (consisting of a double-sided sheet of A4 describing various aspects of PSA testing) reduced the proportion of recruited men who intended to be screened for prostate cancer. However, although the study is stated to be a pragmatic trial, it is unclear how the intervention and associated findings apply to standard practice. Specifically, men appear to have been provided with the decision aid despite having given no indication that they were interested in PSA screening or concerned about prostate cancer, whereas these are the scenarios in which a decision aid is more likely to be used (notwithstanding possible differences between general practice in the UK and France). It is likely that men who spontaneously raise the issue of PSA screening with their general practitioner have preconceptions about the harms and benefits that are different to men who are not yet aware of it, which would lead them to respond to the decision aid quite differently. Moreover, the control condition, in which participants received only a questionnaire about prostate screening, may have had the paradoxical effect of increasing intentions among men who had not previously been considering prostate screening by raising the option without giving any indication of the associated harms.

We also discussed characteristics of the decision aid itself. Inevitably, designing information for lay people involves a balance between competing priorities: it needs to be concise enough to be manageable within a given context (general practice, in this case) but comprehensive enough to convey all the desired detail. It also needs to be comprehensible to the target audience, most of whom will not be familiar with medical terminology or statistics. These competing trade-offs are made clear in this study, in which it appears that brevity has been prioritised over completeness. For example, we noted that there is no explicit information about the (limited) benefits of PSA screening on the first page of the decision aid, nor is there an estimate of the risk of false positives and overdiagnoses within the icon array. One might take the principled view that it is important to provide this information in order for men to be able to make an informed choice. Alternatively, one might take a pragmatic view that such information would burden participants with unnecessary detail. However, what constitutes the optimal method is subject to debate and is often a matter of personal opinion.

A strength of the design was the follow-up question on the reasons underpinning participants’ screening intentions since this highlighted some of the specific viewpoints that were altered by the intervention. However, the study was limited by omitting a measure of knowledge, which is a necessary component of informed decision-making. For example, the study could have assessed whether the intervention was successful in terms of making participants aware of the possibility of overdiagnosis and lack of evidence to support a reduction in all-cause mortality.

The HBRC Journal Club found this to be an interesting study, which benefited from its large sample size, randomised design and ‘intention reasons’ as a secondary outcome measure. However, it was limited by unclear applicability to standard practice and lack of additional secondary outcomes. In particular, this study illustrates the challenges of generating universally accepted information about screening.

Conflicts of interest. We report no conflict of interests and note that the comments produced by the group are collective and not the opinion of any one individual.