On 2014 Aug 05, David Keller commented:

Women sometimes refuse mammography due to the pain it causes - how should they be screened?

In her reply to my letter (1), Dr. Hwang did not address my suggestion of using MRI to screen women who refuse compression mammography due to the pain it causes, or their wish to avoid ionizing radiation to their breasts. I pointed out that these issues affect mainly younger women who are sent for mammograms, due to their higher breast content of glandular tissue.

Dr. Hwang wrote: "Most breast cancer screening guidelines recommend against mammographic screening in women younger than 40 years owing to the low breast cancer incidence in this population”

To clarify, I agree, and I support the American Cancer Society recommendation that routine annual screening mammography should begin at age 40 (2).

Dr. Hwang wrote: “Furthermore, it has been clearly demonstrated that premenopausal women experience MRI changes with the menstrual cycle, which can often lead to false-positive MRI findings."

I agree again, and menstrual cycle variations in breast imaging characteristics (in both MRI and mammography) can and should be mitigated by the proper timing of the examination. A European guideline states: "The optimal time in pre-menopausal women to perform a breast MRI is between the 5th and 12th day after the start of the menstrual cycle during week 2 of the menstrual cycle" (3).

Most importantly, I would like to know what Dr. Hwang recommends be done to screen women who refuse mammography. If not MRI, what would she suggest?

References

1: Keller, DL. In Defense of Screening for Breast Cancer With Magnetic Resonance Imaging. JAMA Intern Med. 2014;174(8):1417. doi:10.1001/jamainternmed.2014.810.

2: American Cancer Society website, accessed on 8/4/2014 at the following URL: http://www.cancer.org/cancer/breastcancer/moreinformation/breastcancerearlydetection/breast-cancer-early-detection-acs-recs

3: Mann RM, Kuhl CK, Kinkel K, Boetes C. Breast MRI: guidelines from the European Society of Breast Imaging. Eur Radiol. 2008 Jul;18(7):1307-18. doi: 10.1007/s00330-008-0863-7. Epub 2008 Apr 4. PubMed PMID: 18389253; PubMed Central PMCID: PMC2441490.

On 2014 Jan 13, Sergei Jargin commented:

This is a continuation of: Jargin SV. Overestimation of Chernobyl consequences: poorly substantiated information published. Radiat Environ Biophys. 2010;49(4):743-5; author reply 747-8. PMID: 20640449

On 2013 Dec 01, James C Coyne commented:

This study is the largest ever evaluation of the Penn Resiliency Program for Children and Adolescents, with more participants than all past studies combined.

Results are disappointing and may even be less than reported. Read more at http://blogs.plos.org/mindthebrain/2013/11/25/positive-psychology-in-the-schools-the-uk-resilience-project/ .

Intervention does not seem distinctly positive psychology, with elements of cognitive therapy of Beck and Ellis' rationale emotive therapy dominating. Why would the authors have expected effects if samples were low in depressive symptoms at baseline?

Such investments of public resources and such demands on student time should have better prior evidence to be justified.

On 2016 Mar 18, ZHONGMING ZHAO commented:

My lab recently moved to the University of Texas Health Science Center at Houston. The web site for this database is now available at https://bioinfo.uth.edu/CNVannotator/.

On 2014 Jan 24, guoan zhang commented:

a new mechanism underlying BRAF V600E-promoted NIS silencing in thyroid cancer by Xing M, one of the leader in the area of thyroid cancer study.see Xing M, 2013

On 2014 May 07, John Roger Andersen commented:

Open Access to the article (Springer Nature Sharing):click here.

On 2016 Aug 30, A Dahan commented:

We agree, the clinicaltrial.gov registration number is indeed NCT01631149.This will be corrected in the journal. Many thanks, Albert Dahan MD PhD

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 NCT01361149. We believe the correct ID, which we have found by hand searching, is NCT01631149.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2014 Feb 05, Peter Uetz commented:

Neither the title nor the abstract says which species is studied here. Only digging in the text reveals it is yeast, Saccharomyces cerevisiae.

On 2016 Feb 05, Kristina Hanspers commented:

The graphical abstract for this publication is available as a pathway in the "Open Access Publication" Collection at WikiPathways: http://wikipathways.org/index.php/Pathway:WP3299. This pathway can be used for data visualization or for network analysis in tools like Cytoscape and PathVisio.

On 2014 Aug 30, Michelle Lin commented:

Great landmark publication about TTM. A week-long discussion with ALiEM-Annals of EM journal club discussed the nuances of the study. It also featured the first author, Dr. Nielsen, in a videocast with our discussants.

http://www.aliem.com/aliem-annals-em-journal-club-targeted-temperature-management/

On 2014 Jun 12, Gordon Warren commented:

This is not a meta-analysis and does not claim to be.

On 2013 Nov 18, James C Coyne commented:

Yikes, this is a really badly conducted and interpreted meta analysis. Thanks, Hilda Bastian, for calling this to our attention and offering alternative references.

On 2013 Nov 18, Hilda Bastian commented:

The conduct and reporting of this systematic review falls so far short of the standards and criteria covered by PRISMA for reporting (Moher D, 2009) and quality appraisal tools such as AMSTAR, that this review does not meet current expectations of a systematic review.

While conclusions about effectiveness are made, result data from the primary studies are not provided, nor are methods of data extraction and analysis discussed. Despite the large number of included trials, no meta-analyses of suitable data were performed and no reason for this was given.

What constituted exercise was not specified and the reason for excluding studies prior to 2000 is not given. The reasons for inclusion and exclusion of studies are not entirely clear: for example, studies were excluded because of concomitant drug therapy, which, while a reasonable criterion, was not included in their list. A full list or explanation of exclusions is not provided.

The search strategy as reported appears to be simplistic and does not include adequate search terms or key databases such as PEDRO. The number of studies for the stages in PRISMA’s flow diagram are not provided (duplicates removed, records screened). The quality of included studies is not assessed.

If you are interested in reading a systematic review on this question, consider Umpierre D, 2011 - see the DARE critical appraisal.

On 2015 Oct 15, Christopher Southan commented:

We now have an updated database publication at www.ncbi.nlm.nih.gov/pubmed/26464438

On 2014 Nov 18, Helen E Benson commented:

Details of the latest IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb) release can be found on the blog maintained by the curation team.

On 2014 Mar 04, Dale D O Martin commented:

After reading this paper, it appears to be quite thorough and well presented. Their results are very interesting. There are a few typos in the figures, but they do not take anything away from the data presented.

On 2013 Nov 16, Ellen M Goudsmit commented:

The authors do not define ME and assume equivalence with CFS which is defined more broadly and covers a heterogeneous population. The assumption of equivaleance has yet to be validated. In light of the literature on ME, I note that evidence of differences between this disease and MS have not been discussed, e.g. type and distribution of UBOs on MRI cf Posner, reproduced in the textbook on ME by Hyde, B. Many findings on CFS are inconsistent due to the heterogeneity of the samples so data should be interrpeted with caution. My study comparing 50 patients with ME, 50 with MS and 50 healthy controls showed no differences between the patients groups on a neuroticism scale. Both had higher scores than healthy controls and this was almost certainly due to the inclusion of somatic symptoms to assess neuroticism.

On 2014 Sep 04, Kevin P. Foley commented:

Commentary on this article from chemist Derek Lowe:

http://pipeline.corante.com/archives/2014/09/04/are_your_compounds_ugly_do_you_know.php

On date unavailable, commented:

None

On 2014 Aug 05, Michael Baudis commented:

Thanks for the notes, and your usage of our resource. Regarding the other comments, you are obviously perfectly right that one has to do a critical evaluation of the data, beyond what we can provide.

But regarding the specific criticism about the DCIS data, I am not sure if I can find real issues:

• For Progenetix, by accepting only publication derived data, we rely on the peer review process running due course - there will be errors, but limited through standard operating procedures inherent to the process.
• All the 76 samples, as far as I can follow this up without producing a review of the field, had been labeled as DCIS in the papers or supporting information; so the number stands. Frequently the DX contained addl. specifications (e.g."poorly differentiated").
• Most importantly, for the analysis results it doesn't matter if the clinical diagnosis was incomplete due to needle biopsy (i.e. if the patient had an undetected infiltrating component) as long as the profiling was derived from the DCIS cells. Also, in hindsight and with some thousands of IDC available through www.progenetix.org and www.arraymap.org, the CGH profiles overall support the DCIS statements.

However, we are absolutely delighted about community support in improving our annotations! So if you have clear per sample corrections (and there will be plenty of opportunities I guess) - just help us through providing specific comments.

Best,

Michael.

On 2014 Aug 05, Swapnil Rane commented:

It is fantastic effort on part of the authors to provide such a resource. However, I noticed few problems on running a sample query. I searched for ductal carcinoma in situ cases in this database and initially I was very happy to see copy number information on 76 cases. But on looking at the 5 papers from which the query sourced the information, only two of them seemed valid sources. The remaining three papers according to me are not valid, as they either do not report the CNA in DCIS separately from the coexisting IDC or the technique itself by which samples were obtained(FNAC) for genetic analysis did not differentiate between DCIS and IDC. Even if I took into account only those two papers which exclusively report on DCIS and the pure DCIS cases from other three papers, the total number of cases does not exceed 43.... How did they reach a number of 76?.. Atleast, the database should annotate that the data is derived from mixed cohort of pure DCIS and DCIS with coexiting IDC. While I have not run any other query on the resource and it is possible that this glitch is only seen for this particular query, but it has made me sceptical about the reliability of the information provided by any such resource. It seems we cannot take any information at face value, no matter how reliable the source might seem to be!!

On 2014 Mar 14, Jonathan Eisen commented:

The first author of the paper, Rachel Adams, wrote a post about this paper for the "microbiology of the built environment network" (microBEnet) blog. See Fungi on residential surfaces: sinks are sources, other surfaces are sinks

On 2014 Mar 29, Sergio Stagnaro commented:

None

On 2014 Mar 25, Abdalla Elhwuegi commented:

This review state that EDRF was discovered by Moncada, which is not the case. It is well known that EDRF was discovered by Furchgott and Zawadzki.

On 2016 Jun 01, David C. Norris commented:

One must lament that our toxic politics did not countenance a proper nomination and Senate confirmation process for Dr Berwick. This would have given national audience to his passionate and infectious faith in the promise of healthcare improvement, stimulating meaningful debate on its moral and scientific basis at a most fortuitous time. In this JAMA Viewpoint, Berwick assays our healthcare politics for the activity of numerous paralytic toxins responsible for this and other lamentable lost opportunities. Of these toxins, I wish to address specifically the "Suspicion of Science" Berwick invokes, since it strikes at the heart of the medical profession's capacity to elevate our politics to a higher form – through persuasion.

One hardly need invoke the lay public's suspicion of Science (capitalized and singular, if you will)¹ to account for the medical profession’s credibility gap as it now endeavors to appeal – so often in the name of cost containment, of all things – to the several sciences that fall under the heading of comparative effectiveness. Indeed, this invocation risks seeming to absolve Medicine of the responsibility to scrutinize its own professional norms and practices for modifiable factors that widen this gap. Such self-scrutiny is entirely in the spirit of the remainder of Berwick's argument, being essential to the professional mobilization he so rightly calls for.

It would surprise few laypersons to learn of clinical medicine's troubled relationship with elementary scientific behaviors and modes of thought, as demonstrated for example by the fact that Braithwaite's excellent piece² on there-is-no-evidence-to-suggest was rightly judged necessary to publish in this same journal in 2013. Laypersons enjoy a ready access to a wide variety of subtle observations and distinctions that would alarm the Profession if appreciated more fully. In particular, alert laypersons perceive the contrast between the powerful sciences underlying medical technology, and the pervasive disorder in a clinical practice from which scientific method is largely absent.³ It may well be the expression of a uniquely American genius that, regardless of what obtains abroad, until Americans routinely experience medical practice as a profound application of scientific method to optimizing their care as individuals, they will harshly censure as premature any attempt by this profession to invoke the sciences in the service of global optimizations like cost containment.

[1] Kitcher P. Science in a Democratic Society. Amherst, NY: Prometheus Books; 2011.

[2] Braithwaite RS, 2013

[3] Weed LL, Weed L. Medicine in Denial. Charleston, SC: CreateSpace; 2011.

On 2014 Nov 26, Harri Hemila commented:

Ludwig M, 2013 write in their background section that vitamins and zinc are not effective against the common cold when systematically reviewed. This is not correct.

A systematic review on vitamin C and the common cold showed that vitamin C administration reduced common cold incidence by 52% (95%CI: 36% to 65%) in people who were under short term heavy physical activity Hemilä H, 2013. In addition, regular administration of 1 g/day vitamin C shortened the duration of colds in adults by 8% (95%CI: 3% to 12%) and in children by 18% (95%CI: 9% to 27%) Hemilä H, 2013. Ludwig et al. specifically refer to the Karlowski et al. (1975) study. Karlowski TR, 1975 found that 6 g/day of vitamin C was twice as effective as 3 g/day, indicating dose dependency in the high dose region, see Hemilä H, 1996, Hemilä H, 1999.

A systematic review on zinc lozenges found 13 placebo-controlled trials Hemilä H, 2011. There was substantial heterogeneity between the studies, but the heterogeneity was explained by the dose of zinc and the zinc salt that was used. On the basis of 3 RCT:s, high dose zinc acetate lozenges shortened the duration of colds by 42% (95%CI: 35% to 48%).

There is strong evidence that vitamin C and zinc acetate lozenges have an effect on the common cold.

On 2014 Nov 19, Helen E Benson commented:

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

On 2014 Jan 09, David Mage commented:

Randall et al. studied serotonin receptor binding in a non-probability (convenience) sample of case infants dying suddenly and unexpectedly without explanation (SIDS) and control infants dying of known causes, from San Diego County, CA. As pointed out previously to some of these same authors Mage DT, 2010 their results do not apply to any populations not probability sampled for this study and therefore statistical testing for significant differences between their cases and controls has no theoretical statistical basis and may lead to meaningless results. The authors' reply (op. cit.) leads one to believe that they think they are excused because they know of no "reason to believe that the levels of serotonin in brainstems of SIDS and non-SIDS in San Diego would be different than in infants elsewhere." Here are a few such reasons that may be relevant: 1) All cases and controls were autopsied at the San Diego County Medical Examiner's Office. It is well known that different pathologists independently looking at the same cases without any discovered obvious prima facie cause of death can give different causes of death by SIDS and non-SIDS such as positional asphyxia Emery JL, 1972 , Kim SY, 2012. Consequently their case definitions of SIDS may not apply elsewhere where different operative decisions for choice of cause of death are made by different medical examiners; 2) Serotonin does not cross the blood brain barrier, so all cerebral serotonin must come from its precursor dietary tryptophan (TRY). Because the infants' TRY in utero comes from their mothers' diet during pregnancy and after birth from their own diet it may make a big difference if they are breast fed or given milk formula as breast milk has higher TRY content than ordinary formula, that can be enriched in TRY (Young SN, 2007). The authors noted the higher percentage of Hispanic ethnicity and lower percentage of African Americans compared to the U.S. infant population. Consequently the frequency of breast feeding and the dietary carbohydrate intake of the Hispanic nursing mothers during and after pregnancy can be quite different in San Diego County compared to the rest of the U.S.; 3) Hispanic ethnicity mothers in San Diego may wean their infants at different ages than other non-Hispanic mothers and the infants' diets after weaning may also differ between Hispanic and non-Hispanic ethnicities; 4) Because the cause of SIDS is unknown, there may be yet unknown SIDS risk factors that vary between their cases and controls and all other cases and controls not sampled. In summary the authors' conclusions strictly apply to only those cases and controls they measured. The statistical testing and confidence intervals they report do not apply to all the other cases and controls that were not in the sample frame from which their cases and controls were chosen because they had no known finite probability of selection for this study.

On 2014 Nov 27, Guillaume Filion commented:

This article is one of the "CISCOM meta-analyses", which are very similar papers written by different authors. For more information about the CISCOM meta-analyses, check the blog post "A flurry of copycast on PubMed" at the following link http://blog.thegrandlocus.com/2014/10/a-flurry-of-copycats-on-pubmed

On 2014 Feb 03, George McNamara commented:

Prof. Couchman's editorial for this issue included this paragraph on PubMed Commons:

"However, undaunted, PubMed Commons has been launched, at least in trial format (as of October 2013). This allows anyone with an account to add comments to any article that is lodged with PubMed. This therefore includes JHC content. It will be interesting to see how this feature evolves. Naturally, the aim is constructive discourse and the rules make clear what constitutes unacceptable activity, which may be removed. The question is whether added comments will be useful or subject to misuse and, indeed, if this commentary is “peer” reviewed. Will comments be applied to papers by contributors with real expertise in the area? In addition, will authors of papers that are listed in PubMed check regularly to see who is attaching comments and respond? I have to confess that I am not sure this will be a high priority for me."

John and readers - I have used PubMed Commons to comment on several papers, including updates on some of my own. At this point, evolution is not needed here - use is!

With respect to the reproducibility in the title, it is the responsibility of the authors to provide full and correct details on what they did to generate the data, and calculate the statistics, that went into their work. It is unrealistic for peer reviewers to go through the manuscript or data to look for bad data or bad judgement. These are things the authors should deal with as they are doing their experiments, presenting/discussing their data in their lab meetings, at department seminars, retreats, poster sessions (would help if scientists visited posters at poster sessions), before the work is packaged into a manuscript.

I also recommend that all journals should encourage - even demand - that all the data that underlies a peer reviewed manuscript be available as Open Data in a public repository(ies). Having all the data available lets anyone check it out. GenBank has been "standard of care" for DNA sequence data for years.

For another recent editorial on this topic, see M. McNutt 2014 Reproducibility. Science 343(6168):229. doi: 10.1126/science.1250475. http://www.ncbi.nlm.nih.gov/pubmed/24436391

On 2014 May 07, David Keller commented:

Just leave them alone

Agitated elderly demented long-term care patients become more agitated when they are given the quiet presence of an unfamiliar research assistant, and even more agitated when the research assistant massages their feet. The best thing to do for agitated elderly demented long-term care patients, if you are an unfamiliar research assistant, appears to be to simply leave them alone.

On 2015 Oct 27, Lydia Maniatis commented:

Perceived slant can be in any direction, not only around the horizontal.

On 2015 Aug 13, Lydia Maniatis commented:

The authors' claim here, that foreshortening is a "cue" to slant, is logically untenable. They define foreshortening as the change in the ratio of width to length (compression), i.e. the difference in the proportions of the object and the proportions of the projection of the object. More specifically, for each of their stimuli, they define this change with respect to a single one of the actually infinite number of 3D object shapes that could have produced the given projection (with some wiggle room since they are assuming orthographic and not perspective projection). But the viewer does not have access to this one object, and thus does not have access to the change in aspect ratio that the investigators have in mind. The shape of the object must be inferred from the projection, on the basis of shape constraints. Having been inferred, the degree of slant/foreshortening then follows as a secondary inference. It is in no way present as a cue in the stimulus/projection.

The reason that the investigators' predictions for the slant of single shapes were confirmed is that the 3D object on which they based their definition of foreshortening was the most regular shape that could have produced the given projection, that is, the 3D shape possessing the characteristics preferred by the visual system when interpreting a projection. If the visual system were partial to skew symmetrical rather than symmetrical shapes, then the stimulus would have been perceived as fronto-parallel with no foreshortening, and the prediction would have failed. Again, foreshortening is not a feature of the 2D stimulus.

The investigators' proposed dichotomy between single shapes and "textures" with respect to the role of the "foreshortening cue" is also false, and results from their failure to appreciate the role of shape constraints. The textures to which they refer were composed of rectangles subjected to orthographic projection. They were compressed/foreshortened, but the compressed projections were similarly rectangular, and thus would not have caused the visual system of the observer to infer a different shape (i.e. the shape based on which the investigators calculated the predicted degree of foreshortening), and thus a non-fronto-parallel orientation plus foreshortening. Rectangles just don't slant, even if they happen to be orthographic projections of taller rectangles.

Also, the discussion by Ivanov et al seems to take it for granted that the direction of foreshortening is from top to bottom as happened to be the case for their stimuli (since they treat it as a given), but the visual system may infer foreshortening in any direction, it just depends on the shape of the projection and what is required to regularise it as much as is consistent with the projection.

On 2017 Oct 06, Peter Gøtzsche commented:

The authors compared inhalers with combination drugs (a steroid plus a long-acting beta-2 agonist), with placebo and write in their abstract that the number needed to treat to prevent one death with fluticasone/salmeterol was 42 (1). They explain, just before Objectives, that the largest randomised trial of combination therapy (TORCH) demonstrated a significant reduction in mortality versus placebo (P = 0.052) and that they wished to see whether other combined inhalers had a similar effect. Just above “Implications for research,” we are told that “whether a combination is better than the two components taken separately was not addressed in this review,” and under “Authors’ Conclusions” the authors advocate that the combination should be compared with its two components.

This information is misleading. Firstly, the review authors overlook that the TORCH trial (and several other trials) was designed to answer what they call for in future research, namely whether the combination was better than any of its components.

Secondly, the authors give the readers the impression that the combination reduces mortality. However, the fact is that the steroid contributes absolutely nothing to the mortality benefit. The primary outcome in the TORCH trial was total mortality (2). GlaxoSmithKline randomised 6184 patients to four groups: placebo; salmeterol; fluticasone; and both drugs together. By definition, this design is factorial. It is powerful, as it allows the investigators to study three research questions with a sample size that would usually only allow one question to be answered. Such a trial can tell us whether the two drugs are effective, and whether the combination is better than any of its components. However, the analysis in the TORCH trial included only half of the patients, thereby spoiling the advantage of the factorial design, although the published trial protocol stated that a factorial analysis was to be performed (3).

Nowhere in the 15-page trial report is the factorial analysis to be found, and the abstract of the TORCH trial gives the readers the clear impression that the combination was better than any of its components, which is the result the authors of the Cochrane review quoted.

The authors of a letter to the editor used a factorial analysis and showed that the effect of the combination was entirely due to salmeterol (4); the hazard ratio for fluticasone was 1.00 (0.87 to 1.15), p = 0.99. In other similar trials, both GlaxoSmithKline and AstraZeneca did not perform a factorial analysis (5).

1 Nannini LJ, Poole P, Milan SJ, et al. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013;11:CD003794.

2 Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–89.

3 Gøtzsche PC. Questionable research and marketing of a combination drug for smoker’s lungs. J R Soc Med 2014;107:256-7.

4 La Vecchia C and Fabbri LM. Prevention of death in COPD. N Engl J Med 2007;356:2211–2.

5 Suissa S, Ernst P, Vandemheen KL, et al. Methodological issues in therapeutic trials of COPD. Eur Respir J 2008;31:927–33.

On 2017 Aug 24, Peter Gøtzsche commented:

None

On 2017 Jul 13, WALTER LUKIW commented:

As originally reported by the authors, we find miRNA-168a abundant in dietary plant(s) and in the systemic circulation (and other really, really, really interesting places) of animals who consume these plants as part of their diet (unpublished observations); in our hands RT-PCR is a very easy but very inconsistent method to detect ANY type of microRNA abundance anywhere from any biological fluids or tissues, either plant or animal; we use RNA-sequencing, miRNA array-based (microfluidic hybridization) approaches, LED-Northerns, regular Northern dot blots and yes, RT-PCR - although RT-PCR approaches clearly yield the most inconsistent results.

Walter J. Lukiw BS, MS, PhD Professor of Neurology, Neuroscience and Ophthalmology Bollinger Professor of Alzheimer’s disease (AD) LSU Neuroscience Center, Louisiana State University Health Sciences Center 2020 Gravier Street, Suite 904 New Orleans LA 70112 USA TEL 504-599-0842 EMAIL wlukiw@lsuhsc.edu

On 2013 Dec 24, Kenneth Witwer commented:

Along with the study mentioned by M Mangan, some other primary publications on the topic are noted in this comment.

On 2013 Nov 16, M Mangan commented:

This article is an important attempt to replicate the outcomes published in a previous article: Zhang L, 2012. This follow-up work was unable to obtain the same results as the original claims, and should be considered in comparison with that prior paper.

For more detail on this story you should also see this explanation from the publisher about this work: Anonymous, 2013.

On 2013 Nov 16, M Mangan commented:

This editorial provides an interesting explanation for why this journal chose to publish an article that generated a negative result, which was an attempt to replicate previous work. It provides an interesting discussion of the philosophy of replicating work and of publishing replications, which not all journals will elect to do, apparently. The replication article they published this one: Dickinson B, 2013.

The new article described the inability to replicate the claims from this prior article: Zhang L, 2012.

On 2016 Aug 31, Pavel Nesmiyanov commented:

Authors say "Of note, however, the chemotherapeutic pressure selected an evolutive conversion of some non-SP cells into SP cells over-expressing both ABCG2 and the stem cell marker BMI-1 [45]." However, ref.45 doesn't support this statement.

On 2013 Dec 18, Meghan Lane-Fall commented:

The I-PASS curriculum referenced in this article can be accessed via the AAMC's MedEdPortal. On this site, the six components of the I-PASS curriculum along with supporting documents can be accessed without charge after registration: https://www.mededportal.org/

On 2016 Jan 23, Eric Gamazon commented:

Reference #60 should be:

Gamazon ER, Im HK, Liu C, Members of the Bipolar Disorder Genome Study (BiGS) Consortium, Nicolae DL, and Cox NJ. The convergence of eQTL mapping, heritability estimation and polygenic modeling: Emerging spectrum of risk variation in bipolar disorder. arXiv, arXiv:1303.6227, 2013. http://arxiv.org/abs/1303.6227

On 2016 Aug 30, 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 NCT00123456. This trial ID does not appear in ClinicalTrials.gov.

We have contacted the corresponding author on the study to ask them for the correct trial ID on 18/08/2016, but received no reply. We have also searched manually for this trial on ClinicalTrials.gov and found no matching study. We therefore believe that this trial may not have been registered on ClinicalTrials.gov.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2014 Apr 05, Jonathan Eisen commented:

I believe some of the claims in this paper regarding the connection between ethnicity and the microbiome and the mechanisms behind such connections are not justified.

For example, in the discussion the authors write "Our data demonstrates that ethnicity exerts a selection pressure on the oral microbiome, and that this selection pressure is genetic rather than environmental, since the two ethnicities that shared a common food, nutritional and lifestyle heritage (Caucasians and African Americans) demonstrated significant microbial divergence. "

I see no evidence presented here of ANY genetic component to the microbiome differences reported here.

I and others have written blog posts critiquing this paper and the claims (such as the one mentioned above) by the authors in press releases associated with the paper. For more detail see

http://phylogenomics.blogspot.com/2013/11/short-post-bad-taste-in-my-mouth-for.html

and

http://phylogenomics.blogspot.com/2014/03/guest-post-by-jay-kaufman-bad-taste.html

On 2014 Sep 02, Attila Csordas commented:

associated dataset available via PRIDE/ProteomeXchange: http://www.ebi.ac.uk/pride/archive/projects/PXD001277

On 2013 Nov 15, Rolando Garcia-Milian commented:

Interesting paper though I would add "in a murine model of inflammation-associated colorectal cancer" to the title. The specific organism that was studied should be part of the title.

On 2013 Nov 15, Morgan Langille commented:

Really great paper showing the first instance that their is a causal relationship between the microbiome and colorectal cancer and not just correlation.

On 2013 Nov 08, Allison Stelling commented:

The molecular characterization for glioblastoma section of this paper was a bit weak; unfortunately due to a paucity of work in this field. I realize the whole field is desperate for cures for this rather frightening class of brain tumor. However, its very heterogeneity renders it a formidable foe. We need better maps of this undiscovered molecular territory if we are to even hope for a targeted strategy with chemotherapies. Genetic and morphological information gives me a few pieces of the picture, but I need to know the spatially resolved biochemistry to mount an effective chemical attack.

The authors state in their neurosurgery section "In inoperable tumors, stereotactic biopsy may be performed for histologic diagnosis, but the limited amount of tissue acquired may preclude full molecular characterization."

Optical methods like Raman and infrared spectroscopy can help to directly address this issue, since they are (a) non-invasive and (b) you can get reliable phenotype information about the biochemistry from quite small tissue samples (for example, ratios of lipids to proteins) fairly rapidly (see my paper Stelling AL, 2013; as well as recent work on skin cancer Kong K, 2013 for more).

On a final note: I've chatted with a few neuropathologists. Even when the entire brain hemisphere with the tumor in it is removed, there's still recurrence. I strongly suspect after the cancerous cells are present (after they have evolved from the stem cells etc), they leave behind carcinogenic contamination. There's some studies on the extracellular matrix of gliomas pointing to a role for these structural proteins and sugars in progression and recurrence as well. (See Payne LS, 2013 for a recent review.)

On 2014 Jun 11, Jorge H Ramírez commented:

Linked editorial related to the original research paper published in the BMJ (Nov 5, 2013) by Bird and colleagues.

Additional rapid responses by this author (available in the website of the BMJ):

November 15, 2013 | Comments about the rapid response “Prevention of hypotension and first dose phenomenon due to postsynaptic alpha-2 blockers”. URL: http://www.bmj.com/content/347/bmj.f6320/rr/672217

May 16, 2014 | Expression of concern about tamsulosin: at least 78.4% of the studies are unpublished. URL: http://www.bmj.com/content/347/bmj.f6320/rr/698284

June 6, 2014 | Correction: "Expression of concern about tamsulosin: at least 78.4% of the studies are unpublished" URL: http://www.bmj.com/content/347/bmj.f6320/rr/700980

Expression of concern is also available via Figshare: http://dx.doi.org/10.6084/m9.figshare.1094338 URL:http://figshare.com/articles/Expression_of_concern_about_tamsulosin_over_three_quarters_of_human_studies_are_unpublished/1094338

On 2014 Jul 13, Jorge H Ramírez commented:

PubMed Commons comment

I would like to make the following remarks about this study.

• The sample size (n=383567) and time of patient follow-up (16 weeks, interquartile range 5-50 weeks) of Bird ST, 2013 study is clearly superior to the registered (published and unpublished) previous studies of tamsulosin (n=83201; median time of follow-up=6 weeks, interquartile range 2-12 weeks).1,2

• "The available scientific evidence supports the association of tamsulosin with serious adverse cardiovascular drug reactions, probably more than any other pharmacological effect attributed to this drug. I urge doctors to reconsider the use of tamsulosin as a first line treatment in patients with lower urinary tract symptoms."1

• Tamsulosin is not uroselective.1,2

• Over three quarters of tamsulosin studies are unpublished.1,2

References

1. Ramirez JH. Re: Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: risk window analyses using between and within patient methodology (May 16, 2014) http://www.bmj.com/content/347/bmj.f6320/rr/698284

2. Ramirez, Jorge H (2014): Expression of concern about tamsulosin: over three quarters of human studies are unpublished. figshare. http://dx.doi.org/10.6084/m9.figshare.1094338

On 2014 Jan 09, B Martini commented:

In their recent article (1), The Brugada brothers reported that “Martini et al had published a series of patients with idiopathic ventricular fibrillation and, upon retrospective analysis, one had an electrocardiogram (ECG) with similar characteristics. However, in contrast to the report in JACC, their patients had structural heart disease with no evidence for a hereditary disorder”. This statement is again a personal interpretation of the contribution of Italian and Japanese Colleagues who published the syndrome 5 years before the Brugada article (1-4). It is not true that only 1 patient had the discussed ecg, and that there was no evidence of hereditary disorder. We have recently re-discussed and documented all the true history (5). Moreover also the “recently discovered” depolarization theory was fully proposed and demonstrated in those early articles. We wrote and still believe that all these patients have some underlying heart disease, and that there is not a distinguished functional syndrome, different from an organic one.<br> I personally have an high respect for the Brugada contribution to the syndrome, but the repeated authorital attempts to erase the true history of the discover, do not further enhance the importance of their contribution.

1. Brugada P,Brugada J, Roy D. Brugada syndrome 1992–2012: 20 years of scientific excitement, and more. Eur Heart J 2013 in press

2. Nava A, Canciani B, Schiavinato, M. L, Martini B: La repolarisation precoce dans le precordiales droites: trouble de la conduction intraventriculaire droite? Correlationse l'electrocardiographie- vectorcardiographie avec l'electro-physiologie. Mises a Jour Cardiologiques 1988;17:157-159

3. Martini B, Nava, A, Thiene, G, et al: Ventricular fibrillation without apparent heart disease: description Of six cases. Am. Heart J. 1989; 118: 1203-1209

4. Aihara, N, Ohe, T, Kamakura S, et al: Clinical and electro physiologic characteristics of idiopathic ventricular fibrillation. Shinzo 1990;22 (suppl. 2). 80-83

5. Martini B, Wu J. Nava A. A rare lethal syndrome in search of its identity: Sudden death, right bundle branch block and ST segment elevation. In Wu J, Wu J Editors: Sudden Death. Nova Biomedical New York, pp.1-39

On 2014 Aug 05, Andrew Sharp commented:

A recent paper (PMID: 25079557) that performed DNA methylation analysis of developing embryos made some interesting observations that are potentially relevant to our findings in this paper. A quote from this paper: "...we found that SINEs and LINEs with different evolutionary ages showdifferent demethylation patterns (Fig. 4a–d and Extended Data Fig. 10d–f). For example, both LINE-1 (L1) and LINE-2 (L2) belong to the LINE family of transposable elements, with L1 being evolutionarily younger than L2 (ref. 25).The younger L1 shows a higher methylation level than L2 in oocytes, whereas they show a comparable level of methylation in sperm. More importantly, we found that during the genome-wide demethylation process, the evolutionarily younger L1 retains higher levels of residual methylation than L2. L1 was also remethylated to a higher methylation level after implantation (Fig. 4d)."

I think it is an interesting idea that this differential demethylation/remethylation might potentially explain the association of younger LINEs with the spread of X inactivation?

On 2014 Nov 17, Pavel Baranov commented:

Due to a software error in an earlier version of the browser, the data in Figure 1 are not represented correctly. Apologies. The correct image is published here.

On 2017 Apr 28, Robert Badgett commented:

Regarding recommendations of the International Committee of Medical Journal Editors for trial registration:

• The initial registration of this trial was on April, 27, 2010 and states the the study was executed earlier from May, 2009 through October, 2009.
• The initial April, 2010 registration indicates that the primary outcome was "Difference in pain intensity as measured on the Visual Analog Scale (VAS)." The July, 2013 version changes to "Percentage of Participants With Reduction in Pain Intensity".

On 2014 Sep 13, Vahid Rakhshan commented:

The formatted version of this unpublished letter to the editor can be found at this address (LINK).

I read with interest the valuable article of Ferreira et al. [PMID: 24182586]. Although it was a very good research, few points were unclear to me.

1. Gold standard preparation was extremely vague (P.699). The numbers of examiners, their calibration/training/inter-rater agreements, and the number of assessments per each skull were not mentioned. Measuring the bone defects might first appear as an easy task and not needing detailed clarification. However (A) the gingival bone margin does not exist in dehiscence (Figure 1) and evaluator needs to guess from where to measure the distance. (B) If there were irregularities in the bone defect, which distance would be measured? The longest one? Or the shortest one? Or the vertical one? What about horizontally expanded defects? (C) The distances do not seem perfectly vertical and similar in Figure 1. The angle of the gauge can affect the measured length as well. Therefore calibration and inter-rater agreement are critical.

2. I wonder how the evaluators could certainly identify the bone “marrow” absence by the naked eye for fenestration diagnosis (P. 699).

3. It is stated that “the level of agreement proved that…” and also “the assessments do reflect reality” (P.701). These two strong conclusions were made based on agreements between 0.47 and 0.76.

4. Surprisingly, there was absolutely No P value reported for any test/correlation/kappa, which disallows any generalizations/validations. So how statistically unsubstantiated kappa values can prove anything?

5. There is mention of a chi-square used on sagittal and axial reconstructions (P.701). However, there are no P values or results for chi-square reported throughout the study.

6. In the last paragraph of the Results, the sensitivity / specificity / accuracy of sagittal reconstructions were stated but none was stated for axial reconstructions. Yet immediately after that part (after a semicolon), the authors concluded that the sagittal reconstructions performed better than axial. How did they do so without any comparisons?

7. Perhaps the authors had used the previous paragraph that stated agreements with the gold standard. The agreements for sagittal and axial reconstructions were 78.5% and 73.3%, respectively. I would much appreciate to know how the authors compared these two without (A) first identifying whether or not these two agreements were significant; and (B) whether or not there was a statistically significant difference between these two correlation coefficients? The authors needed to run a t-test between the two agreements to see if the 78.5% was significantly greater than 73.3% or the difference was not reliable (statistically non-significant).

8. K=0.4509 and K=0.3131 are considered 78.43% and 73.33% agreement, respectively (P.701). I think it is not correct and they respectively mean 45.09% and 31.31% agreements.

9. Making decisive conclusions from a report without any P values or confidence intervals should be avoided. The findings were not substantiated statistically, and thus should be approached cautiously.

10. The conclusions of text and abstract contradict completely. The abstract concludes “There was no difference in the performance of the axial and sagittal reconstructions.” The text concludes “The sagittal section is more reliable than the axial section, mainly in the middle third.” Which conclusion to take home?

On 2014 Sep 13, Vahid Rakhshan commented:

The formatted version of this unpublished letter to the editor with tables can be found at this address (LINK).

Sufficient test powers are necessary for validating non-significant results

1. The sample size was not based on power calculations. This might be justified partly by difficulty of finding surgery patients. However, compounded with next issues, this might become serious.

2. Except one, no pairwise comparison was significant. It is why the power becomes serious. Given the rather small sample size (2×13 for each t-test), it was possible that many of those non-significant results were merely type II errors (false negative results).

3. No exact P values had been reported for the comparisons. It was only stated that “P>0.05”. Reporting P values is necessary to distinguish non-significant cases like P=0.053 [which are still pointing to some difference] from cases like P=0.999.

4. When it comes to interclass correlations, only correlation coefficients had been reported. It was not mentioned whether those coefficients were significant or non-significant (even as any “P>0.05” or “P≤0.05” statements). The statistical significance is needed to verify if a correlation result is generalizable to the population. No matter how big is a correlation coefficient, unless it is not verified statistically (P≤α), it remains unsubstantiated and should not be used as a finding.

5. The authors have stated as a limitation, “the few subjects (6) with Le Fort advancement surgery”. However, their serious (and ignored) limitation was their lack of power calculations, even a post-hoc one. Certain studies [like this one] might favor the absence of significant differences between a new approach and the gold standard (i.e. P>0.05). Power calculations are extremely essential, especially in such studies. Without a sufficient power, the non-significant results are not reliable as they can be simply false negative errors.

6. The Discussion/Conclusion/Abstract are full of strong conclusions regarding the proper accuracy of evaluated programs. In this design with unknown/low power and many non-significant results, I could not be so sure about the accuracy of the programs.

7. The sample size (2×13) seemed rather small for a paired t-test. Authors might need to justify using a parametric test in this sample via proper normality assessments.

8. In Tables II–V [last columns], the “(maximum error)” was calculated incorrectly for some rows (Table I of this letter).

9. The 95%CIs are critical and also used for authors’ interpretations. At first look, some of the 95%CIs did not accord with the reported means. For example, in Table II, the mean error for “Stomion Superior” is +0.10±0.004 (minimum: –0.30, maximum: +1.02). However, its 95%CI was –0.36 to +0.13, which did not accord with the given information. Or, in the case of “Bridge of Nose” in Table V, the 95%CI was not even around the mean (mean = –0.063, CI= –0.20, –0.57)! Hence, I re-calculated the CIs using the provided means, SDs, and n=13, based on two distributions: normal and t (Tables II–III). The t distribution produced completely different CIs, while the normal distribution provided some similarities to the original report. However, even in that case, many original CIs were extremely different from CIs calculated using means/SDs. I think many calculated CIs are seriously erroneous. Any clarifications are appreciated.

Table I. The corrected “(maximum error)” values alongside the originally reported incorrect ones. Both columns show the original 95%CIs on the left of each column (exactly the same in both columns and borrowed from Nadjmi et al). On the right side of each column, stands the “(maximum error)” within the parentheses block. In the left column, this value is incorrectly calculated (in red font). The corrected one is visible in the right column.

Table II. The 95% confidence intervals (based on normal distribution) for the means reported in Tables II to IV of Nadjmi et al. Only the rows in bold blue font comprise original CIs matching my CIs from means and SDs. The rest of original CIs were inconsistent with the mean/SD (highlighted in yellow). Moreover, of those questionable original CIs (highlighted in yellow), some were strangely different from what they should be according to the reported means and SDs. They are written in red bold font.

Table III. The 95% confidence intervals for the means reported in Tables II to V of Nadjmi et al.1 calculated based on the t distribution. None of these CI values were similar to the CI values reported by Nadjmi et al.

On 2014 Apr 03, David Geter commented:

The reference within of Gollapudi et al., 2011 detailing the dose-response of phenobarbital in CD-1 mice is now published as: Geter DR, V Bhat, BB Gollapudi, R Sura, S Hester. (2014). Dose-response modeling of early molecular and cellular key events in the CAR-mediated hepatocarcinogenesis pathway. Toxicological Sciences. 138(2):425-45. PubMed ID: 24449422.

On 2015 Jun 18, NephJC - Nephrology Journal Club commented:

This study, along with another study in the same area, was discussed on May 27th and June 3rd 2015 in the open online nephrology journal club, #NephJC, on twitter.

Introductory comments are available at the NephJC website. The discussion was quite animated, with more than 50 participants, including nephrologists, fellows and residents.

A transcript and a curated (i.e. Storified) version of the tweetchat are available at the NephJC website.

The highlights of the tweetchat were:

• The participants thought true diuretic resistance requires higher doses and correct combinations of diuretics (e.g. furosemide, metolazone and spironolactone), and were hence not convinced with the data presented. Similar concerns were expressed about the severity of heart failure, and the low rate of device usage (e.g. defibrillators)

• Given the negative outcomes from a similar trial with ultrafiltration, CARESS-HF, the discussants were not impressed with the hypothetical increased sodium removal compared with diuresis.

• However, there was unanimity that peritoneal dialysis is a promising approach, and that this should be tested in a properly designed randomized trial. There was much discussion around possible inclusion criteria, comparators (standard care or left ventricular assist devices) and feasibility of arranging peritoneal dialysis. One such trial is already underway in UK and those results will be keenly followed.

Interested individuals can track and join in the conversation by following @NephJC or #NephJC, or visit the webpage at NephJC.com.

On 2014 May 22, David Goldfarb commented:

This article was selected as CJASN's electronic journal club (eJC) for January 2014. The discussion can be accessed (with a free log-in for the American Society of Nephrology) at: http://ejc.cjasn.org/phpBB3/EJCArchives.php

On 2013 Dec 02, MARK VRABEL commented:

Thanks for writing this, Jon -- Blair told me about it. In addition to the 47 references in your article, there are several Cochrane systematic reviews on antiretroviral therapy, topical microbicides, etc. for HIV prevention, such as PMID 23633367, 22786505, and 22696373.

On 2013 Nov 05, Allison Stelling commented:

The ECM section of this paper ((c) Tumor-stromal extra-cellular matrix-ECM-dependent interactions) lends weight to the idea that the ECM constituents of cellular secretions themselves may constitute a viable biomarker for "tumor-like" microenvironments.

Further physiochemical investigations into the unique biochemical phenotypes generated by tumor cells may be quite helpful for addressing issues with drug delivery, and provide new targets for drug design. (For example, the degree of cross-linking seen between collagens in the matrix would alter the density, possibly things like polarity/ability to H-bond, etc.)

On 2014 Jul 30, Jim Woodgett commented:

This compound was not tested in vitro against GSK-3alpha. Given the virtual identity in the active (ATP binding) site of these two isoforms, it is extremely probable that these compounds also inhibit GSK-3alpha with very similar potency to GSK-3beta. The authors also measured the effect of compound 21 (in comparison to LiCl) on tau phosphorylation in brains of mice. Notably, GSK-3alpha also phosphorylates tau and the observed effects are likely a result of combined inhibition of these related kinases.

On 2014 Jan 08, Brett Snodgrass commented:

Dear Authors,

Thank you for the excellent article.

The vessels you report are consistent with those reported by Wearn. http://bit.ly/JTWearn

Whether the definition "Fistula" is applied depends on how that term is defined. Strictly speaking it is not a "true fistula," as the connection is likely a normal structure, a vessel of Wearn. http://bit.ly/JTWearn

The vessels described by Wearn are distinct form those described by Thebesius. http://bit.ly/Thebesius

For additional commentary, please see https://twitter.com/BrettSnodgrass1/status/412316776702021632

Comments and suggestions are welcome.

Thank you kindly.

On 2014 May 23, Leonid Teytelman commented:

Indeed, using MNase may be the solution. Please see Kasinathan S, 2014 "High-resolution mapping of transcription factor binding sites on native chromatin".

On 2014 May 22, L. Norton commented:

Nice work. Background is certainly an issue in ChIP-Seq studies and I think one way to deal with this is to examine gene expression of the proposed targets following knock-down of the transcription factor. Although this is not a perfect solution, after doing these experiments it becomes apparent that very few ChIP-Seq binding events are 'functionally significant' in a way that we expect (i.e. effect transcription). As a side note, I wonder if you or anyone else has examined the impact of sonication vs. MNase digestion on this phenomenon?

On 2014 Apr 10, Leonid Teytelman commented:

Below are other publications reporting the expression-associated ChIP artifact.

Fan X, 2009 "Where Does Mediator Bind In Vivo?" (Work in S. cerevisiae questioning reports of pervasive genome-wide binding of the Mediator complex.)

Waldminghaus T, 2010 "ChIP on Chip: surprising results are often artifacts" (Work in E. coli; also see arising correspondence Schindler D, 2013.)

Park D, 2013 "Widespread Misinterpretable ChIP-seq Bias in Yeast" (Analysis very similar to ours.)

Kasinathan S, 2014 "High-resolution mapping of transcription factor binding sites on native chromatin" (Questions specificity of standard ChIP in S. cerevisiae and at HOT regions of Drosophila. This work possibly provides a solution to the artifact with a modification of the ChIP technique.)

On 2013 Nov 15, Taneya Y. Koonce, MSLS, MPH commented:

Full report is available on the CDC website at http://www.cdc.gov/nchs/data/databriefs/db133.htm

On 2014 Nov 13, Robert Eibl commented:

Dear Readers,

Here is a link to my critical comment on this paper, which might be interesting to the reader: http://scitation.aip.org/content/aip/journal/apl/104/23/10.1063/1.4882182

Pubmed does not include my comment as a reference, although it recently added the response to my comment. This seems to be due to the publisher who only recommends NIH-funded comments and replies to be listed in Pubmed. In contrast, my comment is accurately mentioned in other scientific libraries, for example IEEE Xplore. For those interested in my research field of specific cell adhesion on living cells measured by nanotech methods and on a single-molecule level, I include a list of references; some of my book chapters are also not included in Pubmed.

Best regards,

Dr. Robert Eibl

REFERENCES

1. Moy VT et al. , Science (1994)

2. Eibl RH and Moy VT, Atomic force microscopy measurements of protein-ligand interactions on living cells. In: Protein-Ligand Interactions, (Editor: G.Ulrich Nienhaus), Humana Press, Totowa, NJ, U.S.A., pp. 437-448 (2005)

3. Benoit M et al. Nature Cell Biology (2000)

4. Eibl RH and Benoit M, Molecular resolution of cell adhesion forces. IEE - Nanobiotechnology 151(3):128-132 (2004)

5. Eibl RH, Direct force measurements of receptor-ligand interactions on living cells. In: Applied Scanning Probe Methods XII - Characterization. Bhushan B, Fuchs H (Editors), Springer, pp. 1-31, (2009)

6. Eibl RH, Cell adhesion receptors studied by AFM-based single-molecule force spectroscopy. In: Scanning Probe Microscopy in Nanoscience and Nanotechnology 2, Bhushan B. (Editor), Springer, pp.197-215, (2011)

7. Eibl RH, Single-molecule studies of integrins by AFM-based force spectroscopy on living cells. In: Scanning Probe Microscopy in Nanoscience and Nanotechnology 3, Bhushan B. (Editor), Springer, pp.137-169, (2013)

8. Eibl RH, Comment on “A method to measure cellular adhesion utilizing a polymer micro-cantilever” [Appl. Phys. Lett. 103, 123702 (2013)]. Applied Physics Letters, 104, 236103 (2014)

On 2015 Feb 11, Michael E Miller commented:

The subgroup analyses reported in our paper were in fact not affected by imbalance between groups. Our finding that “Compared to standard therapy, ACCORD’s intensive glycemia strategy resulted in a higher incidence of cardiovascular mortality in the younger participants but not in older participants (p=0.03 for interaction)” was not a comparison of cardiovascular mortality in younger versus older participants in the same treatment. It compared the effect of the allocated intervention within younger (HR=1.71) versus the effect within older participants (HR=0.97). Thus, among younger participants, the intensive strategy resulted in a higher CV mortality rate compared to the standard strategy; whereas, this treatment group effect was not observed among the older participants. With approximately 3400 participants in both intensive and standard glycemia groups within younger participants and 1700 participants in each group among older participants, baseline characteristics of the intensive and standard groups within age groups were well-balanced. The suggestion that “differences in the baseline characteristics, not the glycemic control in the intensive group might have been responsible for increased mortality in younger participants” is therefore incorrect. Indeed, mortality was not greater in the younger group (see Figure 1). We wrote: “As expected, the older subgroup had higher absolute event rates for all outcomes considered within both treatment arms.” Were we to statistically compare incidence rates in younger versus older participants within the same treatment (which our paper did not do), then clearly many health related characteristics of younger and older participants would be different (as we reported in Supplementary Table 1 of the online appendix) and this would contribute to any differences within treatment groups between age groups.

On 2015 Feb 07, Jayaprakash Sahoo commented:

We read with interest the article by Miller et al in which they have analyzed the impact of baseline age on the effect of intensive blood glucose lowering in the ACCORD trial(1). One of the conclusions of this analysis is that intensive glycemic strategy results in a higher incidence of cardiovascular mortality in the younger but not in older participants. This odd conclusion has to be subjected to scrutiny.

There is a concept that the quality of output is determined by the quality of the input and this applies to statistical analysis also. The basic requirement for comparison of two groups (input data) prior to any analysis is matching of their baseline characteristics. Any conclusion (output data) reached as a result of an analysis without matching is bound to be associated with bias. The baseline characteristics of the intensive and standard therapy arms of the original ACCORD trial were perfectly matched (2). So, the increased mortality in the intensive arm might have been the effect of glycemic control per se in that study. However, the post hoc analysis of the original ACCORD data comparing the adverse events, cardiovascular disease and mortality in older versus younger adults has discrepant baseline characteristics like body mass index (BMI), waist circumference (WC), glycated hemoglobin (HbA1c), blood pressure (BP), and lipid profile. It is probably because this was not the primary objective of the original study. The older participants had a favorable risk factor profile of significantly lower BMI, WC, HbA1c, diastolic BP, LDL cholesterol, triglycerides and high HDL cholesterol as compared to younger participants. The differences in the baseline characteristics, not the glycemic control in the intensive group might have been responsible for increased mortality in younger participants. The authors have discussed role of hypoglycemia and rate of decline in HbA1C as possible causes of increased mortality, but they could not reach any conclusion (3-4). They have not touched upon the impact of differences in baseline characteristics on mortality. In addition, the contributions from blood pressure and lipid control towards the end points leading to inferences in this study has to be taken into account(5). So, the conclusions drawn from analysis of retrospective data, where two groups compared had different baseline characteristics should be taken with caution.

References:

1. Miller ME, Williamson JD, Gerstein HC, et al. Effects of randomization to intensive glucose control on adverse events, cardiovascular disease, and mortality in older versus younger adults in the ACCORD trial. Diabetes Care 2014; 37:634-643.

2. Gerstein HC, Miller ME, Byington RP, et al.; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559.

3. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 2010; 340:b4909.

4. Riddle MC, Ambrosius WT, Brillon DJ, et al.; Action to Control Cardiovascular Risk in Diabetes Investigators. Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow up of glycemic treatment in the ACCORD trial. Diabetes Care 2010; 33:983–990.

5. Margolis KL, O'Connor PJ, Morgan TM, et al. Outcomes of combined cardiovascularrisk factor management strategies in Type 2 diabetes: The ACCORD randomized trial. Diabetes Care. 2014 Mar 4.

On 2013 Nov 12, Christophe Dessimoz commented:

A preprint of this book chapter can be freely downloaded from arXiv: http://arxiv.org/abs/1211.2160.

On 2015 Aug 15, John Tucker commented:

A major shortcoming of the paper is a lack of detailed comparison of the characteristics of published and non-published trials. Although the authors speculate that non-publication of large studies may result from a "discrepancy between observed and desired results" or the desire to protect intellectual property, a quick survey of the unpublished trials listed in the supplementary material shows that most involved drugs that never received regulatory approval for marketing. Thus the leading cause of non-publication appears to be simple irrelevance.

On 2014 Jan 21, Amanda Capes-Davis commented:

As a small comment on this study: INT-407 cells are not intestinal. The INT-407 cell line is known to be cross-contaminated and is actually HeLa. A list of known cross-contaminated cell lines can be found at http://iclac.org/databases/cross-contaminations/.

On 2014 Oct 15, Amanda Capes-Davis commented:

The cell lines used here - HEp-2 and KB - are both known to be cross-contaminated. Unfortunately, that means that both of these models are actually HeLa, from cervical carcinoma.

HEp-2 and KB are widely used in the literature as models for head and neck SCC, even though they are not appropriate models for this tissue type. Always be careful to test cell lines to check that they are not cross-contaminated, using a consensus method such as short tandem repeat (STR) profiling.

For a list of known cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2013 Nov 06, Brian Walcott commented:

Without reversal agents readily available, novel oral anticoagulants can result in catastrophic hemorrhage. While the absolute risk reduction for intracranial hemorrhage may be lower with these agents, there is no way perform emergent reversal (indicated to arrest hematoma growth or allow for emergency surgery). The development and availability of rapid reversal agents are necessary prior to widespread use of this next generation of anticoagulation.

On 2013 Nov 06, Rafael Najmanovich commented:

None

On 2013 Nov 06, Rafael Najmanovich commented:

As someone involved in the development of the field (see Najmanovich R, 2008, http://f1000research.com/articles/2-117/v2 and Najmanovich RJ, 2005) I find the subject area of this article highly relevant for the goal of understanding protein function and its prediction from structure. However, I have several reservations concerning the current paper. These are presented in what follows in decreasing order of importance which is in fact the exact opposite order in which the results mentioned here are presented in the paper followed by some final remarks.

1 - Recovery of Holo Structures using the Apo Structure as a Query. In this section the authors calculate binding site similarities between each Apo protein form (unbound) and the entire set of Holo protein forms (bound). The authors set out, in their words to assess 'the likelihood of correctly identifying the cognate parter of each detected apo binding site’. This language is unclear as we don’t know if they are assessing the probability of finding as most similar a binding-site that binds a similar ligand or the binding-site of the Holo protein that is identical to the Apo form used as query. They find that in 87% of cases ‘the binding sites were correctly matched’. The authors appear to show that they are able to detect based on binding-site similarities the Holo form of a given Apo form for the same protein in 87% of cases. That is to say, the method is capable of accounting for whatever amount of flexibility exists between Apo and Holo forms in 87% of cases as it detects an identical binding site (except for flexibility) as top ranking. This result does not in any way measure the ability of the method to predict function (defined as detecting the correct binding ligand). As a side note, a simple sequence alignment would obviously detect the correct holo partner from the Apo in 100% of cases. To test the prediction capabilities of the method, the authors should use a truly non-redundant dataset (see point 3) and detect as high scoring the Holo forms of other proteins (not the one that pairs with the query) that bind the same or highly similar ligands (for details see Najmanovich R, 2008).

2 - Detection of Binding Sites on Structures with or without Ligands Bound. In this section the authors seek to quantify the ability of the method to detect the cavity that represents the binding site (i.e., where the bound ligand is found) out of all possible cavities. They search against the cavities in the holo or the Apo sets and report 91% and 88% success rates respectively. While these results may at first seem impressive, it is important to note, as reported already in 1996 that the largest volume cavity is the cavity that contains the binding-site in 83% of cases (Laskowski RA, 1996). The challenge is not to detect the cavity that contains the binding-site but the actual binding-site, that is, the residues with atoms in contact with ligand atoms.

3 - Curated LigASite Database. The authors mention that they use the non-redundant LigASite dataset (Dessailly BH, 2008), however, it is important to highlight that redundancy is always relative to the question at hand. The context here is the prediction of function from structure. In such a context, it is necessary to use a dataset that from the point of view of the proteins within, does not contain any redundancy at the level of protein folds in addition to sequence. As an example, human protein kinases can have very low sequence identity, below the 25% threshold used in LigASite, but almost 100% binding site similarity, sequence or otherwise. Additionally from the point of view of the ligands, a quick inspection of the originally reported LigASite non-redundant dataset shows an over-representation of nucleotide-containing molecules (MG ADP MN ATP NAG NAD GOL GDP PO4 GLC NAP GAL COA AMP ANP).

Finally, the authors apply some extra filters to the LigASite dataset available at the time of their study but do not publish the final dataset, thus preventing any careful analysis of non-redundancy or allowing future works to compare their results to the ones reported here. In summary, the data presented here does not allow a reader to evaluate in any way the quality of the method. To truly test a method one has to compare it to existing methods that perform the same tasks (such as IsoCleft above and many others that exist) as well as use a dataset that is non-redundant for the particular questions.

On 2014 Feb 15, Amanda Capes-Davis commented:

There are a number of references that refer to KB as oral cancer. Unfortunately, Gartler showed in 1967 that KB is cross-contaminated with HeLa and is actually cervical adenocarcinoma. For a list of known cross-contaminated cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2014 Jun 20, James Q Zheng commented:

Thank you for your comment and it is a good point. However, in the discussion, 3rd paragraph, we explicitly discussed the possible involvement of GSK3alpha. Quoted here:

It should be noted that these studies do not preclude a similar role for the GSK3b homologue, GSK3a, in dendritic development and maintenance. The kinase domains of both GSK3a and GSK3b are highly similar, and there are numerous contexts where both have been demonstrated to be at least partially functionally redundant (39,40).

On 2014 Jun 19, Jim Woodgett commented:

Disappointing that the authors did not assess (or even mention) the possible role of GSK-3alpha in these processes, since it is highly redundant with GSK-3beta, has tightly overlapping substrate specificity, similar ubiquitous expression and is equivalently regulated by PI3K and Wnt. For example, does GSK-3alpha also bind Gephryn?

On 2014 Jan 28, Vardan Karamyan commented:

Editorial Highlight by Dr. Frédéric Checler. Experimental stroke: neurolysin back on stage.

On 2014 Aug 07, Raha Pazoki commented:

The study by Lambert and co-workers is an interesting piece of work on a sample consisting of more than 50,000 cases and controls. The authors performed a multi-stage genome wide association study with meta-analysis of the results and identified several new loci for Alzheimer disease. The final loci were searched for eQTL effects in online eQTL database from Pritchard laboratory which provides eQTLs from different resources.

While this is a comprehensive approach to identify functional genetic loci, there are still other eQTL databases available online that may provide more information about the functionality of these loci. For example, a quick search in the GTEx online eQTL database (GTEx Consortium., 2013) shows that rs1476679 (identified in the present work of Lambert and co-workers) is additionally an eQTL for the gene PVRIG2P with effect size of 0.34 and P<2× 10^-6. PVRIG2P has not been previously implicated in Alzheimer’s disease but could be a target for further research along with other findings of Lambert and co-workers.

On 2013 Oct 31, Ben Busby commented:

Congratulations to these authors for acquiring a staggering amount of data, the production of which was funded by various government and non-profit sources; this made for some interesting findings that may be directly relevant in the clinic. It is my sincere hope that the researchers will go even farther in investigating subsets of this data, and in doing so, identify genomic subgroups of patients with the Alzheimer's phenotype. I would recommend this paper to anyone interested in using patient-sequence datasets to investigate disease.

On 2016 Nov 03, Morten Oksvold commented:

None

On 2016 Apr 05, Md. Shahidul Islam commented:

Please read "Expression of concern—Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study".

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30091-5/fulltext?rss=yes

On 2016 Feb 23, Md. Shahidul Islam commented:

Please read the comments of the Royal Swedish Academy of Science http://www.thelancet.com/pb/assets/raw/Lancet/pdfs/S0140673616005201.pdf

On 2016 Feb 23, Md. Shahidul Islam commented:

Please read the comment of Richard Horton editor of Lancet in this link http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00341-X/fulltext?rss=yes

On 2015 Aug 12, Md. Shahidul Islam commented:

Please read Vogel G 2015 Regenerative medicine. Report finds misconduct by surgeon. Science 2015 May 29;348(6238):954-5. doi: 10.1126/science.348.6238.954-b

On 2015 May 26, Md. Shahidul Islam commented:

None

On 2013 Oct 29, John Cannell commented:

I congratulate the authors on an important work but it shows how little communication is occurring among autism scientists. Each scientist seems to be immersed in his or her own research interest but oblivious to the larger body of autism research.

While the below Harvard study was published to late for the authors to cite, it showed that preterm infants have significantly lower serum 25(OH)D levels than do full term infants.

Burris HH, Van Marter LJ, McElrath TF, Tabatabai P, Litonjua AA, Weiss ST, Christou H. Vitamin D status among preterm and full-term infants at birth. Pediatr Res. 2013 Oct 11. doi: 10.1038/pr.2013.174. [Epub ahead of print]. Burris HH, 2014

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

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

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

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

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

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

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

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

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

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

70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day.

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

Some autism researcher seem cognizant of the entire body of autism research. For example a group of well-known European autism researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into vitamin D and autism. However, these scientists appear to be in the minority.

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

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

John J Cannell Vitamin D Council http://www.vitamindcouncil.org

On 2013 Oct 30, Woo Jae Kim commented:

I agree, however, we need strong genetic tools that we can use in Drosophila from other species we will use to study complex behaviors. I guess evolutionary biologists and Drosophila geneticists should meet for this common purpose to build strong genetic tools in other insect species.

On 2014 Nov 24, Roger Keller Celeste commented:

If I read correctly, authors were looking for failure of implants placed after radiotherapy versus those place in bone not irradiated.

Time after radiotherapy is an important variable that was not considered. Implants placed in irradiated bone, after long time since radiotherapy, may have similar success probability to those placed in non-irradiated bone. The idea that 6 months of healing is enough may not be true.

We have conducted a similar review Claudy MP, et al. Time Interval after Radiotherapy and Dental Implant Failure: Systematic Review of Observational Studies and Meta-Analysis, but comparing implants placed in bone irradiated between 6-12 months after radiotherapy versus implants placed after 12 months.

In our finding, the difference between groups was smaller, and we also detected influence of one study in the results. We were also able to include more studies, so to assess influence of publication bias and heterogeneity. Thanks, Roger Keller Celeste, PhD in Epidemiology Federal University of Rio Grande do Sul, Brazil Faculty of Dentistry

On 2013 Oct 28, Leslie Vosshall commented:

Feng Zhang and co-workers present a further optimization of the CRISPR-Cas9 system that that minimizes off-target cleavage. This technique keeps getting more compelling as a genome-editing tool because unlike TALENs and ZFNs, CRISPR-Cas9 can be implemented cheaply and easily in any laboratory.

On 2013 Oct 31, John Cannell commented:

I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day and few to

On 2014 Feb 13, Bruno Ramalho Carvalho commented:

In their interesting article, Gizzo et al affirmed that modern concepts on fertility sparing consider ovarian reserve to be the most important independent female fertility predictor, even being more important than chronological age. I would say that, based on scientific evidence, such an affirmative is at least controversial.

First of all, that affirmative was attributed to a narrative review article and an article on fertility preservation in women with cancer, which are supposed to be unaproppriate references. Adequate evidences should include prospective and controlled studies, with large populations.

Until today, the bulk of literature supports age as the single most important factor in determining theoretical reproductive capability of women. In historical cohorts, the respective rates of infertility among married women at the age groups of 20-24, 25-29, 30-34, 35-39 and 40-44 years were 6%, 9%, 15%, 30% and 64% [Menken et al, Science 1986].

Women undergoing artificial insemination with donor sperm because of partner azoospermia presented with lower rates of conception or needed more cycles to achieve it after 35 years of age [Schwartz & Mayaux N Eng J Med 1982]. According to recent data, similar results were obtained in in vitro fertilization (IVF) cycles using non donor fresh eggs; birth rates for age groups of < 35, 35-37, 38-40, 41-42 and > 42 years were 36%, 28%, 18%, 10% and 4% per cycle, respectively [CDC, http://apps.nccd.cdc.gov/art/Apps/NationalSummaryReport.aspx].

Data from Red Latinoamericana de Reproducción Asistida demonstrated a significant age-dependent reduction of pregnancy rates per IVF cycle: 38% for women with 30-34 years of age; 31% for women with 35-39 years of age and 16% for older patients [Zegers-Hochschild et al, 2008; http://www.redlara.com/imagens/arq/2008_registro 2008.pdf]. Furthermore, studies have shown that women of advanced maternal age unable to achieve pregnancy through IVF were able to conceive using donor oocytes from younger women [Steiner & Paulson, 2006].

Despite the points enhanced along Gizzo et al discussion, some should note that their results clearly demonstrate that age is the best predictor of IVF results, since they reported ongoing pregnancy rates of 6.7% in the fifth decade of life, with no pregnancy after 46 years of age. It is noticeable that the authors did not mention live birth rates, which should be expected to be lower, as late pregnancy loss are very probable among the study population.

A recent study by Luke et al demonstrated that the results of cycles of IVF/ICSI diminish in direct relationship with increasing maternal age and the number of cycles performed with autologous oocytes. Live birth rates were estimated, respectively, to be of 63.3 % and 74.6 %, in conservative and ideal perspectives for women under 30 years of age, 18.6% and 27.8 % after 41 or 42 years of age, and 6.6% and 11.3 % for women after 43 or more years of age at the end of a third cycle of IVF/ICSI with their own oocytes. However, those rates were higher than 60% and 80% for all ages when donors’ oocytes were used [Luke et al. N Eng J Med 2012].

The literature suggests that follicle development is impaired in women with advanced age, even if they present apparently normal steroidogenesis and regular menstrual cycles. In such a population, deficiencies in insulin-like growth factors (IGF) I and II, and even in the endogenous luteinizing hormone secretion, have been suggested as cofactors to explain the phenomenon [Santoro et al. JCEM 2003].

Finally, it is well known that both the quantity and quality of ovarian follicles significantly decrease as a woman advances in age, and that many women who postpone maternity may be infertile at the time they are willing to become pregnant. The main purpose of ovarian reserve evaluation, especially before ART, is to identify women with poor ovarian reserve for their chronological age. This is exactly the reason why age must always be the first marker to be considered in ovarian reserve assessment.

In my opinion, it is very clear that older women may benefit from ovarian reserve tests and the authors have reinforced it. However, their results do not support to exclude women’s chronological age as the main element to define treatment chances in the management of “elderly” infertile couples. They may help clinicians to find out acceptable chances of pregnancy through IVF, but, until now, it is not acceptable to guarantee positive results based on ovarian reserve tests, alone or in association.

On 2015 Apr 02, Harri Hemila commented:

The Cochrane review “vitamin C supplementation for asthma”, withdrawn by Kaur B, 2013, misled readers for over a decade.

The first version of this Cochrane review “vitamin C supplementation for asthma” was published in 2001 by Kaur B, 2001. The 2001 version had serious errors in the extraction and analysis of data, which are summarized in Pubmed Commons. Those 2001 errors were thereafter passed on to the 2004 update by Ram FS, 2004 and thereafter on to the 2009 update by Kaur B, 2009. See a summary of the major errors in the 2009 version of the Cochrane review in Pubmed Commons. Thus, the Cochrane review “vitamin C supplementation for asthma”, initially published in 2001 by Kaur B, 2001, misled readers for over a decade before it was withdrawn.

On 2014 Mar 20, Jonathan Eisen commented:

Lynn Schriml, the senior author of this paper, wrote a guest post for the "Microbiology of the Built Environment (microBEnet)" blog about the development of these standards. See Guest Post: Metadata for the Built Environment – MIxS-BE package.

On 2016 Apr 09, Sergio Uribe commented:

Strange results. The Fuji II LC had a mean microleakage of 7.99 and SD of 9.57. Hence some samples had a leakage of -1.58 um....

also, a group with mean(SD) of 1.28(0.98) was not statistically different from another with 7.99(9.57), but both were different from a third with 4.36(5.64). (See Table 2)

After reading the paper, is it not clear if they compared the repeated meaures against the baseline measurement or against each other. The description of the statistical procedure in the paper states: "Finally, the data were analyzed by repeated measures and Duncan (a=0.05) tests." Uninformative.

Maybe the authors can give a more detailed explanation on how they assess the differences among groups.

On 2015 Oct 05, Jan Egger commented:

For a video demonstrating the interactive real-time segmentation of a prostate central gland (PCG) in 2D, please see here: https://www.youtube.com/watch?v=dr6QLwmxoOg

Best wishes, Jan

On 2013 Nov 01, Erick H Turner commented:

A related idea that might be interesting would be to see how many journals explicitly welcome submissions regardless of the strength and direction of results. The ICMJE has declared that its members journals have an "obligation to publish negative studies" (http://www.icmje.org/publishing_1negative.html), but it seems that few journals have incorporated this directive into their policies.

On 2016 Feb 07, Fang-Cheng Yeh commented:

The tool and source code are available at http://dsi-studio.labsolver.org/

On 2013 Oct 23, Rafael Najmanovich commented:

It would be interesting to study this gene in patients with colitis caused by C. difficile infections.

On 2013 Dec 12, Matthew Inglis commented:

In a post to the "Had I Been A Reviewer" blog, Lucy Cragg and I raised four questions about the statistical analyses used in this paper. Briefly, we ask about (i) the appropriateness of using one-tailed tests, (ii) the sampling methods, (iii) the appropriateness of using a Fisher's r-to-z transform to compare dependent correlation coefficients, and (iv) the lack of Bonferroni corrections.

The full post is available here: http://ow.ly/qCri6

On 2014 Feb 06, Simon Young commented:

This paper, demonstrating that giving humans tryptophan (TRP) in order to increase brain serotonin promotes interpersonal trust, is an interesting contribution to the literature on serotonin and social behavior. However, the authors’ interpretation of the results in relation to nutrition is problematic. They conclude their paper by stating:

“Food may thus act as a cognitive enhancer that modulates the way one thinks and perceives the physical and social world. In particular, TRP supplements, or TRP-containing diets, may promote interpersonal trust in inexpensive, efficient, and healthy ways.”

The word diet can refer to the food that a person habitually eats, or foods that are eaten for a special reason. In relation to the first definition of diet the Introduction of the paper mentions:

“TRP is an essential amino acid contained in food such as fish, soybeans, eggs, and spinach.”

TRP is a constituent of nearly all proteins and therefore all foods that contain protein contain TRP. Fish, soybeans and eggs are high in protein and are therefore relatively high in TRP, while spinach is low in protein and therefore TRP. Among the amino acids TRP is the least abundant in most proteins Heine W, 1995. While ingestion of normal foods containing protein will increase plasma TRP levels, it will not increase brain TRP or serotonin Sainio EL, 1996. This is because TRP is taken up into the brain from the blood by a transport system that is active towards all the large neutral amino acids (LNAA). The different amino acids compete with each other for the transport system, and as a rough approximation brain TRP levels will follow the plasma ratio of TRP to the other LNAA (TRP/LNAA). Because of the low abundance of TRP in most proteins this ratio will decline after ingestion of a normal meal. While the decline is small enough that there is unlikely to be any important decline in brain TRP and serotonin synthesis, normal protein-containing meals definitely do not raise brain serotonin Teff KL, 1989. Thus, normal meals would not promote trust by increasing serotonin. The statement in the paper that food may act as a cognitive enhancer may be true, but has nothing to do with TRP and serotonin. The acute improvement in memory after a meal is well known and is associated with an increase in blood glucose Smith MA, 2011. All macronutrients may have beneficial effects on cognition as protein, carbohydrate and fat meals all improve performance on different cognitive tests in humans Kaplan RJ, 2001. Among the dietary components that can potentially influence brain function acutely, in addition to TRP, are tyrosine and phenylalanine, which are precursors of the catecholamines, histidine, the precursor of histamine, choline, the precursor of acetylcholine, and threonine, after conversion into glycine Young SN, 1996. Furthermore, while real meals can have acute effects on cognition and mood these effects are influenced by context Sommer W, 2013. If normal meals were found to increase interpersonal trust such an effect would not be mediated by changes in TRP and serotonin. The second meaning of diet is foods, that may be specially prepared, that are eaten for a special purpose. One such specially prepared food that has been studied is alpha-lactalbumin, a protein that is a minor constituent of milk and has a higher than normal proportion of TRP Heine W, 1995. When purified alpha-lactalbumin is given to humans it increases the TRP/LNAA Markus CR, 2008 and can in some circumstances have effects on mood and cognition Markus CR, 2000. However, alpha-lactalbumin could not be considered a special diet that may “promote interpersonal trust in inexpensive, efficient, and healthy ways”. Colzato et al. gave the participants in their study 0.8g of TRP. When humans were given either 0.8g of pure TRP or 0.8g of TRP in alpha-lactalbumin (15g) the rise in TRP/ LNAA is much greater after the TRP than after the alpha-lactalbumin, because the alpha-lactalbumin contains the other LNAA Markus CR, 2008. Furthermore, the TRP/LNAA reached a peak 2 hours after ingestion of the alpha-lactalbumin and then declined. To increase serotonin synthesis sufficiently to promote interpersonal trust would presumably involve doses of alpha-lactalbumin greater than 15g, taken at relatively frequent intervals throughout the day. This would not be inexpensive and efficient as suggested by Colzato et al., and might not even be healthy given that the effects of frequent ingestion of a protein supplement that has calories but no minerals, vitamins or antioxidants could potentially have adverse effects on total dietary intake. In some countries TRP is sold as a dietary supplement (although in others such as Canada it is regulated as a prescription drug). This raises the question of whether TRP could be given long-term in pure form to promote interpersonal trust. When TRP is given for a few weeks it can help regulate behavior in pathologically aggressive patients Morand C, 1983, and promote more pro-social behavior in healthy people Moskowitz DS, 2001 aan het Rot M, 2006. However, taking TRP long-term to promote trust would be neither inexpensive, convenient, given that TRP has to be taken several time a day to ensure that brain serotonin remains elevated Moskowitz DS, 2001, or without risk Fernstrom JD, 2012. Barriers to obtaining more information on the effects of diet on mood and behavior include the complexities of the effects of dietary components on brain function, the fact that effects of food intake on brain function can be modulated by the setting, and the difficulties of carrying out randomized trials with altered diets. At this time research has not revealed any simple dietary strategy to increase brain serotonin, in spite of the potential benefits of such an approach.

On 2014 Apr 08, Dr Nicholas D Gollop commented:

Dear Jamil Hajj-Chahine, thank you for your comments on our paper: ‘Comparison of drug-eluting and bare-metal stents in patients with diabetes undergoing primary percutaneous coronary intervention: what is the evidence?’ [1].

Percutaneous coronary intervention (PCI) is the preferred method of revascularization in the management of acute ST elevation myocardial infarction (STEMI). However, in a specific subset of patients, CABG may be appropriate.

For example, coronary angiography may reveal anatomy that is unsuitable for balloon angioplasty or stenting. In these patients, CABG may be indicated for the treatment of acute STEMI.

Furthermore, CABG is indicated when primary PCI has failed to achieve reperfusion of the myocardium in addition to persistent hemodynamic instability or life-threatening ventricular arrhythmia due to extensive ischemia (left main or 3-vessel disease). There are several limitations to CABG in the management of acute STEMI.

It has been shown that CABG performed within 2 days of hospitalization for acute STEMI is associated with a higher incidence of mortality in comparison to CABG carried out 3 or more days after acute STEMI [2].

The incidence of Rethoracotomy is significantly greater when CABG is performed within the first 3 days following acute STEMI in contrast to CABG carried out between day 4 and 30 [3]. Furthermore, post-operative intra-aortic balloon pump devices are required for longer, there is a higher incidence of bleeding complications, more inotropic drugs are required and there is a longer intensive care and total hospital stay when CABG is carried out within 3 days of presentation.

When compared against PCI, CABG is associated with a higher risk of stroke within the 30 day post-operative period [4].

References

[1] Gollop ND, Henderson DB, Flather MD. Interact Cardiovasc Thorac Surg. 2014 Jan; 18 (1): 112-6. In diabetic patients does the utilization of Drug Eluting Stents (DES) instead of Bare Metal Stents (BMS) reduce restenosis rate without compromising the efficacy and safety of Primary Percutaneous Coronary Intervention? [2] Weiss ES, Chang DD, Joyce DL, Nwakanma LU, Yuh DD. J Thorac Cardiovasc Surg. 2008 Mar; 135 (3): 503-11, 511.e1-3. Optimal timing of coronary artery bypass after acute myocardial infarction: a review of California discharge data. [3] Gu YL, van der Horst IC, Douglas YL, Svilaas T, Mariani MA, Zijlstra F. Neth Heart J. 2010 Aug; 18 (7-8): 348-54. Role of coronary artery bypass grafting during the acute and subacute phase of ST-elevation myocardial infarction. [4] Palmerini T, Biondi-Zoccai G, Riva DD, Mariani A, Savini C, Di Eusanio M, Genereux P, Frati G, Marullo AG, Landoni G, Greco T, Branzi A, De Servi S, Di Credico G, Taglieri N, Williams MR, Stone GW. Am Heart J. 2013 Jun; 165(6) :910-917.e14. Risk of stroke with percutaneous coronary intervention compared with on-pump and off-pump coronary artery bypass graft surgery: Evidence from a comprehensive network meta-analysis.

On 2014 Jan 18, Jamil Hajj-Chahine commented:

I read with great interest the paper by Gollop et al regarding the best available stenting technology for diabetic patients undergoing percutaneous coronary intervention [1]. After reviewing the relevant literature, they concluded that drug-eluting stents are superior to bare- metal stents in this subset of patients with regard to clinical outcomes.

I would like to take the opportunity to discuss the place of coronary artery bypass grafting (CABG) in the era of drug-eluting stent for diabetic patients with multi-vessel coronary disease. CABG was shown to be more beneficial than bare-metal stent for patients with diabetes and multi -vessel disease [2]. However, the improvement in restenosis rate with drug -eluting stents has accelerated the wide use of stenting in patients with extensive coronary disease and extended to include patients with diabetes. Reports mainly from retrospective studies showed that CABG is the preferred modality of treatment in diabetic patients with multi-vessel disease [3-4].

In 2012, the results of FRREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial were published [5]. This international trial was specially designed to include only patients with diabetes. Freedom trial randomly assigned 1900 patients in140 centres to undergo either percutaneous coronary intervention with drug-eluting stents or CABG. The primary outcome was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke and it did not include the need for repeat revascularization. The primary end point occurred more frequently in the interventional group 26,6% compared with CABG group 18,7% (p=0,005) at five years post-procedure. CABG in patients with diabetes and multi- vessel disease reduced significantly the rates of death and myocardial infarction. However, stroke rate was the major drawback of surgery with 5- year rates of 2.4% in the stenting group and 5.2% in the CABG group (P=0.03).

In this subset of high-risk patients, we can conclude that the substantial survival advantage of surgery is still valid even in the era of drug-eluting stents.

References

[1] Gollop ND, Henderson DB, Flather MD. Comparison of drug-eluting and bare-metal stents in patients with diabetes undergoing primary percutaneous coronary intervention: what is the evidence? Interact Cardiovasc Thorac Surg. 2013 doi:10.1093/icvts/ivt454.

[2] Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 1997;96:1761-9.

[3] Yang JH, Gwon HC, Cho SJ, Hahn JY, Choi JH, Choi SH, et al. Comparison of coronary artery bypass grafting with drug-eluting stent implantation for the treatment of multivessel coronary artery disease. Ann Thorac Surg. 2008;85:65-70.

[4] Hueb W, Gersh BJ, Costa F, Lopes N, Soares PR, Dutra P, et al. Impact of diabetes on five-year outcomes of patients with multivessel coronary artery disease. Ann Thorac Surg. 2007;83:93-9.

[5] Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, et al; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367:2375- 84.

On 2013 Oct 24, John Cannell commented:

Great points. While many know about the role of inflammation on diseases of the elderly like Alzheimer's, fewer know of inflammation's role in diseases of children, such as in autism. Fewer yet know about the profound anti-inflammatory effects of vitamin D. While many will not read any further when they see the word "vitamin," calcitriol is actually a neurosteroid.

The scientists below discovered that the absolute level of an autoimmune anti-neural antibody was inversely related to 25(OH)D levels with a R value of -.86. So far, six anti-neural antibodies have been discovered in autism, as well as elevated levels of inflammatory cytokines. Two studies showed the levels of these antibodies are inversely related to autism severity with high R values.

http://www.ncbi.nlm.nih.gov/pubmed/22898564

http://www.ncbi.nlm.nih.gov/pubmed/23239393

On 2017 Sep 21, Hendrik S. Fischer commented:

In response to Dr. Fleming’s comment: Odds ratios (OR) must not be misinterpreted as risk ratios (RR). If outcomes are rare, OR approximate RR. If outcomes are common, OR and RR differ, but both OR and RR still have specific advantages and disadvantages (Cummings P. The relative merits of risk ratios and odds ratios. Arch Pediatr Adolesc Med. 2009;163:438–45). Importantly, OR cannot exaggerate differences across groups given as RR. They are just two different methods to express these differences. In the present meta-analysis, the odds ratio (95% confidence interval) of death or BPD is 0.83 (0.71–0.96) and the risk ratio is 0.90 (0.83–0.98). Admittedly, both OR and RR may be difficult to interpret from a clinical point of view. We therefore recommend that meta-analyses should calculate a number needed to treat (NNT) as a meaningful measure of effect for the clinician. In our meta-analysis, the NTT was 35, indicating the small but beneficial effect of avoiding mechanical ventilation, which we have discussed in the abstract and in our paper.

On 2017 Jul 12, Robert Fleming commented:

In the meta-analysis presented in this manuscript, the results are presented as odds ratio (OR) rather than relative risk (RR). When an outcome (BPD in this setting) is common (> 10% in the unexposed group, which is the case for these studies), using OR can exaggerate differences across the groups. The original report from the SUPPORT trial reports a RR of 0.9. In this meta-analysis the OR from the same study is reported as 0.81. Likewise, converting the OR from this meta-analysis (0.83) to RR results in a value of 0.9. This point is made not to imply that mechanical ventilation should not be avoided; however the effect of avoiding mechanical ventilation on the incidence of BPD calculates to be less than concluded in this meta-analysis.