14,838 Matching Annotations
  1. Jul 2018
    1. On 2016 Oct 04, Atanas G. Atanasov commented:

      None


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    2. On 2016 Jun 06, Thomy Tonia commented:

      We would like to thank Melissa Vaught for her interesting and stimulating thoughts on our paper. She states that the title and description of our trial’s objective is misleading. However, it is clearly stated in the abstract and in the introduction that we randomised IJPH papers into two arms one of which involved IJPH social media exposure at 3 time points; moreover, our Methods section describes this intervention in detail.

      Melissa Vaught makes a very valid point stating that we did not include any measures of reach/exposure such as re-tweets, shares or other users’ dissemination of our papers in social media etc. We have touched upon this issue when we discussed the limitations of our study.

      She also refers to potential confounding factors. Given the randomised design of our study, however, systematic confounding cannot be an issue; our analysis is what one would call “intention to treat” in clinical trials. There are some interfering factors that we could not control, which we tried to outline in our paper. This is why we standardised our intervention as much as possible, randomising only original articles (and not systematic reviews that generally tend to receive more attention) and stratifying for open access status. We have not issued any press releases for any of the randomised papers but we could not control for any press or other exposure coming from other sources such as authors’ institutions.

      Although we agree that SM strategies could influence outcomes, the studies by Fox CS, 2016 and Adams CE, 2016 cited by Melissa Vaught did not directly compare different intensities of interventions such as multiple postings per day versus less frequent postings. Additionally, as we mention in our limitations, we could not have the data on paper views which could be different from the download data.

      Melissa Vaught mentions that only the study by Sorenson 2014 looked at SM promotion by the journal. However, the studies by Fox CS, 2015 and Fox CS, 2016 which were randomised and bigger in size also assessed the promotion of papers from Circulation journal on their own social media and found no effect on article views.

      We fully agree with the last remark of Melissa Vaught. Indeed, having social media presence as a journal can have benefits that lie beyond downloads and citations and this is one of the reasons our Journal is active on social media.

      Indeed, social media exposure and its effects on scientific is a complex and multi-layered subject. Our trial looked at only one specific aspect of this, namely the effects of exposure of our own papers on our own social media channels. Nevertheless, we believe that it adds useful information to the existing body of literature. We hope that future RCTs will assess the effect of other measures of reach and exposure in order to give a fuller picture of the effect.


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    3. On 2016 May 24, Melissa Vaught commented:

      This interesting article presents the impact of a journal's social media activity on article-level metrics - one of very few randomized trials on the topic. Notably it uses a traditional (citation counts) and an alternative metric (article downloads) as outcomes.

      However, the title and descriptions of the trial's objective and intervention are a bit misleading. The authors state, "We sought to investigate whether exposing scientific papers to social media (SM) has an effect on article downloads and citations." But the study does not evaluate social media exposure. Rather, it measures the effect of a journal promoting its content via its own social media channels. The study did not include any measures of reach or exposure, such as retweets, shares, or likes of their posts. It also did not examine whether other users disseminated articles in the trial via social media.

      Still, this study addresses a pertinent question: Does publisher promotion of publications via social media influence reading or citation? For IJPH, there is no apparent association. Of course, there are potential confounding factors, some beyond the journal's control. Did IJPH or authors' institutions issue press releases for any publications in the trial? Did any articles garner attention in mainstream media or on social media? Would easier access to publications affect outcomes? The authors report no difference in outcomes for social media promotion vs. control, when stratified for open access; however, there were few open access articles in the trial—10% in control, and 5% in intervention group.

      Using citations as an outcome is a valuable contribution of this trial. Other randomized trials have evaluated effects of social media promotion by publishers on article views, which may moderately correlate with citations. In two separate trials (Fox CS, 2015, cited by the authors, and Fox CS, 2016), Circulation found that Facebook and Twitter posts did not significantly affect views at 7 or 30 days. By contrast, the Cochrane Schizophrenia Group (Adams CE, 2016) found a significant increase in 7-day page views for systematic reviews shared on Twitter and Weibo (a popular social media site in China).

      Social media strategies could influence outcomes. By using Weibo, Adams CE, 2016 extended reach to a distinct audience. Post frequency and schedules likely affect audience reach as well. For instance, tweets posted at the same time weeks apart (as in the IJPH trial) might not be as effective as multiple posting over one or two days (as in Fox CS, 2016 and Adams CE, 2016). Overall social media engagement and post volume could also come into play.

      The authors note that many observational studies show positive correlation between social media exposure and article views, downloads, or citations. They suggest the difference may be due to design (randomized vs. observational). Contexts and sizes of the studies could also contribute to differences in results. Only Sorenson M, 2014 looked at social media promotion by the journal; this was only for a small number of publications (3 promoted and 3 non-promoted). Other cited studies looked at third-party or global social media activity, for a handful to thousands of publications.

      Ultimately this trial evaluates whether a journal's social media activity affects reading or citation of its own publications. So who follows journals on social media, and why? Social media uptake in scholarly communities is growing. But it's far from replacing other methods for discovering articles (Ware M, 2015, pp. 52-5, 134-5). Researchers are still likely to read articles recommended by colleagues (Tenopir C, 2015), and we might expect this trend to be reflected in social media. In other words, individuals on social media may have a degree of influence that publishers do not. The benefits of journal social media accounts may lie with other outcomes.


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    1. On 2016 Jun 29, David D Leedahl commented:

      In the accompanying editorial1, Calkins offers some insightful comments regarding the relatively high rate of stroke or TIA observed in the recent investigation by Gillinov et al.2 We would like to offer two important considerations related to these findings.

      First, cardiac surgeons and physicians caring for cardiac surgical patients in the immediate postoperative period have a reluctance to initiate anticoagulant strategies for fear of bleeding complications. Accordingly, bridging strategies with parenteral anticoagulants are infrequently used when initiating warfarin therapy for POAF, potentially resulting in a greater length of time until therapeutic anticoagulation is achieved. Delaying anticoagulant initiation for one to two days to avoid bleeding and another two to three days to become therapeutic may leave patients unprotected for a longer period of time than recognized.

      Secondly, using direct-acting oral anticoagulants for the treatment of POAF may improve the time to therapeutic anticoagulation and lower the bar for surgeons to decide to anticoagulate their patients. Although our hospital has some published experience with this approach,3 the effect on stroke or TIA incidence in patients with POAF remains uncertain.

      Cornelius Dyke, M.D. Sanford Health, Fargo, ND 58122

      David Leedahl, Pharm.D. Sanford Health, Fargo, ND 58122

      1. Calkins H. Is Less More for the Treatment of Atrial Fibrillation after Cardiac Surgery? N Engl J Med 2016;374:1977-8.
      2. Gillinov AM, Bagiella E, Moskowitz AJ, et al. Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery. N Engl J Med 2016;374:1911-21.
      3. Anderson E, Johnke K, Leedahl D, Glogoza M, Newman R, Dyke C. Novel oral anticoagulants vs warfarin for the management of postoperative atrial fibrillation: clinical outcomes and cost analysis. Am J Surg 2015;210:1095-102; discussion 102-3.


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    1. On 2016 May 20, Mayer Brezis commented:

      Did the physical activity increase in the intervention group? Did insulin sensitivity improve? Is it possible that this was the reason for the lack of effect?


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    1. On 2016 May 20, Clive Bates commented:

      The paper raises well-known fire and explosion risks from lithium-ion batteries, which arise in any products that use them. However, the paper goes on to draw an inappropriate and alarmist conclusion that e-cigarettes constitute a "significant public health risk" on the basis two case studies and four inconclusive media reports.

      The problem is that they apply this alarming label without defining what constitutes a significant public health risk, a concept that must depend on the magnitude of the risk involved and how this compares to other risks.

      Comparison to smoking-related accidents and injuries

      The most important feature of e-cigarettes is that they are alternatives to smoking cigarettes. The authors have not made a comparison with smoking-related accidents or injuries (let alone disease) or made an estimate of the net impact that arises from consumers who switch from smoking to e-cigarette use. The accidents and injuries associated with smoking do actually appear like a "significant public health risk". The U.S. National Fire Protection Service provides useful data:

      In 2011, U.S. fire departments responded to an estimated 90,000 smoking-material fires in the U.S., largely unchanged from 90,800 in 2010. These fires resulted in an estimated 540 civilian deaths, 1,640 civilian injuries and $621 million in direct property damage; deaths were down substantially from the year before.

      Home structure fires dominated all these measures of loss except for fire incidents. In 2011, an estimated 17,600 smoking-material home structure fires caused 490 civilian deaths (19% of all home structure fire deaths), 1,370 civilian injuries and $516 million in direct property damage. The other 72,400 smoking-material fires in 2011 were mostly outdoor fires (60,200 fires in trash, vegetation and other outdoor combustibles).

      Comparison to other risks

      Some broader context may be useful - each year there is one significant injury episode for every eight Americans. U.S. data from CDC:

      Morbidity

      Number of medically attended injury and poisoning episodes in the population: 39.5 million

      Episodes per 1,000 population: 126.3

      Mortality

      Number of injury deaths: 192,945

      Deaths per 100,000 population: 60.2

      Just about every practice in everyday life involves some risk: cooking, eating, walking, showering, using a laptop, walking up stairs, anything that involves electricity, heat or glass etc.

      For example, according to the U.S. National Fire Protection Service home grills account for damage and injuries as follows:

      In 2009-2013, U.S. fire departments responded to an average of 8,900 home fires involving grills, hibachis, or barbeques per year. These 8,900 fires caused annual averages of 10 civilian deaths, 160 reported civilian injuries, and $118 million in direct property damage. Almost all the losses resulted from structure fires

      How does the e-cigarette compare to the ubiquitous and much-loved BBQ?

      There are also persistent reports of exploding iPhones. Should iPhones be designated a "significant public health risk"?

      Conclusion

      Claims that products or behaviours cause significant public health risks need to be proportionate and reflect both absolute risks (how much harm is caused) and relative risks - i.e. set in appropriate context by reference to risks arising from other common products and activities. Risk is a quantitative concept or it is meaningless.

      The authors did not reflect on whether there is a net public health gain in terms of accident risk through the substitution of smoking by e-cigarette use, which is by far the most common pattern of use. It is irresponsible to draw attention to one risk associated with a behaviour, without considering whether it reduces more significant risks. Given the rarity of e-cigarette battery incidents and the preponderance of smoking-related fires, it seems more likely that the net impact on accidents through e-cigarette use will be a significant reduction and therefore a public health win.

      This is not a call for complacency but for proportionality. Regulators could have addressed fire risks from e-cigarette batteries some years ago, but have been spending their time on grandiose and excessive regulatory schemes that have yet to achieve anything and may not even solve this problem when they finally apply.


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    1. On 2017 Oct 19, Julien Bobe commented:

      Thank you for pointing this out. We will add a corrigendum to the original publication.


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    2. On 2017 Oct 17, Anne Niknejad commented:

      Error in the list of RNA-seq raw sequence data accessions from NCBI SRA:... ', SRP058863 (cave fish), SRP058865 (Atlantic cod), and SRP058863 (surface fish).'

      should be read

      ', SRP058863 (cave fish), SRP058865 (Atlantic cod), and SRP058866 (surface fish).


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    1. On 2016 Jul 21, Donald Forsdyke commented:

      THEORY-DRIVEN RESEARCH

      The results of Enard et al. Enard D, 2016 "draw a broader picture where adaptation against viruses involves not only the specialized antiviral response, but also the entire population of host proteins." Indeed, Petrov has remarked: "Organisms have been living with viruses for billions of years" so on theoretical grounds alone "those interactions have affected every part of the cell."

      Given recent disparagement of theoretical work Lander ES, 2016, it is nice to see results that are consistent with theory (e.g. Trends Immunol (2002) 23:575-579; Paper with Endnotes). Enard et al. now "conservatively estimate" that "viruses have driven close to 30% of all adaptive amino acid changes in the part of the human proteome conserved within mammals." Such "virus interacting proteins" vastly exceed the known proteins that regularly engage in immune responses to viruses (e.g. protein kinase R).

      This is consistent with the 2002 postulate of the existence of intracellular protein "immune receptors" Forsdyke DR, 2002. Thus, over evolutionary time a protein that primarily evolved for a distinct function, but also happened to cross-react with some virus component, would in addition be selected by virtue of the latter function.


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    1. On 2017 Oct 06, Lily Chu commented:

      Thank you for the response, Dr. Loy. Many medical resources used by clinicians continue to conflate CFS with SEID and suggest that cognitive behavioral and/or graded exercise therapy are appropriate for patients who fit SEID criteria despite there being no trials of CBT and GET using SEID criteria. I was concerned your group's article might contribute to this confusion.

      (In fact, the US Centers for Disease Control and Prevention are working on removing CBT and GET as treatments from their ME/CFS website. See: http://www.npr.org/sections/health-shots/2017/10/02/554369327/for-people-with-chronic-fatigue-syndrome-more-exercise-isnt-better.)


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    2. On 2017 Sep 01, Bryan Loy commented:

      Thank you for commenting on our paper, and for your contributions to this field. We agree that the ME, CFS, and SEID case definitions are not the same, which is why we provided a citation of each major case-defining paper in the first sentence of our introduction. We then wrote in the “Data searches” section that we were looking for papers using any of the 3 major case definitions, and cited them again. We further acknowledge the differences in the “Diagnostic characteristics” section of the paper, where we coded studies based on the criteria used to diagnose the participants within each study that was included in the meta-analysis. As you point out in table 1, we only found studies that had used the CDC or Fukuda criteria. We wrote ME/CFS/SEID in the title, abstract, and paper to be consistent with the naming used in the IOM report “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness” and the first sentence in the report brief, “Between 836,000 and 2.5 million Americans suffer from myalgic encephalomyelitis/chronic fatigue syndrome-commonly referred to as ME/CFS” (https://www.nap.edu/resource/19012/MECFS_ReportBrief.pdf). While our conclusions may pertain only to people diagnosed using the CDC or Fukuda criteria, we wanted to still refer to the disease as ME/CFS/SEID since ME and SEID have been recommended as new names for CFS. We hope the results of this initial summary of the existing literature will encourage future research that includes other case definitions, and improves the lives of people living with the disease.


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    3. On 2017 Aug 24, Lily Chu commented:

      I am one of the co-authors for the SEID (Systemic Exertion Intolerance Disease) case definition. The SEID and ME case definitions are not the same as the CFS case definition. Otherwise we would not have different names for them. The authors of this study seem to think they are equivalent to each other. The title and abstract is misleading: they should be clear that ALL of the studies examined by the authors (in Table 1) used only the 1994 Fukuda CFS case definition. Consequently, any results and conclusions drawn are only about CFS.


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    1. On 2017 Aug 30, Hilda Bastian commented:

      Although the authors draw conclusions here about cost and effectiveness of simply offering badges if certain criteria are met, the study does not support these claims. There are, for example, no data on costs for the journal, peer reviewers, or authors. Any conclusions about effectiveness are hampered by the study's design, and the lack of consideration and assessment of any potentially negative repercussions.

      It was not possible for the authors to study the effects of offering badges alone, as this intervention was part of a complex intervention: a package of 5 co-interventions, announced by the journal in November 2013 to begin taking effect from January 2014 (Eich E, 2014). All were designed to improve research transparency and/or reproducibility, and signaled a major change in editorial policy and practice. Any manuscript accepted for publication after 1 January, while being eligible for these badges, was also subject to additional editorial requirements of authors and reviewers. All authors submitting articles from 2014 faced additional reproducibility-related questions before submission, that included data disclosure assurances. Other authors have shown that although these did not all lead to the changes sought, there was considerable impact on some measures (Giofrè D, 2017).

      Data on the impact on submissions, editorial rejections, and length of time until publication of accepted articles is not provided in this paper by Kidwell and colleagues. These would be necessary to gain perspective on the burdens and impact of the intervention package. I had a look at the impact on publications, though. It is clear from the data as collected in this study, and from a more extended timeframe based on analysis of date of e-publication, that the package of interventions appears to have led to a considerable drop in publication of articles (see my blog post, Absolutely Maybe, 2017). The number of articles receiving badges is small. During the year in this study from the awarding of the first badge, it was about 4 articles a month. That first dropped, then rose since, while at the same time the number of publications by Psychological Science has dropped to less than half the rate it was in the year before this package of interventions was introduced, leading to a substantial increase in percentage, while the absolute numbers of compliant articles remains small.

      Taken together, it appears that it was likely there was a process of "natural selection", on the side of the journal and authors, leading to more rigorous reporting and sharing among the reduced number of articles reaching publication. The part that badges alone played in this is unknowable. Higher rates of compliance with such standards have been achieved without badges at other journals (see the blog post for examples). There is some data to suggest that disinclination to data disclosure is part of a range of practices adopted together more by some psychology researchers than others, in one of the studies that spurred Psychological Science to introduce these initiatives (<PMID:26173121). The data in Giofrè D, 2017 tend to support the hypothesis that there is a correlation between some of the data disclosure requirements in the co-interventions, and data-sharing (see my follow-up blog post).

      In addition to not considering a range of possible effects of the practices, or being able to isolate the impact of one of the set of co-interventions, the study used only one data extractor and coder for each article. This is a particularly critical potential source of bias, as assessors could not be blinded to the journals, and the badging intervention was developed and promoted from within the author group.

      It would be useful if the authors could report in more detail what was required for the early screening question of "availability statement, yes or no". Was an explicit data availability statement required here, whether or not there was indeed additional data than was included in the paper and its supplementary materials?

      It would be helpful if the authors could confirm the percentage of articles eligible for badges, where the offer of a badge was rejected.

      At the heart of this badge approach for closed access journals, is a definition of "open-ness" that enables potentially serious limitation of the methodological information and key explanatory data available outside paywalls. In de-coupling the part of the study included in the paper from the study's data, and allowing it be inaccessible to many who could potentially use it or offer useful critique, the intervention is promoting a limited form of open-ness. The trade-off assumed is that this results in more open-ness than there otherwise would be. However, it may have the reverse effect, for example, by encouraging authors to think fully open access doesn't matter and can be foregone with pride and without concern, and if journals believe this "magic bullet" is an easy way out of more effective intensive intervention.

      Disclosures: I have a long relationship with PLOS (which has taken a different approach to increasing openness), including blogging at its Blog Network, and am a user of the Open Science Framework (which is produced by the group promoting the badges). My day job is at NCBI, which maintains literature and data repositories.

      This comment was updated with the two references and data on the question of correlation between data disclosure and data sharing on 1 September, after John Sakaluk tweeted the Giofrè paper to me.


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    1. On 2016 May 27, Hans Morreau commented:

      Massive Chromosomal Loss with Subsequent Whole Genome Doubling is seen in a Wide Variety of Rare Tumor Types:

      The authors Zheng et al. performed an impressive molecular characterization of 91 cases of adrenal cortical carcinoma (ACC). The integrated analysis is the way to understand the behaviour of this rare disease far better and hopefully will lead to better treatment options. They conclude that there is a subset of ACCs showing massive chromosomal loss with subsequent whole genome doubling (WGD). The authors state that this chromosomal loss leads to a hypodiploid karyotype. Such a phenomenon “was only matched by chromophobe renal cell carcinoma”. The latter is partly correct. In 2012 we published the occurrence near-haploidisation with or without subsequent endoreduplication (whole-genome doubling) in oncocytic follicular thyroid carcinoma (FTC-OV) and anaplastic thyroid carcinoma (ATC) derived from FTC-OV (Corver et al., 2012). In combined SNP array analysis and DNA content analysis the genomes of these lesions were seen as near-homozygous genomes (NHG) with DNA indices of 0.6-1.4 depending on the absence or presence of endoreduplication. Wagle et al. independently confirmed our observations in the New England Journal of Medicine with the description of one ATC patient who showed a spectacular treatment response upon giving the mTOR inhibitor everolimus. The patient’s ATC derived from FTC-OV and high density SNP analysis clearly identified NHG in the tumor. The phenomenon of NHG with or without endoreduplication is similar to the pattern that is seen by Zheng et al, although the terminology to describe this is slightly different. In 2014 we also showed that in a subset of ACC and parathyroid carcinoma NHG and endoreduplication can be seen, especially in tumors with oncocytic metaplasia (Corver et al., 2014). As seen by Zheng et al the “allelic states” (Corver et al., 2008) in ACC indicated the presence of more chromosomal breakpoints than seen in FTC. In fact similar observations of NHG or widespread chromosomal loss with endoreduplication of the complete genome has been described in peripheral chondrosarcomas (Bovee et al., 2000) and a subset of childhood acute lymphoblastic leukemia (Holmfeldt et al., 2013) and other uncommon cancers (Mandahl et al., 2012). It is intriguing what is eventually responsible for the widespread chromosomal loss with or without endoreduplication. In our model we proposed a stepwise process that might be related to metabolic processes, something that still needs to be proven. It might now be a step forward in understanding the underlying biology of endoreduplication/WGD with the observation of Zheng et al. that TERT expression is higher in the WGD group of ACCs. In conclusion the combined analysis of different tumor types with massive chromosomal loss with subsequent WGD might lead to further insights underlying this remarkable process.

      References:

      Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA, Lerario AM, Else T, Knijnenburg TA, Ciriello G, et al. (2016). Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma. Cancer Cell. 29(5):723-36.

      Corver, W. E., Ruano, D., Weijers, K., den Hartog, W. C., van Nieuwenhuizen, M. P., de Miranda, N., van Eijk, R., Middeldorp, A., Jordanova, E. S., Oosting, J., et al. (2012). Genome haploidisation with chromosome 7 retention in oncocytic follicular thyroid carcinoma. PLoS ONE 7, e38287.

      Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ, et al.(2014) Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med. 371(15):1426-33.

      Corver, W. E., van, W. T., Molenaar, K., Schrumpf, M., van den Akker, B., van, E. R., Ruano, N. D., Oosting, J., and Morreau, H. (2014). Near-haploidization significantly associates with oncocytic adrenocortical, thyroid, and parathyroid tumors but not with mitochondrial DNA mutations. Genes Chromosomes Cancer 53, 833-844.

      Corver, W. E., Middeldorp, A., Ter Haar, N. T., Jordanova, E. S., van Puijenbroek, M., van Eijk, R., Cornelisse, C. J., Fleuren, G. J., Morreau, H., Oosting, J., and van Wezel, T. (2008). Genome-wide allelic state analysis on flow-sorted tumor fractions provides an accurate measure of chromosomal aberrations. Cancer Res 68, 10333-10340.

      Bovee, J. V., van Royen, M., Bardoel, A. F., Rosenberg, C., Cornelisse, C. J., Cleton-Jansen, A. M., and Hogendoorn, P. C. (2000). Near-haploidy and subsequent polyploidization characterize the progression of peripheral chondrosarcoma. Am J Pathol 157, 1587-1595.

      Holmfeldt, L., Wei, L., Diaz-Flores, E., Walsh, M., Zhang, J., Ding, L., Payne-Turner, D., Churchman, M., Andersson, A., Chen, S. C., et al. (2013). The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 45, 242-252.

      Mandahl, N., Johansson, B., Mertens, F., and Mitelman, F. (2012). Disease-associated patterns of disomic chromosomes in hyperhaploid neoplasms. Genes Chromosomes Cancer 51, 536-544.

      Hans Morreau, also on behalf of Willem Corver and Tom van Wezel, Dept of Pathology, Leiden University Medical Center The Netherlands Email: j.morreau@lumc.nl.

      Note: This comment was also posted on the website of Cancer Cell attached to the manuscript of Zheng et al 2016. This will however not be visible in the PubMed domain. I do not have conflicts of interest to declare.


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    1. On 2016 Jun 16, thomas samaras commented:

      The increase in BMI is certainly puzzling in view of a recent study by Aune et al.(2016) that found a BMI of 20-22 was best for non-smokers over the long term. The study involved a meta-analysis of 230 studies involving 30 million subjects and almost 4 million deaths. When BMI increases, most biological factors get worse, starting for a BMI of less than 21(Lamon-Fava). This includes increases in blood pressure, total cholesterol, LDL, TG and lower HDL. Other studies have found that insulin and IGF-1 increase with BMI. Higher levels of insulin and IGF-1 have been found to be inversely related to longevity. Also, APO-B increases with BMI and is related to a higher risk of heart disease. In addition, APO-A decreases with increasing BMI and this trend is associated with increasing heart disease.


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    1. On 2017 Jun 30, Pertti Hakkinen commented:

      The authors and readers might be interested in the following publications (these focused on research conducted in the United States):

      1) Neil, N., Slovic, P., and Hakkinen, P.J. 1993. Mapping consumer perceptions of risks. Chemical Manufacturers Association, Washington, D.C.

      2) Hakkinen, P.J. and Leep, C.J. 1996. Industry’s use of risk, values, perceptions, and ethics in decision making. In: Handbook for environmental risk decision making. Values, perceptions, & ethics. C.R Cothern, ed. CRC Lewis Publishers, Boca Raton, FL.

      This is an excerpt from the 1996 publication: “How can risk perceptions of chemical and consumer products be assessed? In 1993, the Chemical Manufacturers Association published a document based on research sponsored by P&G. This document demonstrates how consumer perceptions of risk can be quantified and examined, presents examples of consumer risk perception data for a wide range of consumer products, and discusses the importance of assessing and considering perceptions of risk as part of the development of a product. The 47 household chemical products covered in this document are shown in Table 2. Each of these products was evaluated for the 15 topic areas shown in Table 3.”


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    1. On 2016 Jul 05, Tom Kindlon commented:

      A (science) blogger has written about why he feels these results might be relevant to people with ME/Chronic Fatigue Syndrome* in this: "The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained?" http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/

      *The National Academy of Medicine (previously called Institute of Medicine) after reviewing the evidence suggested that Chronic Fatigue Syndrome be renamed Systemic exertion intolerance disease (SEID) last year.


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    1. On 2016 Aug 01, Gary Goldman commented:

      The study by Kawail et al demonstrates that HZ incidence has increased over a 60 year period from “0.76 per 1000 person-years (PY) (95% confidence interval [CI], .63–.89) in 1945–1949 to 3.15 per 1000 PY (95% CI, 3.04–3.26) in 2000–2007” with a 2.5% per year rate over the time period after adjusting for age and sex (adjusted incidence rate ratio, 1.025 [95% CI, 1.023–1.026]; P < .001). [1] The authors do not provide an explanation for this increase, yet state, “This increase is unlikely to be due to the introduction of varicella vaccination….”

      Unfortunately, Kawail et al do not report details of how widespread the uptake of varicella vaccine was in Olmstead County during 2000-2007. In fact, there were still substantial outbreaks of varicella during 2000 and 2001 (with a period of 9 months that the vaccine was unavailable). Minnesota did not require varicella vaccination for students entering kindergarten and 7th grade who lacked proof of having had chickenpox until 2004. In 1999, based on a CDC National Immunization Survey, varicella vaccine coverage was 61.6% among children aged 19-35 in Minnesota. [2] Approximately 50% of children aged less than 10 years must be vaccinated to effectively reduce exogenous boosting to initiate a noticeable increase in HZ incidence. Likely, only during 2003 through 2007 was varicella vaccination sufficiently widespread in Olmstead County to begin influencing (increasing) HZ incidence rates.

      It was first hypothesized by Hope-Simpson [3] that “The peculiar age distribution of zoster may in part reflect the frequency with which the different age groups encounter cases of varicella and because of the ensuing boost to their antibody protection have their attacks of zoster postponed” [3]. However, prior to 1999, only limited studies existed that supported this hypothesis. For example, in 1983, Arvin et al. noted a boost in cell-mediated immunity (CMI) in 71% of adults who were exposed to varicella patients in the family [4]. In 1995, Terada et al. reported that Japanese pediatricians aged 50–69 who received multiple VZV exposures, demonstrated HZ incidence rates one-half to one-eighth that of the general population [5]. Gershon et al. in 1996 showed an immunologic boost that reduced the risk of HZ among leukemic children by reexposure to VZV, either by vaccination or by close exposure to varicella [6]. A 1998 study by Solomon found that pediatricians who had a greater incidence of exposure to VZV had lower rates of HZ than psychiatrists who had the lowest VZV exposure rates [7]. More recent studies by Thomas et al. [8] and Salleras et al. [9] have also demonstrated that re-exposure to VZV via contacts with children was associated with reduction in the risk of HZ in adults. In more recent times, during the varicella vaccination era, additional studies, including those derived from the Antelope Valley Varicella Active Surveillance Project (VASP) in a community with widespread varicella vaccination, have emerged that have provided data that validates Hope-Simpson’s hypothesis. [10-12]. In support of the VASP trends [10-11] between 2000 and 2006, a more recent 2013 study by Guzzetta et al suggests that each episode of exposure to VZV increases protection against HZ and that ‘‘this mechanism may be critical in shaping HZ patterns’’. [12]

      Thus, while Kawail et al is unable to provide an explanation for the mean 2.5% annual increase in HZ incidence over six decades, one logical hypothesis for the increase is related to societal changes. Living conditions have gradually changed during the past six decades from multiple generations of families residing in a single household, to more independent living as children aged 18 years and over have increasingly moved out of their parent's home and elderly and sedentary individuals are placed in care facilities. Interesting, a Census Bureau reports, “In 2010, there were 40.3 million people aged 65 and above, comprising 13% of the overall population. (This total is 12 times the number it was in 1900, when this group constituted only 4.1% of the population.)” [13] Thus, due to changing trends in society structure and increases in the elderly population, parents and grandparents generally have fewer opportunities for exogenous boosting of their cell-mediated immunity due to reduced contact to children infected with varicella—giving rise to the steady increase in HZ incidence—especially in decades prior to the varicella vaccination era.

      In the Antelope Valley VASP, varicella vaccination was widespread in the community with approximately 50% of children aged <10 years vaccinated by 2000. By 2000, exogenous exposures to natural varicella (producing immunologic boosts) were dramatically reduced, especially after a marked decline in varicella seasonality in 1999. After 2 years of active HZ surveillance (2000 and 2001), the number of HZ case reports had maintained or increased in every adult age category except elderly adults aged 70 years and older. Using the paired t-test, there was a statistically significant (p < 0.042; t = 2.95, dF = 4) 28.5% increase in HZ case reports from 158 to 203 from 2000 to 2001 for the population aged 20–69 years. [10] Moreover, the 2007 VASP annual summary to the CDC presents data (not ascertainment corrected) demonstrating a statistically significant increase in HZ incidence rates, from 3.90 to 4.70 per 1,000 p-y in from 2006 to 2007 among adults aged 50 years and older. [11]

      Finally, there is a further worrying reason to suspect future increases in HZ incidence. When a child is administered the varicella (or Oka-) strain and then later is exposed to either a child with natural chickenpox or an adult with herpes zoster (almost always due to the reactivation of the natural or wild-type strain), the child harbors two similar but possibly sufficiently heterologous strains--that now are both subject to reactivation. This could potentially double the chances for the reactivation of herpes zoster, or at a minimum, at least increase the chances for reactivation of shingles relative to the pre-varicella vaccination era. [14]

      [1] Kawai K, 2016 [2] http://www.cdc.gov/vaccines/imz-managers/coverage/nis/child/index.html [3] HOPE-SIMPSON RE, 1965 [4] Arvin AM, 1983 [5] Terada K, 1995 [6] Gershon AA, 1996 [7] Solomon BA, 1998 [8] Thomas SL, 2002 [9] Salleras M, 2011 [10] Goldman GS, 2013 [11] Goldman GS, 2014 [12] Guzzetta G, 2013 [13] Raphel A. Trends and statistics relating to U.S. seniors, elderly: Census Bureau 2014 report. August 5, 2014. http://journalistsresource.org/studies/society/public-health/trends-statistics-relating-us-seniors-elderly-census-bureau-2014-report [last accessed 07/26/2016] [14] Weinmann S, 2013


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    1. On 2017 May 25, Cicely Saunders Institute Journal Club commented:

      This paper was discussed on 2.5.17, by students on the KCL Cicely Saunders Institute MSc in Palliative Care

      The paper explores the experiences of cleaning staff in a hospital setting on various wards. We thought it was a very interesting and thought-provoking topic which had not been examined in depth before. The study uses a mixed methods approach with qualitative interviewing and focus groups, followed by a questionnaire study for quantitative data.

      The study gives an interesting perspective of staff who have regular and prolonged contact with patients, but are little studied in this regard. It prompted discussion regarding the input that non clinical staff can give.

      Recruitment for the qualitative part was difficult leading to low numbers and saturation not being reached. The recruited participants were all female and many were non-native speaking.

      According to the COREQ criteria, we would have liked more information about who the researchers were, their relationship with the participants, the settings of the interviews and whether this could influence their responses.

      It would also have been beneficial to understand how the questionnaire was developed from the themes identified in the qualitative part of the study and of any attempt at validation etc. We were unclear if they meant to use this questionnaire for future research or service implementation, like for instance psychological support to "non-clinical" staff.

      We noticed the long time interval between the study taking place (questionnaires were distributed in 2008) and publication, and it would be useful to know the reasons behind this and if there was any follow up research in the intervening years.

      Future research would be interesting in other settings: for example in a hospice where patients die more frequently than various hospital areas or among other components of "non clinical" staff, as for instance secretaries or volunteers.

      Anna Oriani, Sarah Hanrott and Konstantina Chatziargyriou


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    1. On 2016 Nov 22, Alex Vasquez commented:

      Correspondence on this article has been published but as of 22 Nov 2016 (more than a month after publication on 19 Oct 2016) has not been appropriately linked; the citation is as follows: Vasquez A. Correspondence regarding Cutshall, Bergstrom, Kalish's "Evaluation of a functional medicine approach to treating fatigue, stress, and digestive issues in women.” Complement Ther Clin Pract. 2016 Oct 19 doi: 10.1016/j.ctcp.2016.10.001 http://www.ctcpjournal.com/article/S1744-3881(16)30107-4/abstract

      Critiques of this article are described in the following paragraphs.

      1. Description of treatments: The authors state that treatments were “personalized” but provide little data on how or why the treatment was allocated other than to divide patients into two groups for the “adrenal protocols” which are faintly outlined in the footnotes; no dosages are provided as all of the product formulations appear to be proprietary. Table 1 which outlines the “adrenal protocols” shows the treatments to be remarkably similar between the high and low salivary cortisol groups. The authors administered “DHEA drops” and “pregnenolone drops” but the varying dosages of the hormones, administered three times each per day, are not provided. Authors need to provide the actual dosages of all treatments, including hormones.

      2. Use of hormonal therapy: The authors need to have described the laboratory methodology. Salivary DHEA levels were found to increase, decrease, and change unreliably, thus rendering these results worthless. Table 5 of the results shows that Cortisol/DHEA ratio started at 5.2 and resulted at 12 at the end of the study. Consistently throughout the medical literature, respectively higher levels of cortisol and lower levels of DHEA are causatively associated with insulin resistance, intra-abdominal obesity, hippocampal atrophy, and bone loss[1,2]; to the contrary of the bulk of the peer-reviewed literature, these authors present these results as beneficial changes. The “DHEA drops” and “pregnenolone drops” are not described either in dosage or formulation. Pregnenolone and DHEA are mood-elevating neurosteroids[3-5]. DHEA administration raises androgens and estrogens[6] which promote cancers[7,8]. The authors should have described appropriate serologic and clinical follow-up, risk considerations, and limits to duration of treatment. By failing to describe the dose of the steroid hormones used, the authors present that these hormones can be used without regard to dosage or duration; this presents a potential hazard by modeling unsafe use.

      3. Accurate description of functional medicine: The authors define functional medicine as “The functional medicine model is focused on restoring optimal functioning of 3 body systems: hormonal, digestive, and detoxification.” The authors’ sweeping statement “Restoring these 3 body systems has positive effects on stress, energy, fatigue, digestive issues, and quality of life” has no citations. The definition of functional medicine provided by these authors is discordant with more authoritative descriptions published by the Institute for Functional Medicine[9] and International College of Human Nutrition and Functional Medicine.[10] The authors use the terminology “adrenal and digestive cleanse protocols” without definition, justification, or citation. In scientific publications, unique statements require substantiation and citation.

      4. Controlling for external influences: The authors describe the dates of the study as “September 2014 through April 2015” but did not control for vitamin D levels and sunlight exposure which are known to affect mood and cognition[11,12]. The severity of depression, pain, and “functional disorders” has been reported to vary seasonally with exacerbations in fall and winter and alleviation in spring and summer.[13,14] The “lifestyle and nutritional counseling” included a 1-hour in-person coaching session at the start of the study, followed by various telephone contacts and “online group sessions” including “nutrition coaching and follow-up with diet compliance.” Patients may have felt better simply as a result of season change or social contact.

      5. Disclosure of commercial interests: The authors deny conflict of interest and that “The study sponsors had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.” However, the authors do not disclose the identity of the sponsors. One of the authors (Kalish) is a consultant/speaker for a large distributor of nutritional supplements[15] and also a consultant/speaker/endorser of the laboratory used in this study[16]; these relationships are not disclosed in the article. According to the authors' interview[17] and press release[18] regarding their publication, they provide "training in functional medicine" and seminars related to the treatments used in this study. The authors fail to provide the identity of the study sponsors and the nature of the conflict(s) of interest.

      6. Fecal microbiologic testing; antimicrobial treatments: The authors fail to detail the laboratory methodology for the microbiologic testing. Per the footnote describing the mastic product, the authors do not clearly describe the identity nor the ingredients of this treatment.

      7. This clinical trial was not registered: The authors make no mention of having registered this clinical trial, and no record of the trial is available at https://clinicaltrials.gov/.

      While the functional medicine approach to healthcare is science-based, eclectic, and effective[19], the field is not benefited by poorly conducted research, especially that which does not accurately reflect the practice, which employs poor methodology, and/or which uses steroid hormones without appropriate risk/benefit considerations. This publication is not an accurate representation of the clinical practice of functional medicine. The study design and description present several errors, the methods are not reproducible, the treatments were not sufficiency described, and the study cannot be either validated or refuted scientifically due to design flaws and/or inadequate description of treatments.

      [1] Brown et al. Biol Psychiatry. 2004 Jan 1;55:1-9 [2] Ferrari et al. Eur J Endocrinol. 2001 Apr;144:319-29 [3] Brown et al. Neuropsychopharmacology. 2014 Nov;39:2867-73 [4] Fung et al. J Autism Dev Disord. 2014 Nov;44:2971-7 [5] Gaby AR. Alt Med Rev 1996;1:60-69 [6] Arlt et al. J Clin Endocrinol Metab. 1999 Jun;84:2170-6 [7] Folkerd E, Dowsett M. Breast. 2013 Aug;22 Suppl 2:S38-43 [8] Stoll BA. Eur J Clin Nutr. 1999 Oct;53:771-5 [9] Vasquez A. Reprint from Textbook of Functional Medicine: Web-like interconnections of physiological factors. Integrative Medicine 2006 April;5:32-37 [10] Vasquez A. Textbook of Clinical Nutrition and Functional Medicine. ICHNFM.ORG; 2016:134-146 [11] Kent et al. Environ Health. 2009 Jul 28;8:34 [12] Vieth et al. Nutr J. 2004 Jul 19;3:8 [13] Schlager et al. Compr Psychiatry. 1995 Jan-Feb;36:18-24 [14] Schlager et al. Br J Psychiatry. 1993 Sep;163:322-6 [15] emersonecologics.com/drkalish and emersonecologics.com/Webinars-DrKalish. June 10, 2016 [16] "BioHealth Adrenal Testing – Dan Kalish", "Premenopause Hormone Profiles: In Brief – Dan Kalish", and "Functional Lab Testing – Dan Kalish". biohealthlab.com/multimedia-archive/. June 17, 2016. [17] Functional Medicine Plan Treats Fatigue, Stress and Digestive Issues in Women. medicalresearch.com/author-interviews/functional-medicine-plan-treats-fatigue-stress-and-digestive-issues-in-women/25012. June 23, 2016. [18] Research Conducted with Mayo Clinic Practitioners and Kalish Institute Confirms Efficacy of Functional Medicine. businesswire.com/news/home/20160524005553/en/ June 23, 2016. [19] Vasquez A. Inflammation Mastery, 4th Edition. http://www.ICHNFM.ORG 2016 Dr Vasquez, Director ICHNFM and Consultant to Biotics Research


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    1. On 2016 Jun 17, Lydia Maniatis commented:

      (This is a response to the abstract only). The authors conclude that perception of distance ratios is relatively accurate, but this result is purely contingent on the stimuli. Perception of relative distances can be more or less accurate. The outcome depends strictly on the structure of the retinal stimulus and the rules of organisation built into the visual system. By choosing a particular physical stimulus to project to the retina, the authors produced relatively accurate outcomes; by choosing a different one, they could have produced very different outcomes. Pictorial images, for example, can obviously produce very inaccurate perception of relative distances. Unless the authors explicitly discuss the relationship between the structure of the environment and the structure of the retinal projection, they haven't added anything to the conversation.


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    1. On 2016 Jul 27, Duke RNA Biology Journal Club commented:

      This is a summary of a journal club discussion:

      This is one of four articles using similar imaging techniques to study translation in living cells published at the same time. These publications add to the growing number of techniques used to image translation such as mature fluorescent proteins Yu J, 2006, TRICK Halstead JM, 2015, and RNA-binding protein/mRNA co-fluorescence Wu B, 2015. The technique presented in this article is similar to the last except that it uses Suntag to image the nascent chain and PP7 aptamers on the mRNA. The colocalization of the two represents active translation in polysomes.

      The technique is novel because co-localization is detected as the protein is translated. This brings fluorescent V4-peptide antibodies into concentrated foci at a single point, and can thus be used to follow multiple rounds of translation. Because of this, only detection of the translated protein is needed and indeed, past the first figure, the mRNA fluorescence is not shown. Fast changes in translation can be detected as shown using the ATF4 ORF construct translational response to stress shown in Figure 4 with the possibility of extending the time of tracking to hours by anchoring the mRNA Yan X, 2016 or using fast 3D imaging techniques. One unusual observation the authors made was the vast heterogeneity of transcript translation within a single cell; at any given time only a subset of the transcripts undergo translation and translation rates may vary depending on as yet unknown factors. A related observation is the diffusion of polysomes within the cell: polysomes translating cytosolic transcripts have slower diffusion rates in the perinuclear region of the cell compared to the cytoplasm. This could be due to the restrictive architecture of a membranous area but the exact mechanism remains unknown. A second surprising observation indicates mRNAs that have begun translation and are associated with polysomes can be transported in dendrites, contrary to earlier reports Besse F, 2008. However, the authors cannot detect if translation is temporarily stalled during transport.

      While this technique makes substantial findings in the area of single transcript translation behavior, there are limitations. All in all, these images are dots that respond to translation inhibitors, meaning the resolution is not good enough to detect codon resolution and should be coupled with other techniques to verify observations and determine their mechanism. Additionally, since detection of the nascent chain wouldn’t be detected until the majority of the V4 peptides were translated, initiation would be overlooked; however, TRICK is an existing technique for studying the first round of translation.Our main criticism with this technique is the extensive construct engineering that must be performed which raises concerns over disturbing the mRNA and protein functions from both the PP7 aptamers, the Suntag peptides and an ornithine decarboxylase tag to facilitate rapid degradation of the protein. These engineering steps add over 2 kb to the original gene. Additionally, an antibody against the Suntag and a fluorescent PP7 coat protein must be expressed in the cytosol. While the constructs studied did not cause harm to the cell, each construct of interest must be tested individually. Along this line, while there is the possibility to multiplex by changing the aptamer loop or peptide-antibody combination, it would be difficult to multiplex above two individual transcripts. Thus large-scale studies involving individual translation dynamics of mRNA subsets would remain time consuming and technically challenging.

      A quick comparison with the three other papers show agreements among all of them Iwasaki S, 2016 however, there is a great opportunity to learn by reading the papers to compare experimental approaches of three groups. We look forward to see what novel findings this technique uncovers as it becomes adopted in different laboratories.


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    1. On 2016 Jun 22, Lydia Maniatis commented:

      Reading the title of this article, one might get the idea that we learn the 3D structure of objects from 2D views. Looking at it a little more closely, we might experience some confusion as to the distinction being made between “structure” and “shape.” Isn't it a little tautological to say that grasping structure depends on grasping shape? And what do they mean by “format”?

      In fact, the idea that we learn 3D structure from 2D views, which the authors want us to take for granted, is false. But isn't it the case that “a large body of research shows that viewpoint-invariant recognition is learned by viewing 2-D examples of an object (Bulthoff, Edelman, & Tarr, 1995; Hayward & Tarr, 1997; Tarr, Williams, Hayward & Gauthier, 1998)”? In fact, the references cited in no way support this bold claim. One of them is irrelevant, and the other two make claims that are highly qualified, tentative, and in need of corroboration. Given that nothing more definite seems to have developed in the two decades or so since these hopeful publications, the relevant body of research seems neither large nor solid. Another claim is also unsupported by its accompanying citation: “It is thought that during learning people use structural information in the 2-D image to infer the 3-D structure of the object (Nakayama, Shimojo, & Silverman, 1989).” In fact, the cited article addresses issues of figure ground segmentation, and not 3-D shape. Its text doesn't even include the terms 3-D, structure, or shape. So the authors are giving readers a false impression that their project is on empirically solid ground.

      In fact, the claim that 3-D structure is learned from 2-D views has long been known to be false on logical and empirical grounds. In a more general sense, the idea that we either can or do learn to perceive in 3-D from 2-D experience is not defensible. No one has to learn to see 3-D objects; it happens automatically. “Newborns can recognize...the same rectangle placed at different slants.” (http://nwkpsych.rutgers.edu/~alan/Gilchrist_NN_2003.pdf). Individual 2D views produce 3D percepts; these percepts may or may not be veridical, but knowledge does not affect the basic process. Each view entails its own necessary 3D perceptual response based on shape rules that assume characteristics such as convexity. View “x” will not produce a different shape percept even if we know the one we see is false, just as a 3D-looking flat image does not look flat even though we know it is. We can't learn to see a Necker cube as flat, from no matter how many angles we inspect it.

      The idea that we learn 3-D structure also fails for logical reasons. How does a collection of 2D images, a pack of flat cards, in effect, become a - qualitatively different - 3D percept? On what basis is this conversion made? Is each new sample - of the infinite number of possible samples - a new piece of information? Multiple 2D views don't resolve the fundamental ambiguity of the projection/3D percept relationship. The Ames window is not correctly seen despite a complete set of views around an axis. Shape ambiguity is resolved on the basis of rules of organization, not on the basis of collecting ever new views which are themselves ambiguous. (Even when we know a shape is unchanging, the necessary link between individual views and 3D percepts can produce a changing percept, e.g. https://www.youtube.com/watch?v=jRqYkQz0G-g). Furthermore, how or when does the visual system draw the conclusion that a series of projections, such as are shown to subjects in the task chosen by these authors, are projections of the same single and unchanging 3D shape?

      Don't the study's subjects exhibit learning of 3D structure form 2D views? If they did it would be a kind of miracle, but the results don't require us to believe in miracles. Subjects' (rather poor) performance in no way requires that their exposure to a series of views of a very strangely-shaped object produce a consistent, learned, 3D percept. Memory for details can do the trick (a single sharper angle, for example, in one of two objects to be discriminated can allow them to eliminate it without having grasped the whole or even part of the 3D shape). And a lot of the time they are just guessing.

      A final thing that should be clear to researchers with some knowledge of perceptual phenomena is that the results of this task are totally contingent on the shapes used. The authors here crudely divide objects into novel and familiar. But whether projections of a single, novel object consistently produce the same 3D percept (which, as we saw, applies to some objects viewed by infants) depends on the shape of the object. There is no absolute expectation of constancy. Different, more rational (as far as the expectations of the visual system) shapes would have produced better outcomes than the random ones used here; others may have produced worse. The numbers here are meaningless because the authors haven't analyzed the role of shape.

      As for the finding with regard to “format,” it is well-known that both line drawings and chiaroscuro drawings can both produce good 3D shape percepts, and that silhouettes tend to look flat, lacking any indication of relief. If the results of this study had not borne this out, these facts would have remained intact.

      In sum, the results of this study can be interpreted as consistent with a false (on the basis of logic and experiment) premise because the task was not designed to distinguish between this (im)possibility and more plausible (and theoretically uninteresting) alternatives.

      It would be nice if people doing research in perception spent a little time actually learning the basics.

      p.s. In their discussion, Tian et al: "suggest that stereo provides a behavioral benefit only if it resolves ambiguity in the interpretation of the 3-D structure of objects that cannot be resolved from other sources of information."

      This is very similar to the titular claim of an earlier article by Pizlo, Li, Steinman (2008): "Binocular disparity only comes into play when everything else fails; a finding with broader implications than one might suppose."


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    1. On 2016 Sep 15, Kelly Drew commented:

      Thank you for this comprehensive contribution to our understanding of pre-hibernation remodeling in the Syrian hamster. Our studies in the arctic ground squirrel suggest that pre-hibernation remodeling and torpor onset involves increased sensitivity of A1 adenosine receptors with a subsequent inhibition of thermogenesis. See Olson et al., Circannual rhythm in body temperature, torpor, and sensitivity to A₁ adenosine receptor agonist in arctic ground squirrels. J Biol Rhythms. 2013 Jun;28(3):201-7. doi: 10.1177/0748730413490667. PubMed PMID: 23735499; PubMed Central PMCID: PMC4423736.

      and Jinka et al., 2011 Season primes the brain in an arctic hibernator to facilitate entrance into torpor mediated by adenosine A(1) receptors. J Neurosci. 2011 Jul 27;31(30):10752-8. doi: 10.1523/JNEUROSCI.1240-11.2011. PubMed PMID: 21795527; PubMed Central PMCID: PMC3325781.


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    1. On 2017 Aug 25, Robert Badgett commented:

      The website referred to in this letter for calculating the time in therapeutic range for the population of patents at a clinical site is http://qitools.github.io/


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    1. On 2016 May 13, thomas samaras commented:

      This study certainly refutes the earlier studies reporting that some overweight was healthy. The World Cancer Research Fund Report (2007)recommended a BMI as low as possible within the normal range of 18.4-24.9. Fontana and Hu (2014) recommended a BMI of 20-21. Also, Hosegood found the optimum BMI for women in S. Asia was about 18.5-19.5. In addition, there are many biological parameters that become worse with increasing BMI from the low end of the BMI range. A few are listed below. Most involve undesirable increases in levels of the following parameters: Homocysteine, C-Reactive Protein, Sex Hormone Binding Globulin (higher is better), left ventricular mass, blood pressure, adiponectin (higher is better), mTOR, total cholesterol, low-density lipoprotein, high-density lipoprotein (higher is better), IGF-1, insulin, glucose, ApoB, and ApoA-1 (higher is better).

      All of these have been found to increase mortality due to one or more of these causes: CVD, cancer, type 2 diabetes and all-cause mortality. Therefore, it is hard to see how higher levels of BMI have health benefits with the exception of special cases, such as frail, elderly people who lack adequate nutrition, suffer from digestive problems or have a chronic illness.


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    1. On 2016 Jun 26, David Smith commented:

      All statistical maps derived from the re-analysis with GingerALE 2.3.6 have been uploaded to the NeuroVault repository: http://neurovault.org/collections/1406/

      We emphasize that the re-analysis confirmed that all of our key claims are valid.


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    2. On 2016 Jul 22, Christopher Tench commented:

      Excellent. This is science!


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    3. On 2016 Jun 24, David Smith commented:

      Thanks for pointing this out. Our original analyses used a conservative threshold, and we have confirmed that our key results hold with a cluster-level FWE of p = 0.05, as implemented in the latest release of GingerALE (v2.3.6).

      Within the main text, two clusters failed to replicate in our new analyses. First, the inferior lateral occipital cortex (iLOC) cluster in Figure 3C (amygdala seed with emotion studies) did not pass cluster-level FWE of p = 0.05 (with a cluster-forming thresholds of p = 0.001 or p = 0.005). Second, the dorsolateral prefrontal cortex (DLPFC) cluster in Figure 3B (DLPFC seed with cognitive control studies) did not pass cluster-level FWE of p = 0.05 (with a cluster-forming thresholds of p = 0.001 or p = 0.005). Additionally, our re-analyses failed to confirm the findings in Supplemental Figure 2.

      We will reach out to the journal (HBM) to address these issues and indicate that our key claims were not affected by the bug in GingerALE (which was corrected after our article was accepted).

      Thanks again for bringing this to our attention.


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    4. On 2016 Jun 14, Christopher Tench commented:

      This article uses a version of GingerALE (2.3.3) that has a known bug, which produces false positive results. The bug was fixed at 2.3.6. There is no evidence of statistical significance.


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    1. On 2016 Jun 21, Andrew W Swartz commented:

      Based upon post hoc questionnaire analysis, Shoag et al. claim that the PLCO was confounded by more prostate cancer (PCa) screening in the control group than in the intervention group. This seems highly unlikely because it is incompatible with other more objective outcomes of this trial.

      First, the cumulative incidence plots for PCa [1,2] are consistent with comparison of a screened group to an unscreened (or at least less screened) group. During the first four years of screening the intervention group was diagnosed with PCa at a rate 48% greater than the control group [2]. Then, after the intervention period, the rate of prostate cancer diagnosis in the intervention group drops to that of the control group and the lines go parallel, implying similar screening exposure from that point forward. These are the expected plot shapes for screening with overdiagnosis. The Shoag et al. claim directly implies that the group with the overdiagnosis (the intervention group) was the LEAST screened. This seems implausible, as it would be contrary to all screening theory and experience.

      Second, the Shoag et al. claim is also incompatible with the previously reported tumor stage-shifting. The intervention group had more favorable staging than the control group [1,3]. Though the magnitude of this effect is smaller in the PLCO than other PCa screening trials, the direction still favors the intervention group. It is highly unlikely that the intervention group would have better tumor staging if the control group had more screening.

      The overdiagnosis and tumor stage-shifting are objectively measured outcomes which indicate that there was more screening in the intervention group than the control group. Therefore Shoag et al. have more likely discovered a bias in the questionnaire answers [4,5] than a flaw in the PLCO. We should also consider the possibility that this is simply the product of the “researcher degrees of freedom” which inherently accompany reanalyses[6].

      Andrew W. Swartz MD, Emergency and Family Medicine, Yukon-Kuskokwim Health Corporation, Bethel, Alaska

      1] Andriole G, Grubb R, Buys S, Chia D, Church T, Fouad M, et al. Mortality results from a randomized prostate-cancer screening trial. New England Journal of Medicine. 2009;360:1310–9. Andriole GL, 2009 Full Text

      2] Andriole GL, Crawford DE, et al. Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up. J Natl Cancer Inst. 2012;104:125–132. Andriole GL, 2012 Full Text

      3] Ilic D, Neuberger MM, Djulbegovic M, Dahm P. Screening for prostate cancer. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD004720. DOI: 10.1002/14651858.CD004720.pub3. Ilic D, 2013

      4] Hebert JR, Clemow L, Pbert L, Ockene IS, Ockene JK. Social desirability bias in dietary self-report may compromise the validity of dietary intake measures. Int J Epidemiol. 1995;24(2):389-98. Hebert JR, 1995

      5] Adams SA, Matthews CE, Ebbeling CB, et al. The Effect of Social Desirability and Social Approval on Self-Reports of Physical Activity. Am J Epidemiol. 2005;161(4):389-98. doi:10.1093/aje/kwi054. Adams SA, 2005 Full Text

      6] Christakis DA, Zimmerman FJ. Rethinking reanalysis. JAMA. 2013;310(23):2499-500. doi: 10.1001/jama.2013.281337. Christakis DA, 2013


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    1. On 2016 Jul 17, Lise Bankir commented:

      Thank you Dr Pontzer for these interesting comments.

      I apologize for saying that you forgot "cooking" since you had indeed mentioned it, briefly. I may have put too much emphasis on cooking.

      Actually, I was very impressed by this brillant TED conference. But I am not a specialist of metabolism and energy needs, and I probably did not appreciate well the relative importance of different factors.


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    2. On 2016 Jul 05, Herman Pontzer commented:

      Thank you for the comment. We haven't forgotten about the importance of cooking: we include it among the critical human adaptations that make more energy available (reference 25, Carmody et al. 2011). In the penultimate paragraph of the main text, we write:

      "...the adoption of cooking<sup>25</sup> ... effectively increase[s] the net energy gained from foraging, and may have had an essential role in the evolutionary expansion of the hominin energy budget."

      However, as we discuss in the paper, increased food energy intake is necessary but not sufficient in accounting for the suite of metabolically costly human traits. To take advantage of the extra calories from cooking (or from other dietary changes that increase the mean calories/gram of food) requires evolved physiological changes to increase the metabolic rate. Previously, the prevailing view of metabolic evolution in humans (and other mammals) assumed that metabolic rates were similar across the hominoids, with no difference in calories/day (accounting for size) across humans and other apes. Our paper shows that humans have undergone an evolutionary increase in metabolic rate that accounts for the (estimated) extra caloric expenditure on brains, reproduction, etc. It will be interesting, in future analyses, to begin parsing the contributions from cooking, dietary changes, and other adaptations to the evolution of human metabolic rate.


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    3. On 2016 Jun 24, Lise Bankir commented:

      In this interesting paper, the authors explore the mechanisms by which the human lineage has experienced an acceleration in metabolic rate, providing energy for larger brains. I think they forgot an important aspect of human evolution, that is the benefit of COOKING our food. This made food nutrients much more efficient and allowed a better energy supply to our body at a lesser cost. This is very well explained in a TED conference entitled "What is special in the human brain?" by Suzana Herculano-Houzel. Here is the link.

      www.ted.com/talks/suzana_herculano_houzel_what_is_so_special_about_the_human_brain.html?utm_medium=on.ted.com-static&utm_campaign=&utm_content=awesm-publisher&utm_source=t.co&awesm=on.ted.com_BrainSoup


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    1. On 2016 Aug 10, Joaquim Radua commented:

      Re: the previous comments, please note that under the null hypothesis of no differences between groups, only 1 out of 20 studies should show differences between groups, which is absolutely not the case when randomizing coordinates or blocks of voxels. Random coordinates and similar approaches, which randomize the location of the findings rather than the individuals between groups, are not a valid way to exactly test this hypothesis. Rather, they are only used to yield approximated p-values that, appropriately thresholded, return a map similar but slightly more conservative than that of FWE-corrected p-values in mega-analyses. Voxel-based meta-analytic methods are young and there is room for improvement, but they are based on evidence.


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    2. On 2016 Aug 09, Christopher Tench commented:

      This is not a result of confusion, but of the definition of statistical inference. Uncorrected p-values do not control the type 1 error rate. A meta-analysis is performed to improve estimates, and is a statistical problem demanding statistical methods. To threshold at an arbitrary p-value controls neither the FDR nor the FWE, so no quantitative evidence that the results are critical of the null hypothesis is available. You cant know if the results are true positives without doing the full experiment, but meta-analysis is used for the case where the full experiment (mega analysis) has not been done. The one, and only, thing that can be done is to make sure that the null hypothesis is appropriately rejected; arguably the whole point of statistical inference. That requires either FWE or FDR control. Using just random coordinates and an uncorrected p-value will produce results that are apparently publishable, but obviously incorrect. Without any estimate of error rate, there is no quantifiable evidence that the results are meaningful.


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    3. On 2016 Aug 01, Joaquim Radua commented:

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


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    4. On 2016 Jun 13, Christopher Tench commented:

      The methods employed provide no control over the type 1 error rate. There is no evidence that the results are statistically significant.


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    1. On 2017 Jun 12, Xue-hai Liang commented:

      The sequence data related to this paper has been deposited to GEO, with the accession number: GSE99658.


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    1. On 2017 Feb 01, Martine Crasnier-Mednansky commented:

      It is astounding that the authors totally ignore the specific effects of cAMP on the lag phase of the glucose-lactose diauxie. Not only does addition of cAMP eliminate the diauxic lag, it also clearly impairs growth on glucose (see figure 1 in Ullmann A, 1968). An increased level of cAMP triggers a 'leaky' expression of CRP-cAMP-dependent genes and operons (including the lactose operon) thereby affecting growth on glucose. Leaky expression of genes reduces fitness in glucose, with a trade-off for a shorter diauxic lag (or, as in figure 1 mentioned above, a complete elimination of the lag phase resulting in biphasic growth). In the Escherichi coli glucose-lactose diauxie, there is a correlation between the cAMP level and the cost-benefit trade-off.


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    1. On 2017 Jun 27, Seán Turner commented:

      According to the JCM web site, the type strain of Lutibacter profundi is JCM 30586. Strain JCM 30585 is the type strain of "Mariprofundus micogutta" Makita et al. 2017 [PubMed Id 27766355].


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    1. On 2016 May 01, Daniel Tsin commented:

      We performed appendectomies using a suprapubic port when the vaginal port access was not feasible in : Tsin DA, Colombero LT, Mahmood D, Padouvas J, Manolas P. Operative culdolaparoscopy: a new approach combining operative culdoscopy and minilaparoscopy.J Am Assoc Gynecol Laparosc. 2001 Aug;8(3):438-41. PMID 11509789

      We later did a small series of 4 appendectomies and 7 cholecystectomies. http://www.slideshare.net/tsin/minilaparoscopy-as-an-alternative-to-natural-orifice-surgery-7832507


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    1. On 2016 Apr 28, Donald Forsdyke commented:

      RNAS ENCODING HBZ AND EBNA1 PROTEINS ARE BOTH PURINE-LOADED

      The sensitive quantification of HBZ protein levels in various clinical conditions (1) is a major advance. Unlike other HTLV1 proteins, the latency-controlling HBZ protein is encoded by the antisense strand. Thus, whereas the main-gene-encoding ‘top’ strand of the latent virus is pyrimidine-rich, the complementary, ‘bottom,’ strand that encodes HBZ is purine-rich. Likewise, most genes in Epstein-Barr virus are encoded by pyrimidine-rich strands, but the latency-controlling EBNA1 protein is encoded by a purine-rich strand.

      The speculation that this purine-loading militates against the formation of double-stranded RNA and hence dampens the host immune response (2) is in keeping with:

      (a) the “extremely low expression and immunogenicity of HBZ in natural HTLV-1 infection,”

      (b) the possibility that “the most important actions of HBZ, which are critical to HTLV-1 persistence, are exerted at the RNA level, and not the protein level,” and

      (c) the view that “minimized HBZ protein translation is a sophisticated viral strategy for evasion from the host T cell response.”

      (1) Shiohama et al. (2016) Retrovirology 13:29 Shiohama Y, 2016

      (2) Forsdyke DR (2014) Microbes and Infection 16, 96-103 Forsdyke DR, 2014


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    1. On 2017 Jul 03, P Jesper Sjöström commented:

      Thanks for your interest in our work. I would like to make the following points:

      1. We did not actually say 'no connections in mature cortex' -- that quote is certainly not lifted from Mizusaki et al Nat Neurosci 2016. We said "In fact, it was recently reported that, surprisingly, pyramidal cells in visual cortex of mature animals do not seem to interconnect at all, neither bidirectionally nor unidirectionally12," where 12 refers to Jiang et al. We thus say that Jiang et al report that PCs do not seem to interconnect, we do not say that there are no PC-PC connections in mature cortex. What Jiang et al state and what our opinion about that statement is, those are different things.

      2. The intention of that passage in Mizusaki et al is to point out that Brunel is using my data from Song et al as a gold standard, but this may or may not be appropriate, since my connectivity data was acquired from a developmental snapshot in time (just after eye opening, typically postnatal day 14-16), whereas Brunel is in fact focussing on the functioning of the mature brain, when circuits are wired up. Our intention was thus to acknowledge that my own data need not be the ground truth, and this has important implications for the validity of the Brunel study. The Tolias study provides an alternative view: "the most compelling and consistent difference across experiments is the age of the animals tested, suggesting that mature cortical circuits are not identical to developing circuits." Such a developmental difference would important in the context of the Brunel study. Again, this is not necessarily my opinion, but as scientists, we have to acknowledge this possibility.

      3. In the Tolias study, they report in Fig S14 that they found precisely zero L5 PC-PC connections even after 150 attempts, which is in stark contrast to my connectivity data presented in Song et al. Indeed, if you do a Chi-squared test for 931/8050 versus 0/150, you will find that this is a highly significant difference. We can debate the accuracy of the Tolias measurement (like they do in Barth et al Science 2016 353:1108, as you point out), but if we do so, we should also debate the accuracy of my measurements in juveniles, as presented in Song et al. While it is true that my data in Song et al is more in line with e.g. Thomson et al Cereb Cortex 2002 than with Jiang et al, the key point in the context of Brunel's theoretical study is that the ground truth is not necessarily well established.

      In summary, I certainly believe in my own connectivity data set, and I think Brunel's study provides a very compelling theoretical framework for explaining such connectivity patterns, but I feel obliged to point out a few possible caveats associated with my connectivity data set. Jiang et al provide one such key caveat. I hope this clarifies somewhat.


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    2. On 2017 Jun 27, Gabriele Scheler commented:

      There is a technical comment from Barthetal2016 in Science which sums this up, and gives more detail as to why the connectivity in Xiangetal2015 is underestimated.


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    3. On 2017 Jun 27, Gabriele Scheler commented:

      Very surprisingly, Mizusaki etal report: " In fact, it was recently reported that, surprisingly, pyramidal cells in visual cortex of mature animals do not seem to interconnect at all, neither bidirectionally nor unidirectionally (12)." The reference (12) is to Xiangetal2015, where they state: "Finally, the connectivity among mature pyramidal neurons, particularly among L5 pyramidal neurons, was much lower than the connectivity among pyramidal neurons within the same range of intersoma distance in juvenile slices [figs. S13B (average, 91 ± 4μm) and S14 and supplementary text]". The percentages noted in the table S14 range from 4,8% to 0% for ~150 connections tested. Quite clearly, the percentages are low, but to summarize this as 'no connections in mature cortex' does not seem to be adequate. Note that the number of connections tested is not very high and that "evoking unitary excitatory or inhibitory postsynaptic potentials [uE(I)PSPs] on postsynaptic neurons with brief depolarizing current pulses applied in presynaptic neurons" may not be sufficient to map all synaptic connections.


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    1. On 2017 Sep 08, Youhe Gao commented:

      A strategy named 4F-acts was proposed a few years ago trying to minimize false positives and false negatives. Fast Fixation is necessary to study real-time protein-protein interactions under physiological conditions. Fast formaldehyde crosslinking can fix transient and weak protein interactions. With brief exposure to a high concentration of formaldehyde during the crosslinking, the complex is crosslinked only partially, so that the complex is small enough to be resolved by SDS-PAGE, and the uncrosslinked parts of the proteins can be used for identification by shotgun proteomics. Immunoaffinity purification can Fish out complexes that include the proteins of interest. Because the complex is covalently bound, it can be washed as harshly as the antibody-antigen reaction can stand; the weak interactions will remain. Even if the nonspecific binding can persist on the beads or antibody, it will be eliminated at the next step. To Filter out these complexes, SDS-PAGE is used to disrupt non-covalent bonds, thereby eliminating uncrosslinked complexes and simultaneously providing molecular weight information for identification of the complex. The SDS-polyacrylamide gel can then be sliced on the basis of the molecular weight without staining. All the protein complexes can be identified with the sensitivity of mass spectrometry rather than sensitivity of the staining method. The advantages are the following: (i) The method does not involve tagging. (ii) It does not include overexpression. (iii) A weak interaction can be detected because the complexes can be washed as hard as the antigen-antibody reaction can stand as the complexes are crosslinked covalently. No new covalent bond can form as a false positive result. (iv) The formaldehyde crosslinking can be performed at the cellular, tissue, or organ level fast enough so that the protein complexes are fixed in situ in real time. Proteome Science 2014, 12:6 doi:10.1186/1477-5956-12-6


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    1. On 2016 Jun 19, Lukas Marti commented:

      We thank Dr. Stanley Goldberg for pointing out, that we do not include in our PSP operation a levatorplasty. We therefore do not as he calls it "tackle the perineal hernia". It might be that adding a levatorplasty to perineal procedures as Rehn-Delorms, Altemeier's sigmoidectomy and the described PSP, lowers recurrence rate. But there is no randomized controlled trial to prove that. On the other hand adding a levatorplasty would make the procedure more complex and therefore it would become probably more prone to complications, something we want to avoid in the very frail patients to which we offer a PSP operation.


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    2. On 2016 Jun 01, Dr, Stanley Goldberg commented:

      This operation does nothing for the perineal hernia which should be attacked in a perineal operation.


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    1. On 2016 Aug 10, Joaquim Radua commented:

      Re: the previous comments, please note that under the null hypothesis of no differences between groups, only 1 out of 20 studies should show differences between groups, which is absolutely not the case when randomizing coordinates or blocks of voxels. Random coordinates and similar approaches, which randomize the location of the findings rather than the individuals between groups, are not a valid way to exactly test this hypothesis. Rather, they are only used to yield approximated p-values that, appropriately thresholded, return a map similar but slightly more conservative than that of FWE-corrected p-values in mega-analyses. Voxel-based meta-analytic methods are young and there is room for improvement, but they are based on evidence.


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    2. On 2016 Aug 09, Christopher Tench commented:

      This is not a result of confusion, but of the definition of statistical inference. Uncorrected p-values do not control the type 1 error rate. A meta-analysis is performed to improve estimates, and is a statistical problem demanding statistical methods. To threshold at an arbitrary p-value controls neither the FDR nor the FWE, so no quantitative evidence that the results are critical of the null hypothesis is available. You cant know if the results are true positives without doing the full experiment, but meta-analysis is used for the case where the full experiment (mega analysis) has not been done. The one, and only, thing that can be done is to make sure that the null hypothesis is appropriately rejected; arguably the whole point of statistical inference. That requires either FWE or FDR control. Using just random coordinates and an uncorrected p-value will produce results that are apparently publishable, but obviously incorrect. Without any estimate of error rate, there is no quantifiable evidence that the results are meaningful.


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    3. On 2016 Aug 01, Joaquim Radua commented:

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


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    4. On 2016 Jun 14, Christopher Tench commented:

      The method employed here offers no protection against type 1 error rate. It cant be considered a meta-analysis. Uncorrected p-values provide no evidence of statistical significance when large numbers of voxel-wise tests are performed.


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    1. On 2017 Jul 19, David Mage commented:

      The authors have done a thorough survey of the sudden unexpected infant death (SUID) investigations in several U.S. states. They report on the autopsy and death scene investigations (DSI) of the case infants performed to determine which if any of the three conditions considered to form SUID may be involved: [ICD-10 sudden infant death syndrome (SIDS R95); unknown causes (UNK R99); accidental suffocation and strangulation in bed (ASSB W75)]. However, it is well known that the DSI have an inherent problem if the infant under review has been moved upon discovery by the parents or other caregiver: “cases of sudden death are associated with so much shock to the family that an accurate history is impossible to obtain” (Farber S. NEJM 211 (4):157;1934); “The suddenness of death so stuns the family that attempts to obtain a reliable history on the first visit to the scene are frequently unsuccessful” (Werne J, Garrow I. AJPH 37(June):678;1947); When a possible SIDS infant is immediately picked up on discovery the final resting position is reconstructed from subjective recall, which complicates the DSI (Willinger M, James LS, Catz C., Pediatric Pathology 11: 677-684, 1991). The writer notes that to calculate accurately the reduction of oxygen and the increase in carbon dioxide from possible rebreathing exhalations at the infant’s nares, the distance between the nares and the possible obstruction must be known to the millimeter, that is lost when the infant is picked up on discovery (Mage DT. Forensic Sci Med Pathol 9:2013; 283.) The reader should note that when a SUID infant is picked up on discovery and the DSI is compromised, the ICD-10 code chosen (R95 or R99 or W75) may be incorrect but the totals for SUID remain unchanged.


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    1. On 2016 May 04, Martine Crasnier-Mednansky commented:

      There are several discrepancies in this paper which cannot be reconciled. For example, figure 1a and table S1 indicate a growth rate of 0.76 hr<sup>-1</sup> for maltotriose with ammonia as nitrogen source. The glucose-maltotriose diauxie with ammonia (Figure 2a, upper and middle panel) indicates a growth rate for maltotriose of 0.37 hr<sup>-1.</sup> In diauxie, the growth rate on each sugar is characteristic of that sugar (Monod, 1942). Therefore, the glucose-maltotriose diauxie should exhibit a growth rate of 0.76 hr<sup>-1</sup> for maltotriose. It is likely that the presence of the reporter gene in the diauxie experiment (figure 2) is affecting the growth rate on maltotriose.


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    1. On 2016 Jun 02, Clive Bates commented:

      The measured markers are not a reliable proxy for disease risk

      The authors are careful not to attribute serious disease risk to these measured changes in vascular function. That caution is well-founded. It is worth pointing out that similar effects are observed in coffee drinkers. See for example:

      Papamichael CM, 2005 Effect of coffee on endothelial function in healthy subjects: the role of caffeine

      The study examined similar effects as they arise from coffee consumption and concluded:

      In conclusion, coffee exerts an acute unfavourable effect on the endothelial function in healthy adults, lasting for at least 1 h after intake. This effect might be attributed to caffeine, given that decaffeinated coffee was not associated with any change in the endothelial performance.

      A comparison with coffee would have made a worthwhile additional arm to this study and may have helped with interpreting whether there is a material risk of harm. If the effects are similar to those experienced by coffee drinkers, that might have provided valuable reassurance for smokers making an informed choice about quitting smoking by switching to e-cigarettes.

      The role of nicotine

      The authors suggest several possible mechanisms for the observed changes in vascular function, including changes induced by nicotine. This is a promising explanatory hypothesis because achieving a satisfactory nicotine dose is common to both smoking and e-cigarette use. One might expect, therefore, similar physiological changes to arise from both ways of taking nicotine if nicotine is the primary cause of these observations.

      However, that would also be reassuring to e-cigarette users. Nicotine has well-documented effects on the body but these effects have not been found to be a significant cause of the diseases attributed to smoking, including cardiovascular disease. The effect of nicotine separated from tobacco smoke exposure has been studied through assessments of medical nicotine replacement therapy (discussed on TreatTobacco.net) and snus, a form of smokeless tobacco that delivers high doses of nicotine - see Lee PN, 2013.

      The danger of over-interpreting these findings

      No one should underplay any potential risks from e-cigarettes. But neither should activists jump to exaggerations about disease risk based on these findings. Overstating the risks of e-cigarettes is logically and ethically equivalent to understating the risks of tobacco smoking. The latter was the practice of tobacco companies 30 years ago and it is essential to challenge the former in today's public health discourse.

      As an example, one campaigner has already declared that this study means "e-cigarettes could be half as dangerous as conventional cigarettes" here.

      I hope the authors will distance themselves from such extreme over-interpretation of their work. The authors could have pre-empted the need for that by explaining in the discussion that disease is not an inevitable consequence of these changed markers of vascular function.

      To be fair, the authors do point to the need for further studies, "to clarify the chronic vascular effects of E-cigarette smoking". To which they might have added "if any" for completeness.


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    1. On 2016 Aug 22, Anthony Jorm commented:

      The Royal Australian and New Zealand College of Psychiatrists (RANZCP) has recently published clinical practice guidelines on schizophrenia Galletly C, 2016, eating disorders Hay P, 2014 and mood disorders Malhi GS, 2015. These guidelines contain a mixture of evidence-based recommendations where there were relevant intervention studies, and consensus-based recommendations where relevant studies did not exist. The consensus-based recommendations comprised a substantial proportion of the guidelines for mood disorders (59%) and schizophrenia (46%), but less so for eating disorders (10%), indicating that expert consensus is an important source of guidance on best practice in psychiatry.

      Given the substantial contribution of expert consensus to these guidelines, it is important that the methods for establishing this consensus are adequate. The Australian National Health and Medical Research Council (NHMRC) has published requirements for development of clinical practice guidelines, but these do not give much guidance on how this should be done, simply mandating that “The method used to arrive at consensus-based recommendations or points (e.g. voting or formal methods, such as Delphi) is documented”. (National Health and Medical Research Council. Procedures and requirements for meeting the 2011 NHMRC standard for clinical practice guidelines. Melbourne: National Health and Medical Research Council; 2011.)

      Another potential source of criteria for evaluating the quality of methods for developing consensus-based recommendations comes from research on ‘wisdom of crowds’ Lorenz J, 2011 Kattan MW, 2016 Baumeister RF, 2016. Based on such research, Surowiecki has proposed four conditions necessary for a group to make good decisions (Surowiecki J. The wisdom of crowds: why the many are smarter than the few. London: Abacus; 2004.): 1. Diversity of expertise. A heterogeneous group of experts will produce better quality decisions than a homogeneous one. For guidelines developers, this may mean that the experts should come from a range of relevant disciplines, including consumer experts where appropriate. 2. Independence. The experts must be able to make their decisions independently, so that they are not influenced by others. For guidelines developers, this means that voting on consensus-based recommendations is carried out privately so that strong individuals cannot dominate the group. 3. Decentralization. Expertise is held by autonomous individuals working in a decentralized way. For guidelines developers, it is important to specify what sources of information the experts had available to them. 4. Aggregation. There is a mechanism for coordinating and aggregating the group’s expertise. For guideline developers, this could involve an independent person who runs the voting and gives feedback to the group.

      If we take these four conditions as appropriate for judging the quality of methods for developing consensus-based recommendations, how well do the RANZCP guidelines meet them?

      An indication of diversity of expertise is the disciplinary composition of the guideline working groups. There was limited diversity for all working groups, with non-psychiatrists comprising 3 of the 8 members for eating disorders, 4 out of the 12 members for mood disorders and 2 out of the 10 members for schizophrenia working group. There were no consumer or carer members of any of the working groups. While the mood disorder and schizophrenia guidelines included consensus-based recommendations s for indigenous peoples, it is not stated whether any of the working groups included indigenous members.

      The mood disorders and schizophrenia working groups did not appear to involve independent decision making. Both groups had discussions until consensus was reached. The eating disorders guidelines did not give relevant information about whether there was independence.

      All three guidelines state that consensus-based recommendations were based on collective clinical and research knowledge and experience. The eating disorder guidelines additionally state that level IV articles were considered where higher-level evidence was lacking and this informed the consensus-based recommendations.

      After drafting, all guidelines had input from a broader group of expert advisers with a wide diversity of expertise. However, it is not clear whether these advisers had the potential to persuade working group members to change consensus-based recommendations.

      Where the guidelines included consensus-based recommendations relevant to indigenous peoples, it is not clear what sources of cultural expertise these were based on.

      None of the guidelines state how judgements were aggregated to determine consensus. The mood disorders guidelines state that agreement on consensus-based recommendations was “in most cases unanimous but allowed one committee member to abstain”. The other guidelines did not define what constituted consensus.

      In conclusion, there are major weaknesses in the procedures used to determine consensus-based recommendations for all three guidelines. These are lack of independence in decision making by experts, a lack of a formal mechanism for aggregating judgments, and a lack of diversity of expertise, particular in areas where consumers and carers could contribute and where cultural expertise is relevant.

      While NHMRC gives quite detailed guidance on how to develop evidence-based recommendations, there is little guidance on best practice for developing consensus-based recommendations. While many of these weaknesses would be overcome by using formal consensus methods such as the Delphi process, there is a need for NHMRC and similar agencies to produce more rigorous quality standards for development of consensus-based recommendations.


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    1. On 2016 Sep 25, Lydia Maniatis commented:

      I would respectfully ask the authors to justify their fundamental assumption, as this is straightforwardly asserted in their opening sentence:

      “Visual sensitivity is limited by both the strength of the neural signals, and the noise in the visual nervous system1 (Levi DM, Klein SA, Chen I. 2005).”

      I am interested in the reference to “the noise in the visual nervous system.” What is the basis of the claim that “noise in the visual nervous system" affects the percepts generated under the conditions of this study? What is the nature of this noise, where does it occur, and what is the evidence for it?

      The single reference provided for the claim doesn’t provide answers as it, too, takes the it for granted. It does provide two other supporting references; but on inspection, these are equally inadequate.

      According to Levi et al (2005) :

      “It has been recognized for well over a century that visual perception is limited by both the strength of the neural signals, and by the noise in the visual nervous system…The notion that internal noise in the visual system acts like light, even in the absence of a stimulus, i.e., dark light, led Barlow (1957) to formulate a very influential model of visual detection which posits that visual sensitivity is limited “by the difficulty of distinguishing a weak signal from the background of spurious signals, or ‘noise’, which occurs without any light signal at all”. Barlow (1957) quantified the dark noise by determining the amount of actual light that produced the same amount of noise in the eye that is present in the dark, using the now widely used prescription for quantifying the noise, known as the equivalent input noise technique (Pelli, 1990).”

      To clarify, Barlow (1957) is suggesting that there are “low levels of intrinsic retinal noise even in complete darkness.” He is interested in absolute thresholds. He states that his results “fit the theoretical predictions for the case of stimuli of short duration and small area (against a background of large area) for a range of background intensities up to about 10 scotopic trohinds [i.e. very, very low intensities].”

      Levi, Klein and Chen (2005) however, are not referring to absolute thresholds or to retinal noise. They tell us that Pelli (1990); Pelli (1981) provided a new description of the equivalent input noise as a contrast function.

      The theoretical rationale provided by Pelli (1990) is as follows:

      Thus [in the case of electronic amplifiers] we can measure [“specify” would be more accurate] the intrinsic noise by finding an equivalent input noise. This is sometimes called 'referring the amplifier's noise to its input'. Essentially the same approach can be applied to vision. Indeed, this is analogous to Barlow's (1957) dark light measurements. By a similar analogy we can apply this idea to the contrast domain.”

      More casual assumptions follow as Pelli (1990) elaborates the application of this analogy to the human visual system.

      I submit that vague analogies should not be admitted the status of theoretical arguments.

      It should be noted that Zomet et al (2016) in no way test the casually adopted and elaborated assumption that I am challenging. They simply interpret data as though it were true; their procedure can’t tell if it’s false. (The claim is, in fact, so vague that it’s not clear how one would go about testing it).

      Postscript: The criteria for publication in Scientific Reports are that: "In this journal a paper is not assessed based on its perceived importance, significance or impact, but it is enough to be just scientifically valid." Testable hypotheses, and testing of assumptions prior to applying them as though they were true, is a fundamental criterion of scientific validity, which I believe is absent in the present case.


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    1. On 2016 Sep 08, Andrea Messori commented:

      Active rheumatoid arthritis with inadequate response to methotrexate monotherapy: incremental benefit for infliximab plus methotrexate versus methotrexate alone

      Andrea Messori, Sabrina Trippoli HTA Unit, ESTAR, Regional Health Service, Firenze, 50100 Italy

      One strength of the meta-analysis by Hazlewood and co-workers [1] is that all pharmacological interventions aimed at rheumatoid arthritis have been evaluated in terms of efficacy. Since infliximab biosimilar has recently become available and its cost is lower than that of infliximab originator, evaluating the magnitude of the incremental benefit for infliximab plus methotrexate versus methotrexate alone is of interest.

      In patients with active rheumatoid arthritis with inadequate response to methotrexate monotherapy, Hazlewood and co-workers [1] report a total of 5 randomised studies.

      According to the end-point of ACR50 response at 30 weeks, the results found in these trials are shown in Table 1. The heterogeneity assessment (carried out according to Higgins and Thompson [2]) showed an I squared of 0% (with p=0.71).

      If one analyses these data based on traditional pairwise meta-analysis (OMA software, Open Meta-Analyst, version 4.16.12, Tufts University, url http://tuftscaes.org/open_meta/), the pooled risk difference in favour of infliximab plus methotrexate vs methotrexate alone is +19.7% (95% confidence interval: +15.4% to +24.1%; fixed-effect model).

      References

      1. Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe D, Bombardier C. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis. BMJ. 2016 Apr 21;353:i1777.

      2. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002 Jun 15;21(11):1539-58.


      Table 1. Data of ACR50 response reported in 5 randomized trials: comparison between Remicade plus methotrexate (R+MTX) vs methotrexate alone (MTX). Detailed references for the 5 trials are given in the Appendix.


      ACR50 response



      Abe 2006: R+MTX=15/49 (30.6%) vs MTX=4/47 (8.5%)

      Lipsky et al 2000 (ATTRACT): R+MTX=18/86 (20.9%) vs MTX=7/88 (8.0%)

      Mac Isaac 2014: R+MTX=6/30 (20.0%) vs MTX=0/31 (0.0%)

      Westovens et al 2006 (START): R+MTX=110/360(30.6%) vs MTX=33/361 (9.1%)

      Zhang 2006: R+MTX=38/87 (43.7%) vs MTX=22/86 (25.6%)


      Overall crude rate R+MTX=187/612 (30.5%) vs MTX=66/613 (10.8%)


      Appendix

      -Abe T, Takeuchi T, Miyasaka N, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol 2006;33:37-44

      -Lipsky PE, Van Der Heijde DMFM, St. Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. New Engl J Med 2000;343:1594-602

      -Mac Isaac KD, Baumgartner R, Kang J, et al. Pre-treatment whole blood gene expression is associated with 14-week response assessed by dynamic contrast enhanced magnetic resonance imaging in infliximab-treated rheumatoid arthritis patients. PLoS ONE 2014;9 (12) (no pagination)

      -Westhovens R, Yocum D, Han J, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial.[Erratum appears in Arthritis Rheum. 2007 May;56(5):1675 Note: Dosage error in article text]. Arthritis Rheum 2006;54:1075-86

      -Zhang FC, Hou Y, Huang F, et al. Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A preliminary study from China. APLAR Journal of Rheumatology 2006;9:127-30


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    1. On 2016 Apr 27, Ana Herrmann commented:

      The authors state that 1) "animals were used for only one experiment and in a single behavioral test, to reduce interference from apparatus exposure", and later they state that 2) "Animals were allowed to freely explore the novel tank for 6 min, after which they were removed from it and exposed to the scototaxis tank". Which one was it?


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    1. On 2016 May 06, Margaret Sampson commented:

      The initial posting for this article contained an error in the order of the authors, as did the article posted on the JCE website on 18 April 2016. The correct author order for "The Single-Case Reporting guideline In BEhavioural Interventions (SCRIBE) 2016 Statement" is as follows: Tate, Perdices, Rosenkoetter, Shadish, Vohra, Barlow, Horner, Kazdin, Kratochwill, McDonald, Sampson, Shamseer, Togher, Albin, Backman, Douglas, Evans, Gast, Manolov, Mitchell, Nickels, Nikles, Ownsworth, Rose, Schmid, and Wilson. As a check, please ensure that Vohra is the 5th author (Posted May 6, 2016, revised May 19, 2016)


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    1. On 2017 Mar 02, Melissa Rethlefsen commented:

      I thank the authors for including the full version of their search strategies in the appendix. This is a valuable tool for readers to more comprehensively analyze the systematic review's methodology and outcomes.

      In the appendix containing the full search strategies, the MEDLINE search and the Embase search appear identical. It is unclear if these databases were searched simultaneously using Ovid's multifile searching capability, or whether the search listed for MEDLINE is in fact not the search used for the MEDLINE search. It is of course also possible that the same search was used for each database, though searched individually.

      The primary complication with the MEDLINE search as reported is that many of the search terms used are Embase-specific Emtree terms that are not searchable in MEDLINE. This includes: "crossover procedure"; "double blind procedure"; "single blind procedure"; "triple blind procedure"; "animal"; "nonhuman"; "human"; "human cell"; and "ulcerative colitis." Because these are not the correct MeSH terms for these concepts, searches for these terms as indicated would produce no results. This unfortunately impacts two major components of the search, from the recommended Cochrane Embase sensitive search for randomized control trials (lines 1-18) and the disease state section (lines 21-24). Multifile Ovid searching does try to map thesaurus terms to corresponding thesaurus terms across databases, which may resolve some of these issues. However, a best practice would be to include both Emtree and MeSH terms in a search instead of relying on multifile term mapping. If the authors did rely on multifile searching, it would be appropriate to note this in the methods section to alert readers.

      In addition, lines 26 and 27 both search for the MeSH heading "Mesalamine," and lines 28 and 29 both search for the MeSH heading "Sulfasalazine." This was perhaps adapted from the previous version of this review (Feagan BG, 2012), which also utilizes this duplication. It is not clear why these terms were duplicated in either case, though this version of the review did update the rest of the search strategy to be more comprehensive and also more specific.


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    1. On 2016 Aug 18, Andrew Kewley commented:

      Expression of concern over un-interpretable statistics of multiple candidate gene association studies.

      The lack of replication of candidate gene association studies has led to much discussion and debate. It is generally considered that each candidate cannot be considered to be an independent hypothesis, hence the alpha level needs to be corrected for multiple comparisons. There is no discussion of this in the paper.

      This research group have published multiple candidate gene manuscripts in addition to this study [1,2,3,4] (Most of which are not listed on pub-med), and may have other unpublished data. Hence it is difficult to know what alpha should be used for significance, after correcting for multiple comparisons. If correcting for 678 comparisons, then none of the results reach significance and the overall conclusion should be quite different.

      In general, future genetic studies should utilise genome-wide association methodology to avoid such biases.

      [1] Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients. Sonya M. Marshall-Gradisnik, Peter Smith, Ekua W. Brenu, Bernd Nilius, Sandra B. Ramos and Donald R. Staines Immunology and Immunogenetics Insights 2015:7 1-6

      [2] Genotype Frequencies of Transient Receptor Potential Melastatin M3 Ion Channels and Acetylcholine Muscarinic M3 Receptor Gene Polymorphisms in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. Marshall-Gradisnik, SM; Chacko, A; Johnston, S; Smith, P; Nilius, B; et al. Immunology and Immunogenetics Insights 8 (2016): 1-2.

      [3] Examination of Single Nucleotide Polymorphisms in Acetylcholine Receptors in Chronic Fatigue Syndrome Patients. Marshall-Gradisnik, Sonya; Smith, Peter; Nilius, Bernd; Staines, Donald R. Immunology and Immunogenetics Insights 7 (2015): 7-20.

      [4] Killer Cell Immunoglobulin-like Receptor Genotype and Haplotype Investigation of Natural Killer Cells from an Australian Population of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. T. K. Huth, E. W. Brenu, D. R. Staines, and S. M. Marshall-Gradisnik. Gene Regulation and Systems Biology 2016:10 43-49


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    1. On 2016 Aug 24, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0255810. We believe the correct ID, which we have found by hand searching, is NCT02558101.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2017 Mar 29, Zvi Herzig commented:

      Despite the fact that this study relates to e-cigarette (EC) vapor dissolved in a liquid medium, the authors surprisingly attribute outcomes to fine particulate matter:

      … our findings suggest it is not nicotine or toxic combustion product that activates the hemostatic system, but instead the hemostatic system is most responsive to fine particulate matter

      This conclusion is puzzling because particulate matter of EC aerosol are in fact liquid droplets. When these are merged with the liquid medium, their former particle sizes become irrelevant. (Solid particles emitted from EC hardware are at quantities below safety limits Farsalinos KE, 2015 and thus unlikely to be of significance).

      It is also unclear what the causes or the relevance of these in vitro platelet effects are. For example, propylene glycol and glycerol are not rapidly metabolized here as they are in vivo. Indeed, Hom et al write:

      There are some important limitations to the work presented here, including the use of an ex vivo static system, without negative hemostatic regulators (such as endothelial cells), to evaluate the effects of e-vapor on platelet functions.

      In contrast, a recent clinical study of smokers switching to Tobacco Heating System 2.2 (whose emissions also include the limited cigarette smoke toxicants present in EC vapor Schaller JP, 2016) shows a level of reduction in platelet activation among switchers approaching those of quitters Lüdicke F, 2018:

      Reductions in 8-epi-prostaglandin F2α (biomarker of oxidative stress), 11-dehydro-thromboxane B2 (biomarker of platelet activation)… occurred in the menthol tobacco heating (mTHS) system group compared with the menthol conventional cigarette group. The changes in the mTHS group approached those in the smoking abstinence group.

      This would indicate that the outcomes of Hom et al are not manifested in real use. While it can be countered that perhaps EC flavorants not emitted by heated tobacco have induced the platelet effects, this is unlikely considering that outcomes were similar for two disparate EC products tested.

      It would also be interesting to consider the effects of air bubbles present from bubbling the aerosol through the extraction buffer. It's well-known that air bubbles induce platelet activation Sandgren P, 2011 and this might help explain the strange outcome.


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    1. On 2016 May 23, Jonathan Heald commented:

      Posted on behalf of the American Academy of Sleep Medicine:

      These recommendations for the use of adaptive servo-ventilation for the treatment of congestive heart failure related central sleep apnea are updates to the 2012 recommendations found in the guideline "The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses." These recommendations serve as an essential supplement to the 2012 practice parameter document:

      Aurora RN, 2012


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    1. On 2016 Jun 06, Christopher Southan commented:

      Since the molecular structure of HM71224 is not disclosed the journal has allowed the publication of work that cannot be reproduced. This consequently obfuscates the clinical trial entry from Eli Lilly

      https://clinicaltrials.gov/ct2/show/NCT02628028


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    1. On 2017 Sep 13, Seán Turner commented:

      According to the CCM catalog of strains, the type of Paenibacillus cucumis Kampfer et al. 2016 is CCM 8655, not CCM 8653. The authors have later assigned CCM 8653 as the type of Isoptericola cucumis Kampfer et al. 2016 (PMID 27045419) which is consistent with the assignment in the CCM catalog of strains.


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    2. On 2017 Sep 13, Seán Turner commented:

      None


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    1. On 2016 Jul 14, Marcus Munafò commented:

      This study provides deeper theoretical insights than might be imagined from a cursory reading. Evolutionary life history theory addresses how organisms, including humans, vary in the allocation of resources to growth, survival and reproduction across the life course. Life history strategies are defined by key decisions that trade off finite resources against competing demands to achieve reproductive goals [1, 2]. Both across and within species, the trade-off between the allocation of resources to growth and to reproductive efforts results in organisms employing varying strategies that can be characterised, loosely, as ‘slow’ or ‘fast’. A ‘slow’ life history strategy is characterized by later maturity and proportionally greater investment of resources in a smaller number of offspring, while a ‘fast’ life history strategy involves more effort directed towards reproduction, such as earlier puberty and sexual activity [2, 3]. Typically, animals pursue a fast life history strategy (‘live fast, die young’) under adverse environmental conditions of high extrinsic mortality. In such conditions, as Day and colleagues suggest, earlier sexual maturation may increase reproductive fitness. However, Day and colleagues also suggest that associations between earlier puberty and a greater propensity for risk-taking behaviours, lower educational attainment, and adverse health outcomes, contradicts this evolutionary perspective. On the contrary, directing effort into risky and aggressive behaviour is best considered as an important part of a fast life history strategy, in which competition for mates is crucial [1]. Viewed in this light, adolescent behaviours of unprotected sex and earlier pregnancy, as well as violence, law breaking, and substance abuse, can be seen as central components or consequences of a fast strategy in which the future is discounted relative to the present [1, 4]. Variation in these physiological and behavioural traits in response to changing environments may reflect a suite of adaptations – psychological and somatic – that increase fitness on average despite poor social and health consequences [5], as resources are diverted from longevity towards short-term reproductive goals under conditions of adversity.

      The human life history literature suggests strategies are contingent on variation in the environment rather than variations in genotype. Day and colleagues illustrate the central role genetics can play in testing key hypotheses arising out of life history theory, where reliance on observational data has previously limited causal inference. The key point is that variants identified in GWAS studies may reflect environmental (and hence modifiable) risk factors, as well as direct genetic effects [6]. An ever-increasing range of social and psychological traits relevant to life history theory are proving tractable to GWAS, including, for example, social deprivation [7] and endocrine biomarkers including cortisol [8] and sex steroids [9]. Genetic instruments associated with social outcomes could be used as a proxy for environmental harshness, while instruments for endocrine status may provide causal evidence for status seeking and reproductive behaviours known to occur in other species, but that are not amenable to experimental analysis in humans. The results of emerging GWAS therefore provide us with unprecedented opportunities for testing the predictions of life history theory, with implications for our understanding of the determinants of health and social behaviour. The elegant demonstration by Day and colleagues of causal links between earlier puberty and both key reproductive traits and adverse outcomes provides compelling evidence that evolutionary life history theory can shed light on human reproductive behaviour, health and disease, even in a modern Western environment. Combining causal analysis from genetic epidemiology and theoretical insights from evolutionary models may help to launch a science of evolutionary social epidemiology, combining knowledge of ‘how’ exposures lead to certain outcomes with an understanding of ‘why’ these relationships may exist. Reframing our understanding of the development of significant social and health outcomes in this way may lead to novel insights to inform future interventions.

      Rebecca Lawn, Abigail Fraser, Marcus Munafò and Ian Penton-Voak

      1. Ellis, B.J. and Bjorklund, D.F. Beyond mental health: an evolutionary analysis of development under risky and supportive environmental conditions: an introduction to the special section. Developmental Psychology, 2012. 48(3): p. 591.
      2. Chisholm, J.S., Death, hope and sex: Steps to an evolutionary ecology of mind and morality. 1999, Cambridge: University of Cambridge Press.
      3. Ellis, B.J., et al., Fundamental dimensions of environmental risk. Human Nature, 2009. 20: p. 204-268.
      4. Simpson, J.A., et al., Evolution, stress, and sensitive periods: the influence of unpredictability in early versus late childhood on sex and risky behavior. Developmental psychology, 2012. 48: p. 674-686.
      5. Gluckman, P.D. and Beedle, A.S. Match fitness: development, evolution, and behavior: comment on Frankenhuis and Del Giudice (2012). Developmental Psychology, 2012. 48: p. 643– 646.
      6. Gage, S.H., et al., G= E: What GWAS can tell us about the environment. PLoS Genet, 2016. 12: e1005765.
      7. Hill, W.D., et al., Molecular genetic contributions to social deprivation and household income in UK Biobank (n= 112,151). bioRxiv, 2016.
      8. Bolton, J.L., et al., Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin. PLoS Genet, 2014. 10: e1004474
      9. Vandenput, L. and C. Ohlsson, Genome-wide association studies on serum sex steroid levels. Molecular and cellular endocrinology, 2014. 382: p. 758-766.


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    1. On 2016 May 15, Arnaud Chiolero MD PhD commented:

      In a life course epidemiology perspective, this is a great review to understand strengths and limitations of intergenerational approach of prevention of obesity and related conditions. In this domain, the words are elegant and the concepts are appealing; the evidence is however weak, letting us short of knowing how to act. We need trials to go further.


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    1. On 2016 Jul 26, Fernando Castro-Chavez commented:

      Dear Reader, This is my most recent article and in it I present the match between the Vigesimal Numerical System of the Maya Culture from the Yucatan Peninsula, in Mexico, and the twenty amino acids with suggested systems of anatomical mnemonics in the Education of Molecular Biology, i.e., using the twenty appendages of our extremities (fingers and toes), and another to remember the purines and pyrimidines with hands and feet. Furthermore, by the suggestion of my chemistry tutoring student Ana Baleva, I have also explored the Icosahedron as an alternate way to represent the twenty amino acids for the Graphics Design in Bioinformatics, containing in one of its triangular cells, an on/off switch. To see the rest of a suggested set of correspondences, please go to my Facebook page and (if you wish) befriend me: https://www.facebook.com/fernando.castrochavez.90. I deeply appreciate feedback, and/or constructive comments, for this and for The Rest of my: Publications in PubMed, by Fernando Castro-Chavez:. And my LinkedIn: https://www.linkedin.com/in/fernando-castro-chavez-6744a322. Sincerely, Fernando Castro-Chavez. P.D. An updated image inspired by this research:

      The First Ten plus Zero Numerals of the Vigesimal Mayan System


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    2. On 2016 Jun 29, Fernando Castro-Chavez commented:

      None


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    1. On 2016 Apr 25, Dita Gratzinger commented:

      Dr. Itkin and colleagues provide a tour de force overview of hematopoeitic stem and progenitor cell maintenance and trafficking within the context of distinctive capillary/arteriolar and sinusoidal vascular beds in the mouse. In parallel to their findings in mouse, we have previously described the analogous vascular beds in intact human marrow, particularly the nestin+ capillary/arteriolar bed, which is tightly wrapped in SMA/CD146+ pericytes/vascular smooth muscle which in turn is wrapped in CD271+ mesenchymal stromal cells (MSCs), as distinct from the nestin-negative sinusoidal endothelium in direct contact with MSCs; the MSCs are then in direct contact with CD34+ hematopoietic progenitor or stem cells Flores-Figueroa E, 2012. CD105 is a specific sinusoidal vascular marker and nestin as a specific capillary/arteriolar marker in intact human bone marrow, allowing for quantification of the distinct vascular beds in the setting of myelodysplastic syndromes Ewalt MD, 2016.


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    1. On 2016 Dec 15, Victoria MacBean commented:

      Plain English Summary:

      Parasternal intercostal electromyography (EMGpara) is a new way to measure breathing difficulty. Research needs to be carried out because body parts used in breathing, like the lungs, need to be properly checked over for breathing problems to be managed, but the testing methods aren’t always suitable for children who are very young or ill. The parasternal intercostal muscles are muscles that move at the same time as the diaphragm (a thin sheet of muscle under the lungs) when you breathe in and out. EMGpara measures signals from the brain which are sent to these muscles without putting any instruments into the body, so it is ideal for children. EMGpara was measured using stickers on the front of the chest while the participants (92 healthy, 20 wheezy and 25 with a machine (ventilator) to help them breathe) were breathing in and out in a resting state. For the wheezy children, measurements were taken before and after a substance to widen air passages (reliever inhaler, or bronchodilator) was used; for the critically ill children, these were taken during ventilator-assisted breathing, then with just mild air pressure to keep the airways open (continuous positive airways pressure). It was found that as age, weight and height increased, EMGpara decreased. This is because when children are growing up, big changes take place in the respiratory system, decreasing the effort needed for breathing. EMGpara in the healthy children was the lowest; in the wheezy children it was higher before the bronchodilator was used, dropping to similar levels to the healthy children afterwards. In the critically ill children, EMGpara was higher than in the wheezy children when the ventilator was used, and even higher with continuous positive airways pressure when they were having to breathe without support. This study has shown that measuring EMGpara is possible in children of a range of ages and levels of health. The results from the healthy children have shown important age-related changes in EMGpara, and those from the wheezy and critically ill children have shown that EMGpara is affected by changes in how hard the breathing muscles have to work because of different diseases and treatments. EMGpara could be a really helpful method in testing the breathing ability of patients who are usually difficult to assess.

      This summary was produced by Lottricia Millett, Year 12 student from Burntwood School, London, as part of the investigators' educational outreach programme.


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    1. On 2016 Aug 31, Joanna Hudson commented:

      We thank Ben Goldacre and the opentrials.net project for bringing this to our attention. We have informed the journal of this anomaly and will ensure all future publications are cited with the correct trial registry ID.


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    2. On 2016 Aug 24, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT023528702. We believe the correct ID, which we have found by hand searching, is NCT02352870.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2016 May 12, Heidi Schulz commented:

      Note that according to HGVS guidelines, the novel variant described as c.717delG in the paper should be referred to as c.718del p.Val240*.


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    1. On 2016 Apr 20, Anderson Santos commented:

      Dear users of the MED pipeline, The MED web server address has been migrated to this new one: http://med.compbio.sdu.dk/ in the Denmark. The MED web server administrator is negotiating a web address forward but no responses from Saarland till now. An important clue about MED: keep the proteins names small and simple, avoid punctuation characters or your processing can fail. I hope to correct such weakness in a further version. Best regards, Anderson Santos - Author


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    1. On 2016 Apr 30, Clive Bates commented:

      Missing the Point

      The priorities elaborated in Matthew Myers' editorial are misplaced will have only trivial impact on the cigarette market. I have proposed five more fundamental tobacco-related regulatory issues for FDA or Congress to address. Please see this e-letter response to the journal Tobacco Control: e-letter Missing the point

      An expanded version of this is available with links in this posting The tobacco control high command has lost its way - what we learn from its views on FDA priorities


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    1. On 2016 May 27, Carmine Pariante commented:

      We are grateful to Dr. Carroll for his comment, which has allowed us to clarify this point. Dr. Carroll is right that we use 'specific' as indicating the outcome of statistical analyses. However, we refer to pathways and genes 'specifically' regulated in depressed patients (or, indeed, in the group that does not develop depression) because these genes/pathways are only regulated in the depressed (or in the non-depressed) group. In this sense, we are using 'specific' to differentiate these genes/pathways from the many genes/pathways that are regulated equally in both groups. We also agree that there are limitations in using IFN-alpha as a model of ordinary major depressive disorder, although we are confident that our findings are relevant to at least the subgroup of depressed patients with high levels of peripheral inflammation. We hope that this reply is helpful.


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    2. On 2016 May 08, Bernard Carroll commented:

      Several issues arise with this report. 1. Authors claimed that "specific signatures" of gene expression changes distinguished depressed versus non-depressed patients. After reading the full paper plus the Supplemental material it is clear that specificity was not established. No data were presented on conditional probabilities or on diagnostic confidence or prognostic confidence. 2. Multiple, misleading, references to specificity in the article actually just denote statistically significant differences in gene expression between the 2 groups of patients. 3.No group-wise differences in cytokine concentrations were found. 4. Validity of IFN-alpha induced depression as a model of ordinary major depressive disorder has not been established.


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    1. On 2016 Jul 20, Rohan Maddamsetti commented:

      While gene flow is certainly important in the evolution of gut microbiota, given current evidence I do not believe that gene flow is a good explanation for synonymous variation in E. coli. I've written a short post on my blog explaining my thinking: http://rohanmaddamsetti.weebly.com/blog/a-retraction-of-sorts


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    1. On 2017 Apr 27, Randi Pechacek commented:

      Katherine Dahlhausen wrote an engaging blog post on microBEnet about this review. She explains how this review emphasizes our "knowledge gaps in the understanding of the fate of antibiotics in our environments."


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    1. On 2016 Apr 13, Anders von Heijne commented:

      Recommended reading - Note the important aspect of including the scale/lexicon as a footnote in all radiology reports!!


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    1. On 2016 Apr 16, Aiguo Ren commented:

      The lowest and highest point estimates of NTD prevalence were obtained from two studies in China. However, these two studies are not comparable in terms of geographical area, time period, and, most importantly, method of calculation. The estimate from Beijing was obtained from a maternity hospital and the numerator was the number of NTD cases in pregnancies of 28 weeks of gestation or greater. In Beijing, every pregnant woman receives ultrasound scanning for fetal structural defects around 20 weeks of gestation, and virtually all fetuses with NTDs will be detected by 28 gestational weeks, and terminated based on informed choice of the mother. This explains, in a larger part, the low NTD prevalence in Beijing. Other national or hospital-bases data from China suffer from the same problem. Please see our most recent report PMID: 26879384.


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    1. On 2016 Aug 01, Joaquim Radua commented:

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


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    2. On 2016 Jul 22, Christopher Tench commented:

      Control in statistics is not achieved by fixed p-value threshold when there are many tests. There are very fundamental reasons for using FWE and FDR, and as a minimum these must be estimated to quantify the risk of false positives. Applying a fixed p-value and fixed cluster extent is a bit like having a fixed steering wheel in a car: it will work really well when the road is straight, but fail terribly when there is a bend! Controlled methods necessarily adapt themselves to the data. Without them, there is no quantifiable evidence that an effect is truly critical of the null.

      I appreciate the validation study. Unfortunately it only tested known positive data. In statistics this cant be considered validation as it promotes confirmation bias. I am aware of the claim that the threshold is equivalent to corrected 0.05, but unfortunately this is not correct. Correction implies adaptation to the data and its null, but fixed thresholds are not able to do this.


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    3. On 2016 Jun 21, Fabio Richlan commented:

      1) Whether or not a study can be considered a meta-analysis does not depend on the use of a correction for multiple comparisons. 2) As usual for coordinate-based meta-analyses, statistical significance was assessed by a permutation test (thresholded at a voxel-level (height) of p < 0.005 and a cluster-level (extent) of 10 voxels). Note that the use of a cluster extent threshold is a way of controlling false positives. In addition, only voxels with z > 1.0 were considered statistically significant. Based on an empirical validation, it was shown that, at least for seed-based d Mapping (SDM), this combination of voxel-level and cluster-level thresholds optimally balances sensitivity and specificity and corresponds to a corrected p-value of 0.05 (http://www.ncbi.nlm.nih.gov/pubmed/21658917). More details on the SDM method can be found at http://www.sdmproject.com/


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    4. On 2016 Jun 15, Christopher Tench commented:

      The method employed in this study offers no control over the 10<sup>5</sup> statistical tests performed. The results are can not be considered statistically significant or a meta-analysis.


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    1. On 2016 Apr 30, Morten Oksvold commented:

      Please note that this publication is actually a retraction of the Leukemia article. There is no indication in this PubMed notice that this is a retraction.

      I will strongly suggest that all retractions in the future are written clearly in the beginning of the article title.


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    1. On 2017 Jul 24, Joseph J Drabick commented:

      Thank you for the comment for our article. We will clarify the literature searching strategy we used in the meta-analysis here. We used Pubmed, Cochrane Library, Ovid Medline and Ovid Healthstar databases, which are accessible from our medical center library. Other details for the search strategy, such as keywords, inclusion and exclusion criteria, are shown in our manuscript.


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    2. On 2017 Jul 20, Irma Klerings commented:

      Remarks concerning the literature search

      The authors state that they conducted the review in accordance with Cochrane guidance, which is commendable. However, both the Cochrane Handbook for Systematic Reviews of Interventions and the Methodological Expectations of Cochrane Intervention Reviews state that the full search strategies for each database need to be included in an appendix of the review.

      Unfortunately, this is not the case here. As far as I can see, this article does not include a replicable search strategy in the text or in an appendix.

      The description of the databases used is also puzzling: “PubMed database, Cochrane database, and Ovid database”

      Ovid is not a database, but a platform that hosts many different databases. Which one(s) were used is not discernible. Similarly, it is not quite clear what is meant by “Cochrane database”. This might refer to the Cochrane Library which contains a number of databases or it might refer to only one of the databases produced by Cochrane (CDSR, CENTRAL).

      In short, the authors may have adhered to Cochrane guidance when they conducted this review. But when it comes to the literature searches there is no way to tell because the reporting is insufficient. This means the reader has no way of judging the comprehensiveness and the quality of the literature search process.


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    1. On 2016 May 08, Amitav Banerjee commented:

      The study by Deshmukh et al,[1] entitled, “Taken to Health Care Provider or Not, Under-Five Children Die of Preventable Causes: Findings from Cross-Sectional Survey and Social Autopsy in Rural India,” published in the current issue of Indian Journal of Community Medicine, raises some serious debatable issues which need to be revisited.

      1. On the whole this cross sectional study, covering rural areas from 16 districts in 8 states of India to identify the causes of death among under-five children and health seeking behavior of caregivers by verbal autopsy, does not yield any novel information. No one with a basic understanding of public health in India would find surprising that mortality was mostly due to neonatal etiologies and preventable causes such as acute respiratory infections, diarrhea, and so on. The fact that most caregivers preferred private health care facilities over government health centers is also to be expected given the poor quality and availability of public health facilities in rural areas. Many studies have brought out these factors ad-nauseam.

      2. This study would have passed as a benign redundant study but for the fact that it has raised a serious debatable issue by some very casual inferences which can misguide the reader, the policy makers and the lay public.

      3. The issue concerns the authors’ claim that this study is the first study on Sudden Unexplained Deaths (SUDS). They found 1.4% (21 out of 1488) of deaths among under-five children otherwise healthy before death which they labeled as SUDS. Well, so far, so good. However, while discussing the implications of this finding vis-à-vis Adverse Effects Following Immunization (AEFI), one wonders why they drag in AEFI in their discussion since it was not one of the study objectives. Further, they also claim, naively, that no vaccination histories were available for these cases. So one would like to know by what stretch of imagination one can conclude, in either direction, the relationship between immunization and these cases of SUDS from the data they provide. Authors have resorted to speculation in absence of scientific reasoning.

      4. They claim that the findings regarding SUDS in their study could serve as a baseline for future assessment of SUDS in Indian children and could be used for analysis and in contextualizing SUDS and AEFI deaths in India. Well, again, so far, so good. Now follows the gaffe.

      5. The authors have made the following statement, “…SUDS and AEFI deaths in India …have been wrongly attributed to new vaccine in the lay press (here they have cited two references, 25 and 26).” This statement and the references labeled as “lay press” are very misleading. Reference number 25 (cited as “lay press”) is a very balanced editorial, published in the Indian Journal of Medical Ethics, a reputed journal indexed in PubMed and Scopus among others. Reference number 26 is “Weekly Epidemiological Record from WHO Geneva!!” One wonders whether the authors have read these references before citing them, otherwise they would not have made this blunder of labeling them as “lay press.”

      6. One would strongly recommend all readers who read Deshmukh et al’s paper[1] to also read these references cited as “lay press” by the authors. Puliyel in his editorial in the Indian Journal of Medical Ethics,[2] has very elegantly with simple calculation (he resorted to all causes mortality since SUDS specific mortality was not available) demonstrated that unexplained deaths after introduction of pentavalent vaccine increased much beyond the base rate for all causes infant mortality rate in Kerala. If Deshmukh et al[1] suggest that data from their present study regarding SUDS be used to contextualize AEFI and SUDS then Puliyel’s caution about adverse effect of pentavalent vaccine becomes stronger as only 2.3% of all cause infant mortality would be expected as SUDS (and co-incidental to administration of pentavalent vaccine). While their data on SUDS supports Puliyel’s concerns about AEFI deaths after pentavalent vaccine (in fact more than Puliyel’s own editorial, since based on this data SUDS would be only a fraction of all causes infant mortality), they casually dismiss his editorial as “lay press.”

      7. Similarly the other reference cited by the authors as “lay press”, i.e. The Weekly Epidemiological Record from WHO[3] cautions that in the context of evaluating a safety signal, it is important that countries understand their own infant mortality rates and underlying causes. If a particular serious AEFI is identified as a concern, additional epidemiological studies should be conducted to ascertain factors that can be used to evaluate the evidence for risk hypothesis. SUDS, among other causes of infant mortality, would benefit from detailed epidemiological studies. The report by WHO in this issue of the WER, concedes that there have been deaths following pentavalent vaccine in Sri Lanka, Bhutan, India and Vietnam leading to temporary suspension of vaccination in some countries. Albeit in the end the report concludes that pentavalent vaccine is to be considered safe. This perhaps may be due to lack of proper baseline data on SUDS and inadequate epidemiological investigations of AEFI.

      8. Based on Deshmukh et al[1] findings on SUDS, the WHO may be persuaded to reconsider its position on safety of pentavalent vaccine. Lastly, we hope Deshmukh et al appreciate their contribution to understanding AEFI – they have raised the bar of vaccine safety – not realizing they have done so!!

      References

      1. Deshmukh V, Lahariya C, Krishnamurthy S, Das MK, Pandey RM, Arora NK. Taken to health care provider or not, under-five children die of preventable causes: Findings from cross-sectional survey and social autopsy in Rural India. Indian J Community Med 2016;41:108-19

      2. Puliyel J. AEFI and the pentavalent vaccine: Looking for a composite picture. Indian J Med Ethics 2013;10:142-6.

      3. Weekly epidemiological record. Geneva: World Health Organization 2013; 88: 301 – 12. .

      Dr Amitav Banerjee, Professor Community Medicine, Dr DY Patil Medical College, Hospital and Research Centre, Pune, India


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    1. On 2016 Apr 08, Dr. Kam Cheong Wong commented:

      Dear readers,

      The full article can be freely accessed via the following open access link: http://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-016-0850-6

      In a spirit of continual improvement, I have updated Figure 3 in this article. The haematological and endocrinological causes of pain in the right upper quadrant of the abdomen have been grouped in “other systems” in the Figure 3, which can be freely downloaded via the following link:

      https://www.researchgate.net/publication/299760713_How_to_apply_clinical_cases_and_medical_literature_in_the_framework_of_a_modified_failure_mode_and_effects_analysis_as_a_clinical_reasoning_tool_-_an_illustration_using_the_human_biliary_system/figures

      This article has referred to the use of Ishikawa diagram. Readers who would like to revisit “how to apply Ishikawa diagram in a clinical setting” can freely access the article via the following link:

      http://jmedicalcasereports.biomedcentral.com/articles/10.1186/1752-1947-5-120

      I look forward to receiving your feedback.

      Thank you.

      Yours sincerely, Dr. Kam Cheong WONG; MBBS(UQ),MSc(NUS),BE(NUS),FRACGP.


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    1. On 2017 Apr 21, Randi Pechacek commented:

      Katherine Dahlhausen, or as I know her, Katie, is the first author on this paper. She wrote an entertaining and honest post on microBEnet about the whole process of using crowdfunding for research. As someone who personally works on her "Koala Project," I highly recommend reading her blog post here.


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    1. On 2016 Aug 24, Jim Woodgett commented:

      A relatively minor point, but the inhibitors used here, lithium and SB216763 (and also BIO, which is mentioned in the Discussion) are not selective for GSK-3beta as they are equipotent towards the GSK-3alpha isoform. This could be simply remedied by deleting the "beta" from each mention of GSK-3beta. Of note, there are currently no isoform-selective small molecule antagonists of GSK-3. Both isoforms are largely redundant (though there are some differences), similarly regulated and widely expressed.


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    1. On 2016 Apr 06, Donald Forsdyke commented:

      PROTEIN SIZE AND CONCENTRATION DETERMINE DOSAGE-SENSITIVITY?

      With the goal of understanding “the evolution of incomplete sex chromosome dosage compensation mechanisms in general,” the authors confirm that, among dosage-sensitive genes, those whose products specifically engage in stoichiometric complexes with other gene products, have a high degree of dosage-compensation. However, most genes are not dosage-limited by stoichiometry and “perplexing questions” remain. It is suggested that “certain loci … simply lack dosage effects” (my italics). In other words, certain loci “simply” contribute more to dosage effects than others.

      While far from simple, this proposal is consistent with dosage compensation being more concerned with collective protein functions than with the specific functions of individual proteins (1). In the crowded cytosol the protein collective should exert an entropy-driven aggregation pressure on individual proteins, as part of a process of intracellular self/not-self discrimination (2). It is predicted that small, low concentration, proteins, will hardly influence aggregation pressure, so here there is no necessity for dosage compensation between the sexes. However, large, high concentration, proteins will greatly influence aggregation pressure, so here regulation of dose, on a gene-by-gene basis or otherwise, should be critical. Failure to regulate such dosage in human females would explain their susceptibility to autoimmune diseases (3-5).

      1.Forsdyke DR (1994) Relationship of X chromosome dosage compensation to intracellular self/not-self discrimination: a resolution of Muller's paradox? J Theor Biol 167:7-12. Forsdyke DR, 1994

      2.Forsdyke DR (2009) X chromosome reactivation perturbs intracellular self/not-self discrimination. Imm Cell Biol (2009) 87:525-528.Forsdyke DR, 2009

      3.Dillon SP et al. (2012) Sex chromosome aneuploidies among men with systemic lupus erythematosus. J Autoimmun 38:J129-J134. Dillon SP, 2012

      4.Forsdyke DR (2012) Ohno's hypothesis and Muller's paradox: sex chromosome dosage compensation may serve collective gene functions. BioEssays 34:930-933. Forsdyke DR, 2012

      5.Wang J et al. (2016) Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. Proc Natl Acad Sci USA doi/10.1073/pnas.1520113113 Wang J, 2016


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    1. On 2016 Sep 30, Jackie Marchington commented:

      The Global Alliance of Publication Professionals (GAPP) submitted a timely response to this article to BMC Medical Ethics in May 2016. In September 2016 we received the author’s response to our correspondence. In the light of current (as of September 2016) correspondence on a subsequent, similar article by the same author in the British Medical Journal (http://www.bmj.com/content/354/bmj.i4578/rapid-responses), we consider our original response to this article to be redundant, but would encourage readers to visit the BMJ correspondence.

      Disclosure: All members of GAPP declare that we have provided or do provide ethical medical writing services to academic, biotechnology, or pharmaceutical clients, and are active in national and international not-for-profit associations that encourage ethical medical writing practices. Details of GAPP members can be found at http://gappteam.org


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    1. On 2016 Apr 05, Christophe Dessimoz commented:

      The paper is published as open access and thus freely available from the publisher: http://dx.doi.org/10.1038/nmeth.3830

      Furthermore we wrote a blog post with the story behind this paper: http://lab.dessimoz.org/blog/2016/04/05/ortholog-benchmark-service


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    1. On 2016 May 02, Ricky Turgeon commented:

      This review required withdrawal for additional important reasons to the outdated search described by the editors, including inappropriate study inclusion, factually incorrect statements and conclusions not supported by the included evidence. As these reasons were not described in the reasons for withdrawal, we share a letter sent to the Cochrane Heart Group on March 30, prior to withdrawal, highlighting these issues:

      "Dear Cochrane Heart Group,

      In performing our own review and synthesis of the evidence for impact of diuretics on mortality and hospitalization in patients with heart failure, we identified critical issues in Cochrane review CD003838 that warrant immediate withdrawal of the review for revision.1 For the purposes of this letter, we focus on the analyses of ‘mortality’ and ‘heart failure worsening’ and 3 of the 4 randomized controlled trials (RCTs) that provided data for at least one of these analyses.2-4

      First, the reviewers defined eligible participants as “adult participants with chronic heart failure, […] a clinical syndrome characterised by breathlessness and fatigue that is caused by an inability of the heart to support an adequate circulation, that may limit exercise tolerance and may lead to pulmonary congestion and peripheral oedema”. Based on these criteria, reviewers should have excluded the trials by Burr, de Jonge, and Myers from this Cochrane review as none or few patients in these trials met this disease definition.1-3

      In the trial by Burr et al,2 investigators excluded patients if “they had had congestive cardiac failure during the previous three months” or “they had ever had left ventricular failure”. The published report further notes that “an attempt was made to discover the original reason for which each patient had been given a diuretic” and that “in most cases, however, this information was not in the hospital notes”. They furthermore note that “ankle oedema was often mentioned in the notes, but in the majority there was no reference to cardiac failure”.

      The trial by de Jonge et al specifically excluded patients with heart failure.3 First, the authors describe their objective as “to determine the effect of withdrawing diuretic drugs on oedema in patients prescribed them for only ankle oedema, excluding patients with cardiac […] failure”. In their methods, the authors describe their approach to excluding patients with a clear diagnosis of heart failure, such as those “[having] congestive heart failure or increased risk of developing it after stopping diuretic drugs,” or “heart failure previously established by a cardiologist, history of severe dyspnoea treated by the general practitioner as cardiac failure, atrial fibrillation, symptoms of right sided heart failure, palpable right ventricular pulsations, or hepatomegaly”. Therefore, de Jonge et al appeared to include only patients in whom heart failure was unlikely or ruled-out as the cause of ankle edema. Additionally, the Cochrane authors describe this trial as only including “participants with decreased ejection fraction (EF) measured by echocardiography”, but this is not described in the published report of the de Jonge trial.1,3

      Similarly, the eligibility criteria in the trial by Myers et al excluded patients with definite or probable heart failure.4 In this trial, “concurrent digoxin therapy” was the most common reason for exclusion, with additional relevant reasons for exclusion being “active heart failure […] (clinical or radiological evidence of heart failure)” or hypertension. Corroborating this is the fact that only 9 out of 77 included patients were noted to have had “previous CHF” according to the study report’s patient characteristics table.

      Based on the above published trial details, it is clear that 3 of the 4 studies contributing data to the Cochrane review’s ‘mortality’ and ‘worsening heart failure’ outcome analyses should be excluded according to the reviewers’ predefined review eligibility criteria.1-4 Exclusion of the Burr and Myers trials leaves only the Sherman trial for the ‘mortality’ analysis, demonstrating no statistically significant difference between diuretics and control (0 versus 2 deaths).1 Additionally, no trials remain for analysis for the ‘heart failure worsening’ outcome with exclusion of the Burr and de Jonge trials. As a result, exclusion of trials not meeting this Cochrane review’s predefined eligibility criteria substantially changes the review’s conclusions.

      Second, further issues arise from attributing a causal role of diuretics in the reported reduction in mortality. In the trial by Burr et al, none of the 3 deaths in the control group were attributable to heart failure.2 Similarly, only 1 of the 8 deaths reported in the control group of the trial by Myers et al was attributable to heart failure, with the others attributed to cancer (3), respiratory disease (2), stroke (1) or gastrointestinal bleed (1).4 Such inconsistencies between all-cause mortality and heart failure-related mortality would deserve, at minimum, description by the reviewers in their Discussion section. Ideally, the impact of inconsistency between outcomes should be considered in the determination of quality of the body of evidence, such as by using the framework provided by the GRADE approach as described in the Cochrane Handbook.5

      Third, the reviewers inappropriately exclude the results of the Myers trial from their analysis of ‘worsening of heart failure’.1 According to the authors, they excluded Myers from this analysis “because of heterogeneity for heart failure worsening in the diuretic group versus placebo (chi-square, 16.03; P = 0.001)”. The heterogeneity noted resulted from the increase in “withdrawal due to heart failure” in the diuretic group compared to the placebo group in this trial (6/29 versus 2/29). Such arbitrary exclusion from analysis constitutes selective outcome reporting bias. Rather than excluding the trial by Myers et al, which contributed greater statistical weight (38.9%) than either trials by Burr or de Jonge, the appropriate course of action according to the Cochrane Handbook would have been to evaluate methodological and clinical sources of heterogeneity, and to abstain from performing a meta-analysis of this outcome.5

      Based on the above appraisal of critical issues present in Cochrane review CD003838, we urge editors of the Cochrane Heart Group to withdraw the aforementioned review from the Cochrane Library and issue a report on the Cochrane Heart Group website describing reasons for withdrawal. Authors of the review should then be provided with the opportunity to revise the review to meet the standards set by their protocol.

      Thank you for your consideration,

      Ricky Turgeon BScPharm, ACPR, PharmD Michael Kolber BSc, MD, CCFP, MSc

      References 1. Faris RF, Flather M, Purcell H, Poole-Wilson PA, Coats AJS. Diuretics for heart failure. Cochrane Database Syst Rev 2012;2:CD003838. 2. Burr ML, King S, Davies HE, Pathy MS. The effects of discontinuing long-term diuretic therapy in the elderly. Age Ageing 1977;6:38-45. 3. de Jonge JW, Knottnerus JA, van Zutphen WM, de Bruijne GA, Struijker Boudier HA. Short term effect of withdrawal of diuretic drugs prescribed for ankle oedema. BMJ 1994;308:511-3. 4. Myers MG, Weingert ME, Fisher RH, Gryfe CI, Shulman HS. Unnecessary diuretic therapy in the elderly. Age Ageing 1982;11:213-21. 5. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org."


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    1. On 2016 Aug 29, CREBP Journal Club commented:

      The three comparisons included in the Hope-3 trial show the effect of a) blood pressure lowering medication b) lipid lowering medication and c) the combination in patients who would traditionally be considered low risk (a risk over 5.6 years of approximately 5% or about 1% pa). The results are broadly consistent with previous trials of blood pressure and lipid lowering therapy, showing similar reduction in risk of cardiovascular events as a proportion of baseline risk. The non-significant results of the blood pressure lowering trial might be explained by either the hypothesis put forward by the study authors (greater effect in patients with higher baseline blood pressure) but could also be explained by the high proportion of patients using non-trial blood pressure lowering drugs at baseline and the difference in the number of patients using non-trial drugs between the active and the placebo arms of the trial. From the results of the lipid lowering arm of the trial, 1000 people would need to take the drug for 5.6 years to prevent 11 events. Whether this is worthwhile needs consideration at both a public and individual patient level.


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    2. On 2016 Aug 29, Jenny Doust commented:

      None


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    1. On 2016 Jun 11, Madhavi Bhargava commented:

      MDR-TB household contacts in 2016

      Madhavi Bhargava, Dept of Community Medicine, Yenepoya Medical College, Yenepoya University, Mangaluru-575018, Karnataka, India

      The opinion piece by David Moore (Moore DA, 2016) regarding multidrug resistant tuberculosis (MDR-TB) is a very important document for caregivers and policy makers alike. One cannot agree more with the author that pending the results of three drug trials until 2020 the alternative to preventive therapy is not to do nothing at all. There is indisputable scientific merit in registering MDR-TB contacts, screening them for active disease, drug-susceptibility testing in co-incident cases and follow-up of remaining MDR-exposed household contacts. The subsequent dilemma of deciding what, if more can be offered to the remaining MDR-exposed household contacts is what is discussed in this comment.

      Moreover, the guidance on prevention of MDR-TB from World Health Organization (“(1) Early detection and high quality treatment of drug susceptible TB, (2) early detection and high quality treatment if drug resistant TB, (3) effective implementation of infection control measures, (4) strengthening and regulation of health systems. (5) Addressing underlying risk factors and social determinants)” needs careful consideration.

      • Regarding effective implementation of infection control, one of the most cost-effective measures is airborne infection control (AIC) and cough-hygiene. In countries like India, AIC systems are found to be poorly developed and implemented (Parmar MM, 2015). Provision for safe sputum disposal and adequate patient education for the same at individual and family level, often gets neglected in chemotherapy centered approach in high-burden developing countries.This has obvious implications on the burden of MDR-TB in a country.

      • Lastly, undernutrition which is often considered a social determinant, should be considered a biological risk factor of tuberculosis (resistant or sensitive) since it has definite influence on immune mechanism of an individual (Schaible UE, 2007). Nutritional support at family level can be added in the battery of interventions for household contacts of MDR-TB patients pending much desired definitive chemotherapeutic agents.

      Conflict of interest: Author declares no conflict of interest


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    1. On 2016 Apr 04, Sujai Kumar commented:

      Disclaimer: I am one of the authors of this paper.

      This is the peer-reviewed version of the bioRxiv preprint that systematically refutes each of the 8 lines of evidence provided by Boothby et al for extensive HGT.

      We hope this paper will correct the scientific record. A blog post describing the behind-the-scenes aspects of this paper is available at Eight things I learnt from #tardigate


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    1. On 2016 Apr 11, Hilda Bastian commented:

      The strongly declarative title of this paper makes a claim that is not supported by its contents.

      The authors argue that only one study (Galesic M, 2009) has reported "a substantial benefit" of natural frequencies. That claim is not based on an up-to-date systematic review of the studies on this question. A systematic review is needed, because there are multiple studies now with varying methods, in various populations, and in relevant contexts, that need to be considered in detail.

      These authors cite some studies that support their position (all in the context of treatment decisions). However, this is only a part of the relevant evidence. Among the studies not cited in this paper, there is at least one looking at medical tests (Garcia-Retamero R, 2013), others at treatments (e.g. Cuite CL, 2008, Carling CL, 2009, Knapp P, 2009 and Sinayev A, 2015), and at least one in a different field (Hoffrage U, 2015). Some find in favor of natural frequencies, others for percentages, and others find no difference. I don't think it's possible to predict what a thorough systematic review would conclude on this question.

      This study by Pighin and colleagues is done among US residents recruited via Mechanical Turk, and includes some replication of Galesic M, 2009 (a study done in Germany). The authors conclude that Galesic and colleagues' conclusion is attributable to the outcome measure they used (the "scoring artifact" referred to in the abstract here). However, their study comes to the same conclusion - better understanding with natural frequencies - when using the same outcome measure. They then applied more stringent outcome measures for "correct" answers, but the number of people scoring correct were too small to allow for any meaningful conclusion. For their two studies, as well as for Galesic M, 2009, both methodological detail and data are thin. Neither the original study nor this replication and expansion, provide "the answer" to the questions they address.


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    1. On 2016 Sep 11, Seth Bordenstei commented:

      The authors write that the hologenome concept is strictly based on a premise that the holobiont evolves as a "single cooperative unit". This central argument is unfortunately not accurate and misrepresents the framework. Holobionts and hologenomes are structural entities subject to ecological and evolutionary forces at varying levels. A clarification and review of the literature can be found here:

      http://msystems.asm.org/content/1/2/e00028-16

      Abstract: Given the complexity of host-microbiota symbioses, scientists and philosophers are asking questions at new biological levels of hierarchical organization—what is a holobiont and hologenome? When should this vocabulary be applied? Are these concepts a null hypothesis for host-microbe systems or limited to a certain spectrum of symbiotic interactions such as host-microbial coevolution? Critical discourse is necessary in this nascent area, but productive discourse requires that skeptics and proponents use the same lexicon. For instance, critiquing the hologenome concept is not synonymous with critiquing coevolution, and arguing that an entity is not a primary unit of selection dismisses the fact that the hologenome concept has always embraced multilevel selection. Holobionts and hologenomes are incontrovertible, multipartite entities that result from ecological, evolutionary, and genetic processes at various levels. They are not restricted to one special process but constitute a wider vocabulary and framework for host biology in light of the microbiome.


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    1. On 2016 Apr 02, Harald HHW Schmidt commented:

      This paper relies on two anti-NOX4 antibodies for which no validation is presented. One alternative interpretation of the finding that two antibodies give different localisations would be that at least one of them has specificity issues. I have yet to see a commercial NOX4 antibody that is specific. The paper also discusses splice variants without showing any data on them.


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    1. On 2016 Dec 20, Pertti Hakkinen commented:

      Readers of this BraCVAM-focused publication might be interested in a 2016 "International Harmonization and Cooperation in the Validation of Alternative Methods" publication ( https://www.ncbi.nlm.nih.gov/pubmed/27671730 ) that notes "the International Cooperation on Alternative Test Methods (ICATM) was established in 2009 by validation centres from Europe, USA, Canada and Japan. ICATM was later joined by Korea in 2011 and currently also counts with Brazil and China as observers."


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    1. On 2016 Oct 05, Cicely Saunders Institute Journal Club commented:

      The Cicely Saunders Institute journal club discussed this paper on 5th October 2016.

      We thought that this review addressed an important question in relation to the pharmacological management of breathlessness at the end of life, and agreed that an update to the previous Cochrane review in this area was warranted.

      We were interested in the selection of papers and the fact that some of the studies in the original Jennings et al review were deemed of insufficient quality to include in the update. We also wondered if more information could have been included about the authors’ definition of “advanced progressive illness”.

      There was a lively discussion about the heterogeneity of included studies, which was attributed to variations in individual study design, and in the drug, dose and route used for the intervention. Some argued that focusing solely on studies evaluating morphine sulphate, which has high affinity for the µ opioid receptor (the subtype present in the lung) and also appeared to have the most promising results in sub-group analysis, might have provided a clearer picture of the benefit of opioids. Others pointed out that pooling studies for meta-analysis provides a larger sample, and that focusing on morphine alone would exclude patients with renal impairment.

      We noted that when reporting the breathlessness outcomes, it would have been useful to define a minimal clinically important difference in breathlessness as well as an effect size, since it is difficult to tell if the standardised mean differences from the meta-analysis would be clinically relevant. In addition lack of standardisation of outcome measurements limited the potential meta-analysis.

      We considered that as presented in this paper, the evidence on opioids in breathlessness is insufficient to guide practice. We agreed with the authors that larger, fully powered studies with adequate wash out periods and standardised dosing schedules are the starting point to improve the evidence base. We thought that focusing future studies on a single opioid (morphine sulphate seems the most promising candidate) might reduce heterogeneity and allow clearer measurement of any benefit.

      Comment written by Dr Simon Etkind and Dr Sabrina Bajwah


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    1. On 2016 May 03, Marcus Munafò commented:

      Joshi and colleagues report that genetic variants in the CHRNA5-A3-B4 gene cluster and the APOE gene are associated with lifespan. This is not surprising – the former influences smoking behaviour, which in turn leads to a number of adverse health outcomes, while the latter influence Alzheimer disease risk. The critical insight here is that genetic studies can provide information about the role of modifiable, behavioural determinants of health and disease, such as smoking [1]. In many cases, this will be the most parsimonious explanation. For example, while we agree with Joshi and colleagues that the effects of CHRNA5-A3-B4 on lung cancer remain after adjustment for self-reported smoking intensity, this is most likely because self-report measures poorly capture actual tobacco exposure, given inter-individual differences in smoking topography (e.g., number of puffs taken per cigarette, depth of inhalation, etc.) [2]. When the association between and CHRNA5-A3-B4 smoking intensity is estimated using cotinine, a precise biomarker of exposure, this is sufficient to fully account for the observed association between CHRNA5-A3-B4 and lung cancer [3]. Joshi and colleagues describe the genes they identify as associated with lifespan as “very pleiotropic”, but the distinction between biological (or horizontal) and mediated (or vertical) pleiotropy is important here (4). The former refers to a genetic variant influencing multiple separate biological pathways, while the latter refers to the effects of a genetic variant on multiple outcomes via a single biological pathway. In our opinion, many effects of CHRNA5-A3-B4 on health outcomes are likely to be the result of mediated pleiotropy. In other words, smoking kills.

      Marcus Munafò and George Davey Smith

      1. Gage, S.H., et al. G = E: What GWAS Can Tell Us about the Environment. PLoS Genetics, 2016. 12(2): e1005765.

      2. McNeill, A. and Munafò, M.R. Reducing harm from tobacco use. Journal of Psychopharmacology, 2013. 27(1): p. 13-8.

      3. Munafò, M.R., et al. Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure. Journal of the National Cancer Institute, 2012. 104(10): p. 740-8.

      4. Davey Smith, G. and Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Human Molecular Genetics, 2014. 23(R1): p. R89-98.


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    1. On 2016 Sep 04, Raphael Stricker commented:

      Study Conclusion is Incorrect This study did not have a true control group because all chronic Lyme disease patients received an additional two weeks of intravenous ceftriaxone therapy. The study clearly shows that this additional antibiotic treatment was associated with significant improvement in the SF-36 quality of life scale in all patient groups (see Figure 2). Thus the conclusion that additional antibiotic therapy was ineffective for chronic Lyme disease is incorrect.

      Disclosure: RBS is a member of the International Lyme and Associated Diseases Society (ILADS) and a director of LymeDisease.org. He has no financial or other conflicts to declare.


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    1. On 2017 Mar 15, Michelle Fiander commented:

      My comment on this paper pertains to the authors' methodology and rationale for it. This paper is not a systematic review and it does not claim to be, but it describes its literature search as systematic, refers to duplicate screening, and includes a study flowchart--each of which are part of systematic review methodology.

      Despite describing its lit search as 'systematic,' there is insufficient detail to reproduce the strategies or to confirm the number of results identified and screened for the review. Table 1 which is not a flowchart but is labeled "Flowchart of all clinical studies included for the final analysis" implies that terms i-v, and "secondary" terms were combined using Boolean OR to create two sets of concepts which were then combined using Boolean AND. If this is the case, the search finds about 100 in Pubmed; 87 in Embase, 7 in Cochrane, 1690 in Google Scholar, 32,200 in Science Direct (sciencedirect.com), and 8 articles and 9 book chapters in Springer Link (springerlink.com). These numbers do not correspond with the number of citations retrieved per Table 1.

      In terms of how references were screened and studies selected for inclusion, the authors describe the process as follows: "Study eligibility was assessed independently by two observers and all assessments were then crosschecked." What is absent here are the stages at which duplicate screening occured, e.g. title/abstract? full-text? both? Further, with dual screening there are typically conflicts, but we are not told how they are resolved.

      Systematic reviews are popular; some might say they are "flavor of the ....decade." Perhaps it is this popularity that has led to a glut of poor quality systematic reviews in the literature. Whatever the reason, using the adjective 'systematic' to describe one or two aspects of a review in the absence of a full and complete systematic approach does, I suspect, contribute to misunderstandings of the purpose, process and value of true systematic reviewing and evidence synthesis.


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    1. On 2016 Dec 31, David Keller commented:

      If placebo works as well as acupuncture, reduce healthcare costs with placebo acupuncture

      The disadvantages of sending patients to a licensed acupuncturist for treatment include the high cost of acupuncture, which must be administered by a licensed acupuncturist, exposure of the patient to the influence of the acupuncturist, who may prescribe other unapproved treatments, such as untested herbal medicines, and the small but finite possibility of injury or infection from the needles. The sham acupuncture procedure in this study employed sharp toothpicks, tapped and twisted on the patient's skin without piercing it, which nevertheless yielded good patient blinding (by standard assessment).

      The investigators chose not to include an observation-only arm in this study, to avoid introducing negative expectation effects and other complications. However, they cite the typically long-lasting duration of the fatigue encountered with Parkinson's disease [PD], and its treatment-refractory nature, thus making a strong argument in favor of treatment of PD-associated fatigue with acupuncture to achieve the substantial placebo benefit seen in both the acupuncture and control groups of this study.

      The fact that acupuncture provides the same benefit as placebo sham acupuncture suggests that the observed benefits can be achieved at a lower cost by having physicians administer sham acupuncture as an office procedure. Sham acupuncture should be easy to learn and administer because it does not require the practitioner to study the concepts of Qi ("chee", life energy), meridians, nor any of the other complex conjectures at the basis of traditional Chinese folk medicine, nor to obtain a special license.

      The question of whether it is ethical for a physician to perform and bill for a sham placebo procedure begs a similar question regarding the ethics of referral to an acupuncturist for treatments which do not differ, in effect, from placebo.


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    1. On 2016 Mar 31, Mojtaba Heydari commented:

      Iranian herbal distillates, as harmful as eating an apple!

      In this paper, Shirani et al, have measured methanol content of 84 samples of herbal distillates from Iran market. The results showed the methanol concentration ranging from 43 to 277 mg/L, more than half of samples (45/84) containing methanol levels beyond the standard limits according to the Iranian standard (100mg/L). The authors concluded necessity for" warning to watch out for the latent risk problem of methanol uptake".

      However the hazard mentioned in conclusion seems to be so exaggerating. Comparing to a potential exposure of 1,000 mg of methanol per day from fruits and vegetables (1), it seems that 277 mg/L (as the maximum amount of methanol in samples of the present study) can not be that hazardous. To become more understandable, each glass (200 cc) from the distillates with the highest amount of methanol, contains just about 50% of methanol in one medium size apple (200 gram, contains about 100 mg of methanol). (1)

      In fact, the problem is the mentioned maximum standard level (100mg/L) for methanol (which is presented without any reference). As author has mentioned the American standard limit for methanol in juices is 460 mg/L, which is far more than highest Iranian distillate sample. According to Australian Register of Therapeutic Goods for complementary medicines, Health Canada for natural products, and European Medicines Agency for Herbal medicinal products, 3000 ppm is mentioned as limit for methanol intake . (2)

      So it can be concluded that, despite the importance of monitoring the methanol content of herbal distillates, current samples shows far less amount of methanol than the upper limits of worldwide standards. If the national scale standard recommends the upper limit of 100 mg methanol, it should be revised to allow eating more than one apple a day!

      References: 1. Food Standards Agency, Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. COT statement on the effects of chronic dietary exposure to methanol. Available here 2. Mundkinajeddu D, Agarwal A. Residual Methanol in Botanical Dietary Ingredients - Perspectives of a Manufacturer. HerbalEGram 2014, 11(8). Available here


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    1. On 2016 Nov 23, Ricky Turgeon commented:

      Critical appraisal of this study is available at http://nerdcat.org/studysummaries/dapt-score


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    2. On 2016 May 22, Daniel Schwartz commented:

      The DAPT Score can be used online or via a mobile app http://qxmd.com/calculate/calculator_373/dapt-score

      Conflict of interest: Medical Director, QxMD


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    1. On 2016 Mar 31, Christophe Dessimoz commented:

      The article is published as open access and is thus freely available from the publisher here: http://dx.doi.org/10.1016/j.tplants.2016.02.005

      Furthermore, the "story behind the paper" is available in this blog post: http://lab.dessimoz.org/blog/2016/03/24/what-are-homoeologs


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    1. On 2016 May 04, Richard Unwin commented:

      Hmmm,

      Care should be taken with the interpretation of results in this study. The age matching between the case (HD) and control groups is not great.

      Cases have a mean +/- s.d. age at death of 57+/-12.3, while the controls are 79 +/- 13.45. A Welch’s T-test comparing these data gives p=0.00011. The observations made in this study could therefore simply be normal changes in the ageing brain, rather than as a result of HD?


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    1. On 2016 Apr 09, Lydia Maniatis commented:

      Turning a blind eye to the well-established role of stimulus structure in all aspects (including thresholds, salience, etc) of perception is a good method for proliferating either reliably falsifiable generalisations or generalisations that can't be challenged because they're so vague.

      In other words a. results are contingent on the stimulus and a different stimulus could well lead to different results, and b. words like "weak target" "highly visible stimuli" describe the percept not the stimulus, and so avoid specifying conditions in physical terms.

      Anyway, what is interesting about "perisaccadic compression"?


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    1. On 2016 Aug 18, Peter Hajek commented:

      Cigarette smoke killed the cells within 24 hours, e-cig vapour damaged them after extended exposure over up to 8 weeks. The abstract ignores this. The authors of this study are Yu et al., the authors listed above are not responsible for this paper, they in fact published a critique explaining the problems in it and in the accompanying media release - see below.


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    2. On 2016 May 19, Clive Bates commented:

      For clarity, it is important to point out that the abstract above is drawn from a different paper Yu V, 2016. It is not the abstract for this PubMed entry.

      This PubMed entry actually refers to a highly critical commentary on the Yu V, 2016 paper and the abstract shown above. Please use the full-text link at the top right of this page or access the commentary here:

      Holliday R, Kist R, Bauld L. Commentary on Yu et al, Evidence-Based Dentistry (2016) 17, 2–3. doi:10.1038/sj.ebd.6401143


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    1. On 2017 Sep 23, Karim Abbas commented:

      I see the data in Figure 3 confusing and might involve a bias. Figure 1 clearly depicts a stable PS-LTP recorded for 15 minutes every day for successive 14 days. However, in Figure 3b the magnitude of PS-LTP with anisomycin (but without "reactivation" (Sic1)) looks decreasing from the values between 0-3 days, albeit non significantly (I guess the lack of significant differences was due to high SD; the values of SD were not reported in the article but can be seen in the figures). There is no explanation though for that tendency of decreasing PS magnitude compared to stable values depicted in Figure 2. More intriguing is why the recording interval following "reactivation" was restricted to 2 days (total 5 days), which is much shorter than the one depicted in Figure 1 (14 days)?


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    1. On 2016 Sep 19, Saurabh Gupta commented:

      This article discusses which of the vascular channels may represent fifth arch artery based on current knowledge of embryogenesis.


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    2. On 2016 Sep 19, Saurabh Gupta commented:

      Fifth arch artery, one of the most controversial topics in the embryology of cardiovascular system.


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    1. On 2016 May 09, M Mangan commented:

      An interesting discussion of this study can be found here: http://www.marklynas.org/2016/04/deformed-gmo-franken-butterflies-not-fast/

      Edit to add: a response from the Rothamsted researchers can be found here as well: <http://rothamsted.ac.uk/sites/default/files/Comment on Hixson et al. 2016_Deformed butterfly wings when feeding on artificial diets containing EPA and DHA.pdf>


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    1. On 2016 Apr 19, S. Hong Lee commented:

      Many thanks for your comments. The two models (response variables) do not simply represent association between genome-wide markers, previously associated with schizophrenia, and woman’s age at first birth. The two models (response variables) are the functions derived from the relationship between the schizophrenia risk in children and their mother’s age, studied in a large national-wide study (please see reference #11 in the paper). So what we tested was that the relationship between the schizophrenia risk in children and their mother’s age found from the previous (totally independent) study was associated with the relationship between schizophrenia risk profile score (inferred from SNP effects estimated in another independent SCZ GWAS data set) and age at first birth. Although we used SNP effects to infer risk profile score, we did not think the test should be corrected for the number of SNPs. We used a response variable and one set of risk profile score (N x 1) in a single test (not multiple sets of risk profile score).

      In addition, I would like to explain a bit more about the variance explained by the predictor in the target data set (R2 in Table 2). The variance explained by the predictor in the target data set is not the actual variance of the underlying effects. It means it can increase more when there is less sampling error (i.e. with a larger samples size). For example, if you estimate SNP effects in a discovery (or training) data set, and the estimated SNP effects are projected into an independent target data set, the R2 explained by the predictor (from the estimated SNPs effects) depends on the estimation error of the SNP effects. So, if the sample size in the discovery data set (SCZ GWAS in our case) is increased, the R2 can be increased (hence lower p value).


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    2. On 2016 Mar 31, Anastasia Levchenko commented:

      Reading the paper, I did not see a clear mention that the calculated p-values (Table 2) were corrected for multiple testing (and if they were, it is not clear which statistical method was used). For instance, “statistically significant” association between a genome-wide marker and a phenotype is represented by a p-value ≤ 5E-08, if the Bonferroni correction is used. Don’t the two models (response variables), used in the present study, represent association between genome-wide markers, previously associated with schizophrenia, and woman’s age at first birth? If they do, then it is not clear based on what grounds the authors claim that the p-value = 4.1E-04 is “statistically significant” in the present study setting. Near the end of Discussion the authors state that “A caveat of our findings is that the genetic association between risk of SCZ and delayed AFB was only marginally significant given the number of analyses performed, perhaps reflecting smaller sample size and correspondingly larger standard errors for women with delayed AFB, and so require replication in a larger sample”, probably referring to the p-value = 1.4E-02. Again, the reader sees no support for the statement that p = 1.4E-02 is “significant”, although “marginally”.


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    1. On 2016 Mar 29, Ludovic Barault commented:

      Hi, People who are interesting in this research area should also read some of the recent studies (from our lab and others) currently unreferenced in the above manuscript:

      • Tumor MGMT promoter hypermethylation changes over time limit temozolomide efficacy in a phase II trial for metastatic colorectal cancer. PMID: 26916096

      • Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer. PMID: 26538496

      • Digital PCR quantification of MGMT methylation refines prediction of clinical benefit from alkylating agents in glioblastoma and metastatic colorectal cancer. PMID: 26113646

      • Activity of temozolomide in patients with advanced chemorefractory colorectal cancer and MGMT promoter methylation. PMID: 24379162

      • A phase II study of temozolomide in patients with advanced aerodigestive tract and colorectal cancers and methylation of the O6-methylguanine-DNA methyltransferase promoter. PMID: 23443801

      • Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer. PMID: 23422094

      • Works from B. Kaina's lab

      Sincerely,


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    1. On 2016 Apr 04, Donald Forsdyke commented:

      COLLECTIVE GENE FUNCTIONS SHOULD BE TAKEN INTO ACCOUNT

      Gene products have both individual and collective functions (e.g. the Donnan equilibrium; 1). Wang et al. suggest that female susceptibility to autoimmune diseases may reflect incomplete dosage-compensation, which results in overexpression of certain X chromosome-located, immunity-related, genes (2). However, they refer to studies by Scofield and colleagues [ref. 11] on diseases with changes in numbers of entire X chromosomes (e.g. XXY), indicating biallelic expression of many genes. Scofield has noted that collective, as well as specific, gene functions must be considered (3). This is in keeping the hypothesis that the cytosolic aggregation pressure exerted by the protein collective is immunologically important (4, 5). <br>

      1.Loeb J (1921) Donnan equilibrium and the physical properties of proteins. 1. Membrane potentials. J Gen Physiol. 3:667-90. Loeb J, 1921<br>

      2.Wang J et al. (2016) Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. Proc Natl Acad Sci USA doi/10.1073/pnas.1520113113 Wang J, 2016<br>

      3.Dillon SP et al. (2012) Sex chromosome aneuploidies among men with systemic lupus erythematosus. J Autoimmun 38:J129-J134.Dillon SP, 2012<br>

      4.Forsdyke DR (2009) X chromosome reactivation perturbs intracellular self/not-self discrimination. Imm Cell Biol (2009) 87:525-528. Forsdyke DR, 2009<br>

      5.Forsdyke DR (2012) Ohno's hypothesis and Muller's paradox: sex chromosome dosage compensation may serve collective gene functions. BioEssays 34:930-933. Forsdyke DR, 2012


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    1. On 2017 Feb 17, Arturo Martí-Carvajal commented:

      Trial authors did not report randomization process. Randomization is oly mentioned into abstract. Where are inclusion and exclusion criteria? This "RCT" is not clear.


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    1. On 2016 May 23, Maurizio Battino commented:

      The post released by AG Atanasov, revealed the wide interest that CoQ has arisen in health debates. He explained, in a a few words and for a public which is not professionally involved in health care, where, how and why CoQ has a critical/strategic role in our physiology and well-being. When I began to investigate CoQ antioxidant properties in health and disease in addition to the well-known role in the mitochondrial respiratory chain of this molecule, about 25 years ago, I was considered one of the pioneer in the field and several criticisms arose from reviewers (e.g., it took more than 2 years to publish DOI: 10.1016/0003-2670(91)80070-A and DOI: 10.1016/0098-2997(94)90016-7 and also DOI: 10.1024/0300-9831.69.4.243 suffered important delays). 25 years later, CoQ is widely recognized as an active compound with important features which go beyond its primitive redox role and also those antioxidant properties my group proposed at the beginning. Nowadays, we have clear proofs of its involvement in several pathologies and we directly found evidences it has, among others, key roles in aging (doi: 10.1093/gerona/glv063, doi: 10.1016/j.freeradbiomed.2011.02.004, doi: 10.1016/j.mad.2009.11.004, DOI: 10.1023/A:1023754305218), in periodontal diseases (doi: 10.1016/j.phrs.2014.10.007, doi: 10.1016/j.fct.2009.06.026, doi: 10.1016/j.numecd.2009.03.003), in fibromialgia (doi: 10.1089/ars.2013.5198, doi: 10.1089/ars.2013.5260), in Papillon-Lefevre Syndrome (DOI:10.1080/1071576031000083116) and in modulating the effects of nutrients as outlined by this very last review (doi: 10.3390/molecules21030373).


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    2. On 2016 May 12, Atanas G. Atanasov commented:

      Consumer Health Digest Scientific Abstract of this article is available at: https://www.consumerhealthdigest.com/anti-aging/coenzyme-q-role-in-dietary-therapy-against-aging.html


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    1. On 2016 Apr 22, Toby Gibson commented:

      Dr. Gack, Thank you for taking the time to comment. One interesting way in which NS3 could potentially regulate 14-3-3 epsilon would be to bind across the top of the groove. Such a binding mode could act as a gatekeeper for phosphopeptide entry/exit into the deep binding pocket. This presupposes that the interaction is direct and strong enough and for this, bacterially expressed proteins need to be assessed in vitro for their dissociation constant.

      Incidentally, regarding the work that you are building upon (Liu et al., 2012, PMID:22607805), there was no attempt to identify a candidate motif. But again, RIG-I is also unlikely to have a 14-3-3 phosphopeptide binding mode. RIG-I is almost entirely structured with a few short interdomain linkers. I don’t see good candidates for canonical 14-3-3 binding motifs in RIG-I. So, in this whole system, in my opinion there are no strong clues toward elucidating the molecular details of how 14-3-3 epsilon might be interacting. Assuming that this interaction also validates in vitro, there is some useful structural biology to be done.


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    2. On 2016 Apr 19, Michaela Gack commented:

      Dr. Gibson’s comment about our manuscript solely stated that the viral RxEP motif identified in the Dengue NS3 protein does not fulfill all of the criteria of conventional 14-3-3-binding motifs found in cellular 14-3-3-interacting proteins. The main conclusions of our study, that the NS3 protein of Dengue virus binds to 14-3-3epsilon and thereby antagonizes RIG-I translocation to mitochondria and type I interferon induction, were never questioned by Dr. Gibson.

      Using mapping experiments and site-directed mutagenesis, we identified that the 64-RxEP-67 motif in the Dengue NS3 protein is essential for 14-3-3epsilon binding. Mutation of the central Glu66 (E66) residue to positively-charged Lys66 (K66) markedly reduced the binding of NS3 to 14-3-3epsilon. Additional mutation of Arg64 to Lys64 (termed ‘NS3(KIKP)’ mutant) led to a nearly complete loss of binding to 14-3-3epsilon. These data together with the similarity of the viral RxEP motif with the cellular 14-3-3-binding motif Rxx(pS/pT)xP, where pS/pT indicates a phosphorylated Ser/Thr residue, suggested that the negatively charged E66 serves as a phosphomimetic residue. Although our study indicated that the RxEP motif is required for 14-3-3epsilon binding, our data also suggested that additional as-yet-unidentified residues in the Dengue NS3 protein are important for 14-3-3epsilon interaction, as introduction of the RxEP motif into the NS3 protein of Yellow Fever virus, which is unable to bind 14-3-3epsilon, did not result in gain of 14-3-3epsilon binding. Thus, the full characteristics of the binding mode of Dengue NS3 and 14-3-3epsilon and their binding affinity remain to be determined in future studies, as well as additional residues in NS3 and 14-3-3epsilon that are engaged in the interaction.


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    3. On 2016 Apr 08, Toby Gibson commented:

      Is there an RxEP motif in Dengue NS3 protein?

      This comment addresses the plausibility that the reported RxEP motif in Dengue NS3 is a genuine 14-3-3 binding motif and as such a target for rational design of therapeutics. It does not address other aspects of this published work, in particular that the NS3 protease plays a role in antagonising the cellular relocation and antiviral activity of RIG-I.

      Viral mimicry of cellular protein motifs is very common and frequently provides a useful insight into the cellular mechanisms that are being disrupted (Davey et al., 2011). Given our interest in these interactions, I was keen to read this new viral motif paper. Given the current importance of flaviviral infections in human health, it then seemed desirable to post here the explanation as to why RxEP cannot be a phosphomimetic for 14-3-3 proteins. It is my hope that this comment will be of value to the Dengue research field e.g. in how follow up experiments might be planned.

      There are several molecular structural issues relevant to 14-3-3 / phosphopeptide interactions:

      Proline is disallowed at the +1 position. There is no ambiguity about this. Phosphopeptide arrays probed by (yeast) 14-3-3 clearly show that Pro is disallowed at +1 (Panni et al., 2011). The structural explanation is that there is no physical space for proline because the backbone peptide bond NH group hydrogen bonds to the 14-3-3 protein (residue Asn176 in the epsilon isoform) as part of local geometry that orients the adjacent phosphorylated side chain (See e.g. Fig. 1D, Molzan et al., 2012). Biologically, rejection of proline at +1 is crucial for separate readout of sites phosphorylated by basophilic kinases (PKA, CAMK etc.) vis-a-vis proline-directed kinases (MAPKs, CDKs etc.) as discussed by Panni et al. (2011).

      Arginine is typically present at either positions -3 or -4 in many well-studied phosphopeptides binding to 14-3-3 proteins. Presence of Arginine at position -2 is also sometimes observed and structures show that the residue orients to H-bond with the phosphate group. Therefore Arg at the -2 position is not an issue in the present context.

      14-3-3 phosphomimetics. We already know that aspartic acid cannot function as a mimetic (de Chiara et al., 2009). This means that the proposed RLDP motif in WNV NS3 can’t work. I am unaware whether a glutamic acid mimetic has previously been evaluated in vitro for its binding affinity. The reason why it may not be possible for any 14-3-3 phosphomimetic is that the PO3- group is complemented by three H-bond donor ligands: in epsilon they are Arg57, Arg130, Tyr131 (Fig. 1D, Molzan et al., 2012). The single negative charge and planar geometry of the carboxyl group rule out an equivalent interaction for glutamate.

      The well-studied 14-3-3-binding phosphomotifs are overwhelmingly, perhaps exclusively, found in regions of intrinsically disordered protein (IDP). As the authors note, the motif postulated in NS3 is on the protein surface but is very well folded. Structurally-embedded motif candidates require a high standard of proof. It is essential that the affinity of the interaction between purified NS3 and 14-3-3 be measured in vitro. In our recent motif discovery guidelines paper, we have explained why a short linear motif is never reliably assigned unless in vitro binding assays using purified components have been undertaken in addition to the in-cell experiments (Gibson et al., 2015).

      In my view the experiments reported here also do not rule out indirect interaction modes. The most direct experiment, in Fig. 1G, used HEK293T cell extracts for the GST-NS3 bead attachment and this might allow bridging proteins to be complexed with NS3 that can secondarily bind the added 14-3-3.

      To recap, the data presented in the paper here indicate that NS3 and 14-3-3 epsilon associate within the same macromolecular complex. In my view, whether the interaction may be direct or indirect has not been unambiguously determined.

      I wish to conclude with two straightforwardly testable predictions:

      1. A synthetic peptide encompassing the viral RxEP sequence will bind 14-3-3 epsilon with an affinity that is millimolar or weaker when measured by ITC or an equivalent solution-based assay.

      2. If NS3 directly and convincingly binds 14-3-3 epsilon at micromolar or nanomolar affinity, when measured by ITC or equivalent, it will do so by an interface that does not involve phosphomimicry.

      References

      Davey NE, Travé G, Gibson TJ. How viruses hijack cell regulation. Trends Biochem Sci. 2011 Mar;36(3):159-69.

      de Chiara C, Menon RP, Strom M, Gibson TJ, Pastore A. Phosphorylation of S776 and 14-3-3 binding modulate ataxin-1 interaction with splicing factors. PLoS One. 2009 Dec 23;4(12):e8372.

      Gibson TJ, Dinkel H, Van Roey K, Diella F. Experimental detection of short regulatory motifs in eukaryotic proteins: tips for good practice as well as for bad. Cell Commun Signal. 2015 Nov 18;13:42

      Molzan M, Weyand M, Rose R, Ottmann C. Structural insights of the MLF1/14-3-3 interaction. FEBS J. 2012 Feb;279(4):563-71.

      Panni S, Montecchi-Palazzi L, Kiemer L, Cabibbo A, Paoluzi S, Santonico E, Landgraf C, Volkmer-Engert R, Bachi A, Castagnoli L, Cesareni G. Combining peptide recognition specificity and context information for the prediction of the 14-3-3-mediated interactome in S. cerevisiae and H. sapiens. Proteomics. 2011 Jan;11(1):128-43.


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    1. On 2016 Mar 24, Jeromy Anglim commented:

      Thanks for posting a comment. I just wanted to add a few thoughts on your points.

      Relationship between type D and outcomes were not moderated by illness group. For us, this was the important conclusion that we want researchers to think about. There is a lot of research done examining Type D in specific illness groups. To some extent implicit in such research is the idea that the effect of Type D might vary based on illness type. While this may be true, this study presents some evidence that at least for the illness groups and variables studied, this is not the case.

      The effect of negative affect on social support and the effect of social inhibition on health behaviours failed to reach statistical significance. I would not say that it failed. This is actually an important finding that supports the idea that the subscales of Type D provide different correlates (i.e., negative affectivity is related more to affective processes, and social inhibition is related more to social processes). Presumably, this is as we would expect. Although if you wanted to be critical, there is the idea that NA is merely neuroticism, and SI is a mix of neuroticism and introversion (see Horwood, Anglim, Tooley, 2015). Whether that is a problem probably depends on how primary you view Big 5 personality.

      Limitations: I think we note the limitations you mention in the limitations section. That said, those limitations only relate to certain points of the paper. For me personally, I think that the paper has two fairly important implications for researchers working with Type D personality. The first relates to the general lack of variation in effects by group as discussed above. Second, we did a comparative regression analysis comparing a range of different scoring systems for Type D personality. The results suggested that binary Type D is a poor predictor, and there was limited evidence for NA by SI interactions effects. Rather entering NA and SI as two separate predictors generally resulted in the best prediction of outcomes. This goes agains the implicit claims of Type D that there is an interactive effect and that cut-offs are appropriate for Type D. Importantly, all these analyses also speak to the novelty of the Type D construct and the rationale for choosing the two particular subscales for inclusion.

      Thus, for me, the paper provides a nuanced and critical assessment of the predictive validity of Type D personality. In particular, I'd encourage other researchers working with Type D personality (and some are doing this already) to run the comparative regression analyses in their samples.


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    2. On 2016 Mar 23, Andrew Kewley commented:

      Given that the main hypothesis was unsupported by the evidence, it seems strange that there is no mention of this in the abstract.

      The hypothesis was stated: "that functional somatic syndromes, conditions that are characterized primarily by general somatic complaints of unclear etiology, such as chronic fatigue syndrome or fibromyalgia, may be more susceptible to the effects of Type D personality than illnesses of known etiology such as type 2 diabetes or arthritis."

      The authors did not find a difference in the prevalence of "Type D personality" between the two chronic illness groups. Likewise, the effect of negative affect on social support and the effect of social inhibition on health behaviours failed to reach statistical significance between the two chronic illness groups after correcting for multiple comparisons.

      The study had key limitations, in particular it was based on a convenience sample and self-report questionnaires rather than objective measures of symptom impact and social support. The sample size was adequate.

      While there was much speculation in the discussion, the most likely directional association between the questionnaire results and illness is simply that chronic illness contributes to affective suffering.


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    1. On 2016 Apr 29, Geriatric Medicine Journal Club commented:

      This article was critically appraised at the April 2016 Geriatric Medicine Journal Club (follow #GeriMedJC on Twitter). While there were concerns about the level of commercial influence in the included studies, the overall young age of the patients, the lack of inclusion of other treatment modalities (exercise, narcotics), and the absence of analysis of harm; this paper brought forth important doubts about effectiveness of acetaminophen. How to reconcile the known harms of NSAIDs and the clinical effectiveness on pain and function is the essence of ongoing discussion.

      Did you miss the #GeriMedJC tweetchat? Check out the transcript in our Archives section: http://gerimedjc.utorontoeit.com/index.php/2015/12/01/missed-gerimedjc-all-archived-here/


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    1. On 2016 Jun 21, Evelina Tutucci commented:

      We have also recently discussed Nelles et al. Nelles DA, 2016. Since we are interested in developing new techniques for studying gene expression and mRNA localization at the single molecule level, a potential tag-less system to detect mRNAs in fixed and live cells would be a further advance. As pointed out by the Duke RNA Biology journal club we think that Nelles et al. represents an attempt to apply the Cas9 System to detect endogenous mRNA molecules. Unfortunately, no evidence is presented to demonstrate that this system is ready to be used to study gene expression at the single molecule level, as the MS2-MCP system allows. The RNA letter by Garcia and Parker Garcia JF, 2015 showed that in S. cerevisiae the binding of the MS2 coat protein to the MS2-loops diminished tagged mRNA degradation by the cytoplasmic exonuclease Xrn1. However, these observations were not extended to higher eukaryotes. Previous work from our lab described the generation of the beta-actin-MS2 mouse, whereby all the endogenous beta-actin mRNAs were tagged with 24 MS2 loops in the 3’UTR (Lionnet T, 2011, Park HY, 2014). This mouse is viable and no phenotypic defects are observed. In addition, control experiments were performed to show that the co-expression of the MS2 coat protein in the beta-actin-MS2 mouse allowed correct mRNA degradation and expression (Supplementary figure 1b, Lionnet T. et al 2011). Furthermore, multi-color FISH (Supplementary figure 6, Lionnet T. et al 2011) showed substantial co-localization between the ORF FISH probes and MS2 FISH probes, demonstrating the validity of this model. We think that the observations by Garcia and Parker are restricted to yeast because of the short half-life of their mRNAs, wherein the degradation of the MS2 becomes rate-limiting. Based on our extensive use of the MS2-MCP system, we think that higher eukaryotes may have more time to degrade the high affinity complexes formed between MS2-MCP, providing validation for this system to study multiple aspects of gene expression. In conclusion, we think that the MS2-MCP system remains to date the best method to follow mRNAs at the single molecule level in living cells. For the use of the MS2-MCP system in S. cerevisiae we have taken the necessary steps to improve it for the study of rapidly degrading mRNAs and are preparing this work for publication.<br> Evelina Tutucci and Maria Vera, Singerlab


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    2. On 2016 May 17, Duke RNA Biology Journal Club commented:

      These comments were generated from a journal club discussion:

      We were excited to read and discuss this paper as many of us have questions pertaining to mRNA localization. This technique theoretically allows for imaging of mRNAs without genetic manipulation meaning mRNAs at native expression levels can be tracked in live cells. However, as with many cutting-edge papers, more work is needed before this will become commonplace in the lab.

      Most current methods to track mRNAs in live cells involve aptamer based methods which require genetic manipulation of mRNA PMCID: PMC2902723. Additionally, the most commonly used aptamer system, the MS2-MCP system, has become controversial in light of recent findings that the MS2 coat protein stabilizes the aptamer bearing constructs Garcia JF, 2015. In this paper, Fig 1F and 1G replicated these findings and also reassured us that the RCas9 technique would not have the same downfall. While this is certainly a good thing, we were unconvinced this technique was better than FISH (Fig 2), other than having the potential for live cell imaging.

      Unfortunately, we found the live cell imaging, which was limited to Fig 3B, to be disappointing. First, we observed that unless an mRNA is strictly localized, as in stress granules, live imaging shows a diffuse mass within the cytosol. Second, imaging was performed with ACTB mRNA which is highly abundant. We don’t think live cell imaging would work as well for low abundance mRNAs due to high background signal. Finally, while specialized imaging software can detect the pile-ups of mRNA in localized foci, we are concerned that tracking individual mRNA may prove a hurdle. Cell models for mRNA localization are large cells such as fibroblasts and neurons, we would be interested to see the ability of this system within these cell types.

      One major flaw with this system is the lack of ability to monitor nuclear localized RNA such as lncRNA or splicing machinery. Since since the RCas9 and sgRNA have to first be produced in the nucleus, the majority of the signal in all the figures came from the nucleus. There is a split-GFP-PUM-HD system that has been used to successfully track mRNA in mitochondria Ozawa T, 2007. Perhaps a similar concept could be used with the Cas9 system. This would prove an advantage to the Pumilio system since only the sgRNA needs to be modified instead of the entire protein.

      Overall, this is a great start towards a new, tagless, method of mRNA tracking. We look forward to future developments and improvements of this exciting technique.


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    1. On 2017 Jul 01, David Keller commented:

      A randomized, controlled trial of ethanol for reduction of cardiovascular mortality is needed

      The reduction of overall mortality observed with moderate regular ethanol ingestion is driven by the much larger and more significant reduction in cardiovascular mortality which is observed [1]. The beneficial effects of moderate ethanol consumption on the lipid profile are significant, along with hypothetical benefits from antithrombotic and relaxation-inducing effects of ethanol. Many cardiologists have lamented the lack of quality data that would allow them to prescribe moderate alcohol intake to patients with elevated cardiovascular risk, and no elevated risk of addictive or hepatic adverse effects of alcohol. In addition, it is clear that the topical carcinogenic effects of ethanol on the gastrointestinal epithelium vary directly with the cytotoxic effects caused by ethanol concentration, with the greatest risk of esophageal cancers seen with high-proof beverages such as straight whiskey, and no significant elevation of risk due to comparatively dilute beer, with its 5% ethanol concentration causing little if any topical cytotoxicity.

      I am calling for a randomized, placebo-controlled interventional trial of ethanol, taken at bedtime to reduce automobile accidents as a source of traumatic mortality, in persons at elevated risk of cardiovascular mortality. Expectation effects could be minimized by administration of the ethanol in capsules, several of which might be required. Oil of peppermint could be included in both the ethanol capsules and in the placebo, for further masking when belching or reflux occur. We have been speculating and correcting observational data for long enough. If a randomized, controlled, interventional trial of ethanol proves to have powerful benefits in persons at high risk of cardiovascular mortality, then populations with average cardiovascular risk can be tested next. Such clinical trials are long overdue. The potential benefits of ethanol are substantial, if properly ascertained.

      Reference

      1: Vogel RA. Alcohol, heart disease, and mortality: a review. Rev Cardiovasc Med. 2002 Winter;3(1):7-13. Review. PubMed PMID: 12439349.


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    1. On 2017 Jul 01, David Keller commented:

      A randomized, controlled trial of ethanol capsules for reduction of cardiovascular mortality is called for

      The reduction of overall mortality observed with moderate regular ethanol ingestion is driven by the much larger and more significant reduction in cardiovascular mortality which is observed. The beneficial effects of moderate ethanol consumption on the lipid profile are significant, along with hypothetical benefits from antithrombotic and relaxation-inducing effects of ethanol. Many cardiologists have lamented the lack of quality data that would allow them to prescribe moderate alcohol intake to patients with elevated cardiovascular risk, and no elevated risk of addictive or hepatic adverse effects of alcohol. In addition, it is clear that the topical carcinogenic effects of ethanol on the gastrointestinal epithelium vary directly with the cytotoxic effects caused by ethanol concentration, with the greatest risk of esophageal cancers seen with high-proof beverages such as straight whiskey, and no significant elevation of risk due to comparatively dilute beer, with its 5% ethanol concentration causing little if any topical cytotoxicity.

      I am calling for a randomized, placebo-controlled interventional trial of ethanol, taken at bedtime to reduce automobile accidents as a source of traumatic mortality, in persons at elevated risk of cardiovascular mortality. Expectation effects could be minimized by administration of the ethanol in capsules, several of which might be required. Oil of peppermint could be included in both the ethanol capsules and in the placebo, for further masking when belching or reflux occur.

      We have been speculating and correcting observational data for long enough. If a randomized, controlled, interventional trial of ethanol proves to have powerful benefits in persons at high risk of cardiovascular mortality, then populations with average cardiovascular risk can be tested next. Such clinical trials are long overdue. The potential benefits of ethanol are substantial, if properly ascertained.

      Reference

      1: Vogel RA. Alcohol, heart disease, and mortality: a review. Rev Cardiovasc Med. 2002 Winter;3(1):7-13. Review. PubMed PMID: 12439349.


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    1. On 2016 Apr 12, Martin Hofmeister commented:

      Do not forget published reviews

      I thank Dr Mat Eil Ismail et al, for their interesting article "Preoperative physiotherapy and short-term functional outcomes of primary total knee arthroplasty", published in the March 2016 issue of the Singapore Medical Journal (SMJ). There is one aspect worth mentioning. In my opinion, systematic reviews of the past five years should be included in an original article consistent with good scientific practice. The reviews of Kwok et al, Jordan et al, Simmons et al and the Australian Agency for Clinical Innovation about the evidence of preoperative physiotherapy on outcomes following total knee arthroplasty are not mentioned in the discussion (1-4). The results of the SMJ study reconfirm the above-mentioned reviews: No statistically significant effect in patient key outcomes (1-4). I refer readers to the latest meta-analysis "Does preoperative rehabilitation for patients planning to undergo joint replacement surgery improve outcomes?" that can be found in the February 2016 issue of the BMJ Open (5).

      REFERENCES

      1) Kwok IH, Paton B, Haddad FS. Does Pre-Operative Physiotherapy Improve Outcomes in Primary Total Knee Arthroplasty? - A Systematic Review. J Arthroplasty. 2015;30:1657-63. Kwok IH, 2015

      2) Jordan RW, Smith NA, Chahal GS, Casson C, Reed MR, Sprowson AP. Enhanced education and physiotherapy before knee replacement; is it worth it? A systematic review. Physiotherapy. 2014;100:305-12. Jordan RW, 2014

      3) Simmons L, Smith T. Effectiveness of pre-operative physiotherapy-based programmes on outcomes following total knee arthroplasty: a systematic review and meta-analysis. Phys Ther Rev. 2013;18:1-10. http://www.tandfonline.com/doi/abs/10.1179/1743288X12Y.0000000035?journalCode=yptr20

      4) NSW Agency for Clinical Innovation (NSW ACI). Musculoskeletal Network: NSW Evidence Review: preoperative, perioperative and postoperative care of elective primary total hip and knee replacement. Chatswood, Australia: Agency for Clinical Innovation, 2012. Available at: http://www.aci.health.nsw.gov.au/__data/assets/pdf_file/0020/172091/EJR-Evidence-Review.PDF. Accessed 22 March 2016.

      5) Wang L, Lee M, Zhang Z, Moodie J, Cheng D, Martin J. Does preoperative rehabilitation for patients planning to undergo joint replacement surgery improve outcomes? A systematic review and meta-analysis of randomised controlled trials. BMJ Open 2016;6:e009857. Wang L, 2016


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    1. On 2016 Apr 30, Ivan Oransky commented:

      Ben Ashby, who reviewed a later paper by Hanna Kokko, one of the authors, in which she corrected an error in this paper, says it should not have been retracted: http://retractionwatch.com/2016/04/29/why-that-evolution-paper-should-never-have-been-retracted-a-reviewer-speaks-out/


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    1. On 2016 Mar 29, Wan map Ni commented:

      It sounds effective. But in fact the gates could be more effective. Furthermore, it is not suitable for many patients with hematological malignancy , especially MDS.


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    1. On 2016 Jul 10, Jihoon Yoon commented:

      I found that the author cited my case report in this article. (Citation No. 121.) However, the citation is inappropriate. The patient in our case represented duplication in 14q11.2 to 14q21.1 region, but the genes mentioned in this article, AMN and HSP90AA1, are located on 14q32 which does not duplicated in our case. There is no overlapping area with the genes and the duplicated region in our case. Therefore, the author should revise the citation or the content. (Contacted with the author.)


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    1. On 2016 May 04, Simon Young commented:

      This review raises a number of issues related to the content and interpretation of articles that are cited.

      1. Paragraph 6 on page 347, about side effects of TRP, cites two placebo controlled trials of TRP (Thomson et al and Steinberg et al) and mentions side effects of TRP. However, the article fails to mention that the study by Thomson et al reported no significant differences in side effects between TRP and placebo, and that in the study of Steinberg et al only 1 of 20 side effects measured (dizziness) was significantly greater after TRP group than after placebo. The same paragraph also contains the sentence “In a study in which 3 g TRP daily was administered to participants for 12 weeks, one patient reported diarrhea as a side-effect of TRP intake (Van Praag et al., 1972)”. However, the van Praag article states “The precursor we used was not tryptophan but dl-5-HTP”. 5-Hydroxytryptohan has a different side effect profile from that of TRP.

      2. Paragraph 6 on page 347 mentions that the dose of TRP in the study of Steinberg et al was 6g daily for 3 months and suggests that “Such high doses might not be recommendable not only because of such side-effects, but also because the TPH enzyme is likely to already be saturated by a dose of TRP up to 3g”. While it is true that the daily dose was 6g it was given in three doses of 2g each (after breakfast, after lunch, and before bed), which would not be likely to saturate TRP hydroxylase, and explains why only 1 of 20 side effects measured was significantly greater in the TRP group than in the placebo group. Also, the article did not mention that TRP altered social behavior, specifically a decrease in irritability, in the study of Steinberg et al.

      3. The article lists the dose of TRP in the study of Volvaka et al as “6g for 3 weeks”. It fails to mention that the daily dose of 6g was given in divided doses, either 3 or 4 times per day. The article lists the dose of TRP in the study of Nemzer et al as 100mg/kg daily for 1 week. TRP was given in divided doses in the morning and afternoon. The article gives the dose of TRP in the study of Cerit et al as “2.8g per day for 6 days”. The TRP was given in 3 doses per day, 0.8g in the morning and afternoon and 1.2g in the evening. These differences are important as a divided dose is likely to increase serotonin synthesis for longer during each day than the same amount given as a single dose, as well as possibly reducing side effects.

      4. Five of the articles listed in Table 1 and discussed in the text involve a technique called acute TRP depletion (ATD). The discussion of all these articles lacks important information. In ATD participants are given a mixture of amino acids that is devoid of TRP (T-), or the same amount of amino acids plus the appropriate amount of TRP as in a balanced protein (B mixture), which for the studies described is 2.3g Young SN, 2013. When the T- mixture is given the amino acid mixture induces protein synthesis and TRP in the blood and tissues is incorporated into protein. Over 5 hours TRP levels fall dramatically and the rate of serotonin synthesis in human brain can decline by more than 90% Nishizawa S, 1997. The B mixture, which contains TRP, will not increase brain TRP or serotonin synthesis, for reasons explained in the paragraph 2 of section 1.1 of the article. Sometimes in ATD studies an additional 8g of TRP is added to the B mixture to raise brain TRP (T+). The problems in the discussion of these articles are: (i) The study of Marsh et al compared the T- mixture, the B mixture, and fasting participants. None of these treatments would increase brain TRP so this was an ATD study, not a TRP supplementation study. The study demonstrated that ATD increases aggressive responding relative to the B mixture. This does not necessarily mean that TRP supplementation would have decreased aggression relative to the B mixture. The fact that the B mixture decreased aggressive responding relative to the fasting condition is irrelevant as the B treatment does not increase brain TRP. While the B and T- mixtures were given under blind conditions, the fasting day occurred after both days in which amino acid mixtures were given, and the participant knew they were not receiving an amino acid mixture. Any effect could have been due to lack of blinding or an order effect, issues not mentioned in the article. Also (a minor point) the article mentions “a control condition (i.e. a low monoamine diet)”. The participants were on a low monoamine diet throughout the study, and the control condition was fasting. (ii) The study of Bjork et al (2000) compared ATD treatment with a T+ treatment containing 10.3g TRP, and a fasting condition. The conclusion given in Fig. 1 of the article by Steenbergen et is that TRP supplementation “Decreased aggressive responding”. However, the article by Bjork et al (2000) states that “TRP depletion increased aggression relative to TRP loading in aggressive men”. Any difference could have been due to increased aggression after ATD, or decreased aggression after TRP loading, or both, so this study did not demonstrate an effect of TRP loading. (iii) The study of Cleare and Bond looked at the effect of ATD and a T+ mixture containing 10.3g TRP. As reported by Steenbergen et al TRP supplementation “was found to reduce self-report ratings of angriness, quarrelsomeness, hostility, and annoyance, but only for males with high trait levels of aggression”. These were changes over time after administration of the amino acids and were relatively small (at most 20%). Given the absence of any control group with unaltered TRP levels these changes cannot necessarily be attributed to the effect of TRP supplementation. (iv) The study of Finn et al compared the effect of a B mixture and a T- mixture. As there was no treatment that increased brain TRP this paper should not have been included in the article.

      5. Section 3 of the article includes the statement “if the TPH1 enzyme in the gut is very active, more TRP is converted there and less will be available to pass through the BBB and be converted into 5-HT in the brain. Thus TRP might have less impact on social behavior in individuals with highly active TPH1 enzyme.” Under normal circumstances only about 1% of ingested TRP is converted into serotonin by TPH (see section 4, paragraph 5 of the article and SJOERDSMA A, 1956). Only in a rare condition, the carcinoid syndrome, which is due to neuroendocrine tumors metastasizing in the liver and producing large amounts of serotonin Molina-Cerrillo J, 2016, is metabolism via TPH quantitatively significant, with up to 60% of TRP converted to serotonin SJOERDSMA A, 1956. The main catabolic route of TRP is along the kynurenine pathway, and flux along this pathway is increased in patients with major depressive disorder Teraishi T, 2015. However, TRP is an effective antidepressant according to a Cochrane review Shaw K, 2002. Therefore, it is unlikely that increased peripheral catabolism of TRP will mitigate the effect of TRP on social behavior to any great extent.

      6. Section 4 of the article states “some of the effects of TRP administration on social behavior might in fact be a result of enhanced sleep and mood”. An effect on sleep cannot apply to the majority of the studies discussed, which were carried out during a single day. When TRP was given for many days TRP was usually given in a divided dose with only a small dose (usually around 1g) given in the evening, sometimes with dinner. When TRP is given as a hypnotic it is usually given shortly before bedtime, as plasma TRP rises quickly after ingestion. Whether the low doses of TRP given in the evening in the studies lasting longer than a day would have had an effect on sleep is not clear. In relation to improved mood as a mediator of more positive social behavior, the study of Moskovitz et al (2001) demonstrated that TRP resulted in more positive social behavior without any change in mood.


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    1. On 2016 Jun 28, Lydia Maniatis commented:

      No real objection to this study, which is refreshingly sensible. I want to note, though, that the term "geometric figure-ground cues" is no more specific than the term "good shape cues," both of which are essentially place-holders for further specification (e.g. convex shape). I want to note this because "good shape" is a Gestalt concept which was trivialised and dismissed, but which evidently is necessary. It's not reducible to points, orientations, angles, "features," "signals," or probabilities. (The probability of a particular seen shape can be, essentially, zero.)


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    1. On 2016 May 11, Wan map Ni commented:

      When will flow cytometry immunophenotyping be included in the classification?


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    1. On 2017 Dec 07, M Mangan commented:

      There was a major correction to this paper, but it's not linked from this page. Their concentrations were 1000x off. de Aguiar LM, 2017 94-101].")


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    1. On 2016 Dec 06, Atanas G. Atanasov commented:

      Excellent, thanks a lot for sharing your experience, I have enjoyed a lot reading :-)


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    1. On 2017 Oct 29, David Keller commented:

      Pharmacists should be enlisted to help physicians monitor PDMP data

      Recommendation #9 is: "Clinicians should review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months."

      Prescribing physicians should obtain and review the patient's PDMP data, if possible, prior to initiating any opioid prescription. In addition, pharmacists must be enlisted to check the PDMP databases whenever they fill a prescription for a Schedule 2, 3 or 4 medication. If the pharmacist discovers evidence of concurrent opioid prescriptions or other red flags, they should inform the prescriber and the patient.

      The 2016 CDC Guideline for Prescribing Opioids for Chronic Pain establishes a de facto standard of care for prescribing opioids, which will enhance patient safety, and thereby increase access to opioids for patients who really need them. Prescribers will gain a degree of protection from lawsuits for adverse outcomes related to opioid therapy by documenting careful adherence to the 12 recommendations in the CDC Guidelines. This adherence (and documentation) will increase the cost of caring for pain patients, as measured in physician time and effort.

      Pharmacists should be required to cross-check the PDMP databases with every opioid fill and refill, and transmit their findings to the prescribing physician, especially red-flag findings. This will be an easy task for pharmacists, and will free up physician time to perform the extensive discussions and documentation required by these Guidelines.


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    1. On 2016 Sep 19, Preben Berthelsen commented:

      The consequence of the statistical problems in this study must be considered before accepting the authors’ contention that dexmedetomidine is better than saline in ICU patients with agitated delirium.

      In the power/sample size calculation and the pre-trial ClinicalTrials registration, a difference of at least 20 hours in ventilator-free time was defined as the minimum difference of clinical interest. The authors found difference of only 17 hours. This finding was statistically significant but not clinically important as the authors - a priori - had defined the 20 hour difference as the minimum difference of interest.

      The trial was stopped early when the sponsor – the manufacturer of dexmedetomidine – lost patience due to slow recruitment of patients. As a consequence, only 71 of the 96 stipulated patients could be included in the final statistical analysis – severely limiting the power of the trial. The authors state in the paper that “no data analysis by the study investigators had occurred prior to this decision.” The decision alluded to is the decision taken by the pharmaceutical company sponsoring the trial. But the essential point is when or why the investigators decided not to finish the trial according to the original plan. Was the decision taken before or after the finding of a statistically significant result? The answer cannot be found in the paper.

      Additionally, analyses of the “hard” secondary end points (length of ICU stay, hospital stay or mortality) do not support the authors’ view that dexmedetomidine is superior to saline in ICU patients with agitated delirium.

      In conclusion, I find that the authors’ hypothesis that dexmedetomidine is effective in ICU patients with agitated delirium not proven. Moreover, I suspect that the chance of reproducing the positive result of this trial to be no better than fifty-fifty.

      P.G.Berthelsen. MD, MIA, DCHA. Charlottenlund, Denmark


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    1. On 2017 Jun 26, David Marks commented:

      This trial was neither randomised, nor controlled, and needs to be retracted. The trial did not compare an abrupt method to a gradual method, as stated, it compared an abrupt method with a mixed bag of complicated gradual methods about which it is impossible to draw solid conclusions. The lead authors have either declared significant conflicts of interest in products used in the research (Aveyard and West) or the ICMJE Form for Disclosure of Potential Conflicts of Interest is incorrect, being the form for the wrong study(Michie). The conclusion that abrupt cessation produces superior cessation rates to gradual cessation cannot be maintained on the basis of this flawed trial for the reasons given below. 1) The gradual-cessation group received short-acting nicotine replacement therapy (NRT) and nicotine patches before the quit day. The abrupt-cessation group received only nicotine patches before the quit day. The treatments are therefore confounded with different pre-exposure levels of NRT. 2) Eligible smokers were booked for an appointment with a research nurse during which the study was explained, eligibility was confirmed, and written informed consent was obtained. What research training did the so-called 'research nurses' receive or were the key study personnel basic grade practice nurses given the task of running the trial? 3) The gradual-cessation group were were supposed to reduce smoking to half of the baseline amount by the end of the first week (known as visit −1) and to a quarter of the baseline amount at the end of the second week (visit 0) in daily increments using a complex variety of procedures that were likely to have been confusing and difficult to follow. 4) The nurses provided the gradual-cessation group with nicotine patches, 21 mg/d, and a choice of short-acting NRT products (gum, lozenges, nasal spray, sublingual tablets, inhalator, or mouth spray) during the reduction period. For such products as gum and lozenges, the instruction was to use 1 dose per cigarette missed. Again, apart from the confounding, and different pre-exposure for the gradual-reduction group, the procedure is unnecessarily complex. 5) Before quitting, participants in the abrupt-cessation group were asked to use nicotine patches, 21 mg/d, but no short-acting NRT. Nicotine patches were used in this group before the quit day, a protocol that aimed to balance the effect between groups. Instead of aiming to balance the effect between groups, there should have been precise balancing, otherwise the trial cannot be described as 'controlled'. 6) Allocation of participants was the responsibility of the so-called 'research nurse' who put patients into blocks of 2, 4, and 6. This allocation was manifestly non-random: “After the participant granted consent, the research nurse opened sealed, numbered envelopes in turn. However, for pairs (for example, husband and wife), one person was allocated randomly and the other was allocated to the same group”. This was a clustered method of allocation, not randomisation. 7) The loss of 300 potential participants also raises questions about how the remaining 697 differed from the original applicants. 8) Unsurprisingly, given their complicated and non-matched treatment, significantly fewer participants in the gradual-cessation group attended visit 0, (67.0% [229 of 342] vs. 83.4% [296 of 355] in the abrupt-cessation group; P < 0.001). Fewer participants in the gradual-cessation group (61.4% [210 of 342]) than the abrupt-cessation group (71% [252 of 355]) (P = 0.007) made a quit attempt. In sum, the trial was a mish-mash of umatched 'treatments', one of which was actually three different treatments counted as one, both confounded by differing pre-cessation exposure to a variety of NRT products chosen by the participants themselves. The trial was carried by 'research nurses' working in GP practices using a batch method for allocating participants. A deliberately uncontrolled, improperly randomised trial, confounded by different NRT products between groups.


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    1. On 2017 Aug 09, Tom Kindlon commented:

      Questioning the exclusion from a diagnosis of CFS of individuals whose symptoms improve with rest

      When I read this paper I was concerned that genuine patients could be excluded unnecessarily.

      A recent paper[1] I believe highlights well the point I am concerned with:

      "Additionally, there is likely to be a good amount of variability in how this case definition is used. In particular, the potential for variation in the methods used to assess substantial reduction has not yet been adequately explored. Operationalizing key concepts outlined in the Fukuda criteria is important. For example, it would be useful to find a reproducible way to specify fatigue as outlined in Fukuda [1]: “chronic fatigue that is of new or definite onset (i.e., not lifelong). The fatigue is not the result of ongoing exertion. The fatigue is not substantially alleviated by rest.” To this end, others have outlined a way to define “lifelong,”3 which is indeed a challenging task [23].

      Let’s examine how Unger and colleagues [3] operationalized “not substantially alleviated by rest.” First the person would need to answer “no” to fatigue was made a lot better by rest to fulfill this requirement. But if they responded “yes” to fatigue was made a lot better by rest, they could be included if their fatigue was relieved by rest “some of the time,” “a little of the time,” “or hardly ever.” They would be not included if they said that their fatigue was relieved by rest “all of the time” or “most of the time.” The problem with this approach stems from the fact that much of the time, rest does relieve fatigue symptoms for many patients with CFS. However, for these patients, rest is not fully curative and does not increase the stamina and endurance necessary to carry on life tasks. Therefore, while it is important to operationalize this part of the Fukuda case definition, it is critical to do so in a way that distinguishes between those who’s rest fully eliminates the symptom complex and those form whom this does not occur (e.g., patients with CFS). It is equally important to determine if CFS induced fatigue is result of ongoing exertion. The failure of the Unger et al. article [3] and the empiric criteria to address this key issue of ongoing exertion causing the fatigue is problematic. In other words, unless questions have been carefully crafted and validated, a person could meet the CFS diagnosis whose fatigue is mainly due to excessive exertion, and with lifestyle issues such as being over-committed."

      References:

      1 Jasaon LA, Gleason K, Fox P (2017) The implications of using a broad versus narrow set of criteria in research. J Med Therap 1: DOI: 10.15761/JMT.1000116


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    2. On 2016 Mar 15, Tom Kindlon commented:

      Possible errors in Table 4?

      Minor point: I think there is a good chance there are errors in Table 4 in terms of listing which groups are different statistically on some criteria. For example, for both Role Physical and Social Functioning, it says the only differences are between M1 only and M2 only but it looks very likely that M1 only would also be different from M1/M2 given that compared to M2, the scores for M1/M2 are worse again, the SEMs are smaller and the sample size is bigger.


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    3. On 2016 Mar 15, Tom Kindlon commented:

      Depression scores in this follow-up study are very different to scores in original study (looking solely at the Reeves et al. (2005) operationalization)

      Leonard Jason and colleagues previously raised concerns about the Reeves et al. (2005) chronic fatigue syndrome (CFS) criteria [which have also been described as an operationalisation of the Fukuda et al (1994) criteria] (1-4). In particular, Jason and colleagues were concerned that some people who did not have CFS might get diagnosed with CFS using this new set of criteria. They found some evidence to support this concern in a study of those with major depressive disorder who did not have CFS: 38% were found to satisfy these new criteria for CFS(4).

      Looking solely at the current study, it would look like there might have been little basis for these concerns. Of 71 people classified with CFS in the current study, only one (1.4%) had a Zung self-rating depression scale (SDS) (5) score of >=60. The mean SDS score for the 71 CFS participants was 44.78 (calculated from the data in Table 4) (6).

      However, it should be noted that the SDS (depression) scores in the follow-up study are very different from the scores in the original Georgia cohort(7). Of the 113 people diagnosed with CFS in the original Georgia cohort, data for 112 (99.1%) was published(7). The average SDS score was considerably higher at 56.2. Possibly more revealingly, 40.2% had a SDS score of >=60. As described in the paper, the SDS scale provides an index score and categories reflecting no (<50), mild (50-59), moderate (60-69), and severe (>=70) depression.

      I am not sure why there should be such a large difference in a cohort between the initial and follow-up studies in the rate of those with moderate or severe depression (40.2% vs 1.4%). But it does mean that caution should be used in terms of interpreting the findings reported in the current paper and their significance regarding the Reeves et al. (2005) criteria (1,6).

      References:

      [1]. Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome--a clinically empirical approach to its definition and study. BMC Med. 2005 Dec 15;3:19.

      [2]. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome; a comprehensive approach to its definition and study. Ann Int Med 1994, 121:953-959.

      [3]. Jason LA, & Richman JA. How science can stigmatize: The case of chronic fatigue syndrome. Journal of CFS 2007;14:85-103.

      [4]. Jason LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control's empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2009;20;93.

      [5]. Zung WW, Richards CB, Short MJ. Self-rating depression scale in an outpatient clinic: further validation of the SDS. Arch Gen Psychiatry.1965;13(6):508-515.

      [6]. Unger ER, Lin JM, Tian H, Gurbaxani BM, Boneva RS, Jones JF. Methods of applying the 1994 case definition of chronic fatigue syndrome - impact on classification and observed illness characteristics. Popul Health Metr. 2016 Mar 12;14:5.

      [7]. Heim C1, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC. Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction. Arch Gen Psychiatry. 2009 Jan;66(1):72-80.


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    1. On 2016 Mar 13, Jim Woodgett commented:

      I commend you Marek for the most honest title ever applied to a review of the proteins associated with Wnt signalling (although could also be applied to most of what is published in all fields of biology).


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    1. On 2016 Apr 03, Michael Brennan commented:

      This is consistent with current guiding principles in pain management. The identification of regional variability is new and begs several new questions.

      What will likely surprise many is the relatively low rate of opioid "abuse or dependence" identified. Some will claim the relatively low number as validation of opioids and as a new indication of relative safety for the prescribing of opioids. Meanwhile others will criticize process, sample or look for bias to explain number as being too low.

      Regardless of ones perspective, this tool offers the next generation in patient assessment.


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    1. On 2016 Apr 28, Jorg Rosgen commented:

      The processes in question are associated with such small energetic changes, that everything happens within the range of normal thermal fluctuations. That's why protein folding can be both spontaneous and reversible.


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    2. On 2016 Apr 14, Ariel Fernandez commented:

      Walter:

      In so far as we agree that protein folding in vitro is spontaneous under suitable renaturation conditions, the process is thermodynamically irreversible. Hence, the intermediate states of the system, comprised of protein chain and solvent statistical bath, are irretrievable [1]. In thermodynamic terms there is no such thing as a spontaneous reversible process. Ariel Fernandez

      [1] Ariel Fernandez Stigliano. Biomolecular Interfaces, Chapter 3 (Springer, Heidelberg, 2015) http://link.springer.com/book/10.1007/978-3-319-16850-0


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    3. On 2016 Apr 13, S Walter Englander commented:

      I disagree with several issues in this comment.

      1. The protein folding question is not a sterile one. It is centrally important to understand how proteins fold and why they fold in that way. The protein folding reaction is essential to all living things, arguably the most important reaction in all of biology. It determines many currently forefront biological behaviors and diseases.

      2. Folding is not irreversible. At the molecular level, free energy downhill processes are spontaneous but certainly not irreversible. Proteins spontaneously fold energetically downhill to their lowest free energy native state, as per Anfinsen, but even under fully native conditions they continue to unfold and refold repeatedly over time, cycling through all possible higher energy states. One result is that all higher energy states, including those that carry the major U to N folding flux, are populated at equilibrium, each one according to its Boltzmann factor [K = e<sup>-G/RT</sup>].

      3. The effort is far from futile. Hydrogen exchange (HX) methods can observe that cycling and characterize the major intermediates (structure, G, ASA). For cytochrome c we found four major partially folded intermediates. Each differs from the next by one native-like foldon unit. In the present paper we used advanced HX MS methods to define the major partially folded cyt c states DURING kinetic folding. They are the same as the high free energy states we found before at equilibrium native conditions. One conclusion is that cyt c and, we suspect, proteins in general fold through defined N-like intermediates, adding one foldon unit at each step.

      4. Summary: Fifty plus years after Anfinsen there is still not general consensus about how protein folding works and why it works that way. The reason is that it has been so hard to define folding intermediates and pathways, although not impossible as Fernandez asserts. Our HX experiments indicate that proteins are made of cooperative foldon units that provide built-instructions for the folding process. Stepwise folding puts a sequence of cooperative foldon units into place, one at a time in an ordered foldon-dependent pathway (the HOW question), just as they are evolutionarily tailored to fit together in the native protein (the WHY question).

      All of this is true for cyt c (the present paper) and for some other proteins as well (see paper for refs).


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    4. On 2016 Apr 05, Ariel Fernandez commented:

      In a recent paper, Hu et al. [1] reported a careful and detailed characterization of the folding pathway for a soluble protein. I am always confused by this kind of results. Under the appropriate enabling conditions, protein folding in vitro is known to be spontaneous [2] and therefore thermodynamically irreversible [3]. The endpoints of the protein folding process, i. e. the denatured random coil ensemble and the native state, are of course recoverable by restoring respectively denaturing or renaturing conditions [2]. Yet, at a variance with thermodynamics, protein scientists incorrectly regard this restoration of folding endpoints as meant to imply that protein folding is a reversible process [2]. Be as it may, according to the tenets of thermodynamics, the folding and unfolding pathways are untraceable and irreproducible as it would be the case for any spontaneous process [3]. In fact, the very notion of “pathway” for a spontaneous process is thermodynamically meaningless because dissipative forces intervene in such processes causing a net increase in the entropy of the universe, the hallmark of irreversibility. Thus, as with any spontaneous process, the actual intermediate states associated with the protein folding process are irretrievable. Therefore I think that the sterile controversy on whether protein folding in vitro is actually a two-state process or proceeds through intermediates is not even an issue: The two–state model is simply a realization that intermediates are irretrievable in a thermodynamically spontaneous process [4].

      Notwithstanding such thermodynamic considerations, an active quest for folding intermediates continues to this day [1, 5]. In my view, this search remains futile from a thermodynamic perspective, unless some sort of paradox holds (thermodynamics is full of paradoxes) that, at the very least, needs to be properly dispelled before the saga of the quest for folding intermediates continues. To the best of my knowledge this has not been done. Real folding intermediates not only remain elusive: I am afraid they do not exist, and claims to the contrary violate the second law of thermodynamics. Ariel Fernandez

      References

      1. Hu W., Kan Z.-Y., Mayne L. & Englander, S. W. Proc. Natl. Acad. Sci. USA 113, 3809-3814 (2016).

      2. Anfinsen, C.B. Science 181, 223-230 (1973).

      3. Planck, M. Treatise on Thermodynamics, 3rd edition, Dover, New York (2010).

      4. Fernandez, A. Biomolecular Interfaces (ISBN 978-3-319-16849-4), Springer, Berlin (2015).

      5. Vendruscolo M. & Dobson, C.M. Nature Chem. Biol. 9, 216-217 (2013).


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    1. On 2016 Aug 30, Duke RNA Biology Journal Club commented:

      This paper brought a new perspective to our discussion by focusing on the structural and biophysical characterization of RNA, in this case the mammalian ribozyme CPEB3, to gain insight into its biological function. Of particular interest to our group is understanding structure in the presence of a biologically relevant amount of magnesium, which remains a challenge in the field of RNA structural biology but is critical for understanding how RNA may function in the cell. In fact, magnesium acts as a crucial cofactor for many catalytic RNAs and is often required for folding of structured RNAs into their functionally competent state.

      NMR is a powerful technique for studying biomolecular structure and dynamics at the atomic level, but much of the current NMR data describing RNA are reported in the absence of magnesium due to experimental limitations on signal sensitivity which worsens with high-conductivity samples.

      This paper used previously established NMR methods such as Diffusion Ordered Spectroscopy (DOSY) and NOESY experiments to probe how CPEB3 ribozyme global conformation and local secondary structure are affected by magnesium. They were able to mitigate sensitivity issues by substituting magnesium with hexamminecobalt (III) Gonzalez RL Jr, 1999 as a probe of outer-sphere metal coordination to identify potential magnesium binding sites. While this technique is a useful starting point, concerns were raised that the authors used NOESY cross peaks of aromatic or sugar protons as the main evidence for direct magnesium binding since these resonances likely shift due to magnesium-induced conformational changes rather than site specific interaction. A better analysis would be to monitor nitrogen cross peaks such as N7 on guanines or adenines Fu DJ, 1992 which are insensitive to secondary structural rearrangements but sensitive to presence of nearby metal ions.

      Nonetheless, this paper successfully characterized the impact of magnesium on secondary structure of a complicated RNA system comprised of a full-length nested double pseudoknot ribozyme which happens to be one of the few self-cleaving ribozymes identified in humans. We are excited for the development of new techniques directed toward studying specific RNA-metal interactions to better understand RNA structure as it exists in the cell.


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    1. On 2017 Feb 04, Stuart RAY commented:

      Ribavirin monotherapy has been studied (summarized in Brok J, 2006), with no beneficial effect detected (an ACP Journal Club commentary was entitled, "ribavirin is not better than placebo" Chen W, 2006). This suggests that if the subset with high IFN-gamma was included in those trials, they did not benefit from ribavirin monotherapy. The comment's author may have conflated interferon gamma (a type II interferon) with interferon alfa (a type I interferon), the latter being a treatment that was enhanced by ribavirin.


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    2. On 2017 Feb 03, Muhammad Aslam commented:

      In my view the patients with high IFNg plasma levels could benefit with Ribavirin only without suplementing with peginterferon.


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    1. On 2017 Jan 05, Melissa Rethlefsen commented:

      Upon reading this article, I came across a small detail that I am curious about. In the flow diagram (Figure 1), the authors note in the final step that they found 127 reports to 15 trials. Generally, I would interpret this as the authors having located 127 references that discuss 15 different trials. In other Cochrane reviews, this is often noted as X number of references to X number of studies, and then all of the references for each study are usually listed under the main study name in the included studies list. In this case, there appear to be only 15 references to 15 studies in the included studies list. Is this a typo in the flow diagram, or are the remaining 112 references that could have been ascribed to the 15 studies erroneously omitted?


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    1. On 2016 Aug 30, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed. The ID given is NCT102577224 - the correct ID is NCT02577224. This has been corrected in a subsequent correction published in the originating journal, but not in the PubMed metadata.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2016 Mar 27, Bruno Ramalho Carvalho commented:

      When we talk about humanization of care, whether in medical area or not, we are talking about the comprehension that the assisted person is the owner of her instincts, needs and desires. Also, that the person is the owner of her past, present and future. Humanization refers to the understanding that any intervention somehow violates the line between the intimate and the notorious. And that exceeding this limit is not always a well received act, even if it was allowed. That is, the intervention can be both visit, as can be invasion. And in the context of humanization only the first option is accepted.


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    1. On 2016 Apr 26, Annalisa Forlani commented:

      We are thankful to Dr. Cooper for his comment and deep knowledge of the literature. However, we have not included the suggested citation for different reasons, as discussed below.

      Images from previous reports of pulmonary hyalinosis may resemble our case. However, there are several histological, histochemical and ultrastructural findings that we believe are not consistent with such diagnosis.

      Based on previous reports (Billups et al., 1972; Dagle et al., 1976), hyaline bodies are intracellular globules usually distributed within the cytoplasm of macrophages and multinucleated cells, occasionally calcified and strongly positive for Periodic Acid-Schiff (PAS), crystal violet and Oil Red O. The histological lesions are described as multifocal granulomas effacing smaller bronchi and the subpleural tissue at the margins of lobes.

      In our case, the eosinophilic granular material was predominantly extracellular and filled the alveolar spaces without any other pulmonary architectural changes. Moreover, histochemistry revealed a negative Von Kossa and Congo red reaction and only variably positivity for PAS.

      Ultrastructurally, the substance in the alveolar lumina was composed by short lamellar thick fascicles rather than whorled intracytoplasmic lamellar membranes as reported for pulmonary hyalinosis. Therefore, our findings were strongly suggestive of accumulation of abnormal surfactant rather than degenerate cells.

      Pulmonary alveolar proteinosis and pulmonary hyalinosis are both rare and poorly characterized conditions whose pathogenesis is still not entirely understood. In 1976, Dagle and collaborators hypothesized a similar pathogenetic mechanism, even an overlap between the two . However, no additional efforts have been made toward a better understanding of the two entities.

      In conclusion, given the differences between the abovementioned studies on pulmonary hyalinosis and our findings, a comparison with pulmonary hyalinosis seems unnecessary, and no additional comments should be included in our manuscript.

      References 1. Billups LH, Liu SK, Kelly DF, Garner FM. Pulmonary granulomas associated with PAS-positive bodies in brachycephalic dogs. Vet Pathol 1972; 9: 294-300. 2. Dagle GE, Filipy RE, Adee RR, Stuart BO. Pulmonary hyalinosis in dogs. Vet Pathol 1976; 13: 138-142.


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    2. On 2016 Apr 12, Timothy K Cooper commented:

      The authors should consider pulmonary hyalinosis of brachycephalic dogs: Pulmonary Granulomas Associated with PAS-Positive Bodies in Brachycephalic Dogs. Billups LH, et al. Veterinary Pathology 1972: 9(5):294-300.


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    1. On 2016 May 10, Kenneth Katz commented:

      Obviously an important and well crafted study. However. while I may have missed it, I do not see what I would have considered a key control: that a different flavivirus, such as Dengue, or West Nile, was unable to infect the progenitors in this system. After all, it is concluded that the infection observed is what distinguishes Zika from other flaviviruses, and implied that this accounts for the equally distinguishing, and tragic, neonatal consequences of infection.


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    1. On 2016 Mar 13, Lise Bankir commented:

      It may be useful to remind that loop diuretics act on the thick ascending limb upstream of the macula densa, whereas the thiazide-type diuretics work donwstream the macula densa. Moreover, loop diuretic block the sodium-chloride cotransporter in the cells of the macula densa. The tubulo-glomerular feedback that permanently regulates the GFR is thus abolished, allowing the GFR to go up. This produces a permanent "hyperfiltration" that is known to induce renal damage when sustained for long periods. Thiazide diuretics, acting beyond, the macula densa should not influence the GFR


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    1. On 2017 Feb 28, Tom Kindlon commented:

      A major limitation was not mentioned: no objective outcome measures were used

      I was amazed to read the long (906-word) limitations section and find no mention of the limitation that the results rely solely on subjective outcome measures[1].

      The most obvious outcome measure to use would have been actometers which measure activity levels objectively. The equipment was available to the researchers as it was used at baseline ["Physical activity was assessed with an actometer, a motion-sensing device worn at the ankle for 14 days"].

      The importance of the use of such a measure can be seen in the results of an earlier study using the the same or very similar intervention on people with chronic fatigue syndrome[2]. That study involved two of the current research team with one of them being its corresponding author. That paper reported improvements in the intervention group on the CIS fatigue severity, SIP8 total score and SF–36 physical functional questionnaires (which were also used in the current study). Subsequently to that, data from the actometers were reported in a paper co-authored by three of the current team[3]. Both the intervention group and the control group had the same change in activity, 4.3 units, during the trial. The intervention group finished at a mean of 67.8 units, significantly less than the actometer scores for healthy controls of 91.

      Numerous response biases could be at play in this nonblinded study with such interventions causing participants to report improvements without their objectively-measured levels of functioning having improved.

      If actometers were used during or after the current study, it is important that the researchers should now release such data, rather than delay for years as they have done with some trials before[3].

      References:

      1 Janse A, Wiborg JF, Bleijenberg G, Tummers M, Knoop H. The efficacy of guided self-instruction for patients with idiopathic chronic fatigue: A randomized controlled trial. J Consult Clin Psychol. 2016 May;84(5):377-88.

      2 Knoop H, van der Meer JW, Bleijenberg G. Guided self-instructions for people with chronic fatigue syndrome: randomised controlled trial. Br J Psychiatry. 2008 Oct;193(4):340-1.

      3 Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Aug;40(8):1281-7.


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    1. On 2016 May 18, MATTHEW MESELSON commented:

      Meiotic Sex in Bdelloid Rotifers

      Debortoli et al. conclude that the patchwork pattern of sequences shared within the group of three isolates of the bdelloid Adineta vaga they sequenced is “…unlikely to arise in cases of PTH (Oenothera-like) meiosis since haplotypes are transferred as entire blocks…” and therefore that “Genetic exchange among bdelloid rotifers is more likely due to horizontal gene transfer than to meiotic sex”. But this assumes without justification that homologous HGT cannot occur in species with Oenothera-like meiosis, for which we have reported evidence in the bdelloid Macrotrachela quadricornifera (Signorovitch et al. 2015 Genetics 200: 581-590). And it does not take account of the possibility that gene conversion followed by outcrossing would also contribute to such a patchwork pattern, even in Oenothera-like systems.

      Moreover, the set of three individuals studied by Debortoli et al., in which the shared sequences are considerably diverged, is not well suited to the detection of sex in an outcrossing population that may include numerous distinct Oenothera-like complexes. For that purpose, one should select individuals whose shared sequences are identical or nearly so in order to enrich for direct descendants of the F1 from a particular cross. Otherwise, further crossing is likely to replace shared complexes with others, removing the evidence for the transfer of entire haplotypes. It is therefore important to note that the shared sequences in the three individuals we studied were either identical or very nearly so, allowing us to observe the specific and unusual pattern of sharing expected for Oenothera-like meiosis.

      Debortoli et al. suggest that HGT of very long fragments, rather than sexual transfer of entire haplotypes, may explain the pattern of sharing we observed. Considering the large size of the M. quadricornifera genome, some 1500 mb, and the fact that there are 10 chromosomes, it is exceedingly unlikely that the sequences from all four regions we studied reside on one of the horizontally transferred segments of DNA required by their suggestion and that the four allelic sequences reside on the other. Moreover, the results of FISH in other bdelloid species suggests that at least three and quite possibly all four regions we studied reside on separate chromosomes.

      While awaiting full genome sequencing of the allele-sharing isolates of M. quadricornifera, present evidence argues strongly for the occurrence of sexual reproduction with Oenothera-like meiosis.

      Ana Signorovitch, Jae Hur, Eugene Gladyshev, Matthew Meselson


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    1. On 2017 Jun 16, Jacob H. Hanna commented:

      The last three papers from Smith group describing human transgene free "Reset cells", including this one, have failed to describe ability to generate teratomas. Mouse naive pluripotent cells have the intrinsic "self organizing capacity" to enter a formative/primed state after in vivo SC injection and make teratomas within 4-8 weeks. I find this stunning and wonder whether the human "reset" cells being induced do not qualify to be annotated as pluripotent cells at all. I hope the authors can clearly point out and directly address this critical caveat.


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    1. On 2016 Mar 12, Sudan Prasad Neupane commented:

      Indeed a very important study. However, I found the conclusions were hardly based on the findings of the present study. In my opinion, the conclusions should be focussed on a deeper understanding of IPV in the studied setting, rather than drawing a sketch of possible interventions. Congratulations on a good study, we need more of these.


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    1. On 2016 Sep 06, Morten Oksvold commented:

      Please note that part of this study is not reliable due to report of falsified/fabricated data in figure 2A:

      "...Respondent falsified and/or fabricated the results in Figure 2A by erasure of a band in the blot image for LYST/CHD-4 that was present in the original data".

      A full report has been published by ORI:

      http://ori.hhs.gov/content/case-summary-cullinane-andrew-r


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    1. On 2017 Mar 12, Andrea Messori commented:

      Promoting the use of Markov simulation models to study outcomes of total knee arthroplasty

      Andrea Messori

      HTA Section, ESTAR Toscana, Regional Health Service, Firenze, Italy

      Correspondence to: Dr. Andrea Messori, PharmD, HTA Unit, ESTAR Toscana, Regional Health Service, Via San Salvi 12, 50100 Firenze, Italy. andrea.messori.it@gmail.com Fax: +39-05-74701319

      In patients receiving total knee arthroplasty (TKA), simulation studies employing Markov models are increasingly being used [1-4]. The aim of these studies is to determine the “typical” clinical outcomes expected on the long term and to generate estimates of cost/effectiveness. If we consider these modelling tools, most of the simulation software published thus far shares the following characteristics:

      a) Health states. The model implements, with minimal variations across different models, the health-states shown in Figure 1 along with the corresponding transitions from one health state to another. The probabilities of individual transitions are shown in Figure 1; these probabilities can be adjusted depending on the specific intervention under examination;

      b) Clinical outcomes after TKA. The following outcomes can occur after the first surgery: i) successful outcome; ii) complications; iii) death; the same outcomes can occur also after a repeat surgery for arthroplasty revision.

      c) Life expectancy. The life-expectancy attributed to the simulated patients is determined by considering: a) the age-related and gender-related mortality of a healthy population [5]; b) the mortality attributable to arthroplasty surgery. These two factors are separately managed in different sections of the Markov model (see Figure 1).

      d) Utilities and estimation of QALYs. Utility of patients is assumed to be around 0.72 [6] after surgery. Over the pre-specified time horizon (e.g. 20 years), QALYs are computed on the basis of the health states of the model, their utilities, and the corresponding transition probabilities.

      e) Discounting. The annual discount rate (e.g. 3.5%) is incorporated in the calculation of QALYs according to standard discounting techniques [6].

      As regards the practical use of these computer programs, the simulation models published in the past years are essentially based on two software tools: on the one hand, some researchers have used a general-purpose spreadsheet (namely: Excel by Microsoft) to develop these Markovian programs; on the other, other researchers [3] have used a specific, commercial program (in most cases: TreeagePro by Treeage Software Inc., Williamstown, Massachusetts, USA). The Markovian subroutines written under Excel, as well as the tools developed under Treeage, share a negative characteristic because they are not freely available. Even NICE does not provide these tools when a Technology Appraisal is released. The unavailability of these programming tools is a serious hurdle that limits the scientific advancement of cost-effectiveness research on TKA. Hence, in the present report we have tried to facilitate the application of Markov models in the setting of TKA by developing a simulation software which is an improved version of the tools previously employed for specific research projects [3]. Our simulation model, that can be downloaded from the following link http://www.osservatorioinnovazione.net/papers/total_knee_arthroplasty.trex, is designed to be run under TreeagePro version 2011 (or subsequent versions). The input variables for the model are shown in the legend to Figure 1. The output of the program is represented by the estimate of total QALYs per patient accrued over the pre-specified time horizon. The software manages only the clinical part of these simulations; however, cost data can be added quite easily by introducing new sections of programming.

      References

      [1] Losina E, Walensky RP, Kessler CL, Emrani PS, Reichmann WM, Wright[ EA, Holt HL, Solomon DH, Yelin E, Paltiel AD, Katz JN. Cost-effectiveness of total knee arthroplasty in the United States: patient risk and hospital volume. Arch Intern Med. 2009 Jun 22;169(12):1113-21.

      [2] Bedair H, Cha TD, Hansen VJ. Economic benefit to society at large of total knee arthroplasty in younger patients: a Markov analysis. J Bone Joint Surg Am. 2014 Jan 15;96(2):119-26.

      [3] Pennington M, Grieve R, Black N, van der Meulen JH. Cost-Effectiveness of Five Commonly Used Prosthesis Brands for Total Knee Replacement in the UK: A Study Using the NJR Dataset. PLoS One. 2016 Mar 4;11(3):e0150074.

      [4] Mari K, Dégieux P, Mistretta F, Guillemin F, Richette P. Cost utility modeling of early vs late total knee replacement in osteoarthritis patients. Osteoarthritis Cartilage. 2016 Dec;24(12):2069-2076.

      [5] ISTAT. Tavole di mortalità della popolazione italiana—Ripartizione: Italia—Maschi—Anno: 2005, Report of 2010. http://demo.istat.it/unitav2012/index.html?lingua=ita (last accessed 7 May 2014).

      [6] Mason J, Drummond M, Torrance G. Some guidelines on the use of cost effectiveness league tables. BMJ. 1993 Feb 27;306(6877):570-2.

      [7] Jørgensen CC, Kehlet H; Lundbeck Foundation Centre for Fast-track Hip and Knee Replacement Collaborative group.. Time course and reasons for 90-day mortality in fast-track hip and knee arthroplasty. Acta Anaesthesiol Scand. 2017 Apr;61(4):436-444.

      Figure 1. States of the Markov model and transition probabilities.

      The starting point of the simulation model is a Markov node (circled M) from which six branches originate. The explanation for these six branches is the following: 1) surgery for TKA; 2) follow-up after first surgery (and also the occurrence of revision surgery): 3) follow-up after revision surgery; 4) follow-up after first surgery with complications; 5) follow-up after revision surgery with complications: 6) death. Second-level branches regard events defined according to the accompanying labels. The symbols adopted in this scheme reflect the syntax required by the Treeage software: Ο, probabilistic node;◄, terminal node.

      Abbreviations: RWD, reward (which in this model represents the incremental increase in quality- adjusted survival).


      The graph of Figure 1 can be downloaded from the following link: http://www.osservatorioinnovazione.net/tenders/tka.gif


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    1. On 2016 Mar 16, Daniel T Gilbert commented:

      Our Technical Comment has elicited lengthy responses from several colleagues and counter-responses from us. For those who have not been following this conversation, here is a brief synopsis:

      OPEN SCIENCE COLLABORATION: “We have provided a credible estimate of the reproducibility of psychological science.”

      GILBERT ET AL: “No, you haven’t, because (1) you violated the basic rules of sampling when you selected studies to replicate, (2) you did unfaithful replications of many of the studies you selected, and (3) you made statistical errors.”

      OPEN SCIENCE COLLABORATION & OTHERS: “We don't think we made statistical errors.”

      Several colleagues wish to challenge our Point 3 while conveniently ignoring Points 1 or 2. But it requires no sophisticated mathematics to see that Points 1 and 2 are simple facts to which the OSC fully admits, and that these simple facts are by themselves sufficient to repudiate the OSC’s claim. We continue to believe that our Point 3 is correct, but even if it were entirely wrong, the conclusion that OSC2015 does not provide a credible estimate of the reproducibility of psychological science is inescapable, and it remains the one and only conclusion of our Technical Comment. Interested readers will find our full discussion HERE


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    2. On 2016 Mar 09, Daniël Lakens commented:

      Invalid statistical conclusions in Gilbert, King, Pettigrew, and Wilson (2016)

      Gilbert, King, Pettigrew, and Wilson (GKPW; 2016) argue that the Reproducibility Project (Open Science Collaboration, 2015) provides no evidence for a ‘replication crisis’ in psychology. Their statistical conclusions are meaningless due to a crucial flaw in their understanding of confidence intervals. The authors incorrectly assume that ‘based on statistical theory we know that 95% of replication estimates should fall within the 95% CI of the original results’. This is incorrect. When original and replication studies have identical sample sizes, 83.4% of confidence intervals from a single study will capture the sample statistic of a replication study. This is known as the capture percentage (Cumming & Maillardet, 2006).

      GKPW use data from Many Labs (another large-scale replication project, Klein et al., 2014) to estimate the expected capture percentage in the Reproducibility Project when allowing for random error due to infidelities in the replication study, and arrive at an estimate of 65.5%. They fail to realize that the capture percentage for studies with different sample sizes (in the Many Labs project ranging from 79 to 1329) can be any number between 0 and 1, and can’t be used to estimate ‘infidelities’ in replications in general. Most importantly, the capture percentage observed for replications in the Many Labs dataset does not generalize in any way to the expected capture percentages between original and replication studies in the Reproducibility Project.

      Nevertheless, GKPW conclude that the capture percentage in a subset of Reproducibility Project studies overlaps with the “the 65.5% replication rate that one would expect if every one of the original studies had reported a true effect.” Due to this basic statistical misunderstanding, the main claim by GKPW that ‘the reproducibility of psychological science is quite high’, based on the 65.5% estimate, lacks a statistical foundation, and is not valid.  

      References

      Cumming, G., & Maillardet, R. (2006). Confidence intervals and replication: Where will the next mean fall? Psychological Methods, 11(3), 217–227. http://doi.org/10.1037/1082-989X.11.3.217

      Gilbert, D., King, G., Pettigrew, S., & Wilson, T. Comment on 'Estimating the reproducibility of psychological science', Science. (4 March 2016), Vol 351, Issue 6277, Pp. 1037a-1037b.

      Klein, R. A., Ratliff, K. A., Vianello, M., Adams, R. B., Bahník, Š., Bernstein, M. J., … Nosek, B. A. (2014). Investigating Variation in Replicability: A “Many Labs” Replication Project. Social Psychology, 45(3), 142–152. http://doi.org/10.1027/1864-9335/a000178

      Open Science Collaboration. (2015). Estimating the reproducibility of psychological science. Science, 349(6251), aac4716–aac4716. http://doi.org/10.1126/science.aac4716


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