14,838 Matching Annotations
  1. Jul 2018
    1. On 2017 Oct 19, Polina Vishnyakova commented:

      Dear colleagues, in order to maintain a healthy scientific debate we need to clarify the statement, which you provided in Discussion of this paper. You wrote: «These findings are inconsistent with the findings of Vishnyakova et al. who reported that OPA1 was upregulated in PE placentas. […] The findings of Vishnyakova et al. were mainly based on gene expression. Levels of DNA or RNA may be unable to predict protein levels accurately, as they do not account for post-transcriptional/translational modifications». It is important to note than in our work we observed changes both on mRNA and protein content level of OPA1 and these findings surely disagree with your data. But we think that this could be explained by the difference in patients characteristic: we divided patients with preeclampsia basing on gestational age while you included women only with severe preeclampsia. Plus in current paper you analyzed only OPA1-L form, but not both forms (full OPA1-L and cleaved OPA1-S). So obtained difference in our findings could be explained with these points. Best regards.


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    1. On 2018 Jan 01, DAVID ALLISON commented:

      A letter to the editor has been published indicating unsubstantiated conclusions in this article due to the use of difference in nominal significance (DINS) analyses.

      See: http://onlinelibrary.wiley.com/doi/10.1111/1753-6405.12755/full

      A response from the authors has also been published: http://onlinelibrary.wiley.com/doi/10.1111/1753-6405.12767/abstract


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    1. On 2017 Aug 05, Pedro Moreno commented:

      Regarding the authors: No (A Moreno P). It is Moreno PA. Please correct this.


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    1. On 2018 Jan 27, Viktor Müller commented:

      While it is true that there is considerable overlap in the recognition of self and (possibly pathogenic) non-self epitopes (Calis et al [1] estimated an overlap of around one third for HLA class I alleles), this is likely to make the job of the immune system harder, rather than easier. The overlapping peptides tend to be non-immunogenic, indicating tolerance, and the immune system needs to be able to target epitopes that are distinguishable from self peptides even with the degenerate recognition of T cell receptors [1]. Furthermore, even if the recognition task was indeed reduced to self and similar peptides, this would still vastly exceed the capacity of a fixed germline-encoded receptor repertoire. The number of distinct potential epitopes (for HLA class I) is of the order of magnitude 10<sup>7</sup> in humans [2] and in mice [3]; this exceeds the maximum number of germline immune receptors found in any species by several orders of magnitude.

      We still maintain that "Distinguishing tumours from normal self is likely to be the most challenging task for Darwinian immunity that could only be added at advanced stages of its evolution" [4], but have never claimed the same for positive selection. Amphioxus has proto-MHC, and positive selection might indeed be an ancient characteristic of (vertebrate) Darwinian immunity. It will be instructive to elucidate whether and how the divergent adaptive system of jawless fish handles positive selection, or anything analogous to MHC restriction in general.

      Finally, we note that the origin of vertebrate adaptive immunity is a notoriously difficult problem. We certainly do not know the whole truth about the complex events that took place more than half a billion years ago -- but we hope that, by surveying the most recent evidence, we have taken a small step in the right direction.

      [1] Calis JJA, de Boer RJ, Keşmir C (2012) Degenerate T-cell Recognition of Peptides on MHC Molecules Creates Large Holes in the T-cell Repertoire. PLoS Comput Biol 8(3): e1002412. https://doi.org/10.1371/journal.pcbi.1002412

      [2] Burroughs, N.J., de Boer, R.J. & Keşmir, C. Immunogenetics (2004) 56: 311. https://doi.org/10.1007/s00251-004-0691-0

      [3] Müller, V. & Bonhoeffer, S. (2003). Quantitative constraints on the scope of negative selection. Trends Immunol 24, 132-5. https://doi.org/10.1016/S1471-4906(03)00028-0

      [4] Müller V, Boer RJ de, Bonhoeffer S, Szathmáry E (2018) Biol Rev 93:505-528. https://doi.org/10.1111/brv.12355


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    2. On 2018 Jan 20, Donald Forsdyke commented:

      PATHOGEN COEVOLUTION AND THE ANTIGENIC UNIVERSE

      The distinction between selective and instructive (Lamarckian) systems of immunity (1) – originating with Paul Ehrlich – was clearly set out in 1957 by Talmage (2) who, with Burnet, can be considered a "father of clonal selection theory" (3, 4). Its historical omissions aside, this bold attempt to place the evolution of immune systems in a broad context raises other concerns.

      Although mentioning "the complex adaptation of the immune repertoire to the antigenic environment," and the need "continuously to acquire and store open-ended information about the antigenic environment," the coevolution of that antigenic environment (e.g. the coevolution of pathogens) does not seem to have been considered.

      While the authors agree with Burnet that "distinguishing tumours from normal self is likely to be the most challenging task for Darwinian immunity," it is not recognized that the most successful pathogens are those that, through mutation, can come close to self. Whereas tumours represent mutations away from self, successful pathogens represent mutations towards self (by means of which they seek to exploit 'holes' in immune repertoires; 5). In both circumstances, this greatly simplifies the evolutionary task of a host. It does not have to depend on "the open-ended nature of the receptor repertoire." It does not have to "constitute a system of 'unlimited heredity' within the immune system." It does not have to "be broad enough to recognize the 'potential universe of antigens'." The scope of its task is greatly reduced.

      As long ago proposed (6), and increasingly recognized (7, 8), it would be evolutionarily advantageous for organisms to focus their immune cell receptors on 'near self' antigenic specificities, rather than to attempt to anticipate the entire universe of antigens. Organisms achieve this, not through negative, but through positive selection of their immune repertoires. From the outset, organisms and their pathogens have coevolved and it would seem incorrect to suppose for the immune system that positive selection "could only be added at advanced stages of its evolution" (9). It is fundamental to immune system evolution.

      1.Muller V, Boer RJ de, Bonhoeffer S, Szathmary E (2018) Biol Rev 93:505-528. Müller V, 2018

      2.Talmage DW (1957) Allergy and immunology. Ann Rev Med 8:239-256 TALMAGE DW, 1957

      3.Forsdyke DR (1996) The origins of the clonal selection theory of immunity. FASEB J 9:164-166.Forsdyke DR, 1995

      4.Lederberg J (2002) Instructive selection and immunological theory. Immunol Rev 185:50-53.Lederberg J, 2002

      5.Calis JJA, de Boer RJ, Kesmir C (2012) Degenerate T-cell recognition of peptides on MHC molecules creates large holes in the T-cell repertoire. PLoS Comput Biol 8:e1002412.Calis JJ, 2012

      6.Forsdyke DR (1975) Further implications of a theory of immunity. J Theoret Biol 52:l87-l98.Forsdyke DR, 1975

      7.Vrisekoop N, Monteiro JP, Mandl JN, Germain RN (2014) Revisiting thymic positive selection and the mature T cell repertoire for antigen. Immunity 41:181-190.Vrisekoop N, 2014

      8.Marrack P. et al. (2017) The somatically generated portion of T cell receptor CDR3alpha contributes to the MHC allele specificity of the T cell receptor. eLife 6:e30918.Marrack P, 2017

      9.Forsdyke DR (2016) Evolutionary Bioinformatics. 3rd Edition. Springer, New York.


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    1. On 2017 Aug 25, Jason R Richardson commented:

      Drs. Blakely and Melikian, thank you both for your insightful comments. In working with these cells over a number of years, we have found that while the cell line expresses all of the necessary components to be identified as dopaminergic, it neither synthesizes a significant amount of dopamine nor has functional dopamine uptake. This is likely because of the diffuse nature of the protein expression identified by Dr. Melikian, which may be because it was generated by immortalizing cells from embryonic day 12 rat. I believe when I was a postdoc, I did some co-labeling and observed that the DAT was primarily present in the ER and golgi in these cells, suggesting that the intracellular machinery may not be mature enough to fully generate a functional and fully glycosylated DAT. I should note that the original group that made the N27 line recently re-cloned it and purified cells from this new clone had higher expression levels of both TH and DAT (Gao et al., 2016). Although, there were no functional studies for DAT-mediated uptake with the re-cloned line, they did show a modest increase in susceptibility to 6-OHDA and MPP+. Our primary goal for this paper was to better characterize the role of histone acetylation and transcription factor binding in the epigenetic regulation of DAT expression based on our previous studies in SK-N-AS cells (Green et al., 2015) in a rat cell line that we could then translate to in vivo studies. I certainly agree that additional studies in cells that display a more mature phenotype that allow for determination of function are warranted. I think both comments bring out a very important point regarding the study of transporter regulation. That is, cell context and system are critical to the interpretation and translation of mechanisms regulating the DAT to in vivo systems.


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    2. On 2017 Aug 19, Randy Blakely commented:

      Thanks Haley for your note. The field studying dopamine transporter regulation would greatly benefit from a a cell line expressing endogenous transporter protein, validated through RNA, western blotting and critically transport activity measurements demonstrating pharmacological sensitivities appropriate to brain DAT. Some cell lines are said to be "dopaminergic", e.g. SH-SY5Y, but these express NET activity not DAT activity, like PC-12 cells.


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    3. On 2017 Aug 19, Haley Melikian commented:

      We have also used the cell line in this study (N27), but have neither detected DAT protein by immunoblot, nor measured specific DA uptake using a standard radiotracer flux assay. While low DAT mRNA levels may be expressed, the evidence presented does not strongly support endogenous DAT protein expression. The immunofluorescence signal shown appears primarily diffuse and intercellular, and not in agreement with the typical plasma membrane DAT localization. Indeed, these cells have been used by transporter biologists, but only in the context of heterologous DAT expression. I would be curious to know whether the authors have measured specific DA uptake in these cells.


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    1. On 2017 Dec 05, Karen Woolley commented:

      Congratulations to Dr Pushparajah on this editorial and congratulations again to her and her colleagues at UCB for generating evidence on the value of making the results of clinical research more accessible to the public via plain-language summaries. http://journals.sagepub.com/doi/abs/10.1177/2168479017738723. Ironically, when clinical research results go public (eg, through a peer-reviewed PUBLIC-ation), the public is rarely involved. This needs to change. Publications should be "of the people, BY the people, FOR the people". We need patients to be engaged - ethically and meaningfully - in the publication ecosystem. We know patients are diverse, but some patients are accessing the peer-reviewed literature for information. We need to work with patients, journal editors, sponsors, and publication professionals to help make the "patient-to-peer-reviewed publication" journey better, easier, and more reliable than their journey to Dr Google.Disclosures: Financial: I am a paid employee of Envision Pharma Group, which provides medical communication services and technology solutions. I have shares in Johnson & Johnson and have been a government-appointed director on the board of 5 hospitals. Nonfinancial: I am an active member and past director of associations that advocate for ethical publication practices. I am a research partner with international patient leaders and advocacy organisations


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    1. On 2017 Oct 11, Harri Hemila commented:

      Zinc lozenges and vitamin C are promising approaches for the common cold

      Papadopoulos NG, 2017 reviewed promising approaches for the treatment and prevention of viral respiratory tract infections, but did not include any meta-analyses or trial reports on zinc lozenges and vitamin C.

      Three randomized trials using zinc acetate lozenges found that common cold duration was shortened by 2.7 days (95% CI: 1.8-3.3 days), Hemilä H, 2016, and that the rate of recovery from colds was increased 3.1-fold (2.1-4.7), Hemilä H, 2017. Although zinc lozenges are dissolved in the oro-pharyngeal region, they also shortened the duration of symptoms in the nasal region: nasal discharge by 34% (17-51%) and nasal congestion by 37% (15-58%), Hemilä H, 2015.

      The binding of zinc to acetate is weaker than to gluconate and there have been suggestions that zinc acetate might therefore be a better salt for lozenges. Nevertheless, it is not evident that differences at the chemical level between these salts are translated into substantial differences at the clinical level. A meta-analysis found no evidence that lozenges formulated from either of these 2 salts differed in their effects on common cold duration, Hemilä H, 2017. In addition, 2 zinc gluconate trials found that the rate of recovery from colds was influenced to a similar extent as that for the 3 zinc acetate trials, Hemilä H, 2017.

      In the trials that reported benefits of zinc lozenges, the total daily dose of elemental zinc was over 75 mg/day. This dose is higher than the recommended intake of 11 mg/day for men and 8 mg/day for women in the USA. However, 100-150 mg/day of zinc has been administered to certain patient groups for months with few adverse effects, and 150 mg/day of zinc is currently one standard treatment for Wilson’s disease, Hemilä H, 2017. Thus, it seems unlikely that 80-100 mg/day of zinc for about a week for treating a cold might lead to long-term adverse effects. There are therefore good reasons for classifying zinc lozenges as a promising approach to treat colds.

      A Cochrane review showed with a narrow confidence interval that vitamin C does not prevent colds in the general community, Hemilä H, 2013. However, a meta-analysis of 5 randomized trials with participants under heavy short-term physical stress showed that vitamin C decreased the incidence of colds by 52% (36-65%). Thus, vitamin C seems to have prophylactic effects albeit only in special conditions.

      A meta-analysis of more than 2 dozen placebo-controlled trials calculated that ≥1 g/day of vitamin C shortens the duration of colds in children by 18% (9-27%) and in adults by 8% (4-12%), Hemilä H, 2013. Furthermore, 2 trials found a linear dose-response association in the effects on common cold duration by up to 6- and 8-g/day of vitamin C, with colds being shortened by about 20% with the higher dose, Hemilä H, 2017. Still higher therapeutic dosages might lead to greater benefits but such dosages have not been investigated yet. More research also on vitamin C is evidently warranted.


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    1. On 2017 Oct 11, Clive Bates commented:

      The most misleading thing about this paper is not merely the paper itself, but the way authors chose to present the findings to the media. As so often happens in academic work in this field, association became causation, uncertainty became confidence and very weak methods became the foundations of an assertive press release.

      The press notice headline is:

      Vaping doubles risk of smoking cigarettes for teens.

      Of course, that is a made-for-media headline but deeply misleading about causation and grossly over-confident, given the study's limitations.

      Much more likely is that the characteristics (personality, social and family context) that cause people to smoke also cause them to vape and the effects measured are the result of uncorrected confounding or reverse causation. It is quite possible that vaping acts to prevent smoking in people who would otherwise be susceptible to taking up smoking - an obvious possibility given the decline in teenage smoking in the US that coincided with the rise of vaping (albeit mostly experimentation and mostly without nicotine) - trends charts here.

      My more detailed review of this study is here: Review of controversial Canadian ‘gateway effect’ study


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    2. On 2017 Sep 18, Neil McKeganey commented:

      This paper will be interpreted by some as proof that using e-cigarettes acts as a gateway to smoking. That misleading impression is actually encouraged by one of the lead authors of the paper who in an interview for the Business New under the headline "E-cigarettes may double risk of tobacco smoking in teenagers" comments that the study provides a "yes" answer to the question of whether vaping lead to smoking. That statement is however in direct conflict with the stated limitations included within the published paper to the effect that "..the current study makes no claim of cause and effect". In fact this study is not even about the relationship between e-cig use and actual smoking but about e-cig use and a constructed variable for individual's susceptibility to smoke with the latter defined in terms of adolescents indication that they had not taken a firm decision not to smoke. So not having decided not to smoke is interpreted here as an indication that the individual is susceptible to future smoking. The authors rightly acknowledge that not all of those who are judged to be susceptible to smoking will actually go on to smoke in the future. Clearly that definition is problematic since it may well have been that many of the younger pupils had not found themselves in a situation where they felt they felt compelled to establish a clear view for themselves on the possibility of their future smoking. What the researchers have found here is that those pupils who in their definition were susceptible to smoking were more likely to have used e-cigarettes. As with other similar studies there is an entirely different possible explanation for that finding which has to do with the possibility that those pupils who reported past e-cig use were indeed more likely to smoke in the future because of the influence of a different variable e.g. willingness to experiment with different substances with that variable influencing both the likelihood of smoking and the likelihood of e-cig use rather than the latter influencing the former. As the authors acknowledge they have no measure here of intensity of e-cig use; rather they used a measure of any past use (of whatever actual frequency) and any use over the last 30 days (again of whatever actual frequency). As a result the e-cig using group could contain individuals who had used e-cigs on a single occasion in the past or a single occasion in the last 30 days. The only real conclusion which the authors can draw from this study is as they say that "use of e cigarettes among never smokers may increase the risk of future cigarette use.." It could equally be pointed out, though the authors choose not to say this, that "e-cigarette use amongst non-smokers may not increase future cigarette use."


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    1. On 2017 Aug 16, Deepa Bhartiya commented:

      Authors report primitive, rare Oct-4 positive neural stem cells (pNSCs) in adult mouse brain that form spheres in vitro and also participate in endogenous regeneration. The pNSCs are activated in response to a stress produced by treatment with an antimitotic agent. Authors claim credit for pNSC to be the only adult stem cell to express OCT-4. But this is not true.

      We have similarly reported that rare, small sized, pluripotent OCT-4 positive stem cells exist in adult testis, survive chemotherapy (https://www.ncbi.nlm.nih.gov/pubmed/27663915) and rather get activated in response to stress produced by busulphan treatment. Similarly OCT-4 expressing stem cells in adult bone marrow survive and are activated after radiotherapy (https://www.ncbi.nlm.nih.gov/pubmed/21034791) and chemotherapy (https://www.ncbi.nlm.nih.gov/pubmed/27095238). OCT-4 positive stem cells exist in all adult organs and are not limited to only the adult brain as claimed by the authors of this study. This needs to be corrected and a bigger picture of existence of pluripotent OCT-4 positive stem cells in various adult tissues needs to emerge.


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    1. On 2017 Oct 31, ANTHONY BAUGHN commented:

      My coauthors and I stand firmly behind the design of our study, methods for data collection, presentation and interpretation, and the major conclusions that were drawn in our manuscript. We look forward to continued dialogue and the objective responses of others in the tuberculosis and antimicrobial drug communities regarding this matter.


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    2. On 2017 Oct 19, Wanliang Shi commented:

      Please see the response: https://www.nature.com/articles/s41598-017-06415-5


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    1. On 2017 Dec 05, Joseph M Barnby commented:

      This letter to the editor was originally submitted to JMIR uHealth and mHealth. The letter was later withdrawn as we became aware it was eligible to have an APC applied to it; in spite of what we understood the JMIR APC policy to be regarding letters to the editor. Neither of our institutions at the time of publication were able to cover the relevant fees. We have posted our reviewed letter here and invited Clare Killikelly to post her submitted response.

      Authors:

      Mr J M Barnby - Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, SE5 8AF. (Corresponding Author; joe.barnby@kcl.ac.uk)

      Dr S A J Fonseca - Division of Psychiatry, University College London, WC1E 6BT.

      The Editor JMIR mHealth and uHealth

      On 20th July 2017, your journal published a useful and wide-ranging systematic review of mobile and web-based technologies for people with psychosis [1] – a field of mental health which has huge potential to shape the way service users are able to take control of their treatment. Authors found service user aid in design, length of intervention, and social support were all important factors in whether a participant would stop using a digital intervention.

      Part of the authors’ summary was that, a) symptom severity may not have a significant effect on drop-out, and b) continuing to develop these interventions alongside users is vital. However, we believe that point a) is not clearly supported by the evidence presented in the article, and point b) misses out (or doesn’t plainly state) a crucial aspect of the technology.

      We believe concluding that symptom severity doesn’t have a significant effect on drop-out is premature. The authors reviewed 20 studies that used web-based or mobile technologies and found 6 that measured the impact of symptom severity, chronicity, and duration on drop-out [2, 3, 4, 5, 6, 7]. However, the review only presents the results of those who stayed in the trials, and we believe it’s safe to assume that participants did not drop out randomly. As there were several individuals who declined to take part or dropped out of the study, and since we have no data for this group, we cannot assume that symptom severity does not affect drop-out. In fact, we would argue that it is likely this group were more symptomatic than those who took part. We believe the authors should have stated this more clearly and commented on it in their conclusions about drop-out, including suggesting ways to test this.

      The authors only mention that intensity, frequency, and duration of interventions are all vital to adherence, but don’t specifically discuss the role of User Experience/User Interface (UXUI) – a role in software design which tries to make interaction with content as smooth and intuitive as possible. This is a separate but related concept to ‘co-production’ – the involvement of service users in intervention design. Commercial mobile-phone and web-based software is continuously developing more sophisticated and visually pleasing versions. It’s reasonable to hypothesise that better UXUI may result in less drop-out of interventions. Testing this hypothesis may give insight into how a more pleasing user experience may affect drop-out, and how extra investment into UXUI with user input may improve symptom control through better engagement. Indeed, research has suggested this approach might be useful in other areas of healthcare [9] and proposed it might be an important aspect to health intervention design [10]. UXUI focus is increasingly more relevant as mainstream software designers find more ways to keep users engaged, and we believe this highlights that digital interventions may have to compete for attention to meet the expectations of the users they wish to benefit.

      In future research aimed at improving user adherence we suggest testing, a) whether simple, text-based designs are as effective as visually pleasing well-designed interfaces when the content is constant (for example, computerised cognitive behavioural therapy), and b) if gamification of therapeutic content improves engagement.

      We would like to thank the authors for their current review in this important and emerging area of mental health research, and hope that these comments serve to constructively build upon the discussion.

      Yours sincerely, Joseph M Barnby & Dr J Andres S Fonseca

      References:

      [1] Killikelly C, He Z, Reeder C, Wykes T. Improving Adherence to Web-Based and Mobile Technologies for People With Psychosis: Systematic Review of New Potential Predictors of Adherence. JMIR Mhealth Uhealth 2017; 5(7):e94

      [2] van der Krieke L, Emerencia A, Boonstra N, Wunderink L, de JP, Sytema S. A web-based tool to support shared decision making for people with a psychotic disorder: randomized controlled trial and process evaluation. J Med Internet Res 2013 Oct 07;15(10):e216

      [3] Ben-Zeev D, Brenner C, Begale M, Duffecy J, Mohr D, Mueser K. Feasibility, acceptability, and preliminary efficacy of a smartphone intervention for schizophrenia. Schizophr Bull 2014 Nov;40(6):1244-1253

      [4] Palmier-Claus J, Ainsworth J, Machin M, Dunn G, Barkus E, Barrowclough C, et al. Affective instability prior to and after thoughts about self-injury in individuals with and at-risk of psychosis: a mobile phone based study. Arch Suicide Res 2013;17(3):275-287.

      [5] Schlosser D, Campellone T, Kim D, Truong B, Vergani S, Ward C, et al. Feasibility of PRIME: a cognitive neuroscience-informed mobile app intervention to enhance motivated behavior and improve quality of life in recent onset schizophrenia. JMIR Res Protoc 2016 Apr 28;5(2):e77

      [6] Kimhy D, Vakhrusheva J, Khan S, Chang RW, Hansen MC, Ballon JS, et al. Emotional granularity and social functioning in individuals with schizophrenia: an experience sampling study. J Psychiatr Res 2014 Jun; 53: 141-148

      [7] Hartley S, Haddock G, Vasconcelos ES, Emsley R, Barrowclough C. An experience sampling study of worry and rumination in psychosis. Psychol Med 2014 Jun;44(8):1605-1614.

      [8] Gleeson J, Lederman R, Wadley G, Bendall S, McGorry P, Alvarez-Jimenez M. Safety and privacy outcomes from a moderated online social therapy for young people with first-episode psychosis. Psychiatr Serv 2014 Apr 01;65(4):546-550

      [9] Boulos MN, Gammon S, Dixon MC, MacRury SM, Fergusson MJ, Rodrigues FM, Baptista TM, Yang SP. Digital games for type 1 and type 2 diabetes: underpinning theory with three illustrative examples. JMIR Serious Games. 2015 Jan;3(1).

      [10] Wilhide III CC, Peeples MM, Kouyaté RC. Evidence-based mHealth chronic disease mobile app intervention design: development of a framework. JMIR research protocols. 2016 Jan;5(1).


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    1. On 2017 Aug 28, Daniel Corcos commented:

      Haymart et al. recommend active surveillance by mammography for ductal carcinoma in situ (DCIS) of the breast, on the basis that it is a low-risk cancer. Actually, DCIS is at low-risk because it is removed soon after diagnosis, so there is no direct evidence for an intrinsic low malignant potential of this form of early breast cancer. The idea that breast cancer is overdiagnosed rests on the observation of an excess of breast cancers concomitant to mammography screening implementation, which is persistent over years. However, mammography-induced cancers better explain this excess, as they occur with a delay and in older women, like the excess cancers that are observed. Delayed surgery has a dramatic effect on breast cancer survival (1). Active surveillance of DCIS would worsen the prognosis of this otherwise low-risk cancer.

      1) Bleicher RJ, Ruth K, Sigurdson ER, et al. Time to Surgery and Breast Cancer Survival in the United States. JAMA Oncol 2016;2:330-9.


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    1. On 2017 Oct 04, Gurpreet K. Rana commented:

      The MEDLINE search strategies are available upon request from the authors as they were not included in article as intended. - G.K. Rana


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    1. On 2017 Jul 30, Zvi Herzig commented:

      The RCTs instructing controls to avoid artificial sweeteners (Peters et al and Blackburn et al) show significantly reduced BMI in the treatment group. It shouldn't be surprising that the other trials, merely assigning controls to water or placebo, fail to show reduced BMI in the treatment group. Artificial sweeteners can only reduce BMI if they're positioned to displace sugar intake. This isn't the case where the controls are given water or placebo instead of the artificial sweetener.


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    1. On 2017 Sep 05, William Davies commented:

      CCN3 has recently been associated with vulnerability to Obstructive Sleep Apnea (Weingarten JA, Bellner L, Peterson SJ, Zaw M, Chadha P, Singh SP, Abraham NG. The association of NOV/CCN3 with obstructive sleep apnea (OSA): preliminary evidence of a novel biomarker in OSA. Horm Mol Biol Clin Investig. 2017 doi:10.1515/hmbci-2017-0029); this is interesting in light of the fact that sleep disruption may precipitate postpartum psychosis (Lewis KJ, Foster RG, Jones IR. Is sleep disruption a trigger for postpartum psychosis? Br J Psychiatry. 2016 May;208(5):409-11)


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    1. On 2017 Jul 31, Tom Kindlon commented:

      Overall averages for Table 2, "Mean change (95% CI) in patient-reported measures between assessment and 1-year follow-up across CFS/ME specialist services":

      Frustratingly, the overall weighted averages for the measures included in Table 2 were not included in the paper.

      Two people have independently calculated them. Here they are: n = 432

      Chalder Fatigue Scale (range 0–33) -6.05

      SF36 Physical Function Subscale (range 0–100) 4.19

      Work & Social Adjustment Scale (range 0–40) -3.40

      Visual analogue pain rating scale (range 0–100) -4.42

      HADS Anxiety Score (range 0–21) -0.56

      HADS Depression Score (range 0–21) -1.35

      Epworth Sleepiness Scale (range 0–24) -1.07

      Jenkins Sleep Jenkins (range 0–20) -1.37

      CIS20R Fatigue Subscale (range 8–56) -4.73

      CIS20R Concentration Subscale (range 5–35) -2.67

      CIS20R Motivation Subscale (range 4–28) -2.42

      CIS20R Activity Subscale (range 3–21) -1.95


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    1. On 2017 Sep 07, Pranay Jindal commented:

      Thank you for your comments and feedback.

      The purpose of the article was to critically analyze the Flesch Reading Ease (FRE) and Flesch-Kincaid Reading Grade Level (FKRGL) and their use in assessing the reading level/perceived difficulty of a written text. We agree with you that grade level as assessed by readability formulas do not equate with readers understanding. In the article, we mention “in their assessments, FRE and FKRGL do not take into account (1) document factors (layout, pictures and charts, color, font, spacing, legibility, and grammar), (2) person factors (education level, comprehension, health literacy, motivation, prior knowledge, information needs, anxiety levels), and (3) style of writing (cultural sensitivity, comprehensiveness, and appropriateness), and thus, inadequately assess reading level”.

      We do not explicitly support the use of readability formulas to assess the reading level/perceived difficulty of a written text, and in our article recommended that “future research needs to develop generic and disease-specific readability measures to evaluate comprehension of a written document based on individuals' literacy levels, cultural background, and knowledge of disease”. We encourage researchers and clinicians to move towards assessment of comprehension of written documents. However, in the absence of a reliable and valid measure to measure comprehension and the ease of using Flesch Reading Ease (FRE) and Flesch-Kincaid Reading Grade Level (FKRGL) via Microsoft office makes them a popular and easy choice.


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    2. On 2017 Jul 24, Donna Berryman commented:

      While the authors do a pretty good job of pulling together the basic information about some popular readability formulas, they tend to support the idea that these formulas are somehow worthwhile. It is time to focus on the idea that grade level or readability formula results do not equate to reader understanding. As Leroy, Kauchak and Hogue (2016) write: "The lack of strong evidence for increased comprehension after using readability formulas may indicate that it is perceived difficulty that is being manipulated: The text looks easier but may not necessarily be easier to understand." (PMID 27043754) Wan et al (2013) do a good job of showing how different readability formulas vary in their calculations (see PMID 22835706). They conclude that "the SMOG formula appears to be more ideally suited for use in a health care context, as it has been validated against 100% comprehension..." But, beyond that, I would heartily encourage that we start thinking beyond written materials. I'd recommend the work of Donald L. Rubin on listenability (see PMID 23030569 for one example). Most health information is dispensed orally.


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    1. On 2017 Sep 01, Seán Turner commented:

      Alou et al. (2016) [PMID 27330818] write that strain Marseille-P2366 (= CSUR P2366 = DSM 102091) is the type strain of Bacillus mediterraneensis. Contradictorily, Cadoret et al. (2017) [PMID 28706723] write that the type strain of Bacillus mediterraneensis is Marseille-P2384 (= CSUR P2384 = DSM 102091), and that strain Marseille-P2366 (= CSUR P2366 = DSM 102112) is the type strain of Bacillus massilinigeriensis.


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    1. On 2017 Oct 02, Serge Ahmed commented:

      This article reports an interesting set of experiments showing that ravens repeatedly choose among a set of different objects, an object that will prove several minutes or hours later to be useful to obtain food. The authors interpret this preference as evidence that ravens would be able to plan for the future. However, since the preferred object was repeatedly and selectively paired with food reward during initial training, one cannot definitively rule out the involvement of non-planning processes. For instance, ravens could prefer the would-be useful object, not because they anticipate its future utility, as hypothesized by the authors, but merely because they attach more affective and/or motivational value to the object due to its past selective association with food reward. To rule out this associative mechanism, it is important to add a control condition where, all else being equal, choice of the previously food-paired object is not followed by an opportunity to use it to obtain food (for a similar criticism and a specific example of a control condition, see: Redshaw et al. https://www.ncbi.nlm.nih.gov/pubmed/28927634).


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    1. On 2017 Sep 05, MARK VRABEL commented:

      Good to see the "Librarian AS" author has been corrected.


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    2. On 2017 Aug 16, MARK VRABEL commented:

      Thanks for commenting after seeing my MEDLIB-L post and #medlibs tweet about this "Librarian AS" error.


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    3. On 2017 Aug 14, Melissa Rethlefsen commented:

      Sam Johnson is the Academic Support Librarian, and he is named as an author. Let's hope this gets updated, though!


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    4. On 2017 Aug 14, Donna Berryman commented:

      It's quite jarring to see that "Academic Support Librarian" - a position, not a person - is listed as an author on this paper. Assuming that an academic support librarian actually did participate, then the person (not the position) should be named. I'm hoping this will be corrected by the time the article is in print (rather than the epub ahead of print status).


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    1. On 2017 Jul 28, Morten Oksvold commented:

      “Dunoyer has been a long-time colleague and collaborator of Olivier Voinnert, and recently a number of their studies, three with Dunoyer as first author, have been retracted while a number more have had formal corrections published to address problems with presented data."

      Please note that Olivier VOINNET is his correct name and Dunoyer's master has so far eight retractions and twenty corrections(only 12 of them are directly searchable in PubMed):

      https://www.ncbi.nlm.nih.gov/pubmed?term=(voinnet o[Author]) AND "retracted publication"[Publication Type]

      https://www.ncbi.nlm.nih.gov/pubmed?term=(Voinnet o[Author]) AND "published erratum"[Publication Type]

      (Link to full report here: https://www.ethz.ch/content/dam/ethz/news/medienmitteilungen/2015/PDF/untersuchungsbericht/Report_of_ETH_Commission_Voinnet.pdf )

      Please also note that in reference 7 in the mentioned article (Incarbone, M et al., Nature Plants, June 2017) they cite Deleris A et al., Science 2006, which represents one of the articles that supposed to be retracted (see quote from the report below).

      From the investigation report: "Although it is obviously the journal's prerogative, the former (category 2) papers, particularly those containing well documented intentional manipulations (PLoS Pathogens 2013 9:e1003435; Plant Cell 2004 16: 1235; Science 2006 313: 68; PNAS 2006 103: 19593 and EMBO J 2010 29: 1699), should be retracted through OV's requests as being non-factual, irrespectively of whether the reported observations have been reproduced by others."

      I find it problematic that Nature Plants accept this kind of practice, by apparently legitimating well documented intentional manipulations as facts.


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    1. On 2017 Aug 20, Daniel Weiss commented:

      This review of Tickborne diseases other than Lyme by Drs. Eickhoff and Blaylock paints a frightening picture of diverse illnesses increasing in prevalence in the United States.

      A recent survey found over 20% of U.S residents reporting a tick attached to themselves or a family member within the previous year(1). Yet, as Eickhoff and Blaylock point out, the absence of a known tick bite “never precludes the diagnosis of a tick-borne infection” and “co-infections with multiple pathogens may occur”. Throughout their review, the authors emphasize that insensitive laboratory testing methods increase the complexity of diagnosis, and result in an unknown risk to the blood supply. All health care practitioners require a high index of suspicion and sound clinical judgment to identify individual tick-borne infections. Simultaneous co-infections increase the diagnostic and therapeutic challenge.

      As examples of the challenges faced, Borrelia miyamoti infection may not demonstrate the erythema migrans rash occurring with B. burgdorferi—the agent of Lyme disease. But up to 70% of patients with Lyme disease have no history of this rash(2). Similarly, there is no proven clinical difference between the rash seen with B. lonestari and B. burgdorferi. Lonestar ticks can transmit both spirochetes(3).

      Because no gold standard exists to prove the absence of any of these infections, practitioners must avoid declaring with certitude that no infection is present—especially if an acute infection has gone untreated or undertreated. In his accompanying editorial, Dr. Mandell reiterated the difficulty of identifying acute tick-borne infection. Therefore, we were confused by his concluding paragraph. Given the diagnostic uncertainties, one must not dismiss dogmatically the possibility of an infection, either acute or chronic. A call for improved diagnostics and more effective therapeutics is the more logical response to the issues raised by this important review.

      1. Hook SA, Nelson CA, Mead PS. U.S. public's experience with ticks and tick-borne diseases: Results from national HealthStyles surveys. Ticks Tick Borne Dis. 2015;6(4):483-8. doi: 10.1016/j.ttbdis.2015.03.017. PubMed PMID: 25887156.
      2. Aucott JN, Seifter A, Rebman AW. Probable late lyme disease: a variant manifestation of untreated Borrelia burgdorferi infection. BMC Infect Dis. 2012;12:173. Epub 2012/08/03. doi: 10.1186/1471-2334-12-173. PubMed PMID: 22853630; PMCID: PMC3449205.
      3. Clark KL, Leydet B, Hartman S. Lyme borreliosis in human patients in Florida and Georgia, USA. Int J Med Sci. 2013;10(7):915-31. doi: 10.7150/ijms.6273. PubMed PMID: 23781138; PMCID: PMC3675506.


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    1. On 2017 Aug 09, David Keller commented:

      Two Large Epidemiological Studies Reach Opposite Conclusions Regarding Dementia Risk From PPI Use

      A recent German study [1] found a significant 44% increased incidence of dementia with regular proton-pump inhibitor (PPI) antacid use, in a cohort of 73,679 baseline non-demented persons over age 75, of whom 29,510 developed dementia over 8 years, and 2950 were regular PPI users. The authors of that study boldly concluded that "avoidance of PPI medication may prevent the development of dementia" and called for a randomized controlled trial of PPIs to better assess this risk.

      The current study [2] looked at the 70,718 cases of Alzheimer disease (AD) diagnosed in Finland over a 7-year period and found no difference in risk based on regular PPI use, and a confirmatory lack of association of risk with dose of PPI, or duration of PPI use.

      Which of these two large, painstaking studies in similar populations is correct? PPI use either does or does not increase the risk of dementia, and it is crucial to know which is true. Millions take PPI medication daily to control acid reflux, but would be better off taking less effective or tolerable treatments if PPIs increase the risk of dementia.

      Taipale and colleagues identified PPI users from medication-purchase data, whereas Gomm and colleagues identified PPI users from prescription data, which did not indicate whether the prescriptions were actually filled. Obviously, persons who purchase a medication are more likely to be taking it than persons who are merely prescribed it. However, the effect of non-compliance with prescribed PPI therapy in the Gomm study is to actually increase the risk of dementia caused by taking PPI medication. The more non-compliance among patients in Gomm's PPI group, the greater the dementia-increasing effect PPIs must have had on compliant patients to explain the observed overall increased dementia in the PPI group. So, the difference in how PPI-takers were identified cannot account for the discrepant results of these studies.

      How much credence can we place in epidemiological results if two large studies can report polar opposite conclusions with such apparent certainty? Is it ethical, or even possible, to randomize patients to less-effective medications than PPIs in a controlled trial, to definitively determine whether PPIs truly increase the risk of dementia?

      References

      1: Gomm W, von Holt K, Thomé F, Broich K, Maier W, Fink A, Doblhammer G, Haenisch B. Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. JAMA Neurol. 2016 Apr;73(4):410-6. doi: 10.1001/jamaneurol.2015.4791. PubMed PMID: 26882076.

      2: Taipale H, Tolppanen AM, Tiihonen M, Tanskanen A, Tiihonen J, Hartikainen S. No Association Between Proton Pump Inhibitor Use and Risk of Alzheimer's Disease. Am J Gastroenterol. 2017 Jul 11. doi: 10.1038/ajg.2017.196. [Epub ahead of print] PubMed PMID: 28695906.


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    1. On 2017 Jul 14, Seán Turner commented:

      The authors cite strain CECT 9186 as type, but this is also cited as the type strain of Blastomonas quesadae (PMID 28631592) and is listed as such in the CECT online catalog.


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    1. On 2017 Jul 17, Donald Forsdyke commented:

      IF G-QUADRUPLEXES, WHY SO MANY ADENINES?

      It is good to see the problem of EBV immune evasion focused, not on the translation product of EBNA1 mRNA (1), but on the mRNA itself (2). However, it is puzzling that the sequence encoding the glycine-alanine repeats is enriched not only in guanines (Gs), but also in adenines (As). In such a GC-rich genome (60% GC), there is a scarcity of As, yet they are concentrated in the glycine-alanine repeat-encoding region. In other words, codons have been selected for their general purine-richness, not just for their G-richness (3). While it is conceivable that the As somehow assist consecutive Gs to form G-quadruplexes, consideration might have been given to the hypothesis that the G-quadruplexes may merely be helpful by-products of the fundamental need to purine-load the mRNA.

      EBV is not alone in this respect. EBV and HTLV-1 share common characters. Both are deeply latent, GC-rich viruses. They persist in their human hosts for long periods often with no obvious detrimental effects. Most of their proteins are encoded by pyrimidine-rich mRNAs. The HTLV-1 provirus encodes its pyrimidine-rich mRNAs in its "top" sense strand. But there is a "bottom" strand transcript. This is heavily R-loaded and is translated into a basic zipper protein (HBZ) which is poorly immunogenic and is increasingly seen, like EBNA-1, as playing a major role in immune evasion (4-6).

      1. 1.Levitskaya, J. et al. (1995) Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375:685–688. Levitskaya J, 1995
      2. 2.Lista MJ et al. (2017) Nucleolin directly mediates Epstein-Barr virus immune evasion through binding to G-quadruplexes of EBNA-1 mRNA. Nature Commun 8:16043. Lista MJ, 2017
      3. 3.Cristillo AD et al. (2001) Double-stranded RNA as a not-self alarm signal: to evade, most viruses purine-load their RNAs, but some (HTLV-1, Epstein-Barr) pyrimidine-load. J Theor Biol 208:475–491.Cristillo AD, 2001
      4. 4.Cook LB et al. (2013) HTLV-1: Persistence and pathogenesis. Virology 435:131–140. Cook LB, 2013
      5. 5.Shiohama et al. (2016) Absolute quantification of HTLV-1 basic leucine zipper factor (HBZ) protein and its plasma antibody in HTLV-1 infected individuals with different clinical status. Retrovirology 13:29 Shiohama Y, 2016
      6. 6.Forsdyke DR EBV Webpage


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    1. On 2017 Sep 08, Falk Leichsenring commented:

      Toward a more Balanced Perspective on Anxiety Treatment

      Falk Leichsenring 1, Allan Abbass 2, Patrick Luyten13

      1 Department of Psychosomatics and Psychotherapy, Justus-Liebig-University Giessen, Ludwigstr. 76, D-35392 Giessen, Germany 2 Department of Psychiatry, Dalhousie University; Centre for Emotions and Health, Halifax, 8203 5909 Veterans Memorial Lane, Halifax, NS, Canada, B3H 2E2 3 Faculty of Psychology and Educational Sciences, University of Leuven, Klinische Psychologie (OE), Tiensestraat 102 - bus 3722, 3000 Leuven, Belgium, and Research Department of Clinical, Educational and Health Psychology, University College London, Gower Street, London WC1E 6BT, UK

      Stein and Craske recently published a viewpoint article entitled "Treating Anxiety in 2017".1 Yet, the treatment section excludes other evidence-based, widely-used non-medical treatment options while exclusively recommending pharmacotherapy and Cognitive Behavioral Therapy (CBT).

      The authors state that most empirical support exists for CBT. However, a recent meta-analysis showed that only one sixth of studies are of high quality.2 In more than 80% of the studies CBT was compared to a waiting list, that is to a relatively weak comparator that may even represent a nocebo condition.2 In panic disorder, CBT was not superior to treatment-as-usual, only to waiting list.2 There was also significant evidence of publication bias.2 Based on these and other findings, this meta-analysis concluded that CBT was “at best probably effective” in anxiety disorders, which markedly contrasts with the overly optimistic depiction of the effects of CBT by Stein and Craske.

      In exclusively recommending CBT, Craske and Stein completely bypass other forms of psychotherapy such as interpersonal therapy or psychodynamic therapy, even though both are efficacious in anxiety disorders. 3,4 Moreover, comorbidity is the norm in anxiety disorders but there is lack of evidence to support CBT in complex or comorbid anxiety populations, whereas brief psychodynamic therapy has been found to be more effective than other treatments in reducing anxiety in patients with depression. 5 The evidence for the proposed working mechanisms in anxiety disorders is also far less clear than Craske and Stein suggest, and their assertion that working mechanisms of CBT are different from other types of psychotherapy is similarly largely unsupported.

      It is also quite perplexing that the authors recommend benzodiazepines for patients for whom SSRIs or CBT failed without consideration of the above mentioned other commonly used, non-medical treatments. Given evidence that long-term effects of pharmacotherapy in anxiety disorders are unknown due to the lack of follow-up studies6, such a suggestion biases patient care in favour of often endless medication treatments.

      This unbalanced discussion of treatments for anxiety disorders is the more perplexing since the authors' attention was recently called to the fact that other types of psychotherapy have been found to be equally effective in anxiety disorders7, based on studies of good quality .4

      Biased clinical guidance such as the one by Stein and Craske is highly undesirable from a scientific and clinical perspective, and can be easily avoided by including proponents of rival approaches (adversarial collaboration).

      References

      1. Stein MB, Craske MG. Treating Anxiety in 2017: Optimizing Care to Improve Outcomes. JAMA. Jul 18 2017;318:235-236.
      2. Cuijpers P, Cristea IA, Karyotak E, Reijnders M, Huibers MHJ. How effective are cognitive behavior therapies for major depression and anxiety disorders? A meta-analytic update of the evidence World Psychiatry. 2016;15:245-258.
      3. Markowitz JC, Petkova E, Neria Y, Van Meter PE, Zhao Y, Hembree E, Lovell K, Biyanova T, Marshall RD. Is Exposure Necessary? A Randomized Clinical Trial of Interpersonal Psychotherapy for PTSD. Am J Psychiatry. May 2015;172:430-440.
      4. Keefe JR, McCarthy KS, Dinger U, Zilcha-Mano S, Barber JP. A meta-analytic review of psychodynamic therapies for anxiety disorders. Clin Psychol Rev. Jun 2014;34:309-323.
      5. Driessen E, Hegelmaier LM, Abbass AA, Barber JP, Dekker JJ, Van HL, Jansma EP, Cuijpers P. The efficacy of short-term psychodynamic psychotherapy for depression: A meta-analysis update. Clin Psychol Rev. Aug 1 2015;42:1-15.
      6. Leichsenring F, Leweke F. Social Anxiety Disorder. N Engl J Med. Jun 08 2017;376:2255-2264.
      7. Steinert C, Leichsenring F. No psychotherapy monoculture for anxiety disorders. Lancet. May 13 2017;389:1882-1883.


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    1. On 2017 Sep 02, Randi Pechacek commented:

      Aaron J. Prussin II, second author of this article, and Amy J. Pruden wrote a blog post on microBEnet. The blog post explores the topic of the exposome of the built environment.


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    1. On 2017 Aug 18, NephJC - Nephrology Journal Club commented:

      The position paper for the ISPD on the length of time on peritoneal dialysis (PD) and encapsulating peritoneal sclerosis (EPS) was discussed on July 11th and 12th 2017 on #NephJC, the open online nephrology journal club. Introductory comments written by Nikhil Shah are available at the NephJC website here

      There was a lot of interest in this updated position paper, with 98 participants in the discussion and nearly 700 tweets. Of note, the PDI editor and the UK authors also joined in to provide further background and context to this paper.

      The highlights of the tweetchat were:

      • There participants agree with the epidemiological challenges as outlined by the authors – difficulty defining EPS, lack of interventions, conflicting data on effect of time on PD, difficulty applying available evidence into individual risk assessment. As such, they recognise that this is only a position statement as opposed to a set of guidelines.

      • Ascertainment bias may affect reported incidence rates. Clearer diagnostic criteria may encourage earlier diagnosis and intervention.

      • Applying empiric time-limitations to PD is probably not the solution.

      • Aggressive nutrition, switching dialysis modality and referral to a specialist surgical centre were the preferred management strategies of this group. Some advocate tamoxifen or steroids in addition.

      Transcripts of the tweetchats, and curated versions as storify are available from the NephJC website.

      Interested individuals can track and join in the conversation by following @NephJC or #NephJC on twitter, liking @NephJC on facebook, signing up for the mailing list, or just visit the webpage at NephJC.com.


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    1. On 2017 Aug 04, Luis Mauricio T. R. Lima commented:

      This is an interesting article showing the pramlintide and zinc interaction, and the role of His18 in zinc interaction such as previously reported for human amylin. https://www.ncbi.nlm.nih.gov/pubmed/20536124 https://doi.org/10.1021/ja1007867

      We have also recently reported (2016) the amyloid aggregation of pramlintide, spontaneously and without zinc. https://www.ncbi.nlm.nih.gov/pubmed/27665170 https://doi.org/10.1016/j.bpc.2016.09.007

      Murine amylin, another "stable" (compared to human) amylin analogue, also behaves as amyloid in solution. https://www.ncbi.nlm.nih.gov/pubmed/23974296 https://doi.org/10.1016/j.bpc.2013.07.013

      Murine amylin can also interact with zinc, and this peptide has no His18, and interaction is mediated by several other contacts, and can result in modulation of the amyloid aggregation process. https://www.ncbi.nlm.nih.gov/pubmed/27693831 http://dx.doi.org/10.1016/j.bpc.2016.09.008

      Collectively, these data suggest an universal amyloid behavior of amylin analogues and interaction with zinc, regardless of the presence of proline or His18.


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    1. On 2017 Jul 05, Jim Woodgett commented:

      Kudos for a super study (and bonus for getting the GSK3 isoforms right).


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    1. On 2017 Jul 04, Parmit Singh commented:

      Very interesting finding that sad-7 is showing localization in cytoplasm, peripheral and in nuclear regions. Understanding the correlation of localization with its function in meiotic silencing might be interesting. Interestingly, its expression is similar to sad-4. Also like sad-4, it produces 50% round spores in a heterozygous cross. Homozygous cross is barren in case of sad-7 whereas it is very less productive in case of sad-4. In case of sad-5 and sad-6 (both sad-5 and sad-6 are nucleus localized suppressors, homozygous crosses are fertile. This suggests that the meiotic function of sad-7 might be related to its perinuclear localization or peripheral part of meiotic silencing similar to sad-4. This is further supported by the fact that recently identified two other suppressors cbp20 and cbp80 (cap - binding proteins) produce 80% round spores (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386863/pdf/1149.pdf). Proteins of both genes cbp20 and cbp80 are localized in nucleus and homozygous crosses are fertile like sad-4.


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    1. On 2017 Oct 22, George Kunos commented:

      We read with interest the above article (Varga B, 2017), comparing the pharmacological properties of a series of cannabinoid receptor 1 (CB1R) blockers, including first generation brain-penetrant compounds and more recently introduced peripherally restricted compounds in various tests, including their anti-obesity effects in a mouse diet-induced obesity (DIO) model. The complete lack of effect of the peripheral CB1R inverse agonist JD-5037 in the DIO mouse model was of particular interest to us, as we have earlier documented its high anti-obesity efficacy in DIO mice (Tam J, 2012, Cinar R, 2014) and in a mouse model of Prader-Willi syndrome (Knani I, 2016), as well as its anti-diabetic efficacy in a rat model of type 2 diabetes (Jourdan T, 2013, Jourdan T, 2014). In these as well as in more recent studies (Tam J, 2017, Hinden L, 2018, Udi S, 2017), JD-5037 was dissolved in 4% DMSO/1% Tween-80 in PBS (vehicle #1) for administration by oral gavage (see Jourdan T, 2013), whereas Varga et al. used a 5% Tween-80 solution (vehicle #2). Because in our hands the inclusion of DMSO was critical for keeping this highly lipophilic compound in solution, we compared the oral bioavailability and peripheral target engagement of JD-5037 dissolved in these 2 vehicles. Using vehicle #1, the peak plasma concentration of JD-5037 measured by LC-MS/MS 1 h after oral administration to lean, male C57Bl6/J mice was 1076 ± 208 ng/mL (1840 nM), similar to values we published earlier (Tam J, 2012). In contrast, using vehicle #2, the plasma level of JD-5037 was 0.38 ± 0.02 ng/mL (0.67 nM), more than 1,000-fold lower and barely detectable. JD-5037 is 99.6% protein-bound in plasma (Tam J, 2012), so its calculated free concentration was 7.4 nM using vehicle #1 versus 2.7 pM using vehicle #2, the latter value being 2 orders of magnitude below the binding Kd of JD-5037 for CB1R (0.4 nM), which predicts no significant CB1R occupancy. We further verified this by using the upper GI motility test as a measure of peripheral CB1R occupancy (Tam J, 2012). In vehicle-treated mice, an oral charcoal bolus traveled 54 ± 3% of the length of the small intestine in 30 minutes, whereas In mice treated with a maximally effective dose of the CB1R agonist ACEA, the charcoal bolus traveled only 25 ± 3%, indicating a 54% inhibition. The inhibitory effect of ACEA was completely blocked by pretreatment with a single dose of 3 mg/kg JD-5037 in vehicle #1 (53 ± 3%), in agreement with our published data (Tam J, 2012). In contrast, the same dose of JD-5037 administered in vehicle #2 was completely without effect, the distance traveled by the charcoal bolus (29 ± 2%) being the same as with ACEA alone. Thus, the negative findings of Varga et al. can be attributed to lack of absorption and a consequent lack of peripheral CB1R occupancy by JD-5037, due to the use of an inappropriate vehicle. Such pitfalls are avoidable by verifying bioavailability and target engagement, which is a basic requirement when testing the in vivo efficacy of novel compounds.

      George Kunos, Joseph Tam<sup>1,</sup> Resat Cinar, Tony Jourdan; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

      <sup>1</sup> Current address: School of Pharmacy, The Hebrew University, Jerusalem, Israel


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    1. On 2017 Sep 15, Cicely Saunders Institute Journal Club commented:

      We chose this paper for our monthly Journal Club on 6th September 2017 and some comments from our discussion are below.

      This is a useful paper to explore the experiences of clinicians and relatives to determine why hospital deaths predominate in haematological cancers. This paper focused on an important and under-researched topic. We felt that this paper would be improved if the authors could

      1) Use Consolidated criteria for reporting qualitative studies (COREQ): 32-item checklist.

      2) State what methodological orientation underpinned the study? E.g. grounded theory, ethnography, phenomenology.

      3) Explain the reasons for the imbalance of sample (45 clinicians vs. 10 relatives) and why patients’ perspectives were not included.

      4) Elaborate the views of ‘co-dependency’ in more detail.

      5) Provide more in-depth cross-comparison of perspectives between different groups of participants (healthcare practitioners across different settings and relatives of deceased patients)

      The paper generated a lively discussion among clinicians, researchers and academics, and we thank the authors for drawing attention to this important area.


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    2. On 2017 Sep 08, Ping Guo commented:

      None


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    1. On 2017 Jul 12, Felipe Santiago commented:

      I don't disagree with their main message, but I think is not addressing the problem at all. I do believe the current environment makes the job look "unattainable" but still is very "desirable". Less than 10% of all the postdocs in my current research-intensive institution actually successfully complete an academic job search, but almost all still try! Most go elsewhere after trying at least 2 cycles. So I disagree with the statement that PIs are discouraging grad students and postdocs to follow this path, they are just been good, realistic mentors, that know the many problems postdocs can face in today's hypercompetitive academic job search.


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    1. On 2017 Oct 10, Shaun Khoo commented:

      Green Open Access: The accepted manuscript is available from the UNSW Institutional Repository (subject to a 12 month publisher embargo).

      Open Data: The underlying data for this paper is available on Figshare.


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    1. On 2017 Jul 26, Mohammed AlJasser commented:

      I cannot access this article although it is labelled as "Free full text".


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    1. On 2017 Aug 09, Thomas Jeanne commented:

      The statement "...with infectious Zika able to be cultured from semen up to 80 days after the onset of symptoms" cites reference 55 (Matheron S, 2016), which does not support it. Matheron et al. found Zika virus RNA in semen at 80 days, but "infectious virus was not cultured." It appears that the longest reported period between symptom onset and detection of infectious Zika virus in semen is 69 days, in a vasectomied patient (Arsuaga M, 2016).


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    1. On 2017 Jul 11, Martine Crasnier-Mednansky commented:

      The cya crp* mutant strain CA-8404 isolated by L. Soll (Sabourin D, 1975), which has been widely used for transduction of its crp* gene (also used in the present work), was finally characterized by Karimova G, 2004 as containing three mutations in the crp gene. Karimova G, 2004 further reported this CRP* was indeed capable of responding to cAMP and therefore was still sensitive to Carbon Catabolite Repression (CCR). Of interest to the present study, and any other studies aimed at releasing CCR in Escherichia coli, Karimova G, 2004 also characterized a novel CRP* with two mutations which totally relieved CCR as compared to the three-mutation CRP*.

      Here cAMP-dependent CCR may not be the main culprit for preventing xylose utilization by the Escherichia coli wild type W strain (the Waksman’s strain). Generally, an increase in cAMP upon glucose depletion allows utilization of less-preferred sugar like xylose. Figure S7-A indicates that upon glucose exhaustion, E. coli W was still unable to use xylose after 96 hours, even though it could use xylose quite efficiently in the absence of glucose (Figure 2-D). In addition, the CRP* isolated by the authors (G141D) for specifically increasing xylose catabolism (Figure 1), and which doubled xylose utilization in the parent strain XW043, did not improve E. coli W xylose consumption at all in the presence of glucose (Figure 4-A). Thus, based on current knowledge, the inability of the Waksman’s strain to use xylose in the presence of a large excess glucose does not appear to relate to cAMP-dependent CCR. Interestingly, E. coli B, unlike W, is unable to use glucose fully when grown in excess glucose, and the typical increase in cAMP does not occur after cessation of growth (figure 2 in Peterkofsky A, 1971). Thus, if some glucose remains unused in the medium, cells may fail to use xylose.


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    1. On 2017 Jul 26, Sally Satel commented:

      Dartmouth demographer Samir Soneji and his co-authors find that the probability of cigarette smoking at follow-up is significantly higher among all e-cigarette users than among individuals who never used a nicotine product. Based on this finding, they conclude that “strong e-cigarette regulation” by the federal, state, and local governments are needed to minimize the potential “future population-level burden of tobacco.” This conclusion is unwarranted based on the nature of their results.

      The article compares the probability of smoking in the post-period conditional on e-cigarette use without smoking to the probability of smoking in the post-period conditional on neither e-cigarette use nor smoking. This is not the relevant comparison for the purpose of assessing public-health risk. The relevant comparison is between smoking behavior conditional on access to e-cigarettes and smoking behavior conditional on no access to e-cigarettes, as such a comparison incorporates both the potential gateway and deterrent/diversion effects of e-cigarette use.

      Such a comparison would take into account any beneficial effects of e-cigarettes on potential smokers who choose to reduce their cigarette smoking or to limit themselves to e-cigarette use altogether, as well as on smokers in the pre-period who switch to e-cigarettes partially or fully, or successfully use e-cigarettes as a cessation aid. It is on this comparison that regulatory choices should be based.

      The nascent market for e-cigarettes in the United States can make robust empirical research on the consequences of these products on tobacco use challenging. The importance of a proper analytical framework is illustrated in a recent National Bureau of Economic Research working paper by economists Mike Pesko of Weill Cornell Medical College and Janet Currie of Princeton. The economists identify an important unintended consequence of minimum legal sale age laws restricting access to e-cigarettes: smoking among underage pregnant teenagers increased by more than 2 percentage points.

      With teen smoking at a new low, policymakers should be celebrating a public health success instead of seeking a new regulatory expansion. Empirically, it is certainly not clear that more vaping has any causal effect on smoking among youth, as Soneji and his co-authors imply but do not demonstrate. Moreover, the type of analyses reported in JAMA Pediatrics fails to offer a reliable basis for developing an optimal regulatory framework for e-cigarettes and other modified risk tobacco products.

      -Alex Brill, Sally Satel, Stan Veuger

      NBER paper: http://www.nber.org/papers/w22792


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    2. On 2017 Jul 21, Samir Soneji commented:

      We thank Joel Nitzkin for his interest in our article, which systematically reviewed 9 US-based longitudinal studies that assessed e-cigarette use and cigarette smoking among >17,000 adolescents and young adults. Our research concluded that e-cigarette use among adolescents who had never tried a cigarette was associated with subsequent cigarette smoking initiation and past 30-day cigarette smoking, with similar effect size across studies of adolescents and young adults. All of the studies used multivariable analysis to adjust for other factors that might make adolescent e-cigarette users at higher risk for use of multiple substances—risk factors such as friends who smoke, sensation seeking tendencies, and use of other substances like alcohol.

      Nitzkin asserted three claims about the research. First, Nitzkin claimed that the studies provided no evidence that e-cigarette use is related to consistent daily cigarette smoking. Second, he claimed that e-cigarette use was simply a marker for high-risk youth who were more likely to smoke anyway. Third, he claimed that the decline in youth cigarette smoking over time at the population level proves e-cigarette use does not increase the probability of cigarette smoking at the individual level. Empirical evidence contradicts these claims, as we describe below.

      Regarding Nitkin’s first claim that e-cigarette use is not related to consistent daily cigarette smoking, few adolescents smoke on a daily basis, which makes assessment of daily smoking impractical for most longitudinal studies that have a 1-2 year timeframe. Logically, smoking initiation is a necessary requisite to daily smoking. Moreover, recent longitudinal research found that smoking initiation identifies about two-thirds of adolescents who will be daily smokers two years later, with a false positive rate of 8 percent.1 In other words, smoking initiation is about as good at predicting eventual daily smoking as screening mammography is at predicting breast cancer.<sup>2</sup> Although not perfect, smoking initiation presents a public health concern especially given the growing body of evidence that e-cigarettes are used by some youth unlikely to have ever smoked cigarettes.<sup>1,3,4</sup> Furthermore, a recent longitudinal study by Leventhal et al. (2016) found that more frequent e-cigarette use at baseline was associated with more frequent and heavier patterns of cigarette smoking at follow-up using data from >3000 adolescents.<sup>5</sup> Thus, smoking initiation, which the studies examined, is a sensible predictor of future daily smoking, and the pattern of e-cigarette use seems to predict the pattern of eventual cigarette smoking.

      Regarding Nitzkin’s second claim that e-cigarette users are just high-risk youth, the combined risk estimate represents a risk that adjusts for many risk factors, as we mentioned above, that would cause some adolescents to be at risk for using multiple substances. The fact that the adjusted estimate is very strong (odds ratio of almost 4) suggests to us that it is unlikely that one or more added covariables would completely confound the e-cigarette effect. Moreover, several studies concluded that adolescents who use e-cigarettes are medium-risk youth, not those who are necessarily destined to begin cigarette smoking anyway.<sup>6–10</sup> Furthermore, several longitudinal studies have reported that the association between e-cigarette use and smoking initiation was strongest among the lowest risk youth (i.e., youth who stated that they were unlikely to try smoking in the future).<sup>9,11,12</sup>

      Regarding Nitzkin’s third claim that the recent decline in youth cigarette smoking proves e-cigarette use does not lead to cigarette use, youth cigarette smoking has been declining steadily in the US for the past 20 years and predates e-cigarettes.<sup>13,14</sup> In other words, this steady decline in youth cigarette smoking began long before the introduction of e-cigarettes into the US in 2007 and before e-cigarette use became prevalent in youth around 2011. So the decline in youth cigarette smoking cannot be attributed to the advent of the e-cigarette.

      We believe our research underlines that the potential risks of e-cigarette use are significant and should not be discounted. Tobacco control efforts, including taxation, youth smoking prevention programs, and restrictions on tobacco advertising reduce youth smoking. The nearly twenty-year decline in youth smoking demonstrates the success of these tobacco control efforts despite youth e-cigarette use. We must acknowledge and address the public health harm posed by youth e-cigarette use to prevent a new generation of nicotine-addicted adult tobacco users.

      References

      <sup>1</sup> Sargent JD, Gabrielli J, Budney A, Soneji S, Wills TA. Adolescent smoking experimentation as a predictor of daily cigarette smoking. Drug Alcohol Depend. 2017;175:55-59. doi:10.1016/j.drugalcdep.2017.01.038.

      <sup>2</sup> Ferrini R, Mannino E, Ramsdell E, Hill L. Screening mammography for breast cancer: American College of Preventive Medicine practice policy statement. Am J Prev Med. 1996;12(5):340-341.

      <sup>3</sup> Barrington-Trimis JL, Urman R, Leventhal AM, et al. E-cigarettes, Cigarettes, and the Prevalence of Adolescent Tobacco Use. Pediatrics. July 2016:e20153983. doi:10.1542/peds.2015-3983.

      <sup>4</sup> Dutra LM, Glantz SA. E-cigarettes and National Adolescent Cigarette Use: 2004–2014. Pediatrics. January 2017:e20162450. doi:10.1542/peds.2016-2450.

      <sup>5</sup> Leventhal AM, Stone MD, Andrabi N, et al. Association of e-Cigarette Vaping and Progression to Heavier Patterns of Cigarette Smoking. JAMA. 2016;316(18):1918-1920. doi:10.1001/jama.2016.14649.

      <sup>6</sup> Wills TA, Knight R, Williams RJ, Pagano I, Sargent JD. Risk Factors for Exclusive E-Cigarette Use and Dual E-Cigarette Use and Tobacco Use in Adolescents. Pediatrics. 2015;135(1):e43-e51. doi:10.1542/peds.2014-0760.

      <sup>7</sup> Kristjansson AL, Mann MJ, Sigfusdottir ID. Licit and Illicit Substance Use by Adolescent E-Cigarette Users Compared with Conventional Cigarette Smokers, Dual Users, and Nonusers. J Adolesc Health Off Publ Soc Adolesc Med. 2015;57(5):562-564. doi:10.1016/j.jadohealth.2015.07.014.

      <sup>8</sup> Thrasher JF, Abad-Vivero EN, Barrientos-Gutíerrez I, et al. Prevalence and Correlates of E-Cigarette Perceptions and Trial Among Early Adolescents in Mexico. J Adolesc Health Off Publ Soc Adolesc Med. 2016;58(3):358-365. doi:10.1016/j.jadohealth.2015.11.008.

      <sup>9</sup> Barrington-Trimis JL, Urman R, Berhane K, et al. E-Cigarettes and Future Cigarette Use. Pediatrics. June 2016:e20160379. doi:10.1542/peds.2016-0379.

      <sup>10</sup> Leventhal AM, Strong DR, Sussman S, et al. Psychiatric comorbidity in adolescent electronic and conventional cigarette use. J Psychiatr Res. 2016;73:71-78. doi:10.1016/j.jpsychires.2015.11.008.

      <sup>11</sup> Primack BA, Soneji S, Stoolmiller M, Fine MJ, Sargent JD. Progression to traditional cigarette smoking after electronic cigarette use among US adolescents and young adults. JAMA Pediatr. September 2015:1-7. doi:10.1001/jamapediatrics.2015.1742.

      <sup>12</sup> Wills TA, Knight R, Sargent JD, Gibbons FX, Pagano I, Williams RJ. Longitudinal study of e-cigarette use and onset of cigarette smoking among high school students in Hawaii. Tob Control. January 2016:1-6. doi:10.1136/tobaccocontrol-2015-052705.

      <sup>13</sup> Johnston L, O’Malley PM, Miech R, Emerson P, Bachman J, Schulenberg J. Monitoring the Future National Survey Results on Drug Use, 1975-2015: Overview, Key Findings on Adolescent Drug Use. Ann Arbor: Institute for Social Research, The University of Michigan; 2016.

      <sup>14</sup> Office on Smoking and Health. Trends in Current Cigarette Smoking. Centers for Disease Control and Prevention http://www.cdc.gov/tobacco/data_statistics/tables/trends/cig_smoking/. Accessed July 13, 2017.


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    3. On 2017 Jul 07, Joel Nitzkin commented:

      This Soneji meta-analysis dealing with e-cigarettes and subsequent teen smoking,1 summarized data from nine studies, all of which share the same flaws, leading to an incorrect conclusion. These studies did not differentiate one-time or occasional use from consistent daily use. None compared smoking at follow-up in e-cigarette experimenters with kids who had experimented with or otherwise used cigarettes at baseline. Such a comparison would have reflected rates of smoking at follow-up in these same populations, had e-cigarettes not been available. Given these flaws, the only conclusion that can reasonably be drawn from the individual studies or this meta-analysis is that teens who are inclined to experiment with products disapproved by adult leadership are more likely to use both e-cigarettes and cigarettes than kids not prone to such experimentation. Neither the individual studies nor this meta-analysis give us reason to expect that reducing access to e-cigarettes or making them unattractive to potential users would reduce the numbers of teens recruited to nicotine addiction. The question as to whether e-cigarettes recruit American teens to nicotine addiction has already been answered. In June 2017, the Centers for Disease Control (CDC) published its 6th annual report showing use of tobacco-related products by high school students, by type or product, including e-cigarettes.2 During this period, e-cigarette use has gone from 1.5% of high school students in 2011 to 16.0% in 2015 and 11.3% in 2016, with significant reductions in cigarette use almost every year and no significant change in the percentage of high school students using any tobacco-related product. The data on middle school students reflects the same pattern, with much smaller numbers. If, as alleged by Soneji et al, e-cigarettes were attracting significant numbers of teens who otherwise would not have used tobacco products, there would have been significant year to year increases in the percent of teens using tobacco-related products. This did not occur. The fact that this has occurred year after year validates the impression that the teens attracted to e-cigarettes are those who would have used cigarettes, had e-cigarettes not been available. The time has come for public health authorities to consider the possibility that e-cigarettes, while not risk free, could be promoted for prevention of smoking and smoking cessation among teens inclined to smoke, without attracting yet more teens to nicotine experimentation. Joel L. Nitzkin, MD, MPH, DPA References 1. Soneji S, Barrington-Trimis JL, Wills TA et al. Association Between Initial Use of e-Cigarettes and Subsequent Cigarette Smoking Among Adolescents and Young Adults. JAMA Pediatrics. 2017 June 26:E1-E10. doi:10.1001/jamapediatrics.2017.1488 2. Jamal A, Getrzke A, Hu SS et al. Tobacco Use Among Middle and High School Students --- United States, 2011-2016. Morbidity and Mortality Weekly Report. 2017;66(23) (June 16):597-603. https://www.cdc.gov/mmwr/volumes/66/wr/pdfs/mm6623a1.pdf


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    1. On 2017 Sep 12, Ryan Jajosky commented:

      For trainees, knowing that Bernard-Soulier syndrome protects against TTP can help you remember the pathogenesis of these conditions.

      Ultra-large vWF multimers bind to GP Ib-IX-V on platelets and cause TTP, but patients with Bernard-Soulier syndrome have deficient / defective GP Ib-IX-V, so the disease process is blocked.


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    1. On 2017 Jun 29, Edward Morrow commented:

      The authors state "Hyslop et al. (2016) demonstrated that global gene expression in early PNT blastocysts did not differ from unmanipulated controls".

      Morrow & Ingleby (2017) demonstrate why the size and experimental design of Hyslop et al (2016) cannot provide conclusive evidence that expression profiles of manipulated or control samples are indistinguishable from one another, due to low power.

      References

      Hyslop et al. (2016) Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature 534:383–386. doi:10.1038/nature18303 Hyslop LA, 2016

      Morrow EH and Ingleby FC (2017) Detecting differential gene expression in blastocysts following pronuclear transfer. BMC Res Notes. 2017 Feb 15;10(1):97 Morrow EH, 2017 DOI: 10.1186/s13104-017-2421-3


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    1. On 2018 Jan 09, Tom Kindlon commented:

      I submitted it to the journal but it was not accepted: "Thank you for submitting your Letter to The Lancet. Having discussed your Letter with the Editor, and weighing it up against other submissions we have under consideration, I am sorry to say that we are unable to accept it for publication. Please be assured that your Letter has been carefully read and discussed by the Editors."

      I will await to see whether any other letters cover the same or similar points.

      There's a reasonable possibility those in the group with an initial score of 45+ on the SF-36 physical functioning subscale actually decreased on average. Unfortunately as this letter wasn't published (unless they publish another letter making the same point or Lucy White, Peter White and the GETSET investigators reply here), I doubt anyone outside the GETSET team will ever know.


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    2. On 2018 Jan 09, Tom Kindlon commented:

      Response to: Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial

      The SF-36 physical functioning (PF) outcomes for those in the guided graded exercise selfhelp (GES) group who had a baseline SF-36 PF score ≥45 (call them group B) must have been particularly poor in the GETSET trial.1 We are told that those with a baseline score ≤40 (group A) made up approximately 40% of the sample and ended with average score of 56.9. This means the average outcome for group B, the higher functioning group at baseline, was actually lower, at around 54.9. Also, by definition, group A increased by an average of at least 16.9 (56.9-40). However the whole sample only increased by an average of 8.4. This means that an upper bound on the average increase for group B would be only approximately 2.7, in comparison to the increase of 16.9 for group A. This is an extreme scenario and the difference in improvements was most likely higher than 14.2. It would be interesting if Clark and colleagues could give the exact figure so everyone would be aware of the magnitude of the difference in the response.

      Clark and colleagues say the poor results may be due to a ceiling effect. More than 90% of healthy working-age people score 90 or more.2 Therefore, the mean score of 54.9 for group B and 55.7 overall suggests that if there is a ceiling in the effectiveness of GES, it is a long way below normal functioning. I do not believe this was made clear to readers.

      Tom Kindlon

      Competing interests: I work in a voluntary capacity for the Irish ME/CFS Association.

      References:

      1 Clark LV, Pesola F, Thomas J, Vergara-Williamson M; Beynon M, White PD. Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial. The Lancet. June 22, 2017 doi:10.1016/S0140-6736(16)32589-2

      2 Wilshire CE, Kindlon T, Matthees A, McGrath S. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue. 2017;5:1–4.


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    1. On 2017 Jul 18, Mohamed Rady commented:

      Kitzinger et al argued in favor of applying “the ‘holistic’ approach outlined in the Briggs judgment” to ascertain, in Court and ‘on the floor’, what in accordance with the Mental Capacity Act 2005 (MCA) ought to be considered a patient’s best-interest assessment.[1] They highlighted the significance of the Briggs judgment because of “the great weight Charles J gave the person’s own views, even when set against ‘sanctity of life’.” There are theoretical and practical problems with Kitzinger et al’s position.

      First, it is incorrect to describe the Briggs case as the clash of ‘sanctity of life’ and ‘self-determination’. There was no self-determination because there was no advance directive that clearly expressed the preference that, if affected by a disorder of consciousness, assisted nutrition and hydration (ANH) is to be discontinued. It was a third-party determination of the acceptability of Paul Briggs’ future quality of life and judgment of what was to be in his best interests. Therefore, the Briggs case is the clash of ‘sanctity of life’ and ‘third-party determination’ of best interests of a disabled person. Kitzinger et al incorrectly labeled the holistic approach to the best interest standard as an extension of self-determination. [1] They validated their claim of superiority of this approach to a best-interest assessment over ‘sanctity of life’ by quoting an article from 1973 calling the concept of ‘sanctity of life’ “impossibly vague and misleading’.” [3] However, the concept of ‘best interests’ is no less vague than the concept of ‘sanctity of life’ in justifying treatment withdrawal. A best-interest assessment of the acceptability of future quality of life on behalf of a disabled person is subjective. Even with today’s dominance of principlism in ethics, none of the four principles (autonomy, beneficence, non-maleficence, and justice) are clear, unambiguous, and uncontested. For instance, the notion of autonomy, which constitutes the foundation underlying the moral and legal notion of the best-interest standard, has evolved over time and continues to do so with significant moral, legal, and social implications.[4] The question is not if treatment can be withdrawn but under which circumstances it is justified. In first-person decision-making, individuals have the right to refuse treatment either through in-person communication or, if unable to express their opinion, through clear expression of preferences of that particular treatment in advance directives. Considering the weight of such decision in life-sustaining treatment, it appears that the judgment in W v M & Ors (2011) requiring clear and convincing evidence that the person had specifically directed not to have ANH administered in case of the presence of a disorder of consciousness is indeed more consistent with the medical principle of first do-no-harm. In absence of an unambiguous, substantive conception of what constitutes ‘the best-interest’ of human beings, mandating clear and convincing evidence of a person’s wishes in matters of life and death reflects without a doubt commitment to both the principle of sanctity of life and that of respect for persons. As it stands, adherence to the ‘sanctity of life’ standard and practicing medicine in accordance with the Hippocratic Oath both uphold the moral obligation of practitioners to avoid inflicting harm on patients.

      Second, as the concept of ‘best interests’ in MCA is grounded in a third-party rather a first-person real time determination of acceptability of future quality of life, its interpretation legitimizes also nonconsensual treatment withdrawal in persons with severe disabilities. Many survivors of serious illnesses adapt to their new reality, cope with severe disabilities, and are satisfied with their quality of life even if greatly diminished from the past. [5-8] Therefore, the reliance on previously held opinions can misrepresent real-time or future preferences of individuals with serious disabilities. As has been argued elsewhere, treatment withdrawal decisions based on third-party determination of best interests can result in fatal errors.[9] Although Kitzinger et al endorsed the introduction of a holistic approach to the third-party determination of best interests, they failed to provide a convincing rationale that it (1) provides a more reliable (and therefore a superior) instrument for making substitute end-of-life decisions, and (2) results in decisions that are more closely aligned with respect for autonomy. The basic tenet of “do-no-harm” in medicine appears to provide more practical guidance towards decision-making under these conditions.

      Third, other commentators have asserted that the ‘sanctity of life’ value in medicine, commonly associated with commitment to religious values, should not be allowed to stonewall secular determination of best interests.[10] It is clear to many that withdrawing of ANH is the proximate cause of a pre-planned death and, thus, a form of physician-assisted death. In other cases, where a patient is dependent on both mechanical ventilation and ANH (e.g., The Supreme Court in the matter of Charlie Gard [2017] EWHC 972 (Fam); https://www.supremecourt.uk/news/latest-judgment-in-the-matter-of-charlie-gard.html), withdrawing these life-sustaining interventions will lead, for the same reasons, to an act of physician-assisted death. In reality, the observed clash is the consequence of secular intolerance and exclusion of equally respected religious values in a pluralistic society.

      From a practical perspective, without additional legislative revisions in the MCA to protect religious values, the best-interest standard and a holistic approach to assessing these interests has now been transformed into a widening of a backdoor approach to justifying nonconsensual euthanasia of vulnerable individuals. The best-interests standard with an expanded domain of potential surrogate decision makers increases the potential for legitimizing a “kill switch” in the MCA. Finally, patients’ religious beliefs and values should be taken into account to ensure that surrogate decisions made reflect commitment to the respect for autonomy.

      Mohamed Y. Rady, Joseph L. Verheijde,

      REFERENCES [1] Kitzinger J, Kitzinger C, Cowley J. When ‘Sanctity of Life’ and ‘Self-Determination’ clash: Briggs versus Briggs [2016] EWCOP 53 – implications for policy and practice. J Med Ethics.2017; 43(7):446-449.

      [2]Briggs v The Walton Centre NHS Trust & Another: [2017] WLR(D) 25, [2016] EWCOP 53 http://www.bailii.org/ew/cases/EWCOP/2016/53.html.

      [3]Clouser K. "the sanctity of life": An analysis of a concept. Ann Intern Med.1973; 78(1):119-125.

      [4]Saad TC. The history of autonomy in medicine from antiquity to principlism. Med Health Care Philos.2017; First Online:10 June 2017. DOI: 10.1007/s11019-017-9781-2.

      [5]Antonak RF, Livneh H. Psychosocial adaptation to disability and its investigation among persons with multiple sclerosis. Soc. Sci. Med.1995; 40(8):1099-1108.

      [6]Lulé D, Zickler C, Häcker S, Bruno MA, Demertzi A, Pellas F, et al. Life can be worth living in locked-in syndrome. Prog. Brain Res.2009; 177:339-351.

      [7]Demertzi A, Jox RJ, Racine E, Laureys S. A European survey on attitudes towards pain and end-of-life issues in locked-in syndrome. Brain Inj.2014; 28(9):1209-1215.

      [8]Buono VL, Corallo F, Bramanti P, Marino S. Coping strategies and health-related quality of life after stroke. Journal of Health Psychology.2017; 22(1):16-28.

      [9]Napier S. Perception of Value and the Minimally Conscious State. HEC Forum.2015; 27(3):265-286.

      [10]Brierley J, Linthicum J, Petros A. Should religious beliefs be allowed to stonewall a secular approach to withdrawing and withholding treatment in children? J Med Ethics.2013; 39(9):573-577. Disclosure: This comment is an edited version of the original Rapid Response published online in JME on 4 July 2017 [http://jme.bmj.com/content/43/7/446.responses]


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    1. On 2017 Jul 13, Thomas Littlejohns commented:

      Thank you for your comment as well as the link to your informative article on selection and collider bias.

      The overall aim of the current paper was to investigate the representativeness of UK Biobank participants on a number of characteristics and health outcomes. The cohort has been described as healthier than the general population (due to the low response rate and voluntary recruitment process), however this is the first time the evidence has been provided to confirm this. Whilst UK Biobank was not set up to be representative, providing the empirical evidence for this, as opposed to informing the research community anecdotally, will hopefully help clarify what questions the resource is well-designed to address. Primarily, exposure-outcome associations and not deriving prevalence and incidence rates that apply to the general population.

      However, we are in complete agreement with Marcus Munafo and colleagues that researchers also need to be aware of the potential for biases to be introduced due to the ‘healthy volunteer’ nature of the cohort and included the following on pg.10 – “As with all observational studies, it is incumbent on researchers to acknowledge potential sources of bias on a case-by-case basis that might affect the generalisability of exposure-disease associations, such as residual confounding, reverse causation and self-selection bias”.

      Essentially, the take home message is that UK Biobank is well designed for providing generalisable associations between exposures and outcomes. But as with all observational studies, researchers should take care when interpreting their findings and acknowledge the range of biases that could drive any associations, including selection bias if applicable.


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    2. On 2017 Jul 05, Marcus Munafò commented:

      This is an important study which makes explicit the very low response rate within UK Biobank (~5%) and presents some of the factors associated with participation, then discusses their potential impact. However, in our opinion the view that this will make little or no difference to association analyses is overly optimistic. We have recently examined the potential impact of selection bias on results obtained from studies with low response rates [1]. We argue that, because selection can induce collider bias (which occurs when two variables independently influence a third variable, and that variable is conditioned upon), selection can lead to biased estimates of associations in some circumstances. The extent to which this will occur will depend on the particular association being explored, and the selection mechanisms operating. We suggest that researchers consider the potential for selection bias affecting their analyses, and carry out sensitivity analyses to assess robustness of their conclusions to selection bias.

      Marcus R Munafò, Deborah A Lawlor, Kate Tilling

      1. Munafò MR, Tilling K, Taylor AE, Evans DM, Davey Smith G. Collider Scope: How selection bias can induce spurious associations. bioRxiv, doi: https://doi.org/10.1101/079707


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    1. On 2017 Jul 02, Louise B Andrew MD JD commented:

      A prior study by this author among others explaining how these ADA impermissible questions that discriminate against those with mental health issues by not differentiating between illness and impairment discourage mental healthcare seeking by physicians (and therefore could contribute to physician suicide) can be found at https://www.ncbi.nlm.nih.gov/pubmed/27796258 and at www.physiciansuicide.com


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    1. On 2017 Aug 21, Luiza Rodrigues commented:

      Hi. Why is the Supplement 2 not available? I would like to see the eFigures 3, 4 and 5. Couldn't find them in the link. Thanks Dr Luíza


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    1. On 2017 Oct 18, Nicoletta Villa commented:

      1. The first question is: how to define this chromosome? It had a complete X banding exactly symmetrical above and below the primary constriction and presented an active centromere in an anomalous position definable as neocentromere, though canonical (repositioning).
      2. According to the International System for Human Cytogenetic Nomenclature (ISCN) 2016, the definition of centric fission is: “break in the centromere resulting in two derivative chromosomes composed of the short and long arms, respectively”. This does not happen in the chromosome X here described since the whole chromosome (old centromere included) constitutes the isochromosome. This was also confirmed by the paracentric inversion that offers us a complicated but responsive mechanism for the isochromosome formation. Regarding the cited review (Lin and Yan, Mutat Res 2008; 658:95), we mentioned it in the introduction and discussion sections. In both cases, we reported general aspects of telomeric-like sequences. We speculated that the paracentric inversion of the entire Xp arm could be a result of a non-allelic homologous recombination mediated by inverted repeats, as reported by Warburton and Dittwald (see article for details). FISH data with pan-telomeric probes revealed the anomalous presence of TTAGGG repeats near the inactive centromeres in a highly symmetrical manner, absent in the Xp terminations. Therefore, we used BAC probes and identified the paracentric inversion of the entire short arm that made the telomere common sequences completely interstitial. Silahtaroglu et al (J Med Genet 1998; 35:682) reported a paracentric inversion that did not involve telomeric region in a XXY male (“Simultaneous hybridisation with biotin labelled "All Centromere" and digoxigenin labelled "All Telomere" probes showed that the telomeric sequences were not inverted). This is not our case.
      3. Rivera et al. (Clin Genet 1999, 55:122) reported a case showing a rearrangement due to a centric fission of chromosome 12 and a translocation on chromosome 8p. This last rearrangement resulted in a fusion between 8ptel and 12cen mediated by interstitial telomeric sequences, as well written in the abstract. In our case there was not a fusion between two different chromosomes, but an isochromosome, confirmed by banding, FISH and by means of microsatellite segregation study. Moreover, we demonstrated the presence of telomeric sequences near to the old centromeres.
      4. We did not perform the androgen receptor inactivation test because the itrc(X) was always inactivated in reverse banding (RBA) as it is possible to see in figure 1B and also the microsatellite polymorphisms never showed a third allele. Moreover, the mosaic situation made a quantitative analysis very difficult or even impossible due to the loss of Xq.
      5. The frequency of chromosomal abnormalities in couples subjected to medically assisted procreation appears to be increased (literature data), but we couldn’t correlate the chromosomal rearrangement here described with PMA. We don’t know parental origin of the rearrangement and parents refused further analyses.


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    2. On 2017 Jul 19, Horacio Rivera commented:

      Centromere repositioning or neocentromere in a tricentric X chromosome? As for the unique tricentric X-cromosome described by Villa et al. (2017), I do the following remarks: 1. The apparent discrepancy between title and content regarding the paper’s key concept illustrates how difficult is to classify the single functional centromere of the rearranged X: did it result from centromere repositioning and is a class III neocentromere as stated in the title or is it a novel kind of neocentromere? Since the former mechanism implies the emergence of a new non-alphoid centromere in otherwise intact chromosomes (Marshall et al. Am J Hum Genet 2008, 82: 261; Liehr et al. Cytogenet Genome Res 2010,128:189), it seems better to opt for the more general term neocentromere despite it being composed of alphoid sequences. 2. Since the authors plausibly ascribe the emergence of the functional centromere at an unexpected place to an initial paracentric inversion of the entire Xp arm “shifting a part of the centromere at the p end”, then they may have designated such centromeric breakage with the specific term centric fission. It is significant that the hypothetical telomere-like sequences mapping at Xp11.21 or 22 and thought by the authors to be involved in the rearrangement, are simply not referred to in the cited review (Lin and Yan, Mutat Res 2008; 658: 95); moreover, the authors appear to contradict themselves when they conclude that “the first event could be a result of a non-allelic homologous recombination mediated by inverted low-copy repeats”. Regardless of the concerned sequences, the exact breakpoint should be revised to Xp10 and the Xp rearrangement designated as a centric inversion after Silahtaroglu et al. (J Med Genet 1998, 35: 682) who described an inverted 12p resulting from a centric fission coupled with a subtelomeric breakpoint. 3. According to the underlying mechanism advanced by the authors, two true centromere-telomere fusions (Rivera et al. Clin Genet 1999, 55: 122) occurred in the rearranged chromosome. Yet, the authors also fail to recognize this phenomenon. 4. Despite the analysis of microsatellite polymorphisms, the parental derivation of the tricentric X chromosome was not determined. Likely, the HUMAR assay could have resolved this point. 5. The fact that the patient was conceived after intracytoplasmic sperm injection recalls other chromosome rearrangements and gonosomal aneuploidies found in children conceived by means of such a technique (Venkataraman and Craft, Hum Reprod 2002, 17: 2560; Alfonsi et al. Cytogenet Genome Res 2012, 36: 1; Rivera and Domínguez, Clinics 2012, 67: 669).


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    1. On 2017 Oct 26, Duke RNA Biology Journal Club commented:

      This paper was chosen based on the well written abstract. The observation in the title appeared interesting and novel with implications for a role of miRNA in epigenetics with response to environmental conditions. However, upon further reading and analysis of the paper, we expect more work will be done to solidify these initial conclusions. We agree that miRNAs are divergent when flies are grown at different temperatures, additionally, piRNAs do seem to be expressed more at lower temperatures. That this holds true when flies are subsequently switched to different temperatures was also fascinating. However, this paper remained mostly observational. We expected, from general patterns observed in narratives of other papers, that the authors would attempt looking at the protein expression of machinery associated with each process, miRNA and piRNA processing, at each temperature to help elucidate a mechanism for these observations. However, what followed was a speculative section on these observations based on RNA-expression, which does not always correlate with protein expression. Overall, we think this article provides a great starting point for future work involving the functional impact that these molecular changes to environmental stimulus can have on an organism.


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    1. On 2017 Jul 28, Morten Oksvold commented:

      In this article the authors cite Deleris, A. et al. Hierarchical action and inhibition of plant Dicer-like proteins in antiviral defense. Science 313, 68–71 (2006) (reference number 7).

      This article represents one of the articles that supposed to be retracted (see quote from the report below):

      From the investigation report: "Although it is obviously the journal's prerogative, the former (category 2) papers, particularly those containing well documented intentional manipulations (PLoS Pathogens 2013 9:e1003435; Plant Cell 2004 16: 1235; Science 2006 313: 68; PNAS 2006 103: 19593 and EMBO J 2010 29: 1699), should be retracted through OV's requests as being non-factual, irrespectively of whether the reported observations have been reproduced by others."

      Link to full report here: https://www.ethz.ch/content/dam/ethz/news/medienmitteilungen/2015/PDF/untersuchungsbericht/Report_of_ETH_Commission_Voinnet.pdf

      I find it problematic that Nature Plants accepts this kind of practice, by apparently legitimating well documented intentional manipulations as facts.


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    1. On 2018 Jan 21, Atanas G. Atanasov commented:

      Thank you so much for the excellent joint work dear Colleagues! I have featured our manuscript on the INPST website: https://sites.google.com/view/inpst/1-xanthohumol


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    1. On 2018 Feb 04, Sin Hang Lee commented:

      The medical profession, including medical schools and hospitals, is now a part of the health care industry, and implementation of editorial policies of medical journals is commonly biased in favor of business interests. PubMed Commons has offered the only, albeit constrained, open forum to air dissenting research and opinions in science-based language. Discontinuation of PubMed Commons will silence any questioning of the industry-sponsored promotional publications indexed in PubMed.


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    2. On 2017 Jun 24, Sin Hang Lee commented:

      Jorge Cervantes proposed a new theory to argue against the existence of chronic Lyme disease with persistent infection [1]. According to this theory, “after antibiotic eradication of Bb, its DNA is able to persist in anatomical locations that coincide with sites of inflammation.” He assumed that the free, naked and water-soluble DNA molecules released from the dying Borrelia burgdorferi spirochetes remain in the extracellular matrix of the patient’s tissues. However, under section “3. Borrelia DNA persistence” of his article, the references cited did not test for free borrelial DNA at all, and therefore do not back up his theory. For examples, in the reference by Li et al. [2], the authors concluded that the DNA detected was in moribund or dead B burgdorferi cells, not in free form. In the reference by Schmidt et al. [3] and the reference by Aberer et al. [4], borrelial DNA was detected in the pellet of patients’ urine samples after centrifugation at 14,000 x g and 36,000 × g, respectively. Since soluble free DNA molecules cannot be pelleted by such a low centrifugal force, the borrelial DNA detected by these authors must be still bound to bacterial cells or cell fragments in the urine. In the reference by Kubanek et al. [5], the authors actually showed by electron microscopy that the tissues tested positive for borrelial DNA clearly contained borrelial bacteria, not free DNA.

      Free, extracellular, naked bacterial DNA is very prone to decay. Foreign DNA experimentally introduced into a mammal is degraded and eliminated from the host’s blood within 48 hours [6]. But the stability of extracellular DNA still depends on its form or even on the sequence of its nucleotide bases. Circular plasmid DNA is more stable in vitro than a segment of linear chromosomal DNA after release from the bacterial cell. Even DNase I does not cleave DNA randomly although not base nor sequence specific. Extracellular bacterial 16S rDNA is known to be degraded much more rapidly in the environment than those bound to cell fragments [7]. Borrelial 16S rDNA extracted by ammonium hydroxide stored in TE buffer is stable, but is degraded rapidly in human serum at room temperature (unpublished personal observation). DNA sequencing-confirmed detection of borrelial 16S rDNA in the pellet of serum or plasma samples derived from patients’ venous blood constitutes solid molecular evidence of spirochetemia in Lyme borreliosis [8, 9]. Whether spirochetemia in chronic Lyme disease needs to be treated with prolonged antibiotics is an important heath care issue which should be further discussed. To push an elusive DNA-binding AMP treatment of chronic Lyme disease can only direct the attention away from the real issue of how to define Lyme disease, acute or chronic, as an emerging infectious disease, like Ebola and Zika, for proper patient management. There is no evidence that free naked borrelial DNA has been demonstrated in any patient samples.

      The author should also cite a reference to back up his claim that human macrophages can remove extracellular Bb DNA. The reference by Brencicova and Diebold [10], cited by the author, clearly stated “Endosomal TLR are situated in the membrane of the endolysosomal compartment of APC and sample the content of these compartments for the presence of nucleic acid agonists. Pathogens or dead cells gain access to the compartment by endocytosis. Alternatively, infection-induced autophagy can shuttle viral nucleic acids and antigens into the endolysosomal compartment and allow for recognition of replicating virus within infected cells by endosomal TLR.” Free DNA was not mentioned.

      References [1] Cervantes J. Doctor says you are cured, but you still feel the pain. Borrelia DNA persistence in Lyme disease. Microbes Infect 2017 Jun 15. pii: S1286-4579(17)30090-4. doi: 10.1016/j.micinf.2017.06.002. [Epub ahead of print] Review. [2] Li X, McHugh GA, Damle N, Sikand VK, Glickstein L, Steere AC. Burden and viability of Borrelia burgdorferi in skin and joints of patients with erythema migrans or lyme arthritis. Arthritis Rheum 2011;63: 2238-47. [3] Schmidt B, Muellegger RR, Stockenhuber C, Soyer HP, Hoedl S, Luger A, et al. Detection of Borrelia burgdorferi-specific DNA in urine specimens from patients with erythema migrans before and after antibiotic therapy. J Clin Microbiol 1996;34:1359-63. [4] Aberer E, Bergmann AR, Derler AM, Schmidt B. Course of Borrelia burgdorferi DNA shedding in urine after treatment. Acta Derm Venereol 2007;87(1):39-42. [5] Kubanek M, Sramko M, Berenova D, Hulinska D, Hrbackova H, Maluskova J, et al. Detection of Borrelia burgdorferi sensu lato in endomyocardial biopsy specimens in individuals with recent-onset dilated cardiomyopathy. Eur J Heart Fail 2012;14:588-96. [6] Schubbert R, Renz D, Schmitz B, Doerfler W. Foreign (M13) DNA ingested by mice reaches peripheral leukocytes, spleen, and liver via the intestinal wall mucosa and can be covalently linked to mouse DNA. Proc Natl Acad Sci U S A. 1997;94:961-6. [7] Corinaldesi C, Danovaro R, Dell'Anno A. Simultaneous recovery of extracellular and intracellular DNA suitable for molecular studies from marine sediments. Appl Environ Microbiol 2005;71:46-50. [8] Lee SH, Vigliotti JS, Vigliotti VS, Jones W, Shearer DM. Detection of borreliae in archived sera from patients with clinically suspect Lyme disease. Int J Mol Sci. 2014;15:4284-98. [9] Lee SH. Lyme disease caused by Borrelia burgdorferi with two homeologous 16S rRNA genes: a case report. Int Med Case Rep J. 2016;9:101-6. [10] Brencicova E, Diebold SS. Nucleic acids and endosomal pattern recognition: how to tell friend from foe? Front Cell Infect Microbiol 2013;3:37.


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    1. On 2017 Oct 26, Duke RNA Biology Journal Club commented:

      We were excited to see another paper on ribosome heterogeneity from Maria Barna’s lab since their 2011 paper linking loss of a ribosomal protein (RP) with developmental phenotypes in mice PMCID: PMC4445650. In comparison, we found this paper less of a complete story but still powerful in the questions it reveals. To summarize, Shi and co-workers used a combination of selected reaction monitoring based proteomics and tandem mass tagging to identify and orthogonally validate 4 RPs as substoichiometric in tissue culture polysomes. We viewed this result as the major breakthrough in the field. The remainder of the paper looked more closely at two RPs, RPS25 and RPL10A, and their associated transcriptome. Interestingly, they found divergent enrichments within the Ribo-seq datasets associated with these proteins. We speculated, from the distinct transcriptome of these RPs, that cellular environment could play a large role in RP composition. However, instead of following up on these observations, the authors instread probe RPL10A’s function in IRES mediated translation. After performing multiple rounds of experiments with bicistronic constructs, they found this protein had the ability to interact with some - such as HCV, host-mRNAs - but not every IRES type. We discussed previous publications linking ribosomal proteins PMCID: PMC4243054 and RP PTMs PMCID: PMC2253395 to proper translation of HCV. Therefore, we found the observations in Fig 6 interesting but unsurprising and wondered how each observation pieced together in the larger picture of viral translation. This conversation brought us to the conclusion of the paper, with a noticeably short discussion section. We were left with two main unanswered questions: are these substochiometric differences ever combined or limited to one RP at a time; and does RP composition change with cell environment and location? This publication makes a big step towards answering these questions, especially with the quantitative lengths used to determine stoichiometric ratios of RPs, but we found the paper lacking in proposing a distinct in vivo role for these substoichiometric ribosomes and will look forward to follow-up publications leading to these answers.


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    1. On 2017 Jun 18, Hilda Bastian commented:

      An assessment of a critical problem, with important conclusions. It would be helpful, though, if the scope of the 4 guidelines were shown. The inclusion criteria are not very specific on this matter, and the citations of the versions of the 4 included guidelines are not provided.

      In addition to the scope, the dating of the guidelines' last search for evidence (if available) with respect to the dates of the systematic reviews would be valuable. Gauging to what extent systematic reviews were not included because of being out of scope, out of date, or not yet published is important to interpreting these findings. Given how quickly systematic reviews can go out of date (Shojania KG, 2007), the non-inclusion of older systematic reviews may have been deliberate.

      The publisher of the article does not appear to have uploaded Appendix A, which includes the references to the systematic reviews. Further, confusion has been created by linking the citations of the first 44 systematic reviews to the references of the article's texts. The end result is that neither the 4 guidelines nor the 71 systematic reviews are identifiable. It would be helpful if the authors would post these 75 citations here.

      Disclosure: I work on PubMed Health, the PubMed resource on systematic reviews and information based on them.


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    1. On 2017 Aug 06, Stuart Buck commented:

      What bothers me most is the following statement from a study author: "Each of these increase LDL-cholesterol compared to carbohydrate and more so when compared to the unsaturated fats. This is sufficient to warn the public about anticipated adverse effects of coconut oil on CVD."

      No, it is not. There are at least 5 treatments that lower LDL without lowering CVD, and sometimes even make CVD worse. See Table 1: http://www.nejm.org/doi/full/10.1056/NEJMp1508120?af=R&rss=currentIssue#t=article.

      Nutritionists should not give advice based on trials about LDL while ignoring that LDL manipulation is often disconnected from or even directly contrary to CVD outcomes.


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    2. On date unavailable, commented:

      None


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    3. On 2017 Aug 02, Hilda Bastian commented:

      Thank you for the reply, Professor Sacks. However, the reply does not address the errors I pointed to, nor respond directly the key problems I raised. Much of it is directed to rebutting claims I did not make.

      ... (1) Lack of reporting on the processes for selecting evidence

      My first point was that although the statement asserts that the totality of evidence and recent studies was reviewed, it does not report the process for identifying the systematic reviews it selected. No validated method for evaluating the systematic reviews is reported, and reasons for excluding each of the trials in the chosen systematic reviews are not reported either (with the exception of 6 trials, accounting for 10 trials in total). Hamley S, 2017, for example, lists 19 randomized trials on the question of replacing saturated with polyunsaturated fat, drawn from 8 systematic reviews/meta-analyses (Table 2). I stress that my point here is not related to the conclusions, but rather to the adequacy and transparency of the methodology.

      The totality of evidence approach considering a variety of research types does not obviate the need to explain how the studies were sought, selected, and appraised (Institute of Medicine (US) Committee on Standards for Developing Trustworthy Clinical Practice Guidelines, 2011).

      ... (2) Singling out coconut oil

      The reply reiterates a statement based on a single survey and people's beliefs about coconut oil. But there is no data to show that dietary coconut oil is consumed at levels that warrant this attention, whereas palm oil, for example, does not. I am not sure whether the data I could find on this is an accurate reflection or not (Bastian, June 2017). If it is, however, then the issue of replacing palm oil in commercially produced food would have warranted more attention than coconut oil. Given the very different standards applied to studies of coconut oil, the question of why it was addressed at all, when so much else in scope was not, remains a relevant one.

      ... (3) Inadequacy of Eyres L, 2016 as a basis for wide-ranging conclusions on health effects of coconut oil

      I reiterate the point I made: the conclusions that clinical trials on the effects on CVD measures have not been reported, and that there are "no known offsetting favorable effects" would require a high-quality systematic review on the effects of coconut oil on both CVD and non-CVD health outcomes of dietary coconut oil. Eyres L, 2016 is not that review. Whichever of the validated and accepted methodologies for assessing the quality of a systematic review you would use (Pussegoda K, 2017), the Eyres review would not fare well. It does not include elements required for a high quality systematic review - such as reporting on the excluded studies and including a study-by-study assessment of the methodological characteristics and risk of bias of included studies. More importantly, its scope is too narrow.

      I identified the 8 trials in the 7 papers I mention, in a quick search to test the adequacy of coverage of the Eyres review. I only included those on CVD outcomes. There are undoubtedly further relevant trials. That short search though, established the limits of scope of the Eyres review, even in CVD health.

      This is how the authors of the Eyres characterize the evidence they found:

      "Much of the research has important limitations that warrant caution when interpreting results, such as small sample size, biased samples, inadequate dietary assessment, and a strong likelihood of confounding. There is no robust evidence on disease outcomes, and most of the evidence is related to lipid profiles."

      I agree with that assessment, and the reply offers no methodologically sound counter to this. Instead, the studies not in the Eyres review were critiqued. The reply cites these criteria for excluding all but 3 of the 8 studies as acceptable for consideration (presumably the 2 reported in a single paper were regarded as a single study):

      [A]mong the 7 studies...4 would appropriately be excluded as result of being non-randomized, uncontrolled, using a very small amount, not including a control group or not even being a trial of coconut oil.

      I don't really know what to make of "uncontrolled" and "not including a control group" as 2 criteria, given all these trials are controlled: the final 3 that aren't rejected don't make it clear to me either. No threshold is offered for what is a large enough dose, so I can't work with that either. However, I took the other 2 - randomized or not, and having a solely coconut oil arm as objective criteria I could apply to the 8 trials within Eyres and the 8 trials outside it (and extracted some additional data). This is reported in full on a blog post (Bastian, August 2017). In summary:

      • The Eyres group has fewer randomized trials: 4/8 compared to 7/8 in the non-Eyres group (or 6/7 for non-Eyres after knocking out the trial with no separate coconut arm).
      • There are fewer randomized participants in the Eyres group: 143 compared to 234 in 6 non-Eyres randomized trials with a separate coconut arm.
      • All the trials in the Eyres group only look at blood lipid profiles whereas most in the non-Eyres group assess at least 1 non-blood-test outcome (5/8 or 4/7). That is in part because of the Eyres exclusion criteria (such as rejecting any trial in a specific population or clinical subgroup, such as overweight people).

      The Eyres group cannot be regarded as an adequate or representative subset of trials. And the same level of critique has not been applied even-handedly.

      ... (4) Errors in representation of the Eyres findings on coconut oil versus other saturated fats

      As this was not addressed in the reply, I'll reiterate it, with additional detail. This is what the Eyres review concludes on this question:

      "In comparison with other fat sources, coconut oil did not raise total or LDL cholesterol to the same extent as butter in one of the studies by Cox et al., but it did increase both measures to a greater extent than did cis unsaturated vegetable oils...[W]hen the data from the 5 trials that directly compared coconut oil with another saturated fat are examined collectively, the results are largely inconsistent".

      This is what the AHA writes:

      "The authors also noted that the 7 trials did not find a difference in raising LDL cholesterol between coconut oil and other oils high in saturated fat such as butter, beef fat, or palm oil".

      As there was no meta-analysis of these trials, there is no single estimate to discuss. Of the 5 that did include a comparison with saturated fats, there were differences among their results: the AHA had pointed out 1 of them just a few sentences previous to their "no difference" statement. This is objectively a mis-statement of the Eyres' review's findings, which results in an exaggeration of the strength of the evidence.

      Nothing in the reply to my comment changes, for me, the conclusion I came to in my first blog post on this:

      "On coconut oil, the AHA has taken a stand on very shaky ground with some major claims – as though they had a very strong systematic review of reliable research on all possible health consequences of dietary coconut oil. They don’t. The people arguing the opposite – that coconut oil is so healthy you should try to use it every day – are also on shaky ground".

      Disclosure: I have no financial, livelihood, or intellectual conflicts of interest in relation to coconut or dietary fats. I discuss my personal, social, and professional biases in a blog post that discusses the AHA advisory on coconut oil in detail. (Bastian, August 2017). This PubMed Commons comment also contains some excerpts from that post.


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    4. On 2017 Jul 24, Frank M Sacks commented:

      On behalf of the authors, I respond to comments by Hilda Bastian about the American Heart Association Presidential Advisory on Dietary Fats and Cardiovascular disease Sacks FM, 2017.

      The comprehensive advisory includes, (i) Clinical trials that tested the effects of dietary saturated fat compared to unsaturated fat or carbohydrate on cardiovascular disease (CVD) events, e.g. heart attack, (ii) Clinical trials that tested the effects of dietary fats on lipid risk factors, e.g. LDL-cholesterol, (iii) Prospective epidemiological studies on dietary fats and carbohydrates and CVD, and (iv) Animal models of diet and atherosclerosis. Thus, it reflects the “totality of evidence”. The confluence of findings provides a very strong scientific case for the recommendation that dietary saturated fat be replaced with unsaturated fat, especially polyunsaturated fat.

      Recent systematic reviews and meta-analyses Mozaffarian D, 2010, Chowdhury R, 2014, Hooper <PMID: 26068959 used well accepted methodologies, and included trials published up to 2009, 2013, and 2014. Only a small number of clinical trials evaluated direct effects of dietary fat on CVD. Most of these studies, and all that have an impact on the overall findings, were conducted years ago, and are well known. Contrary to the Bastian’s comments, there are no more recent trials on this topic. These 3 meta-analyses each confirm the beneficial effect of replacing saturated with polyunsaturated fat. The similarity of findings lends robustness to the overall conclusions of the report. The meta-analyses and all the individual trials are discussed critically in detail in the advisory.

      Because the topic of the advisory is the effect of dietary fats on CVD, coconut oil is well within its scope. Coconut oil is currently rated as a healthy oil by 72% of the American public, despite its composition derived from 98% saturated fats, which increase the blood level of LDL-cholesterol, a cause of atherosclerosis and CVD. The meta-analysis by Mensink reports the quantitative effects on LDL-cholesterol of the saturated fats that are in coconut oil, mainly lauric, myristic, and palmitic acids. Each of these increase LDL-cholesterol compared to carbohydrate and more so when compared to the unsaturated fats. This is sufficient to warn the public about anticipated adverse effects of coconut oil on CVD.

      Some studies tested coconut oil itself, and found that it increases LDL-cholesterol as would be predicted by its saturated fat content. These studies were identified and summarized in the systematic review by Eyres L, 2016 which used rigorous, well-accepted methodology. The criteria for inclusion of an article in the systematic review were well conceived. Eyres et al. concluded, “Overall, the weight of the evidence from intervention studies to date suggests that replacing coconut oil with cis unsaturated fats would alter blood lipid profiles in a manner consistent with a reduction in risk factors for cardiovascular disease.” Bastian implies that this systematic review is composed of weak studies and omitted several studies that would affect the conclusion of the advisory to avoid eating coconut oil. This is not true. Eyres et al. identified eight studies; all were controlled clinical trials that used valid nutritional protocols and statistical analyses. All reported higher LDL-C levels when coconut oil was consumed compared to unsaturated oils, including olive, corn and soybean oils, statistically significantly in 7 of them. Together, these trials included populations from the US, Sri Lanka, New Zealand, Pacific Islands, and Malaysia, demonstrating generalizability. There is no objective scientific reason to disparage them. The only substantive criticisms mentioned by Bastian are a short duration and small sample. These criticisms are unwarranted. Effects of diet on blood lipids, especially LDL-cholesterol, are established quickly, by 2 weeks. A small sample, with careful dietary control and execution, can yield a well-powered trial with valid results. In summary, the 8 trials in the Eyres et al. systematic review provide strong evidence that coconut oil increases LDL-C levels compared with unsaturated oils.

      What about the 7 studies named by Bastian that were not included in the systematic review? McKenney JM, 1995 reported that coconut oil increased LDL-cholesterol significantly by 12% compared with canola oil in 11 patients with hypercholesterolemia. In a second study in 17 patients treated with lovastatin, LDL-C increased nonsignificantly in the coconut oil period. Thus, the results of this small study would add to the overall effects of coconut oil shown in the other studies to increase LDL-cholesterol. Ganji V, 1996 reported that coconut oil increased LDL-cholesterol compared to soybean oil in 10 normal participants. Assunção ML, 2009 reported no difference in the effects of coconut and soybean oils on LDL-cholesterol levels. However, LDL-cholesterol levels increased during the soybean oil period, clearly an anomolous result. Cardoso DA, 2015 conducted a nonrandomized study comparing coconut oil, 13 mL per day, with no supplemental oil. Because there is no control for the coconut oil, it is unclear how to interpret the lack of difference in LDL-cholesterol between the groups. de Paula Franco E, 2015 conducted a sequential study of a calorie-reduced diet followed by coconut flour, 26 g per day. This study was not randomized and did not have a control group. Enns reported in her Ph.D. degree dissertation at the University of Manitoba the results of a randomized trial that compared a 2:1:1 mix of butter, coconut oil, and high-linoleic safflower oil, 25 g per day, with canola oil, 25 g per day. This trial did not claim to be a study on the effects of coconut oil. Finally, Shedden reported in her M.S. degree thesis at Arizona State University the results of a placebo-controlled randomized trial of coconut oil, 2 g per day. This miniscule amount of coconut oil did not affect LDL-cholesterol. In summary, among the 7 studies cited by Bastian not in the Eyers review, 4 would appropriately be excluded as result of being non-randomized, uncontrolled, using a very small amount, not including a control group or not even being a trial of coconut oil. Among the 3 randomized trials, McKenney et al., Ganji et al. and Assuncao et al., the first two found that coconut oil increased LDL-cholesterol levels. The trial of Assuncao et al. would likely fail an outlier test because it is the only one among 12 studies in which LDL-C levels is lower on coconut than soybean oil. Given the differences in study designs, populations, and localities, the results of coconut oil trials are remarkably uniform showing that it increases LDL-cholesterol levels, an established cause of cardiovascular disease.

      Bastian employs a tactic in common with some other critics of good nutritional science, namely, to a) disparage and misrepresent high quality studies that show harmful effects of saturated fat; b) promote and misrepresent seriously flawed and irrelevant studies that report the opposite; and c) cite meta-analyses with faulty designs often based on inclusion of flawed studies. We offer a challenge to those who assert health benefits to coconut oil, or saturated fat, in general. Produce well-designed and executed studies that show that there are beneficial effects on a bona fide health outcome or a recognized surrogate, e.g., LDL-cholesterol.

      Frank M. Sacks, for the authors.


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    5. On 2017 Jun 30, Hilda Bastian commented:

      The authors state that this advisory "reviews and discusses the scientific evidence, including the most recent studies", and that its primary recommendation is made, "taking into consideration the totality of the scientific evidence, satisfying rigorous criteria for causality". They do not report what evidence was sought and how, or the basis upon which it was selected. There is little in this report to suggest that "the totality of scientific evidence" was considered.

      For example, four reviews of trials are referred to:

      However, the more recent systematic review and meta-analysis within Ramsden CE, 2016 (date of last search March 2015) was not mentioned. Nor are, for example, these systematic reviews: Skeaff CM, 2009; Stroster, 2013; National Clinical Guideline Centre (UK), 2014; Schwingshackl L, 2014; Pimpin L, 2016.

      The AHA advisory includes sections reviewing two specific sources of saturated fat, dairy and coconut oil. Dairy products are a major source of dietary saturated fats. However, no basis for singling out coconut oil is offered, or for not addressing evidence about other, and larger, sources of saturated fats in Americans' diets. The section concludes: "we advise against the use of coconut oil".

      There are three conclusions/statements leading to that recommendation:

      • Eyres L, 2016 "noted that the 7 trials did not find a difference in raising LDL cholesterol between coconut oil and other oils high in saturated fat such as butter, beef fat, or palm oil."
      • "Clinical trials that compared direct effects on CVD of coconut oil and other dietary oils have not been reported."
      • Coconut oil increases LDL cholesterol "and has no known offsetting favorable effects".

      The only studies of coconut oil cited by the advisory to support these conclusions are one review (Eyres L, 2016) - reasonably described as a narrative, not systematic, review by its authors - and 7 of the 8 studies included in that review. The date of search of this study was the end of 2013 (with an apparently abbreviated update search, not fully reported, in 2015). Not only is that too long ago to be reasonably certain there are no recent studies, the review's inclusion and exclusion criteria are too narrow to support broad conclusions about coconut oil and CVD or other health effects.

      The AHA's first statement - that Eyres et al noted no difference between 7 trials comparing coconut oil with other saturated fats - is not correct. Only 5 small trials included such comparisons, and their results were inconsistent (with 2 of the 3 randomized trials finding a difference). There was no meta-analysis, so there was no single summative finding. The trials in question are very small, none lasting longer than eight weeks, and have a range of methodological quality issues. The authors of the Eyres review caution about interpreting conclusions based on the methodologically limited evidence in their paper. In accepting these trials as a reliable basis for a strong recommendation, the AHA has not applied as rigorous a standard of proof as they did for the trials they designated as "non-core" and rejected for their meta-analysis on replacing dietary saturated fat with polyunsaturated fat.

      Further, even a rapid, unsystematic search shows that there are more participants in relevant randomized trials not included in the Eyres review than there are randomized participants within it. For example: McKenney JM, 1995; Ganji V, 1996; Assunção ML, 2009; Cardoso DA, 2015; de Paula Franco E, 2015; and Enns, 2015 (as well as another published since the AHA's panel finished its work, Shedden, 2017).

      The conclusions of the coconut oil section of the AHA advisory are not supported by the evidence it cites. A high quality systematic review that minimizes bias is required to draw any conclusion about the health effects of coconut oil.

      Disclosure: I have no financial, livelihood, or intellectual conflicts of interest in relation to coconut or dietary fats. I discuss my personal, social, and professional biases in a blog post that discusses the AHA advisory on coconut oil in detail (Bastian, June 2017).


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    1. On 2017 Jul 07, JEANNIE LEE commented:

      Authors: John E. Froberg,* Chen-Yu Wang,* Roy Blum, Yesu Jeon, and Jeannie T. Lee**

      equal contribution * corresponding author **

      We appreciate the response of Chen et al. to our Technical Comment. However, we do not believe the response satisfies our concerns regarding the genotypes of the cells used in Chen et al. We outline our critique below and invite commentary from the community:

      1. Chen et al. continued to maintain that ∆LBS is a true deletion and stated that they confirmed ∆LBS by Sanger sequencing. They should provide FASTA files containing the Sanger sequence data from the same clone used in the study.

      2. Chen et al. erroneously stated that our idea of an LBS inversion was based on the presence of discordant reads within the Xist locus. The “inversion reads” are a specific subset of discordant reads with one end mapped within the LBS region and the other just outside and where both reads align to the same strand. Whereas discordant reads can indeed be found outside of the LBS region in both WT and ∆LBS cells, such inversion reads can only be detected in ∆LBS and ∆LBS rescue, but not in WT, LBR knockdown, and SHARP knockdown samples. Thus, “inversion reads” are specific to ∆LBS and ∆LBS rescue and not simply an artifact of the discordant RAP reads.

      3. In Figure 2, Chen et al. proposed that the discordant reads that suggest an inversion are simply an artifact of sequencing the RAP capture probes. This cannot be the case. The inversion reads were also found in input samples for both ∆LBS and ∆LBS rescue. The input was set aside before addition of capture probes, therefore the presence of inversion reads in input cannot be explained by sequencing the probes. Thus, the inversion reads likely arose from a genuine inverted sequence at the endogenous locus, not from capture probe contamination.

      4. To explain why we were able to align many reads to the LBS region, Chen et al. proposed that LBS inserted into a repetitive region of chromosome 12 (and that the region was not flipped in situ). The authors provided no data to support this. We were also unable to see an enrichment of chr12 (or any other autosome) among the discordant reads. The authors must provide the inverse PCR Sanger sequence data and confirmation of a chr12 insertion by FISH, southern blot, or other means.

      5. Chen at al. stated that our analysis of the LBS deletion is flawed because we used the wrong coordinates for ∆LBS. We used chrX:100676777-100677593 (mm9). These coordinates completely overlap and are nearly identical to the ∆LBS mm9 coordinates provided by Chen et al. (chrX: 100676791-100677575). Thus, the coordinates are essentially the same and cannot explain our differences.

      6. We raised the major concern that the authors’ CLIP data lacked crossover reads that must be present if a deletion is present. In response, Chen et al. suggested that there were 4 crossover reads. We dispute that these 4 reads cross over the deleted region. Read 1 (1928049) could potentially cross over “∆LBS”, but showed deletions and mismatches that gave the read a poor alignment score (right side pair cigar: 21M3D14M). Read 2 (4677231) could also potentially cross over, but its quality score was also so low that it was filtered out by our pipeline. Read 3 (1928051) does not cross over at all, and was also filtered out due to a low quality score. Read 4 (4677228) also does not cross over and instead aligned upstream of the LBS region. Thus, the 4 reads do not qualify as crossovers, leaving unanswered why the CLIP data failed to reveal a deletion, inversion, or intact sequence.

      7. The RNA FISH experiment in Figure 1F the authors use to argue against inversion may not have worked. Chen et al. argued that the absence of RNA FISH signal with probes antisense to LBS to argue that LBS is deleted and not inverted. The antisense probe should have produced one pinpoint spot in wild-type cells due to Tsix transcription. However, there is no pinpoint spot in wild-type cells.

      8. The ∆A cell line they used for RAP does not have a Repeat A deletion, at least at the endogenous locus. Chen et al. admitted that they used the wrong cell line and published an incorrect dataset. They should provide full characterization of the cells actually used in the published experiment and explain how the data coincidentally supported their conclusions.

      9. Chen et al. claimed that our RAP analysis is different from theirs because we did not properly account for probe sequences. This suggestion fails to explain the differences between our analyses. First, Chen et al. did not describe how they “account for probe sequences”. Second, our RAP patterns were derived after excluding discordant reads. This means that we already excluded the reads Chen et al. claim cause the discrepancy between our RAP patterns and theirs. Finally, excluding probe sequences will not change the global X-chromosomal RAP pattern because probe sequences are only found within Xist.

      10. We question how Chen et al. scaled RAP coverage tracks when comparing different RAP samples. As our analysis showed that, excepting the WT RAP, all RAP experiments showed very limited coverage on the X outside of the Xist locus — thereby strongly indicating a failure of RAP experiments. These observation are not consistent with the continued assertion of Chen et al. that reduced Xist binding is found in ∆LBS and ∆A HPRT (even though they admittedly used the wrong cell line), but not in ∆LBS rescue. It remains unclear how they scaled and normalized different RAPs and how they arrived at these conclusions.

      11. Furthermore, the possibility that the observed phenotypes arise from experimental variability cannot be excluded. Chen et al. argue that the fact that multiple Xist mutants (LBR KD, ∆LBR, an un-described ∆A line) all show the same phenotype eliminates the necessity of replicates. This is simply not true; it is possible that all mutants show a Xist localization defect because all of the mutant RAPs failed. The authors also argue that replicates aren’t necessary since they compare average profiles across all active vs. inactive regions of the chromosome. However, this comparison does not take into account RAP efficiency, and comparing RAP signal between active vs. inactive regions in an inefficient RAP is not biologically meaningful. Biological replicates of the same mutants in parallel with wild-type are absolutely essential for evaluating RAP phenotypes.

      12. Chen et al. utilized FISH to show that perturbing LBR-Xist interaction abolishes the ability of Xist to internalize active genes into the Xist cloud (Chen et al. 2016), a phenotype similar to the ΔA Xist mutants (Chaumeil et al. 2006). Strikingly, the distance from X-linked genes to the ΔA or ΔLBS Xist clouds measured by Chen et al. spanned ~ ½ nuclear radius, far greater than what was described in Chaumeil et al. This very large nuclear distance calls into question the specificity of the FISH experiments.

      13. In the final paragraph, the authors questioned the nucleation site model. However, no evidence was provided. The references they cited in connection to this statement are not relevant to the role of YY1 or to the Repeat F region for Xist nucleation. In fact, the original LBR study of Chen et al. argued that the nucleation site (a.k.a. “LBS region”) is needed for proper Xist spreading. This argument (notwithstanding the questionable genotypes) would be entirely consistent with the original findings of Jeon & Lee in 2011, which reported that deleting this region of Xist inhibits Xist spreading as a consequence of failed nucleation.


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    1. On 2017 Jul 07, Cicely Saunders Institute Journal Club commented:

      The Cicely Saunders Institute journal club reviewed this paper on Wednesday 5th July 2017. We enjoyed discussing this paper and felt that the authors had addressed an important area, especially with the increasing importance on how we coordinate services at the end-of-life. The authors provided detailed information about the settings, which was useful in understanding the context in which the data was collected. Additionally, the authors provide an allied health professional perspective, highlighting the difference that can be made by changes to the environment and equipment.

      We felt that the authors could have applied a theoretical framework to strengthen understanding of the proposed topic and their findings, such as Andersen’s healthcare utilisation model. We were interested in their focus on patient, carer and professional views, but felt that these could have benefitted from triangulation in the narrative of the paper.

      The authors highlighted many interesting aspects (tipping points for carers, how patients will manage increased risk to be able to stay home), we would have liked supplementary materials to explore these further, as the authors collected such a wealth of data from both interviews and observations.

      Commentary by Sophie Pask and Dr Catherine Evans


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    1. On 2018 Feb 04, Sin Hang Lee commented:

      The medical profession, including medical schools and hospitals, is now a part of the health care industry, and implementation of editorial policies of medical journals is commonly biased in favor of business interests. PubMed Commons has offered the only, albeit constrained, open forum to air dissenting research and opinions in science-based language. Discontinuation of PubMed Commons will silence any questioning of the industry-sponsored promotional publications indexed in PubMed.


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    2. On 2017 Jun 23, Samuel Shor commented:

      Marzec, et al (1) described 5 cases of treated chronic Lyme disease that resulted in poor outcomes We are concerned about 3 conclusions: 1. Characterization of chronic Lyme disease as an invalid nebulous condition 2 “…..evidence that the recommended two-tiered serologic testing is actually more sensitive the longer B. burgdeorferi infection has been present” 3. “Studies have not shown that such treatments lead to substantial long-term improvements for patients.” We too are concerned about any individual whose outcomes represent complications to well-intentioned intervention. However, there is substantive support in the literature for the existence of 1. Chronic Lyme disease-Our perspective is that this represents the clinical manifestations of ongoing active infection by Borrelia burgdorferi (Bb) sensu latu complex in the setting of either chronic untreated or inadequately treated individuals. The lilkihood of undiagnosed acute Lyme is increased by the infrequency of patients recalling tick bites. In one study representing CDC criteria diagnosed Lyme disease, only 14% had that recollection. (2) Not all cases of acute Lyme are associated with an erythema (EM) rash. Over 15 years, 31% of the reported surveillance cases lacked an EM rash. (3) The ILADS guidelines (4) describe the Lyme post treatment "….persistence of B. burgdorferi in specific individuals and animal models." The 2012 Embers (5) nonhuman primate and 2014 Hodzic (6) murine studies provide evidence of persistence of Bb infection after MBC adequate courses of antimicrobials. Additional animal and human studies support this concept (7-10). We want to emphasize that other etiologies may be causal, but that a cohort of these patients likely have a perpetuation of chronic signs and symptoms due to an active Bb infection. 2. Sensitivity of two tiered testing in late Lyme: Based upon a 2008 study by Steere et al (11) “the sensitivity of 2-tier testing in patients with later manifestations of Lyme disease was 100%, and the specificity was 99%” Entrance criteria for late stage Lyme: “In all patients with neurologic, cardiac, or joint involvement, a serologic result positive for B. burgdorferi by ELISA and Western blot was required for case inclusion….” “Because the entrance criteria for the aforementioned analysis REQUIRED positive serologies … by definition, all patients with disseminated or persistent Lyme disease were required to have a positive serologic test result. It is disingenuous to define a condition by a positive test result and then state that the test has 100% sensitivity…” (12) By extension, the concept of seronegativity is well-documented in cases of chronic Lyme disease (13-15) In a study, patients with a positive culture and/or PCR results and active late Lyme disease, 63.5% were not two-tier positive. (16) A second study of pcr positive late Lyme patients found that 56.3% were seronegative. (17) 3. “Studies have not shown that such treatments lead to substantial long-term improvements for patients.” A number of studies discount this claim. In 2 of the 4 NIH supported prospective human trials by Fallon (18) and Krupp (19), sub-cohort analysis showed statistically significant benefit to retreatment. In the former study 37 patients who were suspected of having active neuroborreliosis, and were treated with 10 weeks of 2gms/day IV Ceftriaxone. Pain and physical functioning improved at 12 and was sustained at 24 weeks. The authors indicated that “these benefits were felt to be independent of carefully assessed placebo effects.” In the latter study 55 patients who were felt to have active infection by Bb, with persistent severe fatigue of 6 or more months received 28 days of IV Ceftriaxone. A significant improvement in fatigue was sustained at 6 months. Other prospective trials of prolonged antimicrobial treatment were employed that revealed statistically significant improved outcomes. (20-22) In summary, as unfortunate are the 5 cases reported by Marzec, it is this author’s belief that they should not be used to discount a real entity, chronic Lyme disease. Whether due to the lack of timely diagnosis or adequacy of intervention, the literature supports the concept of chronic active Bb infection. That the diagnostic sensitivity of the 2 tiered paradigm is flawed, and seronegative active Bb infection exists. That emphasis should be made to generate a careful differential diagnosis, proactive management with probiotics and careful monitoring in the selective utility of long term antibiotics. As such, these often disabled individuals will more readily have access to the care they deserve, with compassion and empathetic oversight. Samuel Shor, MD, FACP President ILADS [International Lyme and Associated Diseases Society] Associate Clinical Professor George Washington University Health Care Sciences 1. Marzec NS, 2017 2. Berger BW, 1989 3. Bacon RM, 2008 4. Cameron DJ, 2014 5. Embers ME, 2012 6. Hodzic E, 2014 7. Treib J, 1998 8. Steere AC, 1990 9. Dvoráková J, 2004 10. Berglund J, 2002 11. Steere AC, 2008 12. Stricker RB, 2008 13. Breier F, 2001 14. Dejmková H, 2002 15. Schutzer SE, 1990 16. Oksi J, 1995 17. Chmielewski T, 2003 18. Fallon BA, 2008 19. Krupp LB, 2003 20. Cameron D, 2008 21. Wahlberg P, 1994 22. Oksi J, 1998


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    3. On 2017 Jun 20, Sin Hang Lee commented:

      Dear L Ide: I have stopped reading NEJM since its Publisher fired Dr. Jerome Kassirer as the editor in chief. If you have published an article in the NEJM against intravenous or prolonged antibiotic treatment of SBE cases, please list the reference here. Then I will try to read it. What is elispot anyway? Have you used it? I was talking about using borrelial gene sequencing to diagnose chronic Lyme disease. Please write more if you have any objections.


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    4. On 2017 Jun 19, L Ide commented:

      Sin Hang Lee, please read the NEJM. Longterm antibiotics are rubbish. I hope you 're not in favor of the not evidence-based test elispot? Thank you Marzec et al. for your article.


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    5. On 2017 Jun 19, Sin Hang Lee commented:

      Marzec and colleagues presented five “chronic Lyme disease” patients who did not benefit from additional antibiotic treatment when the diagnoses of “chronic Lyme disease” were made on the basis of clinical symptoms and signs (www.cdc.gov/lyme/diagnosistesting/) or by unvalidated tests. The authors have not presented evidence to show that chronic Lyme disease patients with borrelial spirochetemia proven by culture or by gene sequencing do not benefit from additional antibiotic treatment. In medicine, certain chronic infections, such as subacute bacterial endocarditis, may require intravenous or prolonged antibiotic treatment [1] in spite of its potential side effects.

      The CDC should give the practitioners a case definition of Lyme disease, as for Ebola and Zika.

      Conflicts of Interest: Sin Hang Lee, MD is the director of Milford Molecular Diagnostics Laboratory specialized in developing DNA sequencing-based diagnostic tests.

      References 1. Hoen B. Epidemiology and antibiotic treatment of infective endocarditis: an update. Heart 2006 ;92 :1694-700. Review.


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    6. On 2017 Jun 18, Raphael Stricker commented:

      Chronic Lyme Disease Treatment: Science versus Anecdotes.

      Lorraine Johnson, Raphael B. Stricker, MD.

      Lymedisease.org, PO Box 1352, Chico, CA 95927; ILADS, PO Box 341461, Bethesda, MD 20827

      lorrainejohnson@outlook.com; rstricker@usmamed.com

      The article by Marzec et al. published in MMWR purports to show the dangers of treatment in patients diagnosed with chronic Lyme disease (1). Recent reports from the Centers for Disease Control and Prevention (CDC) indicate that more than 300,000 new cases of Lyme disease are diagnosed each year in the USA (2). The MMWR article from the CDC describes five anecdotal cases of treatment complications in these patients while ignoring the significant morbidity related to denial of treatment for chronic Lyme disease (2,3). The resultant biased report raises scientific and ethical issues about the CDC's role in promoting the best care for patients with tickborne diseases.

      The MMWR piece resulted from anecdotal reports gathered by Dr. Christina Nelson of the CDC. The article notes that the information was gathered because “clinicians and state health departments periodically contact CDC concerning patients who have acquired serious bacterial infections during treatments for chronic Lyme disease.” However, an ethics complaint filed against Dr. Nelson by the Lyme disease patient advocacy group LymeDisease.org suggests that these adverse event reports were in fact specifically solicited by Dr. Nelson via emails distributed in 2014 (4). Dr. Nelson asked clinicians from the Infectious Diseases Society of America (IDSA) to provide anecdotal evidence of harm to patients from intravenous antibiotic therapy related to Lyme disease, and she apparently offered coauthorship of her article as an incentive to describe these adverse events. She did not ask for consequences of failing to treat these patients, nor did she solicit commentary from practitioners who treat chronic Lyme disease according to the guidelines of the International Lyme and Associated Diseases Society (ILADS).

      The risk of any medical treatment is extremely context-sensitive. A crucial question is whether the risks of treatment are warranted given the potential benefits, the availability of other treatment options, the severity of the patient's presentation, and the risk tolerance of the individual patient. By asking for an assessment of treatment risks only, Dr. Nelson is framing the issue in a manner that excludes the other half of the equation in a risk/benefit assessment. She is also ignoring an issue that is critical to patients who suffer a profoundly diminished quality of life due to their illness, namely the risk of not treating (5,6). Moreover, by failing to mention that these adverse event reports were rare and specifically solicited, she implies that these rare occurrences are a common concern. In reality, studies of the risks and benefits associated with intravenous antibiotic treatment for Lyme disease indicate that the risks of adverse events are no greater than the risks of intravenous therapy in other unrelated diseases (7,8).

      By asking the question only of those on one side of the controversy, Dr. Nelson is further demonstrating favoritism and a lack of impartiality on the part of the CDC. Accordingly, Dr. Nelson's solicitation of anecdotal adverse events for case studies of Lyme disease is a highly inappropriate partisan act of favoritism toward the IDSA viewpoint at the expense of critical stakeholders - Lyme disease patients and their treating physicians - and an attack on the ILADS viewpoints.

      References 1. Marzec NS, Nelson C, Waldron PR, et al. Serious bacterial infections acquired during treatment of patients given a diagnosis of chronic Lyme disease - United States. MMWR Morb Mortal Wkly Rep. 2017 Jun 16;66(23):607-609. 2. Stricker RB, Johnson L. Lyme disease: Call for a ‘‘Manhattan Project’’ to combat the epidemic. PLoS Pathog. 2014;10(1): e1003796. 3. Stricker RB, Fesler MC. Chronic Lyme disease: A working case definition. Chronic Dis Int. 2017; 4(1): 1025. 4. Leland DK. TOUCHED BY LYME: CDC ignores ethics, attacks “chronic Lyme”. Available at https://www.lymedisease.org/touchedbylyme-cdc-ignores-ethics/. Accessed June 16, 2017. 5. Johnson L, Aylward A, Stricker RB. Healthcare access and burden of care for patients with Lyme disease: a large United States survey. Health Policy. 2011;102: 64–71. 6. Johnson L, Wilcox S, Mankoff J, Stricker RB. Severity of chronic Lyme disease compared to other chronic conditions: a quality of life survey. Peer J. 2014;2:e322. 7. Stricker RB, Green CL, Savely VR, Chamallas SN, Johnson L. Safety of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Minerva Med. 2010;101:1–7. 8. Stricker RB, Delong AK, Green CL, et al. Benefit of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Int J Gen Med. 2011; 4: 639–646. Disclosure: RBS and LJ are members of the International Lyme and Associated Diseases Society (ILADS) and directors of LymeDisease.org. They have no financial or other conflicts to declare.


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    1. On 2017 Sep 02, Lise Bankir commented:

      After we published the paper above " Relationship between Sodium Intake and Water Intake: The False and the True", we rediscovered a publication that we should have mentioned in this paper because it is one more study showing no change in urine volume (= water excretion) in normal subjects in response to marked changes in sodium intake (leading to corresponding changes in sodium excretion). The reference of this paper is : Hormonal responses to gradual changes in dietary sodium intake in humans. Sagnella GA, Markandu ND, Buckley MG, Miller MA, Singer DR, MacGregor GA. Am J Physiol. 1989 Jun;256(6 Pt 2):R1171-5. PMID: 2525347

      Table 1 shows urine volumes in six normal subjects submitted to increasing sodium intakes. After 4 days on a very low sodium intake (12 mmol/24h), sodium intake was increased gradually by 50 mmol/day on successive days. For sodium intakes of 10, 50, 100, 150, 200, 300, 350, 350 mmol/day, urine volumes were 1.43, 1.40, 1.23, 1.38, 1.47, 1.96, 1.69, 1.53 L/24h, respectively. No comment is made in the paper about this relatively stable urine volume.

      This study, like several others cited in our paper, confirms that urine volume, and thus probably fluid intake, do not increase with increasing sodium intake without other changes, when studied in healthy young subjects.

      This observation in 1989 is at variance with the results of an experimental study reported by the same group in 2001, in hypertensive patients (off their usual treatment for 3 months). Effect of salt intake on renal excretion of water in humans. He FJ, Markandu ND, Sagnella GA, MacGregor GA. Hypertension. 2001 Sep;38(3):317-20. PMID: 11566897

      After a few days on a 350 mmol/day salt intake, these hypertensive patients were switched to a low salt intake of 10-20 mmol/day. Urine volume fell significantly from 2.2 ± 0.09 to 1.3 ± 0.05 L/day. The difference between the two studies can possibly be explained by the fact that the 1989 study was conducted in healthy young subjects (age range 19-21 y) whereas the 2001 study concerned hypertensive patients (mean age 48 y, range 19-70).


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    1. On 2017 Jul 29, Alex Vasquez commented:

      As a researcher, author, clinician, and recent (2015) reviewer for PLOS One, I am writing with great concern about the editorial quality and review process of this previously esteemed journal, particularly with regard to the article discussed below. This Letter was sent to the PLOS One Editor by email on 20 July 2017 with receipt acknowledged on 21 July 2017; the response that "We encourage you to contact the corresponding authors of the article directly" is absurd as it will not address either the 1) lack of editorial quality, 2) the defects in the review process, or 3) the [in my opinion] erroneous publication of this article. Oddly, PLOS One does not publish letters and therefore provides no means for the archived biomedical record (e.g., in Pubmed, PubMed Central, Europe PMC, etc) to be corrected. Thus, given the aforementioned lackluster response and nearly nonexistent channels to correct and critique this PLOS One article, this critique is published online publicly https://www.academia.edu/34072801 and also via Pubmed Commons.

      In their 4-week open trial with no control group, no laboratory testing, and which relied on participant-reported "data" for every aspect of treatment compliance and treatment effect, the Lawrence and Hyde [1] prescribed a program of psychosocial support (conference call with in-person/online contact with healthcare provider and support group) and dietary improvements (including avoidance of sugar, alcohol, grains and refined carbohydrates) and then attributed the purported health benefits (including self-reported weight loss and subjective improvements in digestion, cognition, physical and emotional wellbeing) to changes in the participants’ gut microbiome. Participants were a self-selected “convenience sample of people seeking the services of a nutritional therapist. The majority of participants’ primary goal was therefore weight-loss, with several additionally aiming to improve digestive symptoms (chronic acid reflux, bloating, constipation, loose stools, wind), plus energy, and pain issues.” Without providing any data to support their conclusion that the intervention changed a single microbe or metabolite from the gut microbiota, the authors assert that, “This dietary microbiome intervention has the potential to improve physical and emotional wellbeing in the general population but also to be investigated as a treatment option for individuals with conditions as diverse as IBS, anxiety, depression and Alzheimer’s disease.” Similarly and without evidence showing that the intervention modified any parameter of the gut microbiome, the authors assert, “Taken together with our findings, these results suggest that dietary interventions to optimise gut bacteria may have a role to play both in the treatment of Alzheimer’s disease but also in optimising cognitive functioning in non-clinical populations.” The most remarkable aspect of this research is the attribution of the mechanism of action of their diet intervention to gut microbiomal modification without a single original data point of evidence; indeed, the authors acknowledge that the effect of the “diet on the health and diversity of the microbiome has not been directly tested.” The authors utilized a participant-completed medical screening questionnaire which they acknowledge “was not selected specifically for the purpose of research, and is lacking in detailed information relating to its reliability and validity compared to scales used more specifically for research.”

      Therefore in summary, this “research article” has the following attributes: 1. No objective data on health outcomes was collected; the study presents only participant-reported subjective data, 2. No objective data on treatment compliance was collected; we do not know if the participants followed the diet nor to what extent, 3. No objective data on treatment effect/mechanisms: The authors claim that the intervention changes the gut microbiome but failed to measure even a single parameter, microbe, molecule, or metabolite. 4. Participants were a positively self-selected “convenience sample” ripe and ready for a placebo response given their demonstrated positive expectations. 5. Impossible attribution, especially to the gut microbiome: With no control group, no-one knows if the supposed "improvements" were due to the psychosocial intervention, the diet, the season, the natural history the non-disease being non-studied, chance; the attribution of supposed benefit to a mechanism involving the gut microbiome is not supported by any data in this publication. 6. Short duration with no durability of effect: No demonstrated durability to the supposed benefits; the study was of notably short duration (4 weeks), 7. Wild attribution without any shred of evidence: The treatment included 1) diet intervention and 2) psychosocial support and then the authors attributed (without any supporting data whatsoever) the subjective/undocumented/purported benefits to 3) changes in the gut microbiotal composition. 8. Unreliable methods: The authors note that their use of the Functional Medicine Medical Symptoms Questionnaire “was not selected specifically for the purpose of research, and is lacking in detailed information relating to its reliability and validity compared to scales used more specifically for research” and that 9. No previous validation, as the diet plan “has not been directly tested” for its effect on the “health and diversity of the microbiome.” If this had been a follow-up survey or symptom assessment based on previous research, then such a publication might be reasonable; however, such is not the case with this publication. 10. The financial and self-promotional conflict of interest and the prominent mention of their proprietary book not fewer than 16 times in the manuscript. Does PLOS One now publish thinly veiled infomercials—masquerading as clinical research—for proprietary products? Given all these confounding variables and lack of objective data including zero data showing changes in the gut microbiome, a reasonable reviewer and reader can ask “What—if any—scientific value does this article provide?”

      To be sure, we as researchers and clinicians have increasingly appreciated the role of the body-wide microbiome in health and disease, and we appreciate that diet potently shapes the gut microbiome [2,3]. However, to ascribe health benefits to changes in the microbiome from uncontrolled positively-selected participant-collected data following diet modification and psychosocial intervention is premature at best, unscientific at worst; the authors failed to collect even a single data point showing change in any microbe, molecule, or metabolite related to the gut microbiome, and yet the published title of the article is “Microbiome restoration diet.” Studies attributing therapeutic benefit to microbiome improvements should provide evidence supporting their hypothesis via the quantitative correlation of direct microbial analysis (or at the very least via surrogate markers such as serum endotoxin levels or serum 16SrRNA, both of which are also influenced by other factors such as intestinal permeability) with mostly objective data from biochemical markers and reliable tests of neurocognitive and emotional status. The financial and self-promotional conflict of interest and the prominent mention of their proprietary book not fewer than 16 times in the manuscript further calls into question the motive and actual value of this publication in a scientific journal.

      Citations: 1. Lawrence K, Hyde J. PLoS One 2017 Jun:e0179017. 2. Vasquez A. Nutritional and Botanical Treatments against Silent Infections and Gastrointestinal Dysbiosis. Nutr Perspect 2006 Jan https://www.academia.edu/3862817. 3. Vasquez A. Human Microbiome and Dysbiosis in Clinical Disease, Volume 1. Barcelona: International College of Human Nutrition and Functional Medicine; 2015. ISBN13: 978-0990620419


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    1. On 2017 Jun 30, DANIEL BROWN commented:

      Mycobacterium is not the same thing as Mycoplasma. Never has been, never will be.


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    1. On 2017 Jul 05, Suzy Chapman commented:

      As mentioned in my previous comment, in the literature one observes frequent instances where the term "bodily distress disorder" has been used when what is actually being discussed within the paper or editorial is the Fink et al. (2010) "bodily distress syndrome (BDS)" disorder construct.

      For example, "bodily distress disorder" is used interchangeably with "bodily distress syndrome" in the editorial (Creed et al. 2010): Is there a better term than "medically unexplained symptoms"? [1].

      In this (Rief and Isaac 2014) editorial: The future of somatoform disorders: somatic symptom disorder, bodily distress disorder or functional syndromes? the authors are using the term, "bodily distress disorder" while clearly discussing the Fink et al. (2010) BDS construct [2].

      The ICD-11 S3DWG sub working group's proposed term is seen, here, as "Bodily distress disorder (Fink and Schroder 2010)" in Slide #3 of the symposium presentation: An introduction to "medically unexplained" persistent physical symptoms. (Professor Trudie Chalder, Department of Psychological Medicine, King’s Health Partners, 2014) [3].

      This paper: Medium- and long-term prognostic validity of competing classification proposals for the former somatoform disorders (Schumacher et al. 2017) compares prognostic validity of DSM-5 "somatic symptom disorder (SSD)" with "bodily distress disorder (BDD)" and "polysymptomatic distress disorder (PSDD)" and discusses their potential as alternatives to SSD for the replacement of the somatoform disorders for the forthcoming ICD-11 [4].

      The authors state, "the current draft of the WHO group is based on the BDD proposal." But the authors have confirmed that for their study, they had operationalized "Bodily distress disorder based on Fink et al. 2007" [5].

      In the (Fink et al. 2007) paper: Symptoms and syndromes of bodily distress: an exploratory study of 978 internal medical, neurological, and primary care patients, the authors conclude: "We identified a general, distinct, bodily distress syndrome or disorder that seems to encompass the various functional syndromes advanced by different medical specialties as well as somatization disorder and related diagnoses of the psychiatric classification."

      There are other examples in research literature, publications [6] and in the field.

      But these examples above suffice to demonstrate that the term, "bodily distress disorder" is already used synonymously with disorder term "bodily distress syndrome (BDS)" and that many researchers and clinicians do not differentiate between the two.

      These examples also serve to demonstrate that the "bodily distress disorder" term is already being used outside ICD-11 Beta draft to describe a diagnostic construct that subsumes CFS, ME, IBS and FM under a single, unifying disorder construct - which does not correspond with how ICD Revision has defined "BDD" for the ICD-11 core edition, in which these categories remain discretely classified in chapters outside the Mental, behavioural or neurodevelopmental disorders chapter.

      Since researchers/clinicians do not differentiate between "bodily distress syndrome" and "bodily distress disorder" (and in some cases, one also observes the conflations, "bodily distress syndrome or disorder" and "bodily distress syndrome/disorder"), ICD Revision needs to give urgent consideration to the difficulties and implications for maintaining the discrete identity of its proposed disorder, once ICD-11 is released and in the hands of its end users – clinicians, allied health professionals and coders, and to urgently review its current choice of nomenclature.

      1 Creed F, Guthrie E, Fink P, Henningsen P, Rief W, Sharpe M, White P. Is there a better term than "medically unexplained symptoms"? J Psychosom Res. 2010 Jan;68(1):5-8. doi:10.1016/j.jpsychores.2009.09.004. [PMID: 20004295]

      2 Rief W, Isaac M. The future of somatoform disorders: somatic symptom disorder, bodily distress disorder or functional syndromes? Curr Opin Psychiatry September 2014 – Volume 27 – Issue 5 – p315–319. [PMID: 25023885]

      3 Chalder, T. An introduction to "medically unexplained" persistent physical symptoms. Presentation, Department of Psychological Medicine, King’s Health Partners, 2014. [Accessed 27 February 2017]

      4 Schumacher S, Rief W, Klaus K, Brähler E, Mewes R. Medium- and long-term prognostic validity of competing classification proposals for the former somatoform disorders. Psychol Med. 2017 Feb 9:1-14. doi: 10.1017/S0033291717000149. [PMID: 28179046]

      5 Fink P, Toft T, Hansen MS, Ornbol E, Olesen F. Symptoms and syndromes of bodily distress: an exploratory study of 978 internal medical, neurological, and primary care patients. Psychosom Med. 2007 Jan;69(1):30-9. [PMID: 17244846]

      6 Medically Unexplained Symptoms, Somatisation and Bodily Distress: Developing Better Clinical Services, Francis Creed, Peter Henningsen, Per Fink (Eds), Cambridge University Press, 2011.


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    2. On 2017 Jul 05, Suzy Chapman commented:

      In his lecture, Prof Fink discusses DSM-5's "somatic symptom disorder (SSD)" and its alignment with the proposed new diagnostic category, "bodily distress disorder (BDD)", as defined and characterized for the core edition of ICD-11 [1].

      Prof Fink notes that SSD is a diagnosis mainly based on psychological and behavioural characteristics, with a very low symptom threshold - only one chronic, disturbing symptom required to meet the criteria, which may or may not be associated with a general medical condition - and suggests this will include most patients seen in both primary and secondary care.

      That DSM-5's SSD (and the similarly conceptualized BDD, as defined by ICD-11) risk mislabelling millions of patients with an inappropriate mental disorder diagnosis was identified in 2013 by Frances & Chapman [2] and Frances [3][4].

      Prof Fink is rightly concerned that ICD-11's proposed new single category replacement for the ICD-10 somatoform disorders will share the problems inherent in the DSM-5 SSD diagnosis.

      However, Prof Fink omits from his lecture a crucial consideration concerning proposed nomenclature.

      Since at least 2007, the term "bodily distress disorder" is frequently seen in the literature, at symposia and in presentations being used interchangeably with the term "bodily distress syndrome (BDS)" - the diagnostic construct developed by Prof Fink and his colleagues, which he confirms has been rejected by ICD Revision for inclusion in the ICD-11 core edition.

      To the best of my knowledge, no clinician or researcher has published on the potential for confusion and conflation between the two disorder constructs or the implications for maintaining disorder integrity within and beyond ICD-11 - if ICD Revision names its differently conceptualized construct, with its very different criteria set and which potentially captures a different patient population, "bodily distress disorder."

      Thus far, ICD Revision has provided no rationale for re-purposing a disorder term that is already closely associated with the Fink et al (2010) disorder construct and criteria set.

      There is no justification for introducing a new disorder category into ICD-11 that has greater conceptual alignment with the DSM-5 SSD construct but is proposed to be assigned a disorder name that is closely associated with a divergent (and operationalized) construct/criteria set, that is already in use in research and clinical settings in Denmark and beyond.

      This is unsafe and unsound classificatory practice and a very obvious flaw in their recommendations that remains unaddressed.

      It is disappointing, then, that whilst having identified problems with clinical utility and given some consideration to the implications for patients for a diagnosis of SSD or its ICD-11 sister diagnosis, the author misses the opportunity to alert his audience to the potential for disorder conflation between ICD-11's proposed "BDD" and his own divergent, "BDS" diagnostic construct.

      Comment from the author on this specific issue of nomenclature would be welcomed.

      Secondly, there have been two working groups making recommendations to ICD Revision for the revision of the somatoform disorders.

      Within his lecture, Prof Fink also refers to the proposals of the ICD-11 Primary Care Consultation Group (PCCG), that is chaired by Prof Sir David Goldberg.

      The 28 mental disorders proposed for inclusion in the abridged primary care version (ICD-11 PHC) will require a corresponding category within the core edition. However, the PCCG considers that the "BDD" construct, as defined and characterized for the ICD-11 core edition, lacks utility in primary care settings.

      The PCCG's recommendation is for an alternative construct for use in the primary care version which is a modification of the Fink et al (2010) BDS diagnostic construct and criteria set.

      Prof Fink states that the PCCG is recommending the name "bodily stress disorder (BSD)" for the new disorder category which it proposes as the replacement for the ICD-10 PHC "F45 Unexplained somatic complaints" category rather than use the name "bodily distress syndrome (BDS)."

      But according to Goldberg et al (2017), the PCCG would appear to continue to recommend the term "bodily stress syndrome (BSS)" for their modification - not "bodily stress disorder (BSD)" as Prof Fink has reported [4]. It would be helpful to have this apparent anomaly clarified.

      If the PCCG's proposals for the abridged primary care version are approved by WHO/ICD Revision, there will be a lack of correspondence between the ICD-11 core edition replacement for the ICD-10 somatoform disorders and the primary care version.

      A lack of consistency between the two editions risks confusion and conflation between the "BSS" BDS modification, the Fink et al (2010) unmodified BDS and the ICD-11 core edition defined BDD, resulting in loss of disorder definition integrity, lack of clarity over which patient populations these constructs are intended to capture, potential misapplication, confusion between different diagnoses across primary care and specialty settings, and will hamper statistical analyses.

      Furthermore, and crucially, there appear to be no exclusions or differential diagnoses within the PCCG's proposed "BSS" criteria for CFS, ME, IBS and FM - diagnostic categories that are discretely classified within ICD-11 under chapters outside the mental, behavioural or neurodevelopmental disorders chapter.

      This issue is still unaddressed by ICD Revision.

      With only a few months left before the Beta draft needs to be finalized, the revision of the somatoform disorders for ICD-11 and ICD-11 PHC remains an indigestible alphabet soup.

      1 Gureje O, Reed GM. Bodily distress disorder in ICD-11: problems and prospects. World Psychiatry. 2016 Oct;15(3):291-292. doi: 10.1002/wps.20353. [PMID: 27717252]

      2 Allen Frances¹, Suzy Chapman². DSM-5 somatic symptom disorder mislabels medical illness as mental disorder. 1 Department of Psychiatry, Duke University 2 DxRevisionWatch.com Aust N Z J Psychiatry. 2013 May;47(5):483-4.[PMID: 23653063]

      3 Frances A. DSM-5 Somatic Symptom Disorder. J Nerv Ment Dis. 2013 Jun;201(6):530-1. doi: 10.1097/NMD.0b013e318294827c [PMID: 23719325]

      4 Frances A. The new somatic symptom disorder in DSM-5 risks mislabeling many people as mentally ill. BMJ. 2013 Mar 18;346:f1580. doi: 10.1136/bmj.f1580. [PMID: 23511949] 5 Primary care physicians' use of the proposed classification of common mental disorders for ICD-11. Goldberg et al. Fam Pract. 2017 May 4. doi: 10.1093/fampra/cmx033. [PMID: 28475675]


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    1. On 2017 Aug 20, NephJC - Nephrology Journal Club commented:

      The exciting paper “Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes” was discussed on June 27th and 28th 2017 on #NephJC, the open online nephrology journal club.

      Introductory comments written by Swapnil Hiremath are available at the NephJC website here

      Nearly 200 people participated in the discussion with over 1000 tweets. One of the authors, Vlado Perkovic also kindly joined the journal club

      The highlights of the tweetchat were:

      • There has been very heterogenous use of SGLT2 inhibitors (SGLT2i) across the globe to date. They tend to be more commonly started by endocrinologists. There have been some cases of euglycemic DKA noted.

      • The studies were felt to be well-designed followed FDA guidance for non-inferiority meticulously. According to the authors, unexpected effects made it difficult to proceed to larger study without understanding cardiovascular safety in detail – hence CANVAS-R.

      • It was unusual that such a high percentage (70%) of the group had normoalbuminuria.

      • It would be interesting to determine what weight loss was calorific and what was diuretic effect.

      • The excess of amputations and fractures in the canagliflozin group was surprising. Postulated mechanisms for this included expression of SGLT2i elsewhere in the body and differential effects on oxidative phosphorylation.

      • Overall there were promising composite renal endpoints but there is still some concern about the potential adverse events revealed here which time may better delineate the extent of.

      Transcripts of the tweetchats, and curated versions as storify are available from the NephJC website.

      Interested individuals can track and join in the conversation by following @NephJC or #NephJC on twitter, liking @NephJC on facebook, signing up for the mailing list, or just visit the webpage at NephJC.com.


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    2. On 2017 Jun 18, Thomas Heston commented:

      This trial basically shows that treating diabetes helps decrease cardiovascular morbidity, which is not a new finding. To determine if canagliflozin has a unique property in decreasing cardiovascular events beyond simply lowering blood sugar, the analysis would have had to match patients by their hemoglobin A1c, then compare outcomes of placebo vs canagliflozin. Amazingly, this was not done. They did not look at cardiovascular events after correcting for hemoglobin A1c levels. Note that this was a pharmaceutical company funded research project, and the conclusion heavily implies that canagliflozin (as opposed to any agent that lowers blood sugar) has a unique quality of lowering cardiovascular events in diabetics. The authors did not prove that canagliflozin had any unique cardiovascular protective properties [Heston TF, 2017]. By not separating out the potential unique effects of canagliflozin beyond just lowering blood sugar, the results regarding a unique cardiovascular effect are basically meaningless and even worse, misleading.


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    1. On 2017 Jun 14, Kay Tye commented:

      We would like to make a clarification regarding the following sentences addressing the impact of previous social experience or social history on DRN DA dynamics across multiple stimuli:

      In reference to the fiber photometry signals in response to a number of stimuli, Cho and colleagues stated that “These findings did not vary with subject social history, as similar patterns of DRNDA activation were seen in group-housed mice (Figures S2J–S2L)” and “DRNDA activation by a wide variety of rewarding and aversive stimuli, both social and non-social, occurred irrespective of the subject’s social history, as the stimulus-evoked change in DRNDA fluorescence was not influenced by chronic separation from cage-mates (Figures S2J–S2M).”

      However, with respect to the presentation of a social stimulus, Cho and colleagues report a similar trend as Matthews and colleagues, albeit one that was not statistically significant:

      In Matthews et al., Cell (2016) the experiments in Figure 2 showed a significantly greater DRN DA fiber photometry signal (GCaMP6m in TH::Cre male mice) in response to a juvenile male when subjects were acutely (24 hours) single-housed than when group-housed (n=9, within-subject comparison). PMID: 26871628

      In Cho et al., Neuron (2017) the experiments in Figure S2J showed a non-significant trend reflecting a greater mean DRN DA fiber photometry signal (GCaMP6f in TH::Cre male mice) in response to an adult female when subjects were chronically single-housed (at least 4 weeks, standard for sleep studies; n=7) versus group-housed mice(n=4, between-subjects comparison).

      Examining the impact of social stimuli on DRN DA activity was not the focus of the study by Cho and colleagues. Further, as stated in the discussion of Cho and colleagues, a number of experimental parameters such as the nature of social target (male exposed to juvenile vs. female), isolation paradigms (acute vs. chronic) and optical fiber tip location differed between these studies (please see the publications for details). Nonetheless, the experiments related to social behavior in these two studies produce largely consistent results.

      This post was composed by Kay M. Tye, a corresponding author of the Matthews and colleagues study, following discussion with and approval from Viviana Gradinaru, the corresponding author of the Cho and colleagues study.


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    1. On 2018 Jan 04, Marilyn Tirard commented:

      We have published a response to the comment by Wilkinson et al, which can be found with the online version of the original article: https://elifesciences.org/articles/26338#annotations:1fKgOgXREei5NxuiEWEQ0w


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    2. On 2017 Sep 20, Kevin Wilkinson commented:

      Is the His6-HA-SUMO1 knock-in mouse a valid model system to study protein SUMOylation?

      K.A. Wilkinson<sup>1*</sup> , S. Martin<sup>2</sup> , S.K. Tyagarajan<sup>3</sup> , O Arancio<sup>4</sup> , T.J. Craig<sup>5</sup> , C. Guo<sup>6</sup> , P.E. Fraser<sup>7</sup> , S.A.N. Goldstein<sup>8</sup> , J.M. Henley<sup>1*</sup> .

      <sup>1</sup> School of Biochemistry, Centre for Synaptic Plasticity, University of Bristol, Bristol, UK. <sup>2</sup> Université Côte d’Azur, INSERM, CNRS, IPMC, France. <sup>3</sup> Institute of Pharmacology and Toxicology, University of Zurich, Switzerland. <sup>4</sup> Taub Institute & Dept of Pathology and Cell Biology, Columbia University, New York, NY, USA. <sup>5</sup> Centre for Research in Biosciences, University of the West of England, Bristol, UK. <sup>6</sup> Department of Biomedical Science, University of Sheffield, Sheffield, UK. <sup>7</sup> Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada. <sup>8</sup> Stritch School of Medicine, Loyola University, Chicago, USA.

      *Address for correspondence: kevin.wilkinson@bristol.ac.uk or J.M.Henley@bristol.ac.uk.

      Introduction

      There is a large and growing literature on protein SUMOylation in neurons and other cell types. While there is a consensus that most protein SUMOylation occurs within the nucleus, SUMOylation of many classes of extranuclear proteins has been identified and, importantly, functionally validated. Notably, in neurons these include neurotransmitter receptors, transporters, sodium and potassium channels, mitochondrial proteins, and numerous key pre- and post-synaptic proteins (for reviews see Henley JM, 2014, Wasik U, 2014, Peng J, 2016, Martin S, 2007, Luo J, 2013, Craig TJ, 2012, Scheschonka A, 2007, Guo C, 2014, Wu H, 2016, Schorova L, 2016). Furthermore, several groups have reported SUMO1-ylated proteins in synaptic fractions using biochemical subcellular fractionation approaches, using a range of different validated anti-SUMO1 antibodies (Martin S, 2007, Feligioni M, 2009, Marcelli S, 2017, Loriol C, 2012) and many studies have independently observed colocalisation of SUMO1 immunoreactivity with synaptic markers (Konopacki FA, 2011, Ghosh H, 2016, Gwizdek C, 2013, Jaafari N, 2013, Hasegawa Y, 2014). Tirard and co-workers (Daniel JA, 2017) directly challenge this wealth of compelling evidence. Primarily using a His6-HA-SUMO1 knock-in (KI) mouse the authors contest any significant involvement of post-translational modification by SUMO1 in the function of synaptic proteins.

      On what basis do Daniel et al. argue against synaptic SUMOylation?

      Most of the experiments reported by Daniel et al. use a knock-in (KI) mouse that expresses His6-HA-SUMO1 in place of endogenous SUMO1. Using tissue from these mice, followed by immunoprecipitation experiments, they fail to biochemically identify SUMOylation of the previously validated SUMO targets synapsin1a (Tang LT, 2015), gephyrin (Ghosh H, 2016), GluK2 (Martin S, 2007, Konopacki FA, 2011, Chamberlain SE, 2012, Zhu QJ, 2012), syntaxin1a (Craig TJ, 2015), RIM1α (Girach F, 2013), mGluR7 (Wilkinson KA, 2011, Choi JH, 2016), and synaptotagmin1 (Matsuzaki S, 2015). Moreover, by staining and subcellular fractionation, they also fail to detect protein SUMOylation in synaptic fractions or colocalisation of specific anti-SUMO1 signal with synaptic markers. On this basis, they conclude there is essentially no functionally relevant SUMOylation of synaptic proteins.

      What are the reasons for these discrepancies?

      • Inefficiency of His6-HA-SUMO1 conjugation and compensation by SUMO2/3

      A major cause for concern is that there is 20-30% less SUMO1-ylation in His6-HA-SUMO1 KI mice than in wild-type (WT) mice (Daniel JA, 2017, Tirard M, 2012). Moreover, in the paper initially characterising these KI mice, Tirard et al. showed that while total protein SUMO1-ylation is reduced, total SUMO2/3-ylation is correspondingly increased (Tirard M, 2012). Thus, His6-HA-SUMO1 conjugation is significantly impaired and most likely compensated for by increased conjugation by SUMO2/3. Crucially, however, Daniel et al. do not examine modification by SUMO2/3 at any point in their recent study.<br> Given that SUMO modification is notoriously difficult to detect the 20-30% reduction in His6-HA-SUMO1 compared to wild-type SUMO1 conjugation will make it even more technically challenging. Moreover, this deficit in SUMO1-ylation may well be offset by an increase in SUMO2/3-ylation of individual proteins, but this likely compensation was not tested. Since these deficits alone could explain why Daniel et al. failed to detect SUMO1 modification of the previously characterised synaptic substrate proteins it is surprising that they did not attempt to recapitulate SUMO1-ylation of the target proteins under the endogenous conditions in wild-type systems used in the original papers.

      • Lack of functional studies on the substrates they examine

      Daniel et al. confine their studies to immunoblotting and immunolabelling. However, these techniques address only one aspect of validating a bone fide SUMO substrate. It is at least as important to examine the effects of target protein SUMOylation in functional assays. Function-based approaches such as electrophysiology or neurotransmitter release assays are not reported or even discussed by Daniel et al. This is an extremely important omission. We argue that simply because SUMO1-ylation of a protein is beneath the detection sensitivity in a model system that exhibits sub-endogenous levels of SUMO1-ylation, does not mean that protein is not a functionally important and physiologically relevant SUMO1 substrate.

      • Insensitivity or inadequate use of assay systems

      Failure to detect GluK2 SUMOylation

      GluK2 is a prototypic synaptic SUMO1 substrate that has been validated in exogenous expression systems, neuronal cultures and rat brain (Martin S, 2007, Konopacki FA, 2011, Chamberlain SE, 2012, Zhu QJ, 2012). Daniel et al. attempt to detect SUMOylation of GluK2 using immunoprecipitation experiments from the His6-HA-SUMO1 KI mice. However, a key flaw in this experiment is that the C-terminal anti-GluK2 monoclonal rabbit antibody used does not recognise SUMOylated GluK2 because its epitope is masked by SUMO conjugation. Thus, due to technical reasons, the experiment shown could not possibly detect SUMOylated GluK2 whether or not it occurs in the KI mice.

      Subcellular fractionation and immunolabelling

      Daniel et al. perform subcellular fractionation and anti-SUMO1 Western blots to compare His6-HA-SUMO1 KI and SUMO1 knockout (KO) mice. In the KI mice they fail to detect SUMO1-ylated proteins in synaptic fractions. Importantly, however, they do not address what happens in WT mice, which, unlike the KI mice, exhibit normal levels of SUMO1-ylation. While the authors provide beautiful images of SUMO1 immunolabelling in neurons cultured from WT, His6-HA-SUMO1 KI mice and SUMO1 KO mice, in stark contrast to previous reports using rat cultures (Martin S, 2007, Konopacki FA, 2011, Gwizdek C, 2013, Jaafari N, 2013), they detect no specific synaptic SUMO1 immunoreactivity in neurons prepared from WT mice. We note, however, that the nuclear SUMO1 staining in neurons from His6-HA-SUMO1 KI mice is weak, and even weaker in WT neurons. Given that a very large proportion of SUMO1 staining is nuclear, these low detection levels would almost certainly rule out visualisation of the far less abundant, but nonetheless functionally important, extranuclear SUMO1 immunoreactivity.

      In conclusion

      Given these caveats we suggest that the failure of Daniel et al. to detect synaptic protein SUMO1-ylation in His6-HA-SUMO1 KI mice is due to intrinsic deficiencies in this model system that prevent it from reporting the low, yet physiologically relevant, levels of synaptic protein modification by endogenous SUMO1. In consequence, we question the conclusions reached and the usefulness of this model for investigation of previously identified and novel SUMO1 substrates.


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    1. On 2017 Jun 29, David Keller commented:

      Were serum cholesterol levels adequately controlled for?

      Low LDL cholesterol, and low total cholesterol, have been associated with higher risk of Parkinson disease (PD) in recent studies [1]. Consumption of lowfat dairy products, by displacing full-fat dairy products from the diet, certainly leads to lower serum cholesterol levels. Were serum cholesterol levels adequately controlled for? Does a person who consumes a lot of low fat dairy food run a higher risk of PD than a person with the same lipid levels who does not consume low fat dairy?

      Reference

      1: Huang X, Alonso A, Guo X, Umbach DM, Lichtenstein ML, Ballantyne CM, Mailman RB, Mosley TH, Chen H. Statins, plasma cholesterol, and risk of Parkinson's disease: a prospective study. Mov Disord. 2015 Apr;30(4):552-9. doi: 10.1002/mds.26152. Epub 2015 Jan 14. PubMed PMID: 25639598; PubMed Central PMCID: PMC4390443.


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    1. On 2017 Jun 21, Lydia Maniatis commented:

      This paper seems to hinge on a notion that makes no functional sense, has never been corroborated, and has led to an absurd claim by one of its main proponents attempting to salvage it.

      The notion is that the visual system performs a Fourier analysis on the "image" via "spatial frequency filters." As far as I can see, the reasons for the adoption of this functionally absurd notion were an ill-conceived analogy to hearing and the Fourier analysis that happens in the inner ear, combined with a gross over-interpretaion of the early findings of Hubel and Wiesel on the striate cortex of the cat. Psychophysicists were fabulously successful at corroborating the notion, accumulating heaps of evidence in its favor. Unfortunately, as Graham (2011) points out, the evidence generated had been interpreted in terms of a visual system that consisted solely of V1 (which was supposed to contain the orientation/frequency detectors) while it was later understood to be far more complex. The sitmuli that had been interpreted as tapping into V1 had somehow been ignored by neurons in V2, V3, V4, etc.! In these circumstances, Graham considers the "success" of the psychophysical program as something akin to "magic," and decides to explain it by arguing that, in the case of very simple stimuli, the brain becomes "transparent" down to the lower levels. Earlier, Teller (1984) had censured such attitudes as examples of an untenable "nothing mucks it up proviso." Below is the relevant passage from Graham (2011):

      "The simple multiple-analyzers model shown in the top panel of Fig. 1 was and is a very good account, qualitatively and quantitatively, of the results of psychophysical experiments using near-threshold contrasts . And by 1985 there were hundreds of published papers each typically with many such experiments. It was quite clear by that time, however, that area V1 was only one of 10 or more different areas in the cortex devoted to vision. ...The success of this simple multiple-analyzers model seemed almost magical therefore. How could a model account for so many experimental results when it represented most areas of the visual cortex and the whole rest of the brain by a simple decision rule? One possible explanation of the magic is this: In response to near-threshold patterns, only a small proportion of the analyzers are being stimulated above their baseline. Perhaps this sparseness of information going upstream limits the kinds of processing that thehigher levels can do, and limits them to being described by simple decision rules because such rules may be close to optimal given the sparseness. It is as if the near-threshold experiments made all higher levels of visual processing transparent, therefore allowing the properties of the low-level analyzers to be seen." Or, as is well-known, it's always possible to arrange experiments, including employing a very restricted set of stimuli, so as to achieve consistency with any hypothesis.

      I guess the fairly brief exposures used in the present experiment are supposed to qualify then for transparency status, unless the authors have their own views about the anatomical loci of the supposed spatial frequency filters, but all of this really should be discussed and defended explicitly.

      The idea that the visual system performs a Fourier analysis i.e. analyzes the visual stimulation into spatial frequency patterns, is absurd for a number of reasons. First, the retinal stimulation is initially point stimulation, a mosaic of points (photoreceptors) whose activities at any given moment depend on the intensity/wavelength of the photons striking them. Therefore, to organize this mosaic into a set of images based on spatial frequency is not first a problem of detection, but of organization. The spatial frequency kind of organization in no way furthers, but rather impedes, the task that the visual system has to achieve, which is to group points of the mosaic such that the boundaries of those groups correspond to the boundaries of the objects in the visual field. So it is not only incredibly difficult (no mechanism has been proposed), it is a pointless diversion. Even if this were not the case, the requirement for a 'transparency hypothesis" renders it absurd on that basis alone. There is no credible evidence in its favor.

      Other seemingly absurd claims include the statement that: "it recently has been shown that the availability of horizontal structure underlies the face-specific N170 response...." Is there such a thing as an image lacking "horizontal structure," or lacking structure in any direction? In other words, can we test this statement by controlling for "horizontal structure"? The term is too general to serve as a substitute for the much more specific and theoretically baseless image manipulation to which it refers.

      Another problem I have is the problem of sampling. With complex stimuli, the number of potential confounds is large. Not only is the sample of stimuli used here small; in addition, the authors don't indicate that they were randomly selected, only that they were "selected." On what basis? It seems to me that faces with well-defined eyebrows, for example, would be more likely to produce the desired results, given that the vertical filters seem to make them disappear in the sample provided in the article.

      I agree that familiarity makes perceptual tasks easier, and even that we notice relationships across the vertical axis more easily than across the horizontal, but the present experiment has nothing to do with that.


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    1. On 2017 Jun 22, Lydia Maniatis commented:

      This study is an exercise in generating and crunching numbers following a 50-year-old recipe containing many untested and implausible assumptions, i.e. Green and Swets (1966) analogizing of perception to signal detection. I've commented on this issue in detail in a number of PubPeer/PubMedCommons on other articles.

      I'll just make one additional comment here. In the Appendix, we're casually informed, as a preliminary, that:

      "All targets were assumed to be known to the ideal observer."

      In what sense is this omniscient-homunculus-assumption related to human perception? What is the neuroscientific theory behind it, and what is the relationship of this homunculus to the processes doing the "detecting and discriminating?" In other words, what is the relevance of the "ideal observer model" other than to provide an arbitrary value with which to compare the human data?

      (Also, what does it mean, exactly, that the targets were "known" to the ideal observer? What does this knowing consist of?)


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    1. On 2017 Sep 22, Clive Bates commented:

      I am struggling to see any useful purpose in this paper.

      It seems to consist of finding alcohol flavours in tobacco product and e-liquids by looking on the internet. There is no data on volumes or any age-related information about sales or appeal. The authors have done nothing to show an effect that requires a regulatory intervention or anything to justify their policy conclusion.

      The widespread availability of alcohol-flavoured tobacco products illustrates the need to regulate characterising flavours on all tobacco products.

      No so. The widespread availability of a product is not in itself a problem. Nor is the widespread use of a product, unless its use can be linked to a harm - which the authors have not done here, other than by just asserting it. It is likely and certainly plausible that these flavours are beneficial by encouraging adults to switch from smoking to vaping and that a regulatory intervention would cause more harm than good. It is also possible that if young people were attracted to such flavours, they may be diverted from smoking to vaping, which is a benefit. Needless to say, the authors do not consider such real-world possibilities.


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    1. On 2017 Jun 23, Dorothy V M Bishop commented:

      There is some evidence for diagnostic substitution from developmental language disorder to autism. I suspect, unfortunately, that this might be harder to quantify in public data than the substitution from intellectual disability, unless states have been consistent in terminology used for language disorder. Our study on this topic was just based on an adult follow-up of a small sample of children who had been diagnosed with language disorder, but it was striking how some cases who were identified as cases of language disorder (or specific language impairment) 20-30 yr earlier would nowadays been seen as clearcut cases of ASD - not because of any change in their profiles, but rather because of less restrictive diagnostic criteria for autism. Autism and diagnostic substitution: evidence from a study of adults with a history of developmental language disorder By: Bishop, Dorothy V. M.; Whitehouse, Andrew J. O.; Watt, Helen J.; et al. DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Volume: 50 Issue: 5 Pages: 341-345 Published: MAY 2008


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    1. On 2017 Jun 22, Sunil Verma commented:

      Dear Colleagues,

      This paper had used our Universal Primers (mcb398/mcb869 - US patent 7141364) along with other primers and cited our paper, Verma and Singh 2003, Mol Ecol Notes 3:28–31; therefore, I became interested in it.

      Being the inventor of these primers used in this study, I am aware that our primers CAN NOT establish the identity of the species from "Ash". I was really shocked to read the title, that someone may establish species identity from "Ash" using my primers!

      I was eager that all the scientific queries that I had answered so far in last 20 years, and all the arguments that I have done as wildlife forensic expert in the court of law, that species identity can not be established from "Ash" will prove wrong in the light of this paper.

      After going through the abstract itself, I understood the matter. I also went through the full paper, and understood that the title of the paper is misleading. The authors indeed did not establish the identity from ash but they did it from some partially burnt biological material that was recovered from the scene of crime. Thus, the title of the paper should have NOT been "Molecular identification from ash"

      My scientific view-point is that the title of this paper should be corrected as appropriate and erratum be published in the respective journal.

      Dr Sunil Kumar Verma

      [Sunil Kumar Verma]


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    1. On 2017 Jun 21, Lydia Maniatis commented:

      (Comment #2)

      The three sentences of the conclusion (which I annotate below, in its entirety, reflects the article's utter lack of content:

      1. *"Motion information generated by moving specularities across a surface is used by human observers when judging the bumpiness of 3D shapes." *

      The boundaries of specularities are effectively contour lines. It would be thoroughly unrealistic to predict that they would not play a role, moving or not. And the observation had already been made.

      1. "In the presence of specular motion, observers tend to not rely on the motion parallax information generated by the matte-textured reflectance component."

      The two parts of this sentence seem to be a non-sequitur - how could observers of specular motion employ information generated by matte-textured objects (i.e. objects other than the ones they were observing)? What the authors mean to say is that observers don't use the motion parallax info generated by the specular stimulus. While they frame this as though it were an actual finding, it is, as discussed above, a purely speculative attempt to explain the poorer performance with specular objects.

      1. *"This study further highlights how 3D shape, surface material, and object motion interact in dynamic scenes." *

      It really doesn't, given the mixed results and failed predictions. It couldn't for a number of other reasons, discussed below.

      1. All of the heavy lifting in this article is done by computer programmers, whose renderings are supposed to qualify as "specular" "specular motion" "matte-textured" etc. These renderings rest on theoretical assumptions most of which are never made explicit. They are, however, inadequate; we learn that observers sometimes saw the moving specular stimuli as non-rigid. This is a problem. There is no objective description of the phenomenon "specular object in motion around an axis" other than "objects generated by this particular program." Is there any doubt that results would have been different if the renderings had accurately mimicked the physical phenomenon? If the surface of the object is seen as changing, don't this affect the "motion parallax" hypothesis? The speed with which a particular point on a surface is moving optically is confounded with the speed with which it is moving on its own.

      2. The so-called matte-textured objects appeared purely reflective when not in motion. The apparent specularities were "stuck-on" so that they moved with the surface. I have never seen a matte surface with this characteristic. I would be curious to see the in-motion renderings, because I cannot imagine what they look like. What is clear is that a simple reference to matte textured objects is not appropriate. We are talking about a different phenomenon, which may not correspond to any physically actualizable one. This latter fact wouldn't matter if the theoretical framework were tight enough that such stimuli allowed isolation of some particular factor of interest. Here, however, it is just means that "matte" doesn't mean what it normally is thought to mean.

      3. Observers were confused about the meaning of the term "bumpiness." Stimuli involve hills and ridges of various extents as well as varying apparent heights. The authors were interested in height. They instructed observers who asked for clarification (not the others) that they were interested in "the amplitude not the frequency." I would say a large hill or a wide ridge could qualify as more ample for people not thinking in terms of graphs with height in the ordinate. In other words, I think there is a observational confound between extent and height of the bumps.

      4. In the introduction, the authors refer to previous papers which came to opposite conclusions. Presumably, this means that some relevant factors/confounds were not considered. But the authors don't attempt to analyze these conflicted citations, which thus merely function as window-dressing. They move on to their experiments, on the slightest and vaguest of pretexts, with poorly described stimuli and poorly controlled tasks.


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    2. On 2017 Jun 20, Lydia Maniatis commented:

      The term "motion parallax" figures prominently as an (oddly negative) explanatory concept in Dovencioglu et al's (2017) brief conclusion. Which is interesting, since we do not come across it in the title, abstract, introduction, methods or results sections of the paper.

      It shows up for the first time in the discussion, in the form of a highly speculative suggestion aiming to explain the study's unpredicted and uninterpretable results, in particular why it failed to produce an effect that, throughout the paper, the authors create the impression it did produce.

      I don't know if they deliberately meant to mislead, but until I got to a pair of isolated statements in the Discussion, I was under the impression that they were claiming to have shown that "specular motion" (a highly problematic term in its own right, as will be discussed in a subsequent comment) improved observers' ability to make veridical estimates of 3D shape. This is definitely not the case.

      While they're careful not to say it outright in the abstract, and while the title, as is typical of vision papers, is uninformative, the prominence of the "specular" term might lead an unsuspecting reader to assume that the claim that results "provide an additional layer of evidence for the capacity of the visual system to exploit image information for shape inference" is referring to some value-added information provided by "specular" as opposed to non-specular, stimuli.

      Similarly, the text of the final section of the introduction, titled "Does specular flow facilitate or interfere with 3D shape extimation? " might give the impression that the former is the case: For example:

      "...we focus on...whether specular flow...can provide better information on 3D shape than optic flow...specular flows are directly related to 3D curvature and seem to be less sensitive to the particular motion of the object, whereas optic flows vary more substantially with the latter. Thus, if a perceptual task required observers to make judgments abouta an objects' 3D curvature structure...one would expect more consistent shape perception across changes in object rotation axis."

      Given the lead-up, I think a reader would be justified in interpreting the phrase "more consistent shape perception" as equivalent to "better shape perception." Note, by the way, that "more consistent" as distinct from "facilitating" or "interfering" does not seem to be among the choices entertained in the title heading. That dichotomy has effectively disappeared by the end of the passage, because it cannot be settled by the data. In what is effectively a case of "bait and switch," a notion of "consistent" performance has been substituted for "better" (facilitated) performance. Under the circumstances, I think a reader might be excused for forming the impression that the answer to the question posed in the section heading was that specularity facilitates. The idea that more "consistent" performance corresponds to overall worse performance is not something that one would naturally assume.

      In any event, at a couple of points in a very opaque and incoherent text, the authors share with us the fact that "Surprisingly, overall [so-called] specular objects tended to be less discriminable than [so-called] matte-textured objects" (p. 10) and that "for in-depth rotations, discriminability of specular objects was overall lower than that of matte shapes, and for viewing axis rotations, it never exceeded that of mattte objects." (p. 11). (As far as I can see, these facts are not made clear in the Results section).

      So, to make lemonade out of lemons, the authors treat the (unexplained) lesser variability (across conditions) but overall worse performance in the "specular" case across conditions as advantageous relative to the (unexplained) overall better performance but greater variability (across conditions) of the "matte" case. The one specific claim, post hoc, that motion parallax is not used in the specular case, but is used in the matte case, is only a somewhat bizarre and superficial attempt to explain the worse performance (but not the greater "consistency") of the specular case.

      What is, in fact, the case is that the premises (tbd) and methods (tbd) of this project are sloppy, the analysis confused, forced, and misleading.


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    1. On 2017 Sep 12, David Keller commented:

      Pre-Existing Rheumatoid Arthritis Should Increase, Not Reduce, the Risk of Incident Parkinson Disease

      The authors of this editorial ask "Would tamping down the immune system be a good thing for PD (Parkinson disease) symptoms, or would activation of the immune system be advantageous?"[1] They cite epidemiologic studies which showed "a higher risk of PD in patients with type 1 diabetes mellitus (T1DM) and Crohn disease (CD), among others [2]", in conflict with studies that showed a decreased risk of PD in patients with rheumatoid arthritis (RA). So, does the presence of RA increase or decrease the incidence of PD?

      Genome-wide association studies (GWAS) found "enrichment" of loci associated with Parkinson disease conditional on the presence of loci associated with each of 7 autoimmune diseases, to varying degrees. The graphs in Figure 1 [3] demonstrate that for all 7 autoimmune diseases, the greater the population of SNPs associated with autoimmunity, the greater the enrichment of PD SNPs. The authors designate this as "leftward" deviation of the curves, although mathematically it is really UPWARD deviation from the straight line representing the null hypothesis. So, in genetic studies, all seven of the tested autoimmune diseases (T1DM, CD, Ulcerative Colitis, Celiac Disease, Psoriasis, Multiple Sclerosis and Rheumatoid Arthritis) were genetically associated with increased risk of incident PD.

      How can genetic risk of PD increase directly with the genetic risk of RA, yet epidemiological studies demonstrate an inverse association of established RA disease on the incidence of PD? The authors of one such epidemiological study did not believe their own results, and hypothesized that "the decreased risk [of incident PD] among patients with RA might be explained by underdiagnosis of movement disorders such as PD in this patient group, or by a protective effect of treatment with anti-inflammatory drugs over prolonged periods." [4] In other words, early signs of PD, such as bradykinesia, could be masked in RA patients, in whom slow movement might be attributed to pain or joint destruction, and ibuprofen use could have further confounded their results.

      The nonsteroidal antiinflammatory drugs (NSAID) have been studied extensively, and the only one which significantly reduces the risk of incident PD is ibuprofen.[5] A study by Sung and colleagues [6] concluded that pre-existing RA reduces the risk of incident PD, but they corrected their data for the use of any NSAID, rather than the use of ibuprofen, introducing systematic errors in their results, and potentially invalidating their conclusions. [7]

      Can a destructive autoimmune disease like RA reduce the risk of incident PD, in contrast to 6 other autoimmune diseases, which raise risk for PD? Or, do symptom masking and the protective effects of ibuprofen explain the reduction in incident PD seen in patients with RA? In an unpublished reply to these arguments, Sung's group wrote: "[Keller's] criticism focuses on the issue whether [any] non-aspirin NSAID or ibuprofen only, has the truly protective effect against the development of PD", and agreed that "ibuprofen was associated with decreased risk of PD, but not aspirin or other NSAIDs" and concluded that "ibuprofen use should be considered as an important covariable in future correlational research in PD." [8]

      References

      1: McFarland NR, McFarland KN, Golde TE. Parkinson Disease and Autoimmune Disorders-What Can We Learn From Genome-wide Pleiotropy? JAMA Neurol. 2017 Jul 1;74(7):769-770. doi: 10.1001/jamaneurol.2017.0843. PubMed PMID: 28586798.

      2: Lin JC, Lin CS, Hsu CW, Lin CL, Kao CH. Association Between Parkinson's Disease and Inflammatory Bowel Disease: a Nationwide Taiwanese Retrospective Cohort Study. Inflamm Bowel Dis. 2016 May;22(5):1049-55. doi: 10.1097/MIB.0000000000000735. PubMed PMID: 26919462.

      3: Witoelar A, Jansen IE, et al. for the International Parkinson’s Disease Genomics Consortium. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases. JAMA Neurol. 2017;74(7):780–792. doi:10.1001/jamaneurol.2017.0469

      4: Rugbjerg K, Friis S, Ritz B, Schernhammer ES, Korbo L, Olsen JH. Autoimmune disease and risk for Parkinson disease: a population-based case-control study. Neurology. 2009 Nov 3;73(18):1462-8. doi: 10.1212/WNL.0b013e3181c06635. Epub 2009 Sep 23. PubMed PMID: 19776374; PubMed Central PMCID: PMC2779008.

      5: Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk of Parkinson disease. Neurology. 2011 Mar 8;76(10):863-9. doi: 10.1212/WNL.0b013e31820f2d79. Epub 2011 Mar 2. PubMed PMID: 21368281; PubMed Central PMCID: PMC3059148.

      6: Sung YF, Liu FC, Lin CC, Lee JT, Yang FC, Chou YC, Lin CL, Kao CH, Lo HY, Yang TY. Reduced Risk of Parkinson Disease in Patients With Rheumatoid Arthritis: A Nationwide Population-Based Study. Mayo Clin Proc. 2016 Oct;91(10):1346-1353. doi: 10.1016/j.mayocp.2016.06.023. PubMed PMID: 27712633.

      7: Keller DL, Only ibuprofen is associated with reduced PD risk - controlling for use of any NSAID introduces error. PubMed Commons Comment, accessed on 9/12/2017 at the following URL: https://www.ncbi.nlm.nih.gov/pubmed/27712633#cm27712633_34408

      8: Sung YF, Lin CL, Kao CH, and Yang TY. Reply to Keller's unpublished letter to Mayo Clinic Proceedings. Received by email on November 22, 2016.


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    1. On 2017 Jun 21, Lydia Maniatis commented:

      I don't get it; are citations like these valid? They seem to be doing most of the heavy lifting.

      "The finger spread and beauty judgement were recorded by our web app, emotiontracker.com (A.A.B., L. Vale, and D.G.P., unpublished data).

      As previous work has shown (A.A.B., L. Vale, and D.G.P., unpublished data), continuous pleasure ratings are well fit by a simple model, refined here ((Equation 1), (Equation 2) ; (Equation 3) and Figure 1B). The model supposes..."

      What gives the model assumptions their credibility? Are readers now supposed to take claims on faith?


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    1. On 2017 Sep 21, Stuart RAY commented:

      Conclusions revised, here Jakobsen JC, 2017


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    2. On 2017 Jul 05, David Thomas commented:

      Readers should exercise considerable caution interpreting this report. The review correctly identifies a sparse literature comparing placebo to treatment. As they observe, "there were no data on hepatitis C-related morbidity and very few data on mortality." However, they mistakenly conclude in the preceding sentence that "DAAs do not seem to have any effects on the risk of hepatitis C-related morbidity or all-cause mortality." If there are no data, how could this evidence-based review make that conclusion? The lack of evidence of an effect is not evidence of a lack of effect.

      Even greater clarity on the matter comes from understanding why those data are missing. The paucity of long-term mortality data of persons with HCV randomized to placebo versus treatment is because, as Dr. Ray points out, the medical consensus underscored by AASLD/IDSA, EASL, the US National Academies of Sciences, Engineering, and Medicine and others is that treatment with DAAs is beneficial. There would be ethical challenges to randomizing someone to placebo and observing them for 10-20 years to see if they acquire conditions that we know the virus causes when a treatment that eliminates the infection exists. Of course, not all will develop liver cancer or liver failure, but neither does any other complication always occur for conditions for which treatment has universal support.

      Readers should note that the lack of placebo-controlled long-term data is because DAAs are effective not evidence "DAAs do not seem to have any effects".


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    3. On 2017 Jun 28, Stuart RAY commented:

      This review acknowledges some limitations of the evidence, but fails to balance the limitations of examining long-term outcomes in short-term trials that used SVR as a well-founded surrogate endpoint; perhaps more importantly, the review falls short in the larger context of the global HCV epidemic and elimination campaigns. That this is the case is illustrated by the response from organizations such as AASLD and IDSA, EASL, and related groups in Australia and Asia. Each of these statements provides considerations for the Cochrane review and its interpretation.


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    1. On date unavailable, commented:

      None


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    2. On 2017 Jun 05, Lydia Maniatis commented:

      You should be faulted for the nature and extent of the problems, not for making them explicit, which is, indeed, useful. I think the nature of the problems reflect an unproductive approach to science.

      Below, I contrast this approach with an alternative and briefly explain why the latter is productive while the former is not. (The alternative is presented first.)

      1. Someone makes a guess about the causal basis of an effect or phenomenon. These guesses entail various assumptions. The assumptions should be adequate to explain the thing they have been proposed to explain. Additionally, one may derive certain other implications, pointing to effects or facts that have not, as yet, been observed, i.e. predicted effects or facts. The data in an experiment or investigation designed to produce those predicted effects, or discover these predicted facts, thus act as a test of those predictions and the related assumptions. The criterion for provisional acceptance of assumptions is, in other words, the match between their observable implications and observation.

      2. Data collected are interpreted on the basis of assumptions which they are not designed, and cannot, test. Thus, the experiment plays no role in corroborating or falsifying these assumptions. The criterion for adopting them is simply the personal preference of the investigator - a criterion which, again, is independent of experiment.

      Because this approach is not designed to test assumptions, it is inherently uninformative as to their verisimilitude, their relationship to the "ground truth." The titles of the corresponding articles are similarly uninformative. They report "exploring," "characterizing," "measuring," various effects, or simply state the topic area they are addressing without giving any hint of their conclusions.


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    3. On 2017 Jun 05, Michael Tarr commented:

      Interested parties should read the entire paper and make up their own minds. Every scientific study has limitations and we should not be faulted for making them explicit so as to inform interested readers.


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    4. On 2017 Jun 03, Lydia Maniatis commented:

      “Pick your poison”

      I’m speculating, but it seems to me that, no longer able to bar post publication critiques of low quality studies (via muscular refusal to publish critical Letters to the Editor), journal editors have adopted a compromise strategy of continuing to accept low-quality papers, while requiring authors to enumerate (many of) the study’s (often fatal) flaws, in a section referring to “limitations of the study” This is an improvement on the old system; however, this special section should be placed at the front, not at the tail end, of the paper. More often than not, it reveals that methods were confounded and interpretation based on flimsy, vaguely elucidated and untested assumptions; as such, conclusions can carry little or no theoretical weight.

      This is the case here; among the “Issues and limitations,” of the study the authors mention:

      a. That the study lacks an important control condition (“we did not collect neural responses for any untrained face stimuli…” (p. 18)) and that it is not clear how the necessary control might be achieved.

      b. That it is unclear whether results generalize in order to explain what they are supposed to explain; this, we’re told, is contingent on whether certain vague assumptions adopted by the authors, about what observers are doing, actually hold ("we hypothesized that this task prompted subjects to learn...").

      c. That it is not clear that subjects were discriminating faces holistically, or only on the basis of the simple variations used in the stimulus set. The authors explain that they prefer to make the more convenient assumption that “the task used in our study was biased towards facial discrimination rather than facial part discrimination.”

      d. Most interestingly, we learn that, in order for the results of the imaging technique used to be interpretable, it is necessary to impose certain constraints on the analysis, and that the choice of constraints “can lead to source reconstructions that are different from the true activity in the brain.” What should a scientist do, in the absence of information about the proper (true) assumptions to make? I would say, make and test the assumptions you need in order to ascertain the proper constraints. Instead, the authors take a riskier route. In the absence of knowledge, they say, one has to “pick his poison by simply choosing some constraints.” Of course, the authors “tried to choose reasonable constraints…”

      To make situation clear: To interpret their data, collected on the basis of conditions which are heavily confounded (and which the authors unconfound simply on the basis of wishful thinking), they must make further, untested assumptions in a way that is so rigorous that they analogize it to picking a poison. Conclusions are thus wholly contingent on layers of highly speculative assumptions. Until these are clarified, tested, and corroborated, the empirical content of this project - the theoretical weight of the conclusions - is null.

      Assuming these articles are actually written to be read, the poison label should be affixed prominently at the top.


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    1. On 2017 Jun 19, Stefano Casola commented:

      Authors acknowledge the insightful comments. We would like to draw the attention of Dr Woodgett to the following observations:<br> • The antibody used to detect GSK3-beta Serine-9 phosphorylation does not recognize phosphorylated forms of GSK3-alpha (https://www.cellsignal.com/products/primary-antibodies/phospho-gsk-3-beta-ser9-d3a4-rabbit-mab/9322). Thus, whereas our data indicate that loss of the BCR in MYC-driven lymphoma cells leads to a reduction in GSK3-beta Ser-9 phosphorylation, it remains to be investigated whether GSK3-alpha is similarly affected in these cells.

      • GSK3-beta knock-down experiments were performed using six independent shRNAs (referred to in the Methods section of the paper). Data obtained with the two most effective hairpins are shown in Extended Data Figure 5c, d. Importantly, the shRNAs were selected for their ability to target GSK3-beta but sparing GSK3-alpha. Despite only partial GSK3-beta knock-down, lymphoma cells losing BCR expression resisted substantially better to their BCR+ counterparts in competition assays, with the most effective hairpin (shRNA# 2) causing a complete block of their counter selection (Extended Data Figure 5e). These results closely mirror those obtained studying BCR+/BCR- lymphoma cell competitions treated with the GSK3 inhibitor CHIR99021 (Figures 3d and Extended Data Figure 5a).

      Therefore, whereas we cannot exclude a contribution of GSK3-alpha, our data indicate that modest changes in GSK3-beta expression/phosphorylation are sufficient to critically affect BCR-controlled fitness of MYC-driven lymphoma cells.


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    2. On 2017 Jun 15, Jim Woodgett commented:

      This is an interesting paper but from what I can see, the evidence for these effects being dependent on GSK3beta (rather than a combination of GSK-3beta plus GSK-3alpha) is limited to a partial (maximally 35%) knockdown by siRNA in extended data figure 5 - where a marginal effect was observed (partial knockdown of GSK3alpha may have given a similar result). The pharmacological inhibitor used, CHIR99021, has NO significant selectivity for GSK3beta over GSK3alpha (the authors do refer to it being in GSK3 inhibitor in two places). In every example where phosphorylation of Serine 9 of GSK3beta has been examined along with phosphorylation of Serine 21 of GSK3alpha, they are phosphorylated in parallel. There are no kinases that target these sites selectively (not true of a more C-terminal site, Ser389, targeted on GSK3beta by p38 MAPK). Why is this important? Because throughout the paper, there are over 50 mentions of GSK3beta, including the title, yet there was no measurement of GSK3alpha phosphorylation or knockdown.


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    1. On 2017 Aug 03, David Mage commented:

      The authors have performed a thorough study of SUID rates in the entire U.S. for years 1995-1997 and 2011-2013 and test for significant differences (at P<0.05) in Table 2.

      However, they neglected to make the finite population correction (fpc) that adjusts for the sample size n of independent probability samples without replacement from a finite population of size N.

      Given that they sampled the entire U.S. infant populations for SUID during those years so that n = N, the fpc = 0 as shown below because there is no sampling error.

      Consequently footnote 'a' and related discussion could be removed.

      fpc = Sqrt[(N - n)/(N - 1)] = 0 for n = N.


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    1. On 2017 Dec 30, E Naydenov commented:

      The expectations about IRT should be realistic. Our experience so far indicates that it might be usable localization tool only in cases with subcortical convexity tumors. The results are more evident in patients with metastatic brain disease. Another study on the last topic is on the way.


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    1. On 2017 Jun 14, Jean-Jacques Letesson commented:

      To my knowledge this is the first reported bacteriologicaly positive case of Brucella infection into the eye.

      Existing information on uveitis and other affections of the eye structure suggest that these are not so rare complication of brucellosis. Depending on the series, up to 50% of patients (B. melitensis) can show some of these troubles (early observations are in Dalrymple-Champneys, W., 1960. Brucella Infection and Undulant Fever in Man. Oxford University Press, London, pp. 88; also, in a recent work done in an endemic area, about 20% of the patients showed these complications: Gulten Karatas, Set al 2009. Canadian Journal of Ophthalmology 44, 598–601). However, Brucella has never been isolated from enucleated human eyes to confirm the diagnosis (Brucellosis. M. Monir Madkour. ISBN 0-7236-0941-1)

      This ocular localization could be related to the presence of aldose reductase (AR) in these organs. Aldose redutase being probably involved (among other function) in the production of erythritol the favorite carbon source of Brucella. (Erythritol Availability in Bovine, Murine and Human Models Highlights a Potential Role for the Host Aldose Reductase during Brucella Infection Front. Microbiol., 13 June 2017 | https://doi.org/10.3389/fmicb.2017.01088)

      Actualy, lens and retina while not being described as being a site of high AR expression, have also been analyzed for AR content because the expression of AR is induced by high glucose or osmotic stress and because of the role of the polyol in diabetic cataract or retinopathy.


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    1. On 2017 May 31, Lydia Maniatis commented:

      p.s. The fact that references to decomposition into layers are references to perceptual facts also means that simply asking people to qualitatively describe their experience is a necessary and sufficient means for deciding between the authors' two proposed "models" of these experiences, as both refer to perceptual dimensions and only perceptual dimensions (regardless of the presumed physical causes). Thus: "The hybrid decomposition thus suggests that the human visual system may decompose compound BRDF's into two perceptual components..."

      As this simple operation of asking people whether they perceive layers, etc, was not performed, the authors try to guess at whether their results are consistent with one or another description. "To this end, we have performed a number of linear regressions on our experimental data..." but of course "it should be noted that the evidence derived from the current experiment is mixed, so additional, more targeted [less confounded, better rationalized] experiments would be required..." But still, they go on to elaborate a post hoc description of results, for what its worth.


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    2. On 2017 May 31, Lydia Maniatis commented:

      What do Vangorp et al (2017) have to say about the “perception of hazy gloss” (and why don’t they break the news up front)?

      If the final statement of their discussion is any indication, it seems they ended up where they began,: “An exciting avenue of future work is thus to understand how the human visual system encodes hazy gloss and distinguishes it from glare in images.” (p. 14)

      But this study also used images, and its stated goal was “to investigate the conditions in which haze gloss is encoded in the perceptual representation of glossy materials.” (p. 2)

      As reported, the experiments performed were hopelessly confounded, their results uninterpretable, and their rationale conceptually confused. As is too often the case, all the authors can do under the circumstances is to describe their results in a purely self-referential way, offering vague and incoherent post hoc speculations as to the causes of their particular outcomes with respect to their particular conditions. Thus:

      Experiment 1

      Experiment 1 doesn’t actually evaluate perception of a quality that observers would necessarily describe (and which the authors vaguely describe) as “hazy gloss,” but, rather, the ability to match certain parameters of certain graphic images.

      Results are highly variable and don’t possess a form the authors did or could have predicted or are able to interpret: “The space of average matches is severely compressed towards the middle of the valid space. The variance of these average matches is so large that representing it as ellipses would clutter the graph.” (p. 6) Vague speculations follow:

      “One interpretation could be that a perceptual decomposition of sharp and wide specular components [being graphic images, the stimuli do not actually contain specular components, unless we are talking about reflections on the screen] is difficult…” (p. 6)

      “However…these results do not prove that participants perceptually separated the material into two components.” This is partly due to confounds: “In each condition only a single parameter is kept correct, while the other three vary…This means that observers might attend to the narrow shading features to judge…Observers might also attend to other shading features…” (p. 6)

      “Since there is no correct match [in the single component condition], success must be defined as the consistency between participants and consistency with plausible models…” (p. 6) There is, however, no discussion about the plausibility of models.

      “The polar plots show skewed and even bimodal probability distributions…” (p. 6)

      “The findings suggest that, at least for some parameter ranges, particularly in the upper edges of the stimulus space, participants are able to match the properties of two-component specular materials [assuming that the graphics program accurately mimics the optical effects of the referenced specular conditions].” (p. 6)

      It should be clear that the muddled, ad hoc conclusions, to the extent that they are intelligible at all, refer narrowly to the particular experimental conditions and stimuli; the conceptual analysis is not such as to allow us to draw out implications outside of this self-referential space.

      (And yet another confound is referred to in the description of Experiment 2: “The diffuse component in Experiment 1 could have obscured the intended differences in the specular [so-called] components…we performed the 4AFC task in a darkened room …in order to further optimize the performance of the observers.” (p. 9-10) (Further optimize....as in “even more perfect...”)

      Experiment 2 This is a forced choice discrimination task. Forced choice means we don’t really care about what observers are actually perceiving, only that they give some manageable responses.

      Again, there is much post hoc speculation (very briefly, to give the style of the account): “For all three classes of distractors there are ranges of corresponding two component materials that are easily distinguishable.” “The main differences between conditions may be explained by…This would explain the opposite slopes of the performance curves…However, Figure 10 suggests that a simple interpretation…is unlikely… Nevertheless, the discrimination experiment suggests…”

      In any case: “However, this in itself does not tell us about the subjective interpretation of these differences. Does the [presumed, and variable] ability to distinguish between different BRDF’s reflect a distinct perceptual parameter, or are the image differences detectable but not interpretable?”

      Answering this question is a job for Experiment 3, which, naturally, employs entirely different graphic material effects (silvery as opposed to plasticky...Why?) with different graphic lighting effects. (“This experiment used a different lighting environment representing another church interior, Galileo’s Tomb.” Well, as long as it's a church...We’re not told why, or how such a change might be expected to affect the phenomenon of interest.) The authors also give us various other details about the parameters employed, but what’s the point?

      The results of Experiment 3 are as informative as those of the other two. The arguably tautological conclusion is drawn that “the subjective impression of hazy or layered materials is crucially associated with a “bloom” or “halo” around sharp reflections.” (p. 10). (The use of quotation marks indicates that a subjective impression is being explained in terms of a similar, differently-expressed subjective impression.)

      The theoretical discussion generally is conceptually confused, essentially failing to make the crucial distinctions among the distal object, the proximal (retinal) stimulation and the perceptual experience. This is illustrated, for example, by the following phrase: “It is highly unlikely that the human visual system refers to only two specific angles [of reflections] to infer haze gloss…” The angles being referred to have no retinal correlate, so of course they could not be the cause of the percept. These angles of reflection may have a correlate in the percept, but this cannot be used as an explanatory principle for the formation of the percept.

      Another funny thing the authors do (they’re not the only ones) is to express a perceptual fact as though it were a theoretical one, treating a perceptual fact as something yet to be ascertained experimentally. Thus:

      “We therefore propose that the visual system may represent haze by decomposing the material response into two distinct components, or causal layers. One obvious choice for such a decomposition would be the physical components themselves (i.e. the broad and narrow specular terms). [Note that, as usual, the authors are inappropriately treating the physical features of the distal stimulus as explanatory variables]. This decomposition separates the composite reflection into two [and the authors can only be referring to perceived layers, as in their later reference to transparency] superimposed layers…much like the decomposition of image patches...in transparency perception. This would be broadly [a high standard!] consistent with our findings that observers base many of their judgments on the narrow component.”

      We don’t have to guess as to whether the percept contains perceived layers; this is, by definition, a subjective fact and can be directly ascertained by personal experience and/or by asking other people what they see. If they answer in the positive, then any experiment that indicated otherwise would obviously be in error.


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    1. On 2017 May 31, Xiaolin Wu commented:

      This paper raises important safety issue for gene therapy application of CRISPR-Cas9. However, there are serious doubts about the results or interpretation. First of all, the authors listed Top-10 predicted off-target sites. But all genes are wrong! looking at the sequence they listed (supp. figure 3), you will not be able to find it in the genes! After careful inspection, the first predicted off-target is actually the "on-target" sequence for pde6b gene. For such a high-profile journal, you can't be so sloppy. This is not just a typo. I inspected them and they are all assigned to wrong gene. If you can't even get your on-target correct, how do you think people can trust your data? There are some genes are assigned to even wrong chromosomes! Supp fig3 panel b, listed herc1 gene on ch11. That gene is supposed to be on chr9. After this first figure, I don't even know if any other information reported here is correct!

      I then went on to inspect Supp table 1-3. The authors listed all off-targets observed from the WGS. However, Pde6b pTyr347fs/c1041_1050CGTAGCAGAA is actually the on-target indel. and the author did not even notice this is their target gene? and listed it as one of the two off-target genes with mouse phenotype? The CRISPR-cas9 system is supposed to created Indel here! You simply did not repair it. You replaced the stop codon with the indel. I downloaded the raw sequence, and found that this specific deletion (CTGAGCAGAA)can not be found. Only by reading the authors previous paper, I figured out that they mean a 10 bp deletion but they don't even have the correct deletion sequence!

      After seeing all these careless mistakes, I don't even know if they mislabeled the mouse or samples! It is hard for me to imagine CRISPR-case9 causes so many homozygous deletions in two independent mice (all right, it may happen in rare case for specific sgRNA like this one). And even if some of the mutations/indels are real, they may have nothing to do with CRISPR-cas9. For example, the authors see homozygous deletion in Pde9a gene in both animals. Do the authors consider the possibility that this deletion might be created by totally unrelated mechanisms and strongly selected for in vivo? since Pde9a and pde6b are paralogues. The easiest way to test if these are real CRISPR-cas9 off-target is to check these loci in treated cells in vitro. In that setting, you can check millions of cells to see if they do occur or do not occur. Maybe none of them is created by CRISPR-cas9 off-target. But during the embryo development, these mutations are created and strongly selected to compensate for something. I admit that in vitro does not speak for in vivo. But you can't just assume these mutations are generated by CRISPR-Cas9.


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    1. On 2017 Jul 13, Atanas G. Atanasov commented:

      Congratulations for the excellent overview dear colleagues. I have featured your work in my recent science popularization article “Are Probiotics Useful For Therapy of Autoimmune Diseases?”: https://www.consumerhealthdigest.com/general-health/probiotics-and-autoimmune-diseases.html


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    1. On 2017 May 31, Jens Staal commented:

      Interesting. I wonder if the common factor is CARD9, which is known to be required for both pathways in mammals.


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    1. On 2017 Oct 27, Andrea Messori commented:

                            .

       

      THE ADVANTAGES OF NET MONETARY BENEFIT IN HANDLING MULTIPLE SIMULTANEOUS COMPARISONS .

       

      A.Messori, HTA Unit, Regional Health Service, Firenze, Italy .

       

      The paper by Trippoli [1] discusses the main advantages of net monetary benefit (NMB) in comparison with incremental cost-effectiveness ratio (ICER). There is however another important methodological advantage that deserves to be discussed in detail.

      In the “classic” analyses based on ICER, only two comparators are directly managed. For example, if A is the innovative therapy and B is the standard therapy (and assuming that all values of cost and effectiveness are normalised to 1 patient), ICER is defined as follows: .  

       

      Equation 1)    ICERAvsB  =  (costA - cost B) / (effectivenessA - effectivenessB)  <br>  <br>     .<br> After this calculation, ICERAvsB is evaluated against the pre-defined threshold (T) of cost-effectiveness (e.g.£ 30,000 in the UK or around $100,000 in the US) to decide if using A as opposed to B has a favourable cost-effectiveness (ICER<T) or an unfavourable cost-effectiveness (ICER>T).

      In Western countries, the process of in-hospital procurement is often managed by running competitive tenders, particularly in the field of implantable medical devices. The problem is that, while tenders generally evaluate three or more comparators, the design of Equation 1 manages just a single comparison, i.e. two comparators only.

      As pointed out by Trippoli [1], one important advantage of the NMB is that this parameter can be separately calculated for each of the (three or more) comparators under examination. Furthermore, these (three or more) values of NMB can then be compared with one another in any binary comparison and, finally, these values are expressed according to easily understandable units (represented by “differences in benefit”, where all benefits and all costs are expressed in monetary units normalized to 1 patient).

      On the other hand, in the “classic” approach based on ICER the issue of comparing three or more comparators (e.g. four comparators named A, B, C, and D) is usually addressed by applying some methodological tricks. One of these tricks introduces ‘no treatment’ as a further comparator (although ‘no treatment’ is in some cases a reasonable comparator, but in other cases is not). Another one is to identify, as standard treatment (ST), a single comparator among A, B, C, and D (e.g. B so that ST=B), and to calculate ICERAvsST, ICERCvsST, and ICERDvsST; according to this latter solution, if ST=C, the calculation involves ICERAvsST, ICERBvsST, and ICERDvsST; if ST=D, the calculation involves ICERAvsST, ICERBvsST, and ICERCvsST; and so on. The drawback to all of this “classic” approaches is that the units of ICERs (ratio of incremental cost and incremental effectiveness) make their interpretation very difficult, and furthermore finding a role for T in this type of reasoning is difficult as well.

      In conclusion, the NMB is much more efficient than the ICER in performing the simultaneous comparison of three or more comparators.

       

       <br> References

      [1] Trippoli S. Incremental cost-effectiveness ratio and net monetary benefit: current use in pharmacoeconomics and future perspectives. Eur J Int Med 2017 Sep;43:e36.


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    1. On 2017 Jun 09, Lydia Maniatis commented:

      The idea that one can define a spatial extent (an aperture) for which perception of faces is equivalent to perception without such a constraint, is not credible, and the conclusions not interpretable; the conditions under which it was defined here make it all the more uninterpretable. The large difference local details of stimulation can make on the organization of the resulting percept, and the contingency of the effect of that detail on the all of the other local details and their relationship to the entire collection, are facts not compatible with simply additive, spatially-defined predictions.

      In addition, the experiments are highly confounded and the authors address these confounds post hoc, using a hodge podge of analytical tools that entail many untested, untestable, and very likely false, assumptions. Among these is the "Random Field Theory" used to assess similarity between images of faces, which involves a pixel-by-pixel definition of similarity that, given the nature of perception and particularly face perception, is not credible. (It is certain that two faces might have a strong family resemblance which would not be correlated with a pixel-by-pixel definition. Similarity is a notoriously difficult concept and in practice comparisons are highly selective).

      Given the post hoc ad hoc style of the analysis and weak theoretical framework, it is virtually certain that these results could not be replicated using a different sample of images understood as "faces" (the choice of the sample images has no more specificity than that) but otherwise identical procedures and analysis. This, the authors make pretty clear:

      "Following this idea, we emphasize that the Facespan should not be considered as an absolute quantity. Inasmuch as the perceptual span for reading is not absolute, but instead flexible, the Facespan reported here should be considered as an average benchmark obtained under the aforementioned specific viewing conditions and task."

      Obtained - and re-obtainable? It seems contradictory to suggest that a flexible outcome, the parameters mediating whose flexibility are undetermined, can serve as a benchmark, average or otherwise. We're left with a vague, less than credible, not-really-quantified concept - the Facespan.


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    1. On 2017 Dec 15, Ricky Turgeon commented:

      Duplication of PLATO data in meta-analyses

      Upon reviewing this meta-analysis, I noticed that the data from PLATO have inadvertently been duplicated in all meta-analyses of clinical outcomes in this review. This was done by including both the results of the primary publication (Wallentin et al, NEJM 2009 - reference 28 in this article) and the subgroup of PLATO patients planned for an invasive strategy (Cannon et al, Lancet 2010 - reference 21).

      Ideally, this review should be retracted and republished in its corrected form that excludes the double-counting of events and ~13,000 participants from the Cannon, et al Lancet 2010 subgroup analysis of PLATO.

      Sincerely, Ricky Turgeon BSc(Pharm), ACPR, PharmD

      (copy of comment posted on PLOS ONE)


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    1. On 2017 Dec 22, Peter Gøtzsche commented:

      Leucht et al. conclude that “approximately twice as many patients improved with antipsychotics as with placebo” (1). However, no reliable conclusion can be made, as all the 167 double-blind trials were flawed. None of the trials exclusively examined first-episode patients and when patients who already receive antipsychotic drugs are randomised to placebo, serious withdrawal symptoms will occur. Yet, this withdrawal group is mischaracterized as a placebo group. Even trials with a long tapering period before randomization are unreliable. Antipsychotics cause permanent brain damage, e.g. about 5% a year develop tardive dyskinesia but the drugs may mask this, so that it appears for the first time when the drugs are stopped.

      My conclusion is that 60 years of “placebo”-controlled trials of antipsychotics have been wasted. We need to do trials in drug-naïve patients with their first episode of psychosis if we want to know what these drugs to do people. We also need to ensure that the trials are adequately blinded by adding a substance to the placebo that gives side effects. Leucht et al. praise the NIMH study from 1964, but in this trial, the psychiatrists reported the exact opposite of what happens when people get antipsychotics. The drugs were said to reduce apathy, improve motor movement and make patients less indifferent (2).

      1. Leucht S, Leucht C, Huhn M, Chaimani A, Mavridis D, Helfer B, et al. Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 2017;174:927-942.

      2. Cole JO. Phenothiazine treatment in acute schizophrenia; effectiveness: the National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group. Arch Gen Psychiatry 1964;10:246-61.


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    1. On 2017 Jun 17, Randi Pechacek commented:

      Simon Lax, first author of this paper, wrote a brief blog post on microbe.net about the importance of the hospital microbiome in context of this paper.


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    1. On 2017 May 31, Lydia Maniatis commented:

      "In summary, we have shown a nonlinear response to a compound of gratings (plaid) that does not arise purely from contrast normalization between spatial frequency channels."

      There is zero evidence and zero rationale for the existence of "spatial frequency channels" in the visual system. A spatial frequency analysis of the retinal stimulation would not contribute to the derivation of the percept, but only make the job more difficult-to-impossible. The notion has never been tested, and it's not clear how it could be tested. Simple data derived from carefully constrained experimental conditions (for which the assumptions can be made to seem to fit) are simply interpreted as though these untestable/untested/false assumptions were true, and it were only a matter of fine-tuning "models" via data-fitting. Similarly, I could posit other invisible forces as being responsible, and interpret accordingly.

      The notion that EEG's correlated with particular percepts can be directly (theoretically) correlated with the activity of particular populations of neurons in the brain is absurd, and, at any rate, has not been tested, and cannot be tested in the foreseeable future. The many reasons why it is absurd have been discussed by me in various pppr comments and by Teller (1984).


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    1. On 2017 Aug 29, Andreas Lundh commented:

      Comment on Association of streptococcal throat infection with mental disorders

      A recent Danish register-based cohort study(1) concludes that “individuals with a streptococcal throat infection had elevated risks of mental disorders, particularly OCD and tic disorders.” However, some methodological issues need consideration.

      Firstly, the choice of exposure has a risk of misclassification. Exposure (i.e. Group A Streptococcal (GAS) throat infection) was the combination of a rapid antigen test performed by the patient’s general practitioner and subsequent antibiotic prescription. In Denmark use of rapid antigen test and antibiotic prescription are guided by modified Centor criteria(2,3) where symptomatic patients at high risk of GAS throat infection are not tested, but instead receive empirical antibiotic treatment. This leads to patients being misclassified as unexposed since they are never tested.

      Secondly, the choice of outcome has a similar risk of misclassification. Psychiatric diagnoses are identified from national databases that only contain hospital information. Psychiatric patients that are not treated in hospitals (e.g. treated by primary care psychiatrists) are misclassified as not having had the outcome. Misclassification seems likely as only 0.1% and 0.2%, respectively, had a diagnosis of OCD or tics in the study period.

      Thirdly, the analytical strategy has a risk of bias. The authors compared patients that had received both a rapid antigen test and antibiotics with a group that was never tested. GAS throat infection will in most cases resolve spontaneously and many patients will never contact their general practitioner for testing. The group tested therefore likely differs from the group not being tested and represents a group with certain healthcare seeking behavior. This is substantiated by the findings that risk of mental disorders seems to increase with number of tests and regardless of whether the tests are negative or positive. A more reasonable analysis that avoids confounding by test indication would be to compare the group of tested patients prescribed antibiotics with the group of tested patients without prescribed antibiotics. This comparison weakens the association and it is no longer statistically significant for tics.

      Instead of describing this as a possible source of bias the authors conclude that nonstreptococcal throat infection was also associated with increased risk of mental disorders, a theory that was not part of the original study hypothesis. Another interpretation is that these associations can be explained by a certain healthcare seeking behavior of patients and parents leading to an increased probability of receiving an antigen test, being prescribed an antibiotic and being treated in hospital.

      References

      1) Orlovska S, Vestergaard CH, Bech BH, Nordentoft M, Vestergaard M, Benros ME. Association of Streptococcal Throat Infection With Mental Disorders: Testing Key Aspects of the PANDAS Hypothesis in a Nationwide Study. JAMA Psychiatry 2017;74:740-6.

      2) Bjerrum L, Gahrn-Hansen B, Hansen MP, Córdoba G, Aabenhus R, Monrad RN. [Airway infections – diagnosis and treatment. Clinical guideline for general practitioners]. Copenhagen: Danish College of General Practitioners; 2014.

      3) Choby BA. Diagnosis and treatment of streptococcal pharyngitis. Am Fam Physician 2009; 79:383-90.


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    1. On 2017 Sep 28, Guan-Hua Huang commented:

      None


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    2. On 2017 Sep 28, Guan-Hua Huang commented:

      Dear Dr. Bryson:

      Thank you very much for your questions.

      The variance between the outcomes registered on clinical trials.gov and those reported in JAMA Surgery resulted from our delay in updating the final project outcomes. Since the original protocol was written in Chinese and did not translate fully to English at the time, our research nurse started with one primary outcome first, and there was a delay in updating the others. Thank you so much for bringing this important omission to our attention. All outcomes have now been accurately registered on clinical trials.gov. In addition, we have now updated and confirmed that the research protocol, which documented all outcomes and was published on the JAMA Surgery website as a supplement, was approved by the institutional review board at the study site.

      With regards to the sample size estimation, we were also delayed in posting these results. Initially, we had difficulty finding similar studies to estimate the effect size for delirium, as well as in identifying appropriate methodologic approaches to be used in power analysis for cluster-randomized controlled trials when a binary outcome is modeled. We have now updated to include the power analysis for the cluster continuous outcome and found that 270 patients were required for 80% power, and 360 patients were required for 90% power. In the end, we managed to recruit 377 patients, and post hoc analysis indicated that our study was powered at 81% for delirium.

      Thank you for the careful read, and for bringing these important issues to our attention.

      We would be glad to answer any further questions.


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    3. On 2017 Sep 20, Greg Bryson commented:

      Would the authors (or editors) comment on: a) the variance between outcomes registered on ClinicalTrials.gov, those reported in the published manuscript, and those described in the protocol appended as an electronic supplemental file. b) the absence of a formal sample size estimate from the published report (CONSORT 7a) or the protocol (SPIRIT 14). Thank you.


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    1. On 2017 Nov 22, thomas samaras commented:

      Taller people have higher risk of atrial fibrillation, blood clots, pulmonary infarction and abdominal aortic aneurysms. The heart problems of shorter people are not due to inherent biological factors. For example, CHD was rare before the industrial revolution and people were shorter then. In addition, during early 1900s, CHD was low and we were shorter in the US and UK. Women are shorter than men and have lower death rates from heart disease. In addition, many short populations studied in the 20th Century were found to be free of CHD and stroke. Some possible confounders are BMI differences, socioeconomic status, catch-up growth of lower birth weight infants, childhood illnesses which stunt growth and promote adult health problems and poorer quality diets. In addition, shorter people often are more overweight than taller people. Three recent studies by Sohn, Shapiro, and Elsayed found shorter people had lower all-cause and cardiovascular disease mortality.(The Sohn finding for lower CVD was,however, non-significant.)


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    1. On 2017 May 28, Philippe Gorphe commented:

      Please note that . Hep-2 cell line is HeLa cells so originating from the cervix, . M2e cell line does not exist (actually ATCC can provide Me2 cell line, not M2e, but it is melanoma cell line), . TU212 cell line is a misidentified cell line that is thought not to originate from the larynx https://www.ncbi.nlm.nih.gov/pubmed/21868764

      Authors would benefit a strong methodological support in further works


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    1. On 2017 Jun 26, Valerio Cozzani commented:

      Classification of Aerosols formed in the operation of Heat-not-Burn tobacco products.

      “Smoke” is nowadays a term frequently used in colloquial non-technical language to indicate a wide number of different aerosols originated by the combustion or pyrolysis of a material. However, from a technical point of view, due to its importance for fire science, several definitions were adopted to clarify what aerosols should be classified as “smoke” (e.g. see the comprehensive discussions provided by Gross et al. (1967), Mulholland (2008), and Drysdale (2011) to have some examples). A comprehensive definition is given by the National Fire Protection Association (See NFPA 921): smoke is composed of airborne solid and liquid particulates and gases evolved when a material undergoes pyrolysis or combustion, together with the quantity of air that is entrained or otherwise mixed into the mass. Moreover, the above definition clearly remarks that smoke, as evident from the literature, may have a very different chemical and physical nature compared to other aerosols:

      1) from a physical point of view it may be composed of solid and liquid particles with different size distributions and concentrations;

      2) from a chemical point of view, smoke components may be: i) condensed, liquid combustion products, and/or ii) condensed, liquid products of partial combustion (as high molecular weight and/or low vapor pressure organic liquids formed during fuel primary pyrolysis and volatile emission), and/or iii) solid combustion products (mainly graphitic carbon particles as soot, and inorganic fly ashes), iv) and/or unburned or partially oxidized solid or liquid fuel particles.

      Smoke from tobacco combustion has specific features, as reported in reference publications (e.g. see Baker, 2006), and has a very complex composition, including all the above cited chemical components such as: condensed liquid drops of volatiles (tar), soot, and ashes. There is no doubt that the aerosol stream produced by a burning cigarette may be classified as “smoke” according to its definitions reported in the scientific and technical literature.

      Recently, Philip Morris International (PMI) developed a heat-not-burn tobacco product, that operates with very different modalities with respect to conventional cigarettes. Even if also in the operation of the heat-not-burn tobacco product an aerosol stream is formed, its classification as “smoke” is not appropriate. The aerosol generated in the PMI heat-not-burn tobacco product is very different in the chemical composition from the smoke formed by the self-sustained smoldering combustion of tobacco in cigarettes and more in general from smoke formed in combustion processes. The aerosol generated in the heat-not-burn tobacco product is composed mainly of water and of products deriving from the evaporation, in the absence of chemical reactions, of substances present in the original tobacco substrate present in the heat-not-burn tobacco product. Even applying the more comprehensive definitions of smoke reported in the literature, these do not apply to the aerosol produced in the operation of such devices, since:

      i) experimental data have confirmed that combustion processes are absent in the PMI tobacco product when heated in the heat-not-burn device.

      ii) the aerosol produced by the heat-not-burn tobacco product during operation is formed mostly by vaporization phenomena, as proven by the experimental data showing its chemical characterization

      iii) very limited low temperature pyrolysis phenomena may be present in the tobacco substrate present in the device during the operation of the heat-not-burn tobacco product (temperatures during operation are lower than 350°C)

      Nevertheless, it should be remarked that the above only concerns the correct scientific definition of “smoke” and its applicability to heat-not-burn tobacco products, and that in no way what is written above addresses health issues related to the inhalation of such aerosols.

      References

      Baker R.R., Smoke generation inside cigarette: Modifying combustion to develop cigarettes that may be less hazardous to health, Progress in Energy and Combustion Science, 32, 373-385, 2006.

      Drysdale D., Introduction to Fire Dynamics, 3rd Edition, J.Wiley & Sons Ltd, UK, 2011

      Gross D., J.J. Loftus, A.F. Robertson, Method for measuring smoke from burning materials. Symposium on Fire Test Methods – Restraint and Smoke, 1966 ASTM STP 422 (ed. A.F. Robertson), pp. 166–204. American Society for Testing and Materials, Philadelphia, PA.

      Mulholland G.W., Smoke production and properties, SFPE Handbook of Fire Protection Engineering, 4th Ed. (Eds Di Nenno et al.), pp. 2.291–2.302. National Fire Protection Association, Quincy, MA, 2008.

      National Fire Protection Association, NFPA Glossary of Terms, 2016 Edition, Updated September 23rd 2016, 2016; p.1336. http://www.nfpa.org/codes-and-standards/resources/glossary-of-terms. Last accessed June 26th, 2017.

      Valerio Cozzani is Professor of Chemical Engineering at University of Bologna, Italy. This comment is provided on the basis of the results of a scientific evaluation of PMI’s heat-not-burn device committed by PMI


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    2. On 2017 May 31, Manuel Peitsch commented:

      Philip Morris International (PMI) supports scientific data transparency, data sharing and actively encourages the conduct of independent studies on IQOS that are aimed at advancing scientific and medical knowledge or verifying the results we obtained through our assessment program described by Smith MR, 2016. To date we have published over 30 peer-reviewed articles describing studies specifically conducted with IQOS [1]. We have also submitted a Modified Risk Tobacco Product (MRTP) application with the U.S. FDA [2]. It is important that independent studies are conducted with a high degree of scientific rigor, the same degree of rigor that is expected from our company. Key standards for scientific research are:

      1. Studies should be conducted using fit-for-purpose and validated methods
      2. Study results should be interpreted in an appropriate and non-misleading manner

      As independent scientists are starting to analyze our products, it is perhaps not surprising that different methodologies are applied. We note, for example, that Auer R, 2017 reporting on a chemical analysis of the IQOS aerosol used a “smoking device designed and tested in [their] facility”. Without further description of this system, it is hard to compare their analysis with those we have reported previously, using standard and validated smoking machine systems and procedures. While some of the reported results seem consistent with those that we have previously published, significant points of difference in the described methodologies may account for the disagreements in results obtained by Auer et al. in comparison to our peer-reviewed and published data.

      1. Methodologies for smoke and aerosol generation have been amply described in the literature. We are therefore surprised that the authors did not use a recognized smoking regime, but rather used a hybrid between the ISO and the Health Canada Intense (HCI) regime [3], and then used this data to compare their results with those published using the ISO regime (Vu AT, 2015).
      2. We were surprised by the measurement results the authors obtained for the volatile organic compounds. For instance, it is perplexing that they report yields of approximately 1 µg acrolein per stick for both IQOS and the cigarette they used in their study. It appears that the acrolein values reported by the authors for the cigarette are 50 times lower than those published by e.g. Health Canada (Hammond D, 2008). Similarly Auer et al. find 10 times lower levels of formaldehyde in cigarettes than Health Canada. Furthermore, the yields of acetone, crotonaldehyde and propionaldehyde are also underestimated.
      3. It is generally established that the HCI regime is more relevant to how humans smoke than the ISO regime. Under HCI we find that the reference cigarette 3R4F yields 154±20 µg acrolein per stick (Schaller JP, 2016), which is similar to the 142±17 µg/stick reported by Health Canada. We have also reported that IQOS yields 11±2.36 µg acrolein per stick under HCI. Furthermore, under the ISO, IQOS yields 4.89±0.74 µg acrolein per stick (Schaller JP, 2016).
      4. Regarding the polycyclic aromatic hydrocarbons, Auer et al. reported a level of acenaphthene for IQOS that is three fold higher than for cigarettes. Acenaphthene is not part of the list of 58 substances we routinely quantify, nor is it part of any regulatory lists (including the most extensive list, the FDA 93). It is, however, a compound we have measured in the smoke of 3R4F, but could not detect in the IQOS aerosol. Our method is based on mass spectrometry, which is a specific detector, as opposed to the non-specific detection system used by the authors. Their reported level for IQOS may therefore come from an artefact, not linked specifically to acenaphthene.
      5. It is also surprising that for many analytes, the reported standard deviations are close to, or even larger than the mean values.
      6. Taken together, the above-mentioned issues lead us to question the analytical methods that were used. For future studies we recommend that the authors should reduce the measurement variability between the replicas, validate their methods with a reference cigarette (e.g. 3R4F) and compare their results with those published by a recognized regulatory agency.
      7. Unfortunately, the results for carbon monoxide (CO) measurements are reported in ppm (parts per million). We would recommend that they should have been converted to mg/stick. Reporting in the way the authors do precludes a comparison of the measured levels with a standard reference cigarette. In addition, the level of CO for the cigarette was above the measurement range of the used instrument, which precludes a comparison between the IQOS and cigarette yields.
      8. Contrary to the authors’ suggestions, “Heat-not-burn” is not an advertising slogan but a shorthand for a product description. We have clearly demonstrated the absence of combustion in IQOS through robust scientific substantiation, which we summarized on PMIscience [1] and in our MRTP application to the U.S. FDA [2]. This has been corroborated by several combustion experts. Furthermore, we have never claimed that IQOS is devoid of pyrolytic processes, which are well known to increase with temperature, and are responsible for much of the remaining HPHCs found in the IQOS aerosol.
      9. The authors suggest that we are “dancing around the definition of smoke to avoid indoor-smoking bans”. Unfortunately, the authors did not present any data regarding the impact of IQOS on indoor use. Due to the way in which IQOS functions and is used, its impact on air quality cannot be linearly extrapolated from mainstream aerosol chemistry data. Towards that end, proper indoor air quality studies, using validated methods are needed. One such example can be found in Mitova MI, 2016.
      10. PMI has consistently communicated that IQOS aerosol is not devoid of HPHCs, and has transparently published the relative yields of HPHCs in comparison with cigarette smoke. Chemical analysis of the IQOS aerosol shows that it contains on average >90% reduction in the levels of HPHCs when compared with the smoke of the 3R4F reference cigarette. This furthermore leads to a concomitant reduction in cytotoxicity and genotoxicity (Schaller JP, 2016).
      11. Since we understand the skepticism around tobacco industry-generated data, we also commissioned an independent, recognized and accredited laboratory to quantify the 58 analytes we routinely measure in our studies [4]. The data was submitted as part of our MRTP application to the U.S. FDA [2].
      12. The totality of the evidence collected to date, across a broad range on toxicology, systems toxicology and clinical studies, indicates that IQOS has the potential to present less risk of harm compared to continued smoking for adult smokers who switch to it completely [1].

      [1] Smith M, Haziza C, Hoeng J, Lüdicke F, Maeder S, Vanscheeuwijck P and Peitsch MC (2017) The Science behind the Tobacco Heating System: a summary of published scientific articles. Available at: https://www.pmiscience.com/library/pmi-science-ths-executive-summary.

      [2] U.S. Food and Drug Administration (FDA). Philip Morris Products S.A. Modified Risk Tobacco Product (MRTP) Applications. May 24, 2017. Available from: https://www.fda.gov/TobaccoProducts/Labeling/MarketingandAdvertising/ucm546281.htm.

      [3] Health Canada (2000). Health Canada - Tobacco Products Information Regulations SOR/2000-273, Schedule 2. http://laws-lois.justice.gc.ca/PDF/SOR-2000-273.pdf.

      [4] Available at: https://www.pmiscience.com/platform-development/platform-development/aerosol-chemistry-physics/hphcs/levels-hphcs-measured.

      Manuel Peitsch is a fully paid employees of PMI, the manufacturer of IQOS.


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    1. On 2017 Jul 14, Daniel Weeks commented:

      Concerns about the analyses presented in the Han et al (2017) paper have been described by Frank Harrell in his "Statistical Thinking" blog in the "Improper Subgrouping" section of the post entitled "Statistical Errors in the Medical Literature". He points out that this paper "makes the classic statistical error of attempting to learn about differences in treatment effectiveness by subgrouping rather than by correctly modeling interactions. They compounded the error by not adjusting for covariates when comparing treatments in the subgroups, and even worse, by subgrouping on a variable for which grouping is ill-defined and information-losing: age.". For further details and additional concerns, please see the blog post.


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    2. On 2017 Jul 05, David Keller commented:

      Rationale for performing a per-protocol analysis of this study's data

      The percentage of control patients who were switched to statin treatment by their personal physicians reached 29.0 % by the end of the study. Meanwhile, non-adherence to statin therapy grew to 22.2 % in the active treatment group.

      Intention-to-treat (ITT) analysis assigns the events experienced by a patient (e.g. death, heart attack) to the group to which the patient was initially randomized, regardless of whether the patient actually took the study medicine (if he was randomized to take it), or whether he took the medicine off-protocol (despite being randomized to the control group). The net effect of these "crossover" events, from control to active treatment, or vice-versa, is to weaken the apparent benefit of the medication, as calculated using ITT. This is good, because as a sort of "worst-case scenario" evaluation, we are assured that, if our patients actually take the study medication, they should probably benefit at least as much as the patients did in the clinical trial.

      However, in a case where we are evaluating whether there is really no benefit to a medication, we should also consider a best-case scenario evaluation, because if the medicine is not beneficial even when it is evaluated in a manner which is more highly sensitive for detecting benefit, we can be that much more certain that the study medication has no role in treating the study population.

      Per-protocol analysis assigns the outcomes and events experienced by a patient based on his actual behavior during the study. If he crossed over from the control group to active treatment and then had a good outcome, that good outcome would be attributed by per-protocol analysis to the effects of active treatment, not to control treatment. Conversely, if a patient is randomized to active treatment, but never takes a pill, a bad outcome in his case would be "blamed" on the control treatment, not on the study medicine he never took. Per-protocol provides a "best case" scenario evaluation of the study drug; one can think of per-protocol analysis as having increased sensitivity to the benefits of the study medication.

      So, in a study like this, it is not enough to perform an intention-to-treat analysis, because all those crossovers might have obscured a significant signal of benefit. It is important to also perform a per-protocol analysis, to assure ourselves that, even in the best of circumstances, the medicine being studied is not beneficial, if even the per-protocol analysis cannot detect benefit.

      If per-protocol analysis reveals benefit to the study medication, but intention-to-treat analysis does not show any benefit, then a new study should be conducted, which is better-designed and more carefully executed. In this case, a stronger statin, like atorvastatin, could be tested, and the patients and investigators could be double-blinded, and so on...


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    3. On 2017 Jul 05, David Keller commented:

      This randomized trial of pravastatin was not blinded, so expectation effects may run rampant

      Han and colleagues fail to mention in the above abstract that this randomized study of pravastatin for primary prevention of coronary heart disease and mortality was conducted open-label (unblinded). Blinding of subjects and investigators in clinical trials is required to control expectation effects, which can have an important influence in triggering cardiovascular events. The open-label design of this study is mentioned in the Methods section of the body of the paper, but there is no further discussion of the role of uncontrolled placebo, nocebo, Pygmalion and other expectation effects on the outcome of this study. Why was this study not double-blinded, and how dependable are open-label data for making important clinical decisions regarding statin use?


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    1. On 2018 Jan 08, Christopher Southan commented:

      This paper was a follow up to the 2004 "Has the yo-yo stopped? An assessment of human protein-coding gene number" https://www.ncbi.nlm.nih.gov/pubmed/15174140


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    2. On 2017 Jun 02, Christopher Southan commented:

      A revised version is planned in order to incorporate the very useful points raised by the open referees


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    1. On 2017 May 25, Prashant Sharma, MD, DM commented:

      A read-only version of the paper is available at http://rdcu.be/td4R.

      [Author comment] In this series, currently the largest compilation of cases of this entity in literature, we describe the frequencies of three unusual findings on hemoglobin CE-HPLC chromatograms - tiny S-window peaks, small spiky post-HbQ peaks, and split HbA2 peaks, that suggest HbQ-India trait as the likely diagnosis in the north Indian practice setting.


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    1. On 2017 Jun 30, Cicely Saunders Institute Journal Club commented:

      This paper was discussed at the Cicely Saunders Institute Journal Club on Wednesday 7th June.

      This paper reports a well conducted trial of an intervention to improve end of life care in hospitalised elderly people. The authors are to be commended for addressing a clinical priority in a population where end of life care is under-researched.

      We discussed this paper in a clinical-academic journal club. Our discussion of the paper was lively and generated a series of reflections on the methods used in the conduct of the trial as well as broader issues relating to the aims and processes of the study intervention.

      The long study set up period was considered a strength, enabling participating wards to become accustomed to the data collection procedures before the commencement of the study. We discussed the challenges related to selecting the proxy-reported primary outcome measures, and the potential impact of the unblinded nurses assessing outcomes of care they themselves delivered.

      We also discussed whether family recollection of symptom control several weeks into bereavement was a reliable measure of care quality, as it may not capture all the factors contributing to their experience of care, potentially confounding their report. It was suggested that collecting family members’ data via face to face interviews could enhance analysis of the quantitative findings.

      The intervention, as reported in this paper, supported by previously published development work, represents a comprehensive effort to improve the quality of care for elderly people dying in hospital settings. The group recognised the challenges and the range of competencies required of hospital medical and nursing staff delivering end of life care. We wondered how the reported changes to the training components of the intervention addressed criticisms of the Liverpool Care Pathway in terms of improving competencies in compassionate communication with families. We discussed the possibility of measuring family care givers experience of receiving safe, compassionate care as an alternative outcome for this intervention.

      In their discussion the authors report that qualitative work is to be conducted to explore the findings of the study in more depth, particularly those related to poorer family satisfaction with care in the intervention group. We felt this potential negative effect on families should be investigated before further roll out of the intervention We look forward to reading further outputs from this extensive and commendable body of work.

      Commentary by Jo Bayly, Dr Simon Etkind and Dr Wei Gao


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    1. On 2017 Aug 14, Stuart RAY commented:

      These are substantial concerns - I have written to Professor Nowak to invite comment on this discussion.


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    2. On 2017 Jul 29, James M Heilman commented:

      Seriously "sea-buckthorn oil protects against infections, prevents allergies, eliminates inflammation and inhibits the aging process". This sounds like world changing news. Looking for the RCTs that back it up and not finding any. The only RCT listed in the refs found NO benefit. https://www.ncbi.nlm.nih.gov/pubmed/23131570 That paper which found NO benefit is used to support this sentence "Sea-buckthorn oil as well as extracts from its fruit are used as an adjunctive therapy in treatment of many diseases". If it has no effect that is not a treatment.


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    1. On 2017 Aug 17, Ken G Ryan commented:

      Thanks Sarah. Yes you are right of course. This was a typo introduced by the publisher at the last phase of publishing. I tried several times to get them to change it and nothing happened. You will see throughout the paper that the correct epithet is spelled correctly. Its very annoying. Ken


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    2. On 2017 Aug 16, Seán Turner commented:

      The species epithet 'torques' (sic) is misspelled in the title. The correct species name is Psychroflexus torquis.


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    1. On 2017 Jul 07, DANIEL BARTH commented:

      The possible role of spike-wave discharges (SWDs) in epilepsy is a highly controversial. Although we expected our work to generate debate, the eLetter from Blumenfeld et al. is disappointing.

      For a more detailed response to this eLetter, please see: https://www.dropbox.com/s/d8ut94ayf57f8pk/Response to responseBlumenfeld et al2017.pdf?dl=0

      • Partial consciousness and maintenance of cognitive functions during SWD

      eLetter: “Their logic appears to be based on the misperception that seizures in absence epilepsy (AE) are always associated with ‘profound impairment of consciousness,’ leading to the flawed premise of the study and its interpretation that anything less than full loss of consciousness must not be AE.”

      Loss of conscious is stipulated as an inclusion criterion for diagnosis of typical childhood absence epilepsy, versus mild or no impairment of consciousness as an exclusion criterion (Loiseau and Panayiotopoulos, 2000; Engle, 2013). Accordingly, we characterized WAG/Rij rats as mild absence with partial impairment of consciousness during seizures.

      eLetter: “The ‘ability’ to modulate SWD severity in rodent models is not demonstrated since the reduction in number and duration can be explained otherwise.” The alternative explanation put forward is “a sensory cue white noise, which may increase arousal and vigilance known to reduce SWD”.

      We stated that operantly conditioned arousal is what terminates SWD bursts early. The possibility that the arousal is due only to the white noise cue, however, fails to account for the critical result that preemptive pellet checks occurred almost entirely in the seconds after each SWD burst, indicating awareness of the SWD, associative learning, and operant control over SWDs.

      • SWDs occur in several rodent strains

      eLetter: Blumenfeld et al. note SWDs are not observed in most laboratory rodent strains.

      That is not correct. Observations of SWDs are common in outbred Sprague Dawley, Long Evans, Wistar and hooded rats. Unlike human absence epilepsy, SWDs become more prevalent with age). Our conclusion is not that SWDs cannot reflect absence epilepsy, but that their ubiquity in various outbred rat strains suggests their unreliability as a signature of absence epilepsy. We have no vested interest in whether SWDs are genetic epilepsy or part of normal rat behavior. We simply recommend caution that Blumenfeld et al. appear opposed to.

      eLetter: Single gene mutations can lead to SWDs therefore absence epilepsy. We note that while genes can influence innate rhythms, this does not prove that all SWDs are epileptic or that all SWDs model genetic absence seizures. Furthermore, inbreeding does not seem to be a requirement for SWDs, since our outbred Sprague Dawley rats had the same amount of SWDs as our inbred WAG/Rij rats, and Long Evans rats had approximately four times this amount (Fig. 7).

      • SWD/immobility as a model of absence epilepsy

      Blumenfeld et al list characteristics that support SWDs as a model of absence epilepsy. We do not understand why they are raising this issue, since we clearly stated that inbred WAG/Rij rats model mild absence seizures in humans.

      We believe, however, the case that all SWDs in outbred rats serve to model genetic absence seizures in humans is weak. We and others remain skeptical that most outbred rats have developed - or are developing - absence epilepsy; however, as we said, it is possible.

      Conclusion

      The eLetter by Blumenfeld et al. was written by experts with decades of publications in absence epilepsy. We have examined many of these papers, plus ones challenging the epileptic nature of SWDs (e.g. Kaplan, 1985; Wiest and Nicolelis, 2003). None of us have studied absence seizures or SWDs, except recently (Rodgers et al., 2015). The research history and publication record of Blumenfeld et al., however, could incline them toward an imbalanced interpretation of our results. We do not understand what specifically were the “overstatements” and inappropriate “assumptions” in Taylor et al. that Blumenfeld et al. claimed in the beginning of their eLetter. We urge readers to re-read our Significance Statement in the context of the eLetter by Blumenfeld et al.: “Our evidence that inbred and outbred rats learn to control the duration of spike–wave discharges (SWDs) suggests a voluntary behavior with maintenance of consciousness. If SWDs model mild absence seizures and/or complex partial seizures in humans, then an opportunity may exist for operant control complementing or in some cases replacing medication. Their equal occurrence in outbred rats also implies a major potential confound for behavioral neuroscience experiments, at least in adult rats where SWDs are prevalent. Alternatively, the presence and voluntary control of SWDs in healthy outbred rats could indicate that these phenomena do not always model heritable absence epilepsy or post-traumatic epilepsy in humans, and may instead reflect typical rodent behavior.”

      While writing and revising this manuscript in response to successive peer reviews, we responded to the points of Blumenfeld et al. and tried to objectively incorporate reviewers’ suggestions and avoid misinterpretations of our data. We are disappointed that our efforts were either largely ignored or misrepresented in the eLetter, since this unnecessarily complicates an already controversial subject and detracts from what we believe is the importance of this work.

      References

      Engle, J, Jr. (2013) Seizures and Epilepsy, 2nd ed. New York ; London: Oxford University Press. Kaplan BJ (1985) The epileptic nature of rodent electrocortical polyspiking is still unproven. Exp Neurol 88:425–436. Loiseau, P, Panayiotopoulos, CP (2000) Childhood absence epilepsy. In: Neurobase. San Diego: Arbor. Rodgers KM, Dudek FE, Barth DS (2015) Progressive, seizure-Like, spike-Wave discharges are common in both Injured and uninjured Sprague-Dawley rats: Implications for the fluid percussion injury model of post-traumatic epilepsy. J Neurosci 35:9194–9204. Wiest MC, Nicolelis MAL (2003) Behavioral detection of tactile stimuli during 7-12 Hz cortical oscillations in awake rats. Nat Neurosci 6:913–914.


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    2. On 2017 Jun 29, Antoine Depaulis commented:

      This study presents interesting behavioral observations during seizures in absence epilepsy (AE). However, there are many overstatements that could be misinterpreted. This begins with the flawed premise that anything less than full loss of consciousness during spike-wave discharges (SWD) is not AE. The broad group of experts in absence epilepsy who signed this response strongly disagree as outlined below. A more complete collective response can be found at: <https://dl.dropboxusercontent.com/u/3541791/Collective reply to Taylor et al_2017.pdf>

      1. Partial consciousness during SWD The authors claim that patients with AE experience "profound loss of consciousness" during seizures. On the contrary, some preservation of consciousness is quite common in human AE. Many clinical studies have shown highly variable responsiveness depending both on task difficulty and vigilance level, even from one SWD to the next in the same individual (Blumenfeld, 2005, Guo et al., 2016). Perception of sensory stimuli, discrimination between relevant and irrelevant stimuli during absence seizures and preservation of some cortical processing has been shown in both rat models and human patients (e.g., Inoue et al, 1992, Chipaux et al., 2013, Berman et al., 2010, Drinkenburg et al., 2003, Guo et al., 2016). In addition, as the authors acknowledge, external stimuli like those in this study can increase vigilance and reduce SWD. Therefore, preserved ability to respond during a task or to modulate seizure severity is not a surprise; instead it provides further support for face validity of rodent SWD for human absence seizures.

      2. SWD occur in several rodent strains The occurrence of SWD in some animals from outbred rodent strains has been published many times since the 60’s (Marescaux et al., 1992). However, SWDs are not observed in many individual animals in most inbred or outbred rodent strains (e.g., Letts et al., 2014). For example, when rats with SWD (about 30%) were selected from the initial Wistar colony of Strasbourg to produce the GAERS substrain, about 70 % of the colony did not have SWD and were bred as the non-epileptic control (NEC) strain. No NEC display SWD, even when over one year old (Depaulis et al., 2016). Why SWD are so prevalent in some outbred strains is unknown but might be due to preferential selection of dominantly inherited mutated AE genes in docile animals chosen for breeding. The many examples of single gene mutations in mice that lead to SWD/AE not seen in wild type littermates (Maheshwari and Noebels, 2014), provide further evidence that SWD are not normal in rodents. Some monogenic mutations likely result from genetic drift, such as the spontaneous Gria4 gene mutation causing SWD in C3H/HeJ mice, modulated by SWD suppressor mutations in other genes (Beyer et al., 2008, Frankel et al., 2014). Several additional differences between rodents with or without SWD make it very doubtful that SWD reflect “typical rodent behavior” (see PubMed commons for further details).

      3. SWD/immobility as a model of absence epilepsy The authors disregard 4 decades of work firmly demonstrating the face validity, pharmacological predictivity and construct validity of rats and mice with SWD as models for AE (see Jarre et al., 2017 for a recent review).These animals fulfill many features relevant to the human AE (Guillemain et al., 2012). In addition to SWD, immobility and mild facial clonus, rodents models exhibit behavioral, structural, molecular and functional co-morbidities not seen in animals without SWD, but also observed in human patients (Shaw, 2007). Furthermore, the anti-epileptic drug profile in rodent AE models corresponds remarkably well with effects in human patients (Depaulis and van Luijtelaar, 2005, Shaw, 2007, Jarre et al., 2017). Over 20 single gene mutations associated with SWD, have been identified in mice and in rats that are consistent with findings in human AE (Powell et al., 2009, Noebels and Sidman, 1979) (Maheshwari and Noebels, 2014). Finally, many electrophysiological (see Depaulis et al., 2017 for a recent review), and fMRI studies (David et al., 2008, Mishra et al., 2011, 2013) in rat AE models agree with clinical data (Westmijse et al., 2009, Hamandi et al., 2008).

      Based on these lines of evidence, we assert that SWD/immobility represents a form of epilepsy in rodents. In our view, these episodes are not a natural behavior nor do all individuals display this trait. Studying SWD, in both outbred and inbred strains as well as single gene mutations, has already enabled 1) the development of predictive models of the efficacy of antiepileptic drug efficacy (Tringham et al., 2012, Marks et al., 2016, Glauser et al., 2017), and 2) enhanced understanding of the pathophysiology of cortico-thalamic circuitry that generates and maintains SWD and the mechanisms underlying associated comorbidities.

      Contributors and institutions (by alphabetical order) Hal Blumenfeld, Yale University, New Haven, CT, USA Stéphane Charpier, Pierre and Marie Curie University and INSERM, France Doug Coulter, University of Pennsylvania, Philadelphia, USA Vincenzo Crunelli, Cardiff University, Cardiff, UK. Antoine Depaulis, Grenoble Alpes University and INSERM, France Wayne Frankel, Columbia University, NY, USA Martin J. Gallagher, Vanderbilt University, Nashville, TN, USA John Huguenard, Stanford University, Stanford, CA, USA Cian McCafferty, Yale University, New Haven, CT, USA Richard Ngomba, University of Lincoln, UK Jeffrey Noebels, Baylor College of Medicine, TX, USA Jeanne T. Paz, Univ California & Gladstone Institute of Neurological Disease, San Francisco, USA Terence J. O’Brien, University of Melbourne, Melbourne, Australia Filiz Onat, Marmara University, Turkey Gilles van Luijtelaar, Donders Centre for Cognition, Radboud University, Nijmegen, the Netherlands Laurent Vercueil, Grenoble University Hospital, Neurology Department, Grenoble, France

      REFERENCES Berman R et al. (2010) Epilepsia 51:2011–2022. Beyer B et al. (2008) Human Molecular Genetics 17:1738–1749. Blumenfeld H (2005) Epilepsia 46 Suppl 9:21–33. Chipaux M et al. (2013) PLoS One 8:e58180. David O et al. (2008) Plos Biol 6:e315–e2697. Depaulis A, Charpier S (2017) Neurosci Letters 17:30141-6. Depaulis A et al. (2016) J Neurosci Meth 260:159–174. Depaulis A, van Luijtelaar G (2005) In: Models of seizures and epilepsy (Pitkänen A, Schwartzkroin P, Moshe S, eds), pp 233–248. Amsterdam: Oxford: Elsevier Academic. Drinkenburg WHIM et al. (2003) Behavioural Brain Research 143:141–146. Frankel WN et al. (2014) PLoS Genet 10:e1004454. Glauser TA et al. (2017) Ann Neurol 81:444–453. Guillemain I et al. (2012) Epileptic Disord 14:217–225. Guo JN et al. (2016) The Lancet 15:1336-1345 Hamandi K et al. (2008) NeuroImage 39:608–618. Inoue M et al. (1992) Electroencephalogr Clin Neurophysiol. 84:172-9. Jarre G et al. (2017) In: Models of seizure and epilepsy. Second edition (Pitkänen A, Buckmaster P, Galanopoulou AS, Moshe SM, eds). Elsevier, in press. Letts VA et al. (2014) Genes, Brain and Behavior 13:519–526. Maheshwari A, Noebels JL (2014) Monogenic models of absence epilepsy: windows into the complex balance between inhibition and excitation in thalamocortical microcircuits, 1st ed. Elsevier B.V. Marescaux C et al. (1992) J Neural Trans - S35:37–69. Marks WN et al. (2016) Eur J Neurosci 43:25–40. Mishra AM et al. (2013) Epilepsia 54:1214–1222. Mishra AM et al. (2011) J Neurosci 31:15053–15064. Noebels JL, Sidman RL (1979) Science 204:1334–1336. Powell KL et al. (2009) J Neurosci 29:371–380. Shaw FZ (2007) 7-12 Hz J Neurophysiol 97:238–247. Tringham E et al. (2012) Science Transl Med 4:121ra19–121ra19. Westmijse I et al. (2009) Epilepsia 50:2538–2548.


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    1. On 2017 Aug 22, Anton Pottegård commented:

      On the misleading conclusion reached by Wang et al. regarding use of phosphodiesterase 5 inhibitors and risk of melanoma

      Recently, Wang et al. published their findings from a meta-analysis on the putative association between use of phosphodiesterase 5 inhibitors (PDE5i) and risk of melanoma (Wang J, 2017). With this letter, we, the authors of four of the main studies on which their meta-analysis was founded, would like to express our serious concerns as to the conclusions reached by Wang et al.

      The initial report on the potential for an association between use of the PDE5i sildenafil and an increased risk of melanoma was published by Li et al. in JAMA Internal Medicine in 2014 (Li WQ, 2014). A large proportion of melanomas contain mutations that lead to suppression of phosphodiesterase enzyme 5A (Gray-Schopfer V, 2007), which again leads to melanoma cell invasion (Arozarena I, 2011). As PDE5is infer a direct pharmacological inhibition of the same enzyme, the hypothesis that use of PDE5i would infer an increased risk of melanoma is biologically plausible.

      Four different teams subsequently tried to replicate these findings. In a case-control study using nationwide Swedish health registries, Loeb et al. reported a modest increased risk among PDE5i users (adjusted odds ratio (OR) 1.21, 95% confidence interval (CI) 1.08-1.36) (Loeb S, 2015). However, they clearly pointed out that the association was unlikely to be causal, because there was a lack of dose-response in the observed association (i.e. no increase in risk with greater exposure). Further, the strongest association was observed with early stage melanoma, which lacks biological gradient. Lastly, the authors also observed PDE5i users to have an increased risk of basal cell carcinoma, which was a negative control outcome with no hypothesized association with PDE5i use. This last observation suggested possible confounding by UV exposure, which is the key risk factor for both BCC and melanoma.

      The next three studies were published in close succession. Two cohort studies based on data from the UK Clinical Practice Research Datalink (CPRD) found weak evidence of a small increased risk of melanoma among those prescribed a PDE5i (Lian et al (Lian Y, 2016): hazard ratio (HR) 1.18, 95%CI 0.95-1.47); Matthews et al. (Matthews A, 2016): HR 1.14, 95%CI 1.01-1.29). In the study by Lian et al. (Lian Y, 2016), associations were also observed with basal cell and squamous cell carcinoma with respect to certain prescription and pill categories, thereby arguing against a causal association due to lack of specificity. Matthews et al. (Matthews A, 2016) again found no gradient in the association, and observed an association with UV-related negative control outcomes including basal cell carcinoma. They also reported an association between previous solar keratosis and later use of phosphodiesterase inhibitors, strongly suggesting confounding due to PDE5i users having more sun exposure. Lastly, in July 2016, Pottegård et al. (Pottegård A, 2016) published the results of two case-control studies, finding weak evidence of a small positive association in Denmark (OR 1.22, 95%CI 0.99-1.49), and no evidence of an association in the US (OR 0.95, 95%CI 0.78-1.14). Again, no dose-response pattern was found, and as in the analysis by Loeb et al., the highest estimates were obtained for early stage disease.

      In summary, all four papers reported a slightly increased risk of malignant melanoma among PDE5i users. Critically, however, all the studies included analyses that probed Hill's criteria for causality (Hill AB, 2015), and the findings of all four studies suggested the association was unlikely to be causal. In summarizing the evidence from these papers, the systematic review by Wang et al. focuses heavily on the single point estimate obtained in their meta-analysis, disregarding the supplementary analyses and the conclusions regarding causality within the individual papers. For this reason, we believe that the conclusions reached by Wang et al. are misleading.

      Importantly, Loeb et al. have recently performed a similar meta-analysis to that of Wang et al., arriving at an almost identical point estimate, but with a considerably more informed interpretation (https://doi.org/10.1093/jnci/djx086). While acknowledging the weak positive association between PDE5i use and malignant melanoma, they conclude that the association is unlikely to be causal. Having authored the individual papers, we collectively support this conclusion.

      Anton Pottegård (1); Krishnan Bhaskaran (2); Anthony Matthews (2); Laurent Azoulay (3); Pär Stattin (4); Laurel A Habel (5); and Stacy Loeb (6)

      (1) Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark (2) Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK (3) Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada (4) Department of Surgical Sciences, Uppsala University, Uppsala, Sweden (5) Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA (6) Department of Urology and Population Health, New York University, NY, NY, USA


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    1. On 2017 Jun 12, John Sotos commented:

      West describes angiogenesis, erythropoiesis, and vasoconstriction as clinical sequelae arising from chronically hypoxic tissues at altitude. Another, similar, effect is solid-organ hyperplasia.

      In the late 1960s a Peruvian medical student observed several-fold enlargement of the carotid bodies in Andean altitude dwellers (1,2). The degree of enlargment increased with time spent at altitude and, in animal models, reversed after restoration of normoxia(3). Interestingly, this hyperplasia is mediated via endothelin signalling, not by hypoxia-inducible-factors(4).

      Tissue hyperplasia may also occur in hypoxic patients at sea level. For example, even before the Peruvian discovery, hyperplasia -- and sometimes malignancy -- of adrenal chromaffin cells, i.e. pheochromocytomas, were described in adults having uncorrected cyanotic congenital heart disease(5). Carotid body cells and adrenal chromaffin cells have similar lineage (from the neural crest) and function (oxygen sensing).

      (1) Arias-Stella J. Human carotid body at high altitudes. (Abstract). American Journal of Pathology. 1969; 55: 82a.

      (2) Heath D. The carotid bodies in chronic respiratory disease. Histopathology. 1991; 18: 281-283.

      (3) Kay JM, Laidler P. Hypoxia and the carotid body. J Clin Pathol Suppl (R Coll Pathol). 1977; 11: 30-44.

      (4) Platero-Luengo A, González-Granero S, Durán R, Díaz-Castro B, Piruat J, García-Verdugo JM, Pardal R, López-Barneo J. An O2-Sensitive Glomus Cell-Stem Cell Synapse Induces Carotid Body Growth in Chronic Hypoxia. Cell. 2014; 156, 291–303.

      (5) Folger GM, Roberts WC, Mehrizi A, Shah KD, Glancy DL, Carpenter CCJ, Esterly JR. Cyanotic Malformations of the Heart with Pheochromocytoma: A Report of Five Cases. Circulation. 1964; 29: 750-757.


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    1. On 2017 Jul 18, Youhe Gao commented:

      The strategy I posted here last month was published three years ago on Proteome Sci. 2014 Feb 1;12(1):6. doi: 10.1186/1477-5956-12-6. Fast fixing and comprehensive identification to help improve real-time ligands discovery based on formaldehyde crosslinking, immunoprecipitation an... - PubMed - NCBI https://www.ncbi.nlm.nih.gov/pubmed/24484773


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    2. On 2017 Jun 14, Youhe Gao commented:

      I found two "overexpression"s in the paper. "Although the extent of bait overexpression is difficult to judge and varies across IP's, previous experimentation has shown that over-expression has little effect on identification of true interacting partners (Sowa et al., 2009)" "VAPBWT overexpression strongly increased the association of EGFP-LSG1 and OSBP with the ER (Figure 7E,G)" Personally, I am not sure if those are enough. In a system, increasing [A] or [B] will lead to more [AB]. As we know more about protein interaction now, this kind of systematic false positive should not be ignored any more. In cells, overexpression with tag may even change the location of the protein. That is why I think the next generation of massive protein interaction studies should start from in vivo crosslinking. I do not want to overemphasize the problem. Most of the protein interactions identified are probably true in cells. The amount of work done is very impressive and respected. I hope users who is using a particular interaction data as the only clue for their future experiment design, maybe they should start with an in vivo crosslinking as a conformation of that interaction. It may make them more confident to proceed.


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    3. On 2017 Jun 13, J Wade Harper commented:

      These issues have been addressed and discussed in many prior publications (see for example - Cell. 2015 Jul 16;162(2):425-40) and are widely known


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    4. On 2017 Jun 09, Youhe Gao commented:

      I hope that authors can discuss the impact and possibility of false positive and negative made by tagging, overexpression and washing conditions on protein interactions.


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    5. On 2017 May 31, Youhe Gao commented:

      This is a great master piece in the field of protein interaction. It is the largest network so far. It is extremely valuable for all biologists. I guess for the authors to reach such a great throughput, using tagging, overexpression and affinity purification was almost inevitable. These procedures could produce some false positives and false negatives. 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. The throughput of this strategy is probably not high enough. But I hope one day a large-scale study can be conducted with it. No matter what, this is a great milestone!


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    6. On 2017 Jun 03, J Wade Harper commented:

      The results are being loaded now into biogrid. IntAct I believe will take data from biogrid to upload directly.


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    7. On 2017 May 29, Christopher Southan commented:

      Will these valuable results be loaded into the EBI IntAct Molecular Interaction Database? (http://www.ebi.ac.uk/intact/)


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    1. On 2017 Aug 28, Noam Y. Harel commented:

      This article has been RETRACTED. It is an obvious plagiarism of Han et al, Annals of Neurology, PMID 26814620. Please see this link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440146/


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    1. On 2017 Jun 10, Christopher Southan commented:

      This valuable paper would be enhanced by including database links to the structures. In lieu of such, the following URL includes CID links to the 90 TCMD identifiers from Supplementary Data 3 https://www.ncbi.nlm.nih.gov/sites/myncbi/christopher.southan.1/collections/52757717/public/ (this may need a couple of tries for the overloaded Entrez servers). Of these, 26 have vendor matches (maybe more via salt-stripping) and 10 have patent extraction matches (but probably not impinging antinfectives research use)

      The final six from Table 1 (3 with vendor matches) are:

      TCMDC-123767 = CID 1476278, TCMDC-125445 = CID 44522338, TCMDC-141698 = CID 44536555, TCMDC-141070 = CID 44535609, TCMDC-141154 = CID 44535720, TCMDC-124559 = CID 4782980

      https://www.ncbi.nlm.nih.gov/sites/myncbi/christopher.southan.1/collections/52765327/public/


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    1. On 2017 Jun 01, Andrea Brancaccio commented:

      An interesting and solid biochemical work. As the Authors have stated “the POMTs are suggested to have exquisitely narrow glycosylation functions of α-DG”. As an additional note of some interest, it may be worth considering that POMTs predate dystroglycan. In fact, orthologous members of this family can be found in Capsaspora owczarzaki (Accession: XP004363497) or also in Monosiga brevicollis (Accession: XP001744300) belonging respectively to Filasterea and Choanoflagellata, two unicellular groups, close to early-diverging metazoans, in which dystroglycan had not been found (see Adams JC and Brancaccio A., The evolution of the dystroglycan complex, a major mediator of muscle integrity. Biol Open. 2015 4:1163-79, Adams JC, 2015).


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    1. On 2017 Jun 14,     commented:

      On behalf of the authors, I would like to refer readers to our recent study that demonstrated reproducibility of the original work after more than 10-years. http://dx.doi.org/10.1016/j.freeradbiomed.2016.10.456


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    1. On 2017 May 22, Lydia Maniatis commented:

      Part 1 This publication is burdened with an unproductive theoretical approach as well as methodological problems (including intractable sampling problems). Conclusions range from trivial to doubtful.

      Contemporary vision science seems determined to take organization of the retinal stimulation out of the picture, and replace it with raw numbers, whether neural firing rates or statistics. This is a fundamental error. A statistical heuristic strategy doesn’t work in any discipline, including physics. For example, a histogram of the relative heights of all the point masses in a particular patch of the world wouldn’t tell anything about the mechanical properties of the objects in that scene, because it would not tell us about distribution and cohesiveness of masses. (Would it tell us anything of interest?)

      In perception, it is more than well established that the appearance of any point in the visual field –with respect to lightness, color, shape, etc - is intimately dependent on the intensities/spectral compositions of the points in the surrounding (the entire) field (specifically their effects on the retina) and on the principles of organization that the visual process effectively applies to the stimulation. Thus, a compilation of, for example, the spectral statistics of Purves’ colored cube would not allow us either to explain or predict the appearance of colored illumination or transparent overlays. Or, rather, it wouldn’t allow us to predict these things unless we employed a very special sample of images, all of which produced such impressions of colored illumination. Then we might get a relatively weak correlation. This is because, within this sample, a preponderance of certain wavelengths would tend to correlate with e.g. a yellow, illumination impression, rather than being due, as might be true for the general case, to the presence of a number of unified apparently yellow and opaque surfaces. Thus, we see how improper sampling can allow us to make better (and, I would add, predictable) predictions without implying explanatory power. In perception, explanatory power strictly requires we take into account principles of organization.

      In contrast, the authors here take the statistics route. They want to show, or rather, don’t completely fail to corroborate the observation that when surfaces are wet, their look colors are deeper and more vivid, and also to corroborate the fact that changes in perception are linked to changes in the retinal stimulation. Using a set of ready-made images (criteria for the selection of which are not provided), they apply to them a manipulation (among others) that has the general effect of increasing the saturation of the colors perceived. One way to ascertain whether this manipulation causes a surface to appear wet would be to simply ask observers to describe the surface, without any clues to what was expected. Would the surface be spontaneously be described as “wet” or “moist”? This would be the more challenging test, but is not the approach taken.

      Instead, observers are first trained on images (examples of which are not provided - I have requested examples) that we are told appear very wet (and the dry versions), and include shape-based cues, such as drops of water or puddles. They are told to use these as a guide to what counts as very wet, or a rating of 5. They are then shown a series of images containing both original and manipulated images (with more saturated colors, but lacking any shape-based cues), and asked to rate wetness from 1 to 5.

      The results are messy, with some transformed images getting higher ratings than the originals and others not, though on average they are more highly rated. But the ratings for all the images are relatively low; and we have to ask, how have the observers understood their task? Are they reporting an authentic perception of wetness or moistness, or do they believe are they trying to guess at how wet a surface actually is, based on a rule of thumb adopted during the training phase, in which, presumably, the wet images were also more color-saturated? (In other words, is the task authentically perceptual, or is it more cognitive guesswork?) What does it mean to rate the wetness of a surface at e.g. the “2” level?

      The cost of ignoring the factor of shape/structure is evident in the authors’ attempt to explain why the ratings for all images were so low, reaching 4 in only one case. They explain that it may be because their manipulation didn’t include areas that looked like drops or puddles. Does this mean that the presence of drops or puddles actually changes the appearance of the surrounding areas, and/or that perhaps those very different training images included other organized features that were overlooked and that affected perception? Did the training teach observers to apply a cue in practice that by itself produces somewhat different perceptual outcomes? I suppose we could ask the observers about their strategy, but this would muddy the facade of quantitative purity.

      At any rate, the manipulation (like most ad hoc assumptions) fails as a tool for prediction, leading the authors to acknowledge that “The image transformation greatly increased the wetness rating for some images but not for others…” (Again, it isn’t clear that “wetness rating” correlates with an authentically perceptual scale). Thus, relative success or failure of the transformation is image-specific, and thus sample-specific; some samples and sample sets would very likely not reach statistical significance. Thus the decision to investigate further (Experiment 1b) using (if I’m reading this correctly) only a single custom-made image that was not part of the original set (on what basis was this chosen?) seems unwise. (This might seem to worsen the sampling problem, but the problem is intractable anyway. As there is no possible sample that would allow the researchers to generate reliable statistics-based predictions for the individual case, any generalization would be instantly falsifiable, and thus lack explanatory power).

      The degree to which any conclusions are tied to the specific (and unrationalized) sample is illustrated by the fact that the technical manipulations were tailored to it (from Experiment 1a): “In deciding [the] parameters of the WET transformation, we preliminarily explored a range of parameters and chose ones that did not disturb the apparent naturalness of all the images used in Experiment 1a.” Note the lack of objective criteria for “naturalness.”). (We’re not told on what basis the parameters in Experiment 1b were chosen). In short, I don’t think this numbers game can tell us anything more from a theoretical point of view than casual observation and e.g., trial and error by artists, already have.


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    2. On 2017 May 22, Lydia Maniatis commented:

      Part !!

      The authors also generate a hypothesis via data-digging on the statistics of the images used in 1a. This hypothesis is that greater “hue entropy” is correlated with a larger wetness impression (whatever this may mean given the study’s methods). This is tested with a new set of artificial images made using third-party software, which also are also obviously subject to sampling/confounding problems. Results of manipulating this variable were mixed, with one comparison non-significant, one significant if we apply a relatively low standard (p = 0.04), and one significant at the 0.005 level. So the results are inconclusive, even for this particular sample. The authors note, further, that “the effect of hue entropy cannot be explained by ecological optics” and rationalize their (ambiguous) results in the following very casual and logically incoherent manner:

      “Since there is a significant overlap in the distribution of color saturation between dry and wet samples…[t]he key to resolving these ambiguities is to increase the number of samples. When wet-related image features are shared by many different parts in the scene, the image features are likely to be produced by a global common factor, such as wetting. In other words, the more independent colors the scene contains, the more reliably the visual system can judge scene wetness.”

      I don’t see why a larger sample would necessarily be a more colorful sample. Also, the authors are suggesting that a larger patch of the visual scene will be more likely to receive a higher wet score than a small patch; this seems very implausible. A Bayesian gloss of this explanation follows, complete with arbitrarily chosen “prior probabilities.” Such a mechanism would render the verisimilitude of human perception highly unreliable on a case-by-case basis, much more so than is the case. The fact is that the visual system doesn’t have to rely on weak probabilities for weakly correlated features when it has much more reliable structural principles to work with.

      The description of stimulus as “a natural texture” is not informative from an experimental point of view. The potential choices are infinitely variable.

      In the text, the authors are using the term color as though it were an objective feature of the stimulus rather than perceptual factor, which is confusing and should be avoided. (From Wikipedia: “As colorfulness, chroma and saturation are defined as attributes of perception they can not be physically measured as such.”)

      Bottom line: 1. Statistical compilations divorced from reference to principles of organization lack explanatory and general predictive power, in perception as in every other discipline. They are not productive tools of scientific discovery.


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    1. On 2017 Jun 21, Lydia Maniatis commented:

      I don't get it; are citations like these valid? They seem to be doing most of the heavy lifting.

      "The finger spread and beauty judgement were recorded by our web app, emotiontracker.com (A.A.B., L. Vale, and D.G.P., unpublished data).

      As previous work has shown (A.A.B., L. Vale, and D.G.P., unpublished data), continuous pleasure ratings are well fit by a simple model, refined here ((Equation 1), (Equation 2) ; (Equation 3) and Figure 1B). The model supposes..."

      What gives the model assumptions their credibility? Are we supposed to take the claims on faith?


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    1. On 2017 May 21, Amanda Capes-Davis commented:

      The authors tested against "two different cancer cell lines", HeLa and KB. Unfortunately this is an example of a misidentified cell line causing confusion. KB is known to be misidentified and is actually HeLa, from cervical cancer, not oral carcinoma as originally reported - so the authors are comparing two samples from the same tumour and individual.

      A paper has just been published on the impact of KB in the scientific literature: https://www.ncbi.nlm.nih.gov/pubmed/28455420.

      Cell lines are increasingly used by medicinal chemists as models for treatment. The field must consider how to incorporate quality procedures for cell lines as part of manuscript submission if this problem is to be avoided.

      A simple check against a list - in this case the ICLAC list of known misidentified cell lines - would have picked up the problem in this instance. See: http://iclac.org/databases/cross-contaminations/

      To be confident that misidentification has not occurred, human cell lines should be tested for authenticity using short tandem repeat (STR) profiling. See: http://iclac.org/resources/advice-scientists/

      All scientists who use cell lines as models should be aware of guidelines for good cell culture practice. For an example see: https://www.ncbi.nlm.nih.gov/pubmed/25117809


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    1. On 2017 May 15, Preben Berthelsen commented:

      During light chloroform anaesthesia, 1 of 2500 patients succumbed to sudden cardiac syncope – usually when the skin was incised.

      1 in 2000 has a genetically determined defect in repolarisation of the myocardium – the long-QT syndrome. Such patients may likewise succumb to sudden cardiac arrest when experiencing emotional and/or physically stressing events.

      The striking similarity in the mode of dying – the sudden unexpected arrest of the heart during stress - makes it a fair hypothesis/assumption that patients dying during chloroform anaesthesia were individuals with an inherited or acquired delay in myocardial repolarisation.

      No ECG recording from a patient dying during chloroform anaesthesia exists so the hypothesis cannot be proven.

      For 100 years, chloroform was used to alleviate labour pain – remarkably with no maternal deaths. A recent investigation has shown an oestradiol-mediated shortening of the QT-interval - both in normal women and in women with the inherited form of delayed myocardial repolarisation - providing a likely explanation for the safety of the obstetric use of chloroform and lends credence to the hypothesis presented in the paper.

      P.G.Berthelsen. MD. Charlottenlund, Denmark


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    1. On 2017 May 26, Jafar Kolahi commented:

      This is an up-date to the previous research "Kolahi J, Khazaei S. Altmetric: Top 50 dental articles in 2014. Br Dent J. 2016 Jun 10;220(11):569-74. doi: 10.1038/sj.bdj.2016.411."


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    1. On 2017 May 23, Stuart RAY commented:

      The publisher has now added the URLs to references in the publication.


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    2. On 2017 May 13, Stuart RAY commented:

      The reference URLs were lost along the way, but here they are (have also asked publisher to add these to the online version):

      1 - ORI. Guidelines for responsible data management in research. 2006.

      2 - DuBois JM, Chibnall JT, Tait R, Vander Wal J. Misconduct: Lessons from researcher rehab.Nature. 2016;534:173–175. doi: 10.1038/534173a. DuBois JM, 2016

      3 - ICMJE. Recommendations for the conduct, reporting, editing, and publication of scholarly work in medical journals 2015.

      4 - DHHS. Hipaa privacy rule – research. 2013.

      5 - NIH. Grants policy statement. Application and Information Processes. 2016.

      6 - NIH. NIH data sharing policy. 2007.


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    1. On 2017 May 14, Kiyoshi Ezawa commented:

      I think that this commentary is well written overall.

      Unfortunately, it lacks some important facts that would have assisted the readers' fair judgements.

      So, I have posted my post-publication peer review (PPPR), which also contains the aforementioned facts, onto PubPeer (https://pubpeer.com/publications/0BBC818513066058DB929595CE7C32/comments/120820).

      It would be strongly recommended to read the PPPR as well before or after reading this commentary, in order to have unbiased opinions on its subjects.

      Kiyoshi Ezawa, Ph.D., the author of references [53,54,55], which are a part of the main subjects of the commentary.


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    1. On 2018 Jan 05, Mogens Groenvold commented:

      Thank you very much to the Cicely Saunders Institute Journal Club and Javiera Leniz Martelli and Katherine Bristowe for an insightful discussion of key aspects of our article.

      Concerning ‘standard care’ in the control group we are currently analyzing and comparing the health care activities in the two groups. This will map the palliative care activities offered outside SPC and clarify whether there was ‘compensation’ in the control group.

      Regarding the primary outcome, the most important point to make is that while we did indeed devise and employ a new approach aimed at addressing the issue of heterogeneity in palliative care needs (Johnsen AT, 2013 p. 5 and Johnsen AT, 2014 p. 7), we also carried out a fully conventional analysis. The comparison of these two methods suggested that the new approach was slightly superior (Groenvold M, 2017 p. 822).

      In the conventional analysis we compared the change over time between groups according to each of the seven EORTC QLQ-C30 scales selected by our clinicians as the key targets of their SPC. Some of the previous trials found an impact on generic health-related quality of life scales, and we have no reason to believe that our measures are less sensitive (unless our clinicians picked the ‘wrong’ scales; this will be elucidated in a forthcoming analysis of explorative outcomes). Therefore, unfortunately, we do not believe that positive effects have been attenuated in our analysis of the primary outcome.

      In relation to the patient sample we agree that just as we sought to minimize heterogeneity in palliative care needs, the heterogeneity in cancer diagnoses should be minimized if the main concern is observe maximal effects on specific problems. However, we aimed at evaluating the impact of SPC in a mixed population of cancer patients with different needs, and, as suggested, a larger sample size may be required for this.

      Finally, we agree that the possible lack of uniformity of the intervention between the six SPC units may have weakened the ability to detect a positive effect. Future analyses will elucidate whether the interventions differed between the units.

      At this point in time we believe that the two most important explanations of the negative (or, in fact, neutral) trial outcome are that the SPC units may not have had an active, structured approach to early SPC, and that the eight-week trial period was too short. The ongoing analyses are likely to give additional insights.


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    2. On 2017 Dec 19, Cicely Saunders Institute Journal Club commented:

      This paper was discussed at the Cicely Saunders Institute Journal Club on Wednesday 6th December. We appreciated the opportunity to discuss a well conducted RCT and to see it published even after getting a negative result. We enjoyed discussing this paper and it generated a series of reflections on the methods, in particular regarding the primary outcome.

      We positively highlighted the detailed discussion about previous trials regarding early specialist palliative care (SPC) in the introduction, and the clear description of the randomization process as well as the blindness of analysts and the sensitivity analysis. We felt more information about what ‘standard care’ involved for individuals in the control group would have been beneficial.

      We discussed extensively the use of patient’s primary need based on the EORTC QLQ-C30 dimensions as primary outcome. We agree with the authors about the importance of addressing the heterogeneity in palliative care patients needs and we value the use of measurements that are important for patients. We wondered if the nature of the outcome chosen required a larger sample size to show a difference between arms. It is clear that some of the dimensions would be easier to modify by a SPC team than others. That makes the positive effect SPC might have had in some dimensions being attenuated in the weighted mean. In addition, SPC might have a different impact according to type of cancer. Including all type of cancer patients increases the variability of the effect, and might require a larger sample size. We wondered if the lack of uniformity of the intervention among the different centres also contributed to lack of significant difference in the primary outcome.

      Finally, we valued the discussion of the possible reasons for the lack of effect of the intervention, which need to be taken into account for future trials.

      Commentary by Javiera Leniz Martelli and Katherine Bristowe


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    1. On 2017 Nov 08, BSH Cancer Screening, Help-Seeking and Prevention Journal Club commented:

      The BSH Cancer Screening, Help-Seeking and Prevention Journal Club read with great interest this paper, which we feel provides a useful addition to the literature. In this paper, the authors present a framework for the complex relations between cognition and affect in predicting health behaviour. The authors describe the model that is currently used most often in health behaviour research, which looks at the independent effects of cognition and effect on health behaviour (the “main effects approach”). They then convincingly argue that this model does not consider possible interconnections of thought and feeling and describe three alternative models that may be better at explaining subsequent health behaviour: a mediation model (either an affect-preceding-cognition model or a cognition-preceding-affect model), a moderation model, and a contextualised effects model, which are helpfully explained graphically in the Figure on page 3 of the paper. The authors also provide empirical evidence from the health behaviour literature to support each of these models, and argue that these complex relations should be routinely examined in health behaviour research.

      Our group recognised the importance and relevance of this topic to much of our work on the determinants and possible points for intervention in cancer screening, help-seeking, and cancer prevention. The authors provide a good reminder of how theory can be improved to better understand behaviour, which is relevant to our work on, for example, cancer screening as a teachable moment or cancer worry as determinant of screening uptake, but is also applicable to a wide range of other health behaviours such as smoking, exercise, and healthy eating.

      However, the paper also raised some questions in our group. First, it was unclear to us which model would be applicable under what circumstances. For example, is this a function of the behaviour or of the affective state that is under study, or could this also be construed as characteristic of an individual or group of individuals? For example, for some people, perhaps those who are more organised or conscientious, the cognition-preceding-affect model may better predict subsequent behaviour, while for others, perhaps those who are struggling to cope due to life difficulties or mental health issues, the affect-preceding-cognition model may better predict behaviour. The authors acknowledge that the models they present are “not mutually exclusive” (p.4), and so “multiple types of relations could be involved in determining engagement in a particular health behaviour” (p.4), but this does not provide much guidance on how these models might guide our formulation of hypotheses to be tested in a particular study. Relatedly, it is unclear how these models can (or should) be applied to existing health behaviour models, and to what extent they require an overhaul of these existing models. Our group noted that the inclusion of these complex relationships could water down existing theoretical models, especially if the specific relationship cannot be identified a priori on theoretical grounds but is a function of the behaviour, affective state, individual, or group under study. From the empirical examples that the authors provide throughout, it is unclear whether the complex relations in those studies were pre-specified based on theoretical grounds, or merely exploratory in nature. In their Discussion on p.11, the authors seem to acknowledge that inclusion of the often-neglected interconnections between cognition and affect will require an exploratory, theory-building approach. Our group would have found it helpful if the authors had provided more practical advice on how to formulate a priori hypotheses about these complex relations, and perhaps some worked examples.

      Other questions that were raised by our group are of a more pragmatic nature, such as what the implications of the inclusion of complex relations between cognition and affect would have on study sample size and power (especially if not pre-defined a priori but tested post hoc). A related concern was how to practically take the ideas presented by the authors forward, given that mediation and moderation analyses may require a slightly different skill set, and one that many social scientists may not be very familiar with.

      Overall, however, the group felt that these concerns -especially those of a more practical nature- do not override the importance of taking forward the excellent ideas presented in this paper, which could herald a new era for health behaviour research, both in terms of theory and practice.


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    1. On 2017 May 26, Hilda Bastian commented:

      These are interesting results, showing the critical importance of transparency about trials of pharmaceuticals. However, it does not identify the trials it found, or identify the phases of those trials. It would be helpful if the authors were to release these data, for those interested in the results of this study, anyone interested in doing similar work, and those looking for trials on these particular drugs.

      The abstract reports the number of participants in the unpublished trials. It would be good to also provide the number of participants in the published trials.

      Note: I wrote a blog post about this study and its context.


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    1. On 2017 May 14, Lily Chu commented:

      The authors and others might be interested in the following case report from Dr. Nancy Klimas, published in the Journal of Chronic Fatigue Syndrome in 2001. Autologous lymph node transplant was done successfully in one subject with resulting improvements in clinical status and cytokine measurements:

      http://www.tandfonline.com/doi/abs/10.1300/J092v08n01_03?journalCode=icfs20


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    1. On 2017 May 15, Lydia Maniatis commented:

      Below I comment on some serious conceptual and methodological problems with this publication.

      1. Observers are asked to decide which of four briefly presented images is the most blurred, in a forced choice task. Why? The authors tell us that "blur perception is an elemental feature of the human visual system" because it drives accommodation and vergence. The problem, of course, is that we don't perceive the blur driving these responses - at least I don't, as I look around me. So the term "blur perception" isn't valid. In fact, the authors are not talking, here, about the retinal stimulation just preceding and producing proper accommodation etc, but, rather, images that, even post-accommodation, lack sharpness due to the manner in which they were produced or designed. They are asking observers for a conscious assessment of the relationship between an image and the objects of which it might be an imperfect projection. They can call this "blur perception," but this is obviously a very different definition than 'the retinal stimulation preceding accommodation and vergence.' So from a theoretical point of view, I submit that at least the first five paragraphs of this article are irrelevant. The definition of blur perception shifts at paragraph 6, which refers to psychophysical studies. (Given the irrelevance of the exposition, we are left, of course, with the question of the theoretical interest of the present measurements).

      2. In paragraph 6, to accommodate the second definition of blur perception, we are referred to "the variance discrimination model of blur." This model "assumes that the visual system is attempting to estimate the local variance of the luminance profile of an image from a set of luminance samples. Each of these samples is, however, perturbed by some level of internal noise or intrinsic blur." The reference to "internal noise or intrinsic blur" is to be taken on faith (and is part of the untenable "signal detection" view of perception, see below). At best, the idea has never been tested and it is not clear how it could be tested. It is my suspicion that adherence to forced-choice paradigms in the area of psychophysics implicitly serves the purpose of ensuring that something that can be interpreted as "noise" (i.e. the shots in the dark by observers) will be present in the data. The same goes for the very brief presentations (which are also uncritically an irrationally assumed to tap into "lower levels" of visual processing).

      3. "This model well describes the dipper data and is grounded in signal detection theories of sensory discrimination and decision making (Green & Swets, 1966)." Again, signal detection "theories," are not remotely corroborated or conceptually valid. They date from the sixties when perception was crudely analogized to radar operators trying to decide whether a particular blip was a whale or a ship, and judging from the reference provided have apparently not been further developed since. The "model" along with methods amenable to producing data of the right shape in the context of multiple free parameters and post hoc adjustments was simply adopted uncritically. The concept, with its treatment of neurons as "noisy detectors" has been criticized by Teller (1984). I've discussed the problems in various comments, including here: https://pubpeer.com/publications/8B2F3402AFA4F136252567815CB415. The notion is implicitly homuncular, the homunculus observing neural firing rates at various levels of the visual system and assigning them meaning, presumably via other firing rates...

      4. Here's how you explain away discrepancies: "Overall, Intrinsic Blur estimates with our dead leaves stimuli were greater than those reported for border blur discrimination (Watson & Ahumada, 2011) or for blur discrimination with fractal patterns (Mather, 1997), suggesting that blur perception with naturalistic stimuli may be mediated by receptive fields with larger space constants (Mather & Smith, 2002)." It's that easy. Note that the term "naturalistic stimuli" is undefined. Many scholarly perception publications include in this category photos of buildings, sidewalks and shrubbery on college campuses. Not to mention that the "dead leaves" stimulus does not look remotely natural, nor would anyone spontaneously relate it to leaves.


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    1. On 2017 May 07, Lydia Maniatis commented:

      The major assumption of this article is unviable. That it appears premised wholy on early results of Hubel and Wiesel should be a clue:

      “The primary function of the biological visual system is to identify objects in an environment. To achieve this, given that in the earlier stages of visual processing an input image would be decomposed into fragmented components by neural mechanisms with localized receptive fields and specific tuning characteristics (Hubel & Wiesel, 1962, 1968), the visual system must be able to integrate image components into the percept of a coherent object.”

      As I discuss in a comment on a different article (positing “curvature detectors”), the idea that neurons at any level of the nervous system may be described as “local detectors” is unviable:

      (From https://pubpeer.com/publications/8B2F3402AFA4F136252567815CB415):

      “As simple as it may seem, the notion of “curvature-sensitive-filter,” or more generally the notion of neurons as “detectors” is wholly untenable for a number of reasons, including those discussed by Teller (1984). On neurons as detectors: “Single simple cells in area 17 are often described as being triggered by, or detecting, the presence of bars of light at particular orientations [because,] of the stimulus set that has been tried, an oriented bar of light seems to make the cell fire fastest. But to say that the cell has a special role in encoding the stimulus which makes it fire fastest is to commit the same fallacy as to say that a cone with maximum sensitivity at 570 nm is a 570nm detector. It would seem to make more sense to assume that each perceptual element is coded by a pattern of firing among many neurons, and that each different firing rate of each cortical cell is important to the neural code….To use the concept of a trigger feature appears to be to claim implicitly three things: that for any given cortical cell most of the stimuli in the universe are in the null class…that the later elements which receive inputs from the cell ignore variations in the firing rate of the cell and treat the cell as binary…it is hard to set aside the convictions that all of the possible firing rates of cortical cells play a role in the neural code; and that the use of broader universes of stimuli in physiological experiments would reveal the size and heterogeneity of the equivalence classes of neurons….” (p. 1243) The arguments obviously also apply to the case of “curvature-detectors,” for which any correlations to firing rates have not been ascertained, but have only been “modeled” on the basis of a narrow set of stimuli. If the outlines of our RF shapes and circles were constructed of dots, or radiating rays, or shapes producing illusory contours, would the data look different? How would such results connect with the “curvature filter” based model? Would it make sense to make yet more ad hoc models for these cases? The adoption of a particular type of stimulus by many researchers serves to immunize them from inconvenient results and create the illusion of an at least superficially coherent research program.

      Teller also challenges explanations based on firing activity of sets of cells at a peripheral level of the visual system, on the basis that it relies implicitly on a “nothing mucks it up” proviso, ignoring as it does questions of how this pattern is maintained through the system or how it constrains more complete models. Given such gaps, this type of explanation, she notes, amounts to little more than a “remote homunculus theory.”

      A more subtle (and too little appreciated) problem with Schmidtmann and Kingdom’s claims is that they are confusing perceptual cause and effect. The “curves” we are talking about are perceived curves, not actual, objectively curved objects. There are no curves in the retinal stimulation. As we well know, the presence of a particular form in perception is not a passive response to the retinal stimulation, which at its inception consists of points of contact with photons, but an active construction of forms based on principles the outlines of which may be discerned by the products of the process. There are many examples of geometrical forms delineated by luminance differences that are not perceived, e.g. the stimuli used by Gottschaldt (in Ellis (1938) A Source Book of Gestalt Psychology ) and demonstrations by Kanizsa (1979, Organization in Vision). So to say that neurons are detecting curve maxima and minima is basically to say that a form that is first constructed by the visual system, on the basis of dynamic feedback and feedforward mechanisms which we are not even close to understanding, are brought to consciousness, and are secondarily inspected and by a set of detectors said to live at some arbitrary level of the process, which signal the conscious observer in some cryptic way. Again, it’s a hall of mirrors. “

      In addition, one could note that, given the massive interconnectedness and interaction of the visual system, when Hubel and Wiesel were recording from particular neurons in V1 they were in effect recording from the whole visual process. That is, it is not possible to claim that these recordings were isolating the independent behavior of these particular neurons.

      In addition to the premise that neurons in the visual system act as “local linear detectors” another underlying premise that has zero theoretical support is that the conditions, stimuli and data of these experiments are such as to allow them to be used to infer the behavior of such detectors at specific locations of the visual system. Of course, as Graham (1992) has admitted, hundreds of threshold studies “consistent” with the gross over-interpretation of Hubel and Wiesel’s early results (at a time when V1 was thought to be all there was) were generated in the ensuing decades. This is just one of the latest.

      As usual in this type of study, the number of observers is very small (3), two are described as naïve but the third is an author, i.e. not naïve. If naivete matters, then why an author/subject?

      As usual in this type of study, a “model,” involving untested or false premises and various atheoretical free parameters, is constructed post hoc, narrowly tailored to the specific dataset, stimuli and conditions. Observations on all other stimuli, conditions fall outside its purview.

      As is usual in this type of study, we are given very detailed descriptions of stimuli and conditions, but no indication of their theoretical necessity, and how data and interpretation would change if they were even slightly altered. Relatedly it was interesting to note that stimuli were exposed for 167ms, the identical interval used by Wilson and Wilkinson (1998). What is special about this interval?

      “It is known that the visual system cannot group two dots of opposite luminance polarities into a dipole [dot pair] (Glass & Switkes, 1976; J. A. Wilson et al., 2004).” I’m sure this isn’t true. Even if they are the only two dots in the visual field, we will see a pair of dots.

      The intellectual level of theorizing in this line of research is exemplified by the elevation of the observation that like figures tend to be grouped together in the visual percept (as in the case of the classic Gestalt dot demos) into “similarity theory.” (Casually tacking on the word “theory” to observations of effects is typical in psychology in general.) Similarity isn’t the only factor mediating organization of the visual stimulus.


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    1. On 2017 May 06, Hilda Bastian commented:

      The conclusion that implicit bias in physicians "does not appear to impact their clinical decision making" would be good news, but this systematic review does not support it. Coming to any conclusion at all on this question requires a strong body of high quality evidence, with representative samples across a wide range of representative populations, using real-life data not hypothetical situations. None of these conditions pertain here. I think the appropriate conclusion here is that we still do not know what role implicit racial bias, as measured by this test, has on people's health care.

      The abstract reports that "The majority of studies used clinical vignettes to examine clinical decision making". In this instance, "majority" means "all but one" (8 out of 9). And the single exception has a serious limitation in that regard, according to Table 1: "pharmacy refills are only a proxy for decision to intensify treatment". The authors' conclusions are thus related, not to clinical decision making, but to hypothetical decision making.

      Of the 9 studies, Table 1 reports that 4 had a low response rate (37% to 53%), and in 2 studies the response rate was unknown. As this is a critical point, and an adequate response rate was not defined in the report of this review, I looked at the 3 studies (albeit briefly). I could find no response rate in any of the 3. In 1 of these (Haider AH, 2014), 248 members of an organization responded. That organization currently reports having over 2,000 members (EAST, accessed 6 May 2017). (The authors report that only 2 of the studies had a sample size calculation.)

      It would be helpful if the authors could provide the full scoring: given the limitations reported, it's hard to see how some of these studies scored so highly. This accepted manuscript version reports that the criteria themselves are available in a supplement, but that supplement was not included.

      It would have been helpful if additional important methodological details of the included studies were reported. For example, 1 of the studies I looked at (Oliver MN, 2014) included an element of random allocation of race to patient photos in the vignettes: design elements such as this were not included in the data extraction reported here. Along with the use of a non-validated quality assessment method (9 of the 27 components of the instrument that was modified), these issues leave too many questions about the quality rating of included studies. Other elements missing from this systematic review (Shea BJ, 2007) are a listing of the excluded studies and assessing the risk of publication bias.

      The search strategy appears to be incompletely reported: it ends with an empty bullet point, and none of the previous bullet points refer to implicit bias or the implicit association test.


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    1. On 2017 May 25, William McBride commented:

      We have concerns that this paper overestimates the risk of dengue transmission through reliance on a test inadequately specific for blood donor screening. An earlier study of 100 donors from the same group Ashshi AM, 2015 acknowledged that the absence of molecular confirmation was a weakness of that study, but they utilised the same methods in this larger group. A similarly sized study conducted in Australia Rooks K, 2016 showed that of 973 donors tested, 3.3% were positive using the PanBio NS1 assay, but that no samples were positive using the BioRad NS1 assay. Further testing of over 6000 blood samples collected during 2 outbreaks were negative using a nucleic acid amplification assay. The question of the proportion of patients who remain asymptomatic during dengue infection is important, not just for assessing risk from blood donors, but for better understanding transmission of dengue more widely. A recent contribution in our understanding of the importance of asymptomatic dengue in transmission dynamics can be found at Duong V, 2015 which showed that around 7% of people infected with dengue remain asymptomatic. This rate may be even lower in an adult population.


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    1. On 2017 May 05, Donald Forsdyke commented:

      ORGANIC MEMORY

      The view that Richard Semon's work was neglected seems to be based on psychologist Daniel Schacter's 1982 text (1). This was reissued with a new title and a few changes in 2001, without mention of the profound interim account by historian Laura Otis (2). While the authors cite my 2006 text on Samuel Butler and Ewald Hering, later work corroborates and extends Otis’s study and casts a somewhat different light on the authors' prime hero (3, 4).

      Even if offering a list of heroes that is "entirely personal," a paper that extolls the "benefits of exploring the history of science" and of acknowledging our "debts … to those scientists who have offered key ideas," could have mentioned the doubts cast on Semon by Freud and Hertzog, and Semon's dismissal of Butler's work as "rather a retrogression than an advance."

      1. Schacter DL (1982) Stranger behind the Engram: Theories of Memory and the Psychology of Science. Hillsdale, NJ: Erlbaum.

      2. Otis L (1994) Organic Memory. History and the Body in the Late Nineteenth and Early Twentieth Centuries. Lincoln: University of Nebraska Press.

      3. Forsdyke DR (2009) Samuel Butler and human long term memory: is the cupboard bare? J Theor Biol 258:156-164.Forsdyke DR, 2009

      4. Forsdyke DR (2015) "A vehicle of symbols and nothing more." George Romanes, theory of mind, information, and Samuel Butler. History of Psychiatry 26:270-287. Forsdyke DR, 2015


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    1. On 2017 Oct 10, Kevin Hall commented:

      This is a corrigendum to the original article (https://www.ncbi.nlm.nih.gov/pubmed/28074888) with the following correction:

      Since the publication of the original article, the author has noticed that the references at the end of the third paragraph of the section ‘Experimental falsification of the carbohydrate–insulin model’ are incorrectly cited as 13, 14, where they should be 19, 20. The correction is given below:

      ‘In concordance with the model predictions, carbohydrate restriction led to increased fat oxidation reaching a maximum within a few days and remaining constant thereafter. However, neither study found the predicted augmentation of body fat loss with carbohydrate restriction. Rather, despite the reduction in insulin secretion, both studies found slightly less body fat loss during the carbohydrate restricted diets compared with isocaloric higher carbohydrate diets with identical protein.19,20’

      However, for some strange reason, this published corrigendum goes on to incorrectly state the following:

      The authors also noticed an error in reference 9. The correct reference is: Pahlavani N, Jafari M, Rezaei M, Rasad H, Sadeghi O, Rahdar HA, et al. L-arginine supplementation and risk factors of cardiovascular diseases in healthy men: a double-blind randomized clinical trial. F1000Res 2014; 3: 306. doi:10.12688/f1000research.5877.1.

      The original reference 9 is actually correct and the author is mystified as to the source of this error.


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    1. On 2017 Jun 23, Alexander Kraev commented:

      Regretfully, this article has a misleading title and abstract. The correct title should be "Strenuous exercise triggers a life-threatening response in C57BL/6J mice carrying RYR1 Y522S/WT and CASQ1 null mutations". Besides, the authors never care to state that they analyze the pathogenesis of an experimental disease, without attempting to decide, whether it is closely related to the respective disease of man.


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    1. On 2017 Jul 23, Giles Hardingham commented:

      We would like to extend our sincere thanks to Michel Goedert for the use of his Thy1-P301S transgenic mouse (Allen et al. (2002), PMID: 12417659). Regrettably, this note was erroneously absent from the Acknowledgements section of the manuscript.


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    1. On 2017 May 09, Pavel Nesmiyanov commented:

      Funny, but β-endorphin, oxytocin, and dopamine are not neuropeptides. They are not even peptides.


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    1. On 2017 Sep 18, Martine Crasnier-Mednansky commented:

      The model for the chitin catabolic cascade indicates GlcNAc oligomers are degraded in the periplasm to ABC-transported (GlcNAc)2 and PTS-transported GlcNAc (figure 5 in Park JK, 2002 for the original model). The authors used (GlcNAc)4 and, because Enzyme IIA<sup>Glc</sup> was largely phosphorylated in the presence of (GlcNAc)4, proposed there was "some mechanism for which chitin oligosaccharides escape from degradation into GlcNAc in the periplasmic space". If such mechanism occurs under the authors’ experimental conditions, it precludes any major PTS-transport effects on the chitin cascade, i.e. via dephosphorylation of Enzyme IIA<sup>Glc</sup> during GlcNAc transport.

      Working with Vibrio furnissii, Keyhani NO, 1996 argued, "since (GlcNAc)2 is an important inducer in the cascade, it must resist hydrolysis in the periplasm", and further provided an explanation for the stability of (GlcNAc)2 in the periplasm, particularly in sea water. It may well be that the rapid catabolism of (GlcNAc)2 is 'free' from any PTS control, and as such the cAMP necessary for the chitin cascade is provided.


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    1. On 2017 Jul 21, CO Stocco commented:

      Thank you to the authors for such wonderful and detailed description of the extremely complex interaction between FSH and locally produced factors in the regulation of granulosa cells. This review will surely foster innovative ideas and projects to further explore the role of gonadotropins and growth factors in the regulation of female fertility.


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    1. On 2018 Feb 04, Sin Hang Lee commented:

      The medical profession, including medical schools and hospitals, is now a part of the health care industry, and implementation of editorial policies of medical journals is commonly biased in favor of business interests. PubMed Commons has offered the only, albeit constrained, open forum to air dissenting research and opinions in science-based language. Discontinuation of PubMed Commons will silence any questioning of the industry-sponsored promotional publications indexed in PubMed.


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    2. On 2017 May 03, Sin Hang Lee commented:

      In this Reply, Marks and colleagues did not dispute that 16S rRNA gene sequencing has provided objective evidence regarding the existence of chronic Lyme disease.

      Marks and colleagues contended “persistent polymerase chain reaction (PCR) positivity for Borrelia burgdorferi does not signify the presence of active infection or bacteremia that merits prolonged antibiotic treatment.” However, neither PCR positivity, nor prolonged antibiotic treatment, was an issue raised in my Letter to Editor. The issue is: Does chronic Lyme disease exist? The answer is "yes". Whether bacteremia needs antibiotic treatment is beyond the scope of this discussion.

      If a B burgdorferi 16S rRNA gene is detected in the DNA extraction of the pellet of the centrifuged serum or plasma sample from a patient, the positive test result serves to confirm that there were Lyme disease bacteria, dead or alive, circulating in the patient’s blood at the time when the blood sample was drawn – definition of bacteremia.Dead bacteria are quickly removed by the spleen and macrophages in other organs. Free foreign DNA in the blood of living mammals is known to be degraded or removed in 48 hours [1]. Many infectious diseases are diagnosed by testing the nucleic acid of the causative agents, for example the hepatitis C virus and the human papillomaviruses which are difficult to culture. Some of the bacterial strains causing Lyme borreliosis are not easily cultivated in artificial media. The references cited to dismiss the significance of gene sequencing in the diagnosis of Lyme disease are inappropriate.

      Reference: [1] Schubbert R et al. Foreign (M13) DNA ingested by mice reaches peripheral leukocytes, spleen, and liver via the intestinal wall mucosa and can be covalently linked to mouse DNA. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 961-6.

      Conflicts of Interest: Dr Lee is the director of Milford Molecular Diagnostics Laboratory specialized in developing DNA sequencing-based diagnostic tests.


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    1. On 2018 Feb 04, Sin Hang Lee commented:

      The medical profession, including medical schools and hospitals, is now a part of the health care industry, and implementation of editorial policies of medical journals is commonly biased in favor of business interests. PubMed Commons has offered the only, albeit constrained, open forum to air dissenting research and opinions in science-based language. Discontinuation of PubMed Commons will silence any questioning of the industry-sponsored promotional publications indexed in PubMed.


      This comment, imported by Hypothesis from PubMed Commons, is licensed under CC BY.

    2. On 2017 May 05, Sin Hang Lee commented:

      In their Reply, Marks and colleagues did not dispute that 16S rRNA gene sequencing has provided objective evidence regarding the existence of chronic Lyme disease.

      Marks and colleagues contended “persistent polymerase chain reaction (PCR) positivity for Borrelia burgdorferi does not signify the presence of active infection or bacteremia that merits prolonged antibiotic treatment.” However, neither PCR positivity, nor prolonged antibiotic treatment, was an issue raised in my Letter to Editor. The issue is: Does chronic Lyme disease exist? The answer is "yes". Whether bacteremia needs antibiotic treatment is beyond the scope of this discussion.

      If a B burgdorferi 16S rRNA gene is detected in the DNA extraction of the pellet of the centrifuged serum or plasma sample from a patient, the positive test result serves to confirm that there were Lyme disease bacteria, dead or alive, circulating in the patient’s blood at the time when the blood sample was drawn – definition of bacteremia.Dead bacteria are quickly removed by the spleen and macrophages in other organs. Free foreign DNA in the blood of living mammals is known to be degraded or removed in 48 hours [1]. Many infectious diseases are diagnosed by testing the nucleic acid of the causative agents, for example the hepatitis C virus and the human papillomaviruses which are difficult to culture. Some of the bacterial strains causing Lyme borreliosis are not easily cultivated in artificial media. The references cited to dismiss the significance of gene sequencing in the diagnosis of Lyme disease are inappropriate.

      Reference: [1] Schubbert R et al. Foreign (M13) DNA ingested by mice reaches peripheral leukocytes, spleen, and liver via the intestinal wall mucosa and can be covalently linked to mouse DNA. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 961-6.

      Conflicts of Interest: Dr Lee is the director of Milford Molecular Diagnostics Laboratory specialized in developing DNA sequencing-based diagnostic tests.


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    1. On 2017 May 11, Alexis Frazier-Wood commented:

      The key points section of this article, the purpose of which is to isolate the ‘key conclusion and implication based on the primary [study] finding(s)’, states that: “A randomized intervention that increased breastfeeding intensity was not associated with reduced obesity”. This is a selective interpretation of the study data on weight status, which show that maternal participation in the PROBIT intervention (which increased breastfeeding exclusivity and duration) was 1. associated with increased odds of offspring having adolescent overweight/obesity (odds ratio=1.14; 1.02-1.28) but 2. not associated having adolescent obesity (odds ratio=1.09; 0.92-1.29), although it can be seen that both associations were in the same direction. Body mass index (BMI) was also higher in the children from the intervention group by adolescence (mean difference Δ= 0.21, 0.06-0.36).

      The reasons for the difference in significance (according to the specified alpha) between the results specifying BMI and overweight/obesity as outcomes vs. those specifying obesity likely arise from the differential power for the two outcomes. The relationship of breastfeeding to obesity vs. overweight/obesity had less power, largely due to the lower number of cases (obesity N=589 vs. overweight/obesity N=1868). Simulations in R v3.3.3, suggest the power for has “overweight/obesity” vs. has “obesity” was around 74% vs. 17%. These simulations did not account for the intention to treat procedure nor the correction for data clustering (since not enough data on e.g. ICC correlations was available), but due to the effects of these on power being equal across outcomes an assessment of relative power can be made. In addition, the alternative hypothesis (breastfeeding -> overweight/obesity) was formally tested, but the null hypothesis (breastfeeding ≠ obesity) was not, given the absence of any equivalence testing. Positive associations between breastfeeding and offspring adiposity have been reported before, but have not reached statistical significance (see Cope MB, 2008). Therefore, while the association of increased breastfeeding with significantly increased odds of overweight/obesity represents a novel finding which needs to be subjected to replication, without recourse to empirically stronger results, omitting this from the overall interpretation of the study in favor of a lesser powered, untested hypothesis represents a form of bias.

      While the manifestation of bias in the article may be small, its effect can still be pernicious. Several organizations, including the World Health Organization and the American Heart Association, state that breastfeeding provides protection against offspring obesity (see WHO report and AHA Fact Sheets). However, this lacks strong statistical justification, given that any inverse associations between breastfeeding and offspring obesity are derived from observational designs and likely to reflect confounding (Kramer MS, 2002), and that probability theory suggests that the breastfeeding-offspring obesity data in the literature as a whole reflect one of two situations: (1) publication bias, or (2) a true positive association between breastfeeding and offspring obesity in at least one other published sample (Cope MB, 2008). That is not to deny that there may be a number of valid reasons to support breastfeeding, not related to obesity (see e.g. APA report). But perhaps it is this which has lead to a problem with ‘white hat bias’ in the breastfeeding-obesity literature - a term coined by Cope and Allison to denote ‘bias leading to the distortion of research based-based information in the service of what may be perceived as righteous ends (Cope MB, 2010). One such reason to support breastfeeding is to enable personal choice for parents and caregivers. However, this is incompatible with the practice of giving misleading information on the benefits of breastfeeding which actually deprives caregivers of their right to make informed decisions about feeding infants.

      This is a problematic situation, and needs to be corrected. The causes are unknown, but distorted presentation of data has been identified in multiple reports of randomized clinical trials, often in only one section e.g. the abstract (Boutron I, 2010), and often in the secondary literature, such as press releases (Cope MB, 2010). Therefore all authors need express conclusions with great clarity and consistency, and not selectively include and exclude results without recourse to relative empirical strengths. To be accurate in reporting in this article, the results of this study as a whole are most consistent with either (1) an association between breastfeeding and increased offspring overweight/obesity, or (2) a lack of empirical strength in this study to contribute to the debate on whether there is an association between the two constructs.


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