14,839 Matching Annotations
  1. Jul 2018
    1. On 2013 Nov 30, GianCarlo Panzica commented:

      A previous study in the same rat model, demonstrated that also the nNOS system is altered in Tfm males, suggesting that also this system is depending by androgens for its full differentiation Martini M, 2008.


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    1. On 2014 Jan 02, Tom Kindlon commented:

      Two letters were published in reply to this:

      Two letters were published in reply to this piece. One is mentioned above, "What's the problem with sharing research committee's discussions?"

      Then there is also my letter: BMJ. 2013 Sep 25;347:f5731. doi: 10.1136/bmj.f5731. "People want to learn as much as possible from the PACE trial for chronic fatigue syndrome" Kindlon T. Kindlon T, 2013

      This second letter isn't free online. But it's just a slightly shortened version of an e-letter which can be read for free at: http://www.bmj.com/content/347/bmj.f5355/rr/659900 .

      Following a response from the PACE Trial authors, I justified and expanded on my points in these two e-letters: (i) "Author's response: Criticisms of the PACE Trial were justified" http://www.bmj.com/content/347/bmj.f5963/rr/667107 (ii) "PACE trial: Simply giving a reason why an outcome measure was changed is not necessarily sufficient" http://www.bmj.com/content/347/bmj.f5963/rr/670755


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    1. On 2013 Oct 29, John Cannell commented:

      Both isoforms of tryptophan hydroxylase are directly regulated by calcitriol and both isoforms have a vitamin D response element on their genes. Vitamin D down-regulates the peripheral hydroxylase and up-regulates the central tryptophan hydroxylase.

      Wang, T. T. et al. Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol 19, 2685-2695, doi:10.1210/me.2005-0106 (2005) Wang TT, 2005

      Autistic children with vitamin D deficiency have high peripheral serotonin and low central serotonin and thus low central melatonin as they do not have the central serotonin necessary to make melatonin.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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    1. On 2014 Jan 08, Brett Snodgrass commented:

      Dear Authors,

      Thank you for the excellent article.

      Please provide your kind attention to the distinction between the Thebesian veins and the vessels of Wearn.

      http://bit.ly/JTWearn

      http://bit.ly/vasaThebesii

      For additional commentary, please see

      https://twitter.com/BrettSnodgrass1/status/417440058648428544

      Comments and suggestions are welcome.

      Thank you very much.


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    1. On 2013 Oct 31, John Cannell commented:

      The authors reported that immune system dysregulation is common in autism spectrum disorder (ASD). Vitamin D deficiency produces very similar immune dysregulation.

      Prietl B, 2013

      Kamen DL, 2010

      Yang CY, 2013

      Baeke F, 2010

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

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

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

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

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

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

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

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

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

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

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

      70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day and few toddlers or pregnant women get any sunshine due to the sun scare. As vitamin D fortified milk consumption and sun exposure has declined, so have toddlers and pregnant women’s vitamin D levels. The dramatic increase in the incidence of ASD occurred during the same time vitamin D levels were falling in toddlers and pregnant women.

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

      Some autism researchers seem cognizant of the entire body of autism research. For example, a group of well-known European ASD researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into the vitamin D deficiency theory of ASD.

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

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

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


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    1. On 2017 Oct 11, Bhaskar Chandra Mohan Ramisetty commented:

      Does not seem like there is any useful information from this paper. The authors are apparently bold enough to correct their work!!! Good job. Nasty Prophages and the Dynamics of Antibiotic-Tolerant Persister Cells. https://www.biorxiv.org/content/early/2017/10/09/200477.1


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    2. On 2016 Feb 29, Bhaskar Chandra Mohan Ramisetty commented:

      http://biorxiv.org/content/early/2015/07/02/021162 http://journal.frontiersin.org/article/10.3389/fmicb.2016.01882/full

      A biorxiv article with contradictory results. Regulation of yefM/yoeB TA system is independent of inorganic polyphosphate as well as ppGpp.


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    1. On 2014 Feb 19, james brophy commented:

      Prompt revascularization of the culprit lesion with percutaneous coronary interventions (PCI) is a cornerstone in the treatment of acute myocardial infarction (STEMI). Numerous previous studies have suggested that simultaneous additional interventions of other non-culprit is at best unnecessary and at worst potentially dangerous. However this study that compared simultaneous ‘preventive angioplasty’ of non-infarct-related coronary arteries with ≥50% stenosis with primary PCI alone (with optimal medical treatment) found the composite endpoint of cardiac death, nonfatal myocardial infarction, or refractory angina was reduced by a staggering 65% (HR=0.35; 95% CI: 0.21-0.58, p<0.001). Is this result believable?

      First, despite a very slow recruitment period of several years, the trial was prematurely stopped. Premature trial discontinuations for benefits are well known to overestimate treatment effects. This is especially problematic in this small unblinded study with only 16 excess 'hard' events and no formal statistical stopping rule described in their study protocol. The strongly positive results in prematurely stopped small trials are often not confirmed in bigger follow-up studies underlining the important role of chance that arises with repeated looks at the data. Moreover it has been shown that these small prematurely stopped trials have an increased likelihood of being published in high profile journals reinforcing this tendency to early stopping, as in the present case. Second, can medical treatment really be considered optimal in the control group when, despite STEMI and multi-vessel disease patients were discharged in less than 2 days without ischemic testing, the current standard of care (if additional angioplasty has not been performed during the original hospitalization). It seems only 1/3 of patients ever got any ischemic testing and this occurred only several weeks after the acute event, perhaps to late to influence potentially avoidable outcomes. Consequently was the “preventive” up front PCI group not being compared to an inferior "straw man" comparator? Third given the unblinded nature, could not the knowledge of untreated lesions have encouraged a detection bias in the search for clinical outcomes.

      In an accompanying editorial, it was proposed that these additional interventions helped to pacify the inflamed coronary vasculature. However this argument seems specious as the coronary vasculature is diffusely and not locally inflamed. The biases discussed above seem a more likely explanation for this large and unexpected effect size.


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    1. On 2013 Sep 26, Carl Heneghan commented:

      We wrote about all sorts of sports intervention in the BMJ last year and bare foot running was one of the interventions we looked. The evidence underpinning sports performance products: a systematic assessment.

      Heneghan C, Howick J, O'Neill B, Gill PJ, Lasserson DS, Cohen D, Davis R, Ward A, Smith A, Jones G, Thompson M. BMJ Open. 2012 Jul 18;2(4). doi:pii: e001702. 10.1136/bmjopen-2012-001702. Print 2012. PMID: 22815461

      Seems whilst there is lots of biomechanical evidence, as pointed out in the article, there is no actual clinical performance evidence that could aid the decision as to whether to use these shoes.


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    1. On 2014 Jan 17, Amanda Capes-Davis commented:

      A note regarding the tissue studied here: KB is not an epidermoid carcinoma cell line. The KB cell line is known to be cross-contaminated and is actually HeLa, a cervical adenocarcinoma cell line. For a database of cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.


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    1. On 2013 Dec 30, Ben A Inglis commented:

      It seems to me that although the intent was to assess connectivity induced by reading a novel, in the absence of a control task there is no way to know whether the changes were due to the specific act of reading or due simply to the subjects' being engaged in a structured task over the study period. Surely, to be confident that the changes are due to reading, a second group of subjects should have been exposed to a control task that was as similar as possible to the novel reading. For example, control subjects could have been instructed to watch a dramatic TV mini-series, with each evening's exercise lasting approximately the same time as the reading. (Questioning of control subjects could have verified that the task was completed as instructed, in precisely the same manner as the test subjects had their reading task assessed.) An even better control would have been to use the same story but change the medium. For instance, the test subjects might have read the story while the control subjects listened to it on an audio book. Perhaps there is even need for a second control group; subjects are set a task to attend to each night, but there is no plot to follow. In sum, without assessing directly the effects of a structured attention task over the study period there is no way to be sure that reading per se is causing the connectivity changes.


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    1. On 2015 Jan 30, Peter Gøtzsche commented:

      This meta-analysis was fatally flawed

      Based on FDA trial data, Arif Khan et al. report that antipsychotic drugs lower total mortality in schizophrenia by more than 50% and that the drugs also lower suicides (1). These results agree very poorly with the fact that people with schizophrenia live about 20 years less than other people while almost all of them receive antipsychotics; that many experience excessive weight gains and diabetes because of the antipsychotics, which shorten their life substantially; and that a meta-analysis of old people found that double as many died when they got antipsychotics than when they got placebo (2).

      It is difficult to understand how Khan, who has been principal investigator of more than 340 clinical trials sponsored by more than 65 pharmaceutical companies and 30 contract research organizations (1), can publish a meta-analysis that is so intensely misleading as this one (1). The fatal flaw in their analysis is that the authors used person-years instead of using persons. As pointed out in a letter to the editor, a person-year is not just a person-year (3). The average duration of placebo exposure was very short, only 33 days, as compared to 132 days on drug (1). Khan et al. seem to have included not only the double-blind phases of the trials but also safety extension studies (in which patients only receive active drug of course). Such analyses are notoriously unreliable, as those who continue on active drug are those who tolerate it. We need to look at deaths in relation to number of randomised patients, and then we can see that antipsychotics kill people, which we knew beforehand. The relative risk is 1.65, i.e. a 65% increase in total mortality on drug compared with placebo, and for suicides, the relative risk is 2.83.

      Conflicts of interest: none.

      1 Khan A, Faucett J, Morrison S, et al. Comparative mortality risk in adult patients with schizophrenia, depression, bipolar disorder, anxiety disorders, and attention-deficit/hyperactivity disorder participating in psychopharmacology clinical trials. JAMA Psychiatry 2013;70:1091-9.

      2 Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005;294:934–43.

      3 Nordentoft M, Laursen TM. Was Risk of Suicide Underestimated? JAMA Psychiatry 2014;71:716.


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    1. On 2014 Oct 26, Nicholas Rosenlicht commented:

      In evaluating the results of this trial it is important to note that the published results do not correspond to the primary outcomes specified in the trial’s original and updated registrations on ClinicalTrials.gov. The four primary outcome measures initially registered (10/7/2008) were: MADRS at 40 minutes, 120 minutes, 24 hours, and 7 days. These were expanded on 1/12/11 to include the MADRS at 240 minutes, 48 hours, 72 hours, biweekly for up to 4 weeks, and early termination. After publication (1/30/14) all Primary Outcomes except MADRS at 24 hours were removed from the ClincalTrials.gov registration. These changes can be tracked at: http://clinicaltrials.gov/archive/NCT00768430 It would be important to understand why the authors changed the outcome measures several times during the trial. These changes are not mentioned in the publication. The finding that ketamine, a dissociative anesthetic that is abused for its euphoric and other mind-altering properties, transiently suppresses MADRS scores is not surprising. It would be much more important clinically to demonstrate significant effects on the outcome measures at 2 to 4 weeks. These were not presented.


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    1. On 2014 Feb 04, Jean-Jacques Letesson commented:

      In the bacteria and plasmid section of this paper, the readers should be aware that it is impossible to grow B. melitensis in the minimal medium stated "B. melitensis 16 M was routinely cultured in rich medium Tryptic Soy Broth (TSB) or in minimal medium GEM7.0 (MgSO4.7H2O 0.2 g/L, Citric acid•H2O 2.0 g/L, K2HPO4 10.0 g/L, NaNH4HPO4.4H2O 3.5 g/L, Glucose 20 g/L, pH 7.0)" All Brucella strictly require biotin, panthotenate, thiamine and nicotinamide as additional factors. In addition 20g/L of glucose is almost ten times as much as normaly needed.


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    1. On 2014 Mar 16, Jonathan Eisen commented:

      Two of the authors of this paper have written a guest post on my "Tree of Life" blog discussing some of the "Story behind the paper". See Story behind the paper guest post by Corey Nislow (w/ Metka Lenassi) on "Genomics w/o Borders"


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    1. On 2013 Nov 08, Seth Bordenstei commented:

      The Story Behind "Mom Knows Best: The Universality of Maternal Microbial Transmission"

      What types of microbes do mothers transmit to their newborns and how universal is maternal microbial transmission throughout animals?

      http://symbionticism.blogspot.com/2013/08/the-story-behind-mom-knows-best.html


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    1. On 2014 Oct 06, Anders von Heijne commented:

      Yes, the abductive mode of thinking that Peirce described is really very crucial in all forms of diagnostics. Depending on the problem at hand we clearly use different logical strategies. This is a must read, together with Lawson AE1, Daniel ES. Inferences of clinical diagnostic reasoning and diagnostic error.J Biomed Inform. 2011 Jun;44(3):402-12. Sadly this sort of analysis seldom appears in clinical speciality journals. If you are lucky you can find articles on Dual System theory and Bayesian theory, but without abduction there is no place to start using these techniques. We all need a dose of metacognitive musings from time to time.


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    1. On 2015 Sep 25, Amanda Capes-Davis commented:

      Great to see a paper looking at reproducibility of cell culture systems, in this case for replication of HuNoVs, important for the study of acute gastroenteritis. The authors note in their Materials and Methods that two cell lines are used for viral growth, INT-407 and Caco-2, and correctly state that INT-407 has been cross-contaminated with HeLa. So it makes sense that INT-407 is not a good model for culture of HuNoVs. INT-407 was found to be cross-contaminated with HeLa in the 1960s and there are no known authentic stocks remaining for the original intestinal culture; INT-407 has been completely replaced by HeLa cells. HeLa may form microvilli as shown here, but HuNoV replication is likely to require additional tissue-specific factors that HeLa cannot supply.

      Failure of Caco-2 is more puzzling, considering that the authors used a well-known intestinal (colorectal adenocarcinoma) cell line that was successful for the previous study, and obtained their stock of Caco-2 from the same source. However, it is worth noting that viral replication can vary across different strains or subclones e.g. Carson & Pirruccello, PMID 23408555. Caco-2 is well documented as a cell line that can change phenotype with passaging e.g. Briske-Anderson et al, PMID 9083258.

      For a list of known misidentified cell lines, please refer to http://iclac.org/databases/cross-contaminations/. It is also important to authenticate cell line stocks before use. Setting up in vitro culture systems takes a great deal of time - testing can save a great deal of heartache!


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    1. On 2015 Dec 02, David Keller commented:

      Extended-release niacin reduced Lp(a) but not CV risk, when added to statin therapy

      The AIM-HIGH trial yielded a 21% reduction in Lp(a) levels when high dose niacin was added to statin therapy, but without the expected additional reduction in cardiovascular (CV) events. This is puzzling because it is known that CV risk is correlated to Lp(a) level. Niacin is known to lower Lp(a) levels, which was again demonstrated in this study.

      The Coronary Drug Project, conducted in the pre-statin era, demonstrated that monotherapy with high-dose niacin reduced recurrent nonfatal myocardial infarctions, cerebrovascular events, and overall mortality at 15 years compared with placebo [1]. However, more recent studies of patients taking appropriate baseline statin therapy did not demonstrate additional reduced CV risk due to the improvement in lipids caused by the addition of niacin.

      All of the patients in this study were on appropriate statin therapy at baseline. Again, we see that adding niacin to baseline statin therapy somehow fails to yield the additional outcome benefits expected from niacin's improvements in cholesterol and Lp(a) levels.

      Given the evidence of outcome benefits with niacin monotherapy, but not with niacin added to a statin, it may be that statins somehow negate niacin's outcome benefits, despite preserving its improvement of the lipid profile. If so, then statin-intolerant patients remain candidates for niacin therapy, unless and until future clinical trials fail to reproduce the outcome benefits niacin demonstrated in the Coronary Drug Project.

      Reference

      1: Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986 Dec;8(6):1245-55. PubMed PMID: 3782631.


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    1. On 2013 Oct 23, Albert Erives commented:

      The background motivation of this paper is well written and informative. The "fine structure" of transcriptional enhancers underlying animal development is worthy of study and it is refreshing to see affirmation that there may be a range of simple to structured regulatory DNAs. From this report on Svb target enhancers, it will be important to follow-up on whether there are functional consequences to the range of architectures.

      Also of interest is the following. The authors note that: "[t]hese findings highlight a paradoxical discrepancy between the enrichment of putative BSs accumulated in Svb downstream genes and the limited number of those acting as cis-regulatory elements. Is there a role for this evolutionary accumulation of Svb-like motifs in Svb targets?" This is an important question that is related to the broader issues of homotypic site clustering and related phenomenon mentioned in this paper's background. Though my lab's work is nicely integrated into the introduction, there is one additional key study of ours that is most relevant to these issues: "Dynamic evolution of precise regulatory encodings creates the clustered site signature of enhancers" (Crocker J, 2010). I suspect this one issue, and a difficulty in experimentally testing the function of every single sequence component of a homotypic site cluster, has facilitated the generally-assumed working model that each sequence component in a cluster or locus remains functional in the extant organisms from they have been isolated (I take issues with this model on several grounds). To some extent this is a question that preceded the more recent debate about "biochemical functionality" in the ENCODE data sets. This report is another step towards a more versatile, effective, and evolutionarily-grounded language of enhancer biology.


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    1. On 2014 Sep 15, Andrea Messori commented:

      Bayesian models implemented under Winbugs: can they be considered the new standard for conducting a network meta-analysis?

      When multiple agents are available to treat the same disease condition, network meta-analysis of randomized controlled trials (RCTs) has the purpose of synthesising the available evidence. In the application of this technique, both direct and indirect comparisons are made between individual treatments. Direct comparisons are those for which a “real” randomised study is available while indirect comparisons are those for which no real trial has been conducted.

      Initial approaches for conducting network meta-analyses were designed to separately evaluate each indirect comparison; hence, there were as many separate analyses as the number of indirect comparisons [1,3]. More recently, the Bayesian approach for network meta-analysis has emerged as the new standard in this area [4-7]. This method relies on a sort of “all-in-one” modelling in which a single model incorporates the evidence available from all clinical trials and estimates, through a unified approach, all comparative results for both direct and indirect comparisons.

      In network meta-analysis, the phases of literature search and data extraction do not differ from those commonly employed for standard meta-analysis [5,6]. As regards the type of end-points, network meta-analysis favours binary end-points [4] as opposed to continuous ones. Hence, irrespective of whether the analysis is aimed at evaluating effectiveness or safety, the starting material for conducting a network meta-analysis is given by the rates of end-point occurrence (i.e. numerator and denominator) for each arm of each RCT.

      In present times, statistical modelling for network meta-analysis recognises its new standard in these Bayesian approaches based on an “all-in-one” model and implemented in the WINBUGS environment [4,7]. This approach has found a wide acceptance also because the methods and the software, developed by an authoritative institution (the NICE), are freely available [7]. The code for these estimations is available as fixed-effect model and random-effect model.

      The Winbugs Bayesian model employs a random sequence of chains, called a Markov chain Monte Carlo simulation. Each chain must be run for a length of time sufficient to allow model convergence (burn-in) before estimating posterior probabilities. Typically, the random-effect logistic regression model is created according to the binary outcome of subjects reaching the end-point concerned. Randomization within each study is preserved by specifying each arm in each study separately, thus accounting for the effect of the comparator. Results are generally presented as odds ratio or log odds ratio. Heterogeneity among studies can be accounted by applying meta-regression techniques and by consequently generating an index of heterogeneity [4,7].

      As regards the software, these analyses can be conducted by using the software package WinBUGS 1.4.3 (Cambridge, United Kingdom) in combination with the meta-analysis code developed by the National Institute for Health and Care Excellence[7]. Odds-ratio is the typical outcome measure of this software; however, odds-ratios can be converted into risk ratios or risk differences by application of standard equations [8,9]

      Sobieraj and co-workers [10] have published an article that reviews all previously published studies that have adopted the Bayesian approach.

      In conclusion, the present literature clearly indicates that Bayesian network meta-analysis can be considered the new standard in this field.

      References

      1. Lumley T. Network meta-analysis for indirect treatment comparisons. Stat Med 2002, 30; 21(16): 2313-24

      2. Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 1997;50(6):683–91

      3. Wells GA, Sultan SA, Chen L, Khan M, Coyle D. Indirect treatment comparison [computer program]. Version 1.0. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009. Software available at:http://www.cadth.ca/preview/en/resources/itc-user-guide

      4. Greco T, Landoni G, Biondi-Zoccai G, D'Ascenzo F, Zangrillo A. A Bayesian network meta-analysis for binary outcome: how to do it. Stat Methods Med Res. 2013 Oct 28.

      5. Hoaglin DC, Hawkins N, Jansen JP,. et al. Conducting Indirect-Treatment-Comparison and Network-Meta-Analysis Studies: Report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices—Part 2. Value Health 2011;14:429-37.

      6. Jansen JP, Fleurence R, Devine B, et al. Interpreting Indirect Treatment Comparisons and Network Meta-Analysis for Health-Care Decision Making: Report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: Part 1. Value Health 2011;14:417-28.

      7. NICE Clinical Guidelines, No. 92. National Clinical Guideline Centre – Acute and Chronic Conditions (UK). London: Royal College of Physicians (UK); 2010. Available at http://www.ncbi.nlm.nih.gov/books/NBK116530/ Accessed 14 August 2014

      8. Zhang J, Yu KF. What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA. 1998 Nov 18;280(19):1690-1.

      9. ClinCalc Website. Odds-ratio to risk ratio. http://clincalc.com/Stats/ConvertOR.aspx

      10. Sobieraj DM, Cappelleri JC, Baker WL, Phung OJ, White CM, Coleman CI. Methods used to conduct and report Bayesian mixed treatment comparisons published in the medical literature: a systematic review. BMJ Open. 2013 Jul 21;3(7). pii:e003111. doi: 10.1136/bmjopen-2013-003111. Print 2013.


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    1. On 2013 Oct 23, Stephen Shea commented:

      What is the basis for the statement that CO2 is odorless? Because it is to humans? This paper that the authors cite (http://www.ncbi.nlm.nih.gov/pubmed/17702944) quite convincingly demonstrated low concentration responses to CO2 in the olfactory sensory neurons and main olfactory bulb?. What reason is there to conclude that these are trigeminal in origin? Aren't these neurons the most likely source of the responses you see in cortex? I don't see how you can make your central claim without inactivation of trigeminal and olfactory sensory neurons.


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    1. On 2014 May 22, Jacob Puliyel commented:

      Post-marketing surveillance cannot properly estimate risks

      The authors must be congratulated for conducting a study whose scope was so vast. However it must be recognized that RCTs are the best method to look for risks and benefits. Post-marketing surveillance is relied on to detect rare adverse events. It has severe limitations in quantifying the magnitude of risks. The present study highlights the problem well.

      1 The authors estimate the risk of intussusceptions (IS) in two window periods after immunization. Previously surveillance had found that the incidence of IS was significantly increased in the first 3 weeks and more after the first dose than after the second dose. But that does not imply the risk of IS is limited to this window period alone. Only long term RCTs can really identify the full risk of IS after immunization and can categorically confirm that there is no risk in other periods.

      2 For estimating reduction of diarrhea the authors use the hospital discharge diagnosis coded rota virus (A08.0) or acute gastroenteritis excluding rota virus (A01-A09, K32 excluding A08.0) multiplied by proportion of the cases estimated to be rota virus.

      I am not sure how coding is done in the National Morbidity Database of the Australian Institute of Health and Welfare, but in many countries, diarrhea where rota virus is identified is coded as rota virus diarrhea, even where other pathogenic organisms are identified alongside and rota virus may not be the cause of the episode of diarrhea. The new rota virus vaccine strain from India, the monovalent human-bovine (116E) rotavirus, was cultured from an asymptomatic neonate in India. http://www.ncbi.nlm.nih.gov/pubmed/24629994. Some strains of rota virus could be a harmless commensals. The harmless rota virus may be protecting the individual imparting natural immunity without need for vaccines. Just because an organism is identified in a child with diarrhea, it does not necessarily imply that the organism is the cause of the diarrhea.

      Furthermore, there are obvious problems in assuming that a fixed proportion of all diarrhea which are 'not coded as rota virus,' are due to rota virus.

      Given these drawbacks, the estimate of 6500 rota virus hospitalizations avoided in Australia may not be accurate.

      The judgment on acceptability of the risk-benefit equation pivots on the trade off between the putative 6500 rota virus admissions avoided on the one hand and the 14 cases of IS caused by the vaccine on the other, and these figures may not be reliable in the first place.

      3 In their conclusions in the Abstract the authors say the "balance of risks and benefits at population level was highly favorable – a finding likely to extend to other settings despite varying incidence of IS and potentially higher morbidity and mortality from gastroenteritis and IS." This conclusion is clearly debatable.

      The morbidity and mortality from gastroenteritis may be high in developing countries, but the morbidity and mortality for IS is disproportionately higher. Most developing countries can manage dehydration but facilities for surgical and radiological management of IS may not be available in large areas, making the risk unacceptable in accordance with the principle of primum non nocere.

      4 Another factor the authors do not consider in their conclusion (that the findings are likely to extend to other countries,) is the varying vaccine efficacy seen in different countries. While the efficacy is nearly 90% in Western countries it is barely 50% in the tropics. Although the authors do not refer to the study by Madhi et al http://www.ncbi.nlm.nih.gov/pubmed/20107214 it is often quoted in this context. Severe rota virus gastroenteritis (SRVGE) was more common in Malawi than South Africa (13.1 vs. 5.4) and even though efficacy was lower in Malawi (49.4% vs. 76.9%) more cases of SRVGE were prevented by vaccination (6.7 vs. 4.2) in Malawi. This is often given as the justification for using the vaccine (with such low efficacy) in poor tropical countries.

      This does not apply to all nations in the tropics. Although the incidence of gastroenteritis is high in India, the incidence of rota virus diarrhea was even less than South Africa. The incidence SRVGE in the unvaccinated in India was 3.4% compared to 13.1 in Malawi and 5.4 in South Africa. The absolute risk reduction (ARR) by vaccination was tiny in India (1.7). This is much lower than the benefit in Malawi (6.7) and even South Africa (4.2). It raises questions about the need for the vaccine in countries like India using the ‘disease burden’ argument. http://www.ncbi.nlm.nih.gov/pubmed/24629994#cm24629994_3808. Clearly each country needs to evaluate local risks and benefits and a blanket recommendation for all countries for the vaccine is perhaps not appropriate.

      5 In conclusion: This study clearly shows the problems of relying on post marketing surveillance to evaluate harms. After unusual adverse events have been identified during post marketing surveillance, (if they are serious in nature) the vaccine must be withdrawn and reassessed in RCTs of sufficient size.

      6 The data from the small 2-year follow-up RCT of the Indian vaccine 116E (4500 children received the new rota virus vaccine) will help understand if the '3 week window' is adequate to identify all adverse events. This follow-up paper is awaited. The preliminary report is available http://www.ncbi.nlm.nih.gov/pubmed/24629994#cm24629994. From the initial data it appears that the incidence of IS may be higher with this vaccine and so it may be a good vaccine to study the ‘window period’ of increased risk of IS.


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    1. On 2014 Nov 14, Curtis Corum commented:

      Stephen,

      Interesting comment...

      I am not as familiar with standard imaging reporting for PC. For PC it is the various Gleeson scores that are of final interest, but structured imaging reporting is not necessarily as far along as in breast?

      In Breast the BI-RADS reporting is standard, and now includes qualitative/semi-quatnitative DCE and morphological MRI. Efforts to process emerging modalities such as quantitative DCE and DWI/ADC are still research topics... for example http://www.ncbi.nlm.nih.gov/pubmed/23504036 as far as I can tell.

      For treatment monitoring in breast (and many others icluding PC?) there are the various RECIST etc. http://www.ncbi.nlm.nih.gov/pubmed/18316345 that are continuously being updated as volumetric and other information becomes more readily available.

      will review more...


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    2. On 2014 Aug 27, Stephen Strum commented:

      My comment is limited by obviously not having read the full text of the article. What I have found in reviewing data on Multi-Parametric MRI (MPM) in PC (prostate cancer) is a lack of objective reporting, aka "structured" reporting. Therefore, I wonder if BC (breast cancer) reporting is similar.

      What is needed is consensus on reporting the important objective data e.g., for DWI, indicating the Apparent Diffusion Coefficient (ADC) and b values; for DCE, reporting Ktrans (transfer constant min-1) or signal intensity-time curves (SITCs), and of course dimensional measurements for T2WI (T2 weighted images).

      Such an attempt at a structured report would not only be of great value to clinicians for evaluating initial response to neoadjuvant therapy but also for ongoing responses to any form of treatment.


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    1. On 2014 Mar 14, Jonathan Eisen commented:

      The last author of the paper, Amy Pruden, wrote a post for the "microbiology of the Built Environment network" (microBEnet) blog about this paper. See Probiotics for Plumbing?


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    1. On 2014 Feb 20, Markus Meissner commented:

      Thank you very much for your feedback and the constructive criticism regarding our paper. We agree with some of the criticism regarding the nature of the localisation of TgStx6. Based on the co-localisation data with proM2AP, VP1 and GRASP we were initially convinced that Stx6 is localising to early endosomes, similar to the situation in ophistokonts. However, EM and IEM analysis did not result in the identification of EE but rather it appears that Stx6 is localising to the TGN as mentioned in the manuscript. However, we do not rule out that EEs exist and propose it as a hypothesis that apicomplexans have a more plant-like configuration.

      With respect to other co-localisations with Rab5 or GalNac, we had some technical problems with these assays. As described in Kremer et al., 2013 overexpression of Rab5A (and Rab5C) leads to significant defects in the secretory system and therefore colocalisation analysis of parasites (over-) expressing both markers turned out to be not reliable. However, we agree that colocalisation with GalNac on transgenic parasites expressing endogenously tagged Stx6 would add additional information and should be performed in the future.

      As you point out there is currently much confusion in the field if we can call something endosomal or endosomal-like. As one anonymous reviewer put it:” The authors are very generous in their use of the tern “endosome” in an organism where no form of endocytosis has even been seen. It might be better to define the process studied here as post-golgi membrane trafficking. “ We believe that unless one is very familiar with the terminology surrounding vesicular trafficking in Toxoplasma, the literature is very confusing. Therefore it might be the time where we have to agree on a common nomenclature based on the localisation of known markers, so that everyone has a clearer idea of the endomembrane system.


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    2. On 2014 Feb 19, Vernon B Carruthers, PhD commented:

      Our group reviewed this paper for journal club recently. The group appreciated the novelty and importance of the study in defining new players in the elaborate vesicular transport system of the parasite. The main point raised was the unclear basis for stating that the study provided no "conclusive evidence for early endosomes in the parasite" and that the parasite likely harbors a fused TGN-EE similar to plants. The study did not attempt to look for early endosomes. It is widely acknowledged that there is limited published evidence that T. gondii can internalize exogenous material into its endocytic system. Nonetheless, Rab5, which is a classic marker for early endosomes has been used in several studies to define a mid-apical compartment that is associated with other markers of endosome-like compartments. Likewise, a previously characterized marker for the TGN, UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase or GalNac for short, was not tested. Comparing the localization of TgStx6 with these markers would help clarify the issue of a merged or separate TGN-EE in T. gondii.


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    1. On 2015 Sep 04, Casey M Bergman commented:

      Orignally posted at PubPeer: https://pubpeer.com/publications/B37A9BD035CAEA3EEE79C48DDB0378

      This paper provides a nice example of natural selection operating on a new gene duplicate at the Resistance to dieldrin (Rdl) locus in in D. melanogaster. Starting with an amino acid variant that is known to confer resistence to the insecticide dieldrin, the authors query whole genome sequences in the Drosophila Genetic Reference Panel (DGRP) [1] and find four strains that contain the resistance mutation. In three of the four strains, the resistance mutation is found unexpectedly in a heterozygous condition. The DGRP strains are highly inbred but are known to contain regions of residual heterozygosity scattered throughout the genome that could arise from incomplete inbreeding or segmental duplication.

      By genotyping the offspring of "heterozygous" stocks, the authors find that 100% of progeny retain the heterozygous state, consistent with a segmental duplication. Analysis of the depth of sequence coverage in "heterozygous" strains confirms a 2-fold increase in the depth of coverage for a ~110 kb region containing Rdl and several other genes. The segmental duplication is flanked by two Roo transposable elements, suggesting it arose by ectopic recombination between repetitive sequences. The outcome of the duplication is that one duplicate contains the resitance allele and the other duplicate contains the susceptibility allele. Both copies are expressed. Transgenic analysis confirmed that the cause of the resistence allele is due to a single amino acid change in the Rdl gene only.

      This paper shows how a newly arising allele with partial dominance can achieve a state of "permanant heterozygosis" by segmental duplication, conferring immediate adaptive advantage via the new allele while also retaining ancestral function via the old allele. This result nicely confirms a theoretical model developed by Spofford (1969) [2] (not cited in the current work) to explain selective forces that would govern the fixation of a new, polymorphic segmental gene duplicate. This work also shows that the "residual heterozygosity" in the DGRP lines may be more than just background noise from the vagaries of inbreeding, and may in fact point to many other functional segmental duplications in these lines.

      [1] Mackay, Trudy FC, et al. "The Drosophila melanogaster genetic reference panel." Nature 482.7384 (2012): 173-178. http://www.nature.com/nature/journal/v482/n7384/full/nature10811.htm

      [2] Spofford, Janice B. "Heterosis and the evolution of duplications." American Naturalist (1969): 407-432. http://www.jstor.org/stable/2458991


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    1. On 2013 Oct 31, John Cannell commented:

      I congratulate the authors on a fine study. I wonder if they are aware that Mostafa et al found that an anti neural antibody found in autism had a -.86 correlation coefficient with 25(OH)D levels? If not it goes to show that scientists become experts in their own niche but apparently do not keep up with relevant science in other fields.

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

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

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

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

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

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

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

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

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

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

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

      70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day. As milk consumption has fallen, so have toddler’s vitamin D levels.

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

      Some autism researchers seem cognizant of the entire body of autism research. For example, a group of well-known European autism researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into the vitamin D deficiency theory of ASD.

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

      However, these scientists appear to be in the minority. Until all autism researchers become cognizant of the wider body of scientific research, we will continue to wonder how to prevent - and perhaps even treat - this modern day plague.

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


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    1. On 2014 Sep 26, George Ntoumenopoulos commented:

      The ability to determine the need for and deliver physiotherapy for patients managed on VV-ECMO is challenging, both from the acute respiratory and rehabilitative perspective. The cannulae type, location (e.g. femoral and/or jugular veins) and stability of delivery of VV-ECMO may impact on the clinicians opinions (physiotherapy and medical staff) about physiotherapy care. Deep sedation levels during ECMO may limit the ability the deliver physiotherapy and we need to explore this further. The use of ultra-low tidal volume delivery during mechanical ventilation for lung protective ventilation may also mask the detection of problems such as secretion retention, with standard methods such as"sawtooth" patterning on expiratory flow waveforms. We need to further investigate the role of physiotherapy (both acute respiratory and rehabilitative) in this complex patient group.


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    1. On 2014 Oct 15, Gerd Heusch commented:

      The skepticism of Dr. Berthelsen is well taken. However, contrary to his expectation, the results of our study with its primary endpoint troponin release have already been replicated, see Candilio L, 2015.


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    2. On 2014 Oct 13, Preben Berthelsen commented:

      This study was registered with ClinicalTrials (NCT01406678). According to the registration, the authors planned to include 500 patients in a randomised study of remote ischaemic preconditioning (RIP) in isoflurane anaesthetised patients. No interim statistical analyses were planned. The study was, however, stopped early after the inclusion of 162 patients in the RIP-group and 167 patients in the group where no RIP was used. (Only 121 and 137 patients could be included in a per protocol analysis).

      It is an indispensable rule not to break the randomisation code before all patients have completed the investigation. The authors have not followed this imperative. They have kept running track of the results as can be seen from the admission on page 598 of this paper “After use in some patients, however, we became aware of apparent interference of propofol with remote ischaemic preconditioning and discontinued its use in the remainder of the study”. So at least theoretically, it has been possible for the authors to analyse the data continuously and therefore stop the investigation – when a statistical difference was demonstrated – and before the stipulated number of patients had been reached.

      A re-calculation of the power of the study using the 17% difference in 72h-troponin AUCs and a SD of 200 (standardised difference 0.27) shows that there is less than a 50% chance that another study would replicate the authors’ findings. It is my opinion that the result of this investigation must be viewed with some scepticism. Preben G. Berthelsen MD. Charlottenlund, Denmark.


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    1. On 2014 May 21, Amanda Capes-Davis commented:

      INT 407 is a widely used cell line. However, many scientists are unaware that it is NOT an intestinal cell line. INT 407 is cross-contaminated by HeLa, which comes from cervical carcinoma. For a list of known cross-contaminated cell lines, see http://iclac.org/databases/cross-contaminations/.


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    1. On 2013 Oct 26, Lorene M Nelson commented:

      This article provides an excellent summary of the state of knowledge regarding the role of pesticides in the etiology of Parkinson’s disease, and nicely highlights the challenges faced by environmental epidemiologists in identifying specific pesticide chemicals that are associated with PD. I agree with Dr. Kamel that it has been difficult to make substantial progress in identifying specific pesticide chemicals that increase PD risk except in unique circumstances, such as the two recent high-quality cohort studies that she cites. Another notable example is the retrospective (case-control) study conducted in central California by Dr. Ritz (UCLA investigator) whose group has produced findings implicating workplace and ambient pesticide exposure in PD [Wang A, 2011; also cited by Dr. Kamel], well-water consumption Gatto NM, 2009, specific pesticide combinations Costello S, 2009, and gene-pesticide exposure interactions Manthripragada AD, 2010.


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    1. On 2014 Nov 17, Raphael Levy commented:

      This article belongs to the “stripy nanoparticles” series. The evidence behind the structure and special properties of these nanoparticles has been challenged by Cesbron Y, 2012. The publication in 2012 of Cesbron Y, 2012 took three years and has been followed by post-publication peer review of the various existing and new stripy articles on my blog, PubPeer, etc.

      A detailed analysis of this body of work is published today in PloS One by Stirling et al; from the abstract: “through a combination of an exhaustive re-analysis of the original data with new experimental measurements of a simple control sample comprising entirely unfunctionalised particles, we conclusively show that all of the STM evidence for striped nanoparticles published to date can instead be explained by a combination of well-known instrumental artefacts, strong observer bias, and/or improper data acquisition/analysis protocols.


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    1. On 2014 Jun 30, Karel Koberna commented:

      The method described in the article of Cappella et al. was patented by us in 2012 and at the end of the same year published in great detail in our article “Atomic Scissors: A New Method of Tracking the 5-Bromo-2′-Deoxyuridine-Labeled DNA In Situ” PLoS (7(12): e52584). This fact is not evident as the paper of Cappella et al. contains incorrect reference to our original paper. We asked editor of Cytometry A to correct this error so we believe that it will be corrected soon.


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    1. On 2013 Dec 02, Kenneth N Litwak commented:

      This study, by Ruff et al, attempted to demonstrate negative effects of excess sugar consumption on mouse survival, competitive ability, and reproduction, as a means of demonstrating the utility of Organismal Performance Assays (OPAs) in quantifying toxicities. However, there are multiple methodological issues in the article affecting its value.<br> 1. In the discussion, the authors state that the diet was “analogous to human subjects consuming a healthy diet plus the equivalent of ~3 cans of soda per day”. This statement does not correctly reflect the study diet vs. control diet, as the two diets were isocaloric. Adding 3 cans of soda to the diet would add additional calories to a diet, not replace a source of carbohydrates.<br> 2. The authors correctly noted that this experiment would have ideally maintained the different groups on their original diets for duration of the study; however, all mice were given the F/G diet once they entered the OPA enclosures at 26 weeks of age and for the next 7 – 8 months. This change in diet is a major confounding point of the entire experiment. It might be reasonably assumed that initial outcomes in the OPA enclosures would be due to different diets, but the authors do not provide any data to support this premise, for initial or long-term outcomes.<br> 3. Mouse pups were only counted every six week to determine reproductive success (Methods). The long duration between counts would likely result in an under-count of reproductive success, as cannibalism and early pup death would be difficult to determine. Further, the duration between counts was sufficient to allow multiple litters to be born to founder mice and to F1 mice.<br> 4. The confounding effects of the OPA enclosures and their locations (Supplementary Figure S3) are potentially significant. Each enclosure was immediately adjacent to others. However, some enclosures were only bounded by two enclosures, while some were bounded on three sides by other enclosures. Stress associated with territorial boundaries has been repeatedly documented in mice. Due to the small size of this study, the potential space interaction could have had significant effects on the outcomes.


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    1. On 2017 Jul 08, David Keller commented:

      Why Physicians Favored Lipitor Over Simvastatin

      In their commentary on generic drug use, Alldredge and Kayser state the following:

      "In 2011, fewer prescriptions for generic simvastatin were written than for Lipitor (atorvastatin calcium; Pfizer Inc) despite a significant cost differential and no apparent clinical differences in efficacy and safety." [1]

      That statement is an unfair criticism of physicians and conflicts with the expressed views of the Food and Drug Administration (FDA). On June 8, 2011, the FDA issued a safety warning concerning simvastatin [2] in which physicians were advised to discontinue the use of simvastatin, 80 mg (except in patients who had already been taking it safely for over 1 year).

      For patients taking amlodipine, the FDA warned against prescribing more than 20 mg of simvastatin, and for patients taking diltiazem or verapamil, the dose of simvastatin was limited to 10 mg. These safety warnings were based on reports of adverse events including serious myopathy caused by simvastatin, 80 mg, and by lower doses of simvastatin when combined with widely prescribed calcium channel blockers.

      As a result, physicians were left with a maximum safe simvastatin dose of 40 mg, which lowers low-density lipoprotein cholesterol level by approximately 40%, whereas atorvastatin, 80 mg, lowers low-density lipoprotein cholesterol level by approximately 55%.[3] The FDA has not deemed it necessary to issue similar safety restrictions on the use of atorvastatin, which may explain why physicians favored Lipitor over generic simvastatin in 2011.

      References

      1: Alldredge BK, Kayser SR. Bending the curve toward increased use of generic drugs. JAMA Intern Med. 2013;173(3):233-234. PubMed Article

      2: FDA Drug Safety Communication: new restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. www.fda.gov/Drugs/DrugSafety/ucm256581.htm. Accessed February 21, 2013.

      3: Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003;326(7404):1423. PubMed Article

      Author's note: the format of the above letter is scrambled and difficult to read, as published online at the following URL:

      https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1726968

      Due to the difficulty of getting the published version corrected, I have posted the corrected version above.


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    1. On 2014 Jan 15, Satoko Hattori commented:

      "ImageLD" and "ImageEP", image analysis application softwares used in this article, are now freely available from http://www.mouse-phenotype.org/software.html.


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    1. On 2013 Nov 14, Gareth Highnam commented:

      Awesome study, are cancerous areas changed to a uniform density across ethnicities? Or does density of cancerous areas also have an ethnic component? All factors for an optimized detection model, I suppose. [CoI - RH is my favourite published uncle :) ]


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    1. On 2013 Nov 20, Jamie Horder commented:

      It would be wrong to say that reverse coded items are rarely not unconfusing!


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    2. On 2013 Nov 17, James C Coyne commented:

      Formal Correction: This article has been formally corrected to address the following errors.

      As a result of an error by PLOS ONE, an incorrect version of the article was typeset. Below is a link to a version of the article based on the correct manuscript.
      

      http://www.plosone.org/annotation/listThread.action?root=71757


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    1. On 2013 Nov 05, Pedro Mendes commented:

      This yeast metabolic reconstruction improves on the work described in Herrgård MJ, 2008, Dobson PD, 2010, and Heavner BD, 2012. The data set is available at http://yeast.sf.net/


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    1. On 2017 Jun 10, Casey Greene commented:

      We used this method in our own preprint. Our preprint is available on bioRxiv: https://doi.org/10.1101/147645

      For the convenience of the research community, we have made our implementation available as an open source python package. It is currently maintained on GitHub (https://github.com/kathyxchen/crosstalk-correction) and distributed via PyPI (pip install crosstalk-correction). We hope that others will also find this useful.


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    1. On 2014 Jul 12, Jorge H Ramírez commented:

      The overall quality of this randomized clinical trial is poor:

      • Limited time of follow-up (12 weeks) to determine the safety and effectiveness of an active pharmacological principle or a fixed-dose combination (i.e., solifenacin plus tamsulosin).

      • The study evaluates surrogate instead of definitive outcomes.

      • No description of allocation concealment mechanisms.

      • No description of methods used to generate the random sequence used in the randomization of patients to each study arms

      • The article does not describe methods for the implementation of the random sequence.

      • No appropriate description of blindings in the study.

      • No intention-to-treat analysis

      • Cardiovascular adverse events were not appropriately described in this article.

      • Haemodynamic variables were not included as primary or secondary outcomes in this study.

      Tamsulosin is a nonuroselective alpha blocker associated with severe hypotension in men.(1,2) Moreover, over three quarters of the studies with tamsulosin in humans are unpublished.(3)

      A recent publication entitled "Solifenacin/tamsulosin FDC squeezes out competitors."(4) supports that this combination is cost-effective only based in the pharmacoeconomic analysis of this study (Neptune trial. van Kerrebroeck and colleagues. Eur Urol 2013).

      I have the following open-question for anyone reading this comment:

      What would happen with pharmacoeconomic evaluations involving solifenacin/tamsulosin in the treatment of lower urinary tract symptoms after considering the risk of severe hypotension and the results of unpublished studies?

      Finally, I personally think that the title "Solifenacin/tamsulosin FDC squeezes out competitors." resembles more a pharmaceutical marketing campaign (a misleading one) than a serious paper reporting the results of a pharmacoeconomic analysis.

      References

      1. Bird Steven T, Delaney Joseph A C, Brophy James M, Etminan Mahyar, Skeldon Sean C, Hartzema Abraham G et al. Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: risk window analyses using between and within patient methodology BMJ 2013; 347:f6320 http://www.bmj.com/content/347/bmj.f6320

      2. Ramirez Jorge. Severe hypotension associated with α blocker tamsulosin BMJ 2013; 347:f6492 http://www.bmj.com/content/347/bmj.f6492

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

      4. Nazir, J. Solifenacin/tamsulosin FDC squeezes out competitors." PharmacoEconomics & Outcomes News 706 (2014): 10-5.


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    1. On 2013 Nov 01, Gerard Ridgway commented:

      This is an updated version of Weiner MW, 2012, with additions highlighted in the PDF version. Somewhat confusingly, the abstract still refers to "results as of February 2011", but the masthead on the PDF clarifies that it was "Updated April, 18, 2013". To give a rough idea of the scale of the update, the number of cited references has increased from 225 to 349. Li Shen has been added as an author.


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    1. On 2013 Nov 19, Ilene Mizrachi commented:

      The genome assembly is available in GenBank. The assembly was recently updated to version 2, APWK02000000 and is retrievable at http://www.ncbi.nlm.nih.gov/nuccore/APWK00000000


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    2. On 2013 Nov 19, Gustavo Costa commented:

      The Genbank Acession APWK01000000 for the contigs, mentioned in the paper, is unavailable. Maybe the submitting authors should inform Genbank to release the sequences publicly.


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    1. On 2014 Dec 07, Harri Hemila commented:

      Rerksuppaphol S, 2013 reports a highly significant baseline imbalance on age

      Rerksuppaphol S, 2013 randomized 100 children to the zinc and placebo groups using blocks of two. According to their Table 1, average age was 10.0 yr (SD 0.5 yr) in the zinc group, but 11.4 yr (SD 0.8 yr) in the placebo group; the authors calculated P=0.0001 for the difference in baseline age. In their paper, Rerksuppaphol S, 2013 do not comment on their calculation of highly significant imbalance on age.

      As the most interesting finding, Rerksuppaphol S, 2013 report that coughs and runny noses were shorter in the zinc group, with P=0.01. The median “duration for cough” was 1.0 days in the zinc group, and 6.0 days in the placebo group. The total duration of the trial was 3 months and it seems obvious that many participants had more than 1 cold episode per 3 months. However, the Methods and Results do not describe whether the “duration of cough” means duration per episode or duration per person. Thus the outcomes are not well described. Given the reported baseline imbalance and the lack of transparency in the outcomes, it is difficult to trust the reporting on coughs and runny noses.

      Rerksuppaphol S, 2013 refer to the Cochrane review on zinc for the common cold by Marshall I, 2000 (ref. 19), which was withdrawn several years ago in Marshall I, 2007. Thereafter a new Cochrane review was written by Singh M, 2011 which is also cited (ref. 25), without any mention that the latter replaced the old withdrawn Cochrane review (2000), which was also cited (ie ref. 19). Such a presentation of previous literature on zinc and colds gives an impression of sloppiness.

      Rerksuppaphol S, 2013 has been cited in JAMA by Das RR, 2014. Therefore the validity of this study is a relevant issue.


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    1. On 2017 Nov 29, Liz Dooley commented:

      This Cochrane Review has been superseded. A new author team will publish a new protocol 'Vitamin C for pneumonia'. This information has been provided by the Cochrane Acute Respiratory Infections Group.


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    1. On 2014 May 14, Martine Crasnier-Mednansky commented:

      The feedback strategy established by Doucette CD, 2011 relates to data obtained under conditions of 'extreme' catabolite repression elicited by nitrogen limitation. A direct inhibitory effect of α-ketoglutarate on Enzyme I inhibits phosphorylation of the components of the phosphotransferase system (PTS), including phosphorylation of EnzymeIIAGlc which activates adenylate cyclase. Therefore, cAMP-mediated catabolite repression occurs in these conditions. Another not-yet propounded effect of an increase in α-ketoglutarate is an enhanced inducer exclusion, which further hinders uptake of carbon sources other than PTS substrates. Under nitrogen-limited conditions, β-galactosidase synthesis in a wild-type strain growing on glucose is most likely affected by inducer exclusion. Thus, nitrogen-limited growth may not 'rely completely' on cAMP-mediated gene regulation as transcriptional regulation by cAMP and inducer exclusion both interfere with β-galactosidase synthesis Crasnier-Mednansky M, 2008. By not taking into account inducer exclusion the authors undermine the power of 'quantitative physiology'. Within the same frame of thought, using pts strains grown on lactose to measure β-galactosidase activity is physiologically irrelevant.

      In sharp contrast with the present data, Daniel J, 1986 reported that α-ketoglutarate (or pyruvate indirectly by accumulation of α-ketoglutarate) caused repression of the lac operon - but not oxaloacetate. In addition repression did not occur in crr strains (lacking Enzyme IIAGlc) in support of Doucette CD, 2011.


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    1. On 2013 Oct 31, John Cannell commented:

      The authors found markers oxidative stress is present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

      Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      70% of American toddlers do not take the Ameri


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    1. On 2014 May 07, Matthias Girndt commented:

      The full title of this article in German is: "Paresthesia and muscle cramps after dialysis: can they be prevented?"


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    1. On 2016 Nov 20, Morten Oksvold commented:

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

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

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

      This article should therefore no longer be cited.


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    1. On 2013 Oct 31, John Cannell commented:

      The authors found markers oxidative stress is present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

      Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      70% of American toddlers do not take the Ameri


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    1. On 2014 Jan 03, Ian Lyons commented:

      In this paper, Park and Brannon showed that training adult subjects on an approximate, nonsymbolic arithmetic task (adding and subtracting estimates of the number of dots in various dot arrays) led to improvement on a symbolic arithmetic task (i.e., using Indo-Arabic numerals). The authors suggest this result points to a causal role for the ‘approximate number system’ (ANS) in more complex, symbolic math processing and may thus inform the development of interventions designed to improve mathematical competence in children and adults. We believe the authors’ work takes an important step forward in terms of understanding the building blocks of mathematical performance, and, using their work as a jumping board, we offer several points of reflection concerning (1) the nature of the ANS, and (2) what it means to train performance on a task versus the process it is meant to measure.

      Park and Brannon’s crucial experimental condition trained participants using approximate, nonsymbolic addition. This differs from tasks used more commonly in the literature to measure individual differences in the ANS – adaptation and comparison – which involve simply distinguishing between two approximate quantities (e.g., in comparison tasks, one typically decides which of two arrays contains more dots). The difference in tasks is significant because previous attempts to train participants on just a nonsymbolic comparison task failed to show significant improvement in individuals’ symbolic math performance [Wilson et al., 2006 (http://www.ncbi.nlm.nih.gov/pubmed/16734906); DeWind & Brannon, 2012 (http://www.ncbi.nlm.nih.gov/pubmed/22529786)]. Why, then, does training on nonsymbolic arithmetic lead to improvement in symbolic arithmetic skills, but training on nonsymbolic comparison does not, even though both have been shown to correlate with symbolic arithmetic [e.g., Gilmore et al., 2010 (http://www.ncbi.nlm.nih.gov/pubmed/20347435); Halberda et al., 2012 (http://www.ncbi.nlm.nih.gov/pubmed/22733748)]? One possible conclusion is that it is not enough simply to tap the ANS; instead, accessing the ANS must be structured in a manner that more directly parallels the target skill – symbolic arithmetic. From a broader perspective, such a conclusion suggests that it is time to take a deeper look at what exactly we mean by an ‘approximate number system’, as Park and Brannon’s results may in fact point to an important division between approximate quantity representation and manipulation within the ANS. The view that the ANS is not a unitary construct is also leant support by the fact that performance on nonsymbolic quantity comparison and nonsymbolic arithmetic tasks are uncorrelated [Gilmore et al., 2011 (http://www.ncbi.nlm.nih.gov/pubmed/21846265)].

      That nonsymbolic arithmetic (but not nonsymbolic comparison) training leads to improved symbolic arithmetic brings us to a second point: It is crucial to make a distinction between a task meant to measure or be an index of some underlying process, and the process itself. To cure a fever, one does not build a more precise thermometer; and by extension, if one demonstrated that using a more precise thermometer indeed failed to reduce one’s fever, it would be rather rash to conclude ambient bodily temperature is irrelevant to one’s health. A nonsymbolic number comparison task may act like a thermometer, where the underlying process it indexes is ANS acuity. Training on nonsymbolic comparison tasks does not improve math skills (Wilson et al., 2006; DeWind & Brannon, 2012), but this does not mean that the ANS is irrelevant for math. By training on nonsymbolic arithmetic instead of nonsymbolic comparison, Park and Brannon showed that one’s training regimen simply needs to tap the ANS in a way that better parallels the types of cognitive operations used in symbolic arithmetic.

      One sees a similar distinction between tasks that index versus train an underlying process elsewhere in the numerical domain: when a person is asked to mark the location of a number on a number line, the linearity of their estimates predicts math achievement [Booth & Siegler, 2006 (http://www.ncbi.nlm.nih.gov/pubmed/16420128), 2008 (http://www.ncbi.nlm.nih.gov/pubmed/18717904)]; but rather than train on this task per se, researchers found success using a board game that trained children to linearize their visuo-spatial representations of symbolic numbers – i.e., the underlying process that was presumably being measured by the number line task. Training on the board game improved performance on both the numberline task as well as math achievement [Siegler & Ramani, 2009 (http://psycnet.apa.org/journals/edu/101/3/545/)].

      Further, we believe that Park and Brannon’s own dataset provides yet another example illustrating the distinction between a task meant to measure or be an index of some underlying process, and the process itself. The authors show a correlation between numerical ordering ability and symbolic math ability, replicating our previous work [Lyons & Beilock, 2011 (http://www.ncbi.nlm.nih.gov/pubmed/21855058)]. Nevertheless, training on the ordering task did not lead to improvement in symbolic math beyond what was seen for vocabulary training. If one concludes from this result that understanding ordinality is irrelevant for developing math skills, one is in danger of mistaking a means of measurement for the thing being measured – much as one might have done with the dot comparison or number-line tasks discussed above.

      In conclusion, Park and Brannon’s recent paper showing a causal relation between nonsymbolic and symbolic arithmetic, represents a step toward understanding the building blocks of complex arithmetic. Perhaps missed in the excitement, though, is that this work underscores the need for researchers – especially those interested in educational applications – to carefully consider what their tasks and paradigms truly mean with respect to the processes and representations they aim to investigate. Failing to do so risks conflating the means of measurement with what is being measured, and may in turn lead to recommendations for educators to train the wrong thing.

      Signed, Ian Lyons and Sian Beilock


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    1. On 2017 Oct 10, L David Sibley commented:

      We appreciate the posting of the comment by Dr. Meissner and also the primary data provided by the Kursula group (Kumpula et al., Kumpula EP, 2017). Although we agree that there are differences in the conclusions, we feel that these stem primarily from differences in methodology and biological substrates. As such, it would be premature from this new study to make sweeping statements about the polymerization behavior “apicomplexan” actins.

      First, we note that our study used Toxoplasma gondii actin (TgACT1) Skillman KM, 2013, while Kursula group studied Plasmodium actin, PfACT1 more specifically. We agree that the two actins are somewhat similar, and so it would be surprising if they had an intrinsically different mechanism of polymerization. However, our previous studies have noted differences between these substrates and found that polymerization of PfACT1 is more efficient than that of TgACT1 as shown by light scattering and microscopy Skillman KM, 2011.

      Second, Kumpula et al., suggest that sedimentation may not be a reliable method for monitoring polymerization kinetics of apicomplexan actins due to the formation of small oliogmeric species that do not fully sediment at 100,000g or even 450,000g. We are well aware of this limitation, and indeed it is also shown in our paper by several methods Gershon D, 1990. We considered the formation of heterogenous small oligomers in the experiments we performed, including in the simulations and determination of rate constants. Importantly all of our findings show that a simple isodesmic model can fit the data for assembly and turnover. These findings further predict that if there is a cooperative component, it is exceedingly small relative to conventional actins. Moreover, our conclusion that TgACT1 polymerizes by an isodesmic mechanism was not based solely on sedimentation but was supported by light scattering assays, which demonstrate a lack of a lag period associated with a normal critical concentration (Cc) Skillman KM, 2013.

      Third, Kumpula et al., used a modified pyrene assay to monitor the “kinetics’ of filament formation. We agree that the pyrene assay is normally well suited for studying kinetics, but may not be ideal for monitoring thermodynamics associated with the intrinsic polymerization mechanism. Kumpula et al., report that at low concentrations of PfACT they detect evidence for a Cc, based on plotting the fluorescence signal vs. actin concentration. However, under these conditions where pyrene labeling was done at sub-stochiometric levels, the lack of a signal below a particular concentration may be due to lack of sensitivity, rather than an actual Cc. It would be important to determine whether such a Cc could also be detected by intrinsic tryptophan quenching, which may be more sensitive. We would also like to point out that unlike these two assays that attempt to monitor the Cc at very low concentration of protein, the estimate of Cc from sedimentation assays is based on behavior across a wide range of concentrations and thus it is more robust to small fluctuations, variability in protein levels, or assay differences.

      Finally, we note than both our study and that of Kumpula used recombinant actin produced in insect cells. Hence, the previous suggestion that apicomplexan actins cannot be functionally expressed heterologously Olshina MA, 2016 is incorrect and not the reason for the differences described in polymerization behavior. Rather, it is clear that recombinant actins produced in an appropriate manner exhibit many interesting functional properties. Further studies may reveal to what extent these features are shared vs. unique among divergent actins.


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    2. On 2017 Sep 23, Markus Meissner commented:

      A recent report from the Kursula group demonstrated that the sedimentation assays used in Skillmann et al., 2013 are unlikely to obtain reliable results for apicomplexan actins. In this study the Kursula group (see: https://www.nature.com/articles/s41598-017-11330-w) used a protocol based on pyrene labelling and demonstrated that polymerisation of apicomplexan (Plasmodium) actin is occurring in a cooperative manner, meaning it requires a critical concentration. Surprisingly, the Cc is very similar to canonical rabbit actin. Furthermore, it was shown that shorter filament lengths result from higher depolymerisation rate. In conclusion, it appears that -like all other known eukaryotic actins- apicomplexan actin polymerises in a cooperative manner, requiring a nucleation reaction (see Kumpula et al., 2017).


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    1. On 2016 Jul 06, David C. Norris commented:

      In addition to the images above, an animation cited in the article may also be of interest: http://hemonc.org/docs/CMLhistory.avi


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    1. On 2013 Nov 18, vaigundaragavendran jegadeesan commented:

      The review provides us with an in-depth overview of the multifarious mechanisms that underpin the pathophysiology of PCIBP. In particular, the pictorial representations are very informative and explain the critical steps more clearly. A nice read to concatenate PCIBP mechanisms to those underlying various other pain conditions to eventually form a string of plausible therapeutic approaches.

      Highly recommended.


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    1. On 2013 Oct 28, John Cannell commented:

      Didn't Finland start supplementing their children with vitamin D in 2003? I think increased vitamin D levels account for the reduction in type 1 diabetes in Finland.


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    1. On 2016 Apr 12, Oliver Kuss commented:

      This is a clearly written paper on proportional hazards model for interval-censored data. I especially liked the authors sharing their SAS code for the piecewise constant model with which I was able to recalculate the results for the breast cancer data set as given by Lindsey/Ryan.

      However, there are also two things that concern me a bit:

      (1) The SAS code seems to be a only slightly shortened version of the %recurr macro of Lu/Liu (2008). It would have been fair by Gong/Fang to point to this source.

      (2) The estimated hazard ratios for the breast cancer data set (table 6) do not coincide with the previous literature. For example, Lindsey/Ryan report 0.930 (0.287) as the hazard ratio from the piecewise constant model and I found the same results. However, the authors report 0.392 ...

      Lindsey JC, Ryan LM. Tutorial in biostatistics methods for interval-censored data. Stat Med. 1998 Jan 30;17(2):219-38.

      Lu L, Liu C. Analysis of Correlated Recurrent and Terminal Events Data in SAS®. www.lexjansen.com/nesug/nesug08/sa/sa16.pdf


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    1. On 2014 Nov 17, Raphael Levy commented:

      I discuss the interpretation of the energy profiles shown in this paper (fig 4C) on my blog. I compare with two other articles addressing the same problem: Li Y, 2012 and Gkeka et al. One of the author of Gkeka et al, Lev Sarkisov (Edinburgh), left a detailed and helpful comment on the blog.

      Beyond the theoretical work, detailed analysis of the stripy nanoparticle experimental evidence is published today in PloS One by Stirling et al; from the abstract: “through a combination of an exhaustive re-analysis of the original data with new experimental measurements of a simple control sample comprising entirely unfunctionalised particles, we conclusively show that all of the STM evidence for striped nanoparticles published to date can instead be explained by a combination of well-known instrumental artefacts, strong observer bias, and/or improper data acquisition/analysis protocols.


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    1. On 2013 Nov 16, M Mangan commented:

      Oh, sure, now they changed the title so nobody will understand the issue. The original title was "Environmental stress and transposon transcription in the mammalian brian."


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    2. On 2013 Oct 31, M Mangan commented:

      So does this affect only Brians? All Brians?


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    1. On 2013 Dec 09, John Cannell commented:

      The authors report that immune system dysregulation is common in autism spectrum disorder (ASD). They discuss a number of nutritional relationships to the immune system. If it is dietary, the question is why does this immune dysregulation occur and what has caused such dysregulation to skyrocket in recent decades?

      Vitamin D deficiency produces very similar immune dysregulation to what the authors reported.

      Prietl B, 2013

      Kamen DL, 2010

      Yang CY, 2013

      Baeke F, 2010

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

      Gong ZL, 2014

      Meguid NA, 2010

      Mostafa GA, 2012

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

      DeLuca GC, 2013

      Eyles DW, 2013

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

      Cannell JJ, 2010

      Cannell JJ, 2008

      70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day and few toddlers or pregnant women get any sunshine due to the sun scare. As vitamin D fortified milk consumption and sun exposure has declined, so have toddlers and pregnant women’s vitamin D levels. The dramatic increase in the incidence of ASD occurred during the same time vitamin D levels were falling in toddlers and pregnant women.

      Some autism researchers seem cognizant of the entire body of autism research. For example, a group of well-known European ASD researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into the vitamin D deficiency theory of ASD.

      Kočovská E, 2012

      As the authors point out, immune dysregulation is common in ASD. The question is why now and what is causing it?

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


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    2. On 2013 Oct 29, John Cannell commented:

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

      The vitamin D theory of autism (vitamin D deficiency is the environmental risk factor for this highly heritable disorder) is entirely consistent with the authors work, as they briefly discuss in their paper. However, vitamin D's effect on the immune system is pervasive and robust and deserves much more attention as the factor implicated in both autism and immunity.

      Schwalfenberg GK A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency.Mol Nutr Food Res. 2011 Jan;55(1):96-108. doi: 10.1002/mnfr.201000174. Epub 2010 Sep 7. Review. Schwalfenberg GK, 2011

      Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with autism. Two of the studies below (Mostafa et al and Gong et al) also found autism severity, as rated on standard autism rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with autism severity.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


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    1. On 2013 Nov 04, AARON HSUEH commented:

      This paper neglected earlier work. For example: Extrapituitary action of gonadotropin-releasing hormone: direct inhibition ovarian steroidogenesis. Hsueh AJ, Erickson GF. Science. 1979 May 25;204(4395):854-5.

      Gonadotropin-releasing hormone analogue binds to luteal cells and inhibits progesterone production. Clayton RN, Harwood JP, Catt KJ. Nature. 1979 Nov 1;282(5734):90-2.

      Extrapituitary actions of gonadotropin-releasing hormone. Hsueh AJ, Jones PB. Endocr Rev. 1981 Fall;2(4):437-61. Review.


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    1. On 2014 Jan 07, Brett Snodgrass commented:

      Dear Author,

      Thank you for the excellent report. Please provide your kind attention to the difference between the vessels of Wearn and Thebesius. Approximately fifty percent of the medical literature applies the term "Thebesian veins" to the "vessels of Wearn."

      Arteriosinusoidal vessels described by Wearn connect to myocardial sinusoids. The myocardial sinusoids are often pathologically altered and readily apparent on microscopy in pulmonary atresia with intact ventricular septum.

      Dr. Wearn's work work detailing the difference between the Thebesian veins and the vessels of Wearn (which he referred to as arterioluminal vessels). http://bit.ly/JTWearn

      The myocardial sinusoids are not phantom as they connect to the arteriosinusoidal vessels. The vessels of Wearn include the arteriosinusoidal and the arterioluminal vessels of the heart. Wearn's distinguished Harvey lecture of 1940 again reported the difference between the "Thebesian veins" and the "AL & AS" vessels (vessels of Wearn). However, this was soon obscured in the medical literature. My hypothesis is that with a lack of a pronoun such as the "vessels of Wearn," the vessels were described as Thebesian veins. Related references: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933738/ http://www.ncbi.nlm.nih.gov/pubmed/22704295 http://www.ncbi.nlm.nih.gov/pubmed/23332812 https://twitter.com/BrettSnodgrass1/status/419324443068874752

      I appreciate comments, suggestions, and constructive criticism. Please feel free to E-mail me: brettsnodgrass@hotmail.com Alternatively, you may message me through Twitter https://twitter.com/BrettSnodgrass1

      Thank you kindly.


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    1. On 2016 Aug 24, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT000004592. We believe the correct ID, which we have found by hand searching, is UMIN000004592.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2013 Oct 25, Gregory Francis commented:

      I fear the science in this study does not back up the conclusions. An important part of the scientific process is to check whether the statistical data are consistent with the hypothesized theory. One way to do this is to compute the statistical power of the experiments. This analysis supposes that an experiment accurately measured the reported effect and then computes the probability that a randomly selected sample of data would satisfy the statistical criteria used to justify the scientific claims. For this study, these estimated probabilities are 0.56, 0.52, 0.48, and 0.57. That the values are close to one-half reflects the fact that the data were typically just to one side of the statistical criterion for finding an effect. Due to natural variation, data from some samples should fall on the other side of the criterion.

      The power analysis suggests that, at best, the odds of showing the effect for each experiment is almost the equivalent of a coin flip. As such, the repeated success of the reported experiments is rather unbelievable (multiplying the power values gives 0.08). Scientists should doubt the veracity of the reported experiments; they are too good to be true.

      A Excel file that computes the effect sizes used in the power analysis can be found at http://www1.psych.purdue.edu/~gfrancis/Publications/VohReddenRahinel2013.xls


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    1. On 2013 Nov 18, Gary Ward commented:

      This paper describes a clever high-throughput assay to identify small molecules that disrupt the interaction of Plasmodium falciparum AMA1 and RON2, and can thereby block merozoite invasion of erythrocytes. The data provide promising proof-of-concept for the development of novel antimalarials that disrupt protein-protein interactions critical for invasion. This particular interaction is thought to happen extracellularly, within the blood, which could facilitate access of such drugs to their targets.

      The three inhibitors described have IC50 values in the 20-30 uM range. The authors state that "small-molecule inhibitors will result in reduced or no emission signal depending on the strength of the inhibition". Our group was interested to know what the dynamic range of the AlphaScreen assay is and whether it can capture binding at both ends of the affinity spectrum (subnanomolar to millimolar).

      A 1000-fold molar excess of inhibitor was required to disrupt RON2L-AMA1 interaction in the screen, perhaps because the compound is added after RON2L-AMA1 complex formation and must essentially displace the RON2L from AMA1. The assay may have been done this way purposely, to recapitulate what happens in the blood, i.e., secreted RON2 is probably not exposed on the surface of the red cell for long before it is bound by AMA1. It would nonetheless be interesting to know what happens to the IC50 if compound is added to AMA1 before the addition of RON2L.

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


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    1. On date unavailable, commented:

      None


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    2. On 2014 Mar 22, Andrew R Kniss commented:

      There are now two published criticisms of this work in New Phytologist, the journal that originally published the article.


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    3. On 2013 Oct 23, Andrew R Kniss commented:

      This is a very interesting paper, and it recieved wide media coverage after publication. There are some rather large oversights/deficiencies that should be noted. I have posted a rather long critique of this paper at my blog. There are several problems with the paper, all of which are described in detail at the link. In a nutshell:

      • The breeding methods used did not ensure enough genetic uniformity between GE and non-GE hybrids to attribute differences to the transgene as they claim.
      • The authors provided very little information about the the original transformation event, and how the transformed line differed from its parent line (even after presenting data suggesting the lines had different phenotypes).
      • The authors do not adequately discuss other possibilities that may explain their results, particularly with respect to the promoter they used and the impact of closely linked genes.
      • Closely related traits (tiller production, panicle production, seed production) are presented as independent evidence of an increase in fitness.
      • None of the experiments presented in this study were repeated.


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    1. On 2013 Aug 10, Allison Stelling commented:

      I find it a bit odd that the authors call for a national discussion on a very important topic in a journal that has put their words behind a paywall.

      Biomedical science has a huge public impact, and the public needs to be aware how little we know about how to diagnose many diseases; let alone our lack of information on "cures". They are footing the majority of the bill and have a fundamental right to have the science explained to them. This is not a discussion that the researchers and "qualified experts" can keep within their own limited community; nor is it a one way lecture where interaction with the public is unidirectional. It's a conversation that needs to happen between medical doctors, the public taxpayers, and the scientific researchers.


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    1. On 2016 Aug 23, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the body of the text of the article. The ID given is NCT0005937. We believe the correct ID, which we have found by hand searching, is NCT00059371.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2014 Sep 21, Annie De Groot MD commented:

      I wonder if pathogens use this pathway to escape immune response? See our article at http://bit.ly/NTD_iVAX_2014


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    1. On 2014 Jan 31, Huiqi Qu commented:

      This method is helpful to understand functional effects of some genetic variants.


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    1. On 2014 Apr 21, Morgan Price commented:

      The annotation of DpigGOR10741-DpigGOR10744, which are important for hydrogen utilization and for growth in vivo by Desulfovibrio piger, as "hmc" is a bit misleading. This gene cluster is very similar to nhc (nine-heme cytochrome complex) of D. desulfuricans 27774 (Saraiva LM, 2001). While Hmc has subunits hmcABCDEF including a 16-heme periplasmic subunit (hmcA), nhc lacks the hmcE and hmcF genes, and the hmcA-like subunit is shorter and has nine hemes. Similarly, D. piger lacks hmcEF and has a shorter periplasmic subunit that is very similar to the nine-heme cytochrome (tree browser view).


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    1. On date unavailable, commented:

      None


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    2. On 2017 Apr 23, Barbara L Fredrickson commented:

      The following links provide the authors' responses:


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    3. On 2017 Apr 11, Nicholas J L Brown commented:

      The following articles comment directly on this article:

      Brown et al., 2014: https://www.ncbi.nlm.nih.gov/pubmed/25157145 Walker, 2016: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068350/ Nickerson, 2017: http://www.collabra.org/article/10.1525/collabra.81/


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    1. On 2014 Dec 05, Gaetano Santulli commented:

      Jiang and colleagues report that beta2-adrenergic receptor (B2AR) knockout (KO) mice exhibit a diabetic retinopathy phenotype. We recently demonstrated that B2AR KO mice display a progressive impairment in insulin release that leads to glucose intolerance (1). Our report, which seems to be mechanistically important in the pathophysiology of diabetic rethinopathy (if an animal is glucose intolerant a diabetic retinophaty phenotype appears to be more than obvious) is completely ignored by the Authors. A functional role for B2AR in the regulation of insulin secretion and thereby in the pathogenesis of diabetes had been suggested by the evidence of a decreased number of B2AR in type I diabetes patients (2, 3). Findings from other groups support such a mechanism (4-7). In addition, human polymorphisms in the B2AR gene have been associated with obesity and other metabolic disorders (8, 9). Moreover, the Authors state that B2AR KO mice exhibit attributes of retinal changes common in diabetes, despite normal glucose levels. However, they do not provide any experiment to show glucose (or insulin) levels, nor in basal conditions, nor after a challenge, nor during a clamp assay. Similarly, the Authors also state that in their previous studies they have shown that B1AR KO mice exhibit retinal changes similar to diabetic animals in spite of normal glucose levels, quoting a paper in which there is no experiment showing the claimed normal glucose levels, as well.

      We believe that the Readers will appreciate a clarification on these studies by the Authors and the Editors.

      Gaetano Santulli MD, PhD 1,2, and Guido Iaccarino MD, PhD 3,4

      From the Departments of 1Translational Medical Sciences and 2Advanced Biomedical Sciences, Federico II University, Naples Italy; 3Department of Medicine and Surgery, University of Salerno, Salerno, Italy; 4Multimedica Research Hospital, Milan, Italy.

      Essential References 1. Santulli G, Lombardi A, Sorriento D, Anastasio A, Del Giudice C, Formisano P, et al. Age-related impairment in insulin release: the essential role of beta(2)-adrenergic receptor. Diabetes. 2012;61(3):692-701. doi: 10.2337/db11-1027. PubMed PMID: 22315324; PubMed Central PMCID: PMC3282797; http://www.ncbi.nlm.nih.gov/pubmed/22315324

      1. Schwab KO, Bartels H, Martin C, Leichtenschlag EM. Decreased beta 2-adrenoceptor density and decreased isoproterenol induced c-AMP increase in juvenile type I diabetes mellitus: an additional cause of severe hypoglycaemia in childhood diabetes? European journal of pediatrics. 1993;152(10):797-801. http://www.ncbi.nlm.nih.gov/pubmed/8223779. PubMed PMID: 8223779; http://www.ncbi.nlm.nih.gov/pubmed/8223779.
      2. Noji T, Tashiro M, Yagi H, Nagashima K, Suzuki S, Kuroume T. Adaptive regulation of beta-adrenergic receptors in children with insulin dependent diabetes mellitus. Hormone and metabolic research. 1986;18(9):604-6. Epub 1986/09/01. doi: 10.1055/s-2007-1012385. PubMed PMID: 3023224; http://www.ncbi.nlm.nih.gov/pubmed/3023224.
      3. Panagiotidis G, Stenstrom A, Lundquist I. Influence of beta 2-adrenoceptor stimulation and glucose on islet monoamine oxidase activity and insulin secretory response in the mouse. Pancreas. 1993;8(3):368-74. Epub 1993/05/01. http://www.ncbi.nlm.nih.gov/pubmed/8387193. PubMed PMID: 8387193; http://www.ncbi.nlm.nih.gov/pubmed/8387193.
      4. Loubatieres A, Mariani MM, Sorel G, Savi L. The action of beta-adrenergic blocking and stimulating agents on insulin secretion. Characterization of the type of beta receptor. Diabetologia. 1971;7(3):127-32. http://www.ncbi.nlm.nih.gov/pubmed/4397807. PubMed PMID: 4397807; http://www.ncbi.nlm.nih.gov/pubmed/4397807.
      5. Ahren B, Jarhult J, Lundquist I. Insulin secretion induced by glucose and by stimulation of beta 2 -adrenoceptors in the rat. Different sensitivity to somatostatin. Acta physiologica Scandinavica. 1981;112(4):421-6. http://www.ncbi.nlm.nih.gov/pubmed/6119001. PubMed PMID: 6119001; http://www.ncbi.nlm.nih.gov/pubmed/6119001.
      6. Asensio C, Jimenez M, Kuhne F, Rohner-Jeanrenaud F, Muzzin P. The lack of beta-adrenoceptors results in enhanced insulin sensitivity in mice exhibiting increased adiposity and glucose intolerance. Diabetes. 2005;54(12):3490-5. Epub 2005/11/25. doi: 54/12/3490 [pii]. PubMed PMID: 16306366; http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16306366.
      7. Large V, Hellstrom L, Reynisdottir S, Lonnqvist F, Eriksson P, Lannfelt L, et al. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. The Journal of clinical investigation. 1997;100(12):3005-13. Epub 1998/01/31. doi: 10.1172/JCI119854. PubMed PMID: 9399946; PubMed Central PMCID: PMC508512; http://www.ncbi.nlm.nih.gov/pubmed/9399946.
      8. Thomsen M, Dahl M, Tybjaerg-Hansen A, Nordestgaard BG. beta2-adrenergic receptor Thr164Ile polymorphism, obesity, and diabetes: comparison with FTO, MC4R, and TMEM18 polymorphisms in more than 64,000 individuals. The Journal of clinical endocrinology and metabolism. 2012;97(6):E1074-9. doi: 10.1210/jc.2011-3282. PubMed PMID: 22466342; http://www.ncbi.nlm.nih.gov/pubmed/22466342


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    1. On 2014 Sep 24, Michael Schroda commented:

      Excellent study, a big step forward toward the understanding of Hsp70 function in chloroplasts.


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    1. On 2017 Oct 31, Morten Oksvold commented:

      Please note that this article contains unreliable data, and should not be cited. The central ethical review board in Sweden found research misconduct in six articles by Macchiarini, including this one.

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

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


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    1. On 2013 Oct 31, John Cannell commented:

      The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

      Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      70% of American toddlers do not take


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    1. On 2014 Jan 29, Amanda Capes-Davis commented:

      Please be aware that KB is NOT an oral epithelial cell line. The cell line is known to be cross-contaminated with HeLa and so comes from cervical carcinoma. For a list of known cross-contaminated or misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.


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    1. On 2016 Nov 15, Yuwei Fan commented:

      Thermocycled for only 500 cycles seems to be insufficient to test aging effects.


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    1. On 2017 Jan 13, Yuwei Fan commented:

      The description of CIELab a* and b* range in page 215 is incorrect. The range is ±100 or −128 to +127 (signed 8-bit integer). [https://en.wikipedia.org/wiki/Lab_color_space]. Delta-E equation in same page is wrong (or maybe a typo) apparently.


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    1. On 2017 Jan 11, Misha Koksharov commented:

      It would be cool to also have data on evolution of decapod luciferases (Oplophorus, Systellaspis, etc). Unfortunately, only one is known so far. :( Although, there are plenty of them out there in the sea: http://dx.doi.org/10.1007/BF00347123 http://dx.doi.org/10.1016/j.ympev.2014.11.013


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    1. On 2013 Dec 16, Tarek Tawfik Amin commented:

      This paper addresses a common problem in the developing countries, similar initiatives should be carried in other countries to make use of the available epidemiological data for the sake of comparison and trend exploration. i think the authors have used multiple data sources which strengthen their findings. best wishes and lots of respects.


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    2. On 2013 Dec 14, Mohsen Rostami commented:

      I just read this paper and found it interesting! I think it will be highly cited by those who work in the related field! Reagrds


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    1. On 2013 Aug 08, Winston Timp commented:

      Interesting paper highlighting a pathway which could grant predisposition to allergy. Perhaps more subtle effects on TGF-B signaling pathway (than mutation, e.g. epigenetic change) could lead to allergy in genotypically normal individuals.


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    1. On 2014 Mar 14, Jonathan Eisen commented:

      The first author of this paper, Rachel Adams, wrote a post about the "story behind the paper" for the "microbiology of the Built Environment network" (microBEnet) blog. See How biomass can bias high-throughput surveys of microbial communities


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    1. On 2016 May 04, Lydia Maniatis commented:

      The purpose of the issue of Visual Neuroscience in which this article appeared was to honor the achievements of Davida Teller and also to revisit her critical analysis of the casual use of 'linking propositions.' From the volume intro: “Davida provided critical thinking about criteria for, and approaches to, drawing inferences linking psychophysical phenomena and perception with underlying neural mechanisms (Teller, 1980, 1984; Teller and Pugh, 1983)....It is surprisingly routine today to see claims being made regarding the neural underpinnings of sensory and cognitive phenomena without articulation or even acknowledgment of implicit linking assumptions. With this special issue, Linking Hypotheses in Visual Neuroscience, we seek to...revisit this central challenge in visual neuroscience....”

      Unfortunately, Maertens & Shapely's (2013) never make explicit their implicit linking propositions “Linking appearance to neural activity....” When analyzed, these assumptions contain all of the serious problems, including lack of face validity, flagged by Teller (1984). Additional problems include the vagueness of their use of the term “naturalistic,” which is oddly combined with the narrow tailoring of their conclusions to the specific and highly artificial stimuli employed in this study.

      Below, I discuss the claims and offer critiques of Maertens & Shapley (2013):

      Maertens & Shapely (2013): “The dependence of lightness perception on adjacent and nearby checks could be interpreted as a support for the idea that the neural computations of lightness are strongly influenced by local computations in the primary visual cortex, V1. Several previous studies have shown that responses to visual patterns in V1 resemble lightness perception qualitatively and quantitatively (Kinoshita & Komatsu, 2001; MacEvoy & Paradiso, 2001; Haynes et al., 2004; Paradiso et al., 2006).”

      My response: The idea that a particular stimulus situation (“in the contexts we used...with the checkerboard displays”) specifically activates a particular [and fairly peripheral – see below] set of neurons which are then held to be directly responsible for the percept is untenable. How does the visual system decide, a priori, that this or that stimulus will be processed only by these particular neural populations, up to the point of consciousness, and what happens (with respect to perception) to that part of the process when it is supplemented by others? Here is what Teller (1984) had to say about this type of supposition:

      First, she refers to the notion that “if psychophysical and physiological data can be manipulated in such a way that they can be plotted on meaningfully similar axes, such that the two graphs have similar shapes, then that physiological phenomenon is a major causal factor in producing that psychophysical phenomenon.” One of the problems with such a linking proposition, accordint to Teller, is “its peripherality: it states a causal or explanatory relationship between the activity of single cells at a peripheral level of the nervous system and a perceptual or behavioral phenomenon, without any accompanying proposal as to how this pattern maintains itself through the system. The proposition includes an implicit appeal to the “nothing mucks it up” proviso (Teller, 1980)....In the absence of any explicit treatment of these problems, [such proposals] would seem to amount to nothing more than a remote homunculus theory: the...stimulus sets up the pattern of activity...that “looks like” [the stimulus] and the homunculus peers down [at it].” Area 17, or V1, is referred to by Teller (1984) as a “relatively peripheral stage of neural processing. In that case, if the properties of Area 17 cells are to be used to explain the elements of our perceptions, a “nothing mucks it up” theory is needed to bridge the gap between the Area 17 cell and the still more central sites...”

      Maertens and Shapely (2013) double down on this unviable notion: “Such an interpretation of our data does not preclude that there are significant influences of neural computations beyond V1. There are many phenomena of lightness perception that probably require an explanation in terms of longer distance interactions and higher-order interactions (reviewed in Gilchrist, 2006; Kingdom, 2011). However, in the contexts we used in our experiments, and with the checkerboard displays used (Fig. 1), the nearest-neighbor and next-nearest-neighbor interactions were sufficient to account for most [not all] of the lightness variation (Tables 2 and 3).”

      I would add that, given that a small local change in a part of the visual field can alter the structure – including lightness effects – in the entire field, the idea that some stimuli activate only peripheral systems and local interactions and others more global ones is, if possible, even less plausible.

      Even in the context of their experiments, the authors walk back their claims about the influence of local contrast, and, again, suggest that different neural populations underlie the perception of different stimuli:

      “The data on lightness matches for the transparent condition suggest that more complicated neural computations were employed by the observers when they judged lightness through transparency.” First, I would note that there was no physical transparency in the stimuli – they were all computer generated on a single screen. Second, one must ask, again, at what stage, and why, does the visual system decide to shunt one computer-generated black and white stimulus to be addressed by one peripheral neural process, leading directly to the analogous percept, and another to a different, “more complicated” neural process? Are the activities of V1 supposed to be lost or ignored or altered in some cases, prioritized for conscious consumption in others, and conversely, the effects of higher-level populations shut down, altered, in some and not in others? The decision as to what process to prioritize for what stimulus would necessarily seem to be a high-level decision, because the low-level would not have the “authority” to decide not to send the issue upstairs.

      In the end, the authors do nothing but go to a lot of trouble quantify well-known effects in the context of very specific stimuli, from which they draw conclusions that are purely ad hoc, strictly limited to these stimuli, and then construct an ad hoc and casual neural account lacking face validity. They furthermore fail to acknowledge the well-known effects of structure on lightness; by using checkerboards they avoid even basic figure-ground effects. This is a methodological choice which should have been explained and its consequences for drawing conclusions discussed.

      The artificiality and of the stimuli makes it even more difficult to understand what the authors mean to imply by the term “naturalistic.” The assertion that stimuli contain a wide range of luminances obviously isn't enough. As mentioned above, the claim that they are in a position to make a generalization about “naturalistic” stimuli in general also conflicts with limiting of their claims to ““in the contexts we used...with the checkerboard displays...”


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    1. On 2014 Mar 06, David Keller commented:

      An osteoporosis patient may express excessive anxiety about the risks of jaw osteonecrosis and atypical brittleness fractures ("porcelain bones"), rare harmful side-effects of prolonged bisphosphonate therapy, even though the patient may not yet be at risk. I agree that performing a DEXA scan every 2 to 3 years is probably excessive for medication-compliant patients with moderate risk of osteoporotic fracture, for whom such frequent scans are unlikely to result in a change in treatment. However, these scans can motivate a "change of treatment" if the patient has been surreptitiously skipping her bisphosphonate pills due to publicity about their potential side-effects, and she learns from her DEXA scan that her BMD has decreased as a result, placing her at even higher risk for a typical osteoporotic fracture.

      To facilitate discussion, I respectfully request the person who found this comment "not helpful" to state their reason


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    1. On 2017 Mar 15, Michelle Fiander commented:

      Reproducibility and transparent reporting are among the hallmarks of a methodologically sound systematic review. One aspect of reproducibility and sound reporting (per PRISMA) is the presentation of at least one database search strategy. In this review, one strategy (for OVID Medline) is reported and the authors say the strategy was written by an "expert librarian" whose initials are provided--but who is not an author on the review. I mention this because the strategy looks more like a work in progress than an "expert" or finished product.

      There are quite a few problems with the Medline search strategy in terms of its logic, search terms, syntax and organization, and the outcome is that the strategy does not identify 19 of the 31 included studies. There are a number of reasons for this, the main one of which is the absence of a reasonable set of synonyms for the concept of 'electronic syndromic surveillance. It is always difficult to develop search strategies for concepts not represented by consistent keywords or controlled vocabulary (such as MeSH), but the goal of an expert searcher is to tease out the concept after becoming familiar with the subject matter by examining and reading few relevant discussions/studies and or checking definitions. This does not appear to have happened for this review,and it begs the question as to how the evidence base for this review was assembled, and if it was objective or biased.


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    1. On 2014 Feb 07, Paul Brookes commented:

      A correction was recently issued for this paper... http://www.plosbiology.org/annotation/listThread.action?root=78137

      The correction is a good start, but is deficient on several levels. I have outlined these in detail at a blog post on my lab' website (http://www.psblab.org/?p=268), but here's the short version...

      1) The splicing issue raised WRT Figure 4A has not been addressed at all. 2) The phrase "inadvertently used the wrong blots" is inadequate, since in some cases it was not re-use of blots that was problematic, it was apparent re-use of single bands within blots. How exactly does one use the wrong band in a blot? 3) The correction images provided are askew - they appear to have been scanned in from paper copies and misaligned slightly during this process. There could be any number of reasons why files were not provided in a more direct manner (i.e. straight from the software they were generated in, without inserting a print-scan step). Regardless, the provision of apparent paper scans does nothing to enhance my confidence in these data. 4) The correction contains zero explanation for why it took 7 months to achieve.

      I look forward to hearing from either the authors or the journal, about these remaining unresolved issues.


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    2. On 2013 Oct 22, Paul Brookes commented:

      FYI, the follow up on this...

      It has been known about on PubPeer for some time, as well as tweeted to the NYT author who wrote an article all about [http://well.blogs.nytimes.com/2013/07/17/exercise-in-a-pill-the-search-continues/]("Exercise in a Pill"), and blogged about on In the Pipeline.

      The journal knows this, and was emailed several times over the past 3 months, with minimal responses ("we're still investigating" etc.) My most recent emails last week (13 weeks since the original comment was removed) have been left unanswered. This raises the question as to exactly how one goes about dealing with a paper that contains problematic data? These internal journal commenting systems and blogs and other publicity don't appear to have a very rapid impact on correcting the literature, so let's hope maybe PubMed Commons will be a bit faster?

      Also, I apologize for a stupid mistake made very early on in using this PubMed Commons system - in between logging in via eRA commons and pasting my original comment across from PubPeer, I screwed up and tagged the wrong paper (albeit one with an almost identical title), then I got flustered when the comment was removed, when in fact it was just PubMedCommons staff doing their job! Put it down to a combination of me being stupid and caffeine deprived. Anyway, now the comment is in its right place, thanks to an eagle-eyed editor!


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    3. On 2013 Oct 22, Paul Brookes commented:

      The following comment was left on the PLoS Biology site on July 18th, and promptly removed.

      Fig. 1A, LCAD panel, lanes 2-4, appear identical to Fig. 1B LCAD panel lanes 1-3. Slightly rotated and with different exposure. This is despite these samples allegedly originating from different experimental treatments. Lots of shared features including the shapes and relative orientations of the bands, and the "kink" in the right most band, the relative shapes and orientations of the bands, and the "streak" emitting from the top right corner of the 3rd band.

      Fig. 1A, PGC-1a panel (top one) appears identical to the PGC1a panel in Fig. 1B. They are simply different exposures of the same image, despite allegedly originating from different experimental treatments. Lots of shared features including the white spot in the lower part of the right-most band. The same appears true for the "SUO" blot (3rd from the top) - some "noise" spots added in panel A, but there's no doubt these are the same bands.

      Fig. 4A (and elsewhere), some blots are used as loading controls for other blots, but cannot possibly have originated from the same gels, because some panels are spliced (as indicated by lines), and others are not. Sometimes it is permissible to run your samples on separate gels at the same time, in the exact same order, and then do the phospho vs. total blots separately and re-unite the data at the end. Here we are asked to believe the gels were run separately and with the samples in different order, then some of the blots were spliced (presumably to remove unwanted samples) but the others were not. This is not adherent to the usual standards of data presentation for this type of experiment.

      Fig. 6B. The CYTO C panel appears to be simply a darker exposure of the one above it (COX IV). Lots of shared features, most notably the bubble above the right lane.

      Fig. 3A, compare the band in the right lane of the cyto C panel (2nd blot from the top), with the band in the right lane of the CYTO C blot in Figure 4C. They are both of a shape that is too similar to be coincidental.

      There are numerous other problems here.... the entire paper contains 85 (!!!) panels of western blotting data, every single one of which is "letter-boxed" to show only the band of interest, and none of which are annotated with molecular weight markers. In addition, despite the common origin of most of the samples, there is variability in the properties of the bands. For example in Fig. 4A, the phospho-ACC blot has 2 bands but the total ACC blot only has one band. Why? In Fig. 5B the ATPase blot has 3 bands, but only a single band in Fig. 3B. In several other cases, enhancing the contrast of the western blots reveals that adjacent bands have completely different color histograms - some are grayscale while others are color. As such, it is difficult to believe that these bands originated from the same scanned blot images (which is a prerequisite for being able to splice together blots).

      Note... these are NOT allegations of any type of misconduct. I'm just pointing out what appears to be a very sloppy attitude toward data presentation, which seems to have resulted in a number of the "wrong" western blot images ending up in the published paper. Hey, with 85 almost identical looking images to keep track of, there were bound to be a few that slipped through the net! I'm sure these can easily be attributed to mistakes during electronic figure preparation, and corrected in a manner that in no way affects the conclusions of the paper.


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    1. On 2015 Jan 01, Alexander Minella commented:

      Figure 7A, upper panel, in the Pubmed Central version of this paper contains a formatting error that depicts inverted GATA-1 occupancy results for control and experimental states. The publisher’s PDF version displays the transcription factor occupancy data correctly.


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    1. On 2015 Dec 18, Ahmed Adeel commented:

      The figures for the therapeutic efficacy of AS/SP in this article need to be clarified. The ABSTRACT says: "PCR corrected per-protocol efficacy was 93.7%." Then in the DISCUSSION it is 90.5%:Page5 column2, they say “In the present study the in vivo per-protocol PCR corrected efficacy of AS/SP over 28 days is 90.5%.” The paper does not show how the figure of 90.5% was calculated.

      Do they mean 90.5% rather than 93.7% .They make reference to a previous study in which they reported the figure of 93% for cure rate with AS/SP in a 2004-2005 study .They say (in 2013 paper ) (page 5,column 2 line8):

      “..while we have reported a base-line PCR corrected efficacy of 93% [57]. "

      According to its title the paper is about "declining artesunate/sulphadoxine-pyrimethamine efficacy...". However, the figure of “90.5 %" is more in line with a decline than "93.7%", because 93.7% is not declining from 93 %. Moreover, in this paper they say: “Approximately 10% of patients exhibited recrudescing parasites as confirmed by msp1 and msp2 genotyping during the study.” Approximately 10% is closer to 90.5% than 93.7%.


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    1. On 2013 Nov 09, Claudiu Bandea commented:

      What is a virus?

      With 1 µm in length and 0.5 µm in diameter, and a genome coding for more than 2500 putative proteins, the intriguing parasites isolated in Acanthamoeba cultures by Philippe et al. (1) dwarf numerous cellular microorganisms, including many eukaryotic microbes. To confirm microscopic observations that these parasitic organisms, labeled Pandoraviruses, are indeed viruses, Philippe et al., used negative defining criteria based on absence of components for three “basic cellular functions”: (i) production of adenosine 5’-triphosphate, (ii) binary fission, and (iii) translational machinery.

      However, many cellular microorganisms lack the components for production of adenosine 5’-triphosphate (2, 3), and some, such as yeast (4), produce multiple internal spores by de novo assembly of cellular membranes, rather than by binary fission. Moreover, some cellular microorganisms (2) don’t encode a full set of translational components, and many viruses produce translational components (e. g. tRNAs, amino acid-tRNA ligases, eIF4E translation initiation factor). Therefore, the negative criteria used by Philippe et al. for defining viruses, which were also emphasized in the accompanying article (5) and in ‘About the Cover’ (Science, 19 July 2013), do not differentiate between viruses and cellular microorganisms.

      Are Pandoraviruses viruses? Addressing this question might require a fundamental re-evaluation of the conventional view about the nature of viruses (6-9), not only in light of the vast amounts of data and knowledge about their composition, life cycle and evolution, but also in context of the expanding data and knowledge about the diversity of cellular microorganisms (2,3). One of the fundamental features that differentiate viruses from parasitic or symbiotic cellular organisms is that, during their intracellular development, viruses have their genome and other specific components more or less ‘free’ or dispersed within the host cell, whereas intracellular bacterial, archaeal and eukaryotic microorganisms maintain a cellular membrane and cellular organization throughout their life cycle.

      This view on the fundamental nature of viruses is consistent with a radical evolutionary model proposing that viral lineages originated from parasitic cellular species that started their intracellular development by fusing with their host cell (6, 8). By discarding their cellular membrane within their particular environment, the host cell, these novel parasites increased their access to host’s resources, including the translation machinery. Nevertheless, after synthesizing their specific molecules and replicating their genome using the resources found in their intracellular environment, the parasites produced spore-like transmissible forms, which started a new life cycle by fusing with other host cells.

      Although the life cycle of many extant viruses, including Poxviruses and Mimivirus, fully support the fusion model on the origin of viral lineages (8), Pandoraviruses represent overwhelming evidence. There is also strong evidence, including the absence of ribosomes, that some previously isolated parasitic microorganisms, such as KC5/2 (10) and KLaHel endocytobionts (11), are complex viral organisms. However, as previously discussed (8), there are many other complex parasitic species that are genuine viral organisms although they still produce ribosomes or ribosomal remnants.

      The absence of a cellular membrane within the host cell has presented the viral lineages with unique evolutionary opportunities, not readily available for their relatives that maintained a cellular membrane during their intracellular development. However, similar to all intracellular parasitic or symbiotic cellular species, which have been evolving towards a smaller genome (2, 3), the viral lineages have diversified by reductive evolution into a myriad of viruses with smaller genome and diverse life cycles (6, 8). One of the most remarkable implications of the fusion model is that numerous cellular species have evolved into viral lineages throughout the history of life and that this process is still active.

      This radical evolutionary theory on the nature and origin of viral lineages also addresses one of the most persisting and intriguing issue in biology, an issue that has puzzled scientists and philosophers for more than a century: are viruses alive? If viral lineages originated from cellular microorganisms as proposed in the fusion model, then, there are few remaining arguments against their living status and their rightful place on the Tree of Life (8).

      References

      (1) Philippe N. et al., Pandoraviruses: amoeba viruses with genomes up to 2.5 Mb reaching that of parasitic eukaryotes. Science 341, 281, (2013). Philippe N, 2013

      (2) Keeling PJ, Corradi N. Shrink it or lose it: balancing loss of function with shrinking genomes in the microsporidia. Virulence 2, 67, (2011). Keeling PJ, 2011

      (3) McCutcheon JP, Moran NA. Extreme genome reduction in symbiotic bacteria. Nature reviews. Microbiology 10, 13, (2011). McCutcheon JP, 2011

      (4) Neiman AM. Sporulation in the budding yeast Saccharomyces cerevisiae. Genetics 189, 737, (2011). Neiman AM, 2011

      (5) Pennisi E. Microbiology. Ever-bigger viruses shake tree of life. Science 341, 226, (2013). Pennisi E, 2013

      (6) Bandea CI. A new theory on the origin and the nature of viruses. Journal of Theoretical Biology 105, 591, (1983). Bândea CI, 1983

      (7) Claverie JM. Viruses take center stage in cellular evolution. Genome Biol. 7, 110, (2006). Claverie JM, 2006

      (8) Bandea CI. The origin and evolution of viruses as molecular organisms. Nature Precedings: http://precedings.nature.com/documents/3886/version/1; (2009).

      (9) Forterre P. Giant viruses: conflicts in revisiting the virus concept. Intervirology 53, 362, (2010). Forterre P, 2010

      (10) Hoffmann R, Michel R, Müller KD, Schmid EN. Archaea-like endocytobiotic organisms isolated from Acanthamoeba sp. (Gr II). Endocytobiosis & Cell Res.12, 185, (1998). http://zs.thulb.uni-jena.de/servlets/MCRFileNodeServlet/jportal_derivate_00100794/ECR_12_1997_185-188_Hoffmann.pdf

      (11) Scheid P, Zoller L, Pressmar S, Richard G, Michel R. An extraordinary endocytobiont in Acanthamoeba sp. isolated from a patient with keratitis. Parasitol. Res.102, 945, (2008). Scheid P, 2008


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    1. On 2014 Nov 25, Hongkui Deng commented:

      We are wondering how you decided to search for an Oct4 substitute using the SKM viruses instead of initially screening using the small molecule cocktail that you would ultimately use the substitute with? Or did you do this and just not report this in the paper?

      [reply] When we started to screen for Oct4 replacers, we didn’t know at that time which small molecules would ultimately be used in chemical reprogramming.

      Can you provide an explanation for how come GFP controlled by the Oct4 promoter was expressed but Oct4 protein was not expressed (or at least visualized) after VC6TF induction? (see Figure S3)

      [reply] In our experiments, we used pOct4-GFP (GOF18) transgenic mice, but not endogenous knockin reporter mice. It is possible that the transgenic reporter may not accurately indicate the endogenous expression of Oct4, which was also reported in other studies (Cell. 2010 143:617-27; Cell Stem Cell. 2008; 3:603).

      We would like to know how come you used two the different DOX inducible systems described in the methods section for the screen of late reprogramming molecules? Did you use a second system to replicate the results or were they used on separate molecules for screening? Were the results reported in Figure S4 derived from data using both systems?

      [reply] In the initial screen, we used a viral transduction system to introduce the DOX-inducible expression of Oct4 (Maherali et al., Cell Stem Cell, 2008) in OG-MEFs. To make the Oct4 expression level stable from batch to batch, we then used the transgenic mice with inducible Oct4 expression (Hochedlingeret al., Cell, 2005). These two Oct4-inducible systems were used to screen different small molecule libraries.

      We also are wondering how come you used a DOX inducible system at all for this screen instead of FSK to simulate early reprogramming? Or did you do this and just not report the outcome of that screen?

      [reply] Before we found DZNep, we didn’t know whether a single additional small molecule was sufficient to induce CiPSCs in together with these small molecules. At that time, we only intended to screen for small-molecule candidates that facilitate late stage reprogramming.

      What final concentrations and durations were used after optimization? We cannot find this in the paper, and it seems like this should be reported in order to allow others to reproduce the results?

      [reply] We presented detailed data about concentrations titration in Figure S7A and listed the concentrations that we used in Table S1B. The optimized duration was also shown in figure S7B-C. In the main text, limited by the space, we did not state the optimized concentrations and durations of the small molecules. But the results were clearly presented in these figures.

      Have you performed any experiments to prove that FSK acts at the Oct4 promoter? Versus perhaps at other steps, including even just stabilizing GFP protein expression from a leaky promoter?

      [reply] We found FSK was required in stimulating Sall4, as shown in figure S24B. There is no evidence that FSK acts directly at the Oct4 promoter, as FSK could not induce pOct4-GFP positive cells directly.

      How exactly do you calculate the 0.2% reprogramming efficiency? Calculating efficiency based on the number of cells originally plated may not be accurate if the cells have been passaged several times during long-term culture for reprogramming?

      [reply] The efficiency was calculated according to Yamanaka’s method, by which the number of cell colonies was counted and divided by the number of cells plated (Takasashi et. al., 2007). In addition, I recommend a review paper which carefully discussed how to calculate the reprogramming efficiency: “Guidelines and Techniques for the Generation of Induced Pluripotent Stem Cells”, Nimet Maherali and Konrad Hochedlinger, Cell Stem Cell, 2008. We followed these principles: (1) calculation of plating efficiency, which can be done via cell counts or single-cell plating; (2) eliminating the count of sister clones through single-cell plating; and (3) use of a reliable and stringent method to identify and quantify iPSC colonies. In our study, we only calculated the numbers of CiPSC colonies, characterized by 2i-competent, ESC-like in morphology, and GFP-positive.

      Have you tested these small molecule compounds yet on any human somatic cells for reprogramming?

      [reply] We have tested these small molecules on human fibroblasts, and found that they were not sufficient to induce pluripotency. Maybe some different small molecule combinations are needed for human cells.

      Did you evaluate any off-target effects of these compounds?

      [reply] For the two novel small molecules FSK and DZNep, we have revealed their potential targets in CiPSC induction (Fig. S17 and S18). We did not further evaluated their off-target effects.

      We cannot seem to find the real-time PCR and immunofluorescence results data referenced in figure S21. We see what appears to be the results of a genotyping microarray experiment?

      [reply] The original sentences in our paper are: “To better understand the pluripotency-inducing properties of these small molecules, we profiled the global gene expression during chemical reprogramming and observed the sequential activation of certain key pluripotency genes, which was validated by real-time PCR and immunofluorescence (fig. S21). The expression levels of two pluripotency-related genes, Sall4 and Sox2, were most significantly induced in the early phase in response to VC6TF, as was the expression of several extra-embryonic endoderm (XEN) markers Gata4, Gata6, and Sox17 (Fig. 4, D to F, and figs.S22 to S24).”

      In the sentence referenced in figure 21, we only intended to show the global gene expression profiling data during chemical reprogramming and the initial observation of the sequential activation of certain key pluripotency genes. Actually, “which was validated by real-time PCR and immunofluorescence” was an attributive clause that modifies the initial observations, and is redundant with the next sentence, where the detailed validation results by real-time PCR and immunofluorescence was stated, as referenced to Fig. 4, D to F, and figs.S22 to S24. As the two sentences were written together, we thought the figure citations are not necessary to be duplicated in these two sentences.


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    2. On 2013 Oct 23, Gholson J Lyon commented:

      We reviewed this paper for our lab journal club and we were left with a few questions. We decided to post these questions here in case others have the same questions and/or in case the authors feel like responding to any of them. We posted the same thing to PubPeer.

      1. We are wondering how you decided to search for an Oct4 substitute using the SKM viruses instead of initially screening using the small molecule cocktail that you would ultimately use the substitute with? Or did you do this and just not report this in the paper?
      2. Can you provide an explanation for how come GFP controlled by the Oct4 promoter was expressed but Oct4 protein was not expressed (or at least visualized) after VC6TF induction? (see Figure S3)
      3. We would like to know how come you used two the different DOX inducible systems described in the methods section for the screen of late reprogramming molecules? Did you use a second system to replicate the results or were they used on separate molecules for screening? Were the results reported in Figure S4 derived from data using both systems?
      4. We also are wondering how come you used a DOX inducible system at all for this screen instead of FSK to simulate early reprogramming? Or did you do this and just not report the outcome of that screen?
      5. What final concentrations and durations were used after optimization? We cannot find this in the paper, and it seems like this should be reported in order to allow others to reproduce the results?
      6. Have you performed any experiments to prove that FSK acts at the Oct4 promoter? Versus perhaps at other steps, including even just stabilizing GFP protein expression from a leaky promoter?
      7. How exactly do you calculate the 0.2% reprogramming efficiency? Calculating efficiency based on the number of cells originally plated may not be accurate if the cells have been passaged several times during long-term culture for reprogramming?
      8. Have you tested these small molecule compounds yet on any human somatic cells for reprogramming?
      9. Did you evaluate any off-target effects of these compounds?
      10. We cannot seem to find the real-time PCR and immunofluorescence results data referenced in figure S21. We see what appears to be the results of a genotyping microarray experiment?

      Anyway, we thought we would post our questions and comments here, in case others in the world read this paper and have similar questions. We would of course welcome answers to any of our questions from the authors.


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    1. On 2013 Oct 23, Philip Jones commented:

      (I am an author.)

      The full dataset for this RCT can be found at

      http://dx.doi.org/10.6084/m9.figshare.682404
      

      which includes the native Stata dataset, the Stata .do file necessary to replicate all of the analyses in the manuscript, and the Stata command necessary to calculate the difference in medians used in the bootstrap command.


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    1. On 2013 Dec 09, John Cannell commented:

      The authors report that immune system dysregulation is common in autism spectrum disorder (ASD). The question is why does this immune dysregulation occur and what has caused such dysregulation to skyrocket in recent decades?

      Vitamin D deficiency produces very similar immune dysregulation to what the authors reported.

      Prietl B, 2013

      Kamen DL, 2010

      Yang CY, 2013

      Baeke F, 2010

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

      Gong ZL, 2014

      Meguid NA, 2010

      Mostafa GA, 2012

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

      DeLuca GC, 2013

      Eyles DW, 2013

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

      Cannell JJ, 2010

      Cannell JJ, 2008

      70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day and few toddlers or pregnant women get any sunshine due to the sun scare. As vitamin D fortified milk consumption and sun exposure has declined, so have toddlers and pregnant women’s vitamin D levels. The dramatic increase in the incidence of ASD occurred during the same time vitamin D levels were falling in toddlers and pregnant women.

      Some autism researchers seem cognizant of the entire body of autism research. For example, a group of well-known European ASD researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into the vitamin D deficiency theory of ASD.

      Kočovská E, 2012

      As the authors point out, immune dysregulation is common in ASD. The question is why now and what is causing it?

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


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    2. On 2013 Oct 31, John Cannell commented:

      I congratulate the authors on a fine review. I wonder if they are aware that vitamin D deficiency has been implicated in virtually all the immune abnormalities they review.

      Prietl B, 2013

      Kamen DL, 2010

      Yang CY, 2013

      Baeke F, 2010

      It goes to show how little communication is occurring among scientists in different fields. Each scientist seems to be immersed in his or her own research interest but seemingly oblivious to the larger body of research.

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

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

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

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

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

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

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

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

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

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

      70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day. As milk consumption has fallen, so have toddler’s vitamin D levels.

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

      Some autism researchers seem cognizant of the entire body of autism research. For example, a group of well-known European autism researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into the vitamin D deficiency theory of ASD.

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

      However, these scientists appear to be in the minority. Until all autism researchers become cognizant of the wider body of scientific research, we will continue to wonder how to prevent - and perhaps even treat - this modern day plague.

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


      This comment, imported by Hypothesis from PubMed Commons, is licensed under CC BY.

    1. On 2013 Jul 30, Allison Stelling commented:

      I am confused by one of the author's statements at the end of the paper (page 8):

      "Infrared dyes and Raman spectroscopy have emerged as leading optical technologies, providing excellent selectivity in many different cases of solid tumors (27–30). However, they provide only limited biological or chemical information, and in vivo data suggest that it lacks the sensitivity and specificity of REIMS (31)."

      I am familiar with both vibrational spectroscopic and mass spectroscopic methods for the analysis of tissues. If anything, vibrational (Raman and IR) spectra yield more information than mass spectra; as the techniques are a direct and non-invasive measure of chemical bonds. Mass spectra- as the name implies- give only molecular weight information, and do so in a manner that destroys the sample and permits no further analysis. My recent paper (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3604012/) demonstrates that infrared spectroscopy in particular is quite suitable for intraoperative measurements, is likely more cost-effective and is a goodly bit smaller than the mass spectrometer used in this work.

      It would have been interesting to see the results from an animal model for both healthy and tumor tissue, as such a model might help train the classification programs and aid in data interpretation.

      That being said, this is a quite interesting paper that illuminates the power of traditional analytical chemistry methods for rapid tumor diagnostics. I am mildly skeptical of the results shown in table 2, as the authors show sensitivity and specificity levels over a sampling of, in some cases, n = 2 or even 1 patients. However, I completely understand that these measurements are difficult to orchestrate and this is interesting preliminary work.

      I would have liked to see a plot of variance within individuals with the same diagnosis- the presence of low molecular weight chemical species must surely have a fair amount of variance between patients (or even within the same patient), as the expression of such species depends on individual genotypes and their interrelationships with the chemical micro/nano environment. (Basically, I'd like to be able to see on the plots which spectra came from which patients, as many spectra were acquired from individual patients. The total numbers of spectra and total number of patients are listed in tables 1 and 2, but it would be nice know in each case how many measurements were taken and have this visualized with error bars in the plots shown in figures 3, 4, and 5- or even listed in table S1.) -Dr. Stelling


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    1. On 2014 Feb 03, S Sundar commented:

      Radium-223: Radiobiological conundrum and confounding factors.

      Radium 223 is an alpha emitter with limited tissue penetration as evidenced by minimal myelosuppression in the study.(1) But this bone targeted radioisotope seems to have a major effect on bone secondaries while having minimal effect on the bone marrow. This radiobiological conundrum means that potential confounding factors on the observed survival benefit need to be excluded.

      One significant confounding factor is the liberal use of effective systemic therapies such as anti-androgens, estrogens and steroids in the study. Concurrent use of these effective agents was not controlled in the study and patients were not stratified for use of these agents.

      For instance, dexamethasone and diethylstilbesterol, are widely used in Europe. These therapies are active systemic agents with a median overall survival of 19.4 months in a phase 3 study.(2) Since the median overall survival was only 14 months in Radium 223 study arm, the potential imbalances in the use of these concurrently administered therapies could have significantly biased the overall survival results.

      Furthermore, a significant usage of these systemic hormonal agents in the study arms would imply that Radium 223 ideally should not be used as mono therapy in clinical practice. Abiraterone and Enzalutamide have recently been approved for castration refractory prostate cancer. Widespread use of Radium 223 along with these newer agents, which is likely to occur in routine clinical practice, is not without any biological rationale. . There is an urgent need for combination therapy trials with Radium 223 and newer hormonal agents

      References: 1. Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. 2. Shamash J, Powles T, Sarker SJ, Protheroe A, Mithal N, Mills R, et al. A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol. Br J Cancer. 2011 Feb 15;104(4):620-8.


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    2. On 2014 Feb 03, S Sundar commented:

      None


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    1. On 2013 Oct 29, John Cannell commented:

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

      Vitamin D's effect on the seizure threshold is robust.

      Siegel A, 1984

      Holló A, 2014

      Furthermore, a recent study found supplemental vitamin D reduced seizures in children with severe epilepsy.

      Holló A, 2012

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


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    1. On 2015 Oct 13, Bill Cayley commented:

      An example showing that sometimes for care of atrial fibrillation, "less" is better: https://lessismoreebm.wordpress.com/?s=atrial


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    1. On 2013 Aug 06, Allison Stelling commented:

      This was a wonderful overview of the literature regarding the expression of collagen domains in gliomas. I feel that the microenvironment experienced by the cells has been neglected a bit in the literature, but it is important to recall that natural selection works via the interactions between cells and their nanoscale, biochemical environment. These environments influence the expression of genes through a myriad of mechanisms- from protein protein interactions, to small molecules that activate signaling cascades via (for example) phosphorylation events. The chemical pressures experienced by tumor cells in particular during treatment can lead to selection for drug resistant phenotypes- and, this resistance likely must be considered on an individual, "personal genomics/phenotype" level. Gliomas in particular are what is know within the medical community as "highly malignant", and recent studies highlighted in this review point to these cells as manufacturing their own extracellular collagens to facilitate infiltration of healthly tissue. Given how responsive and adaptable tumor cells can be, I would not find it surprising if these molecules played a role in "converting" or "infecting" healthy cells into tumor cells.

      This review does a fine job of going over the biochemistry of the "major collagen players" discovered thus far in tumors. I particularly enjoyed the section on the effects of the physical properties of the matrix on glioma cell growth and motility. There is much fundamental work to be done in this area, and gaining physical models and insight on the molecular level about the complex microenvironment these malignant cells inhabit will improve our understanding of these tumors and greatly aid in the design of effective therapies.


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    1. On 2016 Aug 23, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0069999. We believe the correct ID, which we have found by hand searching, is NCT00699998.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2014 Nov 30, Michael Wood commented:

      As the first author of this study, I'd like to address a misleading headline that's been making the rounds lately: the idea that this study says that people who believe 9/11 conspiracy theories are better-adjusted than those who do not. This grossly misinterprets our results: this study says nothing about mental health, and its results do not justify any conclusions about one group of people being more or less "sane" than another.

      The main basis for this misinterpretation appears to be the observed difference in hostility between conspiracist (pro-conspiracy-theory) and conventionalist (anti-conspiracy-theory) comments. On average, conventionalist comments tended to be somewhat more hostile. In the paper, we interpret this difference as the product of a fairly specific social situation in which the two rival opinion-based groups use different strategies of social influence according to their relative popularity, rather than as an inherent psychological difference. In fact, previous research by Marina Abalakina-Paap and colleagues has shown that dispositional hostility is positively, not negatively, correlated with beliefs in conspiracy theories - in other words, people who believe more conspiracy theories tend to be more hostile. However, that finding doesn't necessarily justify the conclusion that conventionalists are better-adjusted than conspiracists. Either of these conclusions relies on the unstated premise that hostility is never good or justified, and that less hostility is always better. This is at least an arguable assumption, and there's certainly no evidence for it here.

      In general, I would urge anyone who found this paper via the "sanity" article to please think critically about headlines in the future. It is tempting to believe without question self-serving headlines that validate your prejudices and beliefs, but that's precisely when critical thinking is most important.


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    1. On 2015 Aug 10, Hilda Bastian commented:

      This is an excellent overview of the research on the impact of celebrity and public figure announcements around cancer. The conceptual model proposed for studying impact on behavioral and disease outcomes is an important contribution, but I think it would benefit by being extended in several ways.

      The issue of potentially deepening inequalities in cancer (Lorenc T, 2013) is so critical here, that equity needs to be considered at the outcome end of the picture: incorporating demographics and SES as a mediator/moderator isn't enough. Nor is age the only critical socioeconomic factor about the celebrity/public figure that should be taken into account. The authors point to some notable omissions among the cases that have drawn researcher interest. One of the most striking omissions, though, is the lack of study of non-Caucasian celebrities and public figures (for example Robin Roberts and Donna Summer on the timeline in this article).

      Also striking is the extent to which existing stigma around some cancers is reinforced, both in which cancers are publicly discussed by celebrities, and which are studied by researchers. Are we doing, at the community level (and in the researcher community), what we do in private life as well - reinforcing stigma and poor knowledge of critical diseases in our lives (Qureshi N, 2009)? Take colorectal cancer for example. Whether it's the cases in the timeline (which included only Farrah Fawcett) or the included studies (which included only Ronald Reagan), the under-representation of such a stigmatized condition points to a critical issue for research in this field. Impact on stigma would be a valuable addition to the outcomes in the conceptual model, to emphasize the importance of this dimension of belief.

      In general, it would be good if the potential for adverse effects was more explicit in the model. Critically, impact on over-diagnosis and screening/testing-related harm needs to be included - a key issue the paper discusses, for example, after Kylie Minogue's cancer (Kelaher M, 2008, Twine C, 2006). Accuracy in personal risk assessment, similarly, is an important outcome that is an important outcome to consider.

      Focusing on behavioral and disease outcomes in the model leaves out the impact on resources, and ways systems can best respond to these unpredictable events. That was a major issue after Angelina Jolie's announcement (Evans DG, 2014).

      It would be helpful to understand the impact of famous family members' announcements and pleas around cancer, as well: Katie Couric's public intervention (Cram P, 2003), for example, are relevant to this field.

      Finally, the model of considering these events only in terms of cancer prevention as the end interest, risks missing potentially important impacts of these cultural events. They contribute in the complex ways we think about and deal with life-threatening illness, life, and death (Førde OH, 1998). The lack of studies that address these broader issues is striking, too.

      Note: Rick Nolan noted in a comment on my blog that Dan Fogelberg's is wrongly attributed to pancreatic cancer in this article: he died of prostate cancer. I had discussed these issues, and the studies on Angelina Jolie that occurred after these reviewers completed their search, in this blog post.


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    1. On 2013 Nov 27, R Aldridge commented:

      At a time when there is considerable interest in the potential for the fluoroquinolones to shorten treatment for drug-sensitive tuberculosis, the trial conducted by the National Institute for Research in Tuberculosis (NIRT) in Chennai[1] could represent an important contribution to our understanding of whether this is achievable. Unfortunately, we have serious concerns about the conduct and analysis of this study which makes the interpretation of the results challenging.

      Because moxifloxacin was not available at the start of the study, patients were only enrolled into the gatifloxacin and control regimens during the first 12 months. Thereafter, an attempt was made to equalise the numbers in each treatment arm by changing the allocation ratio to 2:1:1 in favour of the moxifloxacin arm. However, this meant that probably only around half of the 170 patients on the control arm were enrolled concurrently with patients allocated to the moxifloxacin arm. In addition the gatifloxacin arm was terminated 10 months before the moxifloxacin and control arms. No attempt appears to have been made to compare regimens during concurrent enrolment periods of the study in what would be a properly randomised comparison, in order to examine whether the conclusions would have been altered. Known or unknown differences in patient management or between patients enrolled in the different periods of enrolment could have an impact on the differences between regimens in the analyses presented.

      The Data Safety and Monitoring Board (DSMB), whose members and independence are not noted in the report or the study protocol, made a recommendation in February 2006 to terminate the gatifloxacin arm of the study and in October 2006 to terminate the moxifloxacin arm. No information is given either on the guidelines under which the DSMB made this decision, or the results that were available to the DSMB in each case; only that that the decision was due to ‘high TB recurrence rates in these two arms compared to the control arm’[1]. However, most of the data on recurrence (from 24 months follow-up) would have accrued after the study had terminated. The final reported results comparing moxifloxacin with the control arm would suggest there was minimal difference between the outcomes of these two regimens, and that there was no evidence for a difference in the recurrence rate between these two arms (P=0.38). These results suggest the termination of the study is very likely to have been premature. Early termination introduces bias and, as noted in Pocock and White in relation to another trial: ‘the premature pulling out of the trial on insufficiently convincing evidence inhibits the ability of clinical science to resolve an important therapeutic issue’[2].

      The culture results at two months are of particular interest since they suggest that 10% more patients receiving moxifloxacin converted at that time compared to the control arm. The authors fail to comment on what this means for the predictive ability of two month culture conversion for successful treatment shortening, a subject recently addressed by other publications in this journal.[3,4]

      The results of this study might appear to support those of the OFLOTUB randomised controlled trial, presented at the recent conference of the IUATLD in Paris, which failed to show a shortened daily gatifloxacin based arm was non-inferior to the standard six month daily regimen. However, as we have pointed out, there are several serious limitations in the NIRT trial report, in particular the premature closure of enrolment, which need to be recognised when assessing the conclusions of the study and any future meta-analyses which includes these data.

      Rob Aldridge on behalf of the North London TB Journal Club (http://northlondontb.org/). North London TB Journal Club meets monthly; it is organised by the London School of Hygiene and Tropical Medicine, University College London and MRC Clinical Trials Unit. The points above represent concerns raised during a discussion of this paper at a meeting of the Journal Club on 12th November 2013.

      1. Jawahar MS, Banurekha VV, Paramasivan CN, Rahman F, Ramachandran R, et al. (2013) Randomized clinical trial of thrice-weekly 4-month moxifloxacin or gatifloxacin containing regimens in the treatment of new sputum positive pulmonary tuberculosis patients. PLoS One 8: e67030.
      2. Pocock S, White I (1999) Trials stopped early: too good to be true? Lancet 353: 943-944.
      3. Phillips PP, Fielding K, Nunn AJ (2013) An Evaluation of Culture Results during Treatment for Tuberculosis as Surrogate Endpoints for Treatment Failure and Relapse. PLoS One 8: e63840.
      4. Wallis RS, Wang C, Meyer D, Thomas N (2013) Month 2 Culture Status and Treatment Duration as Predictors of Tuberculosis Relapse Risk in a Meta-Regression Model. PLoS One 8: e71116.


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    1. On 2013 Oct 23, Stephen Turner commented:

      This paper presents a new method for species identification and strain attribution using next-generation sequencing data from a cultured pathogen or mixed environmental sample. The paper presented compelling results showing that this new method performed markedly better than a 'naive' mapping approach and other leading read classification methods based on taxonomic binning or compositional analysis. Importantly, the method was shown to work well, even when the species being sequenced was not present in the reference database; sequence data from this organism were assigned to the closest phylogenetic near-neighbor. Finally, the method was also shown to work well when multiple species were present, faithfully recapitulating the actual abundances of organisms present in the sample.


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    1. On 2013 Oct 31, John Cannell commented:

      The authors found markers oxidative stress is present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

      Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      70% of American toddlers do not take the Ameri


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    1. On 2014 Dec 10, Kath Wright commented:

      Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home


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    1. On 2013 Oct 23, Kenneth Daily commented:

      The topic of this paper is very interesting - if there are long-term viruses that rapidly evolve along other more stable viruses. However, there are a few misstatements and omissions that would help strengthen this paper.

      The authors write:

      "Sequence reads from each sample were first assembled individually using MetaIDBA (16)."

      The reference for this statement (Peng Y, 2012) refers to IDBA-UD, however.

      Could the authors comment on which tool was used for metagenome assembly?

      The authors write:

      "The correlation coefficient between replicate samples from the same time point was at least 0.99, indicating a high degree of reproducibility (Fig. S1)."

      In the supplemental methods, a section titled "Reproducibility of Contig Detection" gives the correlation coefficients from Figure S1.

      1. The minimum correlation coefficient given is 0.9743. Hence, the above statement does not seem to be correct. I do not dispute that this is still a high degree of reproducibility across the two sample replicates.

      2. The "day" given in this list does not correspond to the day in Figure S1; it seems to match the sample name given in the SRA submitted data (example: BLS020824_d13-1 and BLS020825_d13-2 would correspond with 13 in this table).

      The methods in this paper are difficult to reproduce. No metadata about each of the samples (most importantly, the day on which they were taken) is present in the data supplied to SRA, BioSample, or BioProject, except for sample SRS413841.

      Details on the versions and parameters for running the various tools are not included (for MetaIDBA, promer, Bowtie2, Glimmer, MetaPhlAn, PILER-CR, Blastn, and the "custom scripts"). Given the complexity and number of steps of the analysis and that most of the tools are openly available, some sort of pipeline of the procedures run on this sequencing data would assure reproducibility.


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    1. On 2014 Mar 06, David Keller commented:

      Patient safety trumps cost containment

      Professor Horowitz is to be congratulated for correctly diagnosing his sister's transient global amnesia (TGA) over the telephone, and for predicting the benign and self-limited course it would take. In my 16 years of practice as a general internist, plus my years of residency training and medical school, I did not encounter a single patient with this condition. Therefore, I sympathize with the internist who was called in to the ER to evaluate this patient. Given an elderly woman who, at first, exhibited total amnesia, including complete disorientation regarding her own identity and surroundings, I would have ordered the same thorough workup that her admitting physician did, unless an experienced neurologist examined her in person and was confident enough of a benign diagnosis to write her discharge orders. If the admitting internist could not obtain a neurological consultation, and did not feel comfortable sending the patient home based on his own findings, then I cannot blame him for ordering an extensive workup to rule out atherosclerotic vascular disease or embolism as the cause of these dramatic symptoms in an elderly patient. When in doubt, patient safety should trump cost containment.

      To facilitate discussion, I respectfully request the person who found this comment "not helpful" to state their reason


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    1. On 2014 May 31, David Keller commented:

      Bravo - Open Access to scientific studies, reviews and comments will accelerate progress

      Based on the history of science over the past 300 years, open access to scientific data and discussions can only be a good thing, and serve to accelerate the pace of discoveries and understanding. In particular, PubMed Commons should be applauded for providing scientists and clinicians an open access platform on which to exchange views in a productive way. For those interested in pharmacology, reading and contributing to CPT:Pharmacometric & Systems Pharmacology will help ensure the success of this new open access venture.

      Often, ideas are created or refined in the open access arena through online discussions of posted comments. However, scientists still rely on print journals, despite their limited or delayed open access, to disseminate scientific contributions more widely, with greater impact, under the imprimatur of a peer-reviewed journal, and with PubMed indexing.

      In addition, many important journals, including Annals of Internal Medicine, JAMA-IM, Mayo Clinic Proceedings, and others, adhere to a strict policy of not publishing material which has been posted on any open-access forum, to avoid the slightest hint of dual publication. This policy is counter-productive. These journals should recognize that work which has been discussed on PubMed Commons, or on any other website used by scientists, has not truly been published yet. For the purposes of publication by a journal, I suggest the following criteria be applied to define prior publication:

      1) Peer review: was this manuscript subjected to peer review?

      2) Indexing: has this manuscript been indexed by PubMed?

      3) Imprimatur: has this manuscript been endorsed by any other journal or publishing entity?

      4) Dissemination: has this manuscript been brought to the attention of a readership of appropriate size and composition?

      If a manuscript has been previously posted on PubMed Commons or a similar website, and it lacks all 4 of the above attributes, I suggest that it not be considered previously published. Good ideas should not have to be kept secret through the long time periods while they await publication, delays which degrade their timeliness and utility.

      It is time for the editors of our major journals to declare themselves solidly in support of open access to scientific data, reviews and comments by adopting the above 4 criteria to define prior publication.


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    1. On 2014 Sep 16, Mohamed Soliman commented:

      I am using remifentanil frequently in monitored anesthesia care alone or in combination with propofol. Occasioally, I use it as a rescue analgesic in special circumstances. In some patients who represent a high risk for general anesthesia, a remifentanil infusion in addition to a local anesthetic were successfully used. The remifentanil infsuion rate should be carefully titrated according to respiratory rate, sedation level and patient analgesic need. Standard anesthesia monitoring including End-tidal Carbon Dioxide should be used.


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    1. On 2014 Mar 25, Pat Arndt commented:

      There is another case of HDFN due to anti-Js<sup>b</sup> that can be added to Table 2; it was the first reported case of fatal hydrops due to anti-Js<sup>b.</sup> The case was presented as an abstract at an AABB meeting in 1987. Additional information not in the abstract has been included below. Publication: Ratcliff D, Fiorenza S, Culotta E, Arndt P, Garratty G. Hydrops fetalis (HF) and a maternal hemolytic transfusion reaction associated with anti-Js<sup>b.</sup> Transfusion 1987;27:534 Maternal age and ethnicity: 22 years old, G4P2 (corrected from abstract), Black Sensitization event: Unknown (pregnancy?) Prior history: Third child was stillborn. Time of presentation: 26 weeks Titer: 64 Management: Neonatal transfusion Source of blood during pregnancy: N/A Fetal outcome: Hydropic fetus delivered at 30 weeks gestation by C-section with birth Hb of 56 g/L. Infant died at about 9 hours of life. Neonatal transfusion requirements: 100 mL Js(b+) RBCs transfused about 5 hours after birth


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    1. On 2013 Aug 08, Winston Timp commented:

      Interesting article suggesting something as simple as exercise can alter the methylome. Pretty much just descriptive, but useful, suggesting further links between epigenome and diabetes risk. More graded time scales would be very interesting - to see how long the effect lasts(from exercise) and how much exercise is needed to provide the effect.


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    1. On 2014 Apr 07, Madhusudana Girija Sanal commented:

      Is there any evidence that decellularized scaffolds are the way to go for a heart! The heart is a syncytium (syncytium is a multinucleate cell which can result from multiple cell fusions of uninuclear cells) and the entire heart should work as a single huge coordinated muscle mass. If millions of cells are not connected to each other in the intricate way life threatening arrhythmia will kill the patient. This cannot be achieved in this model which is described here. Currently there is no convincing evidence in this direction. It is extremely difficult to repopulate the scaffold with live differentiated cardiomyocytes (or even undifferentiated cells) to make anything closer to useful. It is even more difficult to achieve proper blood supply to the repopulated cells in the scaffold to keep the cells alive even for few hours. Moreover, the scaffold proteins of the donor heart can cause graft rejection, even if is derived from 'induced pluripotent stem cells(iPSC)' derived 'patient's own somatic cells' are used to repopulate the scaffold. Totally artificial mechanical pumps (like "Abiocor" or even better ventricular assist devices [VA])) may be closer to reality and justify spending of public money than repopulated scaffolds. Repopulation of scaffolds may work for simple organs such as a urinary bladder (because bladder for example is: (a) relatively simple organ in structure (b) not a vital organ IE; one will not die if one's bladder fails!). We have miles to go before we make a true 'lab made cellular-heart' mainly because of many unresolved fundamental and technological issues. The State and private investment in basic sciences like mathematics, physics, chemistry and fundamental biology is vital to achieve this kind of dreams (compared to investment in the direction of premature 'translation'). Investors and the society need to realize the importance of patience and watchful expectancy when it comes to investment in basic sciences for obvious reasons.


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    1. On 2014 Mar 17, Robert M Flight commented:

      The data and scripts for the "computational analysis" providing evidence of RBP binding is available for download from Figshare, and can be cited: Flight, Robert M; J Harrison, Benjamin; C Petruska, Jeffrey (2014): CamkIV 3 UTR Binding Homology Coverage. figshare. http://dx.doi.org/10.6084/m9.figshare.97560


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    1. On 2013 Nov 26, Steven Salzberg commented:

      It is completely unsurprising that acupuncture provided no benefit to women undergoing IVF. There is no known mechanism of action (and no plausible mechanism) that would explain such a benefit. The authors' plea for "further exploration" is a classic case of moving the goal post: they seem to want to justify putting more effort (and funding) into what is clearly a failed treatment regimen.


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    1. On 2015 Sep 07, Lutz Dürselen commented:

      The name of the first author is not correct. I should read: Seitz AM. Martin is one of the first names of Dr. Seitz and it has been mistakenly interpreted as part of his last name.


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    1. On 2016 Jan 23, Vitória Piai commented:

      The authors used only the period of presentation of the first word to analyse their data. This word was the same across three conditions, which were presented in three different blocks. Now that I'm looking at their Figure 4, isn't it weird that there are different values for the three different tasks, if these are the exact same words? Or is the fact that they have to perform a different task at each block modulating beta power? But in that case, it would mean that word processing, and the amount of lateralisation of function, will differ as function of whether you have to make a phonological, semantic, or orthographic judgement. So beta power and lateralisation would be a task-specific thing, having little to do to word comprehension as such. Or maybe I am missing something here.


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    1. On 2015 Mar 25, Joe Newton commented:

      This article is quite interesting. However, it does not reference Newton JR Medical Hypotheses 1999 which predicted testable intracranial volume differentials in a step-by-step physical and mathematical model with figures for "manic-depression" Also it does not reference Newton JR Psychiatric Genetics 2008 which presented gene ontology categories expected to influence intracranial volume differentials. Apparently the 1999 theory is too difficult for medical people. Your comments are invited on how to increase the succinctness of the 1999 model. Best wishes, Joe Ray Newton joernewton@att.net


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    1. On 2016 Aug 23, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0145303. We believe the correct ID, which we have found by hand searching, is NCT01453036.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2016 Aug 23, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0137868. We believe the correct ID, which we have found by hand searching, is NCT01037868.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2014 Mar 24, Valter Silva commented:

      LOOKing AHEAD... without losing sight plausibility

      The LOOK AHEAD,<sup>1</sup> a rigorous study and paradoxical, showed no reduction in the rates of cardiovascular events or mortality with lifestyle interventions in type 2 diabetic patients. Several hypotheses have been raised:<sup>2</sup> (1) cardioprotective medications in the intervention group; (2) reduced effect after the first year; (3) lifestyle interventions need more follow-up; (4) unreliable outcomes masked the effect. Furthermore, could diabetes support and education (control group) produce beneficial changes by empowering patients? Yes! It is perfectly plausible and supported by a large body of evidence that interventions such as the control group received produces benefits, masking lifestyle intervention possible benefits. Considering the principle of plausibility of evidence-based medicine, exemplified by a systematic review of randomized controlled trials<sup>3</sup> about parachutes effectiveness for preventing death and major trauma, sometimes observational designs bring the best evidence. In brief, even with the findings of the LOOK AHEAD,<sup>1</sup> yet it is not plausible not to recommend interventions to change lifestyle, at the risk of stating that results of large studies (e.g. He J, 2005<sup>4</sup> and Lee IM, 2012<sup>5</sup> ) are not valid. In our viewpoint, instead of to declare "lifestyle intervention does not work", a plausibility conclusion for these results is "lifestyle intervention is quite as good as to receive diabetes support and education".

      Valter Silva, PhD, Research assistant, Universidade Federal de São Paulo, SP, Brazil

      Antonio Jose Grande, PhD, Associate professor, Universidade do Extremo Sul Catarinense, SC, Brazil

      Competing interests: None declared.

      Reference:

      1. The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145-154.

      2. Gerstein HC. Do lifestyle changes reduce serious outcomes in diabetes? N Engl J Med. 2013;369(2):189-90.

      3. Smith GC, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 2003;327(7429):1459-61.

      4. He J, Gu D, Wu X, et al. Major causes of death among men and women in China. N Engl J Med 2005;353(11):1124-34.

      5. Lee IM, Shiroma EJ, Lobelo F, et al.; Lancet Physical Activity Series Working Group. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet 2012;380(9838):219-29.


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    2. On 2013 Oct 20, Carl Heneghan commented:

      Id agree with Naama Constantini comments in that intensive lifestyle interventions do not reduce CVD, based one trials findings alone. It shows the added precision of setting clinical trials in the light of systematic reviews. I believe the Lancet asks for this with all new trials, and it would be helpful for other journals to follow suit, when forming their conclusions.


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    3. On 2013 Sep 28, Mayer Brezis commented:

      We question the authors’ conclusion that an intensive lifestyle intervention does not reduce cardiovascular events among overweight diabetic patients (1). As their results included a subgroup analysis for patients with cardiovascular disease at baseline, this interpretation seems to contradict consistent > 25% reductions in all-cause and cardiac mortality as well in cardiac morbidity from a systematic review of 23 trials on lifestyle modification in 11,085 randomized coronary heart disease patients (2). The paper reveals no information on the effect of the intervention on actual physical activity (pedometers were given to patients but data are not shown). Physical fitness was low, somewhat increased for a couple of years and then reverted to baseline, but is not reported for most of the ensuing years. Since adherence appears to have been low, a per-protocol analysis might have enriched our understanding beyond an intention-to-treat analysis. As for medications, poor adherence is common and deserves better accounting (3). We suggest rephrasing the conclusion to say that a limited lifestyle intervention focused on weight loss had little impact of cardiovascular events.

      Naama Constantini, MD, DFM, FACSM, Dip. Sport Med. (CASM)<br> Mayer Brezis, MD, MPH Hadassah Hebrew University Medical Center Jerusalem, Israel Robert Sallis, MD Department of Family Medicine and Sports Medicine Kaiser Permanente Medical Center Fontana, CA, USA

      (1) The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. New England Journal of Medicine 2013;369:145-54.

      (2) Janssen V, Gucht VD, Dusseldorp E, Maes S. Lifestyle modification programmes for patients with coronary heart disease : a systematic review and meta-analysis of randomized controlled trials. European Journal of Preventive Cardiology 2013;20:620-40.

      (3) Osterberg L, Blaschke T. Adherence to medication. New England Journal of Medicine 2005;353:487-97.


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    1. On 2015 Jun 24, David Mage commented:

      A Possible Cause of SIDS is Found in SIDS Data of Carpenter et al., BMJO 2013, Figure 1 and Table 1

      David T Mage*, Health Scientist, E. Maria Donner# 
      

      *WHO (retired), #DuPont

      SIDS is characterized and diagnosed by exclusion, especially when expert pediatric pathologists, trained forensic investigators, and learned epidemiologists are unable to find a sufficient cause of infant death at autopsy, at the scene, or in the data, respectively. Therefore the cause of SIDS may be invisible or immeasurable. Furthermore, SIDS is characterized by the fact that in every such case that the parents had no premonition that their infant was at imminent risk of death and "there was a complete absence of prodromal symptoms or any departure from the normal sufficient to justify the parent in seeking medical advice (1)." Therefore, most authors now look at risk factors that are not causes of death (prone sleep position, maternal smoking, etc.) However, they overlook three possible causal factors that alone might be insufficient to cause SIDS, but may act simultaneously in order to do so, that appear in this paper, as follows:

      1) An unknown X-linked recessive allele for SIDS susceptibility with frequency q = 2/3, in Hardy-Weinberg-Equilibrium (HWE), that predicts the 50% male excess of SIDS for equal numbers of males and females at risk. The XY male is at risk with q = 2/3 and the XX female is at risk with q x q = 4/9, a 50% male excess. Given a nominal 5% male excess birth rate the expected male fraction is 0.612 for 60 x 1.05 males per 40 females (2). Table 1 reports 898 male and 568 female SIDS, for male fraction = 0.613;

      2) Physiological anemia (3) causing the lognormal-type age distribution of SIDS in their Figure 1 that is its most unique characteristic. Unfortunately, "cases and controls over 1 year of age were excluded", which is like 'throwing the baby out with the bathwater.' The upper 1-year limit for SIDS is an artifact of the perception that SIDS over 1 year may include more false positives, so they should not be included in research studies.(4) Physiological anemia occurs when fetal hemoglobin (HbF) decays rapidly after birth while adult hemoglobin (HbA) slowly begins to replace the HbF. The term infant has its lifetime maximal total Hb at birth and it rapidly falls to their lifetime minimal Hb at or about 2-months of life, and then it follows a slow increase until a new equilibrium Hb concentration is established [we neglect here the different binding strengths of oxygen molecules to HbF and HbA, and pre-term Hb relations]. We estimated 19 as the missing number over 1-year that the authors excluded, by fitting an exponential decay curve to the numbers of SIDS from 8 weeks to 52 weeks in Figure 1 and extrapolating it to 178 weeks as determined previously as the upper limit for SIDS.(5) We then fit these weekly data (w) by the Johnson SB transformation that y = Log[(w + 1.343)/(178 - w)] where y = mu + sigma z, and mu = -1.04, sigma = 0.313, w is age in weeks, and z is a standard normal deviate. We interpret this Figure 1 as the number of the most anemic genetically susceptible infants whose total mix of Hb = HbF + HbA falls below some critical threshold, and therefore cannot survive a respiratory infection (see below) that reduces blood oxygenation in the lungs sufficiently to create an acute anoxic encephalopathy resulting in neuronal death. Hemoglobin concentration cannot be measured accurately at autopsy because of the gravitational settling of red blood cells during hemostasis leading to lividity so it is missing in virtually all SIDS autopsy studies (6); and

      3) A prodromal respiratory infection (PRI) contracted from a family member that begins to fulminate shortly before or after the infant is placed for its final sleep. Farber (7) reported such a case where a baby was cared for by a nurse because the mother had a severe sore throat at the time. After a 2 p.m. uneventful feeding by the nurse, the baby was found dead 1.5 hours later, "lying on his back. There was no evidence of bedclothes, pillow or any other object over his face." We propose that the only thing that could have changed from the immediately previous sleep condition, sufficiently to cause death and be unnoticed, had to be a PRI that began to fulminate and cause fatal anoxic encephalopathy "before an important or appreciable amount of lung parenchyma has been involved." The author's Table 1 can provide no data on a potentially fatal respiratory infection presence in the SIDS cases, because, if such visible evidence existed at autopsy, the diagnosis by definition would not be SIDS. However, these data in Table 1 cast a visible shadow of a fulminating PRI. The authors list the SIDS and Control Live-Birth-Order (LBO) as shown below. We assume that Cohabiting Family Members (CFM) = 2 adults + (LBO - 1) Siblings = LBO + 1. We then assume that the probability of not carrying a communicable respiratory infection (CRI) (symptomatic or asymptomatic) is P so the probability of at least one CFM carrying a CRI is 1 - P<sup>CFM</sup>. Setting P = 0.92 by least squares gives the Model values shown. We previously fit U.S. LBO and SIDS data with P = 0.90 (8). Note that a plot of SIDS Fraction or SIDS Model vs CFM goes to the origin (0, 0) that implies that there are no SIDS cases here that are independent of CFM.

      LBO = 1, SIDS = 407, Control = 1836, SIDS Fraction = 0.181, Model = 0.152;

      LBO = 2, SIDS = 491, Control = 1566, SIDS Fraction = 0.239, Model = 0.219;

      LBO = 3, SIDS = 280, Control = 748, SIDS Fraction = 0.272, Model = 0.280;

      LBO = 4, SIDS = 149, Control = 304, SIDS Fraction = 0.329, Model = 0.337;

      LBO = 5+, SIDS = 122, Control = 200, SIDS Fraction = 0.379, Model = 0.390.

      In summary, SIDS may occur from these three causal factors (genetic susceptibility, physiological anemia, PRI) acting simultaneously that are a function of chance, age and CFM, respectively. There is no explanation we can find in the medical literature , other than an X-linkage in HWE, for a constant male fraction that is different from that of the male birth fraction. There is no explanation other than the maximum hemoglobin at birth for the virtual absence of SIDS immediately after live birth that is the most risky time for all other causes of infant death, the peak SIDS rate at or about the total Hb nadir, followed by an exponential decrease in SIDS rate as the infant's total HbA increases. We know of no other invisible cause of a sudden and unexpected infant death than a fulminating PRI that leaves no visible trace for the pathologist at autopsy or under the microscope in a genetically-susceptible physiologically-anemic infant.

      REFERENCES

      1.Davison WH. Accidental Infant Suffocation. Br Med J. 1945;2(4416):251-2.

      2.Mage DT, Donner EM. A genetic basis for the sudden infant death syndrome sex ratio. Med Hypotheses 1997;48:137-42.

      3.O'Brien RT, Pearson HA. Physiologic anemia of the newborn infant. J Pediat 1971;79:132-8.

      4.Willinger M, James LS, Catz C. Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol. 1991;11(5):677-84.

      5.Mage DT. A probability model for the age distribution of SIDS. J Sudden Infant Death Syndrome and Infant Mortality 1996;1(1):13-31.

      6.Poets CF, Samuels MP, Wardrop CA, et al. Reduced haemoglobin levels in infants presenting with apparent life-threatening events--a retrospective investigation. Acta Paediatr. 1992;81(4):319-21.

      7.Farber S. Fulminating streptococcus infections in infancy as a cause of sudden death. NEJM 1934;211:154-9.

      8.Mage DT, Donner M, A unifying theory for SIDS. Int J Pediat 2009; 2009:368270


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    1. On 2014 Mar 19, Arthur Edelstein commented:

      In Figure 3, the peak DAPI signal (proportional to the amount of DNA present in the cell) increases from ~7500 (before CMR) to ~10000 (after CMR). The gamma-H2AX peak signal (proportional to double-stranded breaks) increases from ~2200 (before CMR) to ~2900 (after CMR). Given that the DAPI signal and the gamma-H2AX signal increase by approximately the same ratio, it looks to me as if the proportion of DNA with double-stranded breaks is unaffected by CMR. Can you rule this out?


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    1. On 2013 Dec 28, Atanas G. Atanasov commented:

      Unexpected and very interesting findings. I will be looking forward for the future studies addressing the detailed molecular mechanisms behind the telomere homeostasis – metabolism connection.


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    1. On 2016 Mar 05, Tamir Tuller commented:

      In this paper Shah et al. propose a computational model for whole-cell translation. This model is used to test a number of hypotheses regarding the contribution of various factors to global protein production in the cell. As we describe below, the study (at least in its current form), is clearly not suitable to be published in Cell. Specifically, the reported results are either wrong or not new. In addition, the described model has many disadvantages that are not discussed, and it is clearly not evaluated accurately. Furthermore, while the authors claim the model is more comprehensive than previous models, many fundamental aspects mentioned in previous studies are not included in it. Below is a partial review; a more comprehensive review can be downloaded also from http://www.cs.tau.ac.il/~tamirtul/Shah_et_al_review.pdf

      Diament & Tuller 5.3.2016

      1) The reported correlation between estimated initiation probabilities and predicted 5'-end mRNA folding energies is significant, but very low (R=0.125). Furthermore, the data presented in Figure 5A is in fact binned. This fact is specifically interesting, as the authors discourage the use of bins, but at the same time note that it is “sometimes appropriate to bin the data for visualization purposes”. ~60 bins are used for 3,795 values, and while error bars denote the variance in each bin, the “visual representation” gives the impression of a strong relation between the two variables using very few points, which is not the case. In addition, the authors should include a control, e.g. partial correlation, for other important variables, such as the Kozak score (Kozak,Cell,1986), when computing this correlation (which eventually may be significantly lower) as well as CAI, amino acid charge, and GC content, at the beginning of the coding region, etc. These variables are known (and were known at the time of writing this paper) to have typical signals in the 5’-end of the ORF that are correlated with expression level (and initiation rate), for example see (Plotkin&Kudla,Nat Rev Genet,2011). We also recommend that statistical significance for this correlation be tested using an empirical null model. For example, amino acid preserving sequences in the relevant window can be generated at random to estimate the probability of observing a correlation of 0.125 between inferred initiation rates and mRNA folding energy. This is important since the distribution of amino acids near the N-terminal of the protein may induce the folding strength via their specific codon coding them.

      2) This is not the first study that includes/suggests the analyses of many intracellular components (mRNA and ribosomes). However, previous studies on the topic such as (Brackley et al.,PLoS-CB,2011; Chu et al.,2011; Cook&Zia,2009; Cook et al., Phys.Rev.E,2009; Greulich et al., Phys.Rev.E,2012; Heldt&Thiel,2009; Jonathan et.al.,2012; Karr et al., Cell,2012; Mather et al.,2013) are not cited.

      3) The major fundamental disadvantage when developing a model with many parameters is overfitting (Babyak,Psychosom Med,2004), or accumulation of error due to individual errors in the different parameters. Surprisingly, the authors do not bother to discuss this issue, and to demonstrate that this is not the case with the model.

      4) All the conclusions reported in this paper based on the model are either wrong or not new. Thus, the ability of this model to provide novel conclusions is not convincing at all. For example (points mentioned in the abstract), the correlation between initiation and folding energy has been suggested many times before (Jia&Li, FEBS Lett.,2005; Kudla et al., Science,2009; Sagliocco et al., J.Biol.Chem.,1993; Schauder&McCarthy, Gene,1989; Wang&Wessler, Plant Physiol.,2001) and is very low (r=0.125); the idea that the ramp is caused by rapid initiation is wrong, among others, due to the fact that the authors did not normalize each profile by dividing it by the mean as was performed in previous studies they cite. The conclusions regarding the fact that “protein production in healthy yeast cells is typically limited by the availability of free ribosomes, whereas protein production under periods of stress can sometimes be rescued by reducing initiation or elongation rates” is not new (Bergmann&Lodish, J.Biol.Chem.,1979) and can’t be accurately evaluated via the model due to overfitting issues mentioned above, and missing fundamental aspects mentioned below and above.

      5) The authors ignore previous studies that suggested that elongation is not only due to adaptation to the tRNA pool. For example, the model does not consider important aspects related to the elongation rate that were previously reported and suggested to have stronger effect on elongation than tRNA levels. Expressly, the effect of mRNA folding (Nackley et al.,Science,2006; Plotkin&Kudla,Nat Rev Genet,2011; Pop et al., MSB,2014; Tuller et al.,GB,2011; Yang et al.,PLoS Biol,2014) and amino acid content (Charneski&Hurst,PLoS Biol,2013; Lu&Deutsch,JMB,2008; Lu et al.,JMB,2007; Muto&Ito,2008; Pavlov et al.,PNAS.,2009), as well as wobble basepairing (Stadler&Fire,RNA,2011). In addition, the analysis is partially based on Ribo-Seq data, but measurements are not used to infer reliable codon decoding rates. Previous studies (e.g. Charneski&Hurst,2013) suggested that these aspects are significantly more important than the tRNA pool adaptation. Thus, without considering these fundamental aspects it is not clear what we can learn from this model (!).

      6) The analysis of the ramp is clearly wrong and was not performed as in previous studies (see, explanations in Figure 5A in (Tuller&Zur, NAR,2015)). Ribosome occupancies must be normalized per gene by its average ribosome occupancy before averaging each codon position across the transcriptome (this is how this was performed in previous studies e.g. (Ingolia et al.,2009)(!)). We must say we are surprised that the authors are not familiar with the details and methodologies used in previous studies.

      7) The reported results contradict previous papers of the authors’ themselves (Kudla et al., Science,2009), but this is not discussed. In (Kudla et al.,2009), the authors claimed that slower codons are related to higher ribosomal densities and vice versa. The 5' end of the ORF has been shown to be enriched with slower codons (Plotkin&Kudla,Nat Rev Genet,2011). Thus, by concluding that the 5' ramp is not related at all to codon usage bias in this Cell paper, the authors contradict themselves (as it is related to the claim that codon bias and ribosome densities are unrelated). The reported results are also contradicted by papers the authors published after this study (Weinberg et al.,2016).

      8) The performance related to all the aspects of the model should be comprehensively compared with that of other models, and include a balanced discussion about the relative advantages of the different models. Otherwise, the advantages of the proposed model are not clear and misleading. The following are some points to be considered: running time, number of parameters needed and the availability of the parameters, the possibility of analytical analysis of the model, predictions using real and simulated data, etc.

      9) “Interestingly, we also found a negative correlation between initiation probability and open reading frame (ORF) length...” This result can be at least partially explained by the fact that in (Ingolia et al., 2009) there is an increased ribosome density at the 5' end (partially due to biases as suggested in (Ingolia et al.,Cell,2011)). This should have a stronger effect on shorter genes. At the time of publishing and working on this study it was already very clear that the higher density of ribosomes at the 5’end of the mRNA was at least partially due to biases in the experiment (see Ingolia et al.,2011); nevertheless, the authors do not mention or consider this fundamental issue in their analysis/conclusions at all(!).


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    1. On 2014 Feb 10, Chetan Phadke commented:

      Very well done study and very relevant work for several populations. I am wondering if there was a significant decrease in spasticity in the ankle plantar flexors. We would assume that the amount of atrophy would be dependent on the amount of toxin injected. How much toxin (total units) was injected in the plantar flexor muscles? Only the overall summed spasticity (MAS) scores and BoNT dosage in units/kg were reported in the manuscript. It would be very helpful to know this. Thank you.

      Chetan Phadke (Recipient of past grant support from Allergan Inc.)


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    1. On 2014 Nov 17, Raphael Levy commented:

      The article appears to contradict an earlier report by the same authors indicating that no protein adsorption could take place on stripy nanoparticles Jackson AM, 2004.

      The evidence behind the structure and special properties of stripy nanoparticles has been challenged by Cesbron Y, 2012. The publication in 2012 of Cesbron Y, 2012 took three years and has been followed by post-publication peer review of the various existing and new stripy articles on my blog, PubPeer, etc.

      A detailed analysis of this body of work is published today in PloS One by Stirling et al; from the abstract: “through a combination of an exhaustive re-analysis of the original data with new experimental measurements of a simple control sample comprising entirely unfunctionalised particles, we conclusively show that all of the STM evidence for striped nanoparticles published to date can instead be explained by a combination of well-known instrumental artefacts, strong observer bias, and/or improper data acquisition/analysis protocols.


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    1. On 2015 Mar 26, Rahul Lall commented:

      Dear Vera,

      Very exciting and interesting paper. I just had a few experimental questions. How was the HA enriched from the cell media from 20 days? If you could share the protocol of the method, would be great. My email is rklall@wisc.edu.


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    2. On 2014 Nov 26, Ruchira Engel commented:

      Dear Vera Gorbunova, Thank you for clarifying our doubts.


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    3. On 2014 Nov 25, Vera Gorbunova commented:

      Dear Ruchira Engel, thank you for your comments. The two concerns you raised could be answered by carefully reading the paper.

      1. “How much does the size actually matter?” When purified HAase is added to the cells, or when Hyal2 enzyme is overexpressed, as in Fig. 4, this does not lead to complete “disappearance” of HA, but rather to a reduced size. HAases cleave the sugar chain into smaller fragments, but these fragments actually stay around, so the experiment you are proposing with adding a shorter HA is pretty much what has been done throughout the study.

      We state in the Abstract that both the size of the size of the sugar and the signaling are different in the naked mole rat: “Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells.” Clearly, both the ligand and the receptor underwent changes together over million of years of evolution; trying to separate the two is rather artificial.

      1. “Is HA degradation really slower in the naked mole rat?” The time needed to accumulate the amount of HA shown on pulse field gels was 20 days (stated in the legend to Fig. 1). That was also the amount of HA used in the degradation assays. Four days used for incubation in the degradation measurements in Fig. 2c is simply not enough time to see a significant contribution of HA synthesis. Furthermore, in Fig. 2d where tissue fragments were used, the incubation time was even shorter (6 hours).


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    4. On 2014 Nov 22, Ruchira Engel commented:

      An interesting study! Earlier this year we discussed this article in our journal-club and agreed that this was a well written article with experiments that support the proposed mechanism. But is there sufficient evidence to suggest that it is the size of HA and not the signalling alone in the naked mole fibroblasts that leads to the cancer free state of the naked mole rats?

      Please check our review of this article.


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    1. On 2014 Feb 10, David Keller commented:

      In this case of a large patient with high creatinine clearance, dabigatran failed to prevent thromboembolic stroke associated with atrial fibrillation, apparently due to hypo-therapeutic serum levels. This case illustrates that the "open loop" use of the new oral anticoagulants (NOA's) may be ineffective or unsafe in patients who differ markedly from the average for populations tested in the NOA’s clinical trials. Dose-adjusted warfarin can be used safely and effectively in many such "outlier" patients because dosing feedback is obtained by monitoring INR. Clinicians who prescribe NOA's must remain vigilant for patients with clinical characteristics which put them at risk for serum NOA levels which are too high or too low. Dose-adjusted warfarin should be the initial therapeutic consideration for these patients. If the patient cannot take warfarin, it may be prudent to check peak and trough levels of the NOA at appropriate intervals.


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    1. On 2013 Nov 01, Richard Frye commented:

      Thank you John for your insightful comment. The many metabolic abnormalities associated autism are most likely interconnected with complex interactions. The notion of abnormalities in vitamin D metabolism being significant is an important one. In the future we need to consider the wide range of abnormalities in the evaluation in order to examine the whole body as a complex interacting system instead of concentrating on one specific system.


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    2. On 2013 Oct 31, John Cannell commented:

      The authors found markers oxidative stress is present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

      Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      70% of American toddlers do not take the Ameri


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    1. On 2017 Mar 20, Lydia Maniatis commented:

      Commonly observable facts falsifying the conclusions of this report were available before it was published.

      The conclusions to which I'm referring are the following: "First, we show that observers tend to take heavily into account the brighter parts of objects when they are asked to match the color or lightness of these objects. Second, we show that observers tend to fixate on the brighter parts of the objects as they make their match."

      Of course, the samples used in the study are consistent with the claims. They consist of figures which produce percepts of partly shaded objects. In these conditions, the lighter part within the boundary of the perceived form is perceived as being "in plain view."

      But there are other possible samples, specifically cases in which the lightest parts are perceived as highlights, or glare. This is the case, for example, for surfaces perceived as glossy. Here, the lightest parts are not perceived as "in plain view."

      Another example from the literature is the cube demo by Purves, Shimpi and Lotto (1999). Here, the color of the upper part of the cube appears darker than its lightest region, which appears overlit.

      The fact that observers, in the cases studied, tended to "fixate on the brighter parts of the objects as they made their match" does not in itself corroborate the authors' conclusion. I would predict that in the case of figures with perceived highlights, rather than perceived shadows, fixations would tend to be more on the darker - i.e. the perceived plain view - regions. This is an obvious control that should have been included in the original study. (I'm not aware that such an experiment has been performed, but maybe I'm not caught up.)

      In other words, I'm claiming the direction of causality is the reverse of what is being proposed - first the percept is formed and lightness/illumination inferred, and then eye movements are organized in light of this prior organization.

      The demonstration in this report that forcing fixations on particular regions affects perceived lightness doesn't undermine the above arguments.


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    1. On 2015 Feb 03, Harri Hemila commented:

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

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

      A summary of the Cochrane review “Zinc for the Common Cold” by Singh M, 2013 was published in JAMA by Das RR, 2014. Concerns have also been expressed about the findings reported in the JAMA summary, see PubMed Commons.

      The previous version (2011) of the the Cochrane review “Zinc for the Common Cold” by Singh M, 2011 also had problems, which are briefly summarized in PubMed Commons.


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    2. On 2015 Jan 04, Harri Hemila commented:

      None


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    1. On 2015 Apr 20, Gunalp Uzun commented:

      In this article, Marino and coworkers investigated the effectiveness of autologous adipose tissue derived regenerative cells in the treatment of chronic lower extremity ulcers in patients with severe arterial obstruction. Adipose tissue, recently, has gained significant attention as a stem cell source and the contribution of adipose tissue derived stem cells (ADSC) to wound healing has been shown in several experimental studies (Cherubino M, 2011). However, the number of studies that use ADSC to accelerate wound healing in a clinical setting is low (Cherubino M, 2011, Uzun G, 2014). The article by Marino et al., in this regard, is an important contribution to this field. We, therefore, read the article with great interest, yet would like to express some of our reservations.

      First, the outcome of patients in the control group was not given in the article (Marino G, 2013). Marino et al. included twenty patients, whose ulcers have not healed despite several months of traditional and advanced wound care methods. Of the 20 patients, 10 have been treated surgically with ADSC and others have been used as ‘controls’. In the Results, they also state that patients who were treated with ADSC and who did not were monitored at days 4, 10, 20, 60, and 90. At the end of the study, ulcers of the 6 (60%) patients in the treatment group completely healed, however, there is no mention about ulcer healing rate in the control group. If the authors have provided this information, the reader would be able to compare the outcomes in the treatment and control groups and to reach a better conclusion on the effectiveness of ADSC.

      Second, there is a discrepancy between the information provided in the text and in the tables. Identification of a factor that predicts those who would benefit from ADSC would be very useful. The authors propose baseline ankle brachial index (ABI) value as a predictor of treatment outcome. In the Results, it is stated that ‘Patients who recovered completely had an ABI between 0.8-0.9, whereas others with a reduction in the diameter of the ulcer had an ABI between 0.5-0.6.’ (Marino G, 2013). Baseline characteristics and ABI values of patients in the treatment and control groups were presented in Table 1 and Table 2, respectively (Marino G, 2013). It is seen on this tables that none of the patients had an ABI higher than 0.39. This issue needs clarification.

      There is a need for more clinical studies that tests ADSC as a potential treatment for non-healing lower extremity ulcers in patients with peripheral arterial disease. We applaud the efforts of Maroni et al., and acknowledge the importance of their study, however, we think that two points mentioned above needs to be clarified.

      Gunalp Uzun & Abdul Kerim Yapici

      References

      1. Marino G, Moraci M, Armenia E, Orabona C, Sergio R, De Sena G, Capuozzo V, Barbarisi M, Rosso F, Giordano G, Iovino F, Barbarisi A. Therapy with autologous adipose-derived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease. J Surg Res. 2013;185:36-44.

      2. Cherubino M, Rubin JP, Miljkovic N, Kelmendi-Doko A, Marra KG. Adipose-derived stem cells for wound healing applications. Ann Plast Surg. 2011;66(2):210-5.

      3. Uzun G, Yapici AK, Ilgaz Y. Adipose derived mesenchymal stem cells in wound healing: a clinical review. Dis Mol Med. 2014;2:57-64. doi: 10.5455/dmm.20150120123357


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    1. On 2014 Feb 04, Jacob Puliyel commented:

      This comment has been written after correspondence through the journal with the authors.

      The WHO considers programmes cost-effective, if they cost less than 3 X GDP per capita per DALY averted. Such thresholds are less meaningful in developing countries where funds are limited and there are numerous worthwhile projects (costing even less than 1 X GDP per capita per DALY), vying for scarce health care resources. Efficient allocation of resources involves selecting programmes that provide the best value for money till the budget is exhausted. The base-case cost-effectiveness is used for this selection of programmes. It is therefore important that this base-case-estimate must be as accurate as possible.

      Clark and colleagues note that the addition of the Hib vaccine will increase the cost of immunization per child four fold in India. They found that incidence of Hib pneumonia deaths and efficacy of the vaccine against Hib pneumonia, were factors that crucially influenced cost effectiveness.

      We find that the authors have used data that overestimates benefits of the vaccine.

      Pneumonia

      Evidence based medicine requires the use of the best evidence available for decision making and when properly conducted RCTs and case control data are available, other less empirical estimates of Hib disease burden should not be used.

      a) The authors write that their estimate that 7% of all pneumonias are caused by Hib is broadly consistent with the pooled 5% reduction in radiological pneumonia found in combining results of 2 Hib vaccine studies in Asia. Gessner BD, 2005, Baqui AH, 2007 They use inverse variance meta analysis with 64% weight assigned to the Indonesian study. However they write, mistakenly, that the Indonesian study found vaccine efficacy of -10% (95% CI -33% to 9), where the study actually reported efficacy of -12% ( 95% CI -33 to 9). In the Bangladesh study vaccine efficacy was 16% (CI -11 to 37) for pneumonia identified by WHO experts (n=675) and not 32% as stated in the cost-effectiveness report.<br> Meta analysis combining the vaccine efficiency from this case control study in Bangladesh with the vaccine efficacy in the cohort study from Indonesia was not possible with the data published in the two papers. However the arithmetic mean using the weights provided by Clark et al (Indonesia (weight 64%): vaccine efficacy -12% and Bangladesh (weight 36%): vaccine efficacy 16%; it gives a pooled efficacy is -1.9% (and not 5% as reported in the paper).

      b) The author did sensitivity testing assuming vaccine efficacy against pneumonia to be 50% of the base case figure used by the authors, which was 7%. In their worst case scenario, vaccine efficacy was 3.5% which is more optimistic than even the calculated base-case rate of vaccine efficacy of -1.9%.

      c) They estimate that 7% of pneumonia deaths in children aged 1-59 months are caused by Hib, just because according to them, Hib is responsible for 7% of all pneumonias. This can be true only is all pneumonia-causing-bacteria are equally lethal. There is no evidence in literature to support this assumption.

      Meningitis

      In the same way the authors used data from the Minz study on Hib meningitis. Minz S, 2008 However they trebled the incidence to 22/100,000, ostensibly to account for children without access to hospitals and cases not detected in the laboratory. Inflating the meningitis numbers was not reasonable for the following reasons:

      a. The Minz study was a community based with households visited fortnightly. Tests were done free of cost at the nearest hospital. Adjusting for poor access here was superfluous.

      b. Minz used a Latex Agglutination Test (LAT) which is particularly sensitive for detecting Hib (Sensitivity 93 per cent for Hib infections but 39 per cent for Neisseria meningitides). LAT would miss only 7% cases of Hib. Most of cases of purulent meningitis where no organism was identified were probably not Hib disease.

      c. The authors assume that parents, who don’t bring children to hospital when they have respiratory infections (a relatively trivial disorder), will not bring them when suffering from meningitis either. In doing so they overestimate the numbers not presenting to hospital with meningitis and in them they assume mortality would be 100%. The burden of Hib meningitis has been exaggerated in this way. The authors have written that even when they tested a scenario with the unadjusted Hib meningitis incidence (7 per 100,000 per year, <5yrs) as a minimal estimate, the cost per DALY averted remained below 3 GDP per capita. As discussed in the introduction such thresholds are not very useful for developing countries.

      Non pneumonia Non meningitis

      As the incidence of non pneumonia non meningitis (NPNM) is taken directly as a fraction of the incidence of meningitis; exaggerating the incidence of meningitis three fold (compared to empirical data from Minz) has the effect of trebling the calculated incidence of NPNM disease. The authors have responded that Hib NPNM accounts for only 1% of the estimated deaths prevented. Reducing the contribution of Hib NPNM would not alter the findings of the paper.

      Conclusion

      We hope the authors will be able to provide a more accurate base-case estimate of costs and benefits in the light of the above discussion. Such a base case estimate must include cost of treating the 1.9% increase in pneumonia in the vaccinated and also include the increased deaths from pneumonia.

      Pinky Bahl MD, Supriya Rastogi DCH, Jacob Puliyel MD


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    1. On 2015 May 12, Melissa Vaught commented:

      The systematic review described by this protocol has been published: Galipeau J, 2015


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    2. On 2014 Jun 05, Karen Woolley commented:

      I look forward to the results of your systematic review. I fear the evidence base will be limited, but that finding would be important in and of itself.

      In your efforts to identify the effectiveness of training, I hope you are able to examine the extent of training conducted by and for professional medical writers. A robust international certification (not just a certificate!) program has been introduced ie, candidates must qualify to undertake an exam on about 150 questions related to ethical and effective publication practices. If they pass, candidates gain the Certified Medical Publication Professional credential, which must be re-earned every 5 years.

      I hope your search strategy or the discussion in your paper also addresses the emerging (albeit limited) published evidence that professional medical writers can help enhance publication speed, promote adherence to CONSORT requirements, and reduce the risk of publication misconduct. A recent peer-reviewed publication concerning current industry publication practices indicates how such training can PREVENT publication misconduct by educating authors and sponsors about unacceptable practices (and leading to the withdrawal of requests to do the wrong thing).

      The most obvious way to enhance publication practices may be to enlist (and appropriately disclose) the support of a publication professional. Sometimes we miss the obvious.

      Professor Karen Woolley

      Disclosures: Researcher of ethical publication practices, Director of not-for-profit organisations focused on raising standards for and certifying publication professionals, paid trainer and provider of ethical and effective publication services...happy to provide additional disclosure details or a copy of my ICMJE standard disclosure form.


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    1. On 2015 Jul 14, Marco Weiergräber commented:

      A comment has been posted on Pubpeer on this publication in Epilepsia. The authors use a transmitter out of its technical specifications, i.e. the transmitter bandwidth is 1-50Hz, the nominal sampling rate 250 Hz. Theoretically, frequency reconstruction is possible up to 125 Hz (see Nyquist-Shannon sampling limit). However, the authors analyze up to 500Hz. This is not possible and not correct.


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    1. On 2013 Oct 31, John Cannell commented:

      The authors concluded markers of oxidative stress is present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

      Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      70% of American toddlers do not take th


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    1. On 2014 Jan 07, Giamila Fantuzzi commented:

      The authors state that "ANXA1 and LXA4 plasma levels were found to be decreased in sepsis patients". However, data in their tables indicate lack of significant differences between the control group and the sepsis group. Therefore, this conclusion does not seem justified. Furthermore, this paper fails to report the source of reagents used for measurement of ANXA1 plasma levels.


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    1. On 2013 Oct 28, Alex Manini commented:

      The reason this trial found no benefit may be due to the fact that IV contrast does not cause AKI, this according to good meta-analysis data performed by Mayo Clinic investigators. See www.ncbi.nlm.nih.gov/pubmed/23319662


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    1. On 2014 Jun 12, Mustapha Umar Imam commented:

      Is it scientifically correct to say "...we evaluate..." in a single author paper?


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    1. On 2014 Mar 15, George McNamara commented:

      Researchers may find more useful the FLIPPi affinity series of fluorescent protein biosensors developed by Wolf Frommer's lab:

      Gu H, Lalonde S, Okumoto S, Looger LL, Scharff-Poulsen AM, Grossman AR, Kossmann J, Jakobsen I, Frommer WB. A novel analytical method for in vivo phosphate tracking. FEBS Lett. 2006 Oct 30;580(25):5885-93. Epub 2006 Oct 2. Erratum in: FEBS Lett. 2007 Feb 6;581(3):579. PubMed PMID: 17034793; PubMed Central PMCID: PMC2748124. http://www.ncbi.nlm.nih.gov/pubmed/17034793

      The Gu et al correction is about details in the FLIPPi-260n sensor. Corrected sequences are available at http://www.addgene.org/13552/ FLIPPi-260n http://www.addgene.org/13556/ FLIPPi-30m and entries in between.


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    1. On 2018 Jan 19, Evgeniy Gorbunov commented:

      The product described in the paper is not homeopathic. During manufacturing process, the technology of consequential decrease of concentrations was used as it is clearly stated in the Materials and Methods of the paper.

      The effect of Subetta on human adipocytes was not assessed in the current study. Animals were assigned randomly to six different groups as it is mentioned in the Materials and Methods. The test samples were supplied encoded. The additional statistical analysis taking into account the adjustment for multiple hypotheses testing confirmed that the effect of Subetta differs from the control effect.

      OOO “NPF “MATERIA MEDICA HOLDING” was a sponsor of the experiment as it is mentioned in the Acknowledgments. The test samples were provided by OOO “NPF “MATERIA MEDICA HOLDING” as it is mentioned in the Materials and Methods. Three authors are employees of the company as it is mentioned at the title pages. Thus, all this crucial information was available to readers and it was not concealed.


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    2. On 2018 Jan 14, Evgenia V Dueva commented:

      In their article Bailbe et al. conclude, that “Subetta and release-active dilutions (RAD) of antibodies to β-subunit insulin receptor treatments are effective to significantly improve glucose homeostasis in GK/Par diabetic rats” and that “chronic oral administration of Subetta and RAD of Abs to β-InsR significantly attenuated fasting hyperglycemia and improved glucose homeostasis in GK/Par rats”. However, they fail to mention that Subetta is made from antibodies diluted beyond Avogadro’s limit (12 consecutive dilutions of 1:100, see Google patents US8535664) and thus contains no active molecules. The authors do not mention homeopathy in their article, but this clearly is a homeopathic drug.

      The results obtained by the authors are likely false positives (due to some technical artifact are human biases) considering the very low prior probability of a drug with no active molecules having any specific effect on human adipocytes. The authors have not attempted to use any randomization or blinding techniques to account for such possibilities. More over the data presented in the original paper does not support the abovementioned conclusion, as far as after correct statistical analysis antidiabetic effect of Subetta, can not be distinguished from the effect of water control.

      On the ethical side, the authors did not declare conflict of interests, though OOO "NPF "MATERIA MEDICA HOLDING" is a Russian Company that markets a number of drugs which contain active ingredients diluted beyond Avogadro’s limit, including Subetta. Three out of four authors work for this company. Furthermore, Oleg Epstein is CEO of the abovementioned Company.


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    1. On 2016 Nov 25, University of Kansas School of Nursing Journal Club commented:

      Team Members: McKee, M., Baker, M., Barnthouse, K., Janner, H., Hess, A., Severson, D, & Yungmeyer, A. (Nursing Class of 2017)

      Background

      Our team selected this article to review since it is relevant to the concepts covered in Section II of our course, Development of a Microsystem Leader, as it aims to explore issues found within the current nursing clinical microsystem. The article was found using CINAHL and it described how nursing and leadership from a large military trauma center developed and implemented evidence based change to create a standardized healthy work environment using the AACN Essential Standards for Establishing and Sustaining Healthy Work Environments: Improved Communication, Collaboration, Decision making, Appropriate Staffing, Staff recognition, and Authentic and transformational leadership skills (Nayback-Beebe, Forsythe, Funari, Mayfield, Thoms, Smith, Bradstreet, & Scott, 2013). Over recent years, many clinicians have focused on patient outcomes and the work environment in acute care setting, however few study have been done looking at the military health care setting. The main effectors of nurse satisfaction, intent to leave, and perceptions of poor quality of care are considered as unfavorable factors in nurse practice environments (Nayback-Beebe et al., 2013).

      Methods

      The article discusses the effects of the implementation of evidence-based leadership initiatives that aim to promote a healthier work environment. Using the military health care facility, the unit practice council first implemented quality improvement measures on their unit, and led to the evidence-based project involving the participation of the interdisciplinary patient care team. The research team compiled a PICOT question using the AACN Standards for Establishing and Sustaining Healthy Work Environments on what evidence-based leadership initiatives can be instituted in the IMCU to create a sustainable, healthier nursing work environment (Nayback-Beebe, et al. 2013). The group used the Iowa Model of Evidence-Based Practice to Promote Quality of Care, and collected, critiques and synthesized evidenced-based, long term solutions and identified leadership strategies that promote healthier work environment. The use of PICOT question allowed for the process improvement to foster a multidimensional research approach that included a staff survey, group sessions that allowed employees to express their views of old and new implementations, and staff/patient turnover data. The Likert-scale questionnaire was also used to determine nurse ratings on unit morale, unit stressors, and staff behavior as a result of the nurse work environment (Nayback-Beebe et al., 2013).

      Findings

      Survey results revealed that 59% of participating staff members rated staff morale in the IMCU as “poor” impacted by stressors on the unit by 96% of participants. These stressors included scheduling, poor communication, staff negativity, and lack of trust in leaders. It was also reported that 38% of staff members had witnessed a reportable event that failed to be documented in a Patient Safety Report. Moreover, 45% of staff members responded that they were dissatisfied or very dissatisfied with their scheduling, and 79% perceived a lack of recognition for positive contributions among the IMCU staff (Nayback-Beebe et al., 2013). Additionally, benchmarks were not met on pain management, fall risk, and medication reconciliation.<br> In order to supplement the planning process of achieving a healthy work environment, the team utilized the well-established AACN guideline to implement changes over a six month period. Interventions were based on the responses of the survey, as well as AACN’s six standards for creating a healthy work environment. After only three months of implementation within those six standards of a healthy work environment, dramatic improvements were seen in all areas. IMCU staff members reported an increase in positive feedback, communication, and teamwork, as well as a greater focus on patient care. Patient falls decreased by 75%, patient safety reports decreased by 20%, and all previously unmet benchmarks had improved from baseline. Evaluation of this evidence-based project showed positive outcomes in terms of nursing retention, patient and nursing satisfaction, and nursing quality indicators (Nayback-Beebe et al., 2013).

      Implications to Nursing

      It is evident in this selected literature that creating and maintaining a healthy work environment is crucial to nursing as it influences all levels of practice, including staff morale and patient outcomes. It was imperative for the unit to take a step back and identify factors contributing to the unhealthy work environment in order for change to happen and improvements to be made. This study demonstrates the process of utilizing evidence-based techniques in enhancing nursing practice and demonstrates the impact of establishing the AACN Standards for Establishing and Sustaining Healthy Work Environment within the healthcare system. While a barriers were found within the study, it remains a great resource for both the organization and nurses in creating a healthy work environment in their own unit (Nayback-Beebe et al., 2013). On a personal level, having a knowledge of what makes a healthy work environment is important to us as graduating nursing students since it is our goal to work on a unit that reflects these characteristics. It is essential to informed on what changes can be made to promote a healthy work environment and what are the processes of implementing those changes consists of. This article is very informative on both the knowledge and skills necessary to make changes that can be accomplish in the microsystem. We think that the consideration of evidence-based practice and the establishment of all of AACN Standards for Establishing and Sustaining Healthy Work Environment are necessary elements in creating and maintaining a healthy work environment. For changes to be made within a microsystem, each individual involved should be well informed on the process and involve in experience the change process that will have a positive impact in the system. Before we can improve the whole microsystem, we have to improve its parts. Each specific problem must be addressed. This perspective is important for microsystem leaders in order to make change to be effective. As future nurses, we can utilize the techniques from this study in terms of improving our own work environment and put emphasis on the establishment of trust with others and how to become authentic leaders. Overall, this literature has reinforced our understanding of a healthy work environment and serves as a reminder that small changes have potential to lead to tremendous outcomes.

      Reference Nayback-Beebe, A. M., Forsythe, T., Funari, T., Mayfield, M., Thoms, W., Smith, K., Bradstreet, H, & Scott, P. (2013). Using Evidence-Based Leadership Initiatives to Create a Healthy Nursing Work Environment. Dimensions of Critical Care Nursing, 32(4), 166-173. doi: 10.1097/DCC.0b013e3182998121.


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    1. On 2013 Oct 24, Felix Greaves commented:

      In their commentary, Seddon and Lee suggest that patients in England “get what they are given”, while making an argument that the National Health Service fails to extract the benefits of a competitive market. In fact, competition and choice have increased substantially in the NHS under reforms undertaken since 2004, with patients now able to choose their hospital for provision of secondary care for almost all conditions. The latest national choice survey found that 49% of patients recall being offered a choice of hospital for their first outpatient appointment (1). The impact of these reforms on health care quality is contested (2). What is known is that despite choice being available, the English public infrequently choose to go further than their local hospital (3). Even in hospitals with high profile quality failings, elective care attendances are resistant to change (4). Seddon and Lee may expect a rational market for health care, but despite being offered a choice of hospital, the English public does not behave as if there is one.

      1) Report on the National Patient Choice Survey - February 2010 England. London: Department of Health; 2010.

      2) Pollock A, Macfarlane A, Kirkwood G, Majeed FA, Greener I, Morelli C, et al. No evidence that patient choice in the NHS saves lives. Lancet. 2011. 378(9809):2057-60

      3) Dixon A, Robertson R, Appleby J, Burge P, Devlin N, Magee H. Patient choice: How Patients choose and how providers respond. London: King’s Fund; 2010.

      4) Laverty AA, Smith PC, Pape UJ, Mears A, Wachter RM, Millett C. High-profile investigations into hospital safety problems in England did not prompt patients to switch providers. Heal. Aff. 2012 ;31(3):593–601.


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    1. On 2014 Feb 28, David Keller commented:

      CoEnzyme Q10 supplements for MSA and, maybe, certain PD sub-types?

      Ozawa commented that the results of this study suggest "that the oral supplementation of COQ10 may be helpful in treating patients who have MSA." (1)

      Multiple-system atrophy (MSA) is a degenerative alpha-synucleinopathy, sharing some similar pathological findings and clinical symptoms with Parkinson's disease (PD) and dementia with Lewy bodies.

      In the past, oral supplementation with coenzyme Q10 was postulated to be neuroprotective in PD, a hypothesis which has been set aside after disappointing clinical trial results.

      If Ozawa's hypothesis that oral CoQ-10 supplementation may be helpful in MSA is proven correct, could it be that there is a sub-set of PD patients who might also benefit from oral CoQ-10 supplementation? Perhaps those PD patients who share certain clinical or pathological findings with MSA patients? Are there any plans for a clinical trial of CoQ-10 supplementation in MSA patients?

      1. Ozawa T. The COQ2 mutations in Japanese multiple system atrophy: Impact on the pathogenesis and phenotypic variation. Mov Disord. 2013 Dec 27. doi: 10.1002/mds.25685. [Epub ahead of print] PubMed PMID: 24375810.

      To facilitate discussion, I respectfully request the person who found this comment "not helpful" to state their reason


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    1. On 2013 Jun 27, Phil Bourne commented:

      Readers may be interested in the various developments around data science that relate to the issues discussed in this article. Refer to http://www.force11.org/


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    1. On 2014 Jan 08, Brett Snodgrass commented:

      Dear Authors,

      Thank you for an excellent article.

      The regression of the vessel is likely due to altered hemodynamics and radiographic disappearance of an anatomic connection described by Wearn (vessel of Wearn).

      http://bit.ly/JTWearn

      For additional commentary, please see. https://twitter.com/BrettSnodgrass1/status/417431071244840960

      Comments and suggestions are welcome.

      Thank you kindly.


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    1. On 2013 Jun 18, Dan Arking commented:

      This paper presents an interesting method using Random Forests to jointly model static (fixed effects across cell types), conditional (cell type specific), and dynamic (drives expression differences between cell types) eQTLs (see Figure 1). They note a large increase in the number of trans eQTLs identified (due to increased power), which actually represent the majority of eQTLs.


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    1. On 2014 Apr 24, Milad Nazarzadeh commented:

      Tramadol hydrochloride is a common prescription pain reliever that is structurally similar to morphine and codeine with its analgesic effects identified as a mu-receptor agonist. Due to its opioid-like stimulant effects, the potential for tramadol misuse is a public health concern. According to our latest research finding, tramadol could be a related factor or co-factor for adolescent alcohol, cannabis and ecstasy abuse. This issue should be considered in tramadol prescription for treatment of premature ejaculation.


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    1. On 2014 Jul 04, Christos Chinopoulos commented:

      Could it be that LPS-induced succinate over-production is due to itaconate formation? LPS induces Irg1, a gene

      coding for cis-aconitate decarboxylase, specifically expressed in cells of macrophage lineage Proc Natl Acad Sci

      U S A. 2013 May 7;110(19):7820-5. doi: 10.1073/pnas.1218599110, yielding itaconate. Itaconate is preferentially

      used by succinyl CoA ligase forming itaconyl CoA, thus generating an accumulation of succinate when the ligase

      operates towards succinyl CoA formation ADLER J, WANG SF, & Lardy HA (1957) The metabolism of itaconic acid by

      liver mitochondria. J. Biol. Chem, 229, 865-879, and WANG SF, ADLER J, & Lardy HA (1961) The pathway of

      itaconate metabolism by liver mitochondria. J. Biol. Chem, 236, 26-30.


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    1. On 2014 Jan 18, Alexander I. Alexandrov commented:

      In my opinion the authors slightly mislead the readers by the title and abstract of the paper. The work demonstrates that in the presence of the prion [RNQ1+], Rnq1 overexpression (in the form a fusion with RFP) results in cell growth defects and oxidative stress. The only key role of Hsp104 in this process is that it is required for the maintenance of the prion form of Rnq1, which is a well established fact. In my opinion the paper would be better named “Rnq1-RFP expression causes prion-mediated oxidative stress in yeast” or something of the sort. Also, the abstract states: “Expression of RNQ1-RFP in Saccharomyces cerevisiae cells led to the generation of the prion form of the protein and increased oxidative stress”. This is also misleading, since the prion form of Rnq1 was probably present in the parental strain before introduction of the fusion protein. It would be better to say that Rnq1-RFP joined pre-existing amyloids of wtRnq1. Notably, the article does not explicitly state that the parental strain was [RNQ1+]. In my opinion, the article lacks a very simple, yet informative experiment, where cells exhibiting oxidative stress could be cured of the prion by GuHCl and then assayed for alleviated growth defects and oxidative stress. This would provide more clear proof that the reduced toxicity and oxidative stress were caused by the prion and not by the deletion of HSP104. In the same vein, it would be interesting to compare cells with and without the [RNQ1+] prion (without any overexpression of Rnq1-RFP) in terms of their oxidative stress. Also, I was surprised to find no reference to papers which were the first to observe the toxic effects of Rnq1 overexpression and to identify the mechanism through which they were realized– PMID’s 18480252 and 22529103. The second article has a mechanistic explanation of the toxic effect and it would be interesting to see if the effects observed in this article are caused by the same mechanism. Notwithstanding these points, I think that the article is interesting and informative.


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    2. On 2014 Jan 17, Alexander I. Alexandrov commented:

      None


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    1. On 2013 Oct 25, Robert Cox commented:

      I agree with the other Robert, especially about the last paragraph.


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    2. On 2013 Jul 25, Robert Tibshirani commented:

      This is a interesting article that summarizes the current role of the Bayesian approach to statistics. The cautionary last paragraph is especially useful.


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    3. On 2013 Jun 13, Robert Tibshirani commented:

      None


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    1. On 2014 Jan 24, Pavel Baranov commented:

      This is an excellent report that reveals the function of a PTEN variant with N-terminal extension produced as a result of translation initiation at a non-AUG codon. The extension is evolutionary conserved and was predicted earlier based on comparative sequence analysis of PTEN mRNA from several mammals, ranked #12 in the table 1 of Ivanov IP, 2011.


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