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

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

On 2014 Nov 13, Robert Eibl commented:

Dear Readers,

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

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

Best regards,

Dr. Robert Eibl

REFERENCES

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

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

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

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

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

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

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

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

On 2015 Feb 11, Michael E Miller commented:

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

On 2015 Feb 07, Jayaprakash Sahoo commented:

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

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

References:

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

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

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

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

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

On 2013 Nov 12, Christophe Dessimoz commented:

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

On 2015 Aug 15, John Tucker commented:

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

On 2014 Jan 21, Amanda Capes-Davis commented:

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

On 2014 Oct 15, Amanda Capes-Davis commented:

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

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

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

On 2013 Nov 06, Brian Walcott commented:

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

On 2013 Nov 06, Rafael Najmanovich commented:

None

On 2013 Nov 06, Rafael Najmanovich commented:

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

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

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

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

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

On 2014 Feb 15, Amanda Capes-Davis commented:

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

On 2014 Jun 20, James Q Zheng commented:

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

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

On 2014 Jun 19, Jim Woodgett commented:

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

On 2014 Jan 28, Vardan Karamyan commented:

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

On 2014 Aug 07, Raha Pazoki commented:

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

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

On 2013 Oct 31, Ben Busby commented:

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

On 2016 Nov 03, Morten Oksvold commented:

None

On 2016 Apr 05, Md. Shahidul Islam commented:

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

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

On 2016 Feb 23, Md. Shahidul Islam commented:

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

On 2016 Feb 23, Md. Shahidul Islam commented:

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

On 2015 Aug 12, Md. Shahidul Islam commented:

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

On 2015 May 26, Md. Shahidul Islam commented:

None

On 2013 Oct 29, John Cannell commented:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

On 2013 Oct 30, Woo Jae Kim commented:

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

On 2014 Nov 24, Roger Keller Celeste commented:

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

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

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

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

On 2013 Oct 28, Leslie Vosshall commented:

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

On 2013 Oct 31, John Cannell commented:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

On 2014 Feb 13, Bruno Ramalho Carvalho commented:

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

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

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

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

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

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

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

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

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

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

On 2015 Apr 02, Harri Hemila commented:

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

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

On 2014 Mar 20, Jonathan Eisen commented:

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

On 2016 Apr 09, Sergio Uribe commented:

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

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

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

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

On 2015 Oct 05, Jan Egger commented:

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

Best wishes, Jan

On 2013 Nov 01, Erick H Turner commented:

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

On 2016 Feb 07, Fang-Cheng Yeh commented:

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

On 2013 Oct 23, Rafael Najmanovich commented:

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

On 2013 Dec 12, Matthew Inglis commented:

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

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

On 2014 Feb 06, Simon Young commented:

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

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

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

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

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

On 2014 Apr 08, Dr Nicholas D Gollop commented:

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

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

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

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

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

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

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

References

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

On 2014 Jan 18, Jamil Hajj-Chahine commented:

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

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

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

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

References

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

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

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

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

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

On 2013 Oct 24, John Cannell commented:

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

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

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

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

On 2017 Sep 21, Hendrik S. Fischer commented:

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

On 2017 Jul 12, Robert Fleming commented:

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

On 2014 Jul 30, David Keller commented:

Doctors should replace handshakes with fist bumps, sanitize stethoscopes and ditch white coats & neckties

The recommendation to substitute fist bumps for handshakes to decrease bacterial transmission makes sense. In addition to the much briefer contact time and much smaller area of skin contact during a fist bump, fist contact occurs only on the dry skin of the dorsal hand, not the moist and sweaty palms which support higher bacterial counts. The widespread neglect of hand-washing has been documented. Fist bumps reduce exposure to gram negative bacteria like salmonella (due to fecal contamination) and gram positive bacteria like Staph Aureus (due to nose-picking) on unwashed hands.

Substituting fist bumps for handshakes is excellent advice for clinicians, along with eliminating other sources of documented pathogen transmission: unsanitary stethoscopes (1) and rarely-laundered neckties (2) & white coats (3).

References

1: Longtin Y, Schneider A, Tschopp C, Renzi G, Gayet-Ageron A, Schrenzel J, Pittet D. Contamination of stethoscopes and physicians' hands after a physical examination. Mayo Clin Proc. 2014 Mar;89(3):291-9. doi: 10.1016/j.mayocp.2013.11.016. PubMed PMID: 24582188.

2: Day M. Doctors are told to ditch "disease spreading" neckties. BMJ. 2006 Feb 25;332(7539):442. PubMed PMID: 16497745; PubMed Central PMCID: PMC1382570.

3: Banu A, Anand M, Nagi N. White coats as a vehicle for bacterial dissemination. J Clin Diagn Res. 2012 Oct;6(8):1381-4. doi: 10.7860/JCDR/2012/4286.2364. PubMed PMID: 23205352; PubMed Central PMCID: PMC3471503.

On 2013 Oct 23, Alfonso Rodriguez-Morales commented:

Excellent article!!!

On 2016 Nov 01, Michael Axtell commented:

The URLs for ShortStack software and test data given in this paper are out of date:

ShortStack software is now available on github .. the latest release is at https://github.com/MikeAxtell/ShortStack/releases

The ShortStack test data / tutorial is now at https://psu.app.box.com/v/axtelldata , in directory 'ShortStack_TestData'

Also note that some of the options and settings in this work no longer apply to current version of ShortStack.

Thanks, Mike Axtell

On 2014 Mar 20, Jae-Weon Kim commented:

As Dr. Wright pointed out, previous report by Walsh et al at 2005 was not a universal finding. Recently we, Korean Gynecologic Oncology Group, reported that the incidence of synchronous ovarian malignancies in young women with endometrial cancer was quiet low (4.5%), unlike previous studies have revealed (11-29%). You can check our report at PMID: 24051220.

On 2014 Apr 19, Karthik Balachandran commented:

The authors describe an industry sponsored and industry designed trial of saroglitazar- a dual PPAR alpha and gamma agonist, explaining establishment of safety and efficacy as the raison de etre. However, closer scrutiny raises several questions.

1.First of all, the value of triglyceride reduction has not been clearly demonstrated in patients with type 2 diabetes. In fact, the largest trial on lipid management in diabetes till date- the ACCORD LIPID trial shows that the additional triglyceride reduction with fenofibrate was not useful for CV mortality reduction. Thus targeting “residual cardiovascular risk” in statin treated patients is questionable, especially with the surrogate endpoints- lab values- instead of real world outcomes like mortality or cardiovascular events.

2.More importantly this trial includes patients whose triglycerides were not adequately controlled on statin therapy. The dose of atorvastatin used(10 mg) given for a period of 4 weeks, is hardly the maximum dose or the duration that can be called as “inadequately controlled on statin." 3.Furthermore, the authors compare saroglitazar with placebo for no sound scientific reason. The use of inappropriate comparator has the potential to make the study drug look superior because it has been compared with a dummy sugar pill!

4.The drug is declared safe with 12 weeks of data and a voluntary(read optional) 24 week visit. This is especially important as the predecessors of the drug(muraglitazar and aleglitazar) were discontinued due to increased all cause and cardiovascular mortality. It is unlikely that the cardiovascular safety of any drug can be ascertained in the short time of 12 weeks. One must bear in mind that drugs for dyslipidemia are taken life long.

5.The study was conducted in 29 centers across India to get a sample size of 302. As the cost of training personnel is less, the integrity of data is more and is eminently possible to get 300 odd diabetics from any single center of a populous country like India, it makes one suspect whether this was a seeding trial. A seeding trial is done with the express purpose of giving marketing advantage to the company and not to glean any useful scientific information. Use of prominent senior academics as the authors means their name exists for the purpose of giving the illusion of scientific rigor. This combined with manuscript preparation and editorial assistance by the company employees manufacturing the drug means, this could be a ghost written document- promotional material masquerading as an academic article.Although seeding trials or ghost writing  is not illegal, it is considered unethical.

6.The article also mentions that the trial was approved by ethics committee of individual sites, many of which are private clinics.It is difficult to believe that private clinics have independent ethics committees. So, the question remains - does the drug do anything that cannot be done at half the cost by existing medicines? Is it safe in the long run?

On 2015 Mar 18, Adrian Barnett commented:

Suffering a hospital-acquired complication is a time-dependent variable as some patients will experience it some days after their admission. These patients cannot be discharged between admission and the complication. Unfortunately the statistical analysis used ignores this fact and hence the estimates are subject to the length bias and are likely to be over-estimates of the extra length of stay. A solution is to use multi-state models combined with Cox survival models with day of admission as the time variable. A hospital-acquired complication is a transient state between admission and discharge. This accounts for the timing of complications and correctly estimates the extra length of stay due to a complication.

On 2013 Oct 22, Jonathan Eisen commented:

This paper represents a landmark study in something that has intrigued many microbial diversity / human microbiome researchers for many years. Early in the history of sequencing rRNA genes from human microbiome samples, researchers discovered something a bit weird - quite a few sequences were coming from what appeared to be close relatives of Cyanobacteria. This was weird because all known Cyanobacteria were thought to be photosynthetic and - well - there is not too much light in the human gut. Now - one possible explanation for this was that these sequences were coming from photosynthetic bacteria but these bacteria were not residents of the human gut but came via consumable items (i.e., food and drink). Perhaps they were actually from chloroplasts of something in the diet (after all - chloroplasts are derived versions of cyanobacteria). This idea was discussed at many meetings I attended. But there was no evidence for this. Another possibility was that there was in fact some light in the human gut - leaking through from the outside or being produced from the inside. And perhaps this was enough to do a little photosynthesis. Sound crazy? Well, not so crazy after reports of photosynthesis in the deep sea. A third possibility was that these sequences were coming from residents of the human gut that were related to (or even within) cyanobacteria but were not photosynthetic. More detail on possible explanations are in this new paper and in some of the material cited therein. Anyway - Ruth Ley has been discussing these unusual sequences for years and now in this paper her group and the group of Jill Banfield at Berkeley (along with some others) has used metagenomics and detailed assembly and phylogenetic analysis to reveal many new insights into these sequences.

(this comment is based on a blog post I wrote about the paper: http://phylogenomics.blogspot.com/2013/10/who-are-microbes-in-your-neighborhood.html)

On 2013 Oct 23, Attila Csordas commented:

associated proteomics data can be downloaded from ProteomeXchange http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD000419

On 2013 Nov 01, Allison Stelling commented:

The FTIR ATR instrument highlighted in the infrared section of this interesting overview was recently used in a study on patients with brain tumors, normal mice, and tissue cell lines by the same authors (and me): Stelling AL, 2013.

On 2014 Jan 01, Qian Liu commented:

This is a special issue for Chinese lung cancer studies. http://www.cancerjournal.net/showBackIssue.asp?issn=0973-1482;year=2013;volume=9;issue=5;month=September;supp=Y

On 2015 Jul 27, Simon Young commented:

While the aims of this article are good it has some problems: 1. The Abstract states “Because serotonin levels in the brain are dependent on the availability of the food-derived precursor tryptophan, foods such as chicken, soyabeans, cereals, tuna, nuts and bananas may serve as an alternative to improve mood and cognition”. However, as the authors state correctly in the Discussion “contrary to popular belief, most common foods high in Trp do not increase the plasma TRP:LNAA ratio enough to exert any positive effects on mood/cognition, because they also contain large amounts of other LNAA.” Ingestion of chicken, soyabeans, cereals, tuna and nuts would certainly not, as suggested in the Abstract, improve mood and cognition due to increased brain serotonin synthesis, as they would not increase brain synthesis. Why bananas are included in the list is not clear. Bananas contain high serotonin levels Feldman JM, 1985, but as mentioned in the article serotonin in food does not cross the blood-brain barrier. Apparently the high level of serotonin in bananas has resulted in the popular belief that bananas must contain high tryptophan levels. A search in Google using the key words banana and tryptophan finds numerous sites stating that bananas have high levels of serotonin. However, the United States Department of Agriculture Nutrient Database http://ndb.nal.usda.gov/ndb/foods gives the tryptophan content of bananas as 9mg per 100g, a very low level that would contribute a negligible fraction of the normal daily intake of tryptophan even if several bananas were eaten. 2. Another problem with the article is that the authors ignore that fact that food may act as a cognitive enhancer through mechanisms other than alterations in tryptophan and serotonin. The acute improvement in memory after a meal is well known and is, in whole or in part, associated with an increase in blood glucose, which may improve cognition through an increase in acetylcholine, but not serotonin Smith MA, 2011. All macronutrients may have beneficial effects on cognition as protein, carbohydrate and fat meals all improve performance on different cognitive tests in humans Kaplan RJ, 2001. Thus, for example, the enhancement of memory due to a high carbohydrate diet mentioned in relation to citation 111 in the article may have nothing to do with changes in brain serotonin synthesis. 3. Hulsken et al discuss the effect of tryptophan supplementation using alpha-lactalbumin, a protein with high levels of tryptophan, and egg protein hydrolysate. They also mention some studies using pure tryptophan, but omit mention of many articles in which mood and/or cognition were measured after administration of pure tryptophan. The first such study was published more than 50 years ago SMITH B, 1962. Many of the missing studies on healthy participants are cited in a recent review Silber BY, 2010. Numerous studies in which tryptophan was given to vulnerable subjects were not cited by Hulsken et al. A Cochrane Database Systematic Review concluded that the available evidence suggests that tryptophan is better than placebo at alleviating depression Shaw K, 2002. Tryptophan has also been used in other conditions. For example, while the article mentions the beneficial effects of a high carbohydrate diet and alpha-lactalbumin on premenstrual mood it does not mention a clinical trial in which tryptophan (6g per day) was better than placebo in treating premenstrual dysphoria Steinberg S, 1999. Given the high dose of tryptophan given, studies such as this clinical trial need to be taken into account when assessing the authors’ suggestion that “Unphysiological high increases in brain Trp lead to negative effects on mood in both healthy and vulnerable subjects”.

On 2014 May 01, Gaetano Santulli commented:

G protein-coupled receptor kinase 2 in patients with acute myocardial infarction. http://www.ncbi.nlm.nih.gov/pubmed/21296320

PMID: 21296320

https://www.researchgate.net/publication/49812640_G_protein-coupled_receptor_kinase_2_in_patients_with_acute_myocardial_infarction

On 2014 Jan 22, Markus Meissner commented:

Regulation of actin cytoskeleton networks is fundamental for cell migration. These networks can power the protrusion of the cell plasma membrane, termed lamellipodia, for movement. Actin-related proteins 2 and 3 (Arp2/3) form a complex which can nucleate or form branching of actin filaments. There has been a number of nucleating promoting factors identified for the Arp2/3 complex in different cellular locations. However, there is less evidence of inhibitory factors for the Arp2/3 complex. To date the only inhibitory factors for Arp2/3 identified are in endocytic pits and endosomes and until recently it was an unknown whether a protein could inhibit Arp2/3 at the lamellipodia.<br> This study is the first to present evidence of an inhibitory protein for the Arp2/3 complex in lamellipodia protrusion which counteracts the WAVE complex in actin polymerisation. The authors demonstrate with convincing experiments that a novel protein, termed Arpin, can inhibit the Arp2/3 complex in vitro. Using a range of different model systems they validate that Arpin controls cell migration and ‘steering’ and hence appears to be evolutionary conserved.. In both, mammalian cells and amoeba, the Arpin knockout causes the cells to cover an extensive territory owing to the inability of the cells to slow down and change trajectories. Moreover, when Arpin is injected into fish keratocytes, they observed a marked alteration in cell movements.<br> Overall, the paper is very interesting and convincingly shows that Arpin is a conserved inhibitor of Arp2/3. Despite the amount of data, demonstrating a highly complex interaction of Arp2/3, Wave and Arp, the authors present a rather simplified model that will certainly increase in complexity over time.

Review by Jamie Whitelaw on behalf of the Glagow Toxoplasma journal club (Allison Jackson, Clare Harding, Elena Jimenez-Ruis, Eleanor Wong, Nicole Andenmatten, Saskia Egarter, Fernanda LaTorre Barragan, Robyn Kent, Johannes Stortz, Gurman Pall, Lilach Sheiner, Gary Ward and Markus Meissner).

On 2013 Nov 08, Tom Kindlon commented:

I posted two replies on the BMJ site.

The first was a short one that was short enough for them to include in the print edition, "Author's response: Criticisms of the PACE Trial were justified" (which can be read by anyone at: http://www.bmj.com/content/347/bmj.f5963/rr/667107).

When it was clear that was not going to be published, I wrote a longer reply: "PACE Trial: Simply giving a reason why an outcome measure was changed is not necessarily sufficient" (which can be read by anyone at: http://www.bmj.com/content/347/bmj.f5963/rr/670755).

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 NCT012073190. We believe the correct ID, which we have found by hand searching, is NCT01307319.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2016 Mar 01, Peishun Shou commented:

A focus on the role of osteopontin (OPN) in MSC differentiation. http://onlinelibrary.wiley.com/doi/10.1002/stem.1567/full

Recently reviewed in a Cell Death & Differentiation paper entitled "Fate decision of MSCs" http://dx.doi.org/10.1038/cdd.2015.168

On 2013 Oct 24, Rebecca Balter commented:

we read this article for our center's journal club. Truly impressive paper, a rare treat to see such good behavioral pharmacology in Nature.

Considering that KYNA acts on the cannabinoid system through modulation of nicotinic ACh receptor activity I wonder how Ro 61-8048 would alter responses to tobacco/nicotine.

On 2013 Oct 24, Farris Timimi commented:

Although hampered, as many behavioral studies focused on social networking, by a lack of granularity or the compliment of attitudinal data, this is a fascinating observational examination of demographic behavior correlate with social comments. Realistically, I suspect that this may well serve as a model for other health-care social media data scraping assays, i.e., adverse drug reactions, etc.

On 2015 Dec 21, Amy Baxter commented:

The authors use the same methodology to evaluate their free-flow collection device versus prolonged Buzzy application as they did previously, using their free-flow device versus a standard tourniquet at varying times from 30 seconds to 180s. https://www.ncbi.nlm.nih.gov/pubmed/21414180 They found similar 2.6-23.8% differences in RBC, HgB, HCT, Eos and Basos when leaving a tourniquet on 2 minutes, as they did with Buzzy in this study which found 2.0-2.2% for RBC, HgB, and HCT only. As the article does not reference the previous work by the authors showing the same changes due to tourniquet application, an invited editorial comment is now linked. Disclosure: I invented and researched Buzzy. The Buzzy device is used for 120s in this study, which is off-label. We do not recommend any prolonged application of the tourniquet/Buzzy device.

On 2014 Nov 02, Ivan Oransky commented:

This paper has been retracted: http://retractionwatch.com/2014/10/29/structure-error-sinks-nih-mit-snu-peptide-paper/

On 2015 Apr 07, Sandro Mandolesi commented:

Reflections on the Canadian study by Traboulsee et al. Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study

http://www.pagepressjournals.org/index.php/vl/article/view/vl.2015.5100

On 2014 Dec 27, Paolo Zamboni commented:

Dear Colleagues,the rate of stenosis in angiography is calculated by comparing the diameter of the stricture with that of the segment immediately preceding it. In this article it has been proposed a novel method which compares, along the entire anatomical length of the internal jugular vein, the widest with the narrowest point.However,the jugular in normal cases is characterized by a big variability in size, with >50% variation of the diameter by comparing the bulb with any other point of the vein. This is the reason because the proposed methodology was unable to separate healthy controls from MS cases. If someone should be interested in the assessment of primary venous obstruction please click the link below http://www.pagepressjournals.org/index.php/vl/article/view/vl.2014.4195

On 2014 Dec 27, Paolo Zamboni commented:

Dear Colleagues,the rate of stenosis in angiography is calculated by comparing the diameter of the stricture with that of the segment immediately preceding it. In the article herein commented, it has been proposed a novel method which compares, along the entire anatomical length of the internal jugular vein, the widest with the narrowest point.However,the jugular in normal cases is characterized by a big variability in size, with >50% variation of the diameter by comparing the bulb with any other point of the vein. This is the reason because the proposed methodology was unable to separate healthy controls from MS cases. If someone should be interested in the assessment of primary venous obstruction please click the link below http://www.pagepressjournals.org/index.php/vl/article/view/vl.2014.4195

On 2013 Dec 09, John Cannell commented:

The authors report that immune system dysregulation is common in depression and autism spectrum disorder (ASD). The question is why does this immune dysregulation occur and, in the case of autism, 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

On 2013 Dec 18, Dorothy V M Bishop commented:

I'm interested in cerebral lateralization in relation to dyslexia, and I would be grateful if the authors could provide additional data that would allow me to relate their work to other findings in the literature. Where atypical lateralization is seen, this could either reflect a reduction in the strength of left-sided lateralization, or inclusion of a higher than usual proportion of individuals with right-sided lateralization (see Illingworth S, Bishop DVM: Atypical cerebral lateralisation in adults with compensated developmental dyslexia demonstrated using functional transcranial Doppler ultrasound. Brain Lang 2009, 111:61-65). It would be good to know how these data compare, and whether the effect size is comparable to previous studies. Could the authors please provide a table showing the laterality indices from vWFA and IFG for all individual subjects in the dyslexic and control groups? I I should add that I think more caution is needed in interpreting the correlational data reported here, given the sample sizes of 15 and 16. For instance, the correlations shown in Figure 4B have overlapping confidence intervals. With N of 15, a correlation of -.12 has 95% CI from -.6 to .42; a correlation of -.66 has 95% CI from -.88 to -.22. Thus the differences between these correlations could be due to sampling error.

On 2013 Dec 06, Rafael Delgado-Ruíz commented:

The long term evaluation of retrieved implants, provide us with the best evidence of the behavior under real daily conditions, so I am really grateful with analysis similar to the presented in this work.

On 2013 Dec 12, Adam Eyre-Walker commented:

I thank Dr. Cherry for another set of insightful comments.

He points out we may have overestimated the stochasticity associated with the accumulation of citations. He correctly notes that if assessors tend to err erroneously in the same direction in their judgments, then the errors associated with their assessments will be correlated. One might imagine, for example, that assessors tend to over-rate papers in high impact factor journals, by particular authors, or from a particular institution. Such correlated errors will mean that the correlation between assessor scores underestimates the error associated with making an assessment and this will in turn imply that the stochasticity associated with the accumulation of citations is less than we have estimated. However, if the error associated the accumulation of citations is also correlated to the error associated with the assessment then the stochasticity associated with the accumulation of citations may have been underestimated. The errors associated with assessments and citations might be correlated given that citations depend, to some extent, on post-publication subjective assessment.

A likely bias, and hence a source of correlated erros, is a tendency for assessors to overestimate papers in high-ranking journals. As we showed, the partial correlation between assessor scores and between assessor scores and the number of citations, controlling for impact factor, are very weak (r<0.20). This suggests that within journals, subjective estimates of merit and the accumulation of citations are dominated by error. The weaknesses of these correlations might be because there is little variation in merit within journals, with most of the variance in merit being between journals. However, it seems unlikely that journals are a perfect arbiter of merit because their judgments are based on subjective assessment, which we have demonstrated to be poor. Furthermore, as noted above, it is quite likely that the errors associated with assessments are correlated to errors associated with the accumulation of citations. The system is clearly complex and it may prove to be very difficult to accurately estimate the variance associated with the accumulation of citations.

We argued in our original paper that the impact factor might be the best of the methods currently available for assessing merit, though we emphasized that it was likely to be very error prone. We argued that it might be a reasonable measure, because the IF is a form of pre-publication review – in accepting a paper for a particular journal, the scientific community has decided that the paper of sufficient merit to be published where it is accepted. This decision is likely to be the consensus of several individuals, with some individuals, such as editors, having a greater say than others. Dr. Cherry points out that using the IF as a measure of merit might potentially be matched by combining the post-publication assessments of several individuals. He shows that if we ignore any potential biases (i.e. correlated errors), for example assessors being influenced by the IF, then the estimated correlation between assessor score and merit is 0.60, and the correlation between the IF and merit is expected to be 0.80. Dr. Cherry arrives at these estimates in the following manner (he elaborated upon this in a subsequent email). If the errors are uncorrelated then the correlation between two variables, which are correlated to X, is expected to be the product of their correlation to X; e.g. if the correlation between variable 1 and X is r1 and the correlation between variable 2 and X is r2 then the correlation between 1 and 2 is expected to be r1*r2. The correlation between assessor scores in the Wellcome Trust data is 0.36, which implies the correlation between a single assessor score and merit is SQRT(0.36) = 0.60. The square of this is the proportion of the variance in score explained by merit, which is equivalent to our equation 1 (the square of the correlation between a single assessor and merit is the expected correlation between two assessors). From this equation we can estimate the ratio of the error to merit variance, which is 1.78 from the Wellcome Trust data. If we have n independent assessors we expect this ratio to be reduced by a factor n; hence the expected correlation between the mean score from n assessors and merit is 0.60 (n=1), 0.73 (n=2) and 0.80 (n=3). The inferred correlation between the IF and merit is 0.80; this comes from noting that the correlation between assessor score and IF is expected to be the product of the correlation between assessor score and merit, and the IF and merit; given that the correlation between assessor score and merit has been estimated to be 0.60, and the observed correlation between assessor score and IF is 0.48, we estimate that the correlation between IF and merit is 0.80. Hence we would need 3 independent assessors to match the correlation between IF and merit. For comparison, the correlation between the number of citations and merit is inferred to be 0.69 if we use the correlation between IF and the number of citations, and 0.63 if we use the correlation between assessor score and the number of citations to make the estimate. Hence the IF is the best measure of merit, and would only be rivaled by subjective assessment if we engage 3 independent reviewers; the number of citations is estimated to be better than a single reviewer, but worse than two reviewers. However, I would emphasise that these estimates all assume that errors are uncorrelated.

Finally, Dr. Cherry points out a problem with using the correlation coefficient on a bounded scale. The correlation coefficient is typically scale independent – i.e. if you add, subtract, multiply or divide one of the variables by some value then the correlation coefficient remains unchanged. However, this is only true if the scale is unbounded; if there is a maximum or minimum value then the correlation may be poor, even if the reviewers agree on the ranking of the papers. For example, if one assessor tends to rate harshly and another generously then the correlation may be poor because most of the harsh reviewer’s scores are the lowest mark and most of the liberal reviewer’s scores are the highest mark. The solution to this problem is to offer an essentially unbounded scale. However, as we pointed out in our original article, the tendency for reviewers to differ in their average mark could potentially have serious consequences in an assessment exercise, particularly if individuals or universities are assessed by a limited number of individuals.

On 2013 Nov 11, Joshua L Cherry commented:

I thank Dr. Eyre-Walker for a wonderful response that should serve as a model for the rest of us.

I have some additional comments about the paper's interpretation of the reported correlation coefficients. I would question the conclusion that journal impact factor (IF) is the "least bad" measure of article merit.

1) The authors conclude that citation is a highly stochastic process and that citation number is a poor measure of article merit. This interpretation rests on assumptions that preclude the possibility that citation information contains any unique wisdom. In technical terms, the problematic assumption is that the errors made by different assessors in judging merit are uncorrelated, so that citation number can at best provide a less noisy estimate of what assessors estimate. It seems quite reasonable that, contrary to this assumption, different assessors tend to systematically err in the same ways, and that citation number is comparatively free of such errors.

Suppose that it had turned out that assessor scores correlated perfectly with each other, but still only moderately well with citation number. The authors' reasoning would compel us to believe that the assessors were correct, and that the low correlation with citation number was entirely due to stochasticity of citation. This is not, however, the only reasonable interpretation. The assessors might simply agree in over-rating the merit of some papers and under-rating that others, while the citation number came closer to the truth.

This point applies even when, as in reality, between-assessor correlation is far from perfect. Imagine, to take an extreme case, that citation number is a flawless measure of merit. Suppose further that different assessors tend to err in the same way in judging merit, but also disagree with each other to some extent. What, then, would the correlation coefficients look like? They might have exactly the values that were observed in this study. Thus, there seems to be no basis for dismissing citation number as a measure of merit.

2) It is enlightening, nonetheless, to consider performance of the metrics under the assumption that assessor errors are uncorrelated. Under this assumption, the average of scores given by a large number of assessors approaches perfect correlation with merit. It is true that IF correlates better with that average (equivalently, with merit) than does a single assessor score (a correlation of ~0.8 as compared to ~0.6 for the WT data). However, we can also calculate that, for the WT data, the mean of two assessor scores would do about as well as IF, and the mean of three or more assessor scores would be superior to IF as a measure of merit.

3) Perhaps the most important observation in the paper is the weakness of the correlation between scores given to the same paper by different post-publication assessors. This is at the heart of the conclusion that assessors do a poor job of assessing merit and that their ratings should not be used.

One possible source of assessor disagreement is that some assessors tend to rate all papers more highly than others do. If a generous assessor is paired with a harsh assessor, the two will often rate a paper differently even if they agree on its merit relative to that of other papers. In principle, even if all assessors agreed perfectly on their ranking of all papers, a low between-assessor correlation could result. The correlation would be high if we considered just two assessors and maintained assessor identity in the calculations. However, the data analyzed in the paper involved many assessors, and assessor order was deliberately randomized, so the correlation would be diminished if assessors effectively use different scales.

This type of disagreement would not be troubling with respect to assessors' ability to discern merit. It would present a practical problem, but this problem would be amenable to correction, which might be extremely valuable. One can imagine schemes of assessor assignment and score analysis that largely remove this effect. This might yield much improved estimates of merit that, with just two assessors per paper, greatly outperform the suggested use of IF. Even with a single assessor per paper, the position of a paper in the assessor's ranking might be superior to IF as a measure of merit.

On 2013 Nov 01, Adam Eyre-Walker commented:

We thank the author for his insightful comments. Unfortunately Dr. Cherry is correct (see below); controlling for merit, using a noisy measure such as the number of citations, will leave a correlation between assessor score and the impact factor whether or not there is a tendency for assessors to overrate papers in high impact journals. Since we did not previously appreciate this problem, and it wasn’t caught by a number of referees that looked at our paper prior to publication, it might be worth elaborating why this is the case. Imagine that we consider all papers that have received 100 citations; we assumed in our analysis that these represented papers of equal merit. However, because the number of citations is a noisy measure of merit, some of these papers will be papers of poor merit that by chance got more than their fair share of citations, and others will be papers of good merit than received less than their fair share of citations. As a consequence there is variation in merit amongst papers that received 100 citations. Hence, if assessors tend to rate better papers more highly and better journals publish better papers, then there will be a correlation between assessor score and the impact factor even when the number of citations is controlled for. Furthermore, the decrease in the correlation between assessor scores, and between assessor score and the number of citations, when the impact factor is controlled for, may simply reflect the decrease in the variance in merit within journals.

So as Dr. Cherry concludes, there is no evidence from our analysis that assessors overrate science in high impact journals. This tendency may exist, but there is simply no evidence from our analysis. However, the majority of our conclusions are unaffected by this insight; there is a rather poor correlation between assessor scores and between assessor score and the number of citations, whether or not the impact factor is controlled for. These correlations demonstrate that either assessors do not agree on what constitutes merit or they are not good at identifying merit, and that the accumulation of citations is highly stochastic.

Finally, we note the correlation between assessor score and impact factor is stronger than either the correlation between assessor scores, and the correlation between assessor scores and the number of citations. These correlations therefore suggest that the impact factor is the best measure of merit if there is no tendency for assessors to be influenced by the journal in which a paper is published.

There might be two approaches to determining whether assessors overrate papers in high-ranking journals. Developing a mathematical model of the relationship between assessor score, the number of citations and the impact factor of a journal – so far our attempts to do this have failed. Or to independently assess a range of papers before and after publication.

On 2013 Oct 29, Joshua L Cherry commented:

This article claims to have demonstrated that post-publication assessors are strongly influenced by their knowledge of the journal in which a paper was published. Specifically, it is claimed that they "tend to over-rate papers published in journals with high impact factors". Furthermore, it is suggested that "scientists have little ability to judge...the intrinsic merit of a paper".

These conclusions, which are based on coefficients of correlation between article metrics, do not follow from the data. The inferences involved are akin to taking correlation as proof of causation.

The authors first observe that journal impact factor (IF) correlates with assessor score even when citation number is controlled for. They interpret this as evidence that (assessor knowledge of) IF directly influences assessor score. The observed partial correlation is in fact expected for imperfect measures of a latent variable even in the absence of causal effects among the measures. If, for example, all three variables (assessor score, IF, and citation number) are noisy measures of article merit with uncorrelated noise, any two are necessarily correlated with each other even when the third is controlled for. Even if we took citation number as a perfect measure of merit (which we have no reason to do), the correlations would show only that assessor score and IF tend to err in the same way, not that one of them influences the other. Note that controlling for citation number does not eliminate the correlation between the scores given by two assessors, but it would be erroneous to conclude that one affected the other. The authors even tell us that citation number is "a very poor measure of the underlying merit of the science, because the accumulation of citations is highly stochastic". Controlling for such a variable could not possibly eliminate the correlation between assessor score and IF, so the authors' reasoning would suggest a strong assessor bias even if no such bias existed.

The authors also point out that controlling for IF significantly reduces the correlation between scores given by different assessors. They conclude that much of the correlation between assessors is due to their both being influenced by their knowledge of IF, rather than reflecting assessment based directly on intrinsic merit. This inference, too, is unfounded. Controlling for one of three intercorrelated variables can reduce the correlation between the other two under a range of conditions that do not involve causal connections. In fact, when two positively correlated variables positively correlate to the same extent with a third, as expected for assessor scores (since ordering of assessors is arbitrary), controlling for the third variable necessarily decreases the correlation between the first two. Thus, the observed reduction in correlation will occur whenever assessor scores correlate positively with IF, which certainly does not require the posited causal effect.

This is not to say that the claimed effect can be disproven or is implausible, but only that it has not been demonstrated. The observed correlation structure is entirely consistent with the complete absence of such an effect, and in the presence of such an effect the authors' reasoning would likely overestimate it drastically.

On 2014 Apr 16, Eric Uhlmann commented:

The further data collection and analysis reported by Silberzahn, Simonsohn, & Uhlmann (in press, Psychological Science) overturn the conclusions of our original paper. Using a matched-names analysis, which compares each noble-meaning name with the 50 most similarly frequent names, we find no differences between noble names and other names in terms of the attainment of managerial roles. Therefore at present no significant relationship between having a noble-meaning name and career outcomes can be confirmed.

For more details, here is a link to the full text and supplementary materials for the Silberzahn, Simonsohn, & Uhlmann (in press) collaborative commentary:

http://www.socialjudgments.com/docs/Silberzahn_Simonsohn_Uhlmann_2014_Collaborative_Commentary_and_Online_Supplement.pdf

The dataset for the new paper is publicly posted at:

http://figshare.com/articles/Dataset_for_SSU_2014/988763

Reference:

Silberzahn, R., Simonsohn, U., & Uhlmann, E.L. (in press). Matched names analysis reveals no evidence of name meaning effects: A collaborative commentary on Silberzahn and Uhlmann (2013). Psychological Science.

-- Raphael Silberzahn and Eric Luis Uhlmann

On 2014 Feb 10, Andrea Messori commented:

We have carried out an equivalence test based on the data published by Signorovitch and co-workers. The end-point was major molecular response at 1 year; the equivalence margins for this end point were set at ±15%. Figure 1 (available at http://www.osservatorioinnovazione.net/papers/bld2014_figure1.pdf) shows the results of this equivalence test. Coauthors: Valeria Fadda, Dario Maratea, Sabrina Trippoli.

On 2013 Oct 31, John Cannell commented:

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

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. 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 American Pediatric Association's recommended vitamin D supplement of 400 IU/day and few toddle

On 2014 Oct 28, Kaccie Li commented:

The treatment of the amplitude component of the pupil function was not provided in this paper, so the results and conclusions may very well be incorrect. I also don't believe any optical surface profiles capable of producing such phase characteristics currently exist. The authors claim that the major impact of this work will be in vision which involve chromatic, monochromatic and off-axis aberrations none of which were mentioned in the manuscript.

On 2014 Jan 29, Peter Beerli commented:

Inheritance patterns in diploid and triploid water frog hybrids (Pelophylax esculentus) – a comment on Pruvost et al.

Jörg Plötner^1, Gaston-Denis Guex^2, Peter Beerli^3, and Thomas Uzzell⁴

(Addresses at the end)

Pruvost et al. (2013) described the gamete production and ploidy of water frogs from five populations in Germany, Poland, and Slovakia. Two populations were composed of P. lessonae (genotype LL), P. ridibundus (RR) and their hybridogenetic hybrid P. esculentus (LR, LLR, RRL) whereas three populations consisted of only diploid LR individuals and triploids (LLR, RRL). Based on crossing experiments involving 64 P. esculentus and the analysis of microsatellites, the authors found that diploid males (genotype LR) produced haploid gametes with a ridibundus (R) genome whereas LR females usually produced diploid eggs containing both parental genomes (LR gametes). Moreover, most of the triploid individuals transmitted to their gametes the genome that was present in two copies; i.e. the L genome was inherited from LLR triploids and the R genome from RRL triploids. Their findings confirm the principal inheritance patterns of P. esculentus, which have been known for more than three decades (e.g. Uzzell et al. 1975; Günther et al. 1979; Uzzell et al. 1980; Vinogradov et al. 1990). Transmission of two L genomes by LLR males, which was observed in the Slovakian population Šajdíkove (Mikulíček and Kotlík 2001, Pruvost et al. 2013), can be considered a rare exception. It is not certain, however, that all LLR males of this population produce only LL sperm (nine of 14 LLR males transmitted only LL gametes, but five such males produced no progeny) nor is it certain that LR males in this population transmit only the R genome (only eight F1 individuals from two crosses involving a single male could be genotyped). That no P. lessonae individuals were found in a sample of 169 individuals from this population (Mikulíček and Kotlík 2001; Provost et al. 2013) suggests that the LR individuals in this population originate from LR x LLR and/or LR x LR crosses; as mentioned by Pruvost et al., both LLR males and occasionally LR males and females are able to produce L gametes (Binkert et al. 1982; Günther 1983). Only a few crosses in which either the diploid or the triploid parent produced L gametes would be sufficient for the persistence of such all-hybrid populations; in a relatively large Polish esculentus population comprising 300-400 females, for example, less than 1% of the eggs laid transformed to tadpoles (Berger 1988). Thus, even a high number of artificial crossing experiments does not guarantee that rare inheritance patterns, which may be critical to population persistence, are discovered. Based on the 10 genetic markers that they used, Pruvost et al. suggested that the two L genomes transmitted by LLR males from Šajdíkove are identical. Identity of markers does not, however, necessarily mean identity of genomes. Mikulíček and Kotlík (2001) investigated one LLR male from this population electrophoretically and found two distinct lessonae-specific alleles at the ldh-1 locus, which is evidence that the L genomes of this male differed from each other. On the other hand, it is not certain that in all cases “triploid hybrids recombine the genome they have in double dose” (Pruvost et al. 2013), although evidence for recombination between the double genomes in triploids comes from enzyme loci (Günther et al. 1979) and microsatellites (Christiansen and Reyer 2009). Because the few polymorphic markers available until recently do not allow distinguishing between the double genomes in many triploids, it cannot be said whether recombination between the two L or the two R genomes has taken place in such individuals. Biases in sex ratio of the progeny from crosses in which triploid individuals were involved (Günther et al. 1979; Berger and Günther 1988; 1991-1992), putative recombination between the L and the R genome in triploids (e.g. Plötner and Klinkhardt 1992; Christiansen et al. 2005), the occasional production of LL and LR eggs by some triploid (LLR) females (Christiansen et al. 2005; Christiansen 2009), the rare production of R or LL sperm by LLR males (Brychta and Tunner 1994; Christiansen et al. 2005), incomplete elimination of the R genome in some spermatogonia (Vinogradov et al. 1990), and chromosomal aberrations in meiosis of triploid males (Günther 1975) reflect the huge complexity of inheritance in triploid P. esculentus. P. esculentus may represent a useful model for hybrid speciation. It is not surprising, however, that hybrid forms in early stages of speciation exhibit a plethora of genetic disturbances and irregularities (Dobzhansky-Muller incompatibilities; e.g. reviewed by Landry et al. 2007; Maheshwari and Barbasch 2011) especially in gametogenesis and embryonic development expressed as fertility disorders in adults (Günther 1973), abnormal cleavage of eggs, malformations in larvae, and high mortality during larval development (e. g. Christiansen et al. 2005; reviewed by Ogielska 2009). The observed differences in the inheritance patterns of triploid water frog hybrids may thus be interpreted as a simple result of selection-mediated interactions between specific genomic features and spatial-environmental conditions of different evolutionary lineages representing a monophyletic group; at present there is no character-based evidence that triploid frogs are of polyphyletic origin as proposed by Pruvost et al. More genomic data are required to answer this and many other questions concerning the genetics and evolutionary history of western Palearctic water frogs.

List of references can be downloaded from here

http://www.peterbeerli.com/papers/misc/Reply_Pruvost_et_al_2013.pdf

1 Museum für Naturkunde, Leibniz-Institut für Evolutions- und Biodiversitätsforschung, Invalidenstraße 43, 10115 Berlin. Germany. Email: joerg.ploetner@mfn-berlin.de

2 Field Station Dätwil, 8452 Adlikon, Hauptstrasse 2, Switzerland

3 Florida State University, Department of Scientific Computing, Tallahassee, FL 32306-4120, USA

4 Academy of Natural Sciences, Laboratory for Molecular Systematics and Ecology, 1900 B. F. Parkway, PA 19103 Philadelphia, USA

On 2013 Oct 26, Tim D. Smith commented:

This work was featured in a Research Highlight In Brief in Nature Reviews Immunology: Macrophages: the shape of things to come.

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 NCT0131821. We believe the correct ID, which we have found by hand searching, is NCT01318213.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2014 Jul 30, Jim Woodgett commented:

From the data published, this compound was not tested against GSK-3alpha. Given the virtual identity in the active (ATP binding) site of these two isoforms, it is extremely probable that 6-(4-Pyridyl)pyrimidin-4(3H)-ones also inhibit GSK-3alpha (and are not specific for GSK-3beta). Notably, this molecule appears to pass through the blood brain barrier unlike many other inhibitors to this kinase providing avenues for targeting this kinase in Alzheimers and other neuropsychiatric conditions.

On 2016 Jul 20, Daniel Schwartz commented:

Interestingly, this trial is using a mobile app (Calculate by QxMD) to facilitate navigation through STARRT-AKI enrolment and exclusion criteria.

https://www.qxmd.com/calculate/calculator_362/starrt-aki-enrollment-criteria

Conflict of interest: Medical Director, QxMD

On 2016 Jun 23, Jaime A. Teixeira da Silva commented:

Teixeira da Silva, J.A., Al-Khatib, A. (2016) Questioning the ethics of John Bohannon’s hoaxes and stings in the context of science publishing. KOME 4(1): 84-88. http://komejournal.com/files/KOME_TdaSAceil.pdf DOI: 10.17646/KOME.2016.16

On 2013 Nov 16, George McNamara commented:

Please read Michael Eisen's column at

http://www.michaeleisen.org/blog/?p=1439

thanks.

On 2014 Feb 21, Serge Ahmed commented:

This remarkable study suggests, perhaps for the first time, that the orbitofrontal cortex (OFC) imposes “its” values to other value-coding brain regions (e.g., dorsal striatum) to guide choice and preference. Under normal circumstances, the values of hierarchically lower brain regions are in line with those of the OFC and no conflict arises. However, when these values diverge, the OFC would take the lead and impose “its” values to guide behavior, even if they are less accurate or up-to-date than those of hierarchically lower brain regions. A key challenge for future research will be to better understand how and under what circumstances the OFC acquires a set of values that diverges from reality and from that acquired by other brain regions.

On 2014 Aug 02, Christopher Southan commented:

For the record, since MeSH did not resolve AR79, the image from http://www.ncbi.nlm.nih.gov/pubmed/23872097 maps to https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=53302375 that incudes a link to https://open.surechem.com/en/document/WO-2011089416-A1/

On 2014 Jul 30, Jim Woodgett commented:

The inhibitor used here, AR79, inhibits both GSK-3alpha and GSK-3beta with very similar potency (as do virtually all small molecule GSK-3 inhibitors developed to date). This is clearly shown in Table 1 of cited reference 11 (http://www.ncbi.nlm.nih.gov/pubmed/23872097) where the Ki against GSK-3beta is 3.2 nM vs an IC50 of 5.5nM for GSK-3alpha. Notably, the Astra-Zeneca authors are careful to term AR7 (and its related compounds) GSK-3 inhibitors.

On 2015 May 17, Gustavo Glusman commented:

The full text in PMC has the wrong author list and abstract - both from this paper: http://www.ncbi.nlm.nih.gov/pubmed/24878723

On 2017 Nov 01, Kenneth Witwer commented:

Thanks for this interesting study. The data link "http://www.ebi.ac.uk/ena/data/view/PRJEB4152" does not appear to be functional. Could an updated link be posted? Thank you.

On 2017 Mar 04, Jing-Dong J Han commented:

The CoCiter website was down for a couple of days due to server maintenance. It is now up and running. Sorry about the inconvenience!

On 2017 Feb 08, Jeff Kiefer commented:

The resource URL is no longer viable so tool is not available.

On 2015 Sep 02, Jeff Kiefer commented:

None

On 2014 Nov 17, Raphael Levy commented:

Comments available at my blog, authored by 1) Mathias Brust, Liverpool, 2) Quanmin Guo, Birmingham and, 3) Philip Moriarty, Nottingham.

A detailed analysis of this article, and more broadly 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.”

On 2017 Oct 16, David Mage commented:

See comments to PMID 28838726 that cite this paper.

On 2016 Oct 16, Jaime A. Teixeira da Silva commented:

This paper has been retracted: "BioMed Research International has retracted this article. The article was found to contain images with signs of duplication and manipulation in Figures 1, 3, 4, 5(A), 5(B), 6, 8(b), 9(C), 9(G), 9(I), and 9(J)."

On 2014 Apr 16, T Eugene Day commented:

This is a very interesting study that uses DES to examine a generic ED model and assess the impact of discharge strategies on length of stay and readmission rates. Though the described model itself is fairly rudimentary with regard to care processes, it shows reasonable accordance to published throughput data, and I was pleased to see that the authors made a point of including their methods of validation, which is too frequently glossed-over, or omitted, in healthcare-based DES work. The bounds on the real-world values obtained from the literature and their expert panel were very large. However, real world variation in LOS is very large, and using expert panels when necessary is appropriate in validation. Ideally, it would be nice to compare the simulation to prospectively gathered multi-site data, but I recognize that that's a high bar to set.

Given the general nature of the simulation, the authors make appropriate conclusions with regard to crowding, and readmissions. With regard to the influence of the discharge strategy on individual patient outcomes, it is of course plausible that this is true, but I am reluctant to draw such a conclusion from simulation alone.

On the whole, an excellent article demonstrating the strength of using DES to glean insight into systemic behavior.

On 2015 Aug 01, Jorge H Ramírez commented:

Any reason not to retract? http://chaoticpharmacology.com/?s=dabigatran

On 2014 Jan 08, Brett Snodgrass commented:

Dear Authors,

Thank you for publishing an excellent report.

Is it possible that a vessel of Wearn was patent throughout life, but unappreciable due to "sloshing?"

http://bit.ly/JTWearn

For additional commentary, please consider https://twitter.com/BrettSnodgrass1/status/413134010991529984

Comments and suggestions are welcome.

Thank you kindly.

On 2016 Jan 16, Arnaud Chiolero MD PhD commented:

A fantastic review to understand the basics of health care regional variation.

On 2015 May 07, Tullio Pozzan commented:

We believe that the discrepancy between the data presented in our paper (Filadi et al. PNAS 2015 Apr 28;112(17):E2174-81. doi: 10.1073/pnas.1504880112. Epub 2015 Apr 13.) and those of Schneeberger et al. (Cell. 2013 Sep 26;155(1):172-87. doi: 10.1016/j.cell.2013.09.003) may be only apparent. In particular, Schneeberger et al. demonstrate (Fig 1 D and E) that in mice rendered obese by high fat diet there is a major reduction in mitochondria/ER contacts in POMC neurons and an early reduction in Mfn2 expression. They then show that mice with a selective KO of Mfn2 in POMC neurons become obese and show, at this stage, a reduction in mitochondria-ER contacts. Given that Schneeberger et al, investigated the reduction in ER-mitochondria close contacts only in 18 week old mice (i.e. when obesity is evident and not after a short high fat diet treatment (4 days), when Mfn2 reduction is already visible, but obesity is not), it is not possible to distinguish whether the change in ER-mitochondria close contacts is a consequence of Mfn2 reduction or of obesity (and/or of the very complex alteration of metabolism occurring in those conditions). In other words, the data presented in the very elegant paper by Schneeberger et al. do not clarify whether the reduction in ER-mitochondria close contacts is a direct consequence of Mfn2-KO in POMC neurons or an indirect effect of different altered pathways that lead to obesity and metabolism alteration. On the contrary, in the experiment by Filadi et al., in cultured MEF cells, acute down-regulation of Mfn2 results in a rapid increase of ER-mitochondria tethering. A similar result, i.e. increase in ER-mitochondria close contacts, has been also observed in a stable Mfn2 ablated cell line (and rescued by Mfn2 re-expression) independently by Filadi et al and by Cosson et al. Thus, in our opinion the role played by Mfn2 in different metabolic pathways leading to obesity is multiple and cell type-specific (see also the paper by Dietrich et al., in the same Cell issue) and not causally linked to its structural function on ER-mitochondria tethering, as actually pointed out by the same Authors suggesting a main role for Mfn2 in POMC neurons as an ER-stress modulating molecule.

On 2014 Jan 02, guoan zhang commented:

a comprehensive review about obestiy and cancer.

On 2013 Oct 23, Hilda Bastian commented:

This paper by Jager and Leek (Jager LR, 2014) challenges Ioannidis' conclusion that "most published research papers are false" (Ioannidis JP, 2005). Ioannidis responds to this discussion, challenging the data and analytical approach here: (Ioannidis JP, 2014). The conclusions of this paper (Ioannidis JP, 2005) were also challenged by Goodman and Greenfield in 2007 (and responded to by Ioannidis JP, 2007). (I discuss this debate in a blog post.)

On 2013 Oct 23, Larry Wasserman commented:

I agree with Rob that this is an interesting paper. However, it does assume that the p-values are uniform under the null. Hidden biases can compromise this assumption leading to a distribution for the p-value that is skewed towards 0.

On 2013 Oct 22, Scott D McGinnis commented:

None

On 2013 Oct 22, Robert Tibshirani commented:

A really interesting paper and discussion, that calls into question Ioannidis' 2007 widely cited paper "Why Most Published Research Findings Are False". Definitely worth reading: includes a discussion by D.R. Cox, probably the world's most famous living statistician.

On 2014 May 06, Swapnil Hiremath commented:

This article was discussed on April 29th 2014 on the open online nephrology journal club, #NephJC, on twitter. An introductory comment is available here and the pdf transcript of the live chat is archived here. A wrap up post, along with some reactions from the authors, is available at the same link (just scroll down).

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

On 2017 Jun 13, David Keller commented:

The above letter to the editor is freely available at the following link, and is posted here to stimulate discussion, and perhaps elicit answers to questions raised in the study:

http://www.nejm.org/doi/full/10.1056/NEJMc1309586#SA1?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed

To the Editor:

Anderson et al. (June 20 issue)[1] describe the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2), in which patients received alpha-blockers, diuretics, combined alpha- and beta-blockers, calcium-channel blockers, nitrates, hydralazine, and other anti-hypertensive agents. These medications lower blood pressure by means of different mechanisms and therefore have different effects on relevant physiological variables such as vascular smooth-muscle tone, intravascular volume, heart rate, and pulse pressure. For example, the authors indicate that 16.2% of patients in the intensive-treatment group received a calcium-channel blocker “such as nicardipine or nimodipine” versus 8.5% of patients in the standard-treatment group. Nimodipine is known to reduce adverse outcomes associated with arterial vasospasm when administered after subarachnoid hemorrhage.[2] If more of the patients in the intensive-treatment group received nimodipine and benefited from this additional protection, independent of its antihypertensive effect, then this imbalance would tend to inflate the apparent benefit of intensive blood-pressure lowering. How much of the overall benefit seen with intensive treatment was due to lower blood pressure per se, and how much was due to pleiotropic effects of the medications used?

David L. Keller, M.D. Providence Medical Group, Torrance, CA

email: davidlouiskeller@gmail.com

No potential conflict of interest relevant to this letter was reported.

References

1: Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368:2355-2365

2: Allen GS, Ahn HS, Preziosi TJ, et al. Cerebral arterial spasm -- a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med 1983;308:619-624

On 2013 Nov 25, Dennis Eckmeier commented:

This study is based on a preceding behavioral study on zebra finch head control in free flight: Gaze strategy in the free flying zebra finch (Taeniopygia guttata).

On 2016 Sep 02, Anderson Santos commented:

Dear Pannotator users, I am pleased to inform a new Pannotator release available at the site: http://pannotator.facom.ufu.br. It is a preliminary version that I'm expecting to become the version 2.0. Notice that the official website, as published by the GMR paper, is outdated till current date (September 2016); It does not contain the novel features presented in this release. I'm working with the site administrators from Virginia Commonwealth University to fix that. Meanwhile, I would like to indicate the version published at http://pannotator.facom.ufu.br.

My best regards, Anderson Santos - First author of the pannotator paper

On 2014 Feb 02, John Armour commented:

Thanks Dorothy - I agree that could be a more incisive test of a weak right-shift model, but I also agree that power is a real problem, because the target population for such an analysis (right-handers with discordant MZ twins) is likely to constitute about 18-20% of monozygotic pairs (in our study, we looked at 862 MZ twins, of which 157 were discordant). In our data set we would therefore be looking at fewer “case” individuals than in a more direct sampling of left-handers as the “case” phenotype, so the extra power gained by specifying the phenotype of interest more precisely could be offset in any data set by the loss of numbers. My guess (though I haven’t done any further exploration to back up this instinct) is therefore that any study that would have enough discordant MZ twins to do this job well would probably also be in a good position to demonstrate the same shift even as a simple additive determinant of handedness, treating each twin as a random member of a wider population. As I’m sure you appreciate, the main aim of our study was to clarify unambiguously that the simplest and strongest formulations of single-gene models are simply untenable in the face of the data; there are ways we could have squeezed more power out the data if we wanted to really give ourselves the best chance of finding even a quite feeble locus, but the absence of a strong determinant was really the main outcome from our point of view.

On 2014 Jan 24, Dorothy V M Bishop commented:

I wondered if the authors could do more with their data, given that the sample consists of twin pairs. The most plausible genetic models are ones in which there is a genotype with no bias to left or right, vs one with a bias to right-handedness. A right-hander could come from either group. However, a right-hander with a left-handed MZ twin is likely to come from the no-bias group. Thus by focusing on MZ twins and reclassifying the phenotype on the basis of the twin pair (RR, RL and LL) one would be able to conduct a better test of association with a realistic phenotype. I suspect this study does not have big enough sample size to do this with adequate power, but I think that, in principle, it ought to work, and so might be a way forward for future studies.

On 2016 Nov 30, Graham Walker commented:

We've made an interactive medical calculator for the Ottawa SAH Rule on MDCalc — it also includes additional supplemental content on how to use the rule, next steps, additional references, and details about the creators.

On 2014 Aug 30, Michelle Lin commented:

Great publication discussing the high sensitivity of the Ottawa SAH Rule. A week-long ALiEM-Annals of EM journal club discussion was held, along with a videocast with Drs. Perry and Stiell.