On 2014 Jan 14, Amanda Capes-Davis commented:

Good to see a panel of cell lines being used for bioactivity screening. Please be aware that KB is cross-contaminated and is actually HeLa, cervical adenocarcinoma. For a database of cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2014 Nov 19, Amanda Capes-Davis commented:

Great to see the correct description of KB-8-5-11 as cervical carcinoma. KB is a known misidentified cell line and is actually HeLa, as correctly noted by these authors in this article and many other publications.

On 2016 Nov 21, Alessandro Rasman commented:

Franz Schelling, M.D. Open letter, reminder https://medium.com/@franzschelling/open-letter-reminder-428f68613db7#.sdwd25m9o

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 NCT0095544. We believe the correct ID, which we have found by hand searching, is NCT00955448.

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 2015 Sep 11, David Reardon commented:

1. With only 44% of the expected rate for abortions in this sample, the concealment rate is very high and means that many women with a history of abortion are misclassified by the authors into the control group (delivering women with "no history of abortion"). Given the diluting effect this would have on results, this suggests that negative findings (lack of statistically significant differences) really don't tell us much. On the other hand, positive findings (statistically significant results) are most likely truly significant since the differences must be pronounced enough to still show up despite the dilution effect caused by concealment and misclassification.

2. Even in Model 4, with all the controls in place, higher rates of subsequent mental illness (RR>1) are seen for women admitting a history of abortion in every classification examined. Given the relatively small sample size, the lack of statistical significance in these cases can very likely be due to small sample size (and the concealment/misclassification problem) rather than lack of any true association.

3. It is unfortunate, and inappropriate, that the authors used history of miscarriage as a control variable on several counts. At the very least, women responding to surveys of this type frequently will disguise a past abortion by describing it as a miscarriage. In addition, abortion may contribute to a miscarriage. At the very least, the authors should reanalyze the data to show us how the results would differ if women reporting a first miscarriage were removed from the sample, which is the only way to properly eliminate any confounding effects that may be associated with miscarriage.

4. The authors chose to control for the number of pre-abortion psychiatric episodes/diagnoses, but they failed to explore whether abortion is associated with an increased rate in the number of episodes subsequent to the event. In other words, the authors made the odd decision to consider the frequency of prior psychiatric episodes but then failed to explore the concern that the intensity and frequency of subsequent mental health problems. If women with prior mental health problems are more likely to have abortions, the question then turns to whether or not having an abortion worsens, decreases, or has no effect on their mental health.

Given the weakness of this study, the authors' conclusions that this study suffices to demonstrate that other studies (including large record based studies) showing associations between abortion and mental illness can be ignored is imprudent and very likely engaging in a Type II error. Record linkage studies which have no dropout problem, have shown that the elevated rates of both inpatient and outpatient psychological treatments following abortion cannot be explained by recent mental health history alone. Similarly, an examination of attempted suicide rates before a pregnancy and after pregnancies ending in abortion, miscarriage, or delivery, that there is a true elevated rate of suicide attempts following abortion while the risk declines after miscarriage or delivery.

Moreover, given the weaknesses inherent in this data set, it is especially concerning that the authors dismissed their own finding that substance use problems remained significantly associated with abortion despite all the controls used which were specifically chosen to reduce significance. Instead of recommending caution and more research, they show their bias by arguing that this outcome, too, could probably be reduced to statistical insignificance if only they were able to find yet more controls to apply to the problem. This assertion, again, ignores the self reports of women who say their abortion loss contributed to their drinking or substance use, or studies showing elevated rates of substance us among women with no prior history of substance use, and despite major reviews of the literature and a meta-analysis showing a consistent link between abortion and elevated rates of substance use.Coleman PK, 2011

In short, the authors rush to dismiss a large body of evidence, including the self reports of self-aware women, suggesting that abortion contributes to mental health problems, based on this analysis of a flawed data set and questionable methodological choices, reaches way too far.

A national longitudinal study designed to specifically explore women's mental health in relation to their reproductive health and experiences is long overdue. The National Comorbidity Survey-Replication data set was not designed for this task and it is a mistake to conclude too much from any analysis of this type.

On 2014 Jan 11, Aurelian Bidulescu commented:

A series of analogies between vitamin D and adiponectin, isn't it? The most intriguing for me (at this point) seems to be the (auto)immune disease and the (common ?) gene-related pathways ! Comments? Thanks.

On 2015 Jan 30, Joe Newton commented:

This consortium study is unusually interesting because it now strongly suggest increased intracranial volume “differentials” in multiple diagnostic categories. (Newton JR Med Hypotheses Jan 1999)<br> A very large body of multidisciplinary evidence, I observed for over 50 years, when combined is consistent with increased volume differentials and other increased kinematic differentials for the “manic-depressive anomalies”. (Newton JR Med Hypotheses Jan 1999) I now call these anomalies because they are not always disabilities and diagnosis is uncertain. This 1999 testable hypothesis was followed by analyses of genes by many authors such as: Linked gene ontology categories are novel and differ from associated gene ontology categories for the bipolar disorders. Newton JR. Psychiatric Genetics. 2007 Feb;17(1):29-34. PMID: 17167342 Pathways-based analyses of whole-genome association study data in bipolar disorder reveal genes mediating ion channel activity and synaptic neurotransmission. Askland K, et al. Hum Genet. 2009 Feb;125(1):63-79. PMID: 9052778 Combinations of SNPs related to signal transduction in bipolar disorder. Koefoed P, et al. PLoS One. 2011;6(8):e23812. PMID: 21897858 Connection between genetic and clinical data in bipolar disorder. Mellerup E, et al. PLoS One. 2012;7(9):e44623. PMID: 23028568 Ion channels and schizophrenia: a gene set-based analytic approach to GWAS data for biological hypothesis testing. Askland K, et al. Hum Genet. 2012 Mar;131(3):373-91. PMID: 21866342 Convergent functional genomics of psychiatric disorders. Niculescu AB. Am J Med Genet B Neuropsychiatr Genet. 2013 Oct;162B(7):587-94. PMID: 23728881 The above data are consistent with thousands of linked/associated genes of low effect. These mainly influence structure suggesting intracranial neuron volume differentials (per Monro-Kelli) and/or myelination structure differentials. Further studies suggest that many of the linked/associated genes are shared by at least three DSM affective categories. (Genes swelling and shrinking: from edema to psychiatry. Newton JR in process) However, the science community has apparently not made the connection between action potential (AP) conduction velocity, AP event dyscoordination, and the state changes in the human information system anomalies.<br> The healthy living intracranial system with the lowest differentials in: volumes, axon calibers, myelinations, velocities and thus the lowest timing differentials accurately: coordinates, integrates, and binds all system AP events. By the same physics, in an unhealthy system, some AP events will be less coordinated and thus more uncertain. Diagnosis of the psychiatric disorder category is uncertain in the total absence of confirmed markers. For example, a diagnosis of “bipolar disorder” of an individual is based on the longitudinal response, e.g. state, which is very subjective as there are unknown numbers of possible states for any individual over time. Increased volume and/or myelination differentials are expected to be structural biomarkers for illness in a very broad range of diagnoses with gene variants in factorial numbers of particular additive combinations as suggested by several scientists, such as Mellerup and others. Such a combination expressed in an individual is expected to increase especially volume differentials due to the Monro-Kelli forces. It’s important to note that increased volume (or myelination) differentials may, or may not, be detectable in all patients with current imaging, and indeed, it’s physically expected that some patients with increased differentials within a ROI can have a normal overall volume of that measured ROI. The same is also very likely of myelination differentials. A consortium has the capability, if carefully managed by a few simple rules, to do truly novel and useful science. As suggested by the authors “selecting phenotypes in a principled way” is expected to be most useful. For example, selecting patients with abnormal hippocampal volumes selected for subsequent genotyping likely will to reveal the associated genetic loci, e.g. particular ROIs are expected. Particular variants are expected to most influence particular intracranial ROI volumes, and volumes are expected to be phenotypes or biomarkers in the psychiatric anomalies.

On 2014 Jan 10, David Mage commented:

The authors note the incidence of SIDS < 1 year has declined but the proportion of neonates < 7 days has increased. This may be because the number of neonate SIDS has remained constant while the number of post neonates (7 < age < 365 days) has decreased. Using U.S. CDC data (wonder.cdc.gov) from 1999 to 2010 for ICDR95 SIDS the number of neonate SIDS per year has held constant at an average of 34 per year while total SIDS has decreased from 2616 to 2036.

On 2014 Feb 25, Krishnaswamy Sampathkumar commented:

This paper resurrects Atenolol back to clinical use. The author has always been a protagonist of use of atenolol in hemodialysis due to its prolonged half life in anuric patients and ease of administration. It outscores ACE inhibitors in many cv adverse events. I will be interested in knowing about the stroke outcomes as atenolol is blamed for increasing the CVA risk as in LIFE trial.

On 2014 Mar 24, Edurne Zabaleta-del-Olmo commented:

I have read with great interest the article. Nurse prescribing are not yet a reality in my country (Spain), so studies like this are very important for take action to advance it. I have just one question about a possible error in the numbers of flow diagram. Is it 456 correct? Congratulations on your article.

On 2015 Sep 15, Ivan Oransky commented:

This paper, along with a related one in JAMA, has been retracted: http://retractionwatch.com/2015/09/14/fabricated-results-retract-jama-clinical-trial-plus-a-sub-analysis-of-the-data/

On 2014 Jan 11, Sergei Jargin commented:

Further details are in Jargin SV. Dermatopathology: Practical & Conceptual 2007;13(1):20 continued in 2008;14(2), 2009;15(1), 15(2), 15(4), 2010;16(1), 16(2), 16(3). Unfortunately, the journal Dermatopathology: Practical & Conceptual is currently unavailable on-line.

On 2015 Oct 28, Peter Gøtzsche commented:

The authors mention in the abstract of this huge review (55 trials and 5,506 patients) without any reservation that akathisia didn’t occur more often in the chlorpromazine group than in the placebo group. The largest trial that contributed data to this outcome even found significantly less akathisia in the active group than in the placebo group, relative risk 0.57, 95% CI 0.37 to 0.88. Since we know that antipsychotics cause akathisia and that placebo cannot cause akathisia, this result speaks volumes about how flawed trials in schizophrenia generally are. What was seen in the placebo group were cold turkey symptoms caused by withdrawal of the antipsychotics the patients had received before randomisation.

I believe this fundamental problem renders the review unreliable and I refer readers to another review. The most reliable placebo controlled trials are those of first episode schizophrenia where none of the patients have ever received drugs before. There is a Cochrane review that approaches this ideal, but even this review is biased, as the trials are not limited to first episode patients; the review includes studies “with a majority of first and second episode schizophrenia spectrum disorders” (1).

The authors of that Cochrane review pointed out that the available evidence doesn’t support a conclusion that antipsychotic treatment in an acute early episode of schizophrenia is effective. They felt this was worrying given the widespread use of antipsychotics in the acute treatment of early episode schizophrenia-type psychoses, and also because the use of antipsychotics for millions of people with an early episode appears based on the trials for those with multiple previous episodes (which we know are highly flawed).

I suppose this means that we don’t have the evidence to support using antipsychotics at all. In fact, despite the trials being flawed by the cold turkey design, what was seen in recent placebo controlled trials in submissions to the FDA was only a 6 point improvement on the Positive and Negative Syndrome Scale (PANSS) (2,3), far below the minimally relevant clinical effect on this scale, which is about 15 points (4). Benzodiazepines should be preferred, when patients need to be calmed down, as they are far cheaper and less toxic than antipsychotics and also seem to sedate patients better (5).

1 Bola J, Kao D, Soydan H, et al. Antipsychotic medication for early episode schizophrenia. Cochrane Database Syst Rev 2011;6:CD006374.

2 Moncrieff J. The bitterest pills. Basingstoke: Palgrave Macmillan; 2013.

3 Khin NA, Chen YF, Yang Y, et al. Exploratory analyses of efficacy data from schizophrenia trials in support of new drug applications submitted to the US Food and Drug Administration. J Clin Psychiatry 2012;73:856–64.

4 Leucht S, Kane JM, Etschel E, et al. Linking the PANSS, BPRS, and CGI: clinical implications. Neuropsychopharmacology 2006;31:2318-25.

5 Dold M, Li C, Tardy M, et al. Benzodiazepines for schizophrenia. Cochrane Database Syst Rev 2012;11:CD006391.

On 2014 Jul 29, JJ van Middendorp commented:

With interest I read the retrospective study by Venkatesan et al.^1, comparing survival outcomes of elderly patients with fractures of the odontoid process of the second vertebral body, the hip and wrist. The authors found that “sustaining an odontoid peg fracture increases the risk of mortality by a factor of seven compared with sustaining a wrist fracture in patients aged >65 years”.¹ I believe, however, that the presented results deserve a more nuanced interpretation.

In contrast to what has been under-reported in a number of other studies on this topic,² the authors presented an informative table on the causes of death of patients with an odontoid process fracture. At the same time this information exposes two critical limitations of presented survival analyses, neither of the two were addressed by the authors. First, the causal description “accidental death” is rather ambiguous, certainly in a group of patients who sustained an isolated odontoid process fracture resulting from a low-velocity fall or accident. Clearly, such injuries do not lead to death directly. Hence the validity of both the retrospectively collected data from the hospital’s bereavement office or coroner’s office and the actual occurrence of ‘isolated’ injuries can be questioned. Second, five of the twelve patients (case 3, 6, 7, 8 and 12) clearly died as a result of medical comorbidities that were pre-existent to, and thus not caused by, the injury of the cervical spine. Considering these two points, it is likely that the unfavourable survival outcome attributed to isolated odontoid process fractures (adjusted hazard ratio of 7.0, 3.6-13.6 95% CI; when compared to wrist fractures) is well overestimated.

Although Venkatesan et al¹ are one of the first authors comparing survival outcomes of patients with odontoid process fractures with those of patients with other types of musculoskeletal fractures, the comparison itself is methodologically flawed. Comparing 6-year retrospective data on cervical injuries from one hospital with 1-year prospective data from a national registry introduces an unacceptable level of heterogeneity. Only age and gender were considered for the multivariate Cox regression analysis. Previously recommended factors like pre-existing comorbidities, concomitant injuries and cause of death were not adjusted for in the analysis.² Moreover, the authors seem to disregard the previously demonstrated adverse effects that bed rest and limited mobility have on mortality rates in elderly patients.^2,3 It may well be that limited physical exercise is the single strongest predictive factor explaining the differences between the survival rates of elderly patients with a cervical spine or hip fracture and those with a wrist fracture.

Whilst the authors rightly point out that the increasingly growing elderly cervical trauma population requires the same medical attention as other ‘major’ musculoskeletal injuries, they failed to identify the underlying factors that lead to relative high mortality rates in this particular group of patients. Simply comparing risk, odds or hazard ratios between specific trauma sub-populations will not assist orthopaedic and spinal surgeons in the everyday management of musculoskeletal injuries. I believe it is time to move away from correlation statistics and pursue the identification and management of true causal factors that have an impact on survival outcomes in elderly patients with cervical spine injuries.

J.J. van Middendorp, MD, PhD, MClinEpid, Research Director of the Stoke Mandeville Spinal Foundation, Aylesbury, UK and Senior Research Fellow of the Harris Manchester College, University of Oxford, Oxford, UK

References

1 - Venkatesan M, Northover JR, Wild JB, et al. Survival analysis of elderly patients with a fracture of the odontoid peg. Bone Joint J. Jan 2014;96(1):88-93. PubMed: Venkatesan M, 2014

2 - van Middendorp JJ, Albert TJ, Veth RP, Hosman AJ. Methodological systematic review: mortality in elderly patients with cervical spine injury: a critical appraisal of the reporting of baseline characteristics, follow-up, cause of death, and analysis of risk factors. Spine (Phila Pa 1976). May 1 2010;35(10):1079-1087. PubMed: van Middendorp JJ, 2010

3 - Siu AL, Penrod JD, Boockvar KS, Koval K, Strauss E, Morrison RS. Early ambulation after hip fracture: effects on function and mortality. Arch Intern Med. Apr 10 2006;166(7):766-771. PubMed: Siu AL, 2006

On 2014 Jul 09, Mathias Wellmann commented:

Comment regarding Kukkonen et al. Treatment of non-traumatic rotator cuff tears. A RANDOMISED CONTROLLED TRIAL WITH ONE-YEAR CLINICAL RESULTS, Bone Joint J 2014;96-B:75–81. PMID: 24395315

Dear Authors,

we read the study with great interest und discussed the clinical implications. We think the authors did a great job respecting formal aspects (prospectively randomized design, equivalent cohort size, homogeneous patient distribution). However, there are a few aspects of the study which are potentially misleading:

1. The title of the study is misleading or to general at best. A more precise title would be: Treatment of small, well compensated non-traumatic supraspinatus tendon tears. We think a study title should be as clear as possible and should especially answer the question: What issue was studied? The study of Kukkonen et al. exclusively investigated patients with small (<10mm) supraspinatus tendon tears, which were well compensated regarding range of motion (full range of motion, inclusion criteria). In its present form the title of the study may lead to a transfer of the results to patients with decompensated full-thickness tears of the supraspinatus tendon. Such transfer is not valid and should be prevented using a more precise study title.

2. All patients with an passive external rotation <30° and an elevation <120° were excluded from the study and the limitation of elevation and external rotation was defined as stiffness. However, a loss of elevation <120° is not a sufficient criterion to define shoulder stiffness. An adequate examination would have quantified passive glenohumeral abduction and external rotation (external rotation in comparison to the contralateral unaffected side). Further, the percentage of patients excluded because of shoulder stiffness should be indicated, since this is not a very common combination in patients with atraumatic rotator cuff tears. In the given form there is a risk that the study design systematically excludes patients with restricted range of motion caused by loss of strength and pain. This is a basic issue, since these are the typical patients, in which we think about rotator cuff refixation.

3. The type of supraspinatus-tears for the patients, that were included in the study should be clearly defined (full thickness versus partial thickness tears). The authors use the term „supraspinatus tendon tear comprising <75% of the tendon insertion and documented with MRI“. Thereby it is unclear, if partial articular und bursal sided tears involving <75% of the tendon substance were also included in the study. In the results section the authors indicate the sagittal diameter of the tears treated by surgery. Does that mean, that all tears were full-thickness tears?

4. It is unclear, if any of the patients had been treated by physiotherapy previous to the inclusion, or if this was an exclusion criterion as well. How did the authors deal with patients, that were randomized to be treated by surgery but did not agree to a surgical intervention.

5. The authors did not perform a follow up MRI or even sonography to determine the rerupture rate of the rotator cuff repairs. This would have been a substantial information estimating the clinical success of rotator cuff repair. If further follow up investigations are planned in the study design, we strongly recommend to perform MRI scans.

6. The Constant Score may not be the most helpful score with regard to outcome discrimination for a patient population with „ full range of motion“, since it strongly estimates range of motion (40 points) compared to pain (15 points) and the level of daily actvities (20 points). For such patients more detailed patient reported outcomes (PROs) should be beneficial.

We recommend to revise the marked aspects to reach the highest possible scientific impact for this publication.

Mathias Wellmann on behalf of the Shoulder committee of the AGA - Society for Arthroscopy and Joint Surgery

On 2014 Jan 17, Marcos Malumbres commented:

I miss a reference to Bueno MJ, 2011; one of the first papers where the bidirectional networks between microRNAs and Myc were described.

On 2014 Feb 12, David Keller commented:

None

On 2014 Feb 12, David Keller commented:

Further arguments in support of PSA screening.

Evidence in favor of PSA screening for prostate cancer detection was summarized in a review by Allan and colleagues (1): “Based on the best available trials, we concluded that prostate cancer screening, specifically PSA, does reduce prostate cancer mortality. The number needed to screen to prevent one prostate cancer death at nine and 14 years of follow-up were 1410 and 293, from the ERSPC and Göteborg studies, respectively.... In comparison, the number needed to screen with mammography to prevent one breast cancer death in women ≥50 years of age is 1235 and 614 for 7 and 13 years, respectively. The number needed to screen with fecal occult blood testing to prevent one colorectal cancer death is 617 over 12 to 18 years. Prostate cancer screening, similar to the other accepted cancer screening programs, does not modify overall mortality."

Note that in the Goteborg study, 24% of the men invited to be screened never actually showed up to have a PSA drawn, yet they were included in the intention-to-treat analysis. If we subtract them from the results, then the number actually screened to prevent one death is reduced to 223. In the PLCO prostate cancer screening study, 52% of the “control” patients actually had PSA testing performed outside the study, and only 86% of patients in the screening arm were compliant with the PSA protocol. This severely contaminated data did not support PSA screening, which tells us little except to disregard any meta-analysis which includes PLCO.

In my letter, I pointed out that clinicians can improve the specificity of PSA screening by the following technique: when an elevated PSA occurs, repeat it a few times at short intervals and discard all but the lowest PSA for comparison to the biopsy threshold. This simple technique can spare many men from undergoing prostate biopsies, reducing potential harms from screening. Arguments against PSA screening often cite patient worry as a potential harm, which actually represents failure by clinicians to communicate the indolent behavior of many prostate cancers. Men offered screening should be informed that prostate cancers exhibit a range of behaviors, and often do not result in metastases or death.

Dr. Katz states that only 7% of men chose watchful waiting for localized prostate cancer in a recent registry, while 83% chose invasive treatments, despite the lack of convincing data to support the superiority of the latter. This again represents a failure of communication by the physicians involved. Patients are generally quite happy to avoid surgery when their clinician assures them it is not necessary or beneficial. We can increase the use of watchful waiting if we communicate effectively with our patients.

Finally, I wish to correct an omission from the last paragraph of my letter, which should have read: “We need a large trial of PSA measured every 3 months during the first year (to establish a baseline PSA)....”

1: Allan GM, Chetner MP, Donnelly BJ, Hagen NA, Ross D, Ruether JD, Venner P.Furthering the prostate cancer screening debate (prostate cancer specificmortality and associated risks). Can Urol Assoc J. 2011 Dec;5(6):416-21. doi:10.5489/cuaj.11063. PubMed PMID: 22154638; PubMed Central PMCID: PMC3235209.

On 2014 Jun 26, Amanda Capes-Davis commented:

The authors use the Chang liver cell line as a model for human hepatocytes. Unfortunately, despite the name, Chang liver is cross-contaminated with HeLa, and so comes from adenocarcinoma of the cervix. A database of known cross-contaminated cell lines can be found at http://iclac.org/databases/cross-contaminations/.

On 2018 Jan 17, Rasmus Hertzum-Larsen commented:

In the results section of the abstract I see: "Cytology coverage was higher among immigrant women compared to Spanish born (51.2 and 39% respectively)". But in figure 1 i see the opposite: 39% among immigrants, and 51.2% among spanish born. Which is correct?

On 2014 Jan 25, Ferenc Zsila commented:

According to my comments outlined below, the peer-review procedure of this poorly written paper was seriously incomplete (page numbering refers to the PDF version).

Ferenc Zsila M.D., Ph.D. Institute of Molecular Pharmacology, Research Centre for Natural Sciences Budapest, Hungary

Missing experimental data (Materials and Methods, pp. 2-3.)

Purity and fatty acid content of the HSA sample used are unknown. The source and chemical character (salt or free acid, racemic or not) of ibuprofen, warfarin, and digitoxin used in site probe studies are unknown. Experimental details of the site probe measurements (see on p. 7) are completely missing. There is not even a word to describe how the protein and LMF molecules were prepared for the docking procedures (p. 3). Docking type information are also missing (blind? targeted? rigid? flexible?). What are the parameters of the docking box used for the proteins? How much docking runs were performed? Where is the docking energy list? Where are the affinity constants calculated from the binding free energy values? How do they relate to the experimental values?

Errors, speculations, and unsupported claims

Page 1: "Based on these characteristics, with increasing amounts of PPIX in the blood, the probability of HSA-PPIX formation increases accordingly." It is a mere speculation which is not supported by research data. Hemopexin is the primary heme binding protein in the serum. "Methemalbumin is an abnormal component of plasma and has been found only in diseases associated with massive hemolysis, when hemopexin-binding capacity is exceeded." (Tolosano et al., Antioxid. Redox. Signal. 2010 (12) 305-320).

Page 4: "When HSA is excited at 285 nm, it radiates strong intrinsic fluorescence at 334 nm." No emission band at 334 nm can be seen either in Fig. 1A or 1B. Fluorescence contribution of the bound PPIX is totally ignored. Origin and nature of the large emission peak centered around 430 nm remain obscure.

Page 4: "To investigate the effect of TF on the binding of LMF to the (HSA-PPIX)-TF complex, steady-state fluorescence spectra of (HSA-PPIX), shown in Fig. 1A, and of (HSA-PPIX)-TF, displayed in Fig. 1B, were run and showed that the fluorescence intensity of the two systems became consistently weakened when increasing the LMF concentration." Just an opposite situation is shown in Fig. 1A and 1B: increase of the LMF concentration enhances the fluorescence intensity in both cases.

In contrast to HSA, transferrin contains 8 Trp residues. It remains a mystery, how the fluorescence contribution of these residues was considered during evaluation of the emission spectra of (HSA-PPIX)-TF.

Page 5: "Fig. 3 shows second-derivative fluorescence spectra of the (HSA-PPIX)-LMF and [(HSA-PPIX)-TF]-LMF complexes (inset). As can be seen, a negative band was observed at 310 nm and 316 nm in the (HSA-PPIX)-LMF and [(HSA-PPIX)-TF]-LMF spectra, respectively. These changes in the protein spectra should be assigned to the combination of environments of the aromatic residues in the protein and indicate that the Trp residue was in a relatively hydrophobic microenvironment." What Trp residue? There are 9 Trp in the [(HSA-PPIX)-TF]-LMF complex.

Page 7: "The corresponding binding constants were evaluated and are listed in Table 3." These are not binding but quenching constants (cf. Table 1). No association constants (Ka) are shown in Table 3. HSA affinity constants as well as the amounts of the site probes added are unknown.

Page 7: "Based on these results, it was concluded that ibuprofen had little effect on the binding of LMF to (HSA-PPIX)-TF while digitoxin removed LMF from the bindings site." Changing of the quenching constants shown in Table 3 contradicts to this claim. The Ksv value of [(HSA-PPIX) LMF] TF was reduced by an order of magnitude upon addition of both ibuprofen and digitoxin. The exact HSA binding location of digitoxin is unknown so it can not be used as a site probe. It may occur that these site probes bind to transferrin as well. Where are the controll experiments?

Page 9: "In summary, this study provides useful information for the pharmacological and pharmacodynamic behavior of LMF and should be taken into account when calculating its dosage." This work deals with one aspect of the pharmakokinetic behavior of LMF (serum protein binding). No data are presented on the pharmacodynamic behavior of the drug.

Confusing binding site designations

Page 7: "In our previous work [18], we showed that PPIX occupied site I in the HSA and LMF bound to site IIA." As it is defined on page 1, site I corresponds to subdomain IIA ("Aromatic and heterocyclic ligands have been found to bind with two hydrophobic pockets in subdomains IIA and IIIA, namely site I and site II"). Therefore, according to the above sentence, both PPIX and LMF is bound in subdomain IIA.

Page 7: "... we believe that the lower-affinity site of LMF, corresponding to the binding site, was switched in the presence of TF, causing LMF to bind to site III in HSA." No definition of site III is given.

Page 9: "For the (HSA-PPIX)-TF complex in solution, the binding site of LMF to HSA-PPIX changed from Sudlow’s site IIA to Sudlow’s site IIIB with low affinity." No such site designations exist in the literature. Moreover, subdomain IIIB binding of LMF is very doubtful since it is not supported by experimental data.

Wrong references

Page 1: "The direct interaction of drugs with TF has been widely studied [9-12]." Ref. 11 is a drug-serum albumin and not a drug-TF binding study.

Page 1: "LMF is very active against both Gram (+) and Gram (2) bacteria through inhibition of their DNA gyrase and is widely used for the clinical treatment of severe systematic infections, such as soft tissue infection, typhoid fever, bone and joint infections, prostatitis blood poisoning and sinusitis [13]." Ref. 13 is a spectroscopic study on the ion-association complex formation between fluoroquinolones and a synthetic dye (erythrosine). Thus, it does not cover the biological activities of lomefloxacin.

Page 7: "In our previous work [18], we showed that PPIX occupied site I in the HSA and LMF bound to site IIA." Ref. 18 is not the authors' paper.

Page 9: "The literature has numerous reports of LMF being located within an alpha-helix and a beta-sheet in the N-lobe of transferrin [46]." Ref. 46 is not about the LMF-transferrin interaction.

On 2014 Feb 28, Walter Vogel commented:

This paper was the cover article of the February issue of TiPS and the subject of the lead segment of the February 2014 Cell Press Podcast: “On Cellular Symphonies and Symbiosis” in a segment titled: “How fine-tuning of transcription factor activity may open up new avenues for disease treatment,” where author Mark Leid was interviewed by the journal editor, Joanna Schaffhausen. Available on the Cell Press website http://www.cell.com and on iTunes https://itunes.apple.com/us/podcast/cell-podcast/id207189884. Released 27 February 2014.

On 2014 Jan 13, Amanda Capes-Davis commented:

Please be aware that KB is NOT an oral squamous cell carcinoma (OSCC). The cell line is cross-contaminated, as shown by Gartler in 1967 (PMID 4864103). For a database of cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2014 Jun 27, Andrea Manca commented:

Beyond the unfortunate misprints for which we apologize and thank the commenter (90 mW instead of 90 W; 30 mW instead of 35 mW), our apparatus was set at the maximum power output for each diode (30 W x 3 diodes = 90 W), within the well-acknowledged therapeutic wavelength emission (904 nm) and for a treatment time of 10 minutes (600 seconds). The laser probe was in firm contact with the skin which allowed an optimal penetration (Prentice et al. 2005). In our sample only one trigger point (TP) had to be treated, since patients with a single TP in the upper trapezius muscle (in position TrP2) were preferentially recruited. This was done to avoid conflicting attributions of effects and sub-group analyses which would have reduced the statistical power. The commenter raised a concern about the power density. The power density measured by the commenter is 8.8 mW/cm2 (35 mW/4 cm2) which is higher than the 5 mW/cm2 recommended by the most recent guidelines for low level laser therapy treatment dosages (World Association for Laser Therapy-WALT, 2010). However, in our case the actual emitting area (2.35 cm2) was smaller than the contact surface of the probe (4 cm2) making the ratio between them even more favorable. In fact, the average output of 35 mW was spread over 2.35 cm2, resulting in a power density of 14.8 mW/cm2, which, is, again, higher than that recommended by WALT. The commenter defines such value of power density “as relatively low”. Basing on which criteria 8.8 or 22 mW/cm2 are rated as “relatively low power densities”, since in the cited WALT recommendations there is no indication on low or high power densities and only minimum requirements are stated? And how can the commenter state: “WALT recommendation for a TP is not 18 J, but 2-4 J per point” if no dosage specifications for trigger points are actually available in the cited most recent WALT recommendations? In summary, regarding the treatment doses for class 3B, 904 nm-GaAs low level laser therapy, the minimum requirements recommended by WALT are: peak pulse output > 1 Watt (here: 90 W); mean output > 5 mW (here: 35 mW), power density > 5mW/cm2 (here: 14.8 mW); irradiation time of 4 minutes per point or cm2 (here: 10 minutes); total dose 4 joules per point (here: 18 joules). All the recommended parameters were fully respected and treatment dosages delivered here were well above the minimum requirements. Moreover, assuming an emitting area of 2.35 cm2 and an average size of a TP in the upper trapezius of 0.16 cm2 (Sidkar et al. 2009), we are confident that the target was effectively irradiated by the laser beam with a definitely adequate power density. Then the conclusions of this trial are based on straightforward results which were obtained through appropriate procedures.

References:

Prentice W, Quillen W, Underwood F. 2005, “Therapeutic Modalities in Rehabilitation”, New York: McGraw-Hill 2005.

Sikdar, S., Shah, J.P., Gebreab, T., Yen, R.-., Gilliams, E., Danoff, J. & Gerber, L.H. 2009, "Novel Applications of Ultrasound Technology to Visualize and Characterize Myofascial Trigger Points and Surrounding Soft Tissue", Archives of Physical Medicine and Rehabilitation, vol. 90, no. 11, pp. 1829-1838.

WALT - World Association for Laser Therapy – Recommended dosages for low level laser therapy (2010). http://waltza.co.za/documentation-links/recommendations/dosage-recommendations/

On 2014 Feb 01, Jan Tunér commented:

In the paper, the parameters are described: According to the acknowledged guidelines (WALT, 2004), delivery parameters were: wavelength 904 nm; pulse duration 200 ns; pulse frequency 1953 Hz; peak power 90 mW; average output 30 mW; power density 22.5mWcm2; treatment time 600 seconds; energy dose 18 J per session; spot size 4 cm2 and treatment frequency five times/week. Laser probe (head size: 4 cm2) was applied steady in skin contact with no pressure over the MTP. The 904 nm laser cannot possibly have a peak power of 90 mW. Let us accept this as a misprint for 90 watt. If so, the average output is 35 mW (not 30), which is reasonable for a TP. However, the “spot” is 4 cm2, so the 30 mW is spread over a large area, producing a power density which is very low. And in fact even lower than the one stated in the paper. Assuming that the peak power is 90 watt instead of 90 mW, the average output power can be calculated to 35 mW. Spot size is said to be 4 cm2. Then the power density will become 7.5 mW/cm2 (if 39 mW is used) or 8,8 mW/cm2 (if 35 mW is used). How are the stated 22.5 mW/cm2 calculated? Anyway, both 22 and 8 mW/cm2 are relatively low power densities. Further, WALT recommendation for a TP is not 18 J, but 2-4 J per point and certainly not one single TP. The conclusion of this study is based upon flawed parameters.

On 2014 Mar 25, Greg Finak commented:

With manual gating still being the standard, we have to assume analysts doing the gating are experts, know the assay, and know what cell populations they're after. Starting from that premise, the normalization algorithm described does aim to emulate manual gating. I think that's pretty clearly described.

However, your concern:

if both datasets were gated by the same person, as seems likely. If that person is also the lead developer of the algorithm, a clear bias in favor of the algorithm becomes a real possibility.

is unfounded. The the manual gating was not performed by the algorithm developers, nor were both data sets gated by the same person. The HVTN data set was gated by experts at the HIV Vaccine Trials Network, and the ITN was gated by experts at the Immune Tolerance Network.

As to comparing manual gating generated by a sampling of individuals.. this has already been done.. see the FlowCAP paper, as well as a number of reviews by Maecker et. al. that show clearly that different analysts will give different results with higher C.V. than having data analyzed centrally. And if you're to have data analyzed centrally, then I'd argue you should use the best expertise possible. We started from that presumption here.

Edit: I would also add that if you would like to scrutinize the manual gating more closely, you can grab the FlowJo workspaces from flowrepository.org, both data sets are now publicly accessible.

On 2014 Mar 23, Yannick Pouliot commented:

One mild concern I have with this paper is the lack of details as to how the manual gating was performed. Given the authors' statement that a "... desirable outcome is to have low bias and low variability relative to the manual gates", what this really means is that the algorithm is trying to emulate the manual gating performance of a single individual if both datasets were gated by the same person, as seems likely. If that person is also the lead developer of the algorithm, a clear bias in favor of the algorithm becomes a real possibility.

This sort of comparison would be much more informative if the algorithm were compared against manual gating results generated by a sampling of individuals with varying degrees of experience in the process and not involved in developing the algorithm.

On 2015 Jan 07, Jim Woodgett commented:

The authors refer to a prior publication (PMID: 20939016) that correctly describes AR28 as a GSK-3alpha/beta inhibitor rather than a GSK-3beta inhibitor as described in the title and throughout most of the manuscript. Given the authors do not address specificity of AR28 in this publication, the Introductory comments seem unsupported: "While LiCl and BIO circumvent this problem by acting on GSK3β, downstream of the ligand/receptor binding, they are not ideal, with off target effects and toxicity (Davies et al., 2000, Meijer et al., 2003 and Liu et al., 2011)." It is also unusual in describing a novel inhibitor to not provide any details of the molecule. This inhibitor is also known as AZD2858 (PMID: 22142634), was developed by Astra Zeneca and is available from several commercial sources (e.g. Selleck Chemicals, Cayman Chemicals).

On 2014 Dec 20, Christopher Southan commented:

Doubt has emerged (2Q2014) as to the drug target status of BACE2 http://cdsouthan.blogspot.se/2014/12/bace2-as-diabetes-target-or-maybe-not.html

On 2014 Jan 26, Christopher Southan commented:

Our independent publication came out essentially back-to-back with "Asynchronous Evolutionary Origins of Aβ and BACE1” Moore DB, 2014. The two papers are complementary in coverage (Moore et.al. include a detailed analysis of APP evolution) and broadly convergent in their conclusions (details at http://cdsouthan.blogspot.se/2014/01/a-tale-of-two-targets-bace1-and-bace2.html including updates regarding TreeBase and the sequence acession number).

APP evolution is also examined in "Origins of amyloid-β" http://www.ncbi.nlm.nih.gov/pubmed/23627794

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

There are possible concerns with images in this paper.

Fig 1e and f appear to be the same section, just rotated and/or with contrast adjusted. In addition, key findings of this study, the “crystal formations”, appear to be inserted objects into the image, at least one of which appears to be a 4-copy carbon copy (purple circles). http://imgur.com/ZcHzSYq

Fig 1g, 1h and 1i “crystal formations” appear to be cloned, in some cases with sizes adjusted. They have remarkably similar features, shape, etc. http://imgur.com/UY82sIQ

Authors and editors and Springer management contacted on June 15, 2016. To date, no response by any party.

On 2014 Aug 20, Claudiu Bandea commented:

Just a few days after I posted the comment above on the remarkable study by Sauvageau et al. published in eLife (Sauvageau M, 2013), in which I questioned the interpretation and validity of some of the results, Bassett et al. published in the same journal an article outlining a series of highly relevant "considerations" when investigating the biological functions of lncRNA (Bassett AR, 2014). Interestingly, Bassett et al. expressed similar concerns about the study by Sauvageau et al., which should incite a response from the authors and eLife reviewing editor, Danny Reinberg.

On 2014 Aug 08, Claudiu Bandea commented:

Multiple knockout mouse models reveal that some lincRNAs might be required for life and brain development

In a recent series of mini-essays on genome functionality and ‘junk DNA’ prompted by Ford Doolittle’s article “Is junk DNA bunk? A critique of ENCODE” (1), I used the article by Sauvageau et al. (2) as an example of poor use of words in communicating scientific observations , which could lead to confusion and misrepresentations (3). In fact, I went so far as to suggest that some of the results in this particular study might be problematic. However, these allegations might be wrong and, therefore, it is important to bring them to the attention of the authors here, so they have the opportunity to respond.

First, I would like to emphasize that the study by Sauvageau et al. is impressive. The problem, however, might be with the interpretation of the results and their integration into the existing body of knowledge, which are as important in advancing science as generating data, if not more. There might also be a problem with the absence of appropriate controls for the knockout mouse models, which questions the validity of some of the results.

Briefly, to investigate the functional relevance of long intergenic noncoding RNAs (lincRNAs), Sauvageau et al. developed a collection of 18 lincRNA knockout mouse strains in which the locus was maintained transcriptionally active. In order to select the best candidates for functional lincRNAs, the authors “have implemented a generalized and logical lincRNA candidate selection process that leverages a collection of cell-based functional assays, RNA-sequencing data and computational analyses….”

Remarkably, in their initial characterization of the 18 lincRNAs knockout strains, Sauvageau et al. found three strains that exhibited peri- or post-natal lethality and two additional strains with distinct developmental defects. Based on these findings the authors concluded that “This study demonstrates that lncRNAs play critical roles in vivo…” and entitled their article: “Multiple knockout mouse models reveal lincRNAs are required for life and brain development.”

However, both the conclusion and the title of the study by Sauvageau et al. can be misleading. Factually, the results reported in the article indicate that 5 out of 18 lncRNAs included in study appear to play critical roles in vivo and, therefore, it should have been entitled something like: “Multiple knockout mouse models reveal that some lincRNAs might be required for life and brain development.”

Moreover, based strictly on the results presented in the article, which showed that only 5 of the 18 lncRNAs were functional, and considering the strong bias introduced in the study by selecting lincRNAs that are most likely to be functional, a more appropriate scientific interpretation of the study would be that: “The results presented in this article indicate that most lncRNAs (i.e. 13 out of 18) do not appear to play critical roles in vivo….” It is possible that the authors will report in future articles results showing that some additional, or all the lincRNAs in their collection are functional; even then, the authors should be cautious about the broad interpretation of the results considering the bias of their collection toward putatively functional lincRNAs (therefore, the inclusion of a few random lincRNAs would have benefited the study).

Whether the assertion about the broad interpretation of the results, which might be considered an 'innocent' case of ‘hype in science’ (4), resonate with the authors or with other readers remains to be seen: however, the allegation that the phenotypes observed in their study might be associated with untargeted genome alterations introduced inadvertently during the procedure of generating the knockout mice, rather than with the deletion of specific lincRNAs, questions the validity of the study, at least for the time being and, therefore, it should be of concern.

Considering the well-recognized problems with generating knockout animal models (see, for example, Refs. 5-9), it is surprising that Sauvageau et al. did not discussed this issue in the context of their study, and that they did not include appropriate controls (e.g. duplicates) at least for some of the lincRNAs knockouts, preferably using mice with different genetic background. Although the data and observations presented by Sauvageau et al. might be correct, for the time being their validity remains questionable; therefore, it would make sense for the authors (and the editors) to add an explanatory note, both here at PubMed Commons and in the journal eLife.

References

(1) Doolittle WF. 2013. Is junk DNA bunk? A critique of ENCODE. Proc Natl Acad Sci USA., 110:5294-300. Doolittle WF, 2013

(2) Sauvageau M. et al., 2014. Multiple knockout mouse models reveal lincRNAs are required for life and brain development. eLife (DOI: 10.7554/eLife.01749) Sauvageau M, 2013

(3) Bandea CI. 2014. Everlasting confusion on ‘functional DNA’ and ‘junk DNA’ in the field of genome biology. PubMed Commons (National Library of Medicine; Bethesda, MD). Comment on: Doolittle WF, 2013

(4) Maderspacher F. 2014. Hype in Halifax. Curr Biol. 14;24(8):R298-301. Maderspacher F, 2014

(5) Wolfer DP, Crusio WE, Lipp HP. 2002. Knockout mice: simple solutions to the problems of genetic background and flanking genes. Trends Neurosci. 25:336-40. Wolfer DP, 2002

(6) Crusio WE1, Goldowitz D, Holmes A, Wolfer D. 2009. Standards for the publication of mouse mutant studies. Genes Brain Behav. 8(1):1-4. Crusio WE, 2009

(7) Eisener-Dorman AF, Lawrence DA, Bolivar VJ. 2009. Cautionary insights on knockout mouse studies: the gene or not the gene? Brain Behav Immun. 23:318-24. Eisener-Dorman AF, 2009

(8) Striebel JF, Race B, Pathmajeyan M, Rangel A, Chesebro B. 2013. Lack of influence of prion protein gene expression on kainate-induced seizures in mice: studies using congenic, coisogenic and transgenic strains. Neuroscience. 15;238:11-8. Striebel JF, 2013

(9) Nuvolone M et al. 2013. SIRPα polymorphisms, but not the prion protein, control phagocytosis of apoptotic cells. J Exp Med. 18;210:2539-52. Nuvolone M, 2013

On 2014 May 06, Serge Ahmed commented:

This study is outstanding. Together with other studies, it confirms that sugar is a double reward. Sugar activates brain dopamine (DA) neurons twice: once during sweet tasting (via an initial polysynaptic brainstem pathway) and once after blood glucose absorption (via an activation of MCH neurons). The latter delayed activation of DA neurons plays a critical role in learned food preferences and may also contribute to maintain the ability of sweet taste to activate DA neurons.

Rather surprisingly, this study also shows that concurrent optogenetic activation of hypothalamic MCH neurons during access to water sweetened with sucralose (a non-caloric sweetener) increases consumption of sweet water and also DA levels in the striatum. The time course of this effect is somewhat paradoxical, however, if one supposes that it mimics activation of MCH neurons by post-absorptive glucose. In fact, this effect is more consistent with a direct modulation of sweet palatability by MCH neurons. It would be interesting to know how glucose activation of MCH neurons during access to sweet water would affect consumption.

On 2015 May 13, Tim Smits commented:

As already commented by James Coyne, there are serious issues with the statistics in this paper as well as with the overall level of academic scrutiny in the write-down of the methodology and findings. These have indeed been discussed in two Letters to the Editor Smits T, 2014 & Smits T, 2015. Though published, the journal has not yet warned its readers of these mistakes in the original article. Next to these two published letters, more concerns about the article are described in this blogpost http://persuasivemark.blogspot.be/2014/02/dont-get-all-psychotic-on-this-paper.html

On 2015 May 12, James C Coyne commented:

This study compares a nurse-delivered cognitive behavior therapy to treatment as usual in a small, convenience sample of older psychotic patients from community care who averaged over 20 years of previous treatment. The treatment as usual is not adequately described or quantified in a way that allows interpretation of any differences between conditions. It cannot be determined whether any effects are due to specific elements of the intervention or to inadequacies in professional contact time, support, or expectations likely to be occurring in the community psychiatric care of patients who have been there over 20 years.

But there are more basic problems. As detailed in letters to the editor Smits T, 2014 Smits T, 2015 and numerous blog posts, there are substantial discrepancies between findings reported in the abstract, in the narrative Results section, and in the tables and figures of this article. Just a sampling:

For Table 2. The confidence intervals were suspiciously wide. The effect sizes seemed too large for what the modest sample size should yield. The table was inconsistent with information in the abstract. Neither the table nor the accompanying text had any test of significance nor reporting of means and standard deviations. Confidence intervals for two different outcomes were identical, yet one had the same value for its effect size as its lower bound.

Figure 2 is mislabeled as a histogram and if results are to be believed, there are no significant pre-post differences between intervention and control group on any of the outcome variables. This is discrepant with what is reported in the abstract and narrative of the Results section.

Figure 5 lacks any metric for the vertical lines.

Their responses to letters about this article clearly indicate that the author Turkington D, 2014 and the statistical editor of the Journal < PMID:25816048 >are now aware of these problems.

It is unclear why there has not been a retraction or correction issued.

You can read more about the problems of this article and the response to criticism at my posts at PLOS Mind the Brain.

Sordid tale of a study of cognitive behavioral therapy for schizophrenia gone bad http://blogs.plos.org/mindthebrain/2015/04/14/sordid-tale-of-a-study-of-cognitive-behavioral-therapy-for-schizophrenia-gone-bad/

On 2014 Jan 04, Dorothy V M Bishop commented:

I was pleased to see that Professor Farthing took the opportunity to tackle the subject of research misconduct in his lecture. He cogently notes the nature of the problem and makes suggestions to deal with it. I thought his analysis was generally on-target, but I was concerned about his second suggested solution: enhanced monitoring and audit, and his failure to consider an additional approach, which is to change the incentive structure for researchers. The following points are taken from a blogpost I wrote on these topics (http://deevybee.blogspot.co.uk/2013/06/research-fraud-more-scrutiny-by.html).

I agree we need to think about how to fix science, and that many of our current practices lead to non-replicable findings. I just don't think more scrutiny by administrators is the solution.

So what would I do? The answers fall into three main categories: incentives, publication practices, and research methods.

Incentives: Currently, we have a situation where research stardom, assessed by REF criteria, is all-important. Farthing notes that RAE/REF criteria have been devised to stress quality rather than quantity of research, which is a good thing, but it is still the case that too much emphasis goes on the prestige of journals (see http://deevybee.blogspot.co.uk/2013/01/journal-impact-factors-and-ref-2014.html).

Instead of valuing papers in top journals, we should be valuing research replicability. This would entail a massive change in our culture, but a start has already been made in my discipline of psychology :see http://www.nature.com/news/psychologists-strike-a-blow-for-reproducibility-1.14232.

Publication practices: the top journals prioritize exciting results over methodological rigour. There is therefore a strong temptation to do post hoc analyses of data until an exciting result emerges. I agree with Farthing that pre-registration of research projects is a good way of dealing with this. I'm pleased to say that here too, psychology is leading the way in extending research registration beyond the domain of clinical trials: http://blogs.lse.ac.uk/impactofsocialsciences/tag/registered-reports/

Research methods: we need better training of scientists to become more aware of the limitations of the methods that they use. Too often statistical training is a dry and inaccessible discipline. All scientists should be taught how to generate random datasets: nothing is quite as good at instilling a proper understanding of p-values as seeing the apparent patterns in data that will inevitably arise if you look hard enough at some random numbers. In addition, not enough researchers receive training in best practices for ensuring quality of data entry, or in exploratory data analysis to check the numbers are coherent and meet assumptions of the analytic approach.

Finally, before any new regulation is introduced, there should be a cold-blooded cost-benefit analysis that considers, among other things, the cost of the regulation both in terms of the salaries of people who implement it, and the time and other costs to those affected by it. My concern is that among the 'other costs' is something rather nebulous that could easily get missed. Quite simply, doing good research takes time and mental space of the researchers. Most researchers are geeks who like nothing better than staring at data and thinking about complicated problems. If you require them to spend time satisfying bureaucratic requirements, this saps the spirit and reduces creativity.

I think we can learn much from the way ethics regulations have panned out. When a new system was first introduced in response to the Alder Hey scandal, I'm sure many thought it was a good idea. It has taken several years for the full impact to be appreciated. The problems are documented in a report by the Academy of Medical Sciences, which noted "Urgent changes are required to the regulation and governance of health research in the UK because unnecessary delays, bureaucracy and complexity are stifling medical advances, without additional benefits to patient safety"

On 2014 Jan 11, David Mage commented:

The authors report an interesting study in regards to sustained hypoxia and respiratory neural control during a critical period of development in rats. However it may have no relation to the phenomenon of human sudden infant death syndrome (SIDS). It has been shown that human SIDS occur between birth and 3.5 years with a 4-parameter lognormal age distribution (Johnson SB) Mage DT, 2009. This distribution is continuous and has no discontinuities between fore and aft portions of the age distribution on either side of "a critical period of development." The SIDS community seems to have forgotten that the operative definiton of modern SIDS as being restricted to under one year from birth was made for research purposes only Willinger M, 1991 and the triple risk model for SIDS cited by these authors does not predict a 50% male excess for SIDS Mage DT, 2014.

On 2014 Jan 24, Tom Kindlon commented:

I questioned the use of subjective outcome measures, particularly as primary outcomes, in trials of lightning process in a referenced comment on the feasibility study here: http://www.ncbi.nlm.nih.gov/pubmed/24304689#cm24304689_2383.

Given the protocol uses subjective measures as primary outcomes, I thought I would highlight it here.

On 2014 Jan 08, Brian Foley commented:

The C. botulinum genome data on which this paper is based is not yet linked to this publication here in PubMed. The genomes are: ATCC 3502 http://www.ncbi.nlm.nih.gov/nuccore/AM412317, Hall A http://www.ncbi.nlm.nih.gov/nuccore/CP000727, ATCC 19397 http://www.ncbi.nlm.nih.gov/nuccore/CP000726, NCTC 2916 http://www.ncbi.nlm.nih.gov/assembly/GCF_000171055.1/

On 2014 Feb 27, FREDERICK DOMANN commented:

For a recent review on PHD3 please see http://www.dovepress.com/getfile.php?fileID=17843

On 2014 Mar 06, David Keller commented:

Cataract pre-ops are driven by the ophthalmologists

The American College of Cardiology and the American Society of Anesthesiologists are in agreement that the routine pre-operative examination is not necessary for stable patients. That is good, but you will not see a decrease in the number of these exams until the ophthalmologists sign on to that agreement. Here is how it works in private practice: an elderly patient shows up in their internist's office one day, after skipping their routine follow-up appointments for way too long, perhaps to the point where their internist has been mailing them reminder letters and enlisting the patient's pharmacist to remind the patient to follow up soon. Finally, the patient shows up with a note from their ophthalmologist requesting certain specific blood tests, an EKG and "clearance" for the cataract procedure. If these instructions are not followed by the internist, the patient's cataract extraction will be postponed, and the internist may lose the patient to a more user-friendly PCP. To improve its impact, this article should be co-published in JAMA - Ophthalmology.

On 2014 Jan 26, Christopher Southan commented:

Our independent publication "A tale of two drug targets: the evolutionary history of BACE1 and BACE2" Southan C, 2013 came out essentially back-to-back with this paper. The two are complementary in coverage and broadly convergent in their conclusions (details at http://cdsouthan.blogspot.se/2014/01/a-tale-of-two-targets-bace1-and-bace2.html).

On 2013 Dec 24, Hilda Bastian commented:

An important initiative. There was animated discussion (and a fair amount of cringing) when this paper was presented at the Peer Review Congress earlier this year (see this blog post). Needing to gather, adequately describe and store the data we analyze in a way that others can use it has major implications for the daily life of many researchers.

Having a spotlight shone on the adequacy of data stewardship is important, but there are some issues to keep in mind. It's in a very specific area of research. Some other fields have particular regulations about the retention, privacy and sharing of all, or some, data. See for example recent analyses of the availability of clinical trial data (Riveros C, 2013).

The numbers of papers in this study at all dwindle in earlier years: 26 in 1991 compared with 80 in 2011. Data within particular categories (such as definitely lost in any one year) are correspondingly small.

It was interesting that only 2.4% of studies had made their data available at the time of publication. (Those studies were excluded.)

The authors practice what they preach: the full data are in Dryad and there's a manuscript in arXiv.

On 2015 May 25, James Tsung commented:

Link to Case Videos: https://youtu.be/ZVR-H4p4GOw?list=PLHg2xyua_KjthYks5X2e0UrzOHdyYf_LN

On 2016 May 10, Morten Oksvold commented:

Please pay attention to the following report from ORI (Office of Research Integrity) before reading this article:

https://ori.hhs.gov/content/case-summary-pastorino-john-g

On 2014 Feb 24, Eugene Koonin commented:

A very interesting paper beyond doubt, demonstrating specific role of codon bias in translation regulation. The following previous publications provide complementary insights into the regulatory effects of codon usage: http://www.ncbi.nlm.nih.gov/pubmed/20403328 http://www.ncbi.nlm.nih.gov/pubmed/24012761

On 2014 Feb 04, Tobias von der Haar commented:

That's interesting - you analysed rare codon clusters as a function of the protein motif, which would be related to folding. There is also evidence that rare codons are over-represented in low-expressed proteins, which could be related to the control mechanism we describe Neafsey DE, 2007. One might also expect rare codons to be over-represented near the 5'-end of messages (where they would exert control without significant ribosome queueing), but I don't think anyone has looked for this yet.

On 2014 Feb 03, Rafael Najmanovich commented:

We have recently performed a large scale analysis of evolutionarily conserved rare codon clusters in protein families that may be of interest for readers of this paper: Chartier M, 2012.

On 2014 Jan 07, Aaron Liston commented:

An important result shown in Figure 1, but not mentioned in the manuscript, is that poplar (Malpighiales) is sister to cacao (Malvales) and Brassicales (Arabidopsis, papaya) in the malvid clade, and not the fabid clade (Fabales, Rosales). This result has been reported in other studies of nuclear gene phylogeny, and conflicts with the widely utilized APG3 classification that is predominantly based on plastid genes.

On 2017 Jun 13, Christina Niederstadt commented:

It would be enlightening to "abstract-only" or "mostly-just-abstract" -readers, if the abstract could contain information regarding the wheight-loss reasons or methods collected within the NWCR (bariatric surgery, anyone?)... (I do not say that I promote "abstract-only-reading" but it would help to decide on whether it would be worthwhile to order the full text of the article.)

On 2014 Feb 24, Zhongheng Zhang commented:

An well written review that comprehensively summarized unusual signs of Px.

On 2013 Dec 30, Raphael Stricker commented:

Raphael B. Stricker, MD* and Lorraine Johnson, JD, MBA*

*International Lyme and Associated Diseases Society, P.O. Box 341461, Bethesda, MD 20827-1461. www.ILADS.org

This editorial by Dr. Lantos was published together with an article by Wressnigg and colleagues from Baxter Bioscience in support of a new Lyme vaccine developed by Baxter Bioscience. Our published Letter to the Editor (http://www.ncbi.nlm.nih.gov/pubmed/24355028/) responded in part to Dr. Lantos.

Both the Baxter Bioscience article and the Lantos editorial make short shrift of patient vaccine safety concerns, which Lantos describes as “largely unsubstantiated”. We note that the previous LYMErix vaccine sparked a class action lawsuit from patients who claimed that they were harmed by the vaccine, which was ultimately pulled from the market by the manufacturer. We also note that "by withdrawing LYMErix when it did, the manufacturer avoided releasing phase 4 post-marketing data that probably would have shown increased side-effects related to the vaccine. The data have never been disclosed."

We conclude that patient trust in new Lyme vaccines will require that legitimate safety concerns regarding the previous vaccine be acknowledged and addressed. Because Lyme vaccines are given to a healthy population, our first priority is to make sure that they are safe.

References

1. Stricker RB. Lymerix® risks revisited. Microbe 2008;3:1-2.
2. Smith P, Gaito A, Marks DH. Transcript of FDA Lymerix Meeting, Bethesda, MD, January 22, 2002. Available at: http://www.lymediseaseassociation.org/index.php?option=com_content&view=article&id=532:lymerix-meeting&catid=129:hhsfood-a-drug-administration-fda&Itemid=531
3. Croke CL, Munson EL, Lovrich SD, et al. Occurrence of severe destructive Lyme arthritis in hamsters vaccinated with outer surface protein A and challenged with Borrelia burgdorferi. Infect Immun. 2000;68:658–63.
4. Rose CD, Fawcett PT, Gibney KM. Arthritis following recombinant outer surface protein A vaccination for Lyme disease. J Rheumatol. 2001;28:2555–7.
5. Latov N, Wu AT, Chin RL, Sander HW, Alaedini A, Brannagan TH. Neuropathy and cognitive impairment following vaccination with the OspA protein of Borrelia burgdorferi. Periph Nerv Syst. 2004;9:165–7.
6. Alaedini A, Latov N. Antibodies against OspA epitopes of Borrelia burgdorferi cross-react with neural tissue. J Neuroimmunol. 2005;159:192–5.
7. Souayah N, Ajroud-Driss S, Sander HW, Brannagan TH, Hays AP, Chin RL. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease. Vaccine 2009;27:7322-5.
8. Marks DH. Neurological complications of vaccination with outer surface protein A (OspA). Int J Risk Saf Med. 2011;23:89-96.
9. Molloy PJ, Berardi VP, Persing DH, Sigal LH. Detection of multiple reactive protein species by immunoblotting after recombinant outer surface protein A Lyme disease vaccination. Clin Infect Dis. 2000;31:42-7.
10. Fawcett PT, Rose CD, Budd SM, Gibney KM. Effect of immunization with recombinant OspA on serologic tests for Lyme borreliosis. Clin Diagn Lab Immunol. 2001;8:79-84.
11. Hanson MS, Edelman R. Progress and controversy surrounding vaccines against Lyme disease. Expert Rev Vaccines 2003;2:683–703.
12. Nigrovic LE, Thompson KM. The Lyme vaccine: a cautionary tale. Epidemiol Infect. 2007;135:1–8.
13. Nardelli DT, Munson EL, Callister SM, Schell RF. Human Lyme disease vaccines: past and future concerns. Future Microbiol. 2009;4:457-69.
14. Smith P. Remarks to Vaccines and Related Biological Products Advisory Committee, Bethesda, MD, January 31, 2001. Available at: http://www.lymediseaseassociation.org/index.php?option=com_content&view=article&id=262:vaccine-remarks&catid=80:controversy&Itemid=76

Disclosure: RBS and LJ are members of the International Lyme and Associated Diseases Society (ILADS) and directors of LymeDisease.org. They have no financial or other conflicts to declare.

On 2015 Sep 25, David Mage commented:

Elder et al. do a thorough analysis of the possible causes of the Black-White infant mortality gap (B > W) and, per above, they show that if Black infants had the same risk factors as White infants then the gap between them would only be reduced by 25%. In our studies of sudden infant death syndrome (SIDS: (ICD-9 798.0; ICD-10 R95) [PMID 20049339, 24164639] we noted this Black infant excess. Given that SIDS is a unique disease because death is its first symptom, the excess Black death rate could not involve a deficiency in medical care of the B infants presenting with SIDS. We then used the tabulated infant mortality statistics for all ICD chapter causes of infant dearth < 1 year, wonder.cdc.gov, and found that B > W for all causes except neoplasms (ICD-10: C00-D48). We wondered at what age this deficit seen in other non-neoplasm codes for infant mortality would disappear and looked at older age ranges up to 65 years. The deficit does not disappear (except for a few years where cystic fibrosis is much higher for W than B) and in each and every age group the B death rate is greater than the W death rate {some genetic reasons not withstanding, such as sickle cell anemia with B > W). We reason that this B > W excess must be systemic and agree with Haider [Racial and ethnic infant mortality gaps and socioeconomic status. Focus; 2014;31 (1) Spring/Summer:18-20] that the poverty of the B population relative to the W population may be the shadow cast by the past history of the Plessy v. Ferguson legal fiction that ʺseparate but equalʺ education was constitutional and would cause no harm. The lingering effect of this past discrimination may be insidious if it resulted in the relative impoverishment of many of those discriminated against and their progeny that delays or reduces their access to adequate medical care. For example, the U.S. death rates from ICD-10 causes of medical errors Y40-Y69, Drugs, medicaments and biological substances causing adverse effects in therapeutic use, and Misadventures to patients during surgery and medical care, are higher for B than W at all ages up to 84 years.

On 2014 Jan 10, Luis Querol commented:

This paper describes an amazing work and links the CD4 T cell responses against H1N1 with those against orexin. This paper has received a lot of mainstream media attention (see here for example) where it has been described as the demonstration that narcolepsy is an autoimmune disease. Although the study provides interesting data re-inforcing the autoimmune hypothesis of narcolepsy, it does not demonstrate so and it's not the first study to suggest the autoimmune hypothesis, as authors correctly point in the discussion. A brief comment summarizing the study and providing context to those mainstream media headlines has been published here

On 2015 Sep 09, Linda Rieswijk commented:

da Silva RP, 2014 in the introduction of the manuscript it is stated that S-adenosylmethionine is abbreviated as AdoHcy. This is however confusing since in the sentence preceding this one it is stated that S-adenosylmethionine is abbreviated as AdoMet. I guess AdoHcy is the abbreviation for S-adenosylhomocysteine. This should be adjusted in the introduction.

On 2016 Sep 10, Morten Oksvold commented:

Before reading or citing this article, please read the reports regarding the Macchirini case:

http://ki.se/sites/default/files/karolinska_institutet_and_the_macchiarini_case_summary_in_english_and_swedish.pdf

http://ki.se/en/news/macchiarini

On 2014 Jan 10, Farooq Rathore commented:

Nobody can deny the importance of social media, but the doctor has to strike a balance between his professional demands and the urge to check the latest facebook post or reply to a tweet ASAP. All social media have the option of customization and if a physician chooses wisely he will be able to have latest knowledge and information from the social media at his finger tips ( literally)

In addition doctors are humans too. We need to socialize and a little bit of socialization on FB, Twitter or G+ might not hurt if we keep a track of the time we need to spend of these social media sites

On 2013 Dec 22, William Brieger commented:

Obviously social media like any other form of expression is an individual choice. The usual social media account by health professionals attracts a limited following of people with specific interests. Social media can be used to keep colleagues up to date on activities in their specific field. When attending professional conferences, physicians and other health workers can use social media to share what they are learning with colleagues who are unable to attend. Various privacy settings are available for those who want to control who reads their postings. Again, use of social media must have a purpose for individual users, and if it does not advance professional practice for an individual, there is no reason she/he should not use social media except among friends and family.

On 2013 Dec 21, Allison Stelling commented:

First of all, thank you Anne Marie for linking to the pdf of your paper.

I must say that I disagree with Decamp about the future and usefulness of social media as a means to distribute medical information. I do feel he is correct that no MD ought to be forced to participate if they do not feel so inclined. Those who are so inclined, however, must be rewarded and guided, not punished.

Several of the phrases Decamp uses in his essay are quite telling ie, "On the contrary, the brevity, lack of control, and permanence of online information make engaging in such activities even more risky in the online realm." Such statements are loaded with fear- fear of loss of control of a conversation that is traditionally held between experts and bypasses any patient interaction. (Also, if one fears brevity, then one can get one's own blog where one can go on a bit.)

This is an unwarranted fear that is eating away at the heart of American medicine. If you fear your public misunderstands you, educate them.

Medicine is a public service, a public good; and as such must be publicly scrutinized (and funded, for that matter, but that is a different topic). Medicine and public health issues are a dialogue that must be had between the medical doctors, the public they serve, and the scientific researchers who lay the foundations for medical discoveries.

The days of dictation and monologues delivered to an unresponding audience are gone. We need an educated and enthusiastic population to further our goals of cures. (I would settle simply for more accurate diagnostics!) And- even if the public is not permitted to speak during a particular conversation that they funded- they do have the right to view it and ask questions afterwards.

Rapid dissemination of solid medical information is a crucial ingredient to my nation's- and the world's- future health. USA tax money pays for quite a percentage of foundational health research, and my nation's taxpayers have a fundamental right to the information and research for which they paid.

Decamp also states that the "role of physician expertise is unclear." Perhaps it is not expertise that patients seek online from MDs, but comfort- and someone who will listen to them.

As for the "mistakes" section- yes, MDs are human. They make mistakes. I've worked with many MDs in the course of my career, and the one prevalent flaw was an unwillingness to admit error. Over-confidence and an idealized image of perfection is haunting the medical community- remnants of a not-to-distant past wherein they were likened to "gods amongst men".

We know very little about life and death, and the chemical differences that separate them. I would suggest it is high time the MDs drop the facade of certainty and confidence, and come into the light of collaborative discourse that social media enables. -Allison (https://twitter.com/DrStelling)

On 2013 Dec 21, Hilda Bastian commented:

That's a useful list of reasons for value in social media for physicians. Further support for the "to learn" argument and finding good curators among peers comes from the growth of social media as a gateway to medical literature. James Colbert et al reported at the 2013 Peer Review Congress that for NEJM, Facebook and Twitter are both in the top 10 referring sites to the journal (at 6 and 10 respectively). Readers might also be interested in reports on the role of social media for journals and societies in dermatology (Amir M, 2014) and ophthalmology (Micieli R, 2012).

On 2013 Dec 21, Anne Marie Cunningham commented:

Full free text pdf of this paper can be found here http://www.rcpe.ac.uk/sites/default/files/decamp_cunningham_curr_cont.pdf The RCPE journal is OA. They even let me retain copyright on this publication and licensed them to publish it. But for some reason PubMed doesn't link to the journal home page etc.

Hope you enjoy- please leave us feedback!

On 2016 Feb 07, Fang-Cheng Yeh commented:

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

On 2014 Mar 21, Pedro Reche commented:

We have enhanced the EPISOPT site (http://imed.med.ucm.es/Tools/episopt.html).The server predicts epitope HLA I binding profiles, compute population protection coverage and select sets of epitopes providing a desired population protection coverage

On 2016 May 30, Heidi Schulz commented:

According to HGVS guidelines, the p.Q238L mutation described as c.713del15 in the paper, should be named c.713_714+13del. The p.A357V variant mentioned in the paper has a MAF=0.02 in ExAc East Asians and has not been reported in patients with Best disease in the papers cited.

On 2014 Mar 14, Jonathan Eisen commented:

Holly Ganz has written a post on the "microbiology of the Built Environment network" blog discussing this paper. See Dog hair and asthma

On 2014 Aug 08, Attila Csordas commented:

associated dataset available via PRIDE/ProteomeXchange: http://www.ebi.ac.uk/pride/archive/projects/PXD001211

On 2016 Sep 26, Holger Schunemann commented:

The Guideline Development Checklist is now shared with the Guideline International Network (GIN) (http://www.g-i-n.net/) and called the GIN-McMaster Guideline Development Toolbox (GET) or checklist and available in several languages in addition to English (Portuguese, Chinese, Spanish and Italian) on: https://cebgrade.mcmaster.ca/guidecheck.html

On 2014 Mar 26, Antonio Martinez-Gimeno commented:

The results of this excellent RCT on the effect of hypertonic saline on infants with acute bronchiolitis can be easily added to current metaanalysis on the issue (Zhang L, 2013 and Chen YJ, 2014) Just download Review Manager 5.2, install it and introduce the previous data and the data from this study (along with the data from two other recently published RCT, Nenna R, 2014 and Sharma BS, 2013) and you will obtain an excellent update of each meta-analysis.

Unfortunately, the authors of this study failed to include the actual numbers of hospital length of stay (group means and SD) in table 5 and that precludes its use in the meta-analysis update.

It would be great if the authors could publicly provide these figures.

On 2014 Oct 17, Joe Newton commented:

Your spatial-temporal correlation is especially suggestive for the pathophysiology expected in multiple neuropsychiatric diagnostic categories. Further work in animal models on measures of action potential speed/velocity are expected to reveal abnormalities in such neuropsychiatric categories. Best wishes, Joe Ray Newton

On 2014 Jan 02, Paul Whiteley commented:

The authors are to be applauded for looking at this potentially important area of autism research. Combined with other research similarly indicating that a proportion of children on the autism spectrum may present with gut hyperpermeability: de Magistris and colleagues (2010): http://www.ncbi.nlm.nih.gov/pubmed/20683204 and de Magistris and colleagues (2013): http://www.ncbi.nlm.nih.gov/pubmed/23984403 an interesting pattern of gut-related pathology is emerging for at least some cases of autism (or should that be the autisms).

Given that this cohort was (I think) drawn from the same participant group as that investigated by the same authors in other study: Chandler and colleagues (2013): http://www.ncbi.nlm.nih.gov/pubmed/23371507 it is a pity that similar values related to intestinal permeability were not reported for an asymptomatic (typically developing) control group as a comparator. Whilst the authors note that their special educational needs (SEN) group did not present with autism (I assume as reaching the diagnostic threshold for a diagnosis of autism) one wonders whether specific behaviours forming the diagnostic triad (or dyad depending on the criteria applied) may overlap and in turn, link autism and SEN participants?

That also de Magistris and colleagues (2010) noted that use of a gluten- and casein-free (GFCF) diet seemed to affect intestinal permeability measurements also brings into play the question of whether similar dietary measures were included in any of the participant group of the current study and exerted an effect on the results obtained.

Those issues aside, the emerging picture of gut hyperpermeability combined with features of a non-coeliac gluten 'sensitivity' in cases of autism as per Lau and colleagues (2013): http://www.ncbi.nlm.nih.gov/pubmed/23823064 and Ludvigsson and colleagues (2013): http://www.ncbi.nlm.nih.gov/pubmed/24068245 offers some new directions for autism research and practice.

On 2014 Nov 25, Harri Hemila commented:

Virtamo J, 2014 analyzed post-trial mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, which included male smokers aged 50 to 69 years at baseline. In this new post-trial analysis, they calculated that post-trial relative mortality was 1.02 (95% CI, 0.98 to 1.05) for vitamin E recipients compared with nonrecipients. Unfortunately, Virtamo et al. ignored the strong evidence that the effects of vitamin E are not uniform over the ATBC Study participants.

A previous analysis of the ATBC Study found that the effect of vitamin E on pneumonia incidence was significantly modified by three different measures of cigarette smoking exposure Hemilä H, 2004, DOI. Another analysis focusing on common cold incidence found significant modification of vitamin E effect by age, smoking and residential neighbourhood Hemilä H, 2006, DOI. The modifying factors on respiratory infections cannot be directly extrapolated to mortality, yet those findings led to an investigation on whether vitamin E effects on mortality might also be heterogeneous in the ATBC Study. During the 5-8 year intervention period of the ATBC Study, overall mortality was 2% higher in the vitamin E participants than in the no-vitamin E participants. However, if the effect of vitamin E is heterogeneous, then the 2% overall estimate might not be valid for a substantial proportion of the ATBC Study participants.

In our analysis of all-cause mortality during the intervention period of the ATBC Study, we found that the combination of age and dietary vitamin C intake modified the effect of vitamin E supplementation to the extent that the heterogeneity over 6 subgroups was highly significant (P = 0.0005) Hemilä H, 2009, DOI. In 11,448 ATBC Study participants aged 50-62 years at the baseline who had dietary vitamin C intake above the median, vitamin E increased all-cause mortality by 19%. In contrast, in 872 ATBC participants aged 66-69 years who had vitamin C intake above the median, vitamin E reduced mortality by 41%. Vitamin E had no influence on mortality among those who had dietary vitamin C intake less than the median. The modifying effect of vitamin C was not explained by other substances in fruit and vegetables. The interaction between vitamins C and E is well documented Bruno RS, 2006, DOI, which may explain the role of vitamin C as a modifying factor for some vitamin E effects.

Furthermore, in the younger ATBC Study participants (50-62 y at the baseline) who had vitamin C intake above average, vitamin E started to increase mortality only after a lag period of 3.3 years. There was no effect on mortality during the first 3.3 years of supplementation, but thereafter mortality increased in the vitamin E participants by 38% Hemilä H, 2009. The effect modification by supplementation-time is not easily explained by chance since the addition of the second vitamin E effect to start at 3.3 years improved the regression model significantly (P = 0.007). Thus, in addition to age and dietary vitamin C intake, the duration of vitamin E supplementation also modified the effect in this subgroup. The lag period may be explained by the fat solubility of vitamin E, since the body stores are changed slowly with changes in intake levels Handelman GJ, 1994, AJCN.

Finally, the decrease in mortality in participants aged 66 and over by vitamin E implies that the survival time might also be influenced. A subsequent analysis found that among ATBC participants with dietary vitamin C intakes above the median who smoked less than a pack of cigarettes per day, vitamin E extended lifespan by 2 years at the upper limit of the follow-up age span Hemilä H, 2011, DOI.

These subgroup findings invite the following questions. Given that mortality in the older ATBC Study participants was decreased by vitamin E, did the discontinuation of vitamin E at the end of the trial period lead to a corresponding increase in post-trial mortality in the oldest vitamin E recipients as compared with nonrecipients? Furthermore, given that after 3.3 years vitamin E started to increase mortality in the younger participants, did discontinuation of vitamin E lead to a corresponding decrease in post-trial mortality after a lag period? Because of the abovementioned subgroup findings, these questions are of obvious relevance and should have been investigated in the post-trial analysis of ATBC Study mortality. Virtamo et al. do not give any justification for dismissing the strong evidence of heterogeneity in the vitamin E effects on mortality.

On 2016 Apr 05, Marko Premzl commented:

The third party data gene data set of eutherian ribonuclease A genes HG328835-HG329089 was deposited in European Nucleotide Archive under research project "Comparative genomic analysis of eutherian genes" (https://www.ebi.ac.uk/ena/data/view/HG328835-HG329089). The 255 complete coding sequences were curated using tests of reliability of eutherian public genomic sequences included in eutherian comparative genomic analysis protocol including gene annotations, phylogenetic analysis and protein molecular evolution analysis (RRID:SCR_014401).

Project leader: Marko Premzl PhD, ANU Alumni, 4 Kninski trg Sq., Zagreb, Croatia

E-mail address: Marko.Premzl@alumni.anu.edu.au

Internet: https://www.ncbi.nlm.nih.gov/myncbi/mpremzl/cv/130205/

On 2014 Jan 14, Amanda Capes-Davis commented:

Sounds like an exciting compound, but it may or may not be relevant to oral cancer. KB is known to be cross-contaminated and is actually HeLa, as shown by Gartler in 1967 (PMID 4864103). For a database of cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2017 Oct 17, thomas samaras commented:

Certainly most Western studies show that taller subjects have lower CHD than shorter ones. The reason for this is not related to inherent biological problems related to shorter height. In fact, shorter people following a good lifestyle and diet have been shown to have much lower risk of CHD. The evidence for this statement follows:

1. Pre-Western people rarely experience Western type chronic diseases, including CHD. In fact, studies during the 20th C found a number of populations where there was no evidence of CHD or stroke. These populations included: Solomon Islands, Papua New Guinea, Kalahari Bushmen, Congo pygmies, and the island of Kitava. All these populations had males who averaged less than 5'4".

2. In the early 1900s, the US and UK had very low levels of CHD. Yet, people were much shorter compared to today.

3. Before 1970, US higher income people had higher rates of heart disease than working class people. After 1970, the situation reversed. In both cases working class people were shorter. The reason for this paradox may be increased overweight in shorter people and the consumption of fast foods, rich in animal protein and calories. Also improved diets based on medical advice may have helped the higher income people after 1970.

4. When pre-Western populations transition to a more Western diet, they see a sharp rise in CHD.

5. In the 20th C, Northern Europe had almost double the mortality from heart disease as shorter Southern Europe.

6. Sardinia had the lowest CVD in Europe and its people were the shortest Europeans.

7. A study of Western Sicilian centenarians found they were short and had no CVD risk factors.

8. Women are shorter than men and have lower CHD mortality.

If bigger size was an advantage in reducing heart problems, then why do Great Danes have 60 times the risk of heart failure vs. miniature Dachshunds? A study found that bigger dogs had more heart failure than smaller dogs. Smaller dogs have much smaller blood vessels and hearts. Their heart rates are also about 40% higher than big dogs.

Part of the problem is that shorter people tend to be more overweight than taller ones. If tall and short people with the same BMI are compared, the taller will be relatively lighter than the shorter ones giving them a lower risk of CHD. Also, it is difficult to separate short people from a study who suffered childhood illness, malnutrition or experienced catch-up growth--all related to increased risk of adult heart problems. More information on the benefits of shorter height and lower CVD are discussed in the Indian Heart Journal, Samaras TT. 65(2013)66-71.

On 2014 Jan 07, Anders von Heijne commented:

Important and well argued paper.

On 2014 Jan 25, Mones Abu-Asab commented:

Have We Learned Anything from Tumor Heterogeneity?!

Sullivan and Chandel wrote about an important topic in cancer biology namely the TCA aberrations and how cancer cells are able to circumvent these defects. However, the authors completely ignored the issue of heterogeneity in tumors and the challenges it poses when extrapolating from tissue culture model to in vivo tumors^1-3. Additionally, the implications of heterogeneity for designing targeted therapies cannot be overemphasized since it has thus far proven to be the Achilles heel of targeted treatments of cancer^{1, 4}. Zeroing in on mitochondrial metabolism for cancer therapy poses even bigger challenges than the targeting of cytoplasmic and nuclear metabolism. Intratumoral heterogeneity confers a selective advantage on a population of cells under many selective pressures targeting their proliferation and migration. Furthermore, the population of mitochondria within each cell is also heterogeneous—a phenomenon known as heteroplasmy that the cancer cell inherits by default. In cancer cells, there are not usually any normal mitochondria⁵. However, the damage of cancer mitochondria is also heterogeneous; each mitochondrion varies in the type of damage it harbors; this has thus far been confirmed by ultrastructural features. In this regard, mitochondria seem to be vulnerable organelles that vary in their sensitivity to insults; this fact extends beyond cancers to other pathologies as well such as age-related macular degeneration, bacterial septicemia, and adverse drug effects. Understanding the abnormal metabolic reactions within cancer cells is very important because it teaches us about the pathways diversity that can be generated in an allostatic environment; the new metabolic reactions confer the adaptive survival advantages upon cancer cells. Therefore, single-cell mitochondrial analyses from patients tumors are in order here if we want to reach an accurate understanding of cancer’s mitochondrial metabolism. Like other evolutionary events within any population, heterogeneity within a tumor arises by independent events within individual cells and their mitochondria. Thus, heterogeneities of tumor cells and their mitochondria permit resistance to treatment and survival in a persistently dynamic process. Fortunately, the tools for studying single cell models are here. Combining the microfluidic chip for single cell characterization⁶ and Next Generation Sequencing (NGS), as well as other techniques, could supply us with needed data. If we are to target mitochondrial metabolism for cancer therapy, as Sullivan and Chandel have suggested, we need first to study the diversity of the mitochondrial population within a single cancer cell and determine the suitable universal targets that will not play “hide and seek” as the case has been with current targeted treatments¹. Hopefully, this approach will bring us closer to applying a predictive paradigm of personalized medicine.

References

¹ Nathanson, D.A., et al., Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science, 2014. 343(6166): p. 72-6.

² Gerlinger, M., et al., Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med, 2012. 366(10): p. 883-92.

³ Horswell, S., N. Matthews, and C. Swanton, Cancer heterogeneity and "the struggle for existence": diagnostic and analytical challenges. Cancer Lett, 2013. 340(2): p. 220-6.

⁴ Abu-Asab, M.S., et al., Biomarkers in the age of omics: time for a systems biology approach. OMICS, 2011. 15(3): p. 105-12.

⁵ Davila, A.F. and P. Zamorano, Mitochondria and the evolutionary roots of cancer. Phys Biol, 2013. 10(2): p. 026008.

⁶ Sun, J., et al., A microfluidic platform for systems pathology: multiparameter single-cell signaling measurements of clinical brain tumor specimens. Cancer Res, 2010. 70(15): p. 6128-38.

On 2014 Apr 29, Amanda Capes-Davis commented:

Although the authors refer to Hep2 as "larynx squamous carcinoma cells", the description is unfortunately not correct. Hep2 is cross-contaminated and is actually HeLa, from cervical carcinoma. For a list of known cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2014 Jan 21, Serge Ahmed commented:

Excellent review. The authors present the VTA as a unique brain hub that integrates a variety of humoral and neuronal signals to regulate the "drive" to eat palatable foods for pleasure, comfort and relief. They appreciate the difficulty of targeting this intricate brain region to selectively reduce the excessive pursuit of food reward without altering other life pursuits.

On 2014 Feb 08, Jenny Doust commented:

An interesting trial which shows that moving to an absolute risk approach for cardiovascular disease prevention is probably more difficult than first thought. The study also shows two things not obvious in the abstract: 1) The problem of overprescribing to patients at low risk of a cardiovascular is a much larger problem than underprescribing to patients at high risk (in this study about 25% of the low risk patients were taking blood pressure or lipid lowering medication which was about 150 people, compared with about the same percentage of patients at high risk not taking either blood pressure or lipid lowering but this is 5 people) 2) The intervention was effective in reducing prescribing of blood pressure lowering medication to patients at low risk - see Figure 2.

On 2014 Nov 27, Guillaume Filion commented:

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

On 2013 Dec 23, Joseph Ana commented:

I want to join Neil P. in his comments about the challenges that researchers, authors and indeed clinicians face in low Income countries when it comes to evidence based practice. Those same points came up in the last annual workshop of the Association of editors of scholarly publication in Nigeria (AESPN) in August this year. In addition, even though access and literature search online is spreading in LICs, the infrastructure is still at snail speed, relatively very expensive and unreliable because of perennial power shortage. What ever the current situation, Meyers's paper has helped to shine global light on the challenges with evidence based practice in LICs and PubMed has given us a unique opportunity to contribute to the discussion. A problem once identified is on its way to a solution. Congratulations.

On 2013 Dec 23, Neil Pakenham-Walsh commented:

Thank you Sascha Meyer for drawing attention to the critical role of systematic reviews in low- and middle-income countries. The finding that only 5.7% of neonatal and 14.3% in neuropaediatrics Cochrane Reviews originate from middle and low-income countries is likely to be a reflection of several factors, including: 1. Most research is conducted in high-income countries, with a disproportionate focus on high-tech, high-cost, specialist medicine (and the benefits of such research are not accessible to the vast majority of the world's citizens)<br> 2. Health professionals and researchers in low-income countries often maintain 2 or 3 jobs simultaneously, and it may be difficult to invest the considerable (and often unremunerated) time to undertake a systematic review.<br> 3. Health professionals and researchers in low-income countries often may not have access to Ovid Medline, which is arguably essential for doing systematic reviews. (Ovid Medline provides more sophisticated search functions as compared with free PubMed.) Ovid regrettably has not joined HINARI, the WHO-publisher initiative that ensures free access to electronic journals, ebooks and databases in low-income countries. 4. It would be helpful if systematic reviews that are relevant to low-resources settings were made more easy to find through use of tagwords. HIFA profile: Neil Pakenham-Walsh is the coordinator of the HIFA2015 campaign and co-director of the Global Healthcare Information Network. He is also currently chair of the Dgroups Foundation (www.dgroups.info), a partnership of 18 international development organisations promoting dialogue for international health and development. He started his career as a hospital doctor in the UK, and has clinical experience as an isolated health worker in rural Ecuador and Peru. For the last 20 years he has been committed to the global challenge of improving the availability and use of relevant, reliable healthcare information for health workers and citizens in low- and middle-income countries. He is particularly interested in the potential of inclusive, transdisciplinary communication platforms to help address global health and international development challenges. He has worked with the World Health Organization, the Wellcome Trust, Medicine Digest and INASP (International Network for the Availability of Scientific Publications). He is based near Oxford, UK. www.hifa2015.org neil.pakenham-walsh AT ghi-net.org

On 2014 Feb 12, Jacob Jolij commented:

This is an interesting and valuable contribution to the TMS-induced blindsight literature. Several studies thus far have claimed to find TMS-induced blindsight, or the ability to respond to visual stimuli that are suppressed from consciousness by stimulating the early visual cortex with TMS. The authors of this paper argue that in order to truly demonstrate unconscious processing, researchers should use bias-free measures of awareness, such as d'. I support this idea. In their discussion, the authors criticize several earlier studies that have not used such measures, including our demonstration of affective blindsight (Jolij J, 2005).

I would like to note that we did report d' in our paper, albeit in the supplementary information. Detection sensitivity as measured with d' did drop to 0, whilst emotion discrimination sensitivity d' remained at 1.5 in the critical condition, where we presented stimuli for 16.7 ms. We therefore feel that the authors' (implicit) conclusion that our study did not provide sufficient evidence of unconscious processing because no bias-free measure was used is unwarranted.

Interestingly, when inspecting the d'-analyses of our work I did notice that d'-values were above 0 for the 32 ms presentation time in our paper. I can therefore not exclude the possibility that there was 'weak conscious processing' in this condition. However, this would only strengthen the conclusion of our study: we claim that conscious processing block access to unconsciously processed information, something that has been found in other domains as well.

On 2014 Feb 17, David Keller commented:

In their discussion of the harms of screening for lung cancer, Harris and colleagues discuss harms associated with earlier initiation of treatments which would have been started later or not at all without screening.

The authors state that screening and earlier treatment delays death for only 20% of patients destined to die from lung cancer. This raises the question of why the other 80% of patients are being exposed to ineffective treatments and the associated harms. Is the problem that we are not able to identify which patients will be among the fortunate 20% to postpone death by being treated? If so, then studies should be done to learn which characteristics differentiate patients who benefit from these treatments (e.g. tumor stage, grade, patient functional status, genetic profile or other factors). Perhaps these treatments are given to the unfortunate 80% for the purpose of palliation of symptoms, with the knowledge that there will be no mortality benefit. If so, then the treatments are beneficial to the patient despite failing to prolong life.

The authors state that the 80% of patients who are identified as having fatal cancers which cannot be treated to prolong life suffer harms from screening by virtue of their early diagnosis, in that they will have longer to live with the knowledge of their fate, causing anxiety and other psychological harms. However, other patients might strongly prefer to be informed as early as possible of their fatal diagnosis, in order to make better use of their remaining time alive and pain-free; for them, the earlier diagnosis afforded by screening is not a harm, but a benefit.

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

On 2014 Mar 06, David Keller commented:

Both sides now...

I would like to learn the orthopedic surgeon's version of why he did not operate on this patient with an elevated c-reactive protein. Did the surgeon express concern about occult infection? If so, was an Infectious Diseases consultation obtained? What did the I.D. consultant recommend? Was the surgeon concerned about malignancy or auto-immune disease? Were those worries addressed fully? A surgeon who is not confident that the patient's medical condition has been optimized may be justified in postponing a non-urgent surgery.

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

On 2014 Feb 03, David Simpson commented:

This is an interesting approach, but I would have liked to see some attempt made to calculate false discovery rates. Something along the lines of the method reported by Qian et al. (J. Proteome Res. 2005, 4, 53–62) would have been great. Requiring a minimum Sequest XCorr score of 1.5 for identification acceptance is very permissive. A high false discovery rate would be a good explanation for the limited overlap reported in Figure 3.

On 2014 Jan 14, Amanda Capes-Davis commented:

Just to clarify: the parental cell line, KB, is cross-contaminated and is actually HeLa. So derivatives of KB, including KB-3-1 and KCP-4, are not epidermoid carcinoma. For a database of cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2013 Dec 27, guoan zhang commented:

a good example of snp and cancer prevention,explaining gwas results is important.

On 2014 Mar 15, Valeria Fadda commented:

Meta-analysis on novel oral anticoagulants vs warfarin for stroke prevention: re-expressing the results as risk difference

In meta-analysis, the risk ratio (RR) and the risk difference (RD) are two commonly used outcome measures. Each of these indexes has its own advantages and disadvantages [1].

The meta-analysis by Ruff et al. [2] adopted the outcome measure of RR. In particular, the values of pooled RR were estimated according to the random-effect model.

We have re-analysed the results reported in Figure 1 of Ruff et al. [2] by expressing the results (event =stroke or systemic embolism) as RD instead of RR. In our re-analysis, the meta-analysis model was random-effect as implemented in the OMA software [3].

Our results were the following (see Ruff et al.[2] for further details on these data sets): RE-LY (dabigatran vs warfarin): RD= -1.10% (95% confidence interval[CI]: -1.68% to -0.52%); ROCKET AF (rivaroxaban vs warfarin): RD= -0.52% (95%CI: -1.17% to 0.13%); ARISTOTLE (apixaban vs warfarin): RD = -0.59% (95%CI: -1.06% to -0.13%); ENGAGE AF-TIMI48 (edoxaban vs warfarin): RD = -0.58% (95%CI: -1.27% to 0.10%); overall (all new oral anticoagulants vs warfarin): RD =-0.70% (95%CI: -0.99% to -0.41%). Expressing this incremental benefit as RD is advantageous because this analysis provides an absolute estimate of the magnitude of the incremental improvement. This meta-analytical result (RD = -0.70%; 95%CI: -0.99% to -0.41%) is statistically significant, but has a small magnitude.

To better interpret this absolute incremental benefit (i.e. a meta-analytical reduction of 0.70%) estimated from the overall analysis of these trials, a useful reference is given by the pre-specified non-inferiority margin that was used in the statistical power calculations of the pivotal trials comparing dabigatran, rivaroxaban, or apixaban with warfarin (RE-LY, ROCKET AF, and ARISTOTLE, respectively). These trials adopted a non-inferiority margin equal to half of the incremental benefit between warfarin and placebo (6 warfarin-vs-placebo trials) found in the meta-analysis by Hart et al. [4].

As pointed out by Fadda et al. [5], while Hart and co-workers considered, as their outcome measure, only RR and not RD, a meta-analysis of the same trials based on RD can be helpful to interpret these findings. The result of this re-analysis is represented by a pooled RD for warfarin vs. placebo of -5.0% (95%CI: -7.5% to -2.4%; random-effect model). Halving this difference yields a margin, expressed as RD, of -2.5%

References

1. Walter SD. Choice of effect measure for epidemiological data. J Clin Epidemiol. 2000 Sep;53(9):931-9.

2. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2013 Dec 3. pii: S0140-6736(13)62343-0. doi: 10.1016/S0140-6736(13)62343-0. [Epub ahead of print]

3. OMA software (Open Meta-Analyst version 4.16.12, Tufts University, U.S., url http://tuftscaes.org/open_meta/).

4. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999 Oct 5;131(7):492-501.

5. Fadda V, Gatto R, Maratea D. Incremental benefit of warfarin over placebo in patients with atrial fibrillation (Comment), PubMed Commons, available at http://www.ncbi.nlm.nih.gov/pubmed/10507957#cm10507957_2944

On 2015 Jul 06, Bill Cayley commented:

A good example of when "less" is "more": https://lessismoreebm.wordpress.com/2015/07/06/clinical-and-cost-effectiveness-of-compression-hosiery-versus-compression-bandages-in-treatment-of-venous-leg-ulcers-venous-leg-ulcer-study-iv-venus-iv-a-randomised-controlled-trial/

On 2014 Jan 06, Paul Whiteley commented:

As per the science and lay media interest in this research at publication, this paper potentially opens up a whole new world of investigations looking at the interplay between the gastrointestinal (GI) tract and brain in respect to lots of different behaviourally-defined conditions. That being said, mouse models of autism still have some way to go to 'mimic' the complexity that is autism (even the 'autisms' according to Whitehouse & Stanley 2013: http://www.ncbi.nlm.nih.gov/pubmed/23545020) and the often substantial risk of heightened comorbidity of various types that follow a diagnosis.

Perhaps to some degree lost in the media translation of this research was the effect that B. fragilis administration seemed to have on gut barrier integrity (and in particular that B. fragilis "improves defects in GI barrier integrity and corrects alterations in tight junction and cytokine expression" p.1454). The notion of a triad of factors: gut barrier - gut microbiota - gut immune function is an important emerging concept in at least some autism research circles; these issues similarly being pursued in other research for example, linked to schizophrenia: Severance et al (2012) http://www.ncbi.nlm.nih.gov/pubmed/22446142

That there may specific types of autism which carry various GI issues including those related to issues with gut flora: Williams et al (2011) http://www.ncbi.nlm.nih.gov/pubmed/21949732 is another emerging concept with some potentially important knock-on effects: Stilling et al (2013) http://www.ncbi.nlm.nih.gov/pubmed/24286462.

Indeed, again drawing on other rodent models thought to reflect some of the complexity of autism, there is increasing understanding that GI issues may also for example, be present in the valproic acid (VPA) model as per the work from de Theije and colleagues (2013) http://www.ncbi.nlm.nih.gov/pubmed/24321212 and Kim and colleagues (2013) http://www.ncbi.nlm.nih.gov/pubmed/24386517.

Further that those with genetic conditions which present with autistic symptoms such as 22q11.2 deletion syndrome might also experience similar GI issues including those related to intestinal permeability as per the work of Giardino and colleagues (2013) http://www.ncbi.nlm.nih.gov/pubmed/24344832 is testament to the fact that further research resources are required to probe this potentially very interesting gut-brain interface.

On 2016 Dec 08, University of Kansas School of Nursing Journal Club commented:

Reviewers: Abigail Spare, Chelsea Gilmore, Haley Orlowski, Amy Toth, Kelley Ebeling, Nadia Grayfer, Mike Kelley, and Lauren Aks. [Team 2: KUSON Class of 2017].

Background Introduction

In our Development of a Microsystem Leader course, we have focused on several elements that enhance and maintain a healthy work environment. These elements include employee motivation, transformational leadership, and meaningful recognition. The article selected touched on many of these elements, and outlined the characteristics of both a transformational and authentic nurse leader from a historical perspective. This article met one of the requirements for the course as well as provided our group with a good understanding of these concepts. It also added a new perspective as to how transformational and authentic leadership was exemplified in the past. It took a closer look at both the character traits and practices of Matron Powell as a transformational and authentic leader through reported narratives. The article identified both the leadership qualities that set her apart from other nurse leaders, as well as her influence amongst the healthcare personnel and the patient population she served.

Methods

The article was found using CINAHL database. This qualitative paper uses secondary data analysis of existing narrative interviews done in the past guided by a natural enquiry that sought to understand the influence of Matron Powell in nursing practice. The data narrative was based on 136 nurses’ transcripts taken from the “Nurses Voices” archives at Kingston University and St. George’s at the University of London. The narrative data consisted of over 1000 face to face interviews of nurses who were trained and have worked at hospitals in London between the years of 1920 and 2000. These interviews were initially recorded, transcribed verbatim, and archived – describing many aspects of the nursing experience over the span of 80 years. Data was collected in several stages using an inductive approach that allowed the researchers to move from the reading of the complete narratives, to discovering similar trends and categories, and identifying overarching themes resulting from the leadership of Matron Powell (Harris, Bennett, Ross, 2014).

Findings

Matron Powell’s impact on St. George’s Hospital resulted in two overarching themes: innovation and open communication. The authors describe innovation as a “leading influence to improve standards of care” (p. 1633). This innovation began with changes driven by Matron Powell as she changed the way the health care team viewed the patient and their plan of care. She advocated for a change in hiring practices so that married women could continue to work as nurses. Matron Powell’s attitude about improving standards of care then began to spread to her staff nurses. An early kind of quality improvement project was used to study the effectiveness of team nursing by pairing an experienced nurse with an inexperienced assistant. The outcome was a success that led to the hospital wide implementation (Harris et al., 2014).

The other theme was open communication, or the “ability to communicate at all levels” (pg. 1632). Many accounts spoke of Matron Powell’s ability to facilitate open communication with the nurses, health care personnel, and even the patients. Through communication she established a culture of mutual respect, camaraderie among the staff, and a general sense of teamwork. “Muriel Powell came in to talk to us in block and of course we all shot to our feet as one did and she said, ‘sit down we are all colleagues’” (pg. 1633). Even though her title gave her a substantial amount of power, she still saw herself as equals to her nursing colleagues. One narrative spoke of her ability to check on the patients and the care they were receiving without making the nurse feel inferior or in the wrong. Many of the interviews spoke very highly of Matron Powell, and this may contribute to some of the limitations of the research. Because all of the data studied had been from archives, there was no way to know why some former employees were interviewed and others were not. It is also limited by the lack of almost any negative comments. This hints at the idea that there may have been some bias in those who chose to participate in the interviews (Harris et al., 2014).

Implications to Nursing

The people interviewed told the story of Matron Muriel Powell’s career, influence, and legacy. They recognized the impact of this nurse’s leadership on nursing practice and patient outcomes. The effects of Powell’s leadership expanded beyond the lines of her profession and impacted the work environment of the whole hospital, demonstrating the need for nurse leaders. Matron Powell’s example is one to be examined and emulated in nursing practice. Her ability to lead was accompanied with vision, compassion, and friendliness, but she also stuck to her job with a firmness that many spoke of with respect (Harris et al., 2014). This can be replicated in our own nursing careers as we strive to become proficient nurses and front line leaders that will provide quality patient care in collaboration with the rest of our healthcare team.

The history of nursing is incredibly intriguing. Being aware of our history and how it influences our nursing profession’s future helps to define the leaders that served as the pillars of our profession and draw from the characteristics that made them effective leaders and nurses. By appraising the example of Matron Powell, we can see specific qualities that made her an effective transformational leader who improved patient care, influenced and empowered nurses, contributed to the improvement of the work environment, and made a significant impact on the improvement of nursing by education at her time.

Today there is a drive toward understanding the impact of nursing leadership on patient outcomes, worker’s satisfaction and motivation, and enhancement of a healthy work environment. The Institute of Medicine’s report on The Future of Nursing calls for nurses to occupy positions of leadership in the work environment, and contribute to the improvement of our healthcare system (IOM, 2011). Analyzing leadership in nursing from a historical perspective brings to light the results of what effective leadership can give to the improvement of nursing practice.

References Harris, R., Bennett, J., & Ross, F. (2014). Leadership and innovation in nursing seen through a historical lens. Journal of Advanced Nursing, 70(7), 1629-1638. doi:10.1111/jan.12325

Institute Of Medicine. (2011). Key messages of the report. The Future of Nursing: Leading Change, Advancing Health. Washington D.C.: The National Academies Press.

On 2016 Dec 05, Anne Carpenter commented:

Please note that there is a typo for the microscope's TexasRed filter. It is listed as excitation/emission (562/642 nm) when it is actually (562/624 nm). This was confirmed with the screening center that performed the microscopy described in the paper.

On 2014 Apr 02, GREGORY CROWTHER commented:

The following is an edited version of an entry in my personal blog (gregcrowther.com).

Calculations of bees’ impact on strawberries’ market value

This paper by Klatt et al. documents how strawberries benefit from pollination by bees, as opposed to pollination by wind or self-fertilization. It turns out that, on average, bee-pollinated strawberries are larger than others and also have fewer odd shapes, better color, and superior firmness. This detailed look at strawberry quality is a useful extension of past studies showing that insect pollination often boosts crop quantity (i.e., yield).

In making their case for the agricultural importance of bees, Klatt et al. say that bee pollination accounts for at least $1.44 billion of the value of the $2.90 billion strawberry market in the European Union (EU). While I accept the take-home message that bees add a lot of value, I sure wish the authors had explained their calculations better.

The $1.44 billion estimate is the sum of two factors: $1.12 billion in market value of the fresh berries, and another $0.32 billion corresponding to improved shelf life. Let’s consider each of these in turn.

The figure of $1.12 billion is introduced in this section of the Results:

"Bee pollination resulted in strawberry fruits with the highest commercial value (figure 1a). On average, bee pollination increased the commercial value per fruit by 38.6% compared with wind pollination and by 54.3% compared with self-pollination. Fruits resulting from wind pollination had a 25.5% higher market value than self-pollinated fruits. Pollination treatments were stronger than differences between varieties and thus had a main effect across all varieties (see table 2 for AICc and likelihood values). Our results suggest that altogether, bee pollination contributed 1.12 billion US$ to a total of 2.90 billion US$ made with commercial selling of 1.5 million tonnes of strawberries in the EU in 2009 [1]—but so far without consideration of the monetary value provided by enhanced shelf life (see below)."

Figure 1 indicates that the mean value of 1000 wind-pollinated berries was ~$13.80 and the mean value of 1000 bee-pollinated berries was ~$22.40. The value of the wind-pollinated berries thus represents a ~38.6% DECREASE in value relative to the bee-pollinated berries; alternatively, the value of the bee-pollinated berries is a 62.9% INCREASE over the value of the wind-pollinated ones. A 62.9% increase takes us from $1.78 billion (the hypothetical value of strawberries only pollinated by wind) up to $2.9 billion, giving us the reported $1.12 billion boost from bees. The authors’ mention of a 38.6% increase when they meant a 38.6% decrease is not exactly a big deal, but initially made their math baffling to me and my students.

Perhaps more significantly, the reported market values reflect the classification of strawberries into commercial grades by the first author. Ideally, the first author would have rated the berries while “blinded,” i.e., without knowing which ones came from which treatments (bees, wind, or self). The paper doesn’t mention blinding, so I fear that there was the potential for a pro-bee bias.

Now for the $0.32 billion due to improved shelf life:

"Bee pollination strongly impacted the shelf life of strawberries by improving their firmness (figure 2a). The firmness values of each treatment and variety were related to shelf life, measured as the number of days until 50% of fruits had been lost owing to surface and fungal decay (see the electronic supplementary material, S3). Higher firmness resulting from bee pollination potentially elongated the shelf life of strawberry fruits by about 12 h compared with wind pollination, and by more than 26 h compared with self-pollination. After 4 days in storage, only 29.4% of the wind-pollinated fruits and none self-pollinated fruit were still marketable, whereas, at the same time, 40.4% of the bee-pollinated fruits remained in a marketable condition. Thus, bee pollination accounted for a decrease of at least 11.0% in fruit losses during storage. These findings suggest that the value for bee pollination calculated in section 3a(i) has to be increased to accommodate this impact on the shelf life of strawberries. Hence, pollination benefits on the shelf life of strawberries potentially added another 0.32 billion US$ to the commercial value of strawberry pollination."

Here it’s clear that the authors got $0.32 billion by multiplying 11% by $2.9 billion. What’s less clear is the meaning of “storage” (did the unspecified storage conditions simulate those typically used by strawberry farmers/distributors/vendors?) and the reason(s) why a duration of 4 days was used in this calculation (is this a typical time between harvesting and consumers’ purchases?).

Such details aside, here’s a more general question relevant to both components of the $1.44 billion estimate. To what extent are commercial strawberries pollinated by bees in the wild?

The calculations assumes that the study site — a field in Germany — is representative of most or all commercial strawberry farms in Europe. The study site was intentionally set up near well-established bee hives and nests; are most or all European strawberry farms situated similarly? Perhaps the answer is obvious to people with relevant expertise, but the paper doesn’t say. It’s worth noting that if only half of commercial strawberry fields enjoy bee pollination, the estimates of bees’ economic impact would need to be cut in half.

Considering that the paper trumpets a billion-dollar claim in its abstract, more information on the calculations underlying that claim would have been helpful.

On 2014 Jan 24, Tom Kindlon commented:

References:

[1]. Crawley E, Mills N, Beasant L, Johnson D, Collin SM, Deans Z, White K, Montgomery A. The feasibility and acceptability of conducting a trial of specialist medical care and the Lightning Process in children with chronic fatigue syndrome: feasibility randomized controlled trial (SMILE study). Trials. 2013 Dec 5;14:415.

[2]. Specialist Medical Intervention & Lightning Evaluation: Comparing specialist medical care with specialist medical care plus the Lightning Process for Chronic Fatigue Syndrome or Myalgic Encephalopathy (CFS/ME) ISRCTN81456207 http://www.controlled-trials.com/ISRCTN81456207 (last accessed: December 20, 2013)

[3]. The Lightning Process Didn't Work For me. http://sallycats.hubpages.com/hub/The-Lightning-Process-Didnt-Work-For-me (last accessed: December 20, 2013)

[4]. LP & ME What is the truth Identities withheld. http://groups.yahoo.com/neo/groups/MERSC-Viewpoint/conversations/topics/840?var=1 (last accessed: December 20, 2013)

[5]. The Skeptic's Dictionary, From Abracadabra to Zombies, Phil Parker Lightning Process http://www.skepdic.com/lightningprocess.html (last accessed: December 20, 2013)

[6]. Kewley AJ. Does Cognitive Behavioral Therapy or Graded Exercise Therapy Reduce Disability in Chronic Fatigue Syndrome Patients? Objective Measures Are Necessary. Clinical Psychology: Science and Practice 2013 20:321-322.

[7]. Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg, G. (2010). How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychological Medicine, 40(8), 1281–1287.

[8]. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36

[9]. Mason A. CBT and GET did not significantly reduce employment losses, overall service costs, welfare benefits or other financial payments. http://www.plosone.org/annotation/listThread.action?root=52797 (last accessed: December 20, 2013)

[10]. Newton JL, Pairman J, Hallsworth K, Moore S, Plötz T, Trenell MI. Physical activity intensity but not sedentary activity is reduced in chronic fatigue syndrome and is associated with autonomic regulation. QJM. 2011 Aug;104(8):681-7

[11]. Cockshell SJ, Mathias JL. Cognitive functioning in chronic fatigue syndrome: a meta-analysis. Psychol Med. 2010 Aug;40(8):1253-67.

[12]. Loge JH, Ekeberg O, Kaasa S. Fatigue in the general Norwegian population: normative data and associations. J Psychosom Res 1998; 45:53-65.

[13]. van Kessel K, Moss-Morris R, Willoughby E, Chalder T, Johnson MH, Robinson E. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom Med. 2008 70:205-13

[14]. Stouten B. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res. 2005 May 13;5:37.

[15]. Goudsmit, EM., Stouten, B and Howes, S. (2008). Fatigue in myalgic encephalomyelitis. Bulletin of the IACFS/ME, 16(3), 3-10.

[16]. Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, Wallace EP. Development of a fatigue scale. J Psychosom Res. 1993;37(2):147-53.

On 2014 Jan 24, Tom Kindlon commented:

The validity of using subjective outcome measures as primary outcomes is questionable in such a trial

Crawley and colleagues suggest dropping school attendance as a primary outcome from the full study, and replacing it with self-report outcomes "such as the SF-36 or the Chalder Fatigue Scale" and using "school attendance as a secondary outcome"(1). And indeed, this is what they have done with the full study which has two primary outcome measures: "Chalder Fatigue Scale at 6 months" and "SF 36 physical function short form at 6 months"(2). I question the wisdom of using self-report measures as primary outcomes for such a trial.

The authors do not give much information about the details of the Lightning Process (they do mention it is "developed from osteopathy, life coaching and Neuro-linguistic programming (NLP))" but here are some descriptions from other sources (individuals who have undertaken a course) (note these are not descriptions from participants from the trial itself):

(a) "It felt very naughty but I whispered to one of the woman (sic) sitting next to me 'how are you, is this working for you?'. She was reluctant to answer, to say anything but that she was doing well would be to go against the process because that is a negative thought. It was pointless asking really. Still I wanted it to work, but I was starting to worry about the fact that I was not only not feeling any better the effort of doing the course, not getting my normal rest was making me feel worse. But these were negative thoughts. I started to ruthlessly suppress them like I had been shown." (3)

(b) “They tell you that you're not allowed to say that you're ill anymore or that you have any symptoms. They force you to ignore the symptoms because they say that the symptoms don't really exist. They force you to do activities even though it's making you really ill, but you're not allowed to say so.” (4)

Another, more thorough, description can be found on the Skeptic's Dictionary website(5).

I have seen many similar descriptions to these in discussions in many private fora. Here's one example: "So the first step in the process is to recognise when you’re in THE PIT. Maybe sometimes or all the time. It’s important to recognise what you say to yourself as you go into the pit. For example “I’m feeling really ill this morning”, “if I do this, then I’ll get exhausted”, “last time I did this I got really ill for days”, “I can never eat this” etc. This takes some practise but we were assured that you always say something in your head as you go into the pit. As soon as you spot one of your “pit” phrases you want to STOP yourself right away. So imagine you’re on the mat and you start to say “I feel really ill today”. Before you get to the end of this phrase you will interrupt with a very firm, loud “STOP” (yes, talk out loud to yourself!) and jump into the STOP position as described above. So you jump outside the mat, to your left. Now you’re here you have interrupted your bad thought patterns."

In essence when one is doing the lightning process, both during the three days training and after, you are to declare yourself well. You are not to say (or think) you have symptoms and you are not to say (or think) you have limitations. In other words, patients are 'trained' to dismiss and deny their symptoms and illness. Patients are instructed not to “do” ME or CFS anymore. In such a scenario, subjective reports from the patient are no longer reliable. Hence the need for objective measures in such trials.

To a lesser extent, it can also be argued that subjective measures are not ideal for all participants in this trial, including the control group. With graded activity-oriented therapies, which all the participants undertake (1), there may be response bias (6). This was seen in a review of three Dutch trials of graded activity-oriented cognitive behaviour therapy (CBT) for CFS. While the CBT participants reported improvements in fatigue (and also SF-36 physical functioning although that was not measured in all of the trials), no improvements in objectively measured activity were reported over the control group(7). Similarly a mediation analysis showed changes in physical activity were not related to changes in fatigue. A similar effect with CBT could be in PACE Trial, the largest such trial in the CFS field(8).

Although participants who had undergone CBT reported improvements in scores on both the Chalder Fatigue Scale and SF 36 physical function subscale, no improvements were reported in the six minute walking distance compared to the group who had undergone no additional individual therapy (all participants had specialist medical care). Similarly, CBT did not significantly reduce employment losses, overall service costs, welfare benefits or other financial payments(9).

Objective measures of physical activity are one type of objective measurement that could be employed. This could be used not just to measure the total quantity of activity but also to check the intensity of activity as people with ME/CFS may perform lower levels of more intensive activity(10). Tests of neuropsychological performance could also be used, given the impairments that have previously been reported(11). If necessary, a webpage could be created that could be accessed remotely.

One particular problem with the 0-33 scoring method for the Chalder fatigue scale is that patients can give unusually low, or artificially good, scores.

The scale consists of 11 questions. For each question (e.g. "Do you have less strength in your muscles?"), patients have to say whether they have the symptom: "Less than usual" (score of 0); "No more than usual" (score of 1); "More than usual" (score of 2) or “Much more than usual” (score of 3). So healthy people should score around 11 and indeed in the only population study I can recall that gave data for a healthy (no disease/current health problem) group, the mean was 11.2 (12).

However, some unusual scoring is possible. This was seen in a multiple sclerosis trial, of a similar CBT intervention to the graded activity-oriented CBT used in CFS (13). Participants in the CBT leg of the trial entered with a Chalder fatigue scale score of mean (sd): 20.94 (4.25). Two months after therapy, the mean (sd) was 7.90 (4.34) i.e. this groups suffering from multiple sclerosis had a much better score than one sees in healthy people!

Such averages could also hide non-responders or, possibly more seriously, people who deteriorated, depending on how the data was analysed. For example, if two participant deteriorated and ended up with a Chalder fatigue scale scores of 32, but 8 others had an average score of 2, this would give an average score of 8, again giving the impression that this group had less fatigue than healthy people. This issue of supranormal scoring with likert scoring (0-3) can be dealt with by utilising the commonly used bimodal scoring method for the Chalder fatigue scale. However, both it and likert scoring suffer from ceiling effects in CFS populations so other scales are likely preferable (14,15). If the Chalder fatigue scale is used, the original developers of the scale suggested, based on their analyses, that "it would probably be more useful to have two scores, one for physical fatigue and one for mental fatigue"(16).

(Message has reached word limit - references are reply)

Competing interests: I am the Assistant Chairperson and Information Officer for the Irish ME/CFS Association. All my work for the Association is voluntary.

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 NCT009176. We believe the correct ID, which we have found by hand searching, is NCT00917631.

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 Jun 17, Pavel Baranov commented:

This PubMed record is wrong. We informed NLM on the Dec 6, 2013.

On 2014 Nov 27, Jürgen Hänggi commented:

Dear community

a study recently published by our group questioned the sex effects reported here. We also conducted two very interesting between sex comparisons in order to tract down whether increased interhemispheric connectivity in women and increased intrahemispheric connectivity in men might be confounded by differences in brain size. One comparison is called "extreme group comparison" and compared small female brains with large male brains. This comparison revealed that the effect under question became much stronger because the difference in brain size between these two groups became stronger as well. The other comparison has been called "control group comparison" and used men with small brains who were compared with women with large brains. This comparison shows that the "apparent sex effect" disappeared because these two groups did not differ in brain size any longer. Although both comparisons involved women and men, the first comparison showed a positive result, whereas the second comparison provided a negative finding. These comparisons alone provide strong evidence that clearly contradicts "increased interhemispheric connectivity in women and increased intrahemispheric connectivity in men". The hypothesis of neuronal interconnectivity as a function of brain size represents a general and fundamental organization principle of the human connectome that is sex-independent and that might be applied also to non-human animals as suggested by our cross-species comparison.

Our study can be found here

http://journal.frontiersin.org/Journal/10.3389/fnhum.2014.00915/full

Further discussion with respect to the effect size as well as comparisons of small, medium and large brain size groups and a network-based statistical analysis similar to the analysis conducted in the study under question can be found here

http://www.juergenhaenggi.ch/index.php?option=com_content&view=category&layout=blog&id=58&Itemid=136

A critical discussion of the problem of overpowered studies and its associated "trivial effects" can be found here

http://www.sciencedirect.com/science/article/pii/S1053811912003990

On 2014 Nov 01, Jürgen Hänggi commented:

None

On 2014 May 29, Gerard Ridgway commented:

This paper reports no effect sizes. An illustrative example based on converting from t and degrees of freedom to an estimate of Cohen's d can be found here: http://figshare.com/articles/Illustrative_effect_sizes_for_sex_differences/866802

On 2013 Dec 05, Allison Stelling commented:

This paper has generated quite a lot of commentary in the press. Here's a sampling of some of the coverage thus far, mostly from the discussion occurring on PubPeer at https://pubpeer.com/publications/3CFCCE950D22E7560E9B07C8B63979:

https://theconversation.com/are-men-better-wired-to-read-maps-or-is-it-a-tired-clich-21096

https://theconversation.com/new-insights-into-gendered-brain-wiring-or-a-perfect-case-study-in-neurosexism-21083

(These links are in Peer 0's post, please see: https://pubpeer.com/publications/3CFCCE950D22E7560E9B07C8B63979/comments/4381)

I personally don't buy fMRI in general to measure anything other than water nuclei in tissues. The physical correlates for "activity" seem murky at best and I tend to take any interpretation other than 'bulk tumor mass' with a grain of salt.

On 2013 Dec 09, John Cannell commented:

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

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

Prietl B, 2013

Kamen DL, 2010

Yang CY, 2013

Baeke F, 2010

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

Gong ZL, 2014

Meguid NA, 2010

Mostafa GA, 2012

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

DeLuca GC, 2013

Eyles DW, 2013

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

Cannell JJ, 2010

Cannell JJ, 2008

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

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

Kočovská E, 2012

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

John J Cannell, MD

Vitamin D Council

http://www.vitamindcouncil.org

On 2017 Mar 25, Anthony Gitter commented:

An open source implementation of the Multi-PCSF algorithm presented in this manuscript is now available under the BSD-2-Clause license. https://github.com/agitter/MultiPCSF contains the latest version, and https://doi.org/10.5281/zenodo.438043 contains an archived copy of the initial release.

On 2014 Mar 06, David Keller commented:

Is that a T-wave inversion, or are you just glad to see me?

DEXA bone densitometry causes a small risk of harm due to ionizing radiation exposure, so I adhere to the recommended guidelines. The USPSTF recommends that routine DEXA screening begin at age 60 for women at increased risk for osteoporotic fractures, and at age 65 for women at average risk. I think your internist jumped the gun by ordering your first scan at age 50. On the other hand, I support her decision to obtain an "unnecessary" ECG, since this test causes no direct harm to the patient and is inexpensive. If the patient has a false-positive abnormality on ECG, it is better to learn about it when she is asymptomatic, rather than in the ER when she is presenting with an acute aortic dissection.

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

On 2014 Aug 13, Jim Woodgett commented:

From the Discussion: "Finally, although numerous specific inhibitors for GSK3β were tested, we cannot entirely rule out that nonspecific GSK3α inhibition may have partly contributed to the observed biological effect. However, the relative contribution of GSK3α in DM-induced EPC dysfunction is unlikely to be significant but remains to be elucidated."

None of the tested inhibitors (AR-A014418, CHIR98014, 6-bromoindirubin-3-oxime, GSK peptide inhibitor or LiCl) are specific for GSK-3beta (over GSK-3alpha), these inhibitors fail to show any degree of isoform specificity and are essentially equipotent in blocking each. GSK-3alpha has been implicated in insulin signalling (e.g. PMID 18781825). It isn't clear whether GSK-3alpha activity is increased in diabetic patients but the mechanisms by which the beta isoform are activated (reduced serine 9 phosphorylation) also act on the alpha isoform (serine 21). It would be interesting to test this directly. As it stands, the conclusions of this current analysis are entirely consistent with combined roles for both isoforms - especially given that the two kinases are entirely redundant with respect to Wnt signalling and are expressed at similar levels in endothelium.

It's also worth noting that GSK-3 is known to regulate protein translation as well as transcription (via eiF2B, TSC1 and other mechanisms).