On 2014 May 01, Giovanni M. Dall’Olio commented:

Interesting article that explores the role of pseudogene formation by retrotranscription of mRNAs in somatic cells in cancer.

After reading the article, my impression is that pseudogene formation is not a major process driving cancer. In fact, the percentage of pseudogenes found in the cancer samples analyzed is relatively low, and only few of these cases seem to be relevant to the cancer process. However, it is very good to have an estimate of how much somatic retrotransposition is important in cancer, and to have a few examples of newly formed pseudogenes causing damage to the expression of cancer genes.

One detail that didn't convince me of the article is the result presented in Figure 3. I don't think there are enough points for the Wilcoxon test, except maybe only for the lung samples. Maybe a permutation test would be more robust, although the real problem is that there are too few data points.

A colleague of mine also noted, from Figure 1, that most of the pseudogenes observed seem to be patient-specific, rather than cancer-type specific. For example patient PD7354 (if we interpret the sample naming scheme right) seems to host half of pseudogene events observed. Can it be that this individual is somehow more prone to this process, e.g. that retrontransposon activity is higher in this individual?

It would also be useful to have an estimate of the overall mutation rate in somatic cells in the samples analyzed, to know if this correlates with pseudogene formation.

Congratulations again to the author for the work presented.

On 2014 Apr 09, David Keller commented:

Are tadalafil and vardenafil also associated with increased risk of melanoma?

Sildenafil (Viagra) was associated with increased risk of melanoma in this study, and a plausible biological mechanism was proposed to explain this association. Two other closely-related phosphodiesterase inhibitors are widely used: tadalafil (Cialis) and vardenafil (Levitra); are these drugs also associated with increased risk of melanoma? One would expect this association to be a class effect.

The results of this study will be of particular concern to men who have used sildenafil and may be at elevated risk of melanoma due to history of extensive sun exposure, basal or squamous cell skin cancers, Parkinson disease (which causes autonomic erectile dysfunction and is associated with elevated risk of melanoma) or family history of melanoma.

A recent editorial advocates adjuvant therapy with vitamin D and melatonin for every stage of melanoma, and as secondary prophylaxis versus melanoma recurrence (1). Given the low risk of harm from these supplements, might it be reasonable for persons at high risk for melanoma to consider taking them as primary prophylaxis?

Reference

1: Slominski AT, Carlson JA. Melanoma resistance: a bright future for academicians and a challenge for patient advocates. Mayo Clin Proc. 2014 Apr;89(4):429-33. doi: 10.1016/j.mayocp.2014.02.009. PubMed PMID: 24684870.

If you find this comment unhelpful, please explain why, to facilitate discussion

On 2014 May 02, Francisco Xavier Castellanos commented:

This appears to be a well-intentioned open trial with unblinded reports provided by the parents as the evidence of improvement. There is no way in which these observations can be interpreted as a "demonstration" of a "beneficial effect." Was this "clinical trial" registered on clinicaltrials.gov?

On 2014 Nov 24, 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 2014 May 03, Stefanie Butland commented:

All interaction data from this paper are freely available at IntAct http://www.ebi.ac.uk/intact/query/24705354 and are featured as Dataset of the Month for May 2014. These include 312 binary interactions from yeast two-hybrid, anti tag coimmunoprecipitation, fluorescence microscopy and luminescence based mammalian interactome mapping (LUMIER) experiments.

We submitted our data directly to IntAct through the IMEx Consortium as part of the publication process. I encourage others to consider this route to making your data available for re-use and re-mixing as the expert biocuration service provided by IntAct was smooth, accurate, and required very little of our time. A very positive experience.

On 2015 Sep 30, Jan Egger commented:

This article is related to: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031064

Best wishes, Jan

On 2014 May 23, Roy Wise commented:

It is interesting that the decrease in dopamine release that Willhun et al. found to correlate with escalated cocaine intake (decreased within-session inter-response times) was a decrease in the core rather than the shell of nucleus accumbens. Like Willhun et al., we have found that attenuated dopamine actions in the core (but not the shell) of accumbens results in greater cocaine intake—shorter inter-response times—during periods of self-administration (Suto, Psychopharmacol 205, 431-439). Conversely, we find that enhanced dopamine actions in the core (but not the shell) result in decreased intake—longer inter-response times (Suto J Neurosci 31, 17917-17922). We expected the opposite: that dopamine antagonists and agonists would increase or increase intravenous cocaine intake when infused (by reverse dialysis) into the ventromedial shell but not the core. Our hypothesis was based on the findings that reinforcing actions of cocaine take place in the shell and not the core (Carlezon, Psychopharmacol, 122, 194-197; Ikemoto, J Neurosci 23, 9305-9311); we assumed that goal of intravenous self-administration was to elevate dopamine levels at the site where dopamine (Ikemoto, J Neurosci 17,8580-8587) is rewarding. On the contrary, our experiments and Willhun’s, suggest that dopaminergic activation in the core serves quite a different function than that served by dopaminergic activation in the shell. Dopamine in the shell serves the functions of establishing and maintaining cocaine self-administration habits, whereas dopamine in the core serves the function of limiting cocaine intake, producing periods of cocaine satiation between successive injections. The mechanisms for establishing, maintaining, and reinstatement of cocaine self-administration have been studied extensively, but have not yet led to a proven medication for cocaine addiction. Perhaps it is time to turn attention to the endogenous mechanisms for what appears to be a state of drug satiety.

On 2014 May 08, Serge Ahmed commented:

This study provides important novel insights into the neurobiological mechanisms that drive escalation of cocaine intake in rats. It shows that escalation of i.v. cocaine self-administration is selectively associated with a loss of cue-induced phasic dopamine in the nucleus accumbens. Reversing this neurochemical deficit with l-Dopa (30 mg/kg) was sufficient to reverse escalated levels of cocaine intake, suggesting that cue-induced phasic dopamine plays a causal role in regulating cocaine intake.

This conclusion is rather unexpected because cocaine cues are generally invoked as key triggers of drug seeking but not as key regulators of drug taking. Perhaps one way to test this hypothesis would be to measure the effects of cue omission (or reduced cue intensity) on maintenance of cocaine self-administration. This intervention should prevent (or reduce) cue-induced phasic dopamine and thus induce an increase in cocaine intake, at least initially.

Finally, to better understand the action of l-Dopa on escalation of cocaine intake, it will be important to check whether and to what extent it also affects tonic dopamine levels during a session of cocaine self-administration.

On 2017 Oct 31, Morten Oksvold commented:

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

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

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

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 2016 Feb 14, Md. Shahidul Islam commented:

None

On 2015 Jun 23, Darko Lavrencic commented:

(R)evolving concept of spontaneous intracranial hypotension: from Georg(es) Schaltenbrand coming back to Georg(es) Schaltenbrand, see http://www.med-lavrencic.si/research/correspondence/

On 2014 Apr 05, GRAHAM COLDITZ commented:

Arising from an ARRA funded award to build capacity for cancer prevention and control in Guatemala, this paper summarizes in a way the power of linking to service providers who are keen to improve outcomes in their population. The value added from these training opportunities and return on investment keeps compounding. See, for example, the Global Health Scholars program in internal medicine at Barnes and Washington University School of Medicine. http://ghs.wustl.edu

On 2014 Dec 10, Kath Wright commented:

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

On 2017 Jul 30, David Keller commented:

This study can't tell whether avoiding sun exposure or the resulting low vitamin D levels were to blame

The authors state that "all-cause mortality is related to low vitamin D levels", and that "exposure to sunlight remains the main source of vitamin D". They did not have access to data concerning vitamin D levels or supplementation in their study. Therefore, they cannot control for vitamin D levels, nor prove that sun exposure confers any benefits beyond those associated with higher vitamin D levels, regardless of whether the vitamin D is obtained from sun exposure or by taking a supplement pill. We know that sun exposure leads to increased risk for malignant melanoma. It is unreasonable to risk a deadly skin cancer to obtain vitamin D, rather than take vitamin D in supplement form. This will not change until a study is performed which controls for vitamin D levels, and thereby demonstrates mortality benefit for sun exposure which is independent of sunlight's effect on raising vitamin D levels.

On 2017 Jul 31, David Keller commented:

Study subjects who exercise indoors, avoid solar radiation exposure & take vitamin D"

PubMed Commons commenters have difficulty responding to anonymous "unhelpful" votes which do not include any explanation or critique. I will have to guess that the study of spelunkers would be impractical (too few spelunkers) or biased (spelunkers are too distinctly different than non-spelunkers). So, instead of spelunking, substitute any form of moderate indoor exercise which includes social contact. For example, subjects who work out at indoor gyms and take vitamin D supplements at adequate doses could be compared with persons who exercise outdoors, to control for vitamin D levels and other confounding sources of bias associated with sun exposure of the skin. This is an important question, because the inherently limited findings of the Melanoma In Southern Sweden (MISS) study are being touted widely in the popular media by sunbathing advocates, which could lead to a future increase in malignant melanoma and even all-cause mortality, depending on the degree to which the MISS trial was confounded by unrecognized biases. The public generally are not informed that the MISS results do not prove that sunbathing promotes health or longevity, independent of vitamin D levels, or some other unrecognized and uncontrolled difference between sun-seekers and sun-avoiders.

On 2017 Jul 28, David Keller commented:

A proposed study to determine whether sun exposure promotes good health, or good health is a result of other factors associated with sun exposure, like sociable moderate exercise

Spelunking, the recreational exploration of caves, is an "outdoor" activity that promotes healthful cardiovascular exertion and social interaction, but zero sun exposure. The null hypothesis is that solar irradiation of the skin is not beneficial per se, and that the mortality benefits observed by Lindqvist and colleagues were due to factors associated with sun exposure, such as higher vitamin D levels, social interactions, and moderate exertion during hikes, volleyball games, etc. If sun exposure was, therefore, at best a "bystander" factor overall with regard to the mortality benefits observed in Lindqvist's study, then we ought to observe similar benefits in mortality among active spelunkers, despite the fact that they derive zero sun exposure from cave exploration. Is spelunking associated with the same benefits as sun exposure (or, are spelunkers equally self-preselected for good health) after correcting for vitamin D status? Spelunking mortality must also be corrected for the high rate of rabies from bat bites, and for trauma associated with spelunking, such as impalement injuries on stalactites and stalagmites, sudden drops into deep holes and other unseen hazards, and spelunkers who get lost in the caves and are never heard from again, who should be presumed dead, by intention to treat. Importantly, the serum vitamin D levels of spelunkers should be raised by oral supplementation until both groups exhibit equivalent levels. After those corrections, if spelunkers are found to be as healthy as those who sun-expose, we would have evidence supporting the null hypothesis, posed above.

On 2017 Jul 24, David Keller commented:

Swedes, and other depigmented peoples, should not engage in "daily, midday....sun exposure" of any duration

Depigmentation of northern peoples may seem like an evolutionary argument in favor of sun exposure to the skin. However, there is no safe threshold of solar radiation, especially for the fair-skinned, who are at the highest risk of melanoma. The risk of mutation accrues with each and every ionizing photon that hits the skin.

If there is benefit to sunbathing, then we should seek to identify and isolate the factors that provide such benefits, and advise the healthy how to maximize the benefits associated with sun exposure while minimizing its risks. The increased mortality from sunbathing is fully expressed over decades, not months or years. Older generations may have been too busy or too embarrassed to lay around near-naked in the sun. Today's generation suffers from no such inhibitions or lack of leisure time, and melanoma is now one of the fastest-increasing causes of cancer death.

My recommendation to patients, in "light" of the findings of Dr. Lindqvist and others, is as follows:

1) Avoid sun exposure to the skin. Never sunbathe. The best sunblock is clothing or shade.

2) Engage in outdoor activities that promote cardiovascular exertion and social interactions, which are healthy, while fully dressed and always seeking shade.

3) Evidence suggests that indirect light exposure can prevent or treat seasonal depression. This means that visual perception of bright light may be beneficial, but avoid direct solar radiation to the retina, which again causes melanoma. Outdoor activities in the shade safely provide this benefit.

4) Strict avoidance of sun exposure can lead to sub-optimum blood levels of vitamin D, which I suggest measuring with blood tests, and treating with vitamin D supplements. I aim for a high-normal vitamin D level.

If any other benefits of sun exposure are isolated, we should strive to find safer ways to attain those benefits. The increased risk of melanoma from sunbathing cannot be mitigated. Doctors who advise sunbathing violate the Hippocratic directive of "Primum non nocere" ("First, do no harm").

On 2017 Jul 18, P G Lindqvist commented:

Are we forcing people to choose health or melanoma? Or having a balanced discussion regarding pros and cons of sun exposure? In our observational study 2014 Lindqvist PG, 2014, we showed a strong inverse relationship between sun exposure and risk of all-cause death. Dr Keller is right that from an observational study we might not show causality. Even if we adjust for age, education, marital status, income, exercise, and smoking there might still be residual bias. The authors draw the conclusion that we might titrate a proper vitamin D dose, without raising the melanoma risk. This might be right, however, we still do not know that vitamin D is “the” mediator. Over exposure of solar radiation is a risk factor for melanoma incidence. However, as we show in our 2016 publication Lindqvist PG, 2016 using the same material. Incidence of melanoma increase with increasing sun exposure, but avoiders of sun exposure have a higher death rate if caching melanoma. Therefore, in Sweden, which is a country with scarcity of UV radiation we suggest daily, midday, short time sun exposure.

On 2017 Jul 07, David Keller commented:

Forcing a choice between vitamin D deficiency and elevated melanoma risk is a fallacy of the inevitable alternative

This observational study demonstrated that sun exposure was inversely associated with all-cause mortality. No epidemiological study, such as this, can distinguish whether lack of sun exposure caused increased mortality, or whether being destined to have increased mortality for other reasons caused reduced participation in outdoor activities that confer sun exposure.

Even if reduced sun exposure does increase mortality due to relative vitamin D deficiency, as the authors theorize, nobody would be forced to risk melanoma by exposing their skin to solar radiation. Vitamin D supplements can be titrated to match the blood levels of vitamin D achieved by sun worshipers, without raising melanoma risk.

The implication that people must choose to either raise their risk of melanoma by exposing their skin to solar radiation, or suffer morbidity and mortality from relative vitamin D deficiency is an example of the logical fallacy known as "the inevitable alternative".

Exposure of the skin to solar radiation is the number one modifiable risk factor for malignant melanoma, a cancer with rapidly rising incidence in the U.S.

The American Academy of Dermatology warns, "There is no scientifically validated, safe threshold level of UV exposure from the sun or indoor tanning devices that allows for maximal vitamin D synthesis without increasing skin cancer risk." [1]

1: American Academy of Dermatology, Position Paper on Vitamin D. Accessed on 7/5/2017 at:<br> https://www.aad.org/Forms/Policies/Uploads/PS/PS-Vitamin D Postition Statement.pdf

On 2014 Apr 23, Attila Csordas commented:

2 associated datasets available via PRIDE/ProteomeXchange, PXD000900 and PXD001258: http://www.ebi.ac.uk/pride/archive/projects/PXD000900 http://www.ebi.ac.uk/pride/archive/projects/PXD001258

On 2014 Apr 23, Attila Csordas commented:

None

On 2016 Mar 02, Atanas G. Atanasov commented:

Consumer Health Digest Scientific Abstract of this article is available at: https://www.consumerhealthdigest.com/general-health/is-yogurt-beneficial-for-healthy-aging.html

On 2014 Apr 04, Kamel Hamzaoui commented:

Yes the paper is very interesting and conclusion was true

On 2014 Jul 26, Borja Ibanez commented:

Fully agree with the comment. It is surprising that the infarct-limiting effect of b-blockers in the context of reperfused STEMI was not properly evaluated. The METOCARD-CNIC is the first trial and should be taken as a pilot endeavor. It shows that metoprolol (most probably not all b-blocker are equal in this regard) reduces infarct size. This was the primary endpoint and the trial was powered just for this outcome. All other benefits are hypothesis generating. Of note, the reduction in heart failure events could be of massive socioeconomic impact if proven in dedicated trials. There is a European multidisciplinary consortium working on the design of a large trial recruiting STEMI Pts in 8 countries randomizing them to pre-PCI metoprolol or placebo. primary outcome will be death or admission due to heart failure. This is the MOVE ON! trial. If positive, clinical practive will change. Until then, these results are the most promising in the field of cardioprotection in STEMI

On 2014 Jul 24, Ryan Radecki commented:

Post-publication commentary:

"The Return of Metoprolol – for Anterior STEMI"

Beta-blockade early in the course of myocardial infarction was once fashionable – until COMMIT demonstrated an excess of early cardiogenic shock detracting from subsequent late, favorable effects. This led to beta-blockade initiation being deferred until after hemodynamic stability established....

http://www.emlitofnote.com/2014/07/the-return-of-metoprolol-for-anterior.html

On 2014 Jul 28, Amanda Capes-Davis commented:

Please be aware that HBL-100 is known to be misidentified and it is unclear if these cells are actually from breast. Some authentic stocks may exist; stocks can be authenticated using a test method such as short tandem repeat (STR) profiling. For a list of known cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2014 Apr 07, Anders von Heijne commented:

This is an interesting and important discussion. However, the cited paper by Geurts et al from 2005, that compares 3D FLAIR and 3D DIR, reports on older versions of both sequences, with scan times around 15 minutes and with rather poor image quality in the published images. Modern versions using parallell imaging renders much better image quality with higher GM-WM contrast. 3D FLAIR is also much better in showing cortical lesions than comparable 2D sequences, if not quite as good as 3D DIR. The most pragmatic approach is then, in my opinion, to use modern 3D FLAIR, with reconstructed 3mm consecutive images in three orthogonal planes for monitoring MS patients, allowing for the best trade off between scan time and detection of WM and GM lesions. 3D DIR has its place in the diagnostic phase of neuroinflammation in order to optimize the process of differential diagnosis.

On 2017 Mar 10, Pavel Nesmiyanov commented:

Logically, simple sugars (e.g. glucose) become available for the lactic bacteria other bacteria, that are cariogenic, after the enzymatic action and the toothpaste with amylase activity only promotes caries.

On 2016 Dec 19, F-C Sung commented:

I am sorry that there was a typo error in the first paragraph of dicussion. The numbers in the abstract and results were correct.

On 2016 Dec 19, Cheng-Yang Hsieh commented:

In the first paragraph of Discussion, the authors mentioned that "ESRD patients undergoing HD had an adjusted HR of 3.67 for SDH and an adjusted HR of 6.54 for SDH-associated mortality, compared with the control cohort." The numbers of "3.67" and "6.54" were different from those described in the Abstract and Results (i.e., "3.81" and "6.34", respectively). Please check.

On 2017 May 18, Misha Koksharov commented:

A version (pdf) with a couple of corrected typos in the Table S1: http://istina.msu.ru/media/publications/article/adc/55d/1722336/Koksharov_Ugarova_stability-mini-review_2012.pdf

On 2014 Apr 04, Arnaud Chiolero MD PhD commented:

An interesting study trying to disentangle the relative contribution of birth weight and weight gain at differents times during the lifecourse on cardiometabolic risk factors

On 2015 Jun 02, Thomas Perls, MD, MPH commented:

The authors of this meta-analysis of largely nonagenarians (Deelen J, 2014) indicate that they were unable to reproduce the associations of the 281 SNPs in Sebastiani P, 2012 and used their negative result to assert that the findings were false positive associations.

In Sebastiani P, 2016 however, we show that the genetic basis of surviving to age 90 years (the 5th and 15th percentiles of survival for men and women belonging to the 1900 birth cohort) is weaker and different from the genetic basis of surviving to the top one percentile, which in turn is different for those surviving to the top 0.1 percentile of survival.

Our analysis of sibling relative risk of extreme longevity (Sebastiani P, 2016) indicates is that one should not be surprised by the lack of consistent results between these studies of people surviving to markedly different percentiles of survival and therefore having substantially different degrees of statistical power to discover variants associated with extreme survival. Reinforcing this point, when studies are similar in terms of a rare percentile of survival, a large number of the associated SNPs are actually replicated (Sebastiani P, 2013).

On 2015 Mar 31, Thomas Perls, MD, MPH commented:

None

On 2014 Apr 11, David Keller commented:

Vitamin D and melatonin for primary prophylaxis of melanoma?

Slominski and Carlson advocate adjuvant therapy with vitamin D and melatonin for every stage of melanoma, and as secondary prophylaxis versus melanoma recurrence. [1] Given the low risk of harm from these supplements, might it be reasonable for persons at high risk of melanoma to consider taking them as primary prophylaxis? An example might be a man with Parkinson disease, associated sildenafil use, a family history of melanoma, and personal history of extensive sun exposure and basal cell carcinomas.

A recent observational study links the use of sildenafil to increased incidence of melanoma, and describes a plausible biological mechanism for this medication side-effect (1). This will be of particular concern to men who have used sildenafil or related phosphodiesterase inhibitors, and who may be at elevated risk of melanoma due to a history of extensive sun exposure, basal or squamous cell skin cancers, Parkinson disease (which causes autonomic erectile dysfunction and is associated with elevated risk of melanoma) or family history of melanoma.

References

1: Slominski AT, Carlson JA. Melanoma resistance: a bright future for academicians and a challenge for patient advocates. Mayo Clin Proc. 2014 Apr;89(4):429-33. doi: 10.1016/j.mayocp.2014.02.009. PubMed PMID: 24684870; PubMed Central PMCID: PMC4050658.

2: Li WQ, Qureshi AA, Robinson KC, Han J. Sildenafil Use and Increased Risk of Incident Melanoma in US Men: A Prospective Cohort Study. JAMA Intern Med. 2014 Apr 7. doi: 10.1001/jamainternmed.2014.594. [Epub ahead of print] PubMed PMID: 24710960.

On 2014 Nov 26, 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 2014 Apr 25, Attila Csordas commented:

proteomics data available via PRIDE/ProteomeXchange http://www.ebi.ac.uk/pride/archive/projects/PXD000916 and http://www.ebi.ac.uk/pride/archive/projects/PXD000917

On 2016 Dec 15, Victoria MacBean commented:

Plain English summary:

Sickle Cell Disease (SCD) is amongst the most prevalent genetic diseases worldwide. Only being inherited if both of one’s parents carry a ‘faulty’ gene in their DNA, SCD affects the Haemoglobin molecules that carry oxygen in the blood, distorting the shape of the red blood cells into so-called crescent shaped ‘sickles’.

It has been shown previously that the majority of adults with SCD have changes in their lungs that can be found on a CT scanner, a high powered X-ray scanner that can create a detailed 3D image of the lungs, including airways and blood vessels.

This study showed that findings like particularly large blood vessels in the lung were linked to reduced lung function. This study aimed to show a link between these changes in the lung and the resulting changes in heart function that one can view on an ‘echocardiogram’ in the same group of patients. An ‘echocardiogram’ is a scanner used to observe the way in which the heart functions, from ultrasound waves ‘bouncing’ off the heart. It can view the structure of the heart and vessels, as well as blood flow. In SCD the heart has to pump more blood through the lungs in order to deliver enough oxygen to the tissues.

Adults with SCD were assessed using CT, echocardiography, and other lung function tests such as lung capacity, between the years 2009-2013. This same group of adults had previously been shown to have lung changes on CT scans between 2003-2005.

Whilst there was a large variety in the lung function of the 28 patients with altered lung features, it was demonstrated that lung structure changes seen on CT scans was related to the patients’ decline in lung function, and changes in the function of the heart displayed on echocardiogram tests. Importantly, the results of the study suggest that some of the changes found in the blood vessels between the heart and lungs may be able to explain the differences in the lungs found on CT scan and the decline in lung function. The results of this study help us to understand the complex relationships between heart, lung and blood vessel function in SCD.

This summary was produced by David Launer, Year 12 student from JFS School, London, as part of the investigators' departmental outreach programme.

On 2014 Oct 05, Christopher Southan commented:

This overview would be much more useful if the authors surfaced the 1543 molecular entites via PubChem CIDs, including the previous seven therapeutic splits.

On 2014 Oct 21, Emmanouil Giorgakis commented:

Interesting findings; however, the conclusions should be treated with caution. Drain Fluid Amylase (DFA) levels are function of both serum fluid amylase ( SFA) levels and the presence of a leak.. It would arguably be useful to introduce SFA levels into the equation and measure DFA/ SFA ratios rather than the absolute DFA levels: not only because a DFA>=100 would be clinically irrelevant if SFA levels were of the same range, but also because a DFA/SFA ratio is a figure independent of measuring units, thus applicable in various laboratory settings. Secondly, various authors have challenged the clinical usefulness of the biochemical diagnosis of an International Study Group on Pancreatic Fistula (ISGPF) Grade A Pancreatic Fistula ( PF), since such fistulae are transient and devoid of clinical sequealae or deviations in the clinical management. Furthermore, Cochrane meta-analysis published by Koti et. al. in 2010 demonstrated that the risk of PF is lower with the use of somatostatin analogues (SA), without this affecting the mortality rates. It would thus be crucial to clarify whether SA had been used perioperatively -and before a diagnosis of an established pancreatic leak was made-, on which case the outcome of the multivariate analysis and DFA1 cutoff should had been controlled for this variable among the rest. Thank you

On 2014 Jul 24, Ryan Radecki commented:

"The Broken ED Sepsis Quality Measure"

Are there yet sufficient mandates in the Emergency Department? Door-to-physician times, door-to-CT time in acute ischemic stroke, door-to-analgesia for long bone fractures – and, on the horizon, National Quality Forum proposed measures for delivery of sepsis bundle components within 3 and 6 hours....

http://www.emlitofnote.com/2014/07/the-broken-ed-sepsis-quality-measure.html

On 2014 Jun 12, Gaetano Santulli commented:

Goldenberg et al. (1) report that cardiac resynchronization therapy with a defibrillator (CRT-D) is associated with a significant long-term survival benefit in patients with mild heart failure, left ventricular dysfunction, and left bundle-branch block (LBB), whereas no benefit was found in patients without LBB. The Authors, however, do not provide data elaborating whether CRT-D improved any measurable variable of mechanical dyssynchrony. Therefore it is unclear whether the long-term clinical failure of CRT-D observed in patients without LBB resulted from persistent mechanical dyssynchrony or other underlying mechanisms, including myocardial fibrosis and myocardial stress (2). This aspect is particularly relevant since CRT-D has been demonstrated to primarily improve electrical dyssynchrony but does not uniformly decrease morbidity and mortality, even in patients with a wide QRS complex (3). Moreover, given the issues recently raised regarding the importance of QRS measurements, the Authors should have provided more data on the methodology used to measure QRS duration (4).

References

1.Goldenberg I, Kutyifa V, Klein HU, et al. Survival with Cardiac-Resynchronization Therapy in Mild Heart Failure. The New England journal of medicine 2014;370:1694-701.

2.Bilchick KC, Kuruvilla S, Hamirani Y, et al. Impact of Mechanical Activation, Scar, and Electrical Timing on Cardiac Resynchronization Therapy Response and Clinical Outcomes. Journal of the American College of Cardiology 2014;63:1657-66.

3.Kass DA. Predicting cardiac resynchronization response by QRS duration: the long and short of it. Journal of the American College of Cardiology 2003;42:2125-7.

4.De Guillebon M, Thambo JB, Ploux S, et al. Reliability and reproducibility of QRS duration in the selection of candidates for cardiac resynchronization therapy. Journal of cardiovascular electrophysiology 2010;21:890-2.

Celestino Sardu, MD¹, Gaetano Santulli, MD, PhD²

¹Second University of Naples, Naples, Italy; ²Columbia University Medical Center, New York, NY, USA

On 2014 Jun 05, Swapnil Hiremath commented:

This article was discussed on May 27th 2014 on the open online nephrology journal club, #NephJC, on twitter. An introductory comment is available on the eAJKD blog here and also on the NephJC website. It was quite a spirited discussion, with participation from nephrologists, cardiologists, electrophysiogists and more. A transcript and a storify'd version of the tweetchat is available at the same NephJC link and also from the Nephrology-on-demand editor here.

On June 3rd, there was a Google Hangout on air, between the NephJC editors, Dr John Mandrola and Dr George Bakris, one of the principal investigators of the trial,which can be viewed on Youtube.

The highlights of the tweetchat were: 1. Symplicity HTN 3 was a great study and the investigators and sponsors were to be commended for carrying out this astutely designed trial, which overcame issues related to regression to the mean, placebo effect and Hawthorne effect. 2. There were some intriguing signals, such as the differential effect based on race, the role of aldosterone antagonists, and technical aspects which should be pursued in future studies. 3. Renal denervation remains an exciting innovation, though carefully designed studies, with emphasis on patient selection, mechanistic and technical aspects and long term safety and efficacy need to be conducted to help delineate the exact role of renal denervation will be in the therapy of hypertension.

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

On 2015 Jan 03, M Mangan commented:

The claims in this work have become the basis for a serious misinterpretation of the incidence of autism that is flying around social media at this time. A couple of medical doctors have weighed in on the claims, and their detailed comments can be found here: Glyphosate – The New Bogeyman and Oh, no! GMOs are going to make everyone autistic!.

On 2014 Dec 29, Jeffrey Beall commented:

None

On 2015 Mar 03, Matthias Kern commented:

My letter to the editor regarding this article will be found here: http://www.ncbi.nlm.nih.gov/pubmed/25702967

On 2015 Feb 25, James Tsung commented:

Links to ultrasound videos for appendicitis: https://youtu.be/2xHvUmLTpQg?list=PLHg2xyua_KjvuvmVLWcqu6jnkOIzJvzgp

Ultrasound videos for normal appendix : https://youtu.be/JmZugcbUerA?list=PLHg2xyua_KjsFcEALjN0B7AGfgcg6qMhr

On 2014 Nov 26, 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 2014 Apr 04, FREDERICK DOMANN commented:

Here is a link to the pdf: http://www.dovepress.com/getfile.php?fileID=17843

On 2016 Feb 07, Fang-Cheng Yeh commented:

The tool and source code are available at http://ws-recognizer.labsolver.org/

On 2014 Apr 14, André R R Freitas commented:

This paper is very good, clearly identifies the risk of introduction of Chikungunya in America. In my view the endemic transmission of Chikungunya in Brazil and the rest of the Americas is a matter of time, too little time. So the vaccine against dengue should not be considered as a relief to the programs used to control Aedes ssp.

On 2014 May 05, J. Andrew Pruszynski commented:

There are two small typos in the paper. The abstract should state that arm muscles and neurons showed goal-dependent responses at ~70 and 35ms, respectively (rather than the other way around). The methods of the Spatial Target Perturbation should state that the monkey received water reward if it returned its hand to the displayed goal target within 500 ms of perturbation onset and remained within it for another 700 ms (rather than returning to the central target area within 750 ms and remaining within it for another 1 s).

On 2014 Sep 01, Wenyi Wei commented:

We would like to make a correction for the author entry of our paper (PMID: 24670654) by adding the middle name "C." for Dr. Lewis C. Cantley.

On 2014 May 06, Madhusudana Girija Sanal commented:

1) The authors argue that the effects of VSG(vertical sleeve gastrectomy) are mediated through FXR but do not provide this VITAL data in THIS paper on bile acid/salt plasma levels before and after the procedure in wild and FXR-KO animals. Bile salts/acids are FXR ligands. 2) The authors correlate the improvement in glucose tolerance and other beneficial effects to changes in gut microflora especially Roseburia (which is associated with butyrate levels). However, I doubt, the data in Extended Data Table -1 does not support this. The highest level of butyrate is in KO-vertical sleeve gastrectomy (KO-VSG) 29.79 microM/g. 3) Do authors have some hypothesis on butyrate levels and improvement in GTT? 4) Fig-5-G It is not clear how the relative abundance is plotted (X-axis) and if it is significant. Compare, with the data in Extended Data Figure 4<br> 5) Antibiotics were given to the animals during surgery? What effect it had on the gut microbiota? A control for anitbiotics is essential in this experiment. 6) Materials and Methods: It is not clear how the animals were monitored during the entire period and how the data was collected with respect to food preference. I was not able to find the actual data in the paper.<br> 7) What was the eating pattern? What if the KO eats much less food all time-a very basal level so a vertical sleeve surgery do not have much effect on eating? 8) If mediated through FXR, treatment with agonist/antagonist in wild animals would have shown some effect. Can administration of INT-747 –FXR agonist nullify/accentuate the effect of VSG in wild animals? What about DDAH Expression? 9) Explanation for associated with a 24% increase in fasting blood glucose in KO-mice? 10) The authors also ignored the endocrine role of resected gastric mucosa-gastric hormone measurement should have been done.

By and large this paper is description of observations of VSG in FXR-KO mouse rather than elucidation of the mechanisms.

According to the authors, they found the association of VSG and FXR through ‘unbiased’ pathway analysis. However, these is a paper by Mencarelli A1, Renga B, D'Amore C, et al. (2013) which correlates the beneficial effects of bariatric surgeries to the selective activation of intestinal nuclear receptors (FXR,LXR). This key paper (perhaps the first paper correlating bariatric surgery to nuclear receptors) is not cited by the authors in the current paper. There is no doubt that this is an area we are still in dark when it comes to the mechanisms. Research in this area will answer many important questions. For example: Some recent studies found the beneficial effects of bariatric surgery is more than medical management –however it is not clear if bariatric surgery can be recommended for non-obese diabetic. Will an FXR modulator will bestow at least some of the positive effects which are currently provided by painful and risky procedures like VSG?

On 2014 May 06, Eric Johnson commented:

The authors make a comparison between RAD and ddRAD and present the higher read coverage at each locus as a favorable feature of ddRAD, but the comparison is not useful. The ddRAD protocol they chose yielded 26,891 ddRAD loci and a per locus depth of 111 for the 3M reads. The RAD-Seq protocol they choose yielded 206,841 loci and a per locus depth of 14 for the same amount of reads.

The protocols could have been easily changed to make the loci number even by merely changing the RAD protocol to use a less-frequently cutting enzyme such as SbfI, which is one of the more common choices in RAD projects because it creates fewer loci needing sequencing. Reducing the RAD loci number would have increased the read depth at each locus.

The only conclusion a reader should draw from this comparison is that sequencing more loci will reduce the read depth at the loci, and that an appropriate enzyme should be chosen for the number of reads planned.

On 2015 Mar 18, Arvind Babu Rajendra Santosh commented:

Dear Author: Greetings, Could you please guide us in metastatic gene markers for oral squamous cell carcinoma tissues. Please respond us with literature support on the markers and methodology for the detection. Sincerely yours with respect, Dr A Babu Santosh.

On 2015 Apr 09, Paola Capparelli Pettersen commented:

It's stated that the mammography screening in Denmark and Norway is from 50 to 69 years old, but in the conclusion the authors say that the mortality has increased in women older than 59 years not invited to screening.

On 2014 Jun 02, Melanie Courtot commented:

We are grateful to Drs. Botsis, Woo and Ball for their comment on our article, and the opportunity to address their questions. We entirely agree on the importance of improving automated analysis of safety data, and we would have welcomed the opportunity to reuse their data. However, our multiple FOIA requests, beginning in May 2012, to obtain the complete datasets from the multiple published works to allow us to directly compare our approach with theirs were unsuccessful. Our correspondence eventually culminated in May 2013 with a response that “After a thorough and diligent investigation, CBERs search did not locate a record that contains the MedDRA terms for the VAERS identification numbers that were the subject of this paper or any document responsive to your request for the list of those records that are the 100 confirmed anaphylaxis cases”. This may cause slight differences in the exact numerical values being compared, and where applicable we attempted to infer possible causes, as stated in [Courtot M, 2014]: “However details of the original analysis approach necessary for reproducing the original results were not made available and we could only hypothesize the cause of results we obtained that were not in concordance with the original publication.” We also added specific mentions of differences (for example, in the legend of Table 2) when we were able to form such a hypothesis. Due to size restriction on this response, we address below the points in the order raised. A version including text from the original comment is available online.

We hope this clarifies the issues raised. We encourage Botsis et al., as well as other interested parties, to release their code and data upon publication as we did and in accordance with PLoS’s Data Policy. The availability of the dataset supporting published results will increase reproducibility or research and foster scientific advances. It will also prevent the need to form hypotheses when trying to interpret existing work, which may be detrimental to interpretation of the scientific content.

Detailed comments:

(1)The total number of potentially positive cases used in [Courtot M, 2014] is 237; this can be verified in the data we published alongside the paper. Table 2 contains information from 2 sources, as mentioned in its legend: (1) values taken from the existing published work from Botsis et al. [Botsis T, 2013], and identified by an asterisk, and (2) values obtained through our own analysis. The former, from [Botsis T, 2013], are the values from the testing set (as mentioned in the legend); it would be of little interest to compare results obtained from the training set. The latter, from our own analysis [Courtot M, 2014], encompass results from the Ontology Classification as well as from the Expanded SMQ. Regarding the Ontology Classification, the method does not use a training phase to compute the classifier results and so there is no basis on which to make the split. Similarly, there is no training done with the ABC tool. We hypothesized that there was a desire in [Botsis T, 2013] to keep the approach consistent across methods used and consequently acknowledge in the legend of the table that this may result in a small difference for the ABC classification row. With respect to the Expanded SMQ results, the table includes the results on the whole dataset. However the text does provide additional information: “Similar results were obtained using a 50/50 training/testing data split: 92% sensitivity (8696% at 95% CI) and 81% specificity (80-82% at 95% CI) in the testing set, AUC 0.93 (0.9-0.95 at 95% CI).”

(2) The original paper [Botsis T, 2013] did not document any deviation of the MedDRA terms used to the standard. The dataset used in our analysis (including the MedDRA terms) is published online. While it would certainly have been of interest to be able to compare our results with the set of MedDRA terms used by Botsis et al., answers to our FOIA requests stated that “no such record were located”.

(3) We provided details about our cosine similarity method and cited the original paper in which the method is described. We indicate that we obtained similar results on the whole dataset as with training/testing split, as we mentioned in point (1) above. In both cases, a cosine similarity score was computed for each pair of vectors (query and vector of PTs from the specific report considered) and the best cut-off point was determined. Regarding the use of additional PTs, we do not agree with the commentators’ assessment that that the additional PTs were commonly reported or unrelated to anaphylaxis. Indeed, the very first term in the list of additional PTs we suggest and provide as supplementary material for review is Hypersensitivity, which we do consider to be related to anaphylaxis. Specifically, the SMQ for anaphylaxis contains the term “type 1 hypersensitivity”. The next 4 PTs in Table S1 are already included in the SMQ; the following one is “pharyngeal oedema”. The SMQ already lists “oedema mouth”, “oropharyngeal swelling”, “laryngotracheal oedema” etc. and it seems appropriate to assume that “pharyngeal oedema” is related.

(4)(a) Using a statistical correlation between MedDRA PTs and outcome is an original contribution made by Courtot et al. in [Courtot M, 2014] and clearly described as such when constructing the Expanded SMQ (and supported by Table S1 in appendix). It was never implied that this had been done in [Botsis T, 2013]. We believe the referred-to excerpt is “Rather than creating a bag of words de novo based on keyword extraction from a training set of reports, we rather chose to expand on a known, already widely implemented, screening method, i.e., the SMQs.” We did not intend to refer to Botsis et al.’s work - we use the word “we”, and expected readers would understand that this referred to the authors of the manuscript [Courtot M, 2014]. We apologize for any confusion.

(4)(b) We are aware that Botsis et al. used the online version of the tool, and that the tool does not require the existence of a tentative diagnosis when data is submitted. However, The ABC tool is a diagnosis confirmation tool based on the Brighton guidelines, and the authors of that tool assume that instructions given with the guideline are being followed. Note that the tool itself is labeled “ANALYZE DATABASE Confirm a diagnosis for all cases in your database (Excel spreadsheet)” on the Brighton Collaboration website. We hypothesized that the diagnosis was automatically pre-selected for the batch entry done by Botsis et al. As a result, we emphasize a discrepancy between the information reported as ‘Insufficient evidence’ by Botsis et al, and what is expected based on the Brighton Case definition: ‘Reported anaphylaxis with insufficient evidence’ [Rüggeberg JU, 2007]. In [Botsis T, 2013], 488 cases are classified as ‘Insufficient evidence’. With the guideline in mind, we reviewed the records and showed that only 3 reports should have been classified as “Reported anaphylaxis with insufficient evidence”. Indeed, only 12 reports in the VAERS dataset were reported as anaphylaxis (and corresponding synonyms) in the VAERS report itself, of which 3 do not meet the Brighton case definition. Our results have been communicated to the Brighton Collaboration, with the aim of emphasizing the process for those users of the ABC tool who may not have a full understanding of the logic of the Brighton guideline.

On 2014 May 08, Taxiarchis Botsis commented:

Commentary on article “The Logic of Surveillance Guidelines: An Analysis of Vaccine Adverse Event Reports from an Ontological Perspective” by Mélanie Courtot, Ryan R. Brinkman and Alan Ruttenberg.

Taxiarchis Botsis¹ , Emily Jane Woo¹ , Robert Ball¹

¹ Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Rockville, MD

In their recent work, we were pleased to see Courtot et al. [Courtot M, 2014] pursue a line of research we initiated [Botsis T, 2011, Botsis T, 2012, Botsis T, 2013, Botsis T, 2013] to improve the efficiency of the application of case definitions to spontaneous reports of adverse events following immunization reported to the US Vaccine Adverse Event Reporting System (VAERS). VAERS is a spontaneous reporting system co-managed by the Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC). Courtot et al. described the development and evaluation of an adverse event ontology and proposed using it to represent the Brighton Collaboration (BC) case definitions. Their work is based on data sets consisting of “possible anaphylaxis” reports identified by FDA VAERS review staff and used in our research [Botsis T, 2011, Botsis T, 2013]. Using data obtained from the FDA through a series of Freedom of Information Act (FOIA) requests, the authors evaluated their system using the BC case definition for anaphylaxis. However, we have some concerns regarding the methods that Courtot et al. used to compare their results with ours [Botsis T, 2011, Botsis T, 2013], and we believe some clarification on the part of the authors would be helpful. First, in Table 2 of their results, Courtot et al. present a comparison of the sensitivity, specificity and AUC of their methods with those previously published by us [Botsis T, 2013]. The values taken for comparison from our report [Botsis T, 2013] were based on a randomly selected 25% testing subset. The authors’ results appear to be based on the entire set of 6034 reports for H1N1 vaccine previously classified by the FDA VAERS review staff as either “possible anaphylaxis” (N=237, not 236 as reported by Courtot et al.) or not “possible anaphylaxis” since they do not state otherwise. This issue is important to understand because the comparison presented in Table 2 of Courtot et al. might not be based on the same data. Second, we are concerned about the source of the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PTs) used in all the analyses because these were not provided in the FOIA responses. While it is possible to obtain MedDRA PTs from public data, these PTs would differ from those used in our analysis because of constraints on the number of PTs available in the public files. It might also be possible to convert the narrative text to PTs, but doing so would certainly produce a different set from ours [Botsis T, 2013]. Both of these differences could explain and contribute to variability in the comparative results.<br> Third, Courtot et al. neither explained whether they used a training/testing split when developing and then testing the expanded Standardized MedDRA Query (SMQ), nor exactly how cosine similarity was calculated for this purpose. They suggest the use of an expanded SMQ by selecting the PTs that are significantly correlated with the outcome and adding 120 new PTs to the original anaphylaxis SMQ. Details about the cosine similarity calculations are not provided, but it appears that Courtot et al. are using the expanded SMQ to perform a cosine similarity based classification on the same set used for estimating the correlations; such an approach could explain the high sensitivity and might not be reproducible if applied prospectively to another data set. Additionally, regarding the established and validated SMQ for anaphylaxis, it seems paradoxical that the addition of PTs which are commonly reported and unrelated to anaphylaxis would increase its performance. Clarification would be helpful. Fourth, the subsection “Automated Case Screening” and the discussion for the appropriate use of Automatic Brighton Classification (ABC) tool contain a number of misinterpretations for the work performed in [Botsis T, 2013]. With regard to the “Automated Case Screening” subsection, we would like to clarify two main points. First, we did not use the statistical correlation between the MedDRA PTs and the outcome (i.e., the “potentially positive” label) as implied by Courtot et al. We used the cosine similarity scores of the report vectors in the training subset to define the best cutoff point for the classification of reports and further evaluated it with the scores in the testing subset. Second, we used only MedDRA PTs in that analysis; we did not follow a “bag of words” approach and the terms were not obtained “based on keyword extraction” as stated by Courtot et al. With regard to the ABC tool, we used the online version of the tool that allows the processing of an appropriately formatted database of reports. While certain fields of the database must be marked as present (‘yes’), absent (‘no’), or even remain blank, the existence of a tentative diagnosis is not necessary to perform the classification. The online ABC tool processes the database and assigns one of the following labels to a report: “Level 1”, “Level 2”, “Level 3”, “Not a case”, “Insufficient evidence”, and “No evidence”. As previously stated [Botsis T, 2013], we prepared the database of 6034 reports to allow their automated classification by the ABC tool without human intervention or further interpretation of either the classification process or the labels produced by the ABC tool; this analysis was performed in collaboration with the ABC tool developer at the Brighton Collaboration. The development of advanced methodologies for the automated processing of safety surveillance data is important considering the large number of reports submitted to the FDA and other public health authorities. We welcome the reuse of our data for serious and constructive research, as well as the exploration of other methodologies that may offer efficient, effective, and rigorous processing of our data. We encourage the authors of this study and any other researchers to follow up with queries about our work, and we welcome them to maintain ongoing communication to ensure the most appropriate use of the data and avoid misinterpretations that might reduce the usefulness of the work and its potential application.

On 2014 Apr 14, Wilma Waterlander commented:

Thank you Andrew for your comment. My apologies that we didn't refer to this paper in our article. An important difference between this paper and ours however is that the tax in this study was added to various unhealthier items and not exclusively on soft drinks (as in our paper). The effects are therefore likely to be different, in particular when you look at substitution effects. Would be great to see more experimental studies on this topic!

On 2014 Apr 03, Andrew Brown commented:

This statement is incorrect: "However, there have been no experimental studies of the effects of price increases on SSBs or the effects on close substitutes such as diet drinks, alcohol or sugary snacks." See: "From Coke to Coors: A Field Study of a Sugar-Sweetened Beverage Tax and its Unintended Consequences" (http://papers.ssrn.com/sol3/papers.cfm?abstract_id=2079840)

On 2014 May 13, Stephen Eglen commented:

Our paper is freely available at the following URL: http://www.gigasciencejournal.com/content/3/1/3

On 2014 Dec 17, Sean Ekins commented:

Another set of slides mentioning this work http://www.slideshare.net/ekinssean/exploiting-bigger-data-and-collaborative-tools-for-predictive-drug-discoverycdd-2014-talk-shorter

On 2014 Dec 17, Sean Ekins commented:

Some relevant slides http://www.slideshare.net/ekinssean/looking-back-at-mycobacterium-tuberculosis-mouse-efficacy-testing-to-move-new-drugs-forward

On 2014 May 21, David Keller commented:

Your wish may have come true!

The latest study concludes "Among smokers who have attempted to stop without professional support, those who use e-cigarettes are more likely to report continued abstinence than those who used a licensed NRT product bought over-the-counter or no aid to cessation. This difference persists after adjusting for a range of smoker characteristics such as nicotine dependence."(1)

Would you please write an editorial entitled "If only there were a cure for Parkinson's disease"? I would personally appreciate that, and although it seems unscientific, your editorials seem to get results in a remarkably quick fashion ;-)

Reference

1: Brown J, et al. Real-world effectiveness of e-cigarettes when used to aid smoking cessation: a cross-sectional population study. Addiction. Pre-publication online at: http://onlinelibrary.wiley.com/doi/10.1111/add.12623/abstract

On 2014 May 09, David Keller commented:

Let the bad be the enemy of the truly horrendous

It has been estimated that “up to 98% of tobacco-related deaths are attributable to combustible products"(1). E-cigarettes deliver nicotine to the lungs as a cooler vapor, without tobacco combustion, or its byproducts such as carbon monoxide, carcinogenic tars and hot smoke. While nicotine is an addictive drug known to increase the risk of heart attacks, the argument for making e-cigarettes available to smokers is that e-cigarettes are predicted to cause fewer lung cancers, due to the absence of hot tobacco combustion products in their vapors. In addition, e-cigarette users are not inhaling the carbon monoxide found in cigarette smoke, which contributes to coronary ischemia among other ill effects. Even if the use of e-cigarettes does not cut down the number of cigarettes smoked, at least we know that when a chain-smoker is inhaling from an e-cigarette at a given moment, he is not also smoking a regular cigarette at that same time. Smoking causes lung cancer and heart attacks, while e-cigarettes cause "only" the latter. Using e-cigarettes is a bad choice, but this is a case of letting the bad be the enemy of the truly horrendous. I advise my patients neither to smoke nor to e-smoke, but if I had to pick which vice is more harmful, I would say the former. For nicotine addicts who prefer the inhaled route of delivery, the FDA has approved the use of Nicotrol, a nicotine inhaler which does not have the flavorings and other questionable ingredients included in e-cigarettes, and which is probably the least bad choice.

Reference

1: Fiore MC, Schroeder SA, Baker TB. Smoke, the chief killer--strategies for targeting combustible tobacco use. N Engl J Med. 2014 Jan 23;370(4):297-9. doi:10.1056/NEJMp1314942 PubMed PMID: 24450888

On 2014 May 13, David Keller commented:

Call for the patent holders of exenatide to help advance Parkinson's research & also profit

Follow-up data gathered a year after the end of the original study strengthens the suggestion that exenatide may have slowed down the progression of Parkinson's disease (PD). Think how much more convincing these results would be if exenatide had been tested in a double-blinded and placebo-controlled fashion. The authors of the original study wrote that the reason they conducted an open label study with no placebo was that they were unable to procure a suitable placebo, which would have required the manufacturer of Byetta (exenatide) to supply the pen injector devices filled with saline solution.

A recent meta-analysis found that Parkinson patients treated with active drug had significantly less objectively measured motor response to the same intervention if they knew there was a chance that they were receiving placebo, even with effective double blinding (1). This decreased response, dubbed "the lessebo effect", could account for up to 4.1 UPDRS units of motor improvement for patients in studies lacking double-blinded placebo controls.

Astra-Zeneca and Bristol-Myers-Squibb should supply these and other scientists with placebo Byetta or Bydureon injector devices, filled with sterile normal saline, to facilitate further research. This would help to advance investigation of exenatide as possibly the first proven disease-modifying medication for PD, which would be of tremendous benefit not only for PD patients, but for the stock-holders of the companies which own the patents on exenatide. This is truly a chance for these companies to do well while doing good.

Reference

1) Mestre TA, Shah P, Marras C, Tomlinson G, Lang AE. Another face of placebo: The lessebo effect in Parkinson disease: Meta-analyses. Neurology. 2014 Apr 22;82(16):1402-9. doi: 10.1212/WNL.0000000000000340. Epub 2014 Mar 21. PubMed PMID: 24658930; PubMed Central PMCID: PMC4001195.

On 2014 Apr 09, David Keller commented:

Let the patient decide when to start medication for Parkinson disease

Reluctance to start medication is not a critical problem for patients with Parkinson disease (PD), because no medication has been proven to affect the underlying progression of PD. Patient "non-compliance" with the use of PD medications does not have the kind of downstream harms associated with non-compliance with statins or aspirin in patients with atherosclerotic vascular disease. On the other hand, delaying the use of levodopa is associated with delayed motor complications, such as dyskinesias. Patients should not be encouraged to take Parkinson medications unless they are needed, and the patient decides when they are needed, based on the way they feel, not the physician.

On 2014 May 17, Mark Rubin commented:

Check out also: Rubin, M., Badea, C., & Jetten, J. (2014). Low status groups show in-group favoritism to compensate for their low status and to compete for higher status. Group Processes and Intergroup Relations. doi: 10.1177/1368430213514122

On 2014 Nov 26, 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 2014 Mar 28, Zhengyang Huang commented:

nice paper.

On 2014 May 19, David Keller commented:

Was this "Lessebo" effect durable for one year after the end of a clinical trial?

A recent clinical trial demonstrated possible beneficial effects of exenatide on slowing the progression of Parkinson disease (1); however, this study was hampered by lack of a double-blinded placebo control arm. Instead, a usual-treatment group was followed passively over time to serve as a comparator. Clearly, some of the benefits seen in the patients who self-injected with exenatide daily could have been due to the "Lessebo" effect during that study, or shortly afterward. But durable benefits were measured in the exenatide intervention group a full year after their last self-injection. How durable is the "Lessebo" effect? Could it account for some or all of the benefit seen with exenatide a full year after the end of that study?

Reference

1: Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Kahan J, Fmedsci PE, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T. Motor and Cognitive Advantages Persist 12 Months After Exenatide Exposure in Parkinson's Disease. J Parkinsons Dis. 2014 Mar 24. [Epub ahead of print] PubMed PMID: 24662192.

On 2015 Jan 20, E DAVID KLONSKY commented:

MMA Fighters Experience Less Head Trauma Compared to Hockey and Football: A Re-Analysis of Data in Hutchison et al. (2014)

E. David Klonsky PhD, Department of Psychology, University of British Columbia

Hutchison et al. (2014) present the most detailed and authoritative analysis to date of head trauma in mixed martial arts (MMA) competitions. The study is a valuable contribution to the literature on the frequency and predictors of head trauma in combat sports. This comment was written to suggest a reinterpretation of a particular aspect of the paper.

Hutchison et al. estimate the number of concussions that occur per 100 ‘athlete exposures’ in MMA, and compare their finding to data from other sports, including hockey and football. The figures reported are: 15.9 per 100 exposures for MMA, 8.8 for football, and 2.2 for hockey. Reported this way, the numbers imply that participating in MMA results in significantly more head trauma than hockey or football.

However, the authors’ choice to standardize concussion figures per 100 athlete exposures overlooks a key consideration: it is not only the rate per exposure that matters, but the sheer number of exposures. It is significant, then, that the number of exposures per year and per career varies systematically across sports.

Consider that a National Hockey League (NHL) regular season consists of 82 games, and that a National Football League (NFL) regular season consists of 16 games. In contrast, MMA fighters average approximately 3 fights per year. If we adjust the Hutchison et al. figures for number of exposures per year, concussion rates become highest for hockey and lowest for MMA: 1.80 for hockey, 1.41 for football, and 0.48 for MMA. In other words, a typical year of competition in professional football or hockey results in 3 to 4 times more concussions than a typical year of competition in MMA.

It is also important to consider head trauma experienced over the course of a career. To do so we must first consider the number of career exposures typical for each sport. As a rough barometer of career exposures, let us consider players recently inducted into each sport’s Hall of Fame. The four 2014 NHL player inductees competed in an average of 1201 career games. The seven 2014 NFL player inductees competed in an average of 206 career games. In contrast, the last four fighters to be inducted into the UFC Hall of Fame competed in an average of 33 career matches.

Notice the massive discrepancy in average career exposures across sports: 1201 (hockey) vs. 206 (football) vs. 33 (MMA).

If we use these differences in career exposures to adjust the concussion figures reported by Hutchison et al., we get the following: 26.4 for hockey, 18.1 for football, and 5.25 for MMA. In short, the concussion rate for an MMA career is 3 to 5 times lower than that of a hockey or football career.

This analysis, like the Hutchison et al. analysis, has limitations. First, the Hutchison et al. figures for MMA concussions were based on official bout results and video analysis rather than medical diagnosis. Second, the figures for hockey and football cited by Hutchison et al. were taken from previous studies using different methodologies and sampling procedures. Third, my analysis focuses on professional sports, which have longer seasons (i.e., more exposures) than sports at collegiate, high-school, or recreational levels. Fourth, I roughly rather than precisely estimated the average numbers of career exposures. Finally, a full understanding of head trauma risk in sports requires data on concussions that occur during practice and training, not just competition.

In sum, understanding the risks of head trauma in sports is critical. Some have been quick to associate MMA with disproportionately high risk of head trauma compared to other sports. However, when the stakes are high, it is important to get the science right. And the available data suggest that professional MMA fighters will experience less, not more, head trauma compared to professionals competing in hockey and football.

On 2014 Jun 27, Serge Ahmed commented:

The authors propose to reclassify addictive drugs, including cocaine, according to their common property of directly evoking a high frequency of de novo dopamine transients that would surpass that normally evoked by “natural” rewards. This property is particularly obvious in awake and behaving rats. This property would be necessary and sufficient to explain why “a higher reward magnitude [would be] conferred to abused drugs compared to natural rewards” and why “drug-associated cues [would acquire] the powerful ability to reinstate drug seeking and taking”.

This is an interesting hypothesis but it totally ignores recent research showing that when rats have a choice between i.v. cocaine and sweet water (a nondrug reward which is “processed by sensory systems”), most rats prefer the latter over the former regardless of the dose of cocaine available and even after a long history of cocaine self-administration (e.g., http://www.ncbi.nlm.nih.gov/pubmed/24260227; http://www.ncbi.nlm.nih.gov/pubmed/22871910; http://www.ncbi.nlm.nih.gov/pubmed/23551949; http://www.ncbi.nlm.nih.gov/pubmed/24886157; http://www.ncbi.nlm.nih.gov/pubmed/24602027; http://www.ncbi.nlm.nih.gov/pubmed/20676364; http://www.ncbi.nlm.nih.gov/pubmed/17668074; but see: http://www.ncbi.nlm.nih.gov/pubmed/23319458). Thus, it seems that the ability of a drug, like cocaine, to directly evoke a high frequency of de novo dopamine transients is not sufficient to explain its addictive potential (see also: http://www.ncbi.nlm.nih.gov/pubmed/23428657).

On 2014 Apr 11, Marcus Peter commented:

None

On 2014 Apr 07, Iffat Sumia commented:

Could CD95 then be a dependence receptor? (a kind of receptor that, when deprived of its ligand, stops its normal function and triggers cell death - Goldschneider D, 2010)

On 2014 Apr 18, Ivan Oransky commented:

This paper has been retracted, quite rapidly and transparently: http://retractionwatch.com/2014/04/18/doing-the-right-thing-physicists-retract-paper-after-becoming-aware-of-a-fundamental-error/

On 2014 Nov 26, 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 2014 Mar 28, Sergio Stagnaro commented:

None

On 2014 Mar 28, Daniel Schwartz commented:

This is a useful review that focuses on the actionable interventions that, based on current knowledge, could reduce the incidence of breast cancer. http://qxmd.com/r/24647877

On 2014 Mar 25, GRAHAM COLDITZ commented:

More resource materials in support of the prevention messages in this manuscript are available at http://tinyurl.com/BCpriorityExtra

On 2014 Apr 02, Daniel J Simons commented:

I wrote an extensive post-publication "HI-BAR" review of this paper on my blog (stands for Had I Been A Reviewer). You can access it at http://blog.dansimons.com/2014/04/hi-bar-benefits-of-lumosity-training.html

I posted a list of my concerns about the paper as a comment on the article at PLoS, and I've duplicated that list below. The blog post gives a more detailed discussion and explanation of each point. If the authors respond on PLoS, I'll update my comment and add a link to their response here as well.

In short, I do not think the paper permits the conclusion that game training produced any reliable benefits on the reported outcome measure.

List of questions and concerns:

1) The sample size of 15 in the training group and 12 in the control group is problematically small, especially for correlational analysis, but also for the primary analyses.

2) The "limited-contact" control group does not permit an inference that anything specific to the training led to the transfer effects. See http://pps.sagepub.com/content/8/4/445.full

3) The paper includes no corrections for multiple tests, and the core findings likely would not be significant with correction.

4) The paper does not report the means and variability for the accuracy data, leaving open the possibility of a speed-accuracy tradeoff.

5) The choice of response time cutoffs and exclusions were somewhat arbitrary, so it's not clear how robust these effects would be to other cutoffs.

6) The contrasts used to measure alertness and distraction were not defined. Which conditions were compared?

7) The alertness and distraction tests do not include a test of the difference between the training and control group. The fact that the training group difference was significant (but see below) and the control group difference was not does not mean that the difference between the groups was significant.

8) The training improvements for the alertness and distraction outcome measures were reported to be p=.05 and p=.04. But, they were truncated from p=.0565 and p=.0451. The first was not significant, and truncating the p-values is inappropriate. (Note that neither would be significant after correcting for multiple tests.)

9) The paper reports 20 correlations (each outcome measure with each of the 10 games in the training condition), but does not correct for multiple tests. And, correlations based on N=15 are of questionable reliability anyway. Moreover, correlations between training improvements and improvements on an outcome measure do not provide evidence for the efficacy of training.

10) The conclusion claims support for the idea that training improved "attention filtering," but the study does not test the mechanism that improved (and, the evidence that anything improved is uncertain).

11) The clinicaltrials.gov registration linked from the paper was posted after the paper was first submitted for publication. It is not a pre-registration.

12) The clinicaltrials.gov registration mentions a number of outcome measures that were not reported in the paper and were not mentioned on the PLoS Protocol and Consort Checklist (in the supplementary materials). If these measures were collected, they should be reported in the paper and in the supplemental materials. It is unclear whether these outcome measures just were not significant or were withheld for other reasons. In either case, the presence of unreported outcome measures makes it impossible to interpret the p-values for the one outcome measure reported in the paper.

13) The clinicaltrials.gov registration also lists a 24-week testing session that wasn't mentioned in the paper. Was the reported testing session an interim one?

On 2015 Jan 21, Alberto Carbonell commented:

Please visit http://p-sams.carringtonlab.org/ for using P-SAMS, the Plant Small RNA Maker Suite, to design artificial microRNAs and synthetic trans-acting siRNAs. P-SAMS also outputs the sequence of the oligonucleotides needed to clone the corresponding small RNA(s) in BsaI/ccdB-based "B/c" vectors.

On 2015 Oct 28, Salomone Di Saverio commented:

Thanks for your reply. You have written: "They still believe fibrin sealants may be beneficial in the setting of liver surgery and they criticize our nonsignificant findings." If you read carefully our letter it was wirtten: "Although from our experience we might agree with the authors' conclusions that fibrin sealant use does not significantly influence the incidence and severity of surface-related complications after liver resection, after looking carefully at the data of the present randomized controlled trial, we have several concerns about a good balance between the 2 groups and percentages and statistical significance given in the article. The generalizability of the results may therefore be affected and the conclusions may not be strongly supported by the data." It does mean that we DO agree that fibrin sealant does NOT influence complications and therefore is NOT beneficial, but we had concerns on the good balance between the 2 groups and percentages and statistical significance in this study. Furthermore many differences between groups, although not reaching merely statistical significance, did show a clinically meaningful significance; e.g. the percentage of patients who underwent preoperative chemotherapy less than 3 months before surgery, even counting the original 20% vs 12%, is still really very close to the boundaries of statistical significance (0.059) and maybe almost double of patients between the two groups (30/154 vs 17/148) can be clinically meaningful? Having said that, we confirm once again our agreement that application of fibrin glue sealant after hepatectomy does not seem justified

On 2014 Apr 16, Joerg Striessnig commented:

This is a very valuable review article providing the reader with a recent update of how histone acetylation state can affect specific brain functions in rodents that bear clinically relevance for human therapies.

On 2014 Apr 04, David Keller commented:

Move Leftward on MultiTarget's Receiver Operating Curve

The MultiTarget test has higher sensitivity but lower specificity than FIT, the standard colon cancer fecal screen (1). MultiTarget detects more colon malignancies but triggers more unnecessary colonoscopies. Colonoscopy is expensive and invasive, limiting the acceptability of false-positive fecal screens. MultiTarget’s Composite Score threshold was set at 183. Increasing this threshold score will increase specificity and lower sensitivity (2). It should be raised until MultiTarget’s specificity equals FIT’s; if, at that point, MultiTarget’s sensitivity remains higher than FIT’s, then replacing FIT screening with MultiTarget will detect more malignancies without forcing patients to undergo more unnecessary colonoscopies.

MultiTarget incorporates fecal hemoglobin testing. Reducing the cofactor X6 in the Logistic Score has the effect of increasing specificity and reducing sensitivity of the fecal hemoglobin component of MultiTarget without affecting the performance of the DNA components of the Composite Score.

Fecal hemoglobin testing should be eliminated from colon cancer stool screening protocols as DNA tests improve, because bleeding commonly originates from benign sources, such as hemorrhoids, degrading specificity.

References

1) Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, Ahlquist DA, Berger BM. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014 Apr 3;370(14):1287-97. doi: 10.1056/NEJMoa1311194. Epub 2014 Mar 19. PubMed PMID: 24645800.

2) Florkowski CM. Sensitivity, specificity, receiver-operating characteristic (ROC) curves and likelihood ratios: communicating the performance of diagnostic tests. Clin Biochem Rev. 2008 Aug;29 Suppl 1:S83-7. PubMed PMID: 18852864; PubMed Central PMCID: PMC2556590.

On 2014 Apr 04, David Keller commented:

Move Leftward on MultiTarget's Receiver Operating Curve

The MultiTarget test has higher sensitivity but lower specificity than FIT, the standard colon cancer fecal screen (1). MultiTarget detects more colon malignancies but triggers more unnecessary colonoscopies. Colonoscopy is expensive and invasive, limiting the acceptability of false-positive fecal screens. MultiTarget’s Composite Score threshold was set at 183. Increasing this threshold score will increase specificity and lower sensitivity (2). It should be raised until MultiTarget’s specificity equals FIT’s; if, at that point, MultiTarget’s sensitivity remains higher than FIT’s, then replacing FIT screening with MultiTarget will detect more malignancies without forcing patients to undergo more unnecessary colonoscopies.

MultiTarget incorporates fecal hemoglobin testing. Reducing the cofactor X6 in the Logistic Score has the effect of increasing specificity and reducing sensitivity of the fecal hemoglobin component of MultiTarget without affecting the performance of the DNA components of the Composite Score.

Fecal hemoglobin testing should be eliminated from colon cancer stool screening protocols as DNA tests improve, because bleeding commonly originates from benign sources, such as hemorrhoids, degrading specificity.

References

1) Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, Ahlquist DA, Berger BM. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014 Apr 3;370(14):1287-97. doi: 10.1056/NEJMoa1311194. Epub 2014 Mar 19. PubMed PMID: 24645800.

2) Florkowski CM. Sensitivity, specificity, receiver-operating characteristic (ROC) curves and likelihood ratios: communicating the performance of diagnostic tests. Clin Biochem Rev. 2008 Aug;29 Suppl 1:S83-7. PubMed PMID: 18852864; PubMed Central PMCID: PMC2556590.

On 2014 Apr 03, David Keller commented:

On 2014 Apr 02, David Keller commented:

We need a colon cancer stool screen which does not equate fecal blood with malignancy

The new "multitarget stool DNA test" studied in this clinical trial actually includes a hemoglobin immunoassay, so it retains a degree of the inherent inaccuracy caused by equating the presence of fecal blood with the presence of cancer. This new screening test for colon cancer uses a composite score computed from the presence of direct molecular markers of cancer (such as cancer-associated DNA strands), but the score also includes a component from the presence of fecal blood. The fecal blood test component cannot distinguish between blood from a benign source, such as a hemorrhoid, versus bleeding from a malignancy; this tends to increase the false-positive rate of the multitarget test, which was actually worse than that of the standard FIT test used as for comparison.

Hemorrhoids are common, and their trace bleeding increases the number of benign (unnecessary) colonoscopies which are ordered as a result of screening for fecal hemoglobin. The presence of stool DNA specific for colon cancer will be a convincing argument in favor of colonoscopy for patients who attribute the presence of blood in their stool to their hemorrhoids. The ideal stool screening test would rely purely on detecting cancer-specific molecules, without the need to enhance sensitivity by including a test for fecal blood.

A Modest Proposal - As a clinician, I would want to see the results of all the individual components of the multitarget stool screening test reported separately, along with the composite score calculated using the complex formula employed in this study. The investigators evidently fine-tuned this formula by altering the constant coefficients applied to each test component, in order to achieve what they hoped would be an optimized combination of sensitivity and specificity. However, whenever several directly-measured quantities are combined into a single number for the purpose of arriving at a binary result, much information is lost. The binary result will be a useful "yes or no" answer to the question of whether a patient requires colonoscopy. But clinicians should also be informed of the individual results of each of the component tests, along with the characteristics and implications of each, to allow a more individualized approach to the care of certain patients.

On 2014 Apr 07, Gary Collins commented:

Thanks for the comments.

The systematic review only included articles published in 2010 in the Core Clinical Journals [Abridged Index Medicus], so articles published in 2007 will not have been eligible, nor will articles published in 2011 onwards. The search string identified a large 11826 potential articles, mainly because of the inclusive search string. Prediction models are not easily identifiable due to inconsistent terminology for such models (e.g. Prognostic models, prediction models/rules, risk scores etc...and many don't even provide this in the title or abstract), no MeSH terms that are consistently used and tagged to such articles etc...

Also, whilst there are clearly some good examples of external validation studies, the majority are not so well done and are poorly reported, yet validation is all what we are interested in - i.e. does a model actually work.

It is very unlikely that including more up-to-date articles will have changed our conclusions. However, a reporting guideline is currently under peer-review to improve the reporting of studies developing or validating multivariable prediction models...

http://blogs.bmj.com/bmj/2011/08/03/gary-collins-opening-up-multivariable-prediction-models/

They will hopefully been out by the summer.

On 2014 Apr 06, Shervin Assari commented:

I wish a file was available to show the 11,826 articles. I am sure I am author of 1 or 2. I wish I could look at the evaluation results related to my work.

Khedmat H, Karami GR, Pourfarziani V, Assari S, Rezailashkajani M, Naghizadeh MM. A logistic regression model for predicting health-related quality of life in kidney transplant recipients.Transplant Proc. 2007 May;39(4):917-22.

On 2014 Apr 06, GRAHAM COLDITZ commented:

A pity this thorough review searched the literature back in February 2011 before our external validation of the Rosner-Colditz log-incidence breast cancer model, using an independent cohort (California Teachers Study) and comparable follow-up time period (calendar years) and endpoints (invasive breast cancer) was reported. see http://link.springer.com/article/10.1007/s10549-013-2719-3

Overall, this rigorous review reminds us to move beyond just publishing risk models but rather to carefully plan and implement validation studies. This paper should move the field forward and exemplifies the value of systematic review of methods to advance the conduct and reporting of studies.

On 2016 Mar 16, Cicely Saunders Institute Journal Club commented:

The Cicely Saunders Institute journal club reviewed this paper on Wednesday 3rd February 2016. We enjoyed discussing it and felt that the authors had addressed an important and understudied area of medical training. On the one hand, it is recognised that junior doctors increasingly need to be able to interact with terminally ill and other vulnerable groups of patients who need specialist palliative care and rehabilitation. On the other hand, there can be a common perception that it is unethical or unnecessary to involve the terminally ill in medical student teaching.

To investigate this issue in greater depth, the authors’ objective was to review available literature on how terminally ill patients feel about being involved in undergraduate medical teaching. Results were presented on a PRISMA flow chart, and studies appraised using a quality scoring system.

We felt that the paper would have been improved by the inclusion of clearer aims. The focus on patients’ views was interesting, and we wondered if the authors had considered extending this to include family perspectives.

Future studies could take the question beyond ‘should we involve terminally ill patients’ to ‘how and when’ it might be more or less acceptable to involve terminally ill patients in undergraduate medical education. Our discussions also considered whether this question could be extended to other life-limiting populations, such as people with complex neurological conditions, and to other cultures, where health systems and beliefs differ from the UK NHS system.

Commentary by Sophie Pask and Diana Jackson

On 2014 Aug 30, Michelle Lin commented:

A great study showing the potential of age-adjusted d-dimer cutoff values for patients >50 years old. ALiEM-Annals of EM Global EM Journal club held August 2014, which includes a webcast with experts.

http://www.aliem.com/adjust-pe-study-aliem-annals-em-journal-club/

On 2015 Jul 14, Marco Weiergräber commented:

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

On 2015 Nov 22, Torsten Seemann commented:

The latest version of Prokka is now available from https://github.com/tseemann/prokka

On 2014 Mar 25, Stephen Turner commented:

The current state of the art pipelines for bacterial genome annotation rely on web-servers with annotation times measuring in hours or days. Furthermore, sensitive data cannot be uploaded to a publicly accessible web-server. In this paper, the author introduces the Prokka software for rapid bacterial genome annotation. Prokka runs on local hardware, and can completely annotate a typical bacterial genome in under 10 minutes on a laptop. Prokka uses several feature prediction tools combined with similarity searching against annotated protein databases (either user-provided or publicly available). Prokka produces standards-compliant output files suitable for downstream analysis or submission to Genbank. Prokka is open-source and freely available.

On 2014 Apr 26, Salvatore Chirumbolo commented:

This interesting paper by Marzotto M et al., evaluated gene expression after 24 hrs incubation with hydroalcoholic/water extracts of Gelsemium sempervirens plant. The authors used human neuroblastoma cell lines SH-SY5Y and also IMR32 cell line, to focus on previously published data on mouse behavioural tests. After an oligonucleotide microarray, the authors selected less than 10 genes for RT-PCR. However, using human neuronal cell line to elucidate results obtained with mouse models appears quite disputable. The Authors referred this study to the previously reported behavioural evidence on animals, when stated (Discussion pag 15) “In previous recent trials, Gelsemium s. showed anxiolytic-like effects in mouse emotional response models and appeared to work even at the high dilutions 9c and 30c [26,27]” ....and moreover “In general, the prevalence of down-regulation seems to indicate a tendency to reduce cell excitability, especially because several of the genes in question belong to surface receptors involved in GPCR signaling and calcium homeostasis. Moreover, this first microarray screening of the effects of Gelsemium s. on neurocytes revealed a significant down-regulation of genes for inflammatory response, olfactory transduction and neuron differentiation” (Discussion pag. 16). This may raise criticism, as the authors studied SH-SY5Y and IMR32 human neuroblastoma cell line, not mouse derived cell lines. Yet, several genes the Authors highlighted do not have homologues in mice. Some examples of this are reported as follows. The gene baculoviral IAP repeat containing 8 (BIRC 8) has no homologues in mice (only orthologue genes in Pan troglodytes), olfactory gene OR4X1 is not expressed (absent) in mouse, gene C1ORF167 has a non characterized orthologue gene LOC102634746 in mouse, certainly not matching the research purpose to relate olfactory gene to the behavioural test. The search for an involvement of neural genes related to anxiety/depression or mood disorders is biased by the expression of human genes having no orthologues/homologues in mice, where the authors reported evidence about Gelsemium action on behavioural tests in animal anxiety models. Genes such as EN2 (engrailed homeobox 2), GALR2 (galanin receptor 2), GPR25 (G-protein coupled receptor 25), KLKBL14, erroneously indicated by the authors as Klkbl14, namely PRSS54 (protease serine 54), tachykinin 4 or TAC4 have orthologues both in human and mouse, while OR5C1 (olfactory receptor 5C1) is an exclusive Homo sapiens gene (mouse has an olfactory receptor 368 gene on chromosome 2). The authors tested Gelsemium hydroalcoholic preparations without a Limulus test to prevent bias from contamination by LPS or bacteria: this may generate bias. Curiously, genes affected by Gelsemium 2c, such as DDl1, are bacterial genes, notoriously absent/non expressed in Homo sapiens: probably is a misprint (delta-like 1 (DLL1) instead of D-alanine-D-alanine ligase (DDl1)). “The genes investigated by quantitative PCR generally confirmed the changes obtained by microarray assay. DDl1, EN2, GALR2, GPR25, OR5C1, Klkbl4 and TAC4 genes were downregulated in Gelsemium s. 2c samples compared to Control 2c in the three replicated experiments” (Results pag. 7). DDl1 is a bacterial gene: maybe the authors would indicate DLL1 (delta-like 1 gene)?

On 2014 Apr 29, Peter Wilson commented:

In the manuscript the authors incorrectly state that the function of the enzyme thymidylate synthase (TS) is the following:

"TS is a key enzyme that catalyzes the methylation of fluorod UMP, the precursor of DNA synthesis, into dTMP"

This is incorrect. Thymidylate synthase catalyzes the reductive methylation of dUMP (deoxyuridine) to dTMP (thymidine monophosphate; thymidylate). Fluoro-dUMP (or FdUMP as it is more commonly abbreviated to) is a potent fluoropyrimidine-derived irreversible inhibitor of TS and has nothing to do with the enzymatic mechanism of TS or the subject content of this manuscript.

The reference provided for the TS enzymatic mechanism is also not specific to TS whatsoever and the proper terms should be given as well as the abbreviations e.g. thymidine monophosphate (dTMP) and deoxyuridine monophosphate (dUMP).

Since the subject of this manuscript is centered around TS, the enzymatic function should be described accurately and precisely and this should be rectified.

The authors also state: "However, this is the first and initial meta-analysis of assessment whether TS expression is associated with objective response in patients with NSCLC treated with pemetrexed-containing chemotherapy."

This is also incorrect. This study is now the third to address this issue with two previous manuscripts published in 2013. According to the BMC Cancer pre-publication record, both previous manuscripts addressing this issue were published for a significant period of time before the final version of this current paper was submitted by March 5th, 2014 and therefore should have been referenced and discussed appropriately.

Liu Y, Yin TJ, Zhou R, Zhou S, Fan L, Zhang RG. Cancer Chemother Pharmacol. 2013 Nov;72(5):1125-32.

Wang T, Chuan Pan C, Rui Yu J, Long Y, Hong Cai X, De Yin X, Qiong Hao L, Li Luo L. PLoS One. 2013 Sep 10;8(9):e74284. doi: 10.1371/journal.pone.0074284.

On 2014 Jun 09, carl voyles commented:

In addition to the age of onset (61), profound weakness with forced retirement from battle (like modern day Parkee's)and numerous references to motor disorder in scripture, King David also suffered from autonomic dysfunction with sexual dysfunction and hypothermia terminally.

On 2016 Jan 03, Lydia Maniatis commented:

In comments on Yang and Purves (2004) in PP and PMC, I noted that the main claim - that perception of lightness is linked to the frequencies with which "visual patterns" have been encountered by organisms - is not only inconsistent with principles of biological evolution, but also lacks any supporting rationale. Interestingly, Purves, Monson, Sundararajan and Wojtach (2014) give the impression that they are going to provide such a rationale, in a short section of their article titled “Why Stimulus Frequency Predicts Perception and Behavior,” (which I quote in full below). (The article itself is one of several quite similar pitches for the “wholly empirical” account of visual perception that use Yang and Purves (2004) as key empirical reference).

It should be noted, first, that the title of the section is misleading; it represents as fact claims that have not been corroborated. As I have discussed in detail, the methods of Yang and Purves (2004) are too vague, arbitrary, opaque, conceptually problematic and incomplete to allow the investigators to make such claims even for the narrow set of cases that was the focus of that study. Thus, what is missing in the account is both a rationale and evidence. This being the case, the extract below does not explain a fact, but offers a rationale for a (quite odd) hypothesis.

This hypothesis, as summarized by Purves et al (2014), is that “perceptual values assigned by the frequency of occurrence of visual stimuli accord with the reproductive success of the species and individual.” Below I quote their rationalizations, interspersed with comments of my own.

“Missing from this account, however, is why the frequencies of occurrence of visual stimuli sampled in this way predict perception. The reason, we maintain, is that the relative number of times biologically generated patterns are transduced and processed in accumulated experience tracks reproductive success.”

[This is not a reason, it is a repetition of the unjustified claim that responding to stimuli (whether “biologically generated” or not) on the basis of their frequency is adaptive.]

In Fig. 3, for example, the frequencies of occurrence of the patterns at the stage of photoreception have caused the central luminance value to occur more often when in the lower luminance surround than in the higher one, resulting in a steeper slope at that point on the cumulative distribution function.

[There is no credible evidence for this claim (see my criticism of Yang and Purves (2004). In addition, Purves, Morgenstern and Wojtach (2015) have conceded that the sampling assumptions were flawed).]

“If the relative ranking along this function corresponds to the perception of lightness”

[the operative word is “if;” Purves and Yang (2004) did not test samples for their perceptual effects on independent observers]

“then the higher the rank of a target luminance (T) in a given surround relative to another target luminance with the same surround, the lighter the target should appear. Therefore, because the target luminance in a darker surround (Fig. 3, Left) has a higher rank than the same target luminance in a lighter surround (Fig. 3, Right), the former should be seen as lighter than the latter, as it is. Because the frequency of occurrence of patterns is an evolved property”

[this reference to frequency of occurrence of patterns being an evolved property makes no sense at all – the data in Yang and Purves (2004) are described and sampled as luminance values occurring in the environment, as an objective property of the environment outside of the evolving organism]

“—and because these relative rankings along the function correspond to perception”

[again, this “fact” lacks empirical evidence, as samples perceptual effects were not tested]

“—the visually guided behaviors that result will in varying degrees have contributed to reproductive success.”

[This is just a truism – a post hoc assumption that typical behaviors of existing organisms are behaviors that have contributed to survival and reproduction].

“Thus, by aligning the frequencies of occurrence of light patterns over evolutionary time with perceptions of light and dark and the behaviors they elicit, this strategy can explain vision without solving the inverse optics problem.”

[Nothing in the preceding paragraph serves to justify this statement. It doesn't explain, for example, why such a strategy would be adaptive.]

The “explanation” thus rests on 1. Our taking on faith the unrationalized, never-really-tested and, in fact, impossible-to-test hypothesis that frequency of occurrence of loosely defined, arbitrarily sampled “visual patterns” over the evolutionary lifetime of the species tracks both perception and reproductive success, and 2. Overlooking the absurdity and contradiction of calling frequency of occurrence of luminances in the environment, as measured, using instruments, by Yang and Purves (2004) an “evolved property.” Even if we could make sense of the statement that “frequency of occurrence of patterns is an evolved [or “biologically generated” or occurring “at the stage of photoreception”] property, we would still need a. evidence and b. a rationale for such a unique assertion.

In sum, this “explanation” contains neither evidence nor a rationale; it is wholly unempirical.

p.s. The introduction of the idea of "evolved frequencies" seems unique to this article, in which the authors were (unusually) called on to rationalise their frequency hypothesis. In two more recent articles, reference is made to the "frequency of occurrence of image patterns" (Purves, Morgenstern & Wojtach, 2015a) that appear to be defined in the normal way, i.e. as the product of the focussing of "incoming light" which the structure and lens of the eye organise to form a "high-resolution image" (Purves, Morgenstern & Wojtach, 2015b). If we are talking about frequencies of images organised on basis of the straightforward focussing of incoming light rays, in the same way a camera's autofocus would, what aspect of these frequencies is "evolved" or "biologically generated"? And, again, redundantly, what's the theoretical rationale of the supposed frequency-perception link?

On 2016 May 03, Brooke Morriswood commented:

Please note that the manuscript contains an error concerning the gene ID of TbPIPKA orthologues. The correct orthologue of Tb427.04.1620 (TbPIPKA) is Tb927.4.1620, and not Tb927.10.1620 as stated in the text. The gene ID Tb927.10.1620 is a typo deriving from the location of the other two PI(4)P 5-kinases (Tb927.10.3890, Tb927.10.4770) on chromosome 10. We apologise for any misunderstanding. Graham Warren, Katy Schmidt, Lars Demmel, Brooke Morriswood.

On 2014 Nov 26, 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 2014 Jul 07, Ryan Radecki commented:

Post-publication commentary:

"Enoximone Miracle for Asthma: Science? Advertising? Both?"

Potential leaps forward in medical science are noteworthy. They should be peer-reviewed, disseminated, and developed – and those responsible, rewarded, to be sure. But, the medical literature is full of grey areas between science and advertising – including routine publication of sponsored trials, to a “Clinical Evidence Synopsis” composed solely by those with COI, to this latest egregious sample....

http://www.emlitofnote.com/2014/06/enoximone-miracle-for-asthma-science.html

On 2016 Aug 24, Ben Goldacre commented:

One of the trials in this article 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 NCT00149913. We believe the correct ID, which we have found by hand searching, is NCT00159913.

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 Mar 19, Paolo Declich commented:

I found this abstract very interesting: patients with sporadic FGPs are in fact patients without concurrent Helicobacter pylori infection. Their gastric antrum are gastritis free, so they can be considered low risk patients for gastric cancer developpment.

On 2014 Mar 19, Jack Dowie commented:

"...compensatory MCDA methods such as weighted sum models are not suitable for oncology decisionmaking problems. In fact, an MDT would be interested in treatments that are both effective (efficacy criterion) with and acceptable safety profile (safety criterion). A compensatory effect would arise if an alternative that exhibits a very good performance on efficacy and a poor performance on safety is preferred to another that has a good performance on efficacy criterion and a fair performance on safety, on the basis of a weighted sum score." This is simply a value judgement and truly person-centred care must allow patients to trade-off 'safety' with other criteria in MCDA-based decision aids or decisions.

On 2014 Apr 16, Martin Myers commented:

beautiful work!

On 2014 Apr 06, Shervin Assari commented:

Great work. Any other publication on the same topic while gender is also considered?

On 2014 Mar 22, Marcos Malumbres commented:

This is a problem here with the nomenclature. Cadherin-1 (mammalian symbol: Cdh1) and the Anaphase-promoting Complex (APC)-cofactor Cdh1 (mammalian symbol Fzr1) are two different genes with separate functions.

On 2014 Aug 19, Nikolai Slavov commented:

The classical work of Goldbeter and Koshland, (1981) described how a cycle of competing enzymes, such as a kinase and a phosphatase, can significantly amplify a signal. This work of Dasgupta et al. makes two very significant contributions to the Goldbeter-Koshland mechanism: (i) it generalizes these classical ideas beyond Michaelis-Menten kinetics to arbitrarily complicated enzyme mechanisms; (ii) it demonstrates how the noise of low copy-number fluctuations can be amplified by Goldbeter-Koshland kinetics and points to an elegantly simple solution, enzyme bifunctionality. It is a must read.

On 2014 Apr 04, Dale D O Martin commented:

It should be noted that N-myristoylation of proteins can only occur on N-terminal Glycines, not internal glycines as they have predicted here and in other papers. That is why it's called N-myristoytlation. The only time that myristoylation can occur internally is following proteolysis of the protein that leads to an N-terminal Glycine on the C-terminal cleavage product. So far, this has only been shown to occur following caspase cleavage at Aspartate residues.

The authors also don't include what prediction program they used nor do they reference any papers on myristoylation.

I have commented on papers that include some of the same authors and this journal previously and I have brought it to their attention.

On 2014 Oct 08, Salah Amasheh commented:

A typographical error occurred in the title. The correct title would start with "Laurate Permeabilizes..."

On 2014 Nov 26, 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