On 2015 Apr 26, Geriatric Medicine Journal Club commented:

This is a systematic review of non-pharmacologic interventions for orthostatic hypotension including exercise, FES, compression, physical countermaneuvers, head of bed up, water intake, and meal strategies. This article was critically appraised at the April 2015 Geriatric Medicine Journal Club (follow #GeriMedJC on Twitter). The full discussion can be found at: http://gerimedjc.blogspot.com/2015/04/april-2015-gerimedjc.html?spref=tw An interesting finding was that an acute bout of exercise may exacerbate orthostatic hypotension in short term. This review did not cover interventions like salt intake.

On 2014 Oct 12, George Ntoumenopoulos commented:

I completely concur with these authors. In addition the potential impact of ventilatory and patient positioning strategy on the movement of airway secretions also deserves attention. Our recent case report (Physiother Res Int. 2014 Jun;19(2):126-8. doi: 10.1002/pri.1563. Epub 2013 Aug 17. Justification for chest physiotherapy during ultra-protective lung ventilation and extra-corporeal membrane oxygenation: a case study.Cork G1, Barrett N, Ntoumenopoulos G.) highlights the potential failings of current recommendations for secretion clearance. The ultra protective ventilator settings combined with head of bed upright positioning may predispose to secretion retention and warrants further investigation.

On 2014 Dec 30, MARK WEST commented:

Comment on “Striatal firing rate reflects head movement velocity” by Namsoo Kim, Joseph W. Barter, Tatyana Sukharnikova and Henry H. Yin

We read the experiments conducted by Kim et al. with enthusiasm. We feel that it is important to comment on previous studies that demonstrated a direct relationship between striatal activity and movement velocity, which Kim et al. support. Originally demonstrated in the nonhuman primate (DeLong, 1973), several studies in rodents have shown relationships between firing rates of dorsolateral striatal neurons and movement velocity. Kim et al. find that both putative dorsal striatal projection neurons and putative fast-spiking interneurons fire during head movements and exhibit a firing rate relationship with the velocity of head movement. Given our previous demonstration of firing rate correlations with head movement velocity in the subpopulation of dorsolateral striatal projection neurons selectively related to head movement (Pederson et al., 1997; Tang et al., 2007), it is interesting that firing of putative striatal interneurons also exhibits a relationship to movement velocity (although not subjected to sensorimotor examination of the entire body by Kim et al). We want to add information regarding dorsolateral striatal projection neurons, over half of which fire selectively in relation to activity of single body parts (Carelli and West, 1991; Cho and West, 1997), as revealed by sensorimotor examination of the entire body. These neurons exhibit movement properties which may have been outside the scope of the authors’ study. First, movement-related firing patterns are not limited to neurons phasically related to head movements, as they are found throughout the dorsolateral striatum containing single body part neurons. For instance, we have also demonstrated similar properties in neurons phasically related to vibrissae movement (Carelli and West, 1991), forelimb movement (Carelli et al, 1997) or tongue movement (Mittler et al., 1994; Tang et al., 2008). Second, each single body part neuron exhibits a preferred direction of movement. Third, though velocity of movement is a major predictor of firing rate change for many single body part neurons, not all these neurons are sensitive to velocity and some may be sensitive to one or a combination of several movement-related characteristics (e.g., movement length, movement position, etc). References: Carelli RM, West MO (1991) Representation of body by single neurons in the dorsolateral striatum of the awake, unrestrained rat. J Comp Neurol 309:231 249. Carelli RM, Wolske M, West MO (1997) Loss of lever press-related firing of rat striatal forelimb neurons after repeated sessions in a lever pressing task. J Neurosci 17: 1804-1814. Cho J, West MO (1997) Distributions of single neurons related to body parts in the lateral striatum of the rat. Brain Res 756:241-6. DeLong, MR (1973) Putamen: Activity of Single Units during Slow and Rapid Arm Movements, Science 179:1240-1242. Mittler T, Cho J, Peoples LL, West MO (1994) Representation of the body in the lateral striatum of the freely moving rat: Single neurons related to licking, Exp Brain Res 98:163-167. Pederson CL, Wolske M, Peoples LL, West MO (1997) Firing rate dependent effect of cocaine on single neurons of the rat lateral striatum. Brain Res 760:261-5. Tang C, Pawlak AP, Prokopenko V, West MO (2007) Changes in activity of the striatum during formation of a motor habit. Eur J Neurosci 25:1212-1227. Tang CC, Root DH, Duke DC, Zhu Y, Teixeria K, Ma S, Barker DJ, West MO (2009) Decreased firing of striatal neurons related to licking during acquisition and overtraining of a licking task. J Neurosci 29(44):13952-13961.

On 2017 May 01, Doug Berger commented:

LACK OF BLINDING IN THIS STUDY WAS A SERIOUS METHODOLOGIC FLAW. ADDITIONALLY, FACULTY SUPERIOR OF LEAD AUTHOR STEVEN HOLLON, DR.STEPHAN HECKERS, EDITOR OF JAMA PSYCHIATRY, BOTH AT VANDERBILT DEPT. OF PSYCHIATRY REQUIRES REPORTING AS CONFLICT OF INTEREST

This study by Hollon et al. compared an antidepressant medication-only arm with a combined cognitive therapy/antidepressant arm and concluded that the cognitive therapy/antidepressant combination enhanced the recovery rates compared with antidepressant alone, and that the magnitude of this increment nearly doubled for patients with more severe depression.

We opine that for subjects with greater severity, there could have been both antidepressant efficacy, as well as more hope and expectation as bias in the group who knew openly that they had received combined cognitive therapy/medication as a possible treatment. This can lead to an erroneous conclusion of greater efficacy for the combined group. The large subject number in this study could also easily lead to an erroneous finding on statistical testing as a small amount of bias in the subjects adds-up.

In addition, it goes against clinical trial logic to compare the unbilnded-cognitive therapy/medication group to the unblinded medication-only group.This is because, as all the study arms were unblinded, the combined cognitive therapy/medication group has an advantage over the medication-only group. The combined group does not filter any hope or expectation bias that may be lurking in the cognitive therapy arm, while the medication-only group engenders no different hope or expectation than the medication arm in the combined group. It is thus logically invalid to compare the cognitive therapy-medication arm that can have an unfiltered cognitive therapy-positive bias from the unblinded nature of receiving cognitive therapy tasks by cognitive therapy trained therapists vs. the medication-only arm which has the same bias possibility as the medication in the combined group, but lacking any possible positive bias from the combined cognitive therapy arm. Medications are required to show efficacy when compared in a double-blind study that includes a blind-placebo control as these controls are necessary to filter bias of any hope or expectation of efficacy. Neither blind controls nor blinded placebo were used in the design of the Hollon et al. study here.

Dr. Hollon should have also noted the conflict of interest in that the Director of his dept. Dr. Stephan Heckers was also on the Editorial Board of JAMA Psychiatry when this paper was submitted and was the Editor-in-Chief of JAMA Psychiatry when it was published.

The paper was retracted once for multiple errors, and it should be withdrawn completely because of poor clinical trial logic in making claims from unblinded subjects and treaters, and in addition due to conflict of interest in having the Editorial Director (Stephan Heckers) of the publication (JAMA Psychiatry) also as head of the Faculty of the lead author's (Hollon) affiliation at Vanderbilt University.

The full comment on the Hollon et al. study above can be read here;

Double blinding requirement for validity claims in cognitive-behavioral therapy intervention trials for major depressive disorder. Analysis of Hollon S, et al., Effect of cognitive therapy with antidepressant medications vs antidepressants alone on the rate of recovery in major depressive disorder: a randomized clinical trial. By D. Berger. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863672/

On 2014 Nov 11, Serge Ahmed commented:

This comment is a follow-up of my previous comment about the difficulty in interpreting this study that contradicts most previous similar studies. After a careful analysis of this paper and after collecting all elements of methods “ectopically scattered” through the text, I think I finally arrived at a satisfactory explanation for why most rats preferred cocaine over sweet water in the present study. Briefly, everything was made to make access to sweet water reinforcement less direct and more difficult than access to cocaine reinforcement, thereby biasing choice towards cocaine!

More specifically, rats had to go through an unusually long chain of behavioral events before getting access to sweet water. A similar chain was not required for cocaine delivery. First, once rats turned the wheel on the operant panel, they had to cross the cage to reach a magazine on the opposite panel inside which there was a retractable drinking spout that delivered sweet water. This arrangement introduces a spatial and thus a time gap between responding and sweet water reinforcement. Both gaps are known to reduce conditioning. Second, once rats have reached the magazine, they did not have directly access to the drinking spout that delivered sweet water. They had first to insert their head into the magazine to make the retractable drinking spout appears. This behavior amounts to a second operant response which thus defines with the first response (i.e., wheel turning) an operant chain. In addition, once rats inserted and maintained their head in the magazine, the drinking spout was not continuously available but came “back and forth in the magazine during 50s.” This is a rather unusual method of fluid delivery (note: the frequency and duration of these back-and-forth movements are not indicated in the Methods).

Thus, to repeat, everything was made in the present paper to make access to sweet water reinforcement more difficult and less direct than access to cocaine reinforcement, thereby biasing choice towards cocaine. This unusual approach may be appropriate for addressing some scientific questions but it is misguided and inappropriate for studying the vulnerability to cocaine addiction which was the main goal of the present paper. If one wants to pursue such a goal, one better tries to make access to cocaine reinforcement equal to or more difficult than access to the nondrug option and not the other way around! Indeed, if one sufficiently weakens the nondrug option, then one will eventually reach a point where most individual rats, even the non-addicted ones, will prefer the drug! To take an extreme example, if one provides rats with ready access to cocaine but ask them to play piano or climb Mt Everest to get access to sweet water, they will surely choose cocaine over sweet water. This is not surprising, this is just trivial! In contrast, if rats take cocaine despite and at the expense of an equally or a more accessible potent nondrug option, then one has got something much less trivial and probably more relevant for studying the vulnerability to cocaine addiction.

On 2015 Mar 28, Amit Kumar Chowhan commented:

Dear Sir,

We read the article by Srikanth S et al.¹ on ‘A comparative study of fine-needle aspiration cytology (FNAC) and fine-needle non-aspiration cytology (FNNAC) techniques in head and neck swellings’ with interest and appreciate the inclusion of multiple organs i.e. lymph node, thyroid and salivary gland located in head and neck region in the study. Although fine needle aspiration cytology is a well-established tool as a first line diagnostic modality, however, a major criticism pertains to its use in highly vascular organs such as thyroid and liver, or in haemorrhagic lesions where large quantities of blood compromise cytologic interpretation. Hence we agree with the authors when they excluded lesions of vascular origin from their study.

We agree with the authors that FNNAC allows greater ease of sampling with better control of the hand during the procedure and a good perception of the lesion consistency, enabling more precise entry into the mass and thus is more user friendly. Apart from being less traumatic and painful to the patient, as suggested by the authors, we would like to add that with this technique the patient would also be less apprehensive about the procedure, when a large syringe with needle and a syringe holder is not seen, thus making FNNAC more patient friendly. Another advantage of FNNAC is that the syringe is used to expel the material after the procedure is completed, whereas in FNA it is used to create a suction force to aspirate the cells in to the needle. A fresh sterile syringe is therefore not necessary for FNNAC, thus reducing the cost of procedure.

In their study the authors concluded that for thyroid lesions the non-aspiration technique was better than aspiration technique with respect to all the five parameters proposed by Mair et al.² i.e. background blood/clot, amount of cellular material, degree of cellular degeneration & trauma and retention of appropriate cellular architecture. In a similar study conducted by us³ on thyroid lesions, we found that the non-aspiration technique was better in relation to all the parameters except for amount of cellular material, which was better with aspiration technique. In cases of colloid goiter, brownish colloidal fluid drained out immediately on putting needle and drenched the fingers holding the needle. This problem was handled by keeping a syringe ready, which was immediately attached to the needle and the fluid collected in the syringe – to be cyto-centrifuged for better cellularity. Another problem encountered was for calcified nodules, which required vigorous aspiration, as it didn’t yield any material on non-aspiration. We therefore, would recommend first non-aspiration technique to be performed and if the material obtained is insufficient then only to go for another pass with aspiration technique.

References:

1.Srikanth S, Anandam G, Kashif MM. A comparative study of fine-needle aspiration and fine-needle non aspiration techniques in head and neck swellings. Indian J Cancer 2014;51:98-9.

2.Mair S, Dunbar F, Becker PJ, Du Plessis W. Fine needle cytology - is aspiration suction necessary? A study of 100 masses in various sites. Acta Cytol. 1989;33:809-13.

3.Chowhan AK, Babu KV, Sachan A, Rukmangdha N, Patnayak R, Radhika K, Phaneendra BV, Reddy MK. Should we apply suction during fine needle cytology of thyroid lesions? A prospective study of 200 cases. Journal of Clinical and Diagnostic Research 2014;8:19-22.

On 2014 Aug 10, Ryan Radecki commented:

Post-publication commentary:

"Get to the Choppa! Or ... Maybe Not?"

Helicopter transport is entrenched in our systematic management of trauma. It is glamorized on television, and retrospective National Trauma Data Bank studies seem to suggest survival improvement – and those with head injury seem to benefit most.

But, these NTDB studies encompass heterogenous populations and are challenged in creating truly equivalent control groups. This study, on the other hand, is a single-center experience, allowing greater consistency across divided cohorts. In a novel approach, these authors collected all HEMS trauma transfer requests to their facility across their 30-county catchement area – and specifically looked at occasions when weather precluded HEMS. This therefore created two cohorts of patients eligible for HEMS, with a subset that was transported by ALS due to chance events. The paramedic crews manning the HEMS and ALS transfers were staffed by the same company, and therefore had roughly equivalent training....

http://www.emlitofnote.com/2014/08/get-to-choppa-or-maybe-not.html

On 2014 Jul 25, Ryan Radecki commented:

Post-publication commentary:

"The Scandal of Dabigatran – A Summary"

We’ve been desperate for a more elegant solution to anticoagulation than rat poison for seemingly an eternity. Now, we have them: direct thrombin and factor Xa inhibitors. The studies supporting their use seem favorable.

But, as the old story goes – and as previously reported on this blog many times – Boehringer Ingelheim has been selectively reporting only the most favorable aspects of their flagship drug, dabigatran. Increased cardiovascular events have been downplayed through study design not powered to detect a difference. Issues with fixed dose therapy – and lack of a range of options for patients with renal impairment – rear their ugly head in multiple case reports....

http://www.emlitofnote.com/2014/07/the-scandal-of-dabigatran-summary.html

On 2014 Sep 27, David Keller commented:

Pembrolizumab first-line for metastatic melanoma & preexisting autoimmune disease?

Patients with preexisting autoimmune diseases were excluded from the landmark trials of ipilimumab and pembrolizumab, which therefore cannot provide high-quality safety data for these patients. The grade 4 (life-threatening) and grade 5 (fatal) adverse events for both medications were primarily autoimmune in nature, in trial patients with no history of autoimmune disease. Pembrolizumab appears to have a somewhat lower rate of severe-to-fatal adverse events than ipilimumab, although no head-to-head comparison is available.

Pembrolizumab was recently approved by the FDA for treating metastatic melanoma patients who have disease progression following ipilimumab. Medicare and private insurers are quite strict about not paying for off-label use of pembrolizumab, even for patients with active autoimmune disease. I have personally corresponded with two authors of this paper who advocate first-line treatment using pembrolizumab in selected clinical scenarios, for enhanced patient safety. Although there is controversy on this question in the immuno-oncology community, it seems reasonable to let treating oncologists decide when pembrolizumab should be used first-line and off-label for selected high-risk patients, pending their inclusion in randomized trials. As matters now stand, the wealthy who can pay cash for pembrolizumab effectively have access to a treatment option not available to less-wealthy melanoma patients. The FDA should reconsider their narrow prescribing indication for pembrolizumab, the adverse effects this may have on melanoma patients with preexisting autoimmune diseases, and the disparity caused by expensive off-label treatment options which are available only to patients who can pay the very large cash price in advance.

On 2015 Oct 10, Peter Good commented:

Baron-Cohen and colleagues here present “the first direct evidence of elevated fetal steroidogenic activity in autism” – primarily elevated androgenic hormones of the Δ4 pathway androstenedione and testosterone. They propose that high fetal testosterone explains the “extreme male brain” of autism [Baron-Cohen S, 2005] – why these children appear to be extreme versions of normal male intelligence, as Asperger noted many years ago [Frith 1991].

But high fetal testosterone does NOT readily explain why autistic children are often anxious, even timid, in the presence of others. Markram and colleagues pointed out that Kanner (1943) observed abnormal anxiety and phobias in these children, as other researchers have since [Markram K, 2010]. Melvin Konner noted that early pioneers of autism research Niko and Elisabeth Tinbergen detected signs of fear in these children in social situations, and “reasoned that exceptionally timid children might be at risk for developing the disorder if they grew up in a sufficiently threatening – or perhaps for them, merely a very intrusive – social environment.”[Konner 1982] Since testesterone allays fear [Konner], why are autistic children timid?

One explanation may be androstenedione, which the present study also found at higher than normal levels in amniotic fluid of these children. Androstenedione is a weak androgen precursor of testosterone, estrone, and estradiol, the primary estrogen. However, Taylor and colleagues concluded that its effects on rat sexual behavior reveal that androstenedione leaves “behavioral footprints” different from testosterone [Taylor GT, 2012]. Jacklin and colleagues assessed timidity in infants by their reaction to fear-provoking toys. Low timidity in boys was associated with higher levels of testosterone at birth – but not androstenedione [Jacklin CN, 1983]. Ward pointed out prenatal stress “causes an increase in the weak adrenal androgen, androstenedione, from the maternal or fetal adrenal cortices, or from both, and a concurrent decrease in the potent gonadal androgen, testosterone.”[Ward IL, 1972] This happens because release of androstenedione and testosterone from the testes is triggered by luteinizing hormone (LH) from the pituitary; high adrenal androstenedione suppresses LH release by negative feedback.” Do high levels of androstenedione differentiate the brain of a male fetus BEFORE they turn to testosterone and estrogen?

A second challenge to high prenatal testosterone is the certainty the brain overgrowth of autism happens after birth, not before. Courchesne and colleagues found that children with autism have smaller heads at birth, then a sudden excessive increase in head size beginning a few months after birth and lasting six to 14 months: “[O]ur study found evidence of neonatal brain undergrowth followed by rapid and excessive postnatal brain growth beginning in the first few months that precedes the clinical behavioral onset of autism.”[Courchesne E, 2003] This sounds like postnatal catch-up growth in infants born prematurely or whose fetal head growth was restrained for any reason [Cockerill J, 2006]. Or was it due to the usual postnatal testosterone surge in male infants within a few months of birth [Swaab DF, 2007]? Courchesne et al. didn’t mention the surge; some of the infants they studied were girls.

Herbert reviewed the pathology of these large brains in ASD: disproportionate proliferation of white matter, yet diminished connectivity, and neuroinflammation and astrogliosis [Herbert MR, 2005]. She and her colleagues previously found the increased brain volume was confined to the subcortical white matter, especially in the frontal lobes, and did not include the deep white matter, e.g. corpus callosum: “This lack of expected association between radiate compartment and corpus callosum volume suggests that the white matter volume increase predominantly involves short and medium-range corticocortical connections within hemispheres, with less, if any, involvement of connections between hemispheres.” [Herbert MR, 2004] Intrahemispheric white-matter tracts are testosterone-dependent; interhemispheric white-matter tracts estrogen-dependent [Baron-Cohen S, 2005]. If postnatal brain overgrowth in ASD is catch-up growth, overgrowth of testosterone-dependent structures implies prenatal undergrowth of the structures. Yet insufficient estradiol might also explain smaller brains at birth. But then why doesn’t postnatal brain overgrowth favor estrogen-dependent structures?

These arguments have also been posted online in my paper Chronic neurochemical cerebral asymmetry and dysconnection in autism. Implications of a personal trial of oral citrulline + taurine at: http://www.autismstudies.net

references

Baron-Cohen S, Knickmeyer RC, Belmonte MK. Sex differences in the brain: implications for explaining autism. Science 2005;310: 819–823.

Cockerill J, Uthaya S, Doré CJ, Modi N. Accelerated postnatal head growth follows preterm birth. Arch Dis Child Fetal Neonatal Ed 2006;91:F184–F187.

Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism. JAMA 2003;290(3):337–344.

Frith U. Autism and Asperger Syndrome. Cambridge, England: Cambridge University Press; 1991.

Herbert MR, Ziegler DA, Makris N, Filipek PA. Kemper TL. Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol 2004;55:530–540.

Herbert MR. Large brains in autism: the challenge of pervasive abnormality. Neuroscientist 2005;11:417–440.

Jacklin CN, Maccoby EE, Doering CH. Neonatal sex-steroid hormones and timidity in 6-to-18-month-old boys and girls. Dev Psychobiol 1983;16:163–168.

Konner M. The Tangled Wing. Biological Constraints on the Human Spirit. New York: Holt, Rinehart and Winston; 1982.

Markram K, Markram H. The intense world theory – a unifying theory of the neurobiology of autism. Front Hum Neurosci 2010;4:224.

Swaab DF. Sexual differentiation of the brain and behavior. Best Pract Res Clin Endocrinol Metab 2007;21:431–444.

Taylor GT, Dearborn JT, Maloney SE. Adrenal steroids uniquely influence sexual motivation behavior in male rats. Behav Sci 2012;2:195–206.

Ward IL. Prenatal stress feminizes and demasculinizes the behavior of males. Science 1972;175:82–84.

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 Aug 28, Niall Duncan commented:

Dr Bishop raises some interesting points. I can't add to those regarding reading ability per se but can perhaps add some information relevant to the MRS-related ones.

Glutamate concentrations appear to be stable over the relevant age range, as do choline concentrations (Dezortova M, 2008 ; Blüml S, 2013). [A longitudinal study in rats has found a continuing increase in Glx over the lifespan which with the higher field strength may be worth taking into consideration (Morgan JJ, 2013).] Creatine concentrations appear to change over the relevant period, which could be an issue as this is taken as the reference substance in the paper. The authors look at this possibility though and say that there is no relationship between reading ability and creatine. I still find it odd that they don't report the age and tissue proportion corrected partial correlations as their main findings as taking these into account is pretty standard in the MRS literature. [That it is standard does not of course mean that it is right and the authors may be able to give a convincing argument as to why their approach is better.]

Also curious is that they don't report anything about glutamine concentrations. As far as I can tell from the methods these are measured (fully accepting that I could be misreading what they have done). There has been a lot of conflation of glutamate with glutamate+glutamine (Glx) in the literature as not all methods allow these to be reliably separated. The two things are not equivalent however. Some clarification along these lines in the case of this paper would be nice.

MRS is probably best described as a trait measure. There are some so-called "functional MRS" studies that find changes in metabolite (generally glutamate or lactate) concentrations when a task is performed. Normally, though, measurements are made "at rest" over a period of 10-20 minutes.

The test-retest reliability of MRS varies between different acquisition/analysis methods, regions, and metabolites. For Glx the CoV seems to be around 7% and for GABA 10%. For creatine it seems to be closer to 5% (relevant where this is taken as the reference substance). Glutamine has poor reproducibility (CoV over 20%), which is worrying when trying to separate this signal from glutamate. These numbers are from adults though and might be different in children.

Related to the difference between children and adults, the issue of head movement is one that has not yet been properly addressed in the MRS literature. These is some evidence that choline concentrations are particularly affected by head motion (Andrews-Shigaki BC, 2011). It could therefore be the case that the children towards one end or the other of the reading score distribution tend to move more (differences in boredom thresholds or suchlike?).

Metabolite concentrations do differ between different parts of the brain but the question is whether they are correlated with each other or not. I'm not aware of anybody specifically testing this yet. It is thus possible that the occipital cortex is acting as a correlated "proxy region" for a different region that is more directly linked to reading. This question of specificity is, I believe, an important one for MRS studies. Alternatively, my naive first take would be that doesn't seem so unlikely that metabolite levels in the visual system are related to "higher-level" functions such as reading.

A few papers that interested people might find useful are:

• An excellent overview of the metabolites being measured with MRS (Rae CD, 2014).
• A review of MRS techniques for measuring Glx (Ramadan S, 2013).
• A review of MRS techniques for measuring GABA (Puts NA, 2012).
• A discussion of how to combine MRS with other measures (Duncan NW, 2014).
• A review of the multimodal imaging (i.e., combining MRS with other measures) literature to date (Duncan NW, 2014).

[Disclaimer - the last two are by colleagues and me.]

On 2014 Sep 21, Bernard Baars commented:

Dear Leonard, --- I admire your range of interesting papers on fundamental questions.

In regard to esthetic pleasure and behavior, I would call your attention to a sizable evolutionary anthropology literature on the cost of social display of primary and secondary sexual signals --- the classical case being the male peacock.

Dan Zahavi called this the Handicap Principle in 1975, and the idea is essentially that sexual selection for mating with the fittest available other-gender mates is so important as an evolutionary driver (only comparable to individual survival itself) that hominins like us, and all of our ancestors among primates, mammals and vertebrates, dedicated a great percentage of biological resources to it. The male peacock posing for sexual selection (by the well-camouflaged females) is endangering his life by attracting predators (by blatant visual, auditory, and presumably olfactory signaling.) The female peahen takes no such chances. Thus the male handicaps himself to look beautiful, and interestingly, humans have used peacock feathers historically to decorate themselves as well.

It is precisely the apparently inutility of esthetic enjoyment that is evolutionarily important, along the lines of Thorstein Veblen's "conspicuous consumption." Biologically, the male peacock is signaling "looking how strong and fertile I am!!!" I can even afford to waste immense personal risk of predation, great metabolic energy, attacks from competing males in heat, the strength to shiver my tail feathers and preen for hours, simply to attract the best female! What healthy offspring we shall have! The easy analogy would be to men who buy muscle cars or Cadillacs when they could drive a mini-car instead. Among recent entertainment stars, Kim Kardashian and her many imitators among women spending hugely on breast and buttocks enlargements imitates varieties of H sapiens sapiens morphology among peoples who evolved large breasts, steatopigous buttocks, and large stomachs in evolutionarily recent times. Fat storage is a great advantage in certain climates (Siberian-descended Inuits and Amerindians are a good example), but encounter handicaps to survival in the face of massive droughts and famine conditions. Since human ancestors are known to have encountered massive drought conditions in the desertification of the Sahara in the millennia prior to the "African Exodus," when the Hss population is thought to have collapsed to 5,000 individuals in North East Africa, famine-adaptibility is plausibly a major Darwinian constraint on human survival.

(Note that the term "African Exodus" does not apply to African humans who escaped the desertification of the Sahara by migrating southwards, and who never left Africa. Nor does it apply to the peoples who remained sub-Saharan, such as plausibly the Khoi San of the Kalahari Desert. Khoi San body morphology is gracile rather than robust, as befits a desert-dwelling people, and their cultural and personal knowledge of semi-arid survival tactics is vast.)

Nicholas Wade has also pointed out the fact that tribal peoples very often perform frequent, vigorous and long-lasting community dancing, and universally harbor other-worldly religious beliefs, which are thought to enhance group harmony and therefore survival. (Mating in tribal peoples tends to obey strict kinship rules, either within the birth group, or between allied groups). The very wide distribution of these human cultural habits has been very well studied since the publication of Stephen Brown's Human Universals (1992) (also called Cultural Universals today).

In human evolution the earliest evidence for artificial body decoration comes from human-related diggings in South Africa of ancient colored clay deposits, thought to have been used for spectacular body decoration by men and women, especially during and after puberty. (At least 200KYA) Personal jewelry involving trading over sizable distances, such as seashells found far from their origins in North Africa, are also ancient. In more recent years mating-related body decoration, hair styles, special clothing, vigorous dancing, music-making, singing and use of instruments (!), seductive movements and gestures, open competition within genders, verbal facility, display of cooking and hunting skills, and an essentially unlimited number of novel attention-catching behaviors can be related to sexual display. Among the American Sioux the male warriors showed their physical size (often 6' or taller), and created new clothing fashions each year (while the women took a more modest role). "Counting coup" --- rushing into an enemy village, physically touching a fierce enemy warrior, and rushing out again to safety was a quantitative measure of masculine heroics. Precisely analogous behavior can be seen today in ever-changing female fashions, in male body building, and in military uniforms for men, including medals and honor ribbons displayed on the left chest, reflecting both combat experience, military skills, and rank in the male hierarchy. The bodily posture of "pride" is also on display (see palace guards throughout Europe, including the Kremlin in Russia). Mammalian positions of pride are anti-gravity postures (head back, body erect, goose-stepping high) which require great physical training, and which oppose the body posures of social defeat, depression and surrender (head down, bowing low, slow non-threatening approach to the victors, etc.) Notice that we instantly recognize those body postures in lions, horses, and humans --- the standard Napoleonic pride statue in European capitals is a proud-looking man on a horse, bearing a sword. The upward direction of the sword, spear or rifle in heroic sculptures may hark back in evolution to the upward-pointing position of the penis during courtship display in our primate relatives. In classical art this is highly visible in 19th century paintings of Napoleon on a white horse, surrounded by battle. The link between male heroics, female fashions, secondary and primary sexual signals, music and the arts is unavoidable in the art of the Romantic period in Europe.

Notice that this bio-anthropological hypothesis accounts for a number of features of esthetics you have raised in your interesting article.

On 2014 Feb 28, Jessie Tenenbaum commented:

This is a great paper for people like me who think about p-values, and yet are by no means statisticians- highly recommended.

I've been trying wrap my head about the fact that p-value does NOT mean the likelihood my hypothesis is correct. Here's what I've come up with:

I could hypothesize that a given male subject has only Y-containing sperm. We could then do the experiment of having him mate 5 times. If all 5 progeny come out as male, the p-value is under .05. That is, there is less than 5% chance those results could be observed by random chance. BUT that does NOT mean there is less than 5% chance that I am wrong, because it was a "long shot" (to use the article's phrase) to begin with.

Does that seem right? Any other examples that would better illustrate this point?

On 2014 Apr 26, Gonzalo Sanchez commented:

In order to explain concurrent signs of spastic hemiparesis with bleeding from the nose and the ear in the closed head injury of Case # 8 of the Edwin Smith Papyrus, JC Ganz states that recent trauma must have occurred in a patient with an already existing hemiparesis. This would be a good explanation if the Papyrus were describing a specific injury in a specific patient. The Edwin Smith papyrus is, rather, a teaching trauma treatise of “Case Types” with Case #8 addressing Closed Head Injuries. Sanchez and Meltzer (2012)1 note (p.5) their clinical interpretation is based on the textual evidence and the structure of the original document.<br> In Appendix II these authors acknowledge Case #8a as a closed head injury that has passed the acute stage “ as development of spasticity takes several weeks”. Fresh bleeding through the nose and the ears would indeed be unlikely present at this stage. Apparent inconsistencies in these clinical issues may be simply related to the various findings observed by the ancient Egyptians in cases of the same type. It is our opinion that strict criticism of the ancient physicians’ clinical methodology in structuring and documenting their teaching text cannot be applied using current criteria.

Gonzalo M. Sanchez MD. and Edmund S. Meltzer Ph.D. gonzalosanchez411@gmail.com

1 Sanchez GM and Meltzer ES. The Edwin Smith Papyrus – Updated Translation of the Trauma Treatise and Modern Medical Commentaries. Lockwood Press. Atlanta Ga. 2012.

On 2014 Feb 01, Jan Tunér commented:

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

On 2014 Jan 24, Tom Kindlon commented:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Message has reached word limit - references are reply)

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

On 2014 Jul 02, Valeria Fadda commented:

Gastrointestinal adverse events of bisphosphonates

Valeria Fadda HTA Unit, Area Vasta Centro Toscana, Regional Health System, Via San Salvi 12, 50100 Firenze (Italy)

In the paper by Tadrous et al. [1], the gastrointestinal safety of bisphosphonates in primary osteoporosis has been assessed. In particular, the safety end-point has been compared for individual agents (i.e. alendronate, zoledronate, risedronate or etidronate) versus placebo; some head-to-head comparisons between active agents were studied too. The original analysis by Tadrous et al. expressed these outcomes according to the outcome measure of odds-ratio (OR). However, since the outcome measure of risk difference (RD) is preferable for analyses aimed at equivalence testing, we have repeated the meta-analysis by Tadrous using RD in substitution for OR. Our results are shown in Figure S1.

Figure S1. Standard pair-wise meta-analysis of the incidence of gastrointestinal adverse events: Forest plot of risk differences for a series of comparisons involving alendronate, risedronate, etidronate, zoledronate, and placebo (data of 103 study arms from 51 randomized trials). The horizontal bars indicate the two-sided 95% confidence interval for RD of individual trials (solid squares) or of subgroup meta-analysis (yellow diamonds). Abbreviations: AE, adverse event; RD, risk difference; P, placebo; A, alendronate; R, risedronate; E, etidronate; Z, zoledronate; Ev, events; Trt, number of patients in the treatment groups; Ctrl, number of patients in the control groups.

This figure is available at url http://www.osservatorioinnovazione.net/papers/figures1fromtadrous.jpg

References

1. Tadrous M, Wong L, Mamdani MM, Juurlink DN, Krahn MD, Lévesque LE, Cadarette SM. Comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis. Osteoporos Int. 2014 Apr;25(4):1225-35. doi: 10.1007/s00198-013-2576-2

On 2014 Oct 15, Amanda Capes-Davis commented:

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

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

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

On 2013 Nov 25, Dennis Eckmeier commented:

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

On 2016 Jan 10, Paul Harch commented:

The response by Dr. Cifu is non-responsive to the scientific points raised in my Comment. In keeping with the purpose of PubMed Commons, an open, non-personal scientific exchange, the request is repeated to respond to the scientific points raised, specifically: 1. Cifu, et al,¹ and all of the DoD HBOT TBI studies,² are dose-finding non-controlled studies, according to a physiologic scientific definition of HBOT. None of them are sham controlled. 2. Cifu, et al,¹ showed no effect of 3 combination doses of hyperbaric therapy on mTBI PPCS and PTSD except in the 2.0 ATA 100% oxygen group which demonstrated a statistically significant improvement in PTSD symptoms. 3. Cifu, et al,¹ attributes the positive outcomes of civilian and other DoD-sponsored HBOT TBI studies to non-treatment effects such as placebo, relocation to a subtropical environment, Hawthorne Effect, etc., yet 5 of 6 outcomes for Cifu, et al,¹ are not positive. 4. This author is requesting that Dr. Cifu and co-investigators reconcile their neutral results with the positive and negative results of other studies on the same subject population. The maximal salutary environment of Pensacola, FL should have generated the most positive results of all studies, if in fact the outcomes are due to the non-treatment effects enumerated by Cifu, et al,¹ yet it did not. The major differences in all of these studies were the doses of hyperbaric therapy employed. The doses in Cifu, et al¹ were ineffective. 5. The claim that the results of HBOT in acute severe TBI are “inconclusive” is contrary to the results of multiple randomized trials.

The points raised in the previous Comment and this Rebuttal are not “…any of a shifting number or false arguments…” They are the same points raised in the peer-reviewed published Letter to the Editor (LTE),³ of the Wolf/Cifu, et al,⁴ paper which informed the data of Wolf/Cifu, ,⁴ et al, and invalidated their conclusions. To this date, the authors have not responded to this Letter to the Editor. I would ask Dr. Cifu again to review the referenced sampling in that LTE³ and the plethora of scientific literature accumulated over the past 70 years showing that small increases in ambient pressure are bioactive across the entire phylogenetic spectrum, including humans.⁵ This is old science just recently brought to the fore³ in the clinical hyperbaric medicine community and is best described as an inconvenient truth, rather than “ridiculous and embarrassing.” Instead of addressing this science Dr. Cifu has lodged the convenient claim of financial incentive to dismiss my Comment: “…the clinicians and lobbyists who make their livings using HBOT for a wide range of neurologic disorders…” This evasive charge was previously lodged by VA researchers in a critique⁶ of this author’s report⁷ and addressed by this author.⁸ The charge is inconsistent with nearly three decades of basic science and clinical research and more consistent with the conflict of interest of VA researchers.⁸ A final point: in no publication has the claim regarding effectiveness of HBOT in mTBI PPCS been predicated on an exclusive or even dominant anti-inflammatory effect of HBOT. Rather, the argument is based on the known micro-wounding of brain white matter in mTBI,⁹ and the known gene-modulatory,¹⁰ trophic wound-healing effects of HBOT in chronic wounding.¹¹ The preponderance of literature in HBOT-treated chronic wound conditions,¹¹ is contrary to Dr. Cifu’s statement of HBOT as a “useless technology.”<br> The implications of getting this science correct and clarifying the confusion in the medical and lay community caused by the confounding DoD studies’ conclusions are enormous. Millions of civilians and brain-injured military service personnel with PPCS or residual neurocognitive sequelae of moderate and severe TBI can be helped by this biological repair therapy. The only “false hope” by patients would be in Cifu, et al,¹ where the patients, by and large, did not improve. In nearly all other studies where proper doses of hyperbaric therapy were employed the “false hope” resulted in positive outcomes.

References:

1. Cifu DX, et al. J Head Trauma Rehabil. 2013 Sep 18. [Epub ahead of print]. DOI: 10.1097/HTR.0b013e3182a6aaf0.<br>
2. Weaver LK, et al. Undersea Hyper Med. 2012;39(4):807–814.
3. Harch PG. J Neurotrauma. 2013 Oct 11. [Epub ahead of print]. doi:10.1089/neu.2012.2799.
4. Wolf G,et al. J Neurotrauma. 2012;29:1–7.
5. Macdonald AG, Fraser PJ. Comparative Biochemistry and Physiology Part A. 1999;122:13-36.
6. Wortzel HS, et al. J Neurotrauma. 2012;29(14):2421-4.
7. Harch PG, et al. J Neurotrauma. 2012;29:168–185.
8. Harch PG, et al. J Neurotrauma. 2012;29:2425-2430.
9. Ryu J, et al. (2014). Acta Neuropathologica Communications. 2014;2:153.
10. Godman CA, et al. Cell Stress Chaperones. 2010;15:431–442.
11. Gesell LB, ed. Hyperbaric Oxygen Therapy Indications. The Hyperbaric Oxygen Therapy Committee Committee Report. 12th ed. Durham, NC: Undersea and Hyperbaric Medical Society;2008.

On 2016 Jan 02, Paul Harch commented:

Cifu, et al¹ characterize the Department of Defense HBOT TBI studies^1-3 as sham-placebo controlled clinical investigations. A sham group “omits a key therapeutic element of the treatment or procedure under investigation”⁴ and a placebo must be inert.⁵ The key therapeutic elements in hyperbaric therapy are pressure and hyperoxia, neither of which are inert.⁶ Therefore, Cifu et al¹ is neither sham, placebo, nor controlled; all groups contain either increased pressure, hyperoxia, or both.^6,7<br> Cifu, et al¹ define HBOT as involving “…breathing high levels of oxygen…at… at least 1.4 times greater than …(1 atmosphere absolute…ATA)…. ¹ This non-physiologic definition sets an arbitrary threshold for HBOT that excludes the contribution of lesser elevated pressures and degrees of hyperoxia (e.g. 1.39999 ATA hyperbaric oxygen is not HBOT?). Hyperbaric oxygen therapy is a combination intervention of increased pressure and hyperoxia,^6,7 that up- and down-regulates both independent and overlapping pressure and oxygen-sensitive genes^6,8-10 to produce well-known clinical effects.¹¹ Cifu et al¹ purported to test the doses of HBOT in previous publications.^12-14. It did not. Cifu et al¹ studied 3 composite doses of hyperbaric therapy by using different doses of oxygen, a single dose of pressure (2.0 ATA), and changing doses of oxygen and pressure during compression and decompression that have not been previously tested in mTBI/PPCS and PTSD. Cifu, et al¹ stands in contrast to Wolf, et al^2, which initially showed statistically significant beneficial effects of two different composite doses of hyperbaric therapy in mTBI/PPCS and PTSD (1.3 ATA air and 2.4 ATA 100% oxygen), and other studies using 1.5 ATA 100% oxygen.^12,15-17 (Wolf, et al’s² findings have been qualified in a subset analysis that demonstrated a trend toward harm with 2.4 ATA oxygen in PPCS).¹⁸ According to Cifu, et al^1, the results of Wolf, et al² and “…prior case reports^14,19-22 are explained by factors other than the effect of HBO2 on PPCS,” i.e., placebo, relocation, reduced duty schedules, Hawthorne Effect, leisure time and activities in a noncombat, semitropical beach environment, and other non-biologic effects of the hyperbaric chamber experience. This explanation has merit if Cifu, et al’s¹ data were uniformly positive. However, it is not, despite the maximal salutary environment of Pensacola, FL. The most logical explanation for Cifu, et al’s¹ data is the independent and differing bioactivity of different combination doses of pressure and hyperoxia on gene expression. ^9,10 Cifu, et al¹ have demonstrated the ineffectiveness of 2 new composite doses of hyperbaric therapy on PTSD and 3 new doses on PPCS, and the effectiveness of one dose on PTSD. The PPCS findings are consistent with the literature on HBOT in chronic traumatic brain injury cited by Cifu and others^{1-3,6,7,12-16,23} that reveal no evidence for the effectiveness of 2.0 ATA of pressure or oxygen on chronic TBI, and negative/toxic effects ≥ 2.0 ATA in acute severe TBI.^24,25 Cifu, et al¹ finish with a claim that the results of HBOT in acute severe TBI are “inconclusive.” There are five randomized clinical trials on HBOT in acute severe TBI,^26-30 a comparative dosing study,²⁵ and two Cochrane reviews^21,31 demonstrating a significant reduction in mortality^26,28-31 (~60%) and improvement in outcome.^25-27,29,30 There is nothing inconclusive about this data, however it’s inclusion in a report on mTBI PPCS is inappropriate. In summary, Cifu, et al¹ is mis-described as a sham placebo controlled study based on a non-physiologic definition of hyperbaric therapy that omits the bioactivity of increased pressure. On this foundation Cifu, et al¹ combine their data with Wolf, et al² and offer sweeping erroneous conclusions about the effectiveness of hyperbaric therapy in PPCS of mTBI and acute severe TBI. Cifu, et al¹ is a 3 dose study of different combinations of pressure and oxygen that demonstrates the ineffectiveness of two doses of hyperbaric therapy in patients with PPCS and PTSD and the effectiveness of a third dose in PTSD and possibly PPCS. Their data complement the effectiveness of multiple other doses of hyperbaric therapy in mTBI PPCS^{2,12,15-17,23} and PTSD^2,12,15,17 which they refer to incorrectly as showing “no symptom relief with HBO2,” and an animal model of HBOT in chronic mTBI.³² The Cifu,¹ Wolf,² and civilian studies^12,15,16 must be appreciated In terms of the effects of different doses of hyperbaric therapy (increased pressure and hyperoxia) on PPCS and PTSD whose doses have different physiologic and gene profiles. Some of these doses are effective while others are not. Conflict of Interest: The author is the co-owner of Harch Hyperbarics, Inc., a C-corporation that provides expert witness testimony and hyperbaric consulting. References: 1. Cifu DX, et al. J Head Trauma Rehabil. 2013 Sep 18. [Epub ahead of print]. DOI: 10.1097/HTR.0b013e3182a6aaf0.<br> 2. Wolf G, et al.. J Neurotrauma. 2012;29:1–7. 3. Weaver LK, et al. Undersea Hyper Med. 2012;39(4):807–814 4. Sham. Available at: http://www.merriam-webster.com/medical/sham. 5. Placebo. Available at: http://medical-dictionary.thefreedictionary.com/placebo+effect. 6. Harch PG. J Neurotrauma. 2013 Oct 11. [Epub ahead of print]. doi:10.1089/neu.2012.2799. 7. Harch P. Undersea Hyper Med. 2013;40(5):469-70. 8. Godman CA, et al. Cell Stress Chaperones. 2010;15:431–442. 9. Chen Y, et al. Neurochem. Res. 2009; 34:1047–1056. 10. Oh S, et al. Cell Stress and Chaperones. 2008;13:447-458. 11. Gesell LB, ed. Hyperbaric Oxygen Therapy Indications. The Hyperbaric Oxygen Therapy Committee Committee Report. 12th ed. Durham, NC: Undersea and Hyperbaric Medical Society;2008. 12. Harch PG, et al. J Neurotrauma. 2012;29:168–185. 13. Rockswold SB, et al. J Neurosurg. 2010;112:1080–1094. 14. Harch PG. In: Joiner JT, ed. Proceedings of the 2nd International Symposium on Hyperbaric Oxygenation for Cerebral Palsy and the Brain-Injured Child. Flagstaff, AZ: Best Publishing Co;2012:31–56. 15. Harch, PG, et al. Cases Journal. 2009;2:6538. http://casesjournal.com/casesjournal/article/view/6538. 16. Wright JK, et al. Undersea Hyper Med. 2009;36:391–399. 17. Data on Cifu, et al1, Wolf, et al3, and HOPPS Army study presented at the 46th Annual UHMS Scientific Meeting in Orlando, FL 6/15/2013 in a special symposium. 18. Scorza KA, et al. Abstract C27, Friday, 6/14/2013, 8:12 a.m. Undersea and Hyperbaric Medical Society Annual Meeting, Orlando, FL. 19. Rockswold SB, et al. Neurol Res. 2007;29(2):162–172. 20. Bennett MH. Extrem Physiol Med. 2012;1(1):14.<br> 21. Bennett MH, et al. Cochrane Database Syst Rev. 2004;(4):CD004609. 22. McDonaugh M, et al. Arch Phys Med Rehabil. 2004;85(7):1198-1204. 23. Harch PG, et al. Hyperbaric oxygen therapy in global cerebral ischemia/anoxia and coma. In: Jain KK, ed. Textbook of Hyperbaric Medicine, 5th revised edition Chapter 19. Seattle, WA: Hogrefe and Huber Publishers;2009:235–274. 24. Holbach KH, et al. J Neurol. 1977;217:17-30. 25. Holbach, KH. In: Schurmann K, ed. Advances in Neurosurgery, Vol. 1. Berlin: Springer;1973:158-163. 26. Holbach KH, et al. Acta Neurochir (Wien). 1974;30:247–256, (Ger) 27. Artru F., et al. Eur Neurol. 1976;14:310-318. 28. Rockswold GL, et al. J Neurosurg. 1992;76:929–934. 29. Ren H, et al. Chinese Journal of Traumatology (English Edition). 2001;4(4):239-241. 30. Rockswold SB, et al. J Neurosurg. 2013;118(6):1317-28. 31. Bennett MH, et al. Cochrane Database Syst Rev. 2012;12:CD004609. doi: 10.1002/14651858.CD004609.pub3. Review. 32. Harch, PG, et al. Brain Res. 2007. 1174, 120–129.

On 2014 Feb 20, Jacob Puliyel commented:

Tozzi and colleagues state that their article describes the new tool for causality assessment of AEFI as set out in the User Manual for the Revised WHO Classification

1) However this manual it seems has been developed without adequate care and without thinking through the consequences of the changes.

a) One pointer to this is how the manual cites an example of vaccines being wrongly blamed for events unrelated to its administration (Page 13). It says that vaccines were wrongly blamed for deaths resulting from consumption of the Cassia occidentalis beans causing a syndrome of acute hepato-myoencephalopathy. However the article they quote describes Japanese B encephalitis being blamed for the deaths – not the vaccine Panwar RS, 2008

b) Dr Madhavi put the new classification to a simple test. She tested how the system would have responded if the revised AEFI classification been in place in 1999. She suggests that the intusussceptions following use of RotaShield would have been classified as ‘inconsistent with causal association’ because:

i) other qualifying factors like previous similar reaction (re-challenge equivalent) were not available

ii) nor was biological plausibility demonstrated at that time

iii) and background rate, other exposures etc were not ruled out.

Under this category ‘inconsistent with causal association’ it would never activate the analysis reserved for ‘indeterminate’ reactions – “Information on AEFIs that are classified as indeterminate should be pooled and analyzed by time and place, in order to understand if the AEFI represents a new signal of an unrecognized event. Should this be the case, a more comprehensive epidemiological investigation should be performed.” Tozzi AE, 2013

These intusussceptions would have continued for years before the vaccine was pulled off the shelves.

2) In my previous comment I had pointed out that the experts investigating the Sri Lanka deaths from Pentavalent vaccine deleted the categories ‘Probable’ and ‘Possible’ from the Brighton classification and reported that although they found no alternate explanation for the deaths, the deaths were unlikely to be related to the vaccine. An apologist for the distorted Brighton Classification told me at that time that it was ‘experts’ who developed the Brighton Classification and it is alright for other experts to alter the classification. That was prescient. The new system makes a virtue of this ability to disregard the algorithm when it suits any expert. It says “Finally, instead of assigning a final category through an automatic classification process, the final outcome of the case investigation depends on the personal judgment of the assessor.” Tozzi AE, 2013

3) Post marketing surveillance is used to monitor the safety of a drug. Since drugs are approved on the basis of clinical trials which involve a relatively small numbers of people who have been selected for this purpose - meaning that they normally do not have other medical conditions which may exist in the general population - post marketing surveillance can further refine, or confirm or deny, the safety of a drug after it is used in the general population by large numbers of people who have a wide variety of medical conditions. (Abridged from Wikipedia)

The effort of the revised WHO Causality assessment of an AEFI is to deny adverse events noticed on post marketing surveillance, are caused by the vaccine (unless they had been observed in the original small clinical trials).

Events that occur 1 in 10,000, for example the intussusceptions with RotaShield will be noticed only in post marketing surveillance.

The AEFI in individuals was responsible for the ‘signal’. Evidence of causality in the individual provided evidence of causality in the population. The new system stands this logic on its head when it says on Page 5 that causality in the population must be known before causality in the individual can be ascribed.

“Causality assessment of AEFI should be performed at several different levels. The first is the population level, where it is necessary to test if there is a causal association between the use of a vaccine and a particular AEFI in the population. Secondly, at the level of the individual AEFI case report, one should review previous evidence and make a logical deduction to determine if an AEFI in a specific individual is causally related to the use of the vaccine. The third level of assessment is in the context of the investigation of signals.”

I am not stating that there is something sacrosanct about the original Brighton Classification but one has to evaluate the two schemes (Brighton vs CIOMS) from the point of view of patient safety to see which scheme would react to rare RotaShield-like-reactions first. The causality scheme that insists on calling all reactions as ‘indeterminate’ or ‘inconsistent/coincidental’ just because they were not noticed in the original small clinical trials, undermines the very raison d'être of post marketing surveillance. Patient safety (meaning protecting patients) rather than vaccine safety (protecting vaccines) is what is important.

On 2015 Aug 23, David Keller commented:

Information theory contradicts Guideline Statement 4: more frequent PSA testing should benefit patients, not harm them

Information theory describes the reconstruction of continuous signals from discrete samples, and the extraction of signals from noise. Screening for prostate cancer involves scrutiny of a man's serial PSA measurements, with the goal of determining the likelihood that his prostate has developed a malignancy which could affect his longevity or quality of life (ie: his mortality or morbidity). Statement 4 from the 2013 Early Detection of Prostate Cancer: AUA Guideline [1] is as follows:

"Guideline Statement 4: To reduce the harms of screening, a routine screening interval of two years or more may be preferred over annual screening in those men who have participated in shared decision-making and decided on screening. As compared to annual screening, it is expected that screening intervals of two years preserve the majority of the benefits and reduce over diagnosis and false positives. (Option; Evidence Strength Grade C)"

Guideline Statement 4 can be proved false using the principles of information theory as follows. Individual PSA blood test results constitute discrete samples of the continuous signal which would result from continuous monitoring of the patient's PSA. The Nyquist-Shannon Sampling theorem states that the minimum sampling rate for perfect reconstruction of a signal is equal to twice the bandwidth of the signal [1]. Expressed another way, the maximum bandwidth of a signal to be perfectly reconstructed from samples taken at a sampling frequency f is f/2.

The crucial signal we wish to detect is a rising PSA consistent with a dangerous prostate cancer. Empirically, the faster a prostate cancer grows, the more rapid the rise in PSA and therefore the higher the bandwidth of the PSA signal. We would like to detect PSA signals which rise rapidly (have high bandwidth) in order to treat the patient while his cancer is confined to his prostate. The more frequently we sample the PSA, the higher the bandwidth of the PSA signal we can detect, meaning the more rapid rises in PSA will not escape detection. So, increasing the PSA sampling rate from once every 2 years to once every year can only improve the detection of the high-bandwidth signal caused by a rapidly growing prostate cancer. In fact, increasing the PSA sampling rate to twice per year, 4 times per year or even higher will only increase the maximum detectable bandwidth of the PSA signal.

Harms associated with PSA screening are generally associated with the prostate biopsy procedure and downstream diagnostic and therapeutic intervetions. The purpose of PSA sampling is to inform us when a prostate biopsy is likely to be more beneficial than harmful. The cumulative harm of multiple biopsies is proportional to the number of biopsies done, so we want to minimize the number of biopsies without missing a dangerous cancer. However, if the PSA signal includes useful information about the presence of cancer, the best way to reduce the number of biopsies is to improve the quality (bandwidth) of the detected PSA signal, which requires increasing the PSA sampling rate.

Reducing the PSA sampling rate in an attempt to reduce the harms caused by prostate biopsy is akin to hiding one's head in the sand. Continuous monitoring of the PSA signal would be ideal, but the maximum practical PSA sampling frequency should be employed to maximize the quality of the reconstructed PSA signal, and thereby increase the likelihood of detecting a fast-growing tumor while it is confined to the prostate. Application of a low-pass filter to the PSA signal should reduce the number of biopsies triggered by noise.

Lastly, the prostate biopsy rate need not be correlated with the PSA sampling rate, and indeed should be inversely correlated with it if the PSA signal has useful information about the presence of dangerous cancer in the prostate.

Reference

1: Shannon CE, Communication in the presence of noise, Proc. Institute of Radio Engineers, vol. 37, no. 1, pp. 10–21, Jan. 1949

On 2015 Apr 20, Ivan Oransky commented:

This paper has become the focus of a lawsuit: http://retractionwatch.com/2015/04/20/former-postdoc-suing-lab-head-for-publishing-paper-he-wrote-without-his-name/

On 2016 Apr 09, Lydia Maniatis commented:

For comments (and author reply) on the craziness of the claim of "orientation averaging" go here: https://pubpeer.com/publications/62E7CB814BC0299FBD4726BE07EA69

Additional craziness (based on conventional visual psychophysics wisdom):

"The voluntary averaging paradigm assumes that we perceive identical samples as slightly different due to noisy sample estimates (i.e. internal noise) and therefore have to average them to find a group estimate." And the contradiction: "However, voluntarily averaging different samples is a demanding task, and we can easily imagine that observers might see no reason to average samples that appear to be identical. Indeed, we do not often perceive identically oriented Gabors as having slightly different orientations except when their signal strength is weak (with brief or noisy presentation. [No citation for this last]. Indeed, we even perceive slightly different orientations as being identical (Morgan et al 2008). This could be due to a thresholding mechanism preventing us from perceiving our internal noise...."

A few things are worth noting. First, the authors seem to be claiming both that the samples don't look identical ("we perceive identical samples as slightly different") and that they do look identical "we do not often perceive identically oriented Gabors as having slightly different orientations." Which is it? Second, the fact that identical samples look identical in no way interferes with the authors "noise" belief system. They just explain it away on the basis of "a thresholding mechanism." But the noise paradigm, aside from being arbitrary, falls at the mere hint of a logical breeze.

Some things that should be taken into consideration: Some orientations are perceived with more precision than others (vertical, horizontal); we don't perceive orientation averages (see link above for discussion); differences in orientation in a field of oriented objects are subject to pop-out effects, not averaging effects.

The casual attitude towards assumptions that I've commented on frequently is of course on display here too: "This function is typically used [so it must be right] to quantify the averaging efficiency...and, based on the averaging model, this efficiency is assumed [in psychophysics, we can assume anything we want, whether Teller (1984) https://pubpeer.com/publications/70EEEA9EF5D6A4AE003C4559D2832C likes it or not] to be the same in low noise."

How many psychophysicists can dance on the head of a pin? I'm sure there's a model for that.

Also: It seems rather strange at first that there was a condition in which people's (supposed) estimation of “average orientation” was better for the case of four patches versus one patch. We can make sense of this if we consider the authors' methods and some of the conclusions of Solomon, May and Tyler (2015) (commented on also in the link above).

First, the location of the single patch in the periphery was both brief and unpredictable. This unpredictability was designed to avoid saccades to the object.

Second, Solomon, May and Tyler (2015) concluded that the observers were “averaging” one or two patches (because there's really no such thing as an orientation averaging percept). It's a little bit of a stretch to refer to an average of a single one out of a group of patches.

Now, in the single patch condition, it takes a little time to locate and focus attention on the single relevant object. In the four patch condition, the observer could already be focussed on any of the four locations, and base their response on that, perhaps they'd also have time to attend to a second one. Since they don't really consider more than one or two anyway, knowing where the patches are going to appear is an advantage, and explains the paradox.

The proper control (assuming the experiment had been worth doing in the first place) would have been to make the four-patch condition locations unpredictable as well. But instead, the authors contrive a strained interpretation in terms of orientation averaging in one “process” vs no orientation averaging in another.

On 2014 Mar 03, Andrea Messori commented:

Overlapping meta-analyses on novel oral anticoagulants in atrial fibrillation

The systematic review by Baker and Phung [1] is probably the most comprehensive analysis presently available on the comparative effectiveness of novel oral anticoagulants in patients with non-valvular atrial fibrillation. One problem for researchers who are interested in this topic is that PubMed now includes 13 meta-analyses or systematic reviews focused on this issue [1-13]. This confirms that a problem exists with multiple overlapping meta-analyses that study the same randomized trials published on the same topic [14,15]. However, there seems to be no simple solution to this problem.

Andrea Messori, HTA Unit, Regional Health Service 50100 Firenze ITALY

1. Baker WL, Phung OJ. Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2012 Sep 1;5(5):711-9.
2. Lip GY, Larsen TB, Skjøth F, Rasmussen LH. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2012 Aug 21;60(8):738-46.
3. Sardar P, Chatterjee S, Wu WC, Lichstein E, Ghosh J, Aikat S, Mukherjee D. New oral anticoagulants are not superior to warfarin in secondary prevention of stroke or transient ischemic attacks, but lower the risk of intracranial bleeding: insights from a meta-analysis and indirect treatment comparisons. PLoS One. 2013 Oct 25;8(10):e77694.
4. Assiri A, Al-Majzoub O, Kanaan AO, Donovan JL, Silva M. Mixed treatment comparison meta-analysis of aspirin, warfarin, and new anticoagulants for stroke prevention in patients with nonvalvular atrial fibrillation. Clin Ther. 2013 Jul;35(7):967-984.e2.
5. Biondi-Zoccai G, Malavasi V, D'Ascenzo F, Abbate A, Agostoni P, Lotrionte M, Castagno D, Van Tassell B, Casali E, Marietta M, Modena MG, Ellenbogen KA, Frati G. Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses. HSR Proc Intensive Care Cardiovasc Anesth. 2013;5(1):40-54.
6. Pink J, Pirmohamed M, Hughes DA. Comparative effectiveness of dabigatran, rivaroxaban, apixaban, and warfarin in the management of patients with nonvalvular atrial fibrillation. Clin Pharmacol Ther. 2013 Aug;94(2):269-76. doi:10.1038/clpt.2013.83.
7. Messori A, Maratea D, Fadda V, Trippoli S. New and old anti-thrombotic treatments for patients with atrial fibrillation. Int J Clin Pharm. 2013Jun;35(3):297-302.
8. Messori A, Maratea D, Fadda V, Trippoli S. Comparing new anticoagulants in atrial fibrillation using the number needed to treat. Eur J Intern Med. 2013 Jun;24(4):382-3.
9. Harenberg J, Marx S, Wehling M. Head-to-head or indirect comparisons of the novel oral anticoagulants in atrial fibrillation: what's next? Thromb Haemost. 2012 Sep;108(3):407-9.
10. Schneeweiss S, Gagne JJ, Patrick AR, Choudhry NK, Avorn J. Comparative efficacy and safety of new oral anticoagulants in patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2012 Jul 1;5(4):480-6.
11. Skjøth F, Larsen TB, Rasmussen LH. Indirect comparison studies--are they useful? Insights from the novel oral anticoagulants for stroke prevention in atrial fibrillation. Thromb Haemost. 2012 Sep;108(3):405-6.
12. Testa L, Agnifili M, Latini RA, Mattioli R, Lanotte S, De Marco F, Oreglia J, Latib A, Pizzocri S, Laudisa ML, Brambilla N, Bedogni F. Adjusted indirect comparison of new oral anticoagulants for stroke prevention in atrial fibrillation. QJM. 2012 Oct;105(10):949-57.
13. Mantha S, Ansell J. An indirect comparison of dabigatran, rivaroxaban and apixaban for atrial fibrillation. Thromb Haemost. 2012 Sep;108(3):476-84.
14. Moher D. The problem of duplicate systematic reviews. BMJ. 2013 Aug 14;347:f5040. doi: 10.1136/bmj.f5040.
15. Siontis KC, Hernandez-Boussard T, Ioannidis JP. Overlapping meta-analyses on the same topic: survey of published studies. BMJ. 2013 Jul 19;347:f4501. doi: 10.1136/bmj.f4501.

On 2013 Dec 19, Scott Federhen commented:

I am Scott Federhen, head of the GenBank taxonomy group, and author of his article. Since this article appeared, we have added a significant new feature to the taxonomy database - we have started to curate type material, and are using these data to flag sequence from type in Entrez. Sequence from type material is an important subset because the species identification is virtually certain to be correct (by definition) - but see Buddruhs N, 2013 for a rare cautionary example.

When a new species of prokaryote is described, the authors are required to designate a type strain and deposit it in at least two different culture collections. These are usually widely distributed between other culture collections and sold to researchers, so we have lots of sequence from type strains of prokaryotes, including many of our complete genomes.

When a new species of eukaryote is described, the authors are required to designate a type specimen and deposit it in a museum (or herbarium) where it is generally not available for subsequent sequence analysis (unless living cultures can be derived from the specimen, as with some of the fungi). We currently have very little sequence from type in the plants and animals, though it is becoming more common to include a little sequence with the description of new species - see Stoev P, 2013 for an extreme example.

See Salmonella enterica and Cercopithecus lomamiensis for examples of type material annotation in the taxonomy database.

The Entrez query sequence from type [filter] can be used to retrieve these sequence entries, and can be used in combination with other queries, e.g.: sequence from type [filter] AND metazoa[orgn].

sequence from type [filter] is also a very useful as an Entrez query to limit your BLAST searches to reliably identified sequences (particularly in the prokaryotes).

On 2013 Dec 06, Lorraine Johnson commented:

It is not possible to keep up. Stepping back down the food chain a moment to RCTs. Consider the use of RCTs to solve combination regimen questions. Answer: cannot be done in our lifetime. We need better (and faster) tools. The summation of these efforts will necessarily incorporate the weaknesses of the underlying data to provide answers. See Saver re combination regimen RCTs and duration to answer.Saver JL, 2001 "Strategies for testing combination regimens include: head to head trials of all combinations, which lead to unwieldy trial numbers; very large multi-arm trials, which impractically delay interval information on regimen utility; and hierarchical, serial clinical trials. Systematic literature review revealed seven classes of agents already approved or in late phase III testing for preventing the development or slowing the progression of Alzheimer disease and five for ischemic stroke prevention. Possible combination regimens number 128 (2(7)) for Alzheimer disease and 32 (2(5)) for ischemic stroke. Hierarchical, serial clinical trials would permit identification of the optimum combination of these agent classes for Alzheimer disease through 127 trials, enrolling 63,500 patients, requiring 286 years; for ischemic stroke through 31 trials, enrolling 186,000 patients, requiring 155 years."

On 2014 Jan 07, Tom Kindlon commented:

Does reduced similarity across timescales really mean reduced complexity?

Despite a good familiarity with the CFS literature and despite taking many mathematics courses in university, including a methods course which included some coverage of non-linear dynamics, I will admit to not fully understanding this paper. However, I think I will not be alone in that and so will put my head above the parapet and ask the following: This study found CFS cases (compared to controls) showed reduced dissimilarity within timescales as well as reduced similarity across timescales. This is summarised by the authors as CFS patients showing a reduction in complexity. But does the second finding not show the CFS cases demonstrated increased complexity compared to controls for that measure? For measurements within a timeframe, the controls are closer to the scores one would see with random patterns (4.75). For measurements across timescales, the scores of the CFS patients are closer to the scores one would see with random patterns (1.5).

On 2015 Oct 27, Peter Gøtzsche commented:

The authors report that escitalopram was significantly more effective than citalopram but caution against the “potential for overestimation of treatment effect due to sponsorship bias.” Indeed. Both substances were patented by Lundbeck, and the rejuvenated “me-again” drug, escitalopram, is merely the active half of the “old me” stereoisomer drug, citalopram.

One would not expect a molecule to be better than itself. I therefore suggest that the Cochrane review mention the results of a 2012 meta-analysis (1), also in the abstract and plain language summary. Independent researchers confirmed the Cochrane review’s findings that escitalopram was better than citalopram in head-to-head trials. All seven trials found this, apart from the single one that was not sponsored by Lundbeck or its affiliates. These researchers also did an indirect comparison of the two drugs based on 10 citalopram and 12 escitalopram placebo controlled trials (1), and now the effect of “me-again” and “old me” was very similar (odds ratio 1.03; 0.82 to 1.30).

Usually, direct comparisons are more reliable than indirect comparisons, but the drug industry routinely distorts its research to such an extent (2) that the indirect comparisons are sometimes the most reliable ones, which I believe is the case here. Lundbeck did not have any particular incentive to manipulate its placebo controlled studies more with escitalopram than with citalopram.

The Cochrane authors note that cost-effectiveness information is also needed in the field of antidepressant trials. Indeed. Even if we take Lundbeck’s results in its head-to-head trials at face value, there is no meaningful difference between the two versions of the drug. In one of Lundbeck’s own meta-analyses, the difference after eight weeks was 1 on a scale that goes up to 60 (2,3), which is totally irrelevant (4).

When I checked the Danish prices in 2009, Cipralex (escitalopram) cost 19 times as much for a daily dose as Cipramil (citalopram). This enormous price difference should have deterred the doctors from using Cipralex, but it didn’t. The sales of Cipralex were six times higher in monetary terms than the sales of citalopram both at hospitals and in primary care. I have calculated that if all patients had received the cheapest citalopram instead of Cipralex or other SSRIs, Danish taxpayers could have saved around €30 million a year, or 87% of the total amount spent on SSRIs.

1 Alkhafaji AA, Trinquart L, Baron G, et al. Impact of evergreening on patients and health insurance: a meta analysis and reimbursement cost analysis of ci¬talopram/escitalopram antidepressants. BMC Med 2012;10:142.

2 Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing; 2013.

3 Gorman JM, Korotzer A, Su G. Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectr. 2002; 7(4 Suppl. 1): 40–4.

4 Leucht S, Fennema H, Engel R, et al. What does the HAMD mean? J Affect Disord 2013;148:243-8

On 2013 Oct 24, Tom Kindlon commented:

Extremes In Activity Levels Of Those With Persistent Fatigue Were Not Investigated

I question the claim in Viner et al¹ that "being highly sedentary or highly active independently increased the risk of persistent fatigue, suggesting that divergence in either direction from healthy levels of activity increases the risk for persistent fatigue."

The authors themselves point out that their "definition of being physically active (1 hour of exercise on >=2 days per week) is roughly similar to the current recommendations for adolescents of the President’s Council on Physical Fitness and Sports and the National Association for Sport and Physical Education: “teens should do at least 20 minutes of vigorous activity 3 days a week and 30 minutes of moderate activity 5 days a week”.² So why is this level of activity, which was reported by 48.7% of the young people, being presented as being excessive? If they wanted to investigate being "highly active" (as opposed to simply being “active”), activity levels should not have been dichotomized at level they were in this study.

The question about sedentary activities was: “Outside school hours, on average, how many hours a day do you usually watch TV or videos, play video games, or play on the computer?” If a young person was sedentary for >4 hours a day, it does not mean they was necessarily inactive; indeed in phase 1, 23% of active young people were sedentary for more than 4 hours per day (compared with 30% of inactive young people). Such a lifestyle could be associated with fatigue for other reasons; for example, it could result in a shortage of sleep, rather than it necessarily causing unhealthily low levels of activity.

1 Viner RM, Clark C, Taylor SJ, Bhui K, Klineberg E, Head J, Booy R, Stansfeld SA. Longitudinal risk factors for persistent fatigue in adolescents. Arch Pediatr Adolesc Med. 2008 May;162(5):469-75.

2 Corbin CB, Pangrazi RP, Le Masurier GC. Physical activity for children: current patterns and guidelines. Res Dig. 2004;5(2):1-8.

On 2014 Jan 09, Tom Kindlon commented:

(contd.)

There are numerous pre-existing instruments out there that measure other symptoms associated with CFS. Off the top of my head, two that come to mind are the Chronic Fatigue Syndrome Symptom List and the CFS CDC Symptom Inventory. It encompasses the 19 most frequently reported symptoms in a sample of 1578 chronic fatigue syndrome patients[8]. In order to assess the severity of the symptoms included in the Chronic Fatigue Syndrome Symptom List, visual analogue scales (100 mm) are used. The Symptom Inventory "collects information about the presence, frequency, and intensity of 19 fatigue and illness-related symptoms" including the 8 CDC criteria symptoms. Perceived frequency of each symptom is rated on a four-point scale (1=a little of the time, 2=some of the time, 3=most of time, 4=all of the time), and severity or intensity of symptoms was measured on a three-point scale (1=mild, 2=moderate, 3=severe). To summarize the degree of distress associated with each symptom, individual symptom scores were calculated by multiplying the frequency score by the intensity score. The scoring would not have to be done like this - for example in the same paper I quoted from for the method of scoring above, the CDC team[8] used the following method: they "transformed the intensity scores into equidistant scores before multiplication (i.e., 0 = symptom not reported 1 = mild, 2.5 = moderate, 4 = severe) resulting in range 0–16 for each symptom." A total score for each person can be calculated by summing the 19 individual symptom scores (possible range from 0 to 304). A Case Definition score can be calculated as the sum of the 8 individual CFS case-definition symptom scores and an Other Symptoms score by considering only the 11 non-CFS symptoms.Calculating levels of various symptoms like this would have given a better overall idea of the health of the patients and how badly affected they were by "CFS/ME".

They could also have been used before and after the exercise testing.

In most management strategies these days, whether they're based on a graded exercise/activity model or a pacing model, patients are discouraged from "boom and bust" i.e. doing too much or pushing themselves and then crashing with lots of symptoms. Faced with the exercise testing, a patient who is good at avoiding "booming and busting" may not push themselves as hard as another patient. That does not mean they are not as well or do not manage their illness as well as another patient. One way of measuring whether this occurred with the exercise testing was if measures were used before and after the exercise testing. Given the post-exertional nature of many of the symptoms of "CFS/ME", it can be good not to restrict testing just to the day of exercise testing.

There are some examples in the literature of patients being followed up after exercise testing. For example, Nijs[10] performed a gentle walking exercise on patients where they walked on average 558m(+/-340) (range: 120-1620) at a speed of 0.9m/s (+/-0.2) (range: 0.6-1.1). This resulted in a statistically significant (p<0.05) worsening of scores in the following areas when comparing pre-exercise, post-exercise and 24 hour post-exercise scores using ANOVA: VAS fatigue, VAS musculoskeletal pain, VAS sore throat, SF-36 bodily pain and SF-36 general health perception. 14 out of 24 subjects experienced a clinically meaningful change (worsening) in bodily pain (i.e. a minimum change of the SF-36 bodily pain subscale score of at least 10).In another study, Lapp [11] reported on the effects of 31 patients to his practice who were asked to monitor their symptoms three weeks before to 12 days after a maximal exercise test. 74% of the patients experienced worsening fatigue and 26% stayed the same. None improved. The average relapse lasted 8.82 days although 22% were still in relapse when the study ended at 12 days. There were similar changes with exercise in lymph pain, depression, abdominal pain, sleep quality, joint and muscle pain and sore throat.

Actometers could also have been used in the period before and after testing to see whether there was "booming and busting" and so to see whether the exercise testing alone is useful or not.

I am unsure whether much of what I've written can be used at this stage for this study but it may be useful for people interpreting the results as well as for others designing further trials.* When quoting from the paper's text, I have changed the reference numbers of papers to ones I've used.

Publications

1 Whiting P, Bagnall A-M, Sowden A, Cornell J, Mulrow C, Ramirez G: Interventions for the treatment and management of chronic fatigue syndrome. A systematic review. JAMA 2001, 286:1360-1368.

2 Friedberg, F. Does graded activity increase activity? A case study of chronic fatigue syndrome. Journal of Behavior Therapy and Experimental Psychiatry, 2002, 33, 3-4, 203-215

3 Prins JB, Bleijenberg G, Bazelmans E, et al. Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 2001; 357: 841-47.

4 Van Essen, M and de Winter, LJM. Cognitieve gedragstherapie by het vermoeidheidssyndroom cognitive behaviour therapy for chronic fatigue syndrome). Report from the College voor Zorgverzekeringen. Amstelveen: Holland. June 27th, 2002. Bijlage B. Table 2.

5 O'Dowd, H., Gladwell, P., Rogers, CA., Hollinghurst, S and Gregory, A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technology Assessment, 2006, 10, 37, 1-140.

6 Roberts AD, Papadopoulos AS, Wessely S, Chalder T, Cleare AJ. Salivary cortisol output before and after cognitive behavioural therapy for chronic fatigue syndrome. J Affect Disord. 2008 Oct 18.

7 Priebe S, Fakhoury WK, Henningsen P. Functional incapacity and physical and psychological symptoms: how they interconnect in chronic fatigue syndrome. Psychopathology. 2008;41(6):339-45.

8 De Becker P, McGregor N, De Meirleir K. A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. J Intern Med 2001; 250: 234–40.

9 Wagner D, Nisenbaum R, Heim C, Jones JF, Unger ER, Reeves WC. Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome. Popul Health Metr. 2005 Jul 22;3:8.

10 Nijs J, Almond F, De Becker P, Truijen S, Paul L. Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial. Clin Rehabil. 2008 May;22(5):426-35.

11 Lapp, C (1997). Exercise limits in chronic fatigue syndrome. Am J Med, 103: 83-84.

On 2013 Oct 29, Michael Eisen commented:

According to recent Frontline documentary "League of Denial" http://www.pbs.org/wgbh/pages/frontline/league-of-denial/ this paper was the first step in a chain of events that has finally led to the NFL acknowledging that repeated head trauma can potentially cause long term problems for professional football players, and to a series of changes in the game designed to reduce head injuries.

Note that, according to Frontline, the NFL originally disputed the finding and attacked the work and its author - see Casson IR, 2006.

Micro.blog can be many things to many people which can be confusing, particularly when you're a very tech savvy person and can see all the options at once. I'd recommend looking at it like a custom feed reader for a community of people you'd like to follow and interact with. Spend some time in the reader and just interact with those you're following and they'll do likewise in return.

It's purposely missing some of the dopamine triggers other social silos have, so you may need to retrain your brain to use it appropriately, but I think it's worthwhile if you do.

I think this is Witman again equating "I" with humanity itself... I like how he says "this is more than churches or bibles or creeds." Implies there is a general human understanding that we have a purpose and an inert spirituality

So what it is saying is that everyone credits their own area of work whether it be a store, factory or bank to the economical success which has been brought about, right?

Medicine

I really worry about how many brilliant students are missed simple because of access. I will make an argument for the rest of my life...most of the students I see that are expelled or at-risk are highly gifted (maybe not in the conventional test taking way) but the type of kiddo that is a self-taught musician, artist, poet and/or empath. Many of my kiddos do math in their head but not on paper, and when they were five could put a Lego set together that was meant for a 15 year old. These are the students we are losing.

One of the histories of contemporary boredom is in askēsis, which English dictionaries now define as the practice of severe self-discipline, typically for religious reasons or meditative purposes. Askēsis is the Greek root of ascetic. The original usage of askesis in antiquity, however, did not refer to the self-denial conjured by the image of an ascetic, but to the physical training required for athletic events. Over the years, various valences of athletic stamina and religious devotion from different discourses have intertwined. In The Pale King, as the character Lane Dean works silently processing tax returns among a room full of silent people processing tax returns, he contemplates his boredom, combats it, and loses, sliding into some liminal state where he hallucinates a phantom who performs this etymology.

The phantom refers to the personification of boredom in antiquity as “the demon of noontide,” who was known to attack monks “in the stillness of the midday hour and empt[y] the world of any meaning” (Dalle Pezze & Salzani 2009, 8).

aamzing and veyr veyr cool

“Testing, testing, one, two three!” the man in the elaborate suit and tie announced, tapping the microphone. Bianca, still in a daze, looked around in her surroundings, finding that she was in a large space with blinding white stage lights in every direction. She glanced at the man, and was staggered to see her father Baptista, with a joker-like smile towards the audience, walking around the stage like a show host.

“Welcome all who are present, especially those who are eager to take this prize off the stage. I am your host Baptista, and we will be giving our audience the chance for the most optimal and successful contestant to take my daughter and the cash prize of $50,000 home,” Baptista says eagerly. “Whoever does the best job of impressing me, or prove that they have the income to take care of my daughter, will have the chance to become her husband.”

Bianca stared at her father with a horrified expression, and tried to move off the stage. However, even though she desperately wanted to move her body, she realized that she was in a fixed position, having no mobility of any of her limbs. Her hands were stuck to her waist, and her feet seemed to be glued to the stage; she was a mannequin without the plastic. She was even encased in a clear glass box, displayed like fancy jewelry.

Baptista began to pick random men from the audience, motioning them towards Bianca. Bianca stood there with no hope of escape. The expression on her face was a still picture, displaying a bright, blinding smile, but her insides churned at the thought of being wed to any of these men in the audience. Suddenly, a man that could have been considered her grandfather approached her, sliding his hand down the glass container. She could slowly feel the bile crawl up her throat as this man stared at her from head to toe.

“I will take her! I have more than enough money to care for her myself,” Gremio exclaimed gallantly to Baptista.

“No, she will not take an old man like you. She will love me!” Hortensio exclaimed angrily, waving his finger in Gremio’s face.

You cannot buy love! Bianca screamed in her mind, distraught by the men in front of her. Love is not an object for you to give away without my consent!

“Well, in order for you to take my daughter and have her love, you both must show me what you possess. Say, Signior Gremio, what can you assure her?” (Shakespeare Act II ll. 365).

.

summary of the qualities of GreatCall Lively Mobile

but it's one hundred homes and i and i got home and what what how hot best the best view that's what it said that at the cinema filmed ben ben and i came up and then that's the audience that that's and that's the tipton says in this tendency to boots honestly say that that i like some of the fire and minds of the head gets them to can sit down and look ahead and that's a lie there and then let them sit out there are less of the maintenance in the long island and now and that's the review that i can feel that i did it in the eye that caught in yet candidates he wants the the eight and has a lot why the asians and sit do ones you've hit it off and son that's a high winds that woman sets that where people as the hundreds of men that's what it wants the man who wore a

I found the repetition in this line thought provoking because of how it juxtaposes the character that Katherine has developed throughout the play and shows Katherine’s supposed acceptance of the gender roles forced on her. Her repetition of the word “thy” in “Thy husband is thy lord, thy life, thy keeper” is unusual because prior to this speech, Katherine is characterized by her sharp and witty commentary. Perhaps such a drastic change in speech and the extensive repetition indicates Katherine’s mocking of Petruchio’s role as her husband and an overall sarcastic tone. The repetition of the word “thy” is especially important considering whom Katherine is addressing. She is speaking to a widow, which furthers the sarcasm because Katherine, a woman who has never before married and was thought to never be able to find a match, is giving marriage advice to a woman with far more experience in the field. The reason I chose the line however, is because it defines perhaps the most crucial part of the play. A line that can resonate with such sarcasm, can also be interpreted as loving and sincere. In poetry repetition is often used to show growing importance, or to depict something in its purest form by enumerating all its qualities. Gertrude Stein for example, in one of the love poems found in her notebooks used the same tactics in writing “ Do you really think I do love you with all me yes I do love you with all me”. The tactics used by Shakespeare can be interpreted as both sarcastic and genuine, leaving the audience unsure and uneasy and sparking continuous debate about Shakespeare's intended message about the roles of women in society.

This portion of text included such vivid imagery that I was moved to illustrate the woman Petruchio has born. Her statement has sexual implication and indirectly compares women to men, compares their purpose and their worth and their physicality. Katherine knows her role as she now recognizes her body, and I depicted that recognition. I used an Art Nouveau style illustration of Oscar Wilde’s Salome as a template. I see comparison and contrast between Katherine and Salome. Katherine is beaten into submission, while Salome breaks societal norms increasingly as the play goes on. The illustration of Salome which I was referring to when drawing was sexual and empowering in its sexuality. (Salome chops of a man’s head, and this violence is associated with her sexuality.) Kate stands in the same empowered and elegant pose, not because she has gained power- she has lost it, rather- but because she is now in the position of taking other women: “Come come you froward and unable worms!” Even now that she is fulfilling a new role, Katherine is able to discover ways to assert her power over others.

Underdevelopment of the brain that causes a child's head to smaller than normal.

Patti Owen was the head of APO when I worked on Biobibs.

Her mind is filled with the stories of their ancestors. "Head" here represents her memories

http://cookislandsnews.com/national/local/item/13335-brown-back-for-documentary/13335-brown-back-for-documentary

Working for CBC?

No. I was not "working for" CBC, the Canadian Broadcasting Corporation. I was funded by CBC to fly back from New Zealand to Rarotonga as a public source for a CBC story. On offshore banking, and the background to offshore banking in the Cook Islands.

My impression? They needed a local "talking head" to illustrate their story, safely. Having gained footage of what they were interested in, the CBC reporter leading the story has rejected my own story about offshore banking.

Good enough to be a CBC headline source, but not good enough to be a CBC investigative source.

The induction of “The Taming of the Shrew” depicts Christopher Sly, a poor drunk, and a “mighty” lord who has copious amounts of money that he doesn’t know what to do with. It’s interesting that Shakespeare creates tragedies and comedies, but all of his comedies have tragic components to them. The induction of “The Taming of the Shrew” is comedic when considering the general plot line; however, the concepts behind the plot are depressing. Christopher Sly is a drunk, who is looking to drown his sorrows in alcohol. After passing out in the forest, Sly is taken from his resting place and brought to the palace by the lord and his servingmen. The sadistic part is that the lord took Sly just for the sheer purpose of screwing with his head. The lord has so much wealth that he can just take a person around and shower them with money just to trick him into believing that he is a noble. The induction of “The Taming of the Shrew” depicts Christopher Sly, a poor drunk, and a “mighty” lord who has copious amounts of money that he doesn’t know what to do with. It’s interesting that Shakespeare creates tragedies and comedies, but all of his comedies have tragic components to them. The induction of “The Taming of the Shrew” is comedic when considering the general plot line however, the concepts behind the plot are depressing. Christopher Sly is a drunk who is looking to drown his sorrows in alcohol. After passing out in the forest Sly is taken from his resting place and brought to the palace by the lord and his servingmen. The sadistic part is that the lord took Sly just for the sheer purpose of screwing with his head. The lord has so much wealth that he can just take a person around and shower them with money just to trick him into believing that he is a noble. Shakespeare illustrats the relationship between these two men in order to draw the audience into the play. However, the induction is very short and the rest of the play has nothing to do with these two characters. The “Taming of the Shrew” is mostly about a woman named Katherine who speaks her mind and refuses to be controlled. She is depicted as very unpleasant because she is a woman and in order to make the play more appealing Shakespeare opens up with an induction about two men who are participating in a very comedic turn of events. The treatment of Sly is very funny which is the point of the induction however the reasoning and analysis behind the plot is saddening and the part that the lord plays is very sadistic. The lord says, “Persuade him that he hath been lunatic, And when he says he is, say that he dreams, For he is nothing but a mighty lord” (IND. sc. 1 lines 66-68). It is sadistic to try and convince someone that they are crazy and that the last 15 years of their life was all a dream. However, what makes it even more comedic and painful, is that Sly easily believes him and then starts to act above everyone, which is ironic because he was originally broke. He starts to act as if he has been a wealthy noble his entire life therefore, justifying this behavior of acting stuck up. The entirety of the induction is heartbreaking, which makes it such a great opening to “The Taming of the Shrew”.

https://youtu.be/vkCZIn88u94

“The Tapping of the Shrew” is a compressed retelling of Katherine’s relationship with Petruchio towards the end of the play. We see her transformation from a shrewish woman fighting against her role in society, to a woman who now believes that she owes her husband the same loyalty that a subject owes his king. Katherine is seen with her father, Baptista, trying to find “Someone to Love,” which is when she meets Petruchio, who attempts to court her, but her strong personality makes it quite difficult, until she succumbs to his will, soon being “tamed” and losing the fiery personality that she once had.- Jared H, Valentina S, Kate S, Shay B, Isabel H

“it”, referring to the wonder of Katherine’s obedience, plays right into the hands of Petruchio’s character. A cocky man who has “tamed the shrew”, calls upon this wonder with peace, love, and a quiet life. Since all of these adjectives are in the same line, they are in the essence of Petruchio’s imagination from his point of view, seeing the world as he wants in, with his heroism at the forefront. However, his “awful rule and right supremacy” belongs to that of this time period, in which only a woman who was molded to fit that of a man’s bride could settle down, and Petruchio accomplished this through his awful rule. The “right supremacy” refers to his right in the time period to a wife that he finds perfect for him. These two phrases are coupled together in the same line in order to say that one can’t exist without the other. The longest line in his short triplet of lines begins with the phrase “and, to be short”, followed by the fact that since he was able to mold Katherine in his perfect image, why should it not be followed by something that is sweet and happy? He has succeeded in finding his wife while keeping his head held high and managing to higher his status in society, while humiliating Katherine even more and stripping her of any of her personality or originality.

Act 5 Scene 2 shows a reverse in the roles the sisters assumed in the beginning of the play. As the couples observe Katherine and the Widow, engaged in a battle of wits, Gremio comments that they argue well together. Rather than displaying the silent and demure personality that had so many suitors calling on her, Bianca responds by saying a rash person may say Gremio was a cuckold, which was often symbolized by a horn. A cuckold is the husband of an adulteress, and considering the number of suitors Bianca had, this may not be a far reach. 
Just as Katherine was slowly broken and reformed into what was considered the ideal woman, Bianca slowly becomes the “shrew” of the play. Perhaps she was hiding her true colors because she saw how it turned out for Katherine. As a married woman, though, she no longer needs to hide her opinions. However, her lines are no worse than what some of the men have said throughout the play and once again the gender norms are called into question. If a man had spoken these lines, it would have been met with laughter, but because Bianca delivers it she is berated, because it is not considered ladylike to make such obscene comments. These double standards are a large source of trouble throughout the play, not just in the terms of gender roles; but also when it comes to questions of status. The characters switching identities and clothing goes to show the frivolity of class, and in a way Bianca and Katherine switching traits displays the frivolity of laying a judgement or opinion on the qualities one openly displays. The roles of the sisters are reversed - not because the women have changed entirely, but because they are revealing who they really are rather than the façade they present to the world. And really the joke is on the men because all the attraction and attempts to woo Bianca were based off the fact that she was silent and therefore the ideal woman.

When considering Katherine’s famous final monologue in The Taming of the Shrew, a closer analysis of William Shakespeare’s choice of diction reveals a comment being made on institutional religion and blind obedience. At a cursory glance, Katherine’s monologue, which is by far the longest in the whole play, appears to be nothing more than a lengthy allocution outlining the duty a proper wife has to her husband. After all, Katherine has begun to exhibit blind obedience towards Petruchio: she does whatever he asks without question or protest. However, Katherine beings line 155 by referring to a woman’s husband as her “lord.” This subtle choice of diction hints at religious undertones which suggest that Katherine is not obeying Petruchio because he is her husband, but rather because she has some sort of religious obligation to worship him. Although the play is firmly rooted in Christianity (since the setting is Italy many years ago), the sentiments expressed by Katherine in her monologue actually exhibit certain notable parallels with those of Islam-- namely that because it is a husband’s duty to provide for the protection, happiness, and well-being of his wife, he has been given some degree of divine power over her. According to Allah in the Qur’an, "Men are the maintainers of women, because Allah has made some of them to excel others...” (4:34). Allah also says, "And women have rights similar to the rights of men in a just manner, and the men have a degree (of advantage) over them..." (2:228).

While Petruchio’s “advantage” over Katherine primarily manifests itself emotionally, it manifests itself physically, as well. Towards the end of the monologue, Katherine is actually observed kneeling at the feet of her husband with her hand outstretched. This does not serve merely as a pose of wifely deference on the part of Katherine (although it is that, too), but also as one often taken by religious subjects during prayer. It seems here that Shakespeare is suggesting that the sort of unquestioning obedience that Katherine has assumed towards Petruchio is not all that different from those who deprive women of control over their bodies in the name of Christianity or kill in the name of Islam. In The Taming of the Shrew, Katherine represents those afflicted by the oppressive nature of institutional religion.

Katherine is comparing an angry or “moved” woman to an unbalanced fountain, almost agitated. She’s muddy, unpleasant, and lacks the beauty seen in most graceful, peaceful fountains. Katherine explains that no one could ever touch a fountain in this condition, much like a husband being disappointed in his unwilling wife. This first and foremost reveals that men living in this era are used to getting what they want, and women serve it to them on a golden platter. Petruchio wants Katherine to be submissive, and Katherine eventually complies. Katherine believes a rebellious or a woman contrary to a docile attitude, becomes useless. The active woman becomes foul water no one can use, not because men don’t want to have anything to do with that sort of woman, but that they cannot, if they wish to uphold the expectations of masculinity of the time period. Men are unable to work the same way and be successful if women didn’t do what they’ve seemingly always done- be compliant to the man’s every need and watch more domestic matters. Being foul is the most selfish act, because no one can use the woman. A contaminated woman disrupts society in Elizabethan England. By the play’s final act, the audience can see that Petruchio’s torture methods of “taming” Katherine as a shrew, have succeeded. In this final speech, Kate believes every word she speaks, ““thy husband is thy lord, thy life, thy keeper, / thy head thy sovereign, one that cares for thee” (V.ii.153), the first three things reflect the views of a marriage in the sixteenth and seventeenth century which Kate now also agrees with. Overcoming her shrewishness, according to this idea, is a triumph for Kate because it allows her to be happy. Contrary to her initial resistance, Kate seems to view her marriage as a chance to find harmony within this prescribed social role, ultimately implying that we should find a new sort of subservient happiness within the roles to which we are assigned, and that women should subjugate themselves to their husbands as well as men in general.

The Taming of the Shrew by William Shakespeare can be interpreted as an account of the tyranny of man over woman. In Elizabethan England men were the head of the household, while the women were expected to be polite, and meek. In The Taming of the Shrew, Petruchio seeks a young and beautiful woman with a wealthy background to be his wife. However Katherine, the woman he sets his sights on, is independent, straightforward, and unapologetic. In this scene Tranio, a servant, explains to Bianca, Katherine’s sister, that Petruchio has attempted to “tame” Katherine. In the story Katherine is viewed as a shrew due to her sharp tongue and harsh attitude to those around her. Tranio says, “He has gone to unto the Taming School.” Here the “He” being referred to is Petruchio. Tranio is setting up the idea that Petruchio is a master teacher that will be able to teach Katherine to control herself, and to conform to the norms of society at the time. Tranio also uses the words such as "tricks" and “charm”. This choice of mystical language makes Petruchio sound like a magician, who is capable of anything. In this case, Petruchio can work his magic on Katherine and change her harsh personality. However this could also mean that Petruchio’s so called “magic” is fake. Even though he has attempted to tame Katherine, all of his tactics are slight of hand, to fool the audience into thinking that Katherine has actually changed. In Act V of the play, Katherine delivers a speech to a room full of women urging them to, like her, conform to their husbands’ wishes. One interpretation of this monologue is that Katherine is speaking literally and that she had been “tamed” by her husband. However others believe that Katherine was speaking ironically and was never truly “tamed”. I believe that although at the end of the story Katherine may appear to have become the typical wife, no one, not even Petruchio can truly change her.

Detached by Korinne Arenas

Affluence is but a trait of mine,

Inherited from the womb of which I was birthed

It is within the air I breathe,

intoxicated by the wealth surrounding me

Tis I the noble man,

whom shall never dream of sleeping cold

Never deign to serve those

ten floors below

Yet Tis I who find it strange

within the meer reflection of my standings

That a false reality catches mine eye

For it is but a single grey hair upon this royal head

That wakes the old fool inside

These roots are ancient,

And mine soul hath roamed the earth for decades

Naked in all its fashions

Empty hands and bare souls made for trudging

Yet here I stand, goblet in hand,

Crown upon my head

For I am a lord, and lord alone

And the ghost of the beggar is dead

Explanation: This poem depicts the detached reality that Christopher Sly faces when he is told that he is a mighty lord. He is forced to believe that he is a lord and would be considered a lunatic otherwise, causing Sly to dissemble his true self as a beggar and espouse the role of a lord. While he is surrounded by nothing but wealth, he sometimes is haunted by his past in remembrance of his life as a beggar, however he pushes these thoughts aside, thinking he must be lunatic and goes back to believing that he is, in fact, just a mighty lord.

Not convinced that these resumes are causal in the failures of these projects.

On Bianca

Angel of yellow hair and fairest skin

Bestow the devil’s curse upon my fate,

Your foot in the door so I'll never win,

For one day when I brush my hair, abate.

Wretched is the day in which you marry,

I to dance below your wedded feet,

Standing on an open grave, warily

That I might burst the subliminal sweet.

Don't tell me this is only in my head;

I hear our neighbors whisper when I leave,

Wishing you would keep me here for dead,

My docility finally retrieved.

I am not who you pray to God for dearly;

All I am is woman, cavalierly.

“Testing, testing, one, two three!” the man in the elaborate suit and tie announced, tapping the microphone. Bianca, still in a daze, looked around in her surroundings, finding that she was in a large space with blinding white stage lights in every direction. She glanced at the man, and was staggered to see her father Baptista, with a joker-like smile towards the audience, walking around the stage like a show host.

“Welcome all who are present, especially those who are eager to take this prize off the stage. I am your host Baptista, and we will be giving our audience the chance for the most optimal and successful contestant to take my daughter and the cash prize of $50,000 home,” Baptista says eagerly. “Whoever does the best job of impressing me, or prove that they have the income to take care of my daughter, will have the chance to become her husband.”

Bianca stared at her father with a horrified expression, and tried to move off the stage. However, even though she desperately wanted to move her body, she realized that she was in a fixed position, having no mobility for any of her limbs. Her hands were stuck to her waist, and her feet seemed to be glued to the stage; she was a mannequin without the plastic. She was even encased in a clear glass box, displayed like fancy jewelry.

Baptista began to pick random men from the audience, motioning them towards Bianca. Bianca stood there with no hope of escape. The expression on her face was a still picture, displaying a bright, blinding smile, but her insides churned at the thought of being wed to any of these men in the audience. Suddenly, a man that could have been considered her grandfather approached her, sliding his hand down the glass container. She could slowly feel the bile crawl up her throat as this man stared at her from head to toe.

“I will take her! I have more than enough money to care for her myself,” Gremio exclaimed gallantly to Baptista.

“She will love me!” Hortensio exclaimed angrily, waving his finger in Gremio’s face.

You cannot buy love! Bianca screamed in her mind, distraught by the men in front of her. Love is not an object for you to give away without my consent!

“Well, in order for you to take my daughter and have her love, you both must show me what you have. Say, Signior Gremio, what can you assure her?” (Shakespeare Act II ll. 365).

This moment of interaction between Katherine and Petruchio as he begins to tame, is a glimpse into how Petruchio uses reverse psychology in order to to marry Katherine. When we are first introduced to her, she is a violent and mal-tempered individual and is especially against the idea of being married off, thus her foul and violent actions towards Petruchio. However, Petruchio isn’t anymore angelic, with his often drunk and chivalrous attempts to handle Kate. By taking all things negative that have been said about Katherine and the warnings delivered to him about her, rather than walk away and never attempt to interact with her, Petruchio uses the moment he has with her to disregard all the outside comments and compliment her with remarks such as “pleasant” and “sweet as springtime flowers”. This catches Katherine off guard considering this is most likely the first time she has a suitor regard her as a charming person, as she has turned away all other previous suitors with her temper and violence. To see Petruchio put himself inside of her head and to begin reconstructing her persona, it shines a light on how he follows his own system to marry a person of interest, one which is both unique, and will eventually lead to Katherine’s obedience of Petruchio.

In these lines, Biondello is describing the ridiculous display that Petruchio puts on as he goes through town to wed Katherine. Everything that he is saying and doing seems extremely silly and overdone, from his clothes (which are old, mismatched, and out of fashion) to his horse (which is old and swollen with disease). Petruchio is doing this to establish his dominance over Katherine, and to humiliate her into submission. By parading through town dressed in an absurd outfit and showing up late to the wedding, he is solidifying a fact that had been only implied earlier: Katherine has no choice but to marry him, no matter how awful he is to her. Baptista has promised him the wedding, and he doesn’t believe that anyone else would want to marry her. It also works to dehumanize Katherine. By refusing to give her a proper wedding (which, at that point, was the only was a woman could achieve success), Petruchio strips her of her womanhood, her identity, and (to an extent) her humanity. He implies that her forward and aggressive nature makes her more of a wild animal and less of a woman. This is his first act in “taming” her, in which Petruchio fully understands the power that he holds above her head.

There is generally an air of misogyny associated with Petruchio’s syntax and treatment towards women, particularly Katherine – the object of his quest for wealth and prosperity – throughout the progression of the play. However, upon closer reading, there is the underlying idea that Petruchio actually views Katherine with respect – in his own twisted way. He states that he “will be master of what is [his] own,” and goes on to compare Katherine to a series of objects in his possession (3.2.235). He says that she is “[his] goods, [his] chattels… [his] house,” which appears misogynistic in the sense that she is only valuable to him as a possession and object, not as a woman he loves. However, on the other hand, one can make the argument that he views Katherine as the most valuable person in his life. By comparing Katherine as someone he sees as equal to his most prized belongings, he shows that there is a desirable value to Katherine, which is new for her. This may still come off as misogynistic in our time, but in the story, this is critical when taken into consideration that Katherine is portrayed as the foil – and the complete opposite – of Bianca, who is perfect and loved. Until Petruchio, Katherine’s poor reputation has repelled potential love interests as the majority of the townspeople see her as abrasive and rough, and instead opt to court Bianca. Petruchio’s desire for Katherine in this way may account for her “transformation” from a brash spirit to a seemingly docile housewife towards the end of the play. At first sight, it appears as if Petruchio had subdued Katherine’s fiery nature into one of compliant domesticity by forcing her to conform to traditional gender roles. Petruchio’s treatment of Katherine at the beginning of their marriage is undoubtedly harsh, but it allows her to undergo a character transformation where she moves from indignated misery to sensible contentment through marriage. Katherine’s final soliloquy in Act 5 Scene 2 echoes this point, as well as Petruchio’s sentiment from his earlier monologue in Act 3 Scene 2. Katherine says,“Thy husband is thy lord, thy life, thy keeper / Thy head, thy sovereign..” (5.2.162-3). In this quote, Katherine reveals that she shares Petruchio’s feelings. From her soliloquy one can still detect her characteristic fierceness, but there is a newfound sense of maturity in her words. Through the similarity of diction and syntax in their speeches, Katherine and Petruchio display a mutual sense of appreciation and respect for one another. Katherine is not simply a target of Petruchio’s misogyny; rather, she shows that the feeling of possession is a reciprocated idea from both parties. Although Petruchio is far from a romantic and perfect husband, Katherine ultimately displays gratitude and respect to him for desiring Katherine when everyone else judged her character and thought poorly of her.

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Hello, fact-checkers! This statement, taken from CNN interviews and discussions, may be worth your scrutiny. It was selected using ClaimBuster, a tool developed in the computer science department at the University of Texas at Arlington.

Linking to the first sentence - "orientation" and "disposition" - the use of these words is pointing me to some intentionality around the piece, and saying something about coaching that speaks to a "way of being (together?)" as compared to an instrumental "get it done" kind of thing. I am realizing that what I'm picking up is a re-crafting of the idea of "coaching" - as an object that exists in our lexicon that carries ideas that either have become invisible (forgotten) or haven't moved to the center (core vs. fringe). This leads me to wonder - am I picking up on something you are trying to do...or am I creating my own meaning (and is this ok - meaning something you hope to achieve)? If the latter, I wonder if this can be something you speak to and be more explicit about - it could help change a dynamic from a knowledge distribution (sets of ideas written down to be read) to something else (a reflective paper for the reader). Something as a simple as an opener (or at end?) that says - "in this essay i share my model of coaching and hope it provides an opportunity for the reader to think about their own model." This is also helping me realize that the first sentence of the essay is really jarring - and my sense is that is intentional - setting up a disruption of a sort. It took me until this place to have this "click" in my head.

3) In this scene Sophie describe the place that she comes from as a burden, carrying pass traumatic experiences on her head. Memory is carried around without no hopes for it fading. She made reference to her mother rape scene, the sadness she endured, trap from that moment on for the rest of her life. Martina never fully recovered from what happened to her as a teenager. Despite her abandoning Sophie at such a young age she never forgot about her baby. She did everything that she could for Sophie by preparing a life for herself in America.

I chose this part of the text because it caused me to think of early care centers such as Head Start that have a mandatory parent involvement requirement. I wonder how the parents feel about this requirement and also how the teachers feel about it? Why does it exist and does it result in the parents feeling more ownership in their child's education or does it only add burden?

One thing I respect most about Head Start schools are acts like this that promote things that are for the best of the children. In fact, it's Head Start's mission to find people who've slipped through the cracks, specifically those at or below poverty level to give each child the best chance to succeed. Viewing parents as teachers, learners, partners, choosers and consumers is a great way to show the parents that you respect and value them, and that you know they have an important job in regards to their child's education. This builds rapport with parents and opens up lines of communication which is so crucial to the child's well-being.

The mother heard and lifted her head. A mist covered her eyes, and her lids were puffed as though she were crying without tears. "Yes, nuh," she whispered, "take it all out my sight, do! Over nine ... hundred odd dollars ... cash throw ...'way..." While she kept without tears, without even a tremor, Selina gathered up the wreckage of the day. (114)

It is not right to judge a historical figure based on modern standards; however, we can apply modern standards and see how such historical figures behave closely to those. In this case, a debate on Napoleon's birth, and by extension his right to rule France, comes into play. Napoleon was born on the island of Corsica, an island which less than a year before his birth came under French possession. Many opponents to the Bonaparte faction try to claim that Napoleon falsified his records only to say that he was French and should receive French benefits. However, church documents and his father's private journal do indeed prove that Napoleon's birthright was that he be French. This popular controversy tests whether it really was in Napoleon's right to become the head of the government of France. But interestingly, the concept of "nationality' is mentioned. While Europe was ruled by monarchs, one could not be a private citizen, but rather, a subject of the king. By this, Napoleon was a subject to the King of France and loyal to him, thus indicating that he could be given the full rights of a Frenchman. However, this controversy also leads to the identity of the man, as it did play a crucial part in his rise to power. Had he not been French, what could've gone wrong?

Another reason he gives for a revolution is using religious text. He states that even a religion that promotes peace encourages people to stand up for injustice.

this paragraph shows me a very convivial and dynamic scene， grassed, water channel, sand, running track, jogging, cycling, rollerblading, horse riding, swimming and rowing. These words make me very welling to go and play.

The city cycling program is beautiful, but it is complicated. The plan needs to consider the urban structure and needs in many ways, so it will take a long time to complete.

What must first be understood about Reagan's references to an "evil empire" is the historical background in which it entails. Provided is a link to a video that entails the commencement Reagan's "Star Wars" program, which was an Anti-Soviet missile defense system implemented by the United States.

Within the context of "STAR WARS," Blockbuster American movie series, the "EVIL EMPIRE" is the tyrannical governing body that serves as an antagonist to the Rebel Alliance.

When analyzing Reagan's use of "evil empire" and his following use of "good vs. Evil," taking into account his previous declaration of "Star Wars," a few points can be drawn in terms of Neo-Aristotelian and Pedantic Criticism.

Reagan, by using terms and rhetorical language relative to Star Wars , it is clear that one method in Reagan's agency here is to create a rhetorical image in the head of the audience that relates to FICTION.

Reagan accomplishes this by creating a distinction between the US and its enemy as being the "Evil Empire" vs "The Good Guys,"

This is an example of Reagan appealing to the Audience through their RELATIVE KNOWLEDGE regarding Star Wars.

He is taking a real-life situation and using a fictional work as an illustration of how HE wants it to be seen for the audience.

The author is upset and putting images in her head that one day her two daughters would return back home to her.

This shows that mall operators have begun to shift their consumer groups' goals. They used to focus on the shopping of upper class people and later on the middle class.

I appreciated that the authors addressed this disconnect head-on. It made me feel a bit baffled, but also had me thinking, "Duh. How can we expect students living in impoverished areas surrounded by drug use and crime not participate in the lifestyle enveloping them?"

I have a personal connection to this point. When I was growing up, my mom was a high school teacher in a nearby public high school that taught many privileged young adults from well-off families. Because the school had such impressive academic records, a grant was created that would bus approximately 30 students from South Minneapolis to this school every day so that they had access to better schools.

Unfortunately, the grant dissipated five years after it was initiated, because the district did not notice any significant improvements in the academics and behaviors of students who were being bused to the public schools in richer areas. The quote I highlighted is an adequate explanation of why it did not work.

comments (other's; positive)

This sentence sort of runs away from you. Break it up into its separate ideas.

This quotation is much too long.

I strongly feel that not all punishments should lead to the person's death. The individuals that perform in the murder, do not feel any kind of regret or sorrow.(values) Religion plays a huge part in this, considering they have no hearts, morals, or any beliefs. (values) Also, the ways that the death was described is extremely vivid and morbid. This would definitely be labeled a low point in the beginning of the text.

His pride seems to overshadow the safety of his brethren. e

Question:What evidence is given for the primary claim? Select all that apply.

Answer:Experts are cited

Highlight:

"Farmers are left with nothing, not event with clean drinking water," said Matthew Marek, the head of disaster response in Bangladesh for the International Federation of Red Cross and Red Crescent.

CredCo Indicator:Quotes from Outside Experts

Question:Highlight each expert cited:

Answer:Expert 2

Highlight:

Matthew Marek, the head of disaster response in Bangladesh for the International Federation of Red Cross and Red Crescent.

Question:What evidence is given for the primary claim? Select all that apply.

Answer:Correlation

Highlight:

Some head injuries can actually increase your risk of developing dementia later in life, especially if it causes 30 minutes to 24 hours of unconsciousness after initial injury (14).

CredCo Indicator:Inference - Type of Claims

Question:Is a general or singular causal claim made? Highlight the section(s) that supports your answer.

Answer:General Causal Claim

Highlight:

Some head injuries can actually increase your risk of developing dementia later in life, especially if it causes 30 minutes to 24 hours of unconsciousness after initial injury (14).

Question:What evidence is given for the primary claim? Select all that apply.

Answer:Experts are cited

Highlight:

Hub’s Health Expert said, “I used to suffer from daily headaches until I realized that I was twisting my neck when I slept.” They recommend surrounding the head with pillows to prevent it from turning.

Question:What evidence is given for the primary claim? Select all that apply.

Answer:Experts are cited

Highlight:

They recommend to, “Sleep with your head elevated… Mucus pools in your sinuses at night when your head is down, so have your head propped up during sleep.”

<br>

Analytic note: These discussion notes are framed as point-by-point responses to Kennedy's memo to Johnson.

Source excerpt:

1. “Do we have a chance of beating the Soviets?”

a.<br> “By putting a laboratory in space?” There is no chance of beating the Soviets in putting a multi-manned laboratory in space since flights already accomplished by the Russians have demonstrated that they have this capability. The U.S. program must include the development of a multi-manned orbiting laboratory as soon as possible since it is essential for the accomplishment of the more difficult flights to the moon.

b.<br> “Or by a trip around the moon?” With a determined effort of the United States, there is a chance to beat the Russians in accomplishing a manned circumnavigation of the moon. The Russians have not as yet demonstrated either the booster capability or the technology required for returning a man from a flight around the moon. The state of their booster technology and other technology required for such a difficult mission is not accurately known. With an accelerated program, it is not unreasonable for the U.S. to attempt a manned circumlunar flight by 1966.

c.<br> “Or by a rocket to land on the moon?” On September 12, 1959, the Russians crash-landed a small package on the moon. This package did not transmit any information from the surface of the moon. The NASA program currently includes impacting instruments on the moon in such a way that they may survive the impact and transmit scientific information back to earth. The first flight in this program is scheduled for January 1962. Close-up television pictures will be obtained of the surface of the moon, as the spacecraft descends to the moon. In August 1963 the current NASA program also includes a soft landing of instruments on the moon. Several flights in succeeding months are included in this program to insure the possibility of success. The Russians can accomplish this mission now if they choose.

d.<br> “Or by a rocket to go to the moon and back with a man?” There is a chance for the U.S. to be the first to land a man on the moon and return him to earth if a determined national effort is made. The development of a large chemical rocket booster, the spacecraft for landing and return, and major developments in advanced technology are required to accomplish this most difficult mission. The Russians initiated their earth orbiting program probably as early as 1954 as evidenced by their flight of a dog in November 1957. In the earth orbiting competition the United States was attempting to accomplish in less than three years what the Russians had worked on for seven years. It is doubtful that the Russians have a very great head start on the U.S. in the effort required for a manned lunar landing. Because of the distinct superiority of U.S. industrial capacity, engineering, and scientific know-how, we believe that with the necessary national effort, the U.S. may be able to overcome the lead that the Russians might have up to now. A possible target date for the earliest attempt for a manned lunar landing is 1967, with an accelerated U.S. effort.

e.<br> “Is there any other space program which promises dramatic results in which we could win?”

(1)<br> The current NASA program provides the possibility of returning a sample of the material from the moon surface to the earth in 1964. An experiment of this kind would have dramatic value and may or may not be a part of the Russian program. The Russians could carry out such an experiment in the same time period or earlier if they choose.

(2)<br> The lead the U.S has taken in developing communications satellites should be exploited to the fullest. Although not as dramatic as manned flight, the direct benefits to the people throughout the world in the long term are clear. U.S. national prestige will be enhanced by successful completion of this program. The current program will provide for the flight of an active communications satellite in mid-1962. The experiment will enable live television pictures to be transmitted across the Atlantic. The continuing program will lead to the establishment of worldwide operational communications systems.

(3)<br> The U.S. lead established in our successful meteorological experiments with the Tiros satellites, should be maintained with a vigorous continuing program. The whole world will benefit from improved weather forecasting with the possibility of avoiding the disastrous effects of major weather disturbances such as typhoons, hurricanes and tornadoes.

Full citation: Dryden Notes, 22 April 1961, in FRUS 1961-1963, Volume XXV, Doc. 362, Online: https://history.state.gov/historicaldocuments/frus1961-63v25/d362

<br> Source excerpt: (Sheehan 2007, 28-29) For Korelev, the head of the Soviet space programme, the purpose of space launches was the scientific exploration of the solar system, leading in time to the permanent presence of human beings in space and on other bodies. For Khrushchev however, it was simply a propaganda tool, with no significant value in itself. In the years 1958 to 1961, the United States launched 56 satellites, while the Soviet Union only launched 12. Unlike the American launches, few of the Soviet missions produced significant gains in scientific knowledge. For Khrushchev, space research for its own sake was of no interest, and follow-up missions were invariably cancelled because they might appear repetitious, even though they would have been scientifically important in confirming and developing knowledge. Instead, Korolev was forced to conform his space launch schedule to Khrushchev’s diplomatic agenda.”

Mice with white coats have a deadly mutation that kills the mice while they are very young. The phenotype (the physical expression from the gene) is called "piebald lethal". Mice with spotted coats have a similar outcome to mice with white coats and their phenotype is called "lethal spotting" or hypo-pigmentation (meaning lacking pigment).

Her account of what happened is such tragedy. I cannot fathom a word that is appropriate in this drop of my stomach in reading what these people went through. Casualties isn't a clear enough description. There is no humanity to a loss that great. From false pretenses no less.

More proof that Gender is important, but not in the typical american sense. Though it was devastating for her to lose her forever person, she still kept on. It was her way to cope. But the only way to tell was to be inside her head.

This piece came from a one-pager in response to "Habits of the Creative Mind" by Richard Miller and Ann Jurecic. The quote really jumped out at me when I went back and reread the piece after I went into Boston and did some observing, as was asked for the reflection. During my adventure, which involved many stops at MBTA stations, one thing that really caught my eye was the immense amounts of homeless people that crowded the T-stops. To me, this was alarming because it was the middle of February and the air was so crisp and frigid that even I, bundled in my expensive high-quality parka, was shivering. Normally, I keep my head down and continue to pass by these people, however because of this assignment, I felt compelled to actually take a second to notice, even if it made me uncomfortable. Personally, I saw how this helped me as a writer because I realized that when I put myself in a situation where I was curious yet unexperienced with a particular subject, I was forced to pay even closer attention and pick up on the small details.This is what really helped strengthen my piece and future pieces as well.

The way that I started this piece was something that I was a little nervous about doing at first. When I first noticed the homeless man that I introduced, he stuck out to me from the others because he just seemed so vulnerable. Never before had I seen someone look so beaten up and crushed, yet so hopeful about the future as he played his guitar. I really wanted to write down some observations so I would remember the exact words that were going through my head. I also didn't want to make it look like I was only taking notes because he is homeless and I didn't want to make him feel even more self-conscious about this defining characteristic. Originally, I didn't include the description because I thought that it was a sad way to start off a piece and didn't want to make the reader feel like they need to put down the essay because it was too emotional for them. However, I think the description of this man, although a sad way to enter my reflection, draws the reader in to give them a picture of someone that they might normally pass by quickly. The fact that I could put myself out there and start off a piece of writing with a sad moment, and be able to use that raw emotion as the center of my essay, is something that I had not done before this class.

I think this is wonderful! It feels like our society doesn't see failure as a good thing. It's often frowned upon when we fail, but I, personally, think we can learn from our failures. We should be failing more and beating our heads against the wall, and we should be teaching students that it's okay to fail.

This keeps rolling around in my head, one marble in a Chinese Checkers tin. And I am not asking what does this mean, but rather what could this mean?

Chapter 2 in Their Eyes Were Watching God represents Janie's conversation with her grandmother. They are discussing Janie's future, in terms of finding a man to marry. Janie insists that she is still young while grandma thinks that she needs someone that can protect her. Grandma had recently seen Janie get kissed by Johnny Taylor which signaled to Grandma that Janie is growing up and she won't always be there to protect her. In my song, the main idea is the conversation between Janie and Grandma discussing Janie's future in terms of men.

Just before we get started there is one thing I noticed while watching some of my peers plays. Most of their songs take an aria form meaning that the plot doesn't move forward. They will sing about something that has already been established, not introducing new information for the watcher. However, my song is more a recitative. The song is an addition to the speaking part of the scene. There is also not a clear form. There are certain themes that come back later in the song, but there is no definite form. I did all of this subconsciously, I had no idea what I was doing, however it added an element of anticipation.

My piece is in the key of F Major. I think the key of F was just running through my head when I thought of this song, however, I do think I chose a major key to signify how Janie and Grandma look forward to Janie's future with happiness. Of course, when your looking at your future your going to try to have positive thoughts when talking about it. Typically, I would have Janie sing a line and then grandma build on top of it. I think this signifies that the two characters are trying to work together to make a new life for Janie.

The main idea that I am trying to convey while singing this song is the idea of Janie and Grandma talking about what they want. The plot develops as the song goes on, and soon Janie agrees to marry Logan.

The song that I chose to write didn't have any instruments in it. The folk songs had very minimal instruments and usually featured the vocals. I also felt the need while writing the song to include harmonies that could enhance the performance. I feel in this case that harmonies are another example of Janie and Grandma trying to work together in order to find a solution for the problem. There are multiple recurring themes with different words that signify similarities in ideas that Janie and Grandma were saying.

Chapter 2 is relatively close to the beginning of the story (chapter 1) and usually the first part of a play usually starts with big vocal parts and loud instruments that can set the mood for the play. Our song is quiet and passionate, which is a huge mood change from the previous chapter.

Steve has told us about different types of songs in a play. I feel like our song comes out as an “I want” song. The two characters are talking about what they want. Janie wants to be left alone to grow up. (Lines “Im still so young, im still a kid) And grandma, who wants to find someone that can protect Janie (Lines “You are a women now you must marry now i'm thinking someone that's very rich)

The way that I started this piece was something that I was a little nervous about doing at first. When I first noticed the homeless man that I introduced, he stuck out to me from the others because he just seemed so vulnerable. Never before had I seen someone look so beaten up and crushed, yet so hopeful about the future as he played his guitar. I really wanted to write down some observations so I would remember the exact words that were going through my head. I also didn't want to make it look like I was only taking notes because he is homeless and I didn't want to make him feel even more self-conscious about this defining characteristic. Originally, I didn't include the description because I thought that it was a sad way to start off a piece and didn't want to make the reader feel like they need to put down the essay because it was too emotional for them. However, I think the description of this man, although a sad way to enter my reflection, draws the reader in to give them a picture of someone that they might normally pass by quickly. The fact that I could put myself out there and start off a piece of writing with a sad moment, and be able to use that raw emotion as the center of my essay, is something that I had not done before this class.

This piece came from a one-pager in response to "Habits of the Creative Mind" by Richard Miller and Ann Jurecic. The quote really jumped out at me when I went back and reread the piece after I went into Boston and did some observing, as was asked for the reflection. During my adventure, which involved many stops at MBTA stations, one thing that really caught my eye was the immense amounts of homeless people that crowded the T-stops. To me, this was alarming because it was the middle of February and the air was so crisp and frigid that even I, bundled in my expensive high-quality parka, was shivering. Normally, I keep my head down and continue to pass by these people, however because of this assignment, I felt compelled to actually take a second to notice, even if it made me uncomfortable. Personally, I saw how this helped me as a writer because I realized that when I put myself in a situation where I was curious yet unexperienced with a particular subject, I was forced to pay even closer attention and pick up on the small details.This is what really helped strengthen my piece and future pieces as well.

here it gives out a description of the statue that was half way sunk in the desert. the statue had a head that's frowning with wrinkle lips. its a face of someone but no clue if the face of the statue is either a feminist or manly.

here the author is talking from the point of view of a traveler who he met from an antique land and then mentions what the traveler said to him. The traveler had seen a statue and described as having trunkless legs, According to OED, trunkless is described as "Having no trunk; esp. without a body, or severed from the body, as a head". The traveler seen this statue with a pair of legs and no body dug halfway through the sand in the middle of a dessert I believe

This makes me think of the phrase "bury my head in the sand" which means that someone either trying to avoid or ignore something or pretend a situation doesn’t exist. Maybe the author is insinuating that this king was in denial or too self-important to see the truth about something

In my one pager I described the paragraph that these quotes came from. The words she chose struck me because I never would have thought of the shore as a "fairy world." Later in the passage, she talks about little aspects of the shore that made me feel that I was on a tour. I felt that I visited rocks, sea caves, passageways, shells, pools, and even wharf piling. I felt like I was at the shore and in my head I pictured Bethany Beach, where I go every summer. I decided to focus more on my feelings of the shore at Bethany Beach in particular and why I also found it to be a constant. As Carson sees the shore as a meeting place of the land and sea, I see the shore as a meeting place for my family.

While writing about the sights and sounds that one would experience in Conte late at night when no one is there, I learned how to pay close attention to detail and ultimately better describe the setting in general. When I wrote my rough draft, I had maybe one or two sentences dealing with this section on the sounds of players playing hockey on the ice late at night. After I wrote it, I wanted to get a better understanding on the detail of what I was writing about to give the reader a better grasp on what I was trying to explain. By going to Conte again late at night to experience this, I used the techniques we learned in class to pay closer attention to detail to have further commentary in my essay and I was able to do just that in the final draft.

Without a doubt, this paragraph, whose ideas weren’t even considered in my rough draft, best illustrates my growth as a writer. After going through all of the sources and ideologies on the issue, I realized that there was something missing from the argument about why humans were superior to animals, something that no source would say. I explored these thoughts in my head, losing myself in thought as I considered the issue in detail. Through my thought, I was able to put my own spin on the sources in my essay, inserting my opinion in a way that builds off of my sources but also goes beyond them, making for original, thought-provoking writing.

Also not in the original draft. I think I was far too scared of beating my audience over the head to the point that what I actually wanted to say didn't come through. I really like this sentence because it connects the new, personal aspect of the essay with the ideas of the stop mentioned earlier. Also, I think it sounds nice, bar incorrect usage of "nauseous."

None of this was in the original draft, mostly because I feared writing myself into it too much, making it more about me and less about the Stop (the intended subject of the piece). When I thought about it more I realized how flat-out idiotic that line of thinking was; experiences are inherently personal, so I can only really talk about my perception of the Stop, and therefore writing myself into the essay wasn't only permissible but necessary in order to truly capture the power of the place.

I wanted to work on this piece further because it meant a lot to me as a writer. It was when I discovered how to be creative so I have always liked this piece. I took Brian's advice and made a few changes. I decided to explain deeper some of my observations like what I was actually thinking and feeling in that class. I think going further in detail improved my piece because it offered more description into how I was feeling at the time. Originally I just had vague sentences like, "As I rode in class I took notice of every time a song made me feel happy or sad, and "I took notice of when I felt myself struggling most," but, I did not go further into what particular song made me feel happy or at what exact point was I struggling the most. In my revisions I tried to go deeper to give the reader more insight of my experience. I wanted them to imagine how I was feeling.

He is expressing what he relates to and likes in comparison to what is relevant around him.

I really like how the author stepped out of her comfort zone and points out the repetitive lectures and things students are taught over and over again. Which i most definitely agree with.

Ross Hamilton is his favorite artist because his words are filled with meaning and he says he can’t understand Picasso’s art because to him its nonsensical. Maybe that is why he likes music, because he tries to find a significance in everything. There are rarely hidden implications in music, words deliver a message and the rhythm, beat and tempo further support that message (or set that “mood”). It delivers a pretty clear message as opposed to poetry and art which are more likely to have veiled meanings.

Here the author now mentions another of his dislikes. The same way he doesn't understand poetry the same way he does not understands Art. This man completely change the subject from music compared to poetry and now Art.

I agree with the author that Picasso's art work is really hard to understand.

**Do not summarize or duplicate the artifact.

How do the artifacts relate to the standard? “How do the artifacts demonstrate that you have met the standard?”

Just after Marjorie’s tenure at Fort Apache, there was a shift in administration in the Board of Indian Affairs. In 1933 John Collier was made the Commissioner of Indian Affairs by Franklin D. Roosevelt, and, by Collier’s authority, Willard Beatty was the Director of Indian Education. Both Collier and Beatty were staunch supporters of the Progressive Education: Collier was at Columbia, while John Dewey (the lauded father of Progressive Educated) was there, and Beatty, beginning in 1933, was the president of the Progressive Education Association. The shift in administration was the shift towards a progressive education system. This note reveals a more active roll in the Board of Indian Affairs trying to improve the conditions of learning for the children. Visitations from those like Mr Peasse, resulted in fewer boarding schools and more day-schools for Native children. (Reynher)

She has won several design awards and is the head of research at the John Hopkins University Museum.

https://generalassemb.ly/instructors/brockett-horne/4067

The 1995 BBC Pride and Prejudice television adaption used the historical Edgcote House as Netherfield. "Edgcote House, located in southwest Northamptonshire, is the setting for Mr. Charles Bingley’s leased estate. The building was built in the 18th century, and was at one time owned by Anne of Cleves, who was Henry VIII’s fourth wife, and one who was actually allowed to keep her head!" (https://austenauthors.net/a-tour-of-estate-houses-used-in-pride-and-prejudice/)

n. temples of the head

This reminds me of a saying I was told when I was little. "Red skies at night, a sailor's delight. Red skies in morning, sailors head warning."

Gibson began with the problem of how airplane pilots integrate the panorama they see as it zooms in every direction during a landing. He later extended his insight to how we know when an object moves and yet keep a fixed awareness of our surroundings as opposed to moving our head. His students later extended this to show that the development of perception is dependent on our ability to move in the environment. Hence the kittens.

If we were to graph the position of the tip of the light wave (the arrow head) along the x-axis and the time that has passed along the y-axis, we would get a graph something like this. (This is the kind of graph we are going to turn in to our Feynman Diagrams in Quantum Mechanics.)

This is amazing writing advice