10,000 Matching Annotations
  1. Sep 2018
    1. Add to all this, that our lives depend upon a single thread; and if, wherever we are in the world, we are to expect death every hour, and to be prepared for it, this is particularly the case here. For not to mention that your Cabin is only, as it were, chaff, and that it might be burned at any [page 93] moment, despite all your care to prevent accidents, the malice of the Savages gives especial cause for almost perpetual fear; a malcontent may burn you down, or cleave your head open in some lonely spot. And then you are responsible for the sterility or fecundity of the earth, under penalty of your life; you are the cause of droughts; if you cannot make rain, they speak of nothing less than making away with you. I have only to mention, in addition, the danger there is from our enemies; it is enough to say that, on the thirteenth of this month of June, they killed twelve of our Hurons near the village of Contarrea, which is only a day's journey from us; that a short time before, at four leagues from our village, some Iroquois were discovered in the fields [65] in ambuscade, only waiting to strike a blow at the expense of the life of some passer-by.

      They commonly feared their life. As though they could be killed at any moment

    1. Throwing back your head and closing your eyes allows you to give the appearance of sexual readiness while concealing revulsion.

      motif of mechanization

    1. On the other hand, you had the situated view, which helped establish a contextu-alized science for learning, in which learning at the minimum required investigating the social and cultural contexts of learning, and at the maximum treated learning as inherently a phenomenon not in the head but in the relationships between person and their context.
    1. There is, said Michael, if thou well observe [ 530 ] The rule of not too much, by temperance taught In what thou eatst and drinkst, seeking from thence Due nourishment, not gluttonous delight, Till many years over thy head return: So maist thou live, till like ripe Fruit thou drop [ 535 ] Into thy Mothers lap, or be with ease Gatherd, not harshly pluckt, for death mature: This is old age; but then thou must outlive Thy youth, thy strength, thy beauty, which will change To witherd weak and gray; thy Senses then [ 540 ] Obtuse, all taste of pleasure must forgoe, To what thou hast, and for the Aire of youth Hopeful and cheerful, in thy blood will reigne A melancholly damp of cold and dry To weigh thy spirits down, and last consume [ 545 ] The Balme of Life.

      Milton here saw us a soft, mild, kind way of our fall, our death. All are coming to an end as the result of our sin. Death come to all of us. In my point of view this is nice, comfortable view, instead our reality. Our painful fall to diseases and death. The end is not peaceful. For the most of the people is painful, violent and hard. But people always tried to calm our violent enviroment. Life never was easy for the human.

    1. On page 118 and 119, there are two works that compare scientific illustration with a more aesthetically pleasing work. The scientific illustration depicts a woman and the various muscles of the limbs. It is different from other scientific examples of humans in that she is juxtaposed in a room, laying. Other examples are usually more splayed out in order to show a clear difference between body parts. However, this woman is seen with her arms held over her head and her legs bent while sitting on a bed. For a scientific illustration of anatomy, it does seem oddly sexual. One thing that I found very interesting is the obsession with anatomy and depicting naturalistic imagery, yet this woman does not look very woman-like. Artists, such as Leonardo, would study cadavers and watch how people around him moved in order to get a better understanding of bodies and muscle movement. However, I am assuming it was harder to observe woman bodies. Many times, woman painted in the Renaissance have very manlike muscles, legs, abdomens and chests. This can be seen here in Estienne’s depiction of the woman’s body.

    1. “Archaic Torso of Apollo.”

      Archaic Torso of Apollo Rainer Maria Rilke, 1875 - 1926

      We cannot know his legendary head with eyes like ripening fruit. And yet his torso is still suffused with brilliance from inside, like a lamp, in which his gaze, now turned to low,

      gleams in all its power. Otherwise the curved breast could not dazzle you so, nor could a smile run through the placid hips and thighs to that dark center where procreation flared.

      Otherwise this stone would seem defaced beneath the translucent cascade of the shoulders and would not glisten like a wild beast’s fur:

      would not, from all the borders of itself, burst like a star: for here there is no place that does not see you. You must change your life.

    1. Sketch to Stretch This sixth grader is using Sketch to Stretch (Harste & Burke, 1988; Beers, 2003) to represent visually a powerful line from Henry's Freedom Box. As he visually represented his thinking about a particular line, he stretched his understanding of the text. When students sketch what a text represents to them, it helps them focus on specific words, especially important when reading nonfiction

      I think this is so important for young readers. Not only because of the idea of focusing on specific words, but also to help children find a love of reading. When I read a book, I am constantly painting a picture, it's basically a movie going on inside my head. It makes reading easier and more enjoyable. I think most people do this, but there are so many children missing this. I believe it really comes down to the fact that some children need more instruction in reading comprehension, but they easily fall through the cracks. This is setting those children up for a lower vocab skills and lost interest in reading, which will help them go further in life.

    1. You have to see the suspect, 30-year-old Nikhom Thephakaysone, sitting on the light-rail train, pulling out his .45 caliber pistol, pointing it across the aisle, putting it back, pulling it out several times again, and at one point wiping his nose with the hand holding the gun — and nobody notices because they’re too busy staring down at their smart phones and tablet computers. We’re talking about a train crowded with commuters and this guy is waving a gun around but nobody sees him, so engrossed are they in texting, tweeting and playing Angry Birds.

      That's a little ridiculous, I'd even say unrealistic. But tunnel vision can be dangerous, that's for certain. I read about a case where a gamer died in an internet cafe due to malnutrition (insanely long session), and even still nobody noticed except for staff, as well as many other cases such as this.But I still think, just at the basis of this argument without reading deeper, this seems like social media itself, or even technology for that matter, isn't exactly the problem. Have you ever seen pictures of old fashioned public transit? Nearly every passenger is absorbed in a newspaper, a book, or asleep with their head in their hands. Yes, self possession and lack of awareness is more readily accessible, captivating, and gratifying with the case of out current tech standards, and because of that I won't deny that they are a factor towards the occurrence of this incident. However they are certainly not the only type of causation?

    1. You don’t know necessarily how tall they are, because I don’t want to force the reader into seeing what I see. It’s like listening to the radio as a kid. I had to help, as a listener, put in all of the details. It said “blue,” and I had to figure out what shade. Or if they said it was one way, I had to see it. It’s a participatory thing.

      "it's a participatory thing", I think this is why am I Toni Morrison fan. She always uses such beautiful description to paint a clear enough picture in your head, but she doesn't give you too much description where you're drowning in it. This is advice that I wish I'd realized sooner.

    1. his squaw gave me some ground nuts; she gave me also something to lay under my head, and a good fire we had; and through the good providence of God, I had a comfortable lodging that night.

      Not all the Indians are bad some do show her kindness but she always thanks god instead of thanking them.

    2. I told them the skin was off my back, but I had no other comforting answer from them than this: that it would be no matter if my head were off too.

      Sort of sounds like complaining or showing off, and the Indians aren't having it. Almost like she's being all high and mighty but they couldn't care less even if she had her "head off"

    3. his squaw gave me some ground nuts; she gave me also something to lay under my head, and a good fire we had; and through the good providence of God, I had a comfortable lodging that night.

      when the Indians do show her kindness, she thanks god, but does not seem to give credit to the Indians themselves?

    1. The mayor shall designate the head of an office of the mayor, or of such other agency headed by a mayoral appointee as the mayor may determine, to act as the city’s chief privacy officer.

      Is there any place where you can see the contact information for all of the current Mayoral appointed officials?

    1. Cast down your bucket among these people who have, without strikes and labour wars, tilled your fields, cleared your forests, builded your railroads and cities, and brought forth treasures from the bowels of the earth, and helped make possible this magnificent representation of the progress of the South. Casting down your bucket among my people, helping and encouraging them as you are doing on these grounds, and to education of head, hand, and heart, you will find that they will buy your surplus land, make blossom the waste places in your fields, and run your factories.

      i feel like this is a call for union. Washington points out to blacks that the whites have been doing all this work for so long with no complaints and that they must they are not alone.

    1. (he actually hurts himself head-butting this time, another new angle for the series)

      Actually this is an error. Reacher's injury is not caused by head-butting, but by a blow to the side of the head.

    1. Six miles’ walk before 6.30a.m., and six miles’ walk after 5p.m., with a hard day’s work of carrying earth-piled baskets on the head in between, does not strike one as being an easy life, but more girls begged for work than we could employ

      The work wasn't ideal but work is work

    1. A little child of six years was extremely [26] sick in the Mission of saint Michel. His mother was unable to contain her tears, seeing the excess of his pain, and the approach of death to this her only son. " My mother," said to her this child, " why do you weep your tears will not give me back my health; but rather let us pray to God together, so that I may [page 111] be very happy in Heaven." After some prayers, his mother said to him, " My son, I must carry thee to Sainte Marie, so that the French may restore thee thy health." " Alas! my mother," said to her thief little innocent, " I have a fire burning in my head could they indeed quench it? I no longer think o life,—have no desire of it for me; but I will wart you of my death, and, when it is near, I will pray you to carry me to Sainte Marie, for I wish to die there, and to be buried there with the excellent Christians." In fact, some days later, this child warned his mother that his death was near, and that it was time to carry him to us. It is the custom in these countries, when any one is near death, to make a solemn feast to which are invited all the friends and the most considerable persons,—about a hundred. The mother would not [27] fail in this obligation,—desiring also to apprise all the people of the sentiments which her son had toward the Faith. This child, having seen the preparations for the feasts said to her: " What! my mother, would you have me sin so nigh to my death? I renounce all these superstitions of the country; I wish to die a good Christian." This child believed that that custom was among the number of those forbidden; and although his mother, an excellent Christian, assured him that there was no evil in that, he would never believe her, and could not resolve to comply with her wish, until the Father who has charge of that Mission had assured him that in that feast there was no sin. This little Angel was brought to us; and he died in our arms, praying even till death, and telling us that he was going straight to Heaven, and that he would pray to God for us; and he even asked his mother [page 113] for which of his relatives she wished him to pray chiefly, when he should be near God,—saying that no doubt he would be heard. He has been; for, shortly after his death, an uncle of his, one of those most rebellious against the Faith in these countries, and an aunt of his, asked us for instruction, and have become Christians.

      A very telling personal story of a dying child with his mother. Even in the ending, he states that the uncle and aunt had changed their views on Christianity.

    2. I saw and touched all parts of his body, which had received more than two hundred blows from a stick. I saw and touched the top of his scalped head; I saw and touched the opening which these barbarians had made to tear out his heart.

      Can just picture the image of this brutality.

    1. thank your lordship, it is very hot. HAMLET No, believe me, 'tis very cold; the wind is northerly. OSRIC It is indifferent cold, my lord, indeed. HAMLET But yet methinks it is very sultry and hot for my complexion. OSRIC Exceedingly, my lord; it is very sultry,--as 'twere,--I cannot tell how. But, my lord, his majesty bade me signify to you that he has laid a great wager on your head: sir, this is the matter,--

      I've noticed that Hamlet has done this to a few people, knowing his power he can say something and the person he is talking to will instantly agree and change their mind.

    1. Like one who, on a lonely road,                Doth walk in fear and dread,           And, having once turn’d round, walks on,                And turns no more his head;           Because he knows a frightful fiend                Doth close behind him tread.

      More lines from Samuel Taylor Coleridge's "The Rime of the Ancient Mariner."

    1. On the return trip from the Pacific Ocean, Ordway was given the task of leading a party of 10 men to the head of the Jefferson River, where the Corps had left its canoes before crossing the mountains.

      This illustrates the trust Lewis and Clark had in him.

    1. your master will knock your child in the head,” and then a second, and then a third, “your master will quickly knock your child in the head.”

      In a way to 'just' knock it out, maybe even put her out of her own misery and theirs for how loud she is being..but not kill her

    2. “your master will quickly knock your child in the head.”

      I mean its better than murdering the child, still cruel tho. however maybe it was just an empty threat? because they kept repeating the phrase, but never hit the child

    3. sometimes one Indian would come and tell me one hour that “your master will knock your child in the head,” and then a second, and then a third, “your master will quickly knock your child in the head.” This was the comfort I had from them, miserable comforters are ye all, as he said.

      They're so comforting. Jeesh.

    1. they would break my face

      Odd how on one occasion or another they treat her kindly by allowing her to see her children sometimes, allowing her to ride on a horse and giving her enough shelter. Then they say something about bashing her child's head and then smashing her face? I'm not sure what makes them decide to be nice or not, but they definitely have an obsession with hurting someone's head. Maybe out of wanting to affect the brain since they see it as the most precious?

    1. Then they set me upon a horse with my wounded child in my lap, and there being no furniture upon the horse’s back, as we were going down a steep hill we both fell over the horse’s head, at which they, like inhumane creatures, laughed,

      Both hospitable and cruel.

    2. Then they set me upon a horse with my wounded child in my lap, and there being no furniture upon the horse’s back, as we were going down a steep hill we both fell over the horse’s head, at which they, like inhumane creatures, laughed,

      Cared enough about her to give her a horse, but then maybe laughed at her because she can't ride a horse like they can

    3. One of the Indians carried my poor wounded babe upon a horse; it went moaning all along, “I shall die, I shall die.” I went on foot after it, with sorrow that cannot be expressed. At length I took it off the horse, and carried it in my arms till my strength failed, and I fell down with it. Then they set me upon a horse with my wounded child in my lap, and there being no furniture upon the horse’s back, as we were going down a steep hill we both fell over the horse’s head, at which they, like inhumane creatures, laughed,

      This relationship is interesting. They carry her baby for her, but when her strength fails, they allow her to ride on the horse. Yes, they laughed when she fell off, but that is undoubtedly because she was their prisoner. I want to know what they are thinking.

  2. arabmideastcinema2018.files.wordpress.com arabmideastcinema2018.files.wordpress.com
    1. Kinawi rubs his nose affectionately against the sideof her head, an act of innocent intimacy that is momentarily acceptable

      Is this actually a well known act of innocent intimacy? I perceived it as kind of crossing boundaries, going a bit too far with Hanouma. I thought he was definitely going to get slapped.

    2. The former was “modern, infi-nitely more attractive”, whereas the “old” city “seems destined to prolong itsagony and not to revive, being unable to struggle against progress and its inevi-table consequences”

      Reading this description of the dichotomous Cairo immediately brought to mind the scene in which Hanouma and Qinawi have a dialogue by the fountain [28:20 - 28:42]. When Qinawi stands up, we see the statue of Ramses II in the background for a second--and the insert shot of Hanouma's gaze / reaction at [28:23] further brings our attention to the Qinawi-Statue two-shot. I felt that, in parallel to the reading, this scene establishes Qinawi as the "old" Cairo, unchanging in its pursuit of unrequited love, "unable to struggle against progress", and rather delusional in his fantasies and obsessions; on the other hand, Hanouma remains sitting with the clean and modern fountain in the backdrop, making it quite easy to then associate her to the "new" Cairo, "ever changing" and "infinitely more attractive".

      Moreover, the content of their dialogue, especially when Hanouma breaks out of their daydreamy talk to scold Qinawi ("Use your head. Look around. I work hard for a living, selling drinks [...] Get a grip on reality. I've had enough.") further embodies the dichotomy described by the author regarding the "old" and the "new" and their incongruous coexistence.

    1. his professor was very unlike his colleague. He appeared about fifty years of age, but with an aspect expressive of the greatest benevolence; a few gray hairs covered his temples, but those at the back of his head were nearly black.

      Mary Shelley uses appearance as a huge part of her novel, focusing on the appearance of which professor Victor prefers, as well as later, on Frankenstein's monster.

    1. One thing that really caught my attention in this chapter was acknowledging scientists as extremely creative people. Thinking about how they must take the world as they and others see it and flip that around on it's head in order to find answers makes sense, but is an idea that has really really came to me before. I don't think scientists get enough credit for the amount of creative thinking they have to do in order to find success.

      I understand that it is important to keep bias out of science, but I struggle to believe that it's possible to keep so many individual's varied biases out of science. I'm sure this is already functional in the scientific community today, but I would be interested to see some of the issues in science regarding bias that we face today.

    1. people who had just fallen in love and observed that their brain chemistrywas “going crazy,” similar to the brain of an addict on a drug high

      I feel like at this age group alot of college students have had that first love and been head over heals about someone, if not them specifically than maybe a close friend of theirs has. Helen Fishers research goes to show that being in love literally changes you as a person, your whole brain is even going through changes and is hyped up all the time. Nowadays I see couples posting picture on social media that say "high on you" or "your love is my drug". Most people when reading these captions would just think they are being sweet or maybe even sarcastic but it is true that being in love is like being on drugs.

    2. The passion component of love is comprised ofphysiological and emotional arousal; these can include physical attraction, emotionalresponses that promote physiological changes, and sexual arousal

      In the show 13 reasons why one of the main characters Alex Standall had a suicidal attempt and shot himself in the head. After this he completely recovered except for sexual arousal. He was having difficulties and it started to effect his relationships with girls on the show. This goes to show that sometimes not having both emotional arousal and physiological can be a problem.

    1. come creeping down, and when it was most abreast of where I stoodI heard a man say, “Stern oars, there! heave her head to stab-board!”I heard that just as plain as if the man was by my side.There was a little gray in the sky now; so I stepped into the woods,and laid down for a nap before breakfast.

      Makes Plan to escape home/ does successfully. But father follows him?

    2. Tom said he slipped Jim’s hat off of his head andhung it on a limb right over him, and Jim stirred a little, but he did-n’t wake. Afterwards Jim said the witches bewitched him and put himin a trance, and rode him all over the State, and then set him underthe trees again, and hung his hat on a limb to show who done it. Andnext time Jim told i

      What happens to Jim in the future. Why explain it now/ relevant?

    1. Did I not put my headwith a god's for days,asking why is there bloodand hair in the snares

      I did not understand what type of Gods the hunter's talking about when he said "Did I not put my head with a god's" is he mean that he has a sharp discussion with Gods to find out about the blood or something else?

    1. We should reject moral absolutes, even as we keep our moral convictions, allowing that there can be right and wrong relative to this or that moral code, but no right and wrong per se.

      I agree with this to an extent. I believe there are right and wrong for the most part, and it does have to do with a "moral code", but what about certain people who dont have the same chemical makeup as others do? We as a society know the difference from right and wrong for the most part, because we have that voice in our head that tells us its wrong, or right, and our conscience eats at us making us feel certain things. But what about other people who dont have that same thing? There is people out there who arent taught right from wrong, so they dont know any better. We see things as, talking down to authority figures, fighting with people for no reason, committing crimes, etc. as wrong decisions because of our moral code we were taught. But to other people, that is just normal things to do, and normal reactions.

    1. Consider two of the most prominent disinvitation targets of 2014: former U.S. Secretary of State Condoleezza Rice and the International Monetary Fund’s managing director, Christine Lagarde. Rice was the first black female secretary of state; Lagarde was the first woman to become finance minister of a G8 country and the first female head of the IMF. Both speakers could have been seen as highly successful role models for female students, and Rice for minority students as well. But the critics, in effect, discounted any possibility of something positive coming from those speeches.

      Ridiculous. Neither are known for hateful statements or even thoughts.

    1. But if men don’t mind and start and act a fool,That’s sure to cause no end of care and strife.My advice to you is this, let us work with a cool head,

      The writer wants to make sure that the stikers maintain their cool and don't allow this to become violent.

    1. CBD oil has been widely available in many stores, from organic local powerhouse Mustard Seed Market to the smallest head shops and convenience stores that serve the city and suburban neighborhoods.

      How were these stores such as Mustard Seed been able to sell it in Ohio if it is illegal?

    1. The little duck, that had been given whiskey,was now on his legs, unsteady legs. With a proudair, he was holding his head high.“Seems as if the whiskey had gone to his head,”said Old Timothy, smiling and winking at me.“Feel pretty happy, Ducky^ Felt like that myself once—felt as if I owned the earth—felt—”

      An all-time favorite quote from the Wayne State University digital collections

    1. They are a North American group living in the territory between the Canadian Cree, the Yaqui and Tarahumare of Mexico, and the Carib and Arawak of the Antilles.

      Never head the United States described as this before! Took me a minute to realize what this "place" was and that I'm a part of it.

    1. That Orpheus self may heave his head [ 145 ] From golden slumber on a bed Of heapt Elysian flowres, and hear Such streins as would have won the ear Of Pluto, to have quite set free His half regain'd Eurydice. [ 150 ]

      Orpheus receives a mention in "Il Pensoroso" as well but only in this poem is his failure to save Eurydice mentioned. In "Il Pensoroso" Orpheus is a flawless musician, but here he is a failure.

    1. When you compare this circuitous route with the far more direct one of the United States, it is quite easy to understand why the United States can sell even our wheat to the Gulf Provinces at lower prices than we ourselves are able to do. I have attempted to reduce the commercial advantages we are promised to their proper proportion. I will now endeavor to show that we can secure every one of these advantages without the Confederation. I shall cite, for that purpose, the very words of the Honorable Minister of Finance :— If we look at the results of the free interchange of produce between Canada and the United States, we shall find that our trade with them increased, in ten years, from less than two millions to twenty millions of dollars. If free trade has produced such results in that case, what may we not expect when the artificial obstacles which hamper free trade between us and the provinces of the Gulf shall have disappeared ? But this fine result was not obtained by means of a Confederation with the United States. What hinders us from having free trade with the Gulf Provinces ? In support of this view, I shall quote the work of the honorable member for Montmorency, not that of 1858, but that of 1865, written in favor of Confederation, pages 32 and 33, where he shews in the most conclusive manner that we have no need of Confederation to improve our commercial relations with the Gulf Provinces. It is under this head of commercial advantages that the Intercolonial Railway fitly comes in. The Honorable President of the Council tells us that he is favorable to Confederation, because it will give us a seaport at all seasons of the year—a most powerful argument, he adds, in its favor. We stand in great need of a seaport in the winter season, more especially if the United States abolish the right of transit. Absolutely, without reference to that, we require it in order to perfect our system of defence.

      §.121 of the Constitution Act, 1867.

    2. MR. CORNELLIER—All the confederations which you have mentioned were or are republican, and had the common fate of republican institutions. You have not said a word about monarchical confederations. MR. JOLY—I have made no mention of monarchical confederations, because none have ever existed, and none can exist. The principle of a monarchy is that the power resides in one person; the principle of confederation is that it resides in all the members of the confederation. A confederation would, therefore, always be a republic, even if formed of several states subject to a monarchy; because the power would not be vested in one person, but in each of the several states, of which no one would acknowledge a head ; it would be a republic consisting of a very small number of members. Before I take leave of all the confederations, the names of which I have mentioned, I intend to say one word, at least, in their favor. We understand that states

      §§.9, 17, 91 and 92 of the Constitution Act, 1867.

    1. I never knew despair could lie.

      Quote reminds me of a person who might think the world is out to get them when in reality, all the bad perceptions are made up in their head

    2. There was the live footage of students fleeing in terror across the green, the boy with the bleeding head being dropped from the window, the SWAT teams moving in.

      Re-visiting the live footage in descriptive terms; helps set the setting of what we start to read.

    1. Behaviors also can affect the environment, as when students eliminate distractions from their environments

      I am one of those people who can't read while having music on, people talking or having the tv on. With that being said, I also struggle with reading on screens. I lose my place and it makes my head and eyes hurt. However, I know this is a route most schools are going. I feel like a tv is considered a distraction, but isn't a computer/iPad? Many students I work with work on iPads and I feel like these can be distractions because students are tempted to play games or search other things when no one is looking at them.

  3. www.sacred-texts.com www.sacred-texts.com
    1. The family was not only the social unit, but also the unit of government clan is nothing more than a larger family, with its patriarchal chief as the natural head, and the union of several clans by inter-marriage and voluntary connection constitutes the tribe.

      inclusion for benefit of health and wellness of everyone

    1. The girl was covering one of her eyes with her hands. The boy was limping, because he had lost one of his bones. Then the people looked at the place where the boy had been sitting, and they found the eye, and a bone from the head of the male salmon. They ordered the boy to throw these into the water. He took the children and the eye and the bone, and threw them into the river. Then the children were hale and well.

      Has almost horrific elements.

    1. llow workers to focus on the human aspects of work

      In this sense, we're re-defining knowledge. It's no longer simply information in one's head. Knowledge is performative; it's what one can do, not what one can remember.

    1. This was not, as I have stated already, because of any predilection on our part for the elective principle. I t was not because we thought that the elective principle was much better than the system of appointment by the Crown—at all events before the introduction of responsible government. Before that, the gentlemen who nominated members of this House were responsible to no one. The appointments then were all made on one side. Even after the union, but before responsible government was established, or before it was put in a thoroughly practical working state, the appointments had been made in a partial manner. (Hear, hear.) And it is not surprising that we experienced the difficulties we did until that period. After the establishment of responsible government the position was very different—the resolutions of the 3rd September, 1841, having declared that no Government could be carried on except by heads of departments having the confidence of the representatives of the people in the lower branch of the Legislature. If, from that moment, bad appointments happened to be made to the Legislative Council, then the Government for the time being was responsible to the people for those appointments. And, when the people wanted an elective Council at that time, they did not base the demand upon constitutional principles, but were led by their passions, which had been excited by their recollections of the past. They did not reason the thing out ; and, in fact, the great majority of the people here, as everywhere else, are not able to reason out constitutional points—they are led by those who are at the head of the different parties.

      §§.24 and 26 of the Constitution Act, 1867.

    1. The picture I took is pretty close to what I see in the mirror but there are photos of me from a party this weekend and they made me want to stay inside with a blanket over my head.

      slefies show the other side of you that we cant always see.

    1. The message was taken to the Red Head, who immediately crossed the lake in his canoe. As it neared the shore White Hawk saw that its framework was of live rattlesnakes, who thrust out their heads and hissed and rattled as he stepped into the boat. The Red Head spoke to them and they quieted down, as dogs at the word of their master.

      Are the snakes for decoration or for intimidation? Both perhaps for such a man as he

    2. but you are the only one who has set out to do it."

      Likes his determination? Why she's willing to help him possibly..Or to end up killing him and Red Head in the end

    3. go to the river after dark will never kill the Red Head." Now, it was the ambition of every Indian boy to kill the Red Head.

      Shaming the heck out of him then, he should know by then it means something to them (his parents)

    1. It envisioned a 1km stretch of dual carriageway between Salford University and Manchester city centre as a 4-lane linear Park. One lane is grassed, another a water channel, another sand and the last a running track. Commuters leave their cars in a multi-storey Car (P)Ark. The interchange also incorporates a suburban train station, cycle docking station, stables, and a boathouse and changing rooms. From the Car (P)Ark commuters head east into Manchester walking, jogging, cycling, rollerblading, horse riding, swimming or rowing. The Park terminates at a Suit Park where commuters can shower, change and get a coffee. (The word “suit” refers to the business suit). Eight hours later, on their way home, commuters deposit their clothes and return through the Park, to the interchange to collect their car or catch a train. The scheme could be extended to each of the radial routes into Manchester and at intervals these Parks could link, completing a comprehensive green commuter infrastructure. Save this picture! The Park + Jog proposal, 1998. Image Courtesy of Henley Halebrown Rorrison Architects Save this picture! Rendering of the Park + Jog proposal, 1998. Image Courtesy of Henley Halebrown Rorrison Architects What is striking about these parks is the positive impact they can have on their surrounding neighbourhoods, particularly when one considers the alternative. With roads, be it a dual carriageway or a street, comes heavy traffic, noise and pollution, at the expense of those who live and work around it. In the case of a High Street we forego certain types of shops, cafés and restaurants that engender a street life. At the scale of the dual-carriageway the A40 that tears through west London illustrates beautifully how dramatic the blight on homes can be, as this Mid-20th Century residential avenue has been transformed into a slum wrapped around a congested commuter road. These zones lack the 'density' of the city centre and the space of the suburb. And, each successive wave of Greenfield development adds to the expanse of this grey space.Active transportation routes and linear parks, on the other hand, regenerate their surroundings, bringing activity and value to blighted sections of the city. They also radically alter the political situation for the suburb and its inevitable commute. Of course, the creation of these green networks need not be at the expense of the motorist. On the 10th July London’s Transport Commissioner Peter Hendy launched a study for London that envisaged burying sections of the North and South Circular ring roads, and stretches of road close to the Thames. The initiative would create linear parks overhead, much as the Big Dig did for Boston. Save this picture! The Olympic Sculpture Park in Seattle, Washington, designed by Weiss Manfredi. Image © Benjamin Benschneider Although originally conceived for Manchester, I believe that Park+Jog may be adapted to any city worldwide and serve as an example for how Cycle Space could lay the ideological foundation to change our cities for the better. Combining new transportation methods that encourage the principles of a healthy life style with traditional roads can raise land values, attract investment and activate the urban environment. The social revolution that Bazalgette offered London in the 19th Century, Cycle Space might just bring to London and our world’s cities in the 21st. Simon Henley is a teacher, author of the well-received book The Architecture of Parking, and co-founder of London-based studio Henley Halebrown Rorrison (HHbR). His column, London Calling, looks at London’s every-day reality, its architectural culture, and its role as a global architectural hub; above all, it will explore how London is influencing design everywhere, whilst being forever challenged from within. You can follow him @SiHenleyHHbR and be a fan of his Facebook page, HHbR Architecture.Further Reading Park+JogLondon’s answer to Boston’s Big DigRogers 80th Birthday retrospective at the Royal AcademyThe Lidoline, YN Studio's "Swim to Work" Proposal AIA Presents 2013 Educational Facility Design Excellence Awards Architecture News Tretyakov Gallery Competition Entry / PAPER | TOTEMENT Unbuilt Project Save this article Share in Whatsapp About this author Simon Henley Author Follow See more: News Articles London CallingLondonBicyclingUrban Planning Cite: Simon Henley. "Why Cycle Cities Are the Future" 06 Aug 2013. ArchDaily. Accessed 3 Sep 2018. <https://www.archdaily.com/409556/why-cycle-cities-are-the-future/> ISSN 0719-8884 Read comments Browse the Catalog Ceramic Sunscreen - ALPHATUBE® Shildan Danpalon 3DLITE - Solar Control Danpal Elevator in Round Stairs Brembo Ascensori - The Elevator Company Upholstery Fastening System - Textile Range Fastmount® Frameless Sliding Doors - Sky-Frame Plain Sky-Frame Stainless Steel Bollards Reliance Foundry Please enable JavaScript to view the <a href='http://disqus.com/?ref_noscript'>comments powered by Disqus.</a> › 世界上最受欢迎的建筑网站现已推出你的母语版本! 想浏览ArchDaily中国吗? 是 否 翻译成中文 现有为你所在地区特制的网站?想浏览ArchDaily中国吗? Take me there » Recommended for you Hawkins\Brown's London Pride Float Celebrates the "Dual Identities" of LGBT+ Architects Bicycle Club / NL Architects 10 Points of a Bicycling Architecture London Skyline Debate Taken to City Hall More Articles Could You Live in 15 Square Meters of Space? SUMATORIA's 'Tiny Home' May Make You Think Twice 17 Spectacular Living Roofs in Detail What it Means to Build Without Bias: Questioning the Role of Gender in Architecture More Articles » most visited 22 of the World’s Greatest Architecture Projects Selected by Time Magazine Dragons, Rocks, and Sails Inspire Sceno Light's Floating Theater in Vietnam's Ha Long Bay New Concrete House / Wespi de Meuron Most visited products Structural wood boards in Freiland-Hof Home | EGGER WEBNET Stainless Steel Frames | Jakob Siding Façade System | Technowood

      This shows that the architect has a clear plan for the bicycle sharing plan.

    1. Nor of the Muses nine

      Here's a picture of the Nine Muses which I just saw in the Museum of Fine Arts Boston this past week. https://mfas3.s3.amazonaws.com/objects/SC309028.jpg The head of the Muses was named Mnemosyne, which means Memory (mnemonic). Before the days of literacy, people paid a lot of attention to developing and maintaining their memory, and indeed Mnemosyne was one of the leading goddesses. Later, under patriarchy, she was split into nine, and all took a subordinate role to the male gods.

    1. Her unadorned golden tresses wore [ 305 ] Disheveld, but in wanton ringlets wav'd As the Vine curles her tendrils, which impli'd Subjection,

      William Blake's image of Adam and Eve in Bk 4 shows them as very classical, if muscular, entities - with Eve of course suitably subject. In the same plate Satan flites about while embracing the serpent (with a bird-like head!). Blake always adds something to a text; I guess just his own imagination.

    1. His words silenced her, cut to the bone. She'd always had a heavy hand in his life, it was true, striving not to control it but to improve it somehow. She had always considered this her responsibility to him. She had not known how to be a sister any other way.

      the way this paragraph cuts between the dialogue slows the moment down and puts readers in Sudha's head

    Annotators

    1. Your hustle is the result of your heart – your values, passions, interests – and head – your strengths and talents, what you know – working in line with each other.

      hustle definition

    1. The Federal Government will have the right of imposing taxes on the provinces without the concurrence of the local governments. Under article five of the 29th resolution, the Federal Government may raise moneys by all modes or systems of taxation, and I look upon this power as most excessive. Thus, in case it should happen, as I said a moment ago, that the Lower Canada Government refused to undertake the payment of the debt contracted for the redemption of the Seigniorial Tenure, the Federal Government would have two methods of compelling it to do so. First, by retaining the amount out of the eighty cents per head indemnity to be accorded to the Local Government, and secondly, by imposing a local and direct tax. The Lieutenant Governor of the Local Government will be appointed by the Federal Government, and will be guided by its instructions. We are not told whether the Local Government will be responsible to the Local Legislature; whether there will be only one or two branches of the Legislature, nor how the Legislative Council will be composed, if there is to be one ; we are refused any information whatsoever on these points, which are nevertheless of some importance.

      Preamble, Part V, §§.90 and 91(3).

  4. Aug 2018
    1. The sheer extent and duration of the European empire and its disintegration after the Second World War have led to widespread interest in postcolonial literature and criticism in our own times.

      because why? things started to head to shit, maybe?

    1. Fixtures might seem like a small thing, but they were key to drawing in postwar shoppers, who were growing hooked on modern convenience and efficiency—at the time, cafeterias, drive-ins, and automats were way more exciting than sit-down restaurants. Of course, high-end department stores, like Ransohoff’s in San Francisco, continued to offer the full-service shopping experience. High-society ladies still enjoyed getting dressed from head-to-toe, the way you see Jimmy Stewart having saleswomen remake Kim Novak in 1958’s “Vertigo.” But by and large, the booming mid-century middle class wanted shopping autonomy. “In the mid-century, Americans were wanting and buying more,” Wood says. “In response, the department stores offered and displayed more, like the same purse in five colors. There was a new desire to let shoppers see and touch all the merchandise. Before this change, department stores would have everything behind the glass case, with just one sample out. You’d have to ask the salesgirl, ‘Hey, do you have any other colors?,’ and she would search the stockroom for you. The new stores would have had everything out so shoppers could walk around, see it all, and then choose something on their own and take it to the sales counter.”

      customer has the decision of what they want buy. and it change the shopping to an very relax and personal experiences.

    1. 9, the events at Columbine High School mesmerized the nation. There was the live footage of students fleeing in terror across the green, the boy with the bleeding head being dropped from the window, the SWAT teams moving in. There was the discovery of what lay beyond the eye of the camera: fifteen dead, a cache of weapons, a large homemade bomb made with two propane tanks and a gasoline canister, the eventual disclosure of an even more sinister fantasy that involved hijacking a plane and crash-ing it in New York City.1

      It draws the reader and informs them deeply into it so they would understand the rest. The information pictures the future events

    2. There was the live footage of students fleeing in terror across the green, the boy with the bleeding head being dropped from the window, the SWAT teams moving in. There was the discovery of what lay beyond the eye of the camera: fifteen dead, a cache of weapons, a large homemade bomb made with two propane tanks and a gasoline canister, the eventual disclosure of an even more sinister fantasy that involved hijacking a plane and crash-ing it in New York City.1

      gives you an idea of how bad it was

    1. The Race unblest, to being yet unbegot. Childless thou art, Childless remaine:

      Eve's despair leads her to the conviction that they should remain childless. Adam argues that they should rise to better hopes. This hope he pins on the part of their sentence which say thy seed shall bruise the serpents head" often in the tradition called the proto-evangelicum.

    2. More miserable; both have sin'd, but thou [ 930 ] Against God onely, I against God and thee, And to the place of judgment will return, There with my cries importune Heaven, that all The sentence from thy head remov'd may light On me, sole cause to thee of all this woe, [ 935 ] Mee mee onely just object of his ire.

      Milton's logic leads him naming Eve the sole cause and doubly guilty, since Adam just sins against God.

    1. "Nowreflectonthistoo,"Isaid."Ifsuchamanweretocomedownagainandsitinthesameseat,oncomingsuddenlyfromthesunwouldn'thiseyesgetinfectedwithdarkness?"

      I find this quote enlightening because the man choses to return to the darkness to share his new knowledge and risk the scrutiny of the other slaves. He wanted to share his enlightenment with others when he could have just stayed in the light. I read this passage as a metaphor of a battle between ignorance and truth. To spread the truth, one must face ignorance head on despite the consequences. The enlightened are obligated to share the truth to advance our society as a whole.

    1. The edge of the operator network (such as the central office for telcos and the head-end for cable operators) is where operators connect to their customers. CORD™ is a project intent on transforming this edge into an agile service delivery platform enabling the operator to deliver the best end-user experience along with innovative next-generation services.

      CORD central office re-architected as d datacenter

      运营商边缘网络(例如电信公司的中心局和有线电视运营商的前端)是运营商连接到客户的地方。

      CORD™旨在将这一优势转变为(agile service delivery platform)灵活的服务交付平台,使运营商能够提供最佳的最终用户体验以及创新的下一代服务 的一个工程

    1. HON. MR. ROSS—As to the export duty on coal from Nova Scotia, it appears from the resolutions that the equivalent given to Upper Canada for this revenue is the duty on Crown timber. HON. MR. SIMPSON—Well, what about the fishery dues given to the Lower Provinces ? HON. MR. ROSS—We will have that by and by. I am only answering one question now. It is in lieu of the duty we levy on timber, and known as ” stumpage dues,” that Nova Scotia is allowed to levy an export duty on coal. The honorable gentleman shakes his head, but it is a fact. HON. MR. SIMPSON—It is not on the stump that we levy dues, but as the hewn timber passes through the slides. HON. MR. ROSS—Well, it is not an export duty at any rate ; but in New Brunswick it pays a duty when exported, either as sawlogs or square timber. In both cases it pays a duty to the Local Government, and it only seems reasonable that Nova Scotia should enjoy a revenue from her coal wherever it goes. (Hear, hear.) HON. MR. MOORE—If the coal were exported to a foreign country, then I could understand why a duty should be imposed, but when a ship is laden in one port of the Confederation, with coal, for another port in the same country, it does not appear much like a free Confederation if an export duty is levied upon the ergo. (Hear, hear.) There would seem, then, to be a distinction—a preference for one portion over another—within the limits of the Confederation. If we are to have a union, I hope we shall have it in fact and

      §.121 of the Constitution Act, 1867.

    1. Gender has been one factor by which family roles have long been assigned. Traditional roleshave historically placed housekeeping and childrearing squarely in the realm of women’sresponsibilities.

      I have always thought of the man to be the head of the household but the wife also needs to put in her part. That is somewhat the traditional way the only difference being that the woman also works instead of being a stay at home mom. As time changes, this is not the case anymore. You see on the news, tv, in your community, and all around you, how families are being broken up, there is a single parent, or a parent dies. This breaks the tradition and completely changes but it all depends on the situation.

    1. And one of the foremost statesmen in England, distinguished alike in politics and literature, has declared, as the President of the Council informed us, that we have combined the best parts of the British and the American systems of government, and this opinion was deliberately formed at a distance, without prejudice, and expressed without interested motives of any description. (Hear, hear.) We have, in relation to the head of the Government, in relation to the judiciary, in relation to the second chamber of the Legislature, in relation to the financial responsibility of the General Government, and in relation to the public officials whose tenure of office is during good behaviour, instead of at the caprice of a party—in all these respects we have adopted the British system

      Preamble and §§.91 and 92 of the Constitution Act, 1867.

    1. But, sir, I am told that though true it is that local matters are to be separated and the burden of local expenditure placed upon local shoulders, we have made an exception from that principle in providing that a subsidy of eighty cents per head shall be taken from the federal chest and granted to the local governments for local purposes.

      §.92(2) of the Constitution Act, 1867.

    1. Yet soon he heal'd; for Spirits that live throughout Vital in every part, not as frail man [ 345 ] In Entrailes, Heart or Head, Liver or Reines; Cannot but by annihilating die; Nor in thir liquid texture mortal wound Receive, no more then can the fluid Aire: All Heart they live, all Head, all Eye, all Eare, [ 350 ] All Intellect, all Sense, and as they please, They Limb themselves, and colour, shape or size Assume, as likes them best, condense or rare.

      Milton invents a physiology of Angel, where in an angel can feel pain, but which is spontaneous healed. He is equal to later day sci fi invention of alien physiology. The problem however is that it is that it does not make angel's spiritual beings, But quasi-physical beings. In other words, he cheating! Calvin's theology especially draws a sharp line between spiritual operation and physical operation. This apples to the above comment "then Satan first knew pain."

    1. As to local taxation, all the provinces will be put upon the same footing, and nothing can be fairer. If Upper Canada, which it is asserted is so much wealthier than the other portions of the Confederation, requires more than the eighty cents per head allowed to all the provinces, its greater wealth will cause it to feel the taxation so much the less.

      §.22 of the Constitution Act, 1867.

    1. in bluefin tuna (Thunnus thynnus) the contraction time tends to increase towards the tail (see also Fig. 1A). This implies that at high speeds, muscles of opposite sides will progressively overlap their contractions towards the tail, stiffening the body.

      Unlike the other fish, the little tunny had muscle contraction times increasing from head to tail, implying that they used their head more than their tail for swimming fast. The authors compared this to another species of tuna, the bluefin tuna because it had a similar trend in muscle contraction. They analyzed this to mean that at high speeds, muscles from opposite sides of the fish (left and right) will contract so that the waves of contraction move towards each other and overlap, which makes the body stiff.

    2. Previous work on other species has suggested that this might aid the transmission of the force

      Previous studies have suggested that this helps move the force from the contractions from the head towards the tail.

    1. The cry was pinched off short as the blood-warm waters of the Caribbean Sea dosed over his head.

      This is an example of rising action, because it is foreshadowing something strange or bad will happen.

    2. The cry was pinched off short as the blood-warm waters of the Caribbean Sea dosed over his head.

      This is an example of conflict. It shows Man vs Nature and that it is getting intense and he is trying hard to survive. The nature surrounding him is not treating him well.

    3. The cry was pinched off short as the blood-warm waters of the Caribbean Sea dosed over his head.

      This is an example of a man vs. nature conflict, because the sea water is making it hard for him to stay above and breathe.

    4. He lunged for it; a short, hoarse cry came from his lips as he realized he had reached too far and had lost his balance. The cry was pinched off short as the blood-warm waters of the Caribbean Sea dosed over his head.

      This is the start of the rising action as it introduces conflict into the story

    5. "Tonight," said the general, "we will hunt--you and I."Rainsford shook his head. "No, general," he said. "I will not hunt."The general shrugged his shoulders and delicately ate a hothouse grape. "As you wish, my friend," he said. "The choice rests entirely with you. But may I not venture to suggest that you will find my idea of sport more diverting than Ivan's?"

      This is a Man vs. Self conflict becuast Rainsford is giving the choice to either be given to Ivan to be taken care of or to go against the general in a hunting game and it is a dicision he has to make himself.

    6. He leaped upon the rail and balanced himself there, to get greater elevation; his pipe, striking a rope, was knocked from his mouth. He lunged for it; a short, hoarse cry came from his lips as he realized he had reached too far and had lost his balance. The cry was pinched off short as the blood-warm waters of the Caribbean Sea dosed over his head.

      This is an example of rising action, the tone is tense and then when Rainsford falls in the reader can sense that something will be happening soon.

    1. So eagerly the fiend Ore bog or steep, through strait, rough, dense, or rare, With head, hands, wings, or feet pursues his way, And swims or sinks, or wades, or creeps, or flyes:

      Satan's entire journey is confused and chaotic so he seems to be ridiculous.

    2. Then shining Heav'nly fair, a Goddess arm'd Out of thy head I sprung; amazement seis'd All th' Host of Heav'n back they recoild affraid At first, and call'd me Sin, and for a Sign

      This is odd, because it resembles Athena fully armed springing out of Zeus' head when he swallowed Metis, for fear that she would give birth to a child that would supplant him. Athena was the highly respected goddess of women who unfortunately strongly favored males over females, and claimed she had no mother, even though Metis was her actual mother. Sin here has no mother - she is born only of Satan. What isn't clear here is why Milton turns the Athena myth on its head (so to speak!) by substituting SIN for the goddess of wisdom.

    3. Ore bog or steep, through strait, rough, dense, or rare, With head, hands, wings, or feet pursues his way, And swims or sinks, or wades, or creeps, or flyes:

      Be he god, hero or mere man, he, Satan here, struggles in the confusion of anarchy and Chaos.

    1. A writer friend of mine suggests opening the jar and shooting them all in the head. But I think he's a little angry, and I'm sure nothing like this would ever occur to you

      I really admire how sudden the change of direction and tone is in such a short time span.

    1. recall and use, in an indexed ‘in-the-head’ reposi-tory called ‘memory’.

      I am currently reading the book "The Power of Habit" and there are a lot of principles from it that relate here. The premise of the book seeks to understand the nature of the brain in creating habits, then applying that to different areas of learning.

    2. Accounts of how an individualinteracts with her material and social contexts, andhow these interactions change over time, replaceaccounts of individual knowledge construction oc-curring ‘in the head’.

      This is a great description on the difference between the two theories. In the head vs. in the community

    1. Typhon

      Typhon or Typhoes was a monster/giant who supposedly was born of Gaia (Earth) and Tartarus (early Titan entity ruling lowest realm of Hades) and attempted unsuccessfully to overthrow Zeus when Zeus seeks to overthrow the Titans and become ruler of the gods. Zeus defeats Typhon, and becomes the head of the gods.

    1. Once she saw in the distance her old grandmother, who had not been to the surface of the sea for many years, and the old Sea King, her father, with his crown on his head. They stretched out their hands towards her, but did not venture so near the land as her sisters had.

      Even though the little mermaid left her whole family they still care about her and come up to the surface to see her. Shows in a way that they are accepting, but there is nothing they can do for her =, but come and see her

    1. she can be discharged. I quickly get her paperwork together and no sooner is she out the door, do I hear I’m getting an admission. I head down the hall before the new patient comes and bladder scan my patient whose foley was removed earlier. Wonderful! He reports he has voided 300ml and only 80ml remain in the bladder. He can go home home too!

      This shows how in a way, even if there are more new patients to be admitted to replace the ones that are discharged, more can be happily discharged than admitted as long as the work is properly done and taken care of.

    1. Anointed universal King, all Power I give thee, reign for ever, and assume Thy Merits; under thee as Head Supream Thrones, Princedoms, Powers, Dominions I reduce: [ 320 ] All knees to thee shall bow, of them that bide

      Is God saying that the Son will rule over and be superior than all but He Himself or has he raised the Son to and above his own role?

    2. Grace cannot be extended towards Man without the satisfaction of divine justice; Man hath offended the majesty of God by aspiring to God-head, and therefore with all his Progeny devoted to death must dye, unless some one can be found sufficient to answer for his offence, and undergo his Punishment.

      So who made these rules? It sounds like God Himself is at the mercy of certain laws of the universe.Or has God actually made them up - which would mean that he would be free to change them.

    3. Affecting God-head, and so loosing all, To expiate his Treason hath naught left, But to destruction sacred and devote, He with his whole posteritie must dye, Dye hee or Justice must;

      I find it interesting that Adam and Eve's original disobedience, on the aspiration of God-head is equated to Treason. A far lesser sin than Satan, who led an open revolt, but still punishable with death and suffering.

    1. The seat of the Federal Government is to be at Ottawa, of course. The Governor General or other head of this magnificent future vice-royalty, or what not, will hold his court and parliament at Ottawa ; but a handsome sop is thrown to Quebec and Toronto, also. They, too, are each to have a provincial court and legislature and governmental departments.

      §.17 of the Constitution Act, 1867.

  5. www.gutenberg.org www.gutenberg.org
    1. mattock

      definition of mattock from OED Mattock (n): An agricultural tool shaped like a pickaxe, with an adze and a chisel edge as the ends of the head.

      The word originates from the Old English word muttac.

  6. course-computational-literary-analysis.netlify.com course-computational-literary-analysis.netlify.com
    1. LILY, the caretaker’s daughter, was literally run off her feet. Hardly had she brought one gentleman into the little pantry behind the office on the ground floor and helped him off with his overcoat than the wheezy hall-door bell clanged again and she had to scamper along the bare hallway to let in another guest. It was well for her she had not to attend to the ladies also. But Miss Kate and Miss Julia had thought of that and had converted the bathroom upstairs into a ladies’ dressing-room. Miss Kate and Miss Julia were there, gossiping and laughing and fussing, walking after each other to the head of the stairs, peering down over the banisters and calling down to Lily to ask her who had come.

      A group of crazy women, they are crazy, they are dancing and screaming crazily. It looks very exciting. In fact, the story of the next story must be quite tragic and cruel. This is the scene of the times of Dublin. People are excited and repressed.

    2. It was well for her she had not to attend to the ladies also. But Miss Kate and Miss Julia had thought of that and had converted the bathroom upstairs into a ladies’ dressing-room. Miss Kate and Miss Julia were there, gossiping and laughing and fussing, walking after each other to the head of the stairs, peering down over the banisters and calling down to Lily to ask her who had come.

      This description is really interesting; before which is the description of a busy girl from a common caretaker's family, she would do lots of things the same with her mother. However, there is a sudden bouncing into a uncanny description and we cannot understand what happens or what the two women are going to do. The uncertainty of the description has pulled me into a muddled place, which has stimulated my interests of further reading.

    3. He knew that he would regret in the morning but at present he was glad of the rest, glad of the dark stupor that would cover up his folly. He leaned his elbows on the table and rested his head between his hands, counting the beats of his temples. The cabin door opened and he saw the Hungarian standing in a shaft of grey light:

      Although Jimmy is happy with being is allowed to play with the rich. He cannot afford their expenses. What's worse, he loses a lot of money in gambling. I think the story reflects the real frustration of the lower class. The inequality in international society will cause the inequality among people from different country.

    4. So Maria let him have his way and they sat by the fire talking over old times and Maria thought she would put in a good word for Alphy. But Joe cried that God might strike him stone dead if ever he spoke a word to his brother again and Maria said she was sorry she had mentioned the matter. Mrs. Donnelly told her husband it was a great shame for him to speak that way of his own flesh and blood but Joe said that Alphy was no brother of his and there was nearly being a row on the head of it. But Joe said he would not lose his temper on account of the night it was and asked his wife to open some more stout.

      What is the purpose in this short story of having dialogue being written in this format, without quotation marks? Since this story is very indirect, is this to add to the writing style?

    5. He knew that he would regret in the morning but at present he was glad of the rest, glad of the dark stupor that would cover up his folly. He leaned his elbows on the table and rested his head between his hands, counting the beats of his temples.

      I think the man was not clear about his life. He wasn't confident about his country and family.

    6. Her time was running out but she continued to sit by the window, leaning her head against the window curtain, inhaling the odour of dusty cretonne. Down far in the avenue she could hear a street organ playing. She knew the air. Strange that it should come that very night to remind her of the promise to her mother, her promise to keep the home together as long as she could. She remembered the last night of her mother’s illness; she was again in the close dark room at the other side of the hall and outside she heard a melancholy air of Italy. The organ-player had been ordered to go away and given sixpence. She remembered her father strutting back into the sickroom saying:

      I have a simple experiment to test the idea that is in my last annotation.I try to figure out what Eveline think about in each paragraph through the number of names of characters. As it is shown in the chart, Eveline recall her lover and family alternatively, which show her great hesitation in making a decision of whether she goes with Frank.

      <img src="https://raw.githubusercontent.com/wangziyi2016/Text-analize/master/mental%20activity.png" width = "550" height = "250" alt="图片名称" align=center />

    1. Paramedics rushed Richards to an area hospital, where he died from his injuries.

      The fact that he was fighting for his life and just couldn't make it breaks my heart. It was on a public street too, where many seen him taking his last breaths and couldn't do anything about it shaking my head.

    1. What does the Federal Farmer mean by “one consolidated government?”  Why does he think this is a bad idea?
      1. Governments need only one head and 2. There were/ are too many different cultures int the U.S to make it work.

      Is this still true?

    1. introductory session on the Textual Encoding Initiative (TEI) offered by Huw Jones, head of the Digital Library Unit

      CUL provides introductions to TEI

    1. In the New Testament, familial metaphors are frequently used to describe Christians and what came to be construed as the universal Church. Christians are “brothers” and “sisters” to one another. Weirdly, collectively they are also the body and the bride of Christ. Wives are commanded to submit to their husbands “as you do to the Lord. For the husband is the head of the wife as Christ is the head of the church, his body, of which he is the Savior” (Ephesians 5:22-23). This teaching of male headship is, of course, a source of much abuse of women in conservative Christian circles, and evangelical pastors have been known to abuse, to sweep abuse under the rug, and to counsel women that they must remain in abusive marriages since, after all, Jesus himself forbade divorce, and God can use suffering for good.

      And of course this also likely the source of American mores which have delivered us the power struggle that results in abuses which have boiled over into the MeToo scandals.

  7. Jul 2018
  8. course-computational-literary-analysis.netlify.com course-computational-literary-analysis.netlify.com
    1. Her time was running out but she continued to sit by the window, leaning her head against the window curtain, inhaling the odour of dusty cretonne. Down far in the avenue she could hear a street organ playing. She knew the air. Strange that it should come that very night to remind her of the promise to her mother, her promise to keep the home together as long as she could. She remembered the last night of her mother’s illness; she was again in the close dark room at the other side of the hall and outside she heard a melancholy air of Italy. The organ-player had been ordered to go away and given sixpence. She remembered her father strutting back into the sickroom saying:

      I found that the writer describes the hesitation of Eveline through alternately recall the life of his family and her lover. I guess we can track the name of character such as Frank and Horry, father through Python3, to figure out how the writer describes Eveline mental activity.

    2. SHE sat at the window watching the evening invade the avenue. Her head was leaned against the window curtains and in her nostrils was the odour of dusty cretonne. She was tired.

      It is obviously a description of a tired person, just like the circumstances around her. The dusty cretonne has suggested that there are lots of things SHE need to do, along with cleaning the cretonne. It just like asking us why she is so tired or how often she got tired like this. And then the stories are keeping going with the basement of the first scene.

    3. In the dark of my room I imagined that I saw again the heavy grey face of the paralytic. I drew the blankets over my head and tried to think of Christmas. But the grey face still followed me. It murmured; and I understood that it desired to confess something.

      The story starts sort of in media res; we know someone is dying, but the narrator only refers to the sick person with male pronouns, and it is until the conversation with the boy's uncle do we know that Father Flynn is dead. Even here, the narrator still speaks of the deceased man using "the paralytic" or a synecdoche such as "the grey face", as if the man's identity is more of the impression he has left in the minds of the other people and the "sins" he committed, and less of a vivid character.

    4. His parents went to eight-o’clock mass every morning in Gardiner Street and the peaceful odour of Mrs. Dillon was prevalent in the hall of the house. But he played too fiercely for us who were younger and more timid. He looked like some kind of an Indian when he capered round the garden, an old tea-cosy on his head, beating a tin with his fist and yelling:

      There are many contrasting elements in the first paragraph: the younger and timid children who never won the battle versus the fierce and robust Joe Dilon; the quite parents versus the yelling child. I'm wondering how these elements will help to drive the story.

    1. But deep inside her a little girl threw her pinafore over her head and sobbed.

      It is truly sad that the girl has not enjoyed the ball but knows the bleak future in advance.

    2. When he coughed the sweat sprang out on his head; his eyes bulged, his hands waved, and the great lump bubbled as a potato knocks in a saucepan.

      There is a simile used in this sentence, the author uses the lump bubbled compares to a potato. Having a lump bubbled is not a pleasant thing, but when the author describes the lump bubbled as a potato, I feel less heavy.

    3. “Mrs. John Hammond!” He gave a long sigh of content and leaned back, crossing his arms. The strain was over. He felt he could have sat there for ever sighing his relief—the relief at being rid of that horrible tug, pull, grip on his heart. The danger was over. That was the feeling. They were on dry land again. But at that moment Janey’s head came round the corner.

      It's so possesive of Mr. Hammond (and even a bit sick) that his feelings of "relief", "safety", and finally not lurching in the sea come from seeing the labels written "Mrs. John Hammond", and from this it can also be inferred that his anxiety when waiting for the ship to dock also originated from this "worry of losing her (heart) to something/someone". However in the next sentence, "but" implies a twist to his emotions again.

    4. her small dark head

      Mansfield expresses her subtlety again in this description of Leila. The youth that are enjoying the ball and the ball itself has so far been described with "light" adjectives (golden., bright, etc.) while the parents and chaperones who have grown out of attending balls have been descried with "dark" adjectives. Since the illusion of balls has been demystified for Leila, she is now described with "dark" adjectives like the adults.

    5. This was so awful that Fenella quickly turned her back on them, swallowed once, twice, and frowned terribly at a little green star on a mast head. But she had to turn round again; her father was going.

      A voyage to where, who will go along with the father. How did Fenella know that thing before? In the very beginning of the article, the author has mined some uncertainty, which should be answered later.

    6. A tiny boy with a head like a raisin and a chocolate body came round with a tray of pastries—row upon row of little freaks, little inspirations, little melting dreams.

      Is this passage describing a slave servant?? The use of language that appeals to the sense of taste mixes with the visual description of the tiny boy serving pastries. ('chocolate body', 'head like a rasin') This is a stunning and problematic passage of the short story. Don't know how this makes me feel... I'm unsure, but surely uncomfortable.

    7. Laura shook her head. She was. Laurie put his arm round her shoulder. “Don’t cry,” he said in his warm, loving voice. “Was it awful?”

      What I saw through the whole story is the difference of class contraries to reason and poverty of lower class. In my opinion, Laura had a kind of Epiphany about life, society and death from What I saw through the whole story is the difference of class contraries to reason and poverty of lower class. In my opinion, Laura had a kind of Epiphany about life, society and death from the death of young man.

    1. Gatov, who is the former head of Russia's state newswire's media analytics laboratory, told BuzzFeed the documents were part of long-term Kremlin plans to swamp the internet with comments. "Armies of bots were ready to participate in media wars, and the question was only how to think their work through," he said. "Someone sold the thought that Western media, which specifically have to align their interests with their audience, won't be able to ignore saturated pro-Russian campaigns and will have to change the tone of their Russia coverage to placate their angry readers."
    1. An oddball taskwas designed to measure sustained attention by the random presentation of a sequence of visual stimuli on a computer screen situated at 100 cm from the participants’ head and at their eye level

      Should be earlier too. I'm sure you haven't, but this kind of implies you've switched the studies around in the way that they're being reported.

    1. 18

      Step 27:

      Secure the 2 122166 into the board with slight dent using 2 109534 screws with a Phillip-Head screwdriver. Consult the graph for proper orientation.

      Step 28:

      Slide the piece into place with previously attached anchor piece. The piece is secured when you head a click.

    2. 11

      Step 15:

      Secure piece assembled in the previous step using the 4 102509 with a Flat-Head screwdriver. Consult the graph for proper alignment.

      Step 16:

      Insert the 8 101345 studs into the pre-drilled holes.

    3. 9

      Step 11:

      Now for the side panels of the desk. Secure the railing using 2 110853 into the smaller pre-drilled holes. Consult the graph for clarification.

      Step 12:

      Secure the 2 124639 into the back panel of the desk using a Phillip-Head screwdriver. Consult the graph for proper alignment.

    4. 8

      Step 9:

      Secure the piece we previously assembled into the underside of the desk using 2 101345 studs.

      Step 10:

      Screw 2 102509 into the larger pre-drilled holes using a Flat-Head screwdriver.

    5. 6

      Step 5:

      Secure the back panel of the drawer by sliding one side in first. There are 2 110519 for each side, secure them by hand or a hammer.

      Step 6:

      Screw 100481 using a Phillip-Head screwdriver into the underside of the desk. Make sure they are secured in the top-most and bottom-most positions.

    6. 5

      Step 3:

      Secure the two 103114 pieces into the side panels, using a Flat-Head screwdriver. Consult the graph for clarification of corresponding pieces.

      Step 4:

      Slide in the base of the drawer, please note that the edge with the cutout should face the front panel of the drawer, as shown in the graph.

    7. 4

      Step 1:

      There are two drawers inside the ALEX desk, we are going to assemble them first. Secure the two 118331 screw inside pre-drilled holes farther away from the cutout of the front panel of the drawer with a Phillip-Head screwdriver in a clockwise motion, consult the graph for clarification of screws used.

      Step 2:

      Connect the side pieces of the drawer by inserting the two 101345 studs into the remaining holes in the front panel.

    8. 2
      1. You will need a Flat-Head screwdriver and a Phillips-Head screwdriver.
      2. Working alone may not be the most efficient or safe, we recommending having a helper for the task.
      3. To avoid damage to the product, place the product on soft surfaces like a rug.
      4. Whenever you encounter difficulties or have any concerns about the product, do not hesitate to contact IKEA customer service.
  9. course-computational-literary-analysis.netlify.com course-computational-literary-analysis.netlify.com
    1. Speaking as a man, I consider you to be a person whose head is full of maggots, and I take up my testimony against your experiment as a delusion and a snare. Don’t be afraid, on that account, of my feelings as a man getting in the way of my duty as a servant! You shall be obeyed. The maggots notwithstanding, sir, you shall be obeyed. If it ends in your setting the house on fire, Damme if I send for the engines, unless you ring the bell and order them first!

      Betteredge is a really stubborn person. However, this personality also makes him stick to his duty. Even if Betteredge thinks that Mr. Jennings is doing something crazy, he still follows his directions.

    2. Neither father nor mother knew more than I knew.

      The author sets Betteredge as the first narrator, who describes most of the story , seems reasonable. Being the Verinders' head servant, Betteredge seems to be trusted by a lot of people, so people are willing to confide in him, which helps him to get a lot of information about the whole event .

    3. the bare idea of a man marrying her for his own selfish and mercenary ends had never entered her head.

      It is more realistic even after the death of her mother. The selfishness gradually float on the surface.

    4. In a minute more, Miss Rachel came downstairs–very nicely dressed in some soft yellow stuff, that set off her dark complexion, and clipped her tight (in the form of a jacket) round the waist. She had a smart little straw hat on her head, with a white veil twisted round it. She had primrose-coloured gloves that fitted her hands like a second skin. Her beautiful black hair looked as smooth as satin under her hat. Her little ears were like rosy shells–they had a pearl dangling from each of them. She came swiftly out to us, as straight as a lily on its stem, and as lithe and supple in every movement she made as a young cat. Nothing that I could discover was altered in her pretty face, but her eyes and her lips. Her eyes were brighter and fiercer than I liked to see; and her lips had so completely lost their colour and their smile that I hardly knew them again.

      Here the narrator goes to extents to depict Miss Rachel's figure, using bright colors of her clothes to contrast her unhappiness, and the description of her facial expressions (brighter, fiercer, lack of smile) also contrast to her sweetness before these events happened.

    5. “Mr. Franklin Blake dropped one of his rings up-stairs,” says Rosanna; “and I have been into the library to give it to him.” The girl’s face was all in a flush as she made me that answer; and she walked away with a toss of her head and a look of self-importance which I was quite at a loss to account for.

      This is the first time that the narrator describe Rosanna as proud and confident. She had been attentive to Franklin before and seemed stupid and poor. What has changed her? How she get the ring Franklin dropped?

    6. “At the sands, of course!” says Nancy, with a toss of her head. “She had another of her fainting fits this morning, and she asked to go out and get a breath of fresh air. I have no patience with her!”

      And Nancy said Rosanna was late again for dinner and OF COURSE she was at the sand, which means she went there a lot and there was really a relationship with Rosanna and the sand. The sand may be a evidence which can be used latter.

    7. “Going to telegraph to London,” says Mr. Franklin. “I have convinced my aunt that we must have a cleverer head than Superintendent Seegrave’s to help us; and I have got her permission to despatch a telegram to my father. He knows the Chief Commissioner of Police, and the Commissioner can lay his hand on the right man to solve the mystery of the Diamond. Talking of mysteries, by-the-bye,” says Mr. Franklin, dropping his voice, “I have another word to say to you before you go to the stables. Don’t breathe a word of it to anybody as yet; but either Rosanna Spearman’s head is not quite right, or I am afraid she knows more about the Moonstone than she ought to know.”

      Why Franklin believed that Rosanna knew about the moonstone? Maybe he guessed it from the strange actions and words of Rosanna, or it was a trick to remove others' attention. However, Betteredge tried to protect Rosanna by didn't tell him the past of her , but still Franklin doubt her.

    8. My girl was in high spirits, and I saw she had something to say to me. She gave me a kiss on the top of my bald head, and whispered, “News for you, father! Miss Rachel has refused him.

      The author creates various characters and builds complicated relations among them. Maybe the exquisite relations imply clues about moon stone. Interesting!

    9. If you are bald, you will understand how she sacrificed me. If you are not, skip this bit, and thank God you have got something in the way of a defence between your hair-brush and your head.

      The author with very humorous tune showed Penelope's excited mood. When reading this paragraph, maybe the bald can't help massaging his head.

    1. no image of the dollar bill has in any sense been ‘stored’ in Jinny’s brain

      There was research using machine learning to "see" pictures that people imagined. It was able to somewhat decode the measurements of brain activity at various locations outside the head and reconstruct something similar to what was being thought of. True, this isn't a memory, but it could be that the "thought" is "stored" in a pattern of electric potentials, and we just can't decode it. A computer stores information bits without any interaction (ideally). Clearly, human memory isn't so orthogonal. But why couldn't it be some type of encoding into a measurable pattern where, whether it's to save space, improve recall through association, or whatever else?

    1. aggregate

      Definition of aggregate : formed by the collection of units or particles into a body, mass, or amount : collective: such as a (1) : clustered in a dense mass or head an aggregate flower (2) : formed from several separate ovaries of a single flower aggregate fruit b : composed of mineral crystals of one or more kinds or of mineral rock fragments c : taking all units as a whole aggregate sales

    1. When the king of this kingdom comes in from a journey a parasol (jitr) and a standard are held over his head as he rides, and drums are beaten and guitars (tunbu-r) and trumpets well-made of horn are played in front of him.

      This style of procession is something I have personally experienced with the Moroccan king. When he goes somewhere or celebrates a national or a religious holiday, he has a similar tradition to King Musa. For example, King Mohammed VI has music accompany him. I can picture this part of the reading because I have seen it many times and I always asked why the King needed to let everyone know if he was coming or going. After doing this reading, I've learned that this tradition dates back to the 1300s, which is very interesting.

    1. But Ms. DeVos’s new head of civil rights, Kenneth L. Marcus, may disagree. A vocal opponent of affirmative action, Mr. Marcus was confirmed last month on a party-line Senate vote, and it was Mr. Marcus who signed Tuesday’s letter.

      Great. So the new head of civil rights wishes to take them away.

    1. suggesting that time has passed quickly for Gawain who wakes on NewYear’s morning with the knowledge that on this day his head will be severed by the GreenKnight: “Now neghes the Nw Yere and the nyght passes, | The day dryves to the derk, asdryghtyn biddes” (4.1998-99).

      This sentence really drives home the theme that I'm trying to highlight in my paper. Should I do more with it here?

    1. On 2017 Nov 30, Donald Forsdyke commented:

      CRISPR SPACERS PROVIDE "JUNK" VLA RNAs

      A "peculiarity of human thinking" invokes sad head-shaking in some quarters. It is argued, not only that "the vast majority of low abundant transcripts are simply junk," but also that such junk is "simple" (1). Those led to think that junk DNA serves the organism (i.e. can under some conditions be functional and hence selectively advantageous) are labelled "determinists." They can scarcely be distinguished from "ID believers"! There is no mention of the two-decade-old view that very low abundance transcripts (VLA RNAs) represent an intracellular antibody-like repertoire, for which much evidence has since accumulated (2-4).

      For microorganisms, the CRISPR system provided a clear example of the functionality of the transcription of their spacer "junk DNA." Ledford notes that the system "adapts to, and remembers, specific genetic invaders in a similar way to how human antibodies provide long-term immunity after an infection" (5). Just as we have germline cascades of V genes that confer immunological specificity on B and T lymphocytes, so microorganisms have their germline spacers that confer a similar specificity on their RNA populations. However, the functionality of an individual spacer "sense" transcript is only tested when a virus with a specific "antisense" sequence enters the cell. Transcription is conditional. The selective advantage can only emerge when the corresponding pathogen attacks.

      Thus, the analytical problem is not so "simple" as showing by experimental DNA deletion that the transcript of a specific eukaryotic gene is functional, or as dismissively postulating a requirement for "unacceptably high birth rates." Deletion of a single human V-region gene could show no selective effect if no corresponding pathogens invaded the body. Even if there were such an invasion, other V-regions would likely be able to compensate for the deletion. Similarly, deleting a segment of "junk" DNA is unlikely to impact survival if some of the wide spectrum of alternative "junk" transcripts can compensate for this defect in the RNA antibody-like repertoire.

      1.Sverdlov E (2017) Transcribed junk remains junk if it does not acquire a selected function in evolution. BioEssays doi: 10.1002/bies.201700164. Sverdlov E, 2017

      2.Cristillo AD, Mortimer JR, Barrette IH, Lillicrap TP, Forsdyke DR (2001) Double-stranded RNA as a not-self alarm signal: to evade, most viruses purine-load their RNAs, but some (HTLV-1, Epstein-Barr) pyrimidine-load. J Theor Biol 208:475-491. Cristillo AD, 2001

      3.Forsdyke DR, Madill CA, Smith SD (2002) Immunity as a function of the unicellular state: implications of emerging genomic data. Trends Immunol 23:575-579. Forsdyke DR, 2002

      4.Forsdyke DR (2016) Evolutionary Bioinformatics. 3rd edition. Springer, New York, pp. 279-303.

      5.Ledford H (2017) Five big mysteries about CRISPR’s origins. Nature 541:280-282. Ledford H, 2017


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    1. On 2017 Dec 13, Franz Schelling commented:

      "Without a good understanding of the vascular pathophysiologic factors that influence the patency of ballooned IJVs, it is difficult to perform any meaningful work relating any neurologic condition that may or may not be associated with constricted venous outflow." ... ought not this point given in the papers 'Discussion' be given in its 'Conclusion' part.

      Three questions asides: (1) Wasn't it observed that the muscular IJV entrapments depend widely on (a) head, (b) shoulder position and (c) jaw bracing? with (a) applying first to the sternal head of the sternocleidomastoid, (a)+(b) to the omohyoid, and (c) to the digastric muscle? (2) What about the often observed efficacy of deep inspiration/chest bracing in terms of flow reversals in the left IJV? (3) MRI findings of a severe hypoplasia of the entire J1 length seem preferentially due to its broad clamping between sternal part of the sternocleidomastoid and anterior scalene muscle - a problem which any good ENT surgeon can solve.

      Just some cues which may prove useful for making further advances.


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    1. On 2017 Oct 04, Brad Rodu commented:

      The study by Feirman et al. (Feirman SP, 2018) described in detail the results from one question in the 2012, 2014, and 2015 Health Information National Trends Surveys: “Do you believe that some smokeless tobacco products, such as chewing tobacco and snuff, are less harmful than cigarettes?” The possible answers were “Yes,” “No,” and “Don’t Know.”

      The article highlighted these findings:

      • “A majority of adults do not think smokeless tobacco is less harmful than cigarettes.” (i.e., didn’t answer “yes.”) • “Believing smokeless tobacco is not less harmful than cigarettes declined from 2012–2015.” • “Perceptions about the harm of smokeless tobacco differed by demographic subgroup.”

      The authors, from the U.S. FDA and National Cancer Institute, commented: “…our findings may help inform public health communications aimed at reducing tobacco-related harms. Additionally, understanding consumer perceptions of tobacco products plays an important role in FDA's regulatory work.”

      This claim is not valid because of one glaring omission throughout the article, which contained 3,800 words, 3 large tables of numbers and 58 references. The article failed to specify that the correct answer is: “Yes, smokeless tobacco products are less harmful than cigarettes.” In fact, it focused almost entirely on the majority of participants who inaccurately answered “No” or “Don’t Know,” which reflects misperception fostered by an effective “quarantine” of truthful risk information by federal agencies (Kozlowski LT, 2016).

      Decades of epidemiologic studies have documented that the health risks of smokeless tobacco use are, at most, 2% those of smoking (Rodu B, 2006; Rodu B, 2011; Fisher M 2017; Royal College of Physicians, 2002; Lee PN, 2009). Unlike cigarettes, smokeless tobacco does not cause lung cancer, heart and circulatory diseases or emphysema. In 2002 the Royal College of Physicians concluded: “As a way of using nicotine, the consumption of non-combustible [smokeless] tobacco is on the order of 10–1,000 times less hazardous than smoking, depending on the product.” (Royal College of Physicians, 2002)

      The low risks from smokeless tobacco use even include mouth cancer. A 2002 review documented that men in the U.S. who use moist snuff and chewing tobacco have minimal to no risk for mouth cancer (Rodu B, 2002), and a recent federal study found no excess deaths from the disease among American men who use moist snuff or chewing tobacco (Wyss AB, 2016).

      As one of us recently wrote, “Deception or evasion about major differences in product risks is not supported by public health ethics, health communication or consumer practices. Public health agencies have an obligation to correct the current dramatic level of consumer misinformation on relative risks that they have fostered.” (Kozlowski LT, 2018)

      Brad Rodu Professor of Medicine University of Louisville

      David Sweanor Adjunct Professor of Law Centre for Health Law, Policy and Ethics University of Ottawa

      Brad Rodu is supported by unrestricted grants from tobacco manufacturers to the University of Louisville, and by the Kentucky Research Challenge Trust Fund.


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    1. On 2017 Sep 26, Clive Bates commented:

      I would like to recommend that the authors (and anyone attempting similar experiments) consult experienced users about the way these products are used in practice in order to ensure their work is relevant and realistic. I am posting a critical review of this paper by an experienced vaper, Paul Barnes, a trustee of the New Nicotine Alliance.

      Paul Barnes' review starts here

      An emerging category of electronic cigarettes (ECIGs) are sub-Ohm devices (SODs) that operate at ten or more times the power of conventional ECIGs

      Sub-Ohming has been a feature of vaping for many years with advanced, or hobbyist, users utilising knowledge of Ohms Law and unregulated mechanical mods (“mech-mods”), along with user-made coils to provide an experience customised to suit the individual user.

      As technology has improved, the need for mechanical mods has waned, bringing forth the era of the regulated devices. These contain a chipset to regulate power output (wattage), include safety cut-off (to prevent over-use), and control thermal safety (to prevent cell failures), among other features. These devices can produce similar, or greater, power output compared with the mechanical device.

      Pre-made coils are now the norm for most users. The coils mentioned in this paper - Smok TF-Q4 (1), Smok V8-Q4 (2), Smok V8-T8 (3) and the Smok V8-T10 (4) - present a unique problem for researchers lacking in an understanding of both the technology and the consumer.

      In this paper, all the chosen coils were used at a constant power of 50W, with the Smok V8-T8 coil head being used at varying power levels (50, 75, and 100 Watts).

      Fundamentally, the design of the coil head is suitable for higher power usage, not low power.

      One of the key problems with this approach is the misunderstanding of a) how these devices are used in the real world, and b) the particular user characteristics.

      For example, the Smok TF-Q4 states (screen printed on the coil head itself) that the “best” range (determined by user experience, the resistance of the coil, and knowledge of consumer preferences) for power (in Watts) is between 80-120W - between the medium and the upper end of the coil-head maximum capability of 140 Watts.

      The power ranges for the other coils are as follows (according to manufacturer specifications):

      Smok V8-Q4: 50-180W and "best between" 90-150W

      Smok V8-T8: 50-260W and "best between" 125-180W

      Smok V8-T10: 50-300W and "best between" 130-190W

      Considering that the coil head chosen for the variable power test (Smok V8-T8) has a “best” operating range of 125-180 W, testing at 100 demonstrates an imbalance between the cooling effects of the e-liquid, aerosol generation and airflow - a factor not directly considered in the paper.

      At a measured resistance of 0.15 Ohms - the culmination of eight physical coils arranged in parallel - (assuming the Joyetech Cuboid used measured the resistance accurately), and a power setting of 100W, the voltage applied to the coil head is 5.33V (35.59A).

      Finding a decrease in VA emissions is obvious, given the coil heads fundamental design and operating parameters. In comparison, the Vapor Fi (5) device used demonstrated high levels of VA emissions when used at 11 W (approximately 6.2V), far and above the power that would generate the "dry puff" phenomenon (6); as commonly seen in the older CE4/CE5 clearomisers favoured by some researchers (7).

      The key difference between the VF coil and the Smok coil-heads is in the construction. The Smok coil-heads utilise multiple physical coils inside a single unit, conversely, the VF coil is a single coil unit. Therefore, the entirety of the 6.2V (at 11W) is being applied to a single resistance material. The unique construction of the Smok coil-heads negates this fundamental problem by providing up to 10 distinct coils within the head. The total effect is the same, 5.33V is being applied to the entirety of the head, but distributed across 4, 8 or 10 distinct paths.

      Coupled with the larger surface area and substantially more wicking material, heat dissipation through the wick, aerosolisation and air inhalation, the Smok coil heads are capable of handling much higher voltage, while using substantially more e-liquid, without generating the dry-puff.

      Prior research (8) on the various types of e-cig coil, including a common Sub-Ohm tank and coil, has previously been performed with a focus on nicotine aerosolisation, suggesting that the liquid consumed through vaping is not proportional to nicotine content.

      In summary

      The central point of this paper is to examine the relationship between increasing power applied to a coil or coil-head and increasing VA emissions. Fundamentally, with a coil-head containing multiple physical coils, the total heating area, relative to a single (or even a dual) coil is substantially greater. The amount of wicking material which, when soaked with e-liquid (with or without nicotine) provides a significant cooling effect, is also substantially greater. With more physical coils in the coil-head, the time taken for a coil-head to reach a temperature that is both a) satisfying for the user, and b) includes the possibility of inducing a dry-puff, is much longer. Further, the material used for the coil alters the overall heat capacity; as demonstrated by the "Coil Wrapping" calculator (9).

      In reality, as power to the coil increases, liquid consumption also increases. In real-world scenarios, human users regulate both power and liquid flow to minimise the risk of dry-puff conditions and therefore avoiding increases in VA emissions.

      References

      (1) Smok TF-V4 Coil - UK ECIG Store: [link]

      (2) Smok Tech Store V8-Q4 core: [link]

      (3) Smok Tech Store V8-T8 core: [link]

      (4) Smok Tech Store V8-T10 core: [link]

      (5) VaporFi Platinum II Tank: [link]

      (6) Farsalinos K, Voudris V, Poulas K - E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions [link] Farsalinos KE, 2015

      (7) CE5 Clearomizer Tank - VapeClub: [link]

      (8) Farsalinos K et al - Protocol proposal for, and evaluation of, consistency in nicotine delivery from the liquid to aerosol of electronic cigarette atomizers: [link] Farsalinos KE, 2016

      (9) For example, see Steam Engine Coil Wrapping Calculator [link]


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    1. On 2017 Oct 01, David Mage commented:

      Altfeld et al., PMID: 28838726, made an excellent study of the recent efforts to reduce sleep-related infant deaths in the U.S. However, they made both an explicit error and an implicit error that needs to be called to the readers’ attention:

      Explicit Error: On page 2, they refer to “mothers of non-Hispanic Black infants” and “mothers of Hispanic infants.” [NB: Hispanic is an ethnicity and not a race] Apparently, the authors did not read carefully their references [1, 2, 21] and the Technical Notes cited therein. The CDC and NCHS both explicitly state that their cited racial data are either the mother’s self-identified race if monoracial, or “To provide uniformity and comparability of these data [to census data, per OMB requirement], multiple race [of mother] is imputed to a single race.” (see NCHS Technical Notes). The authors of reference 21 conducted an evening at-the-door survey of parents of recently born infants, and “Participants were asked: ‘Which of the following best describes [your, or] the mother's race or ethnic background?’ They were then read a list but also given the option to name one that was not listed.” The mother answered 84% of the time and 16% of the time another adult person responded for her;

      Implicit Error: The authors seem to have forgotten that the father of an infant often plays a role in the determination of the race of the infant. I used the word “often” instead of always because “Tis a wise child that knows its own father.” [Puddn’head Wilson, Mark Twain] {Old Burlesque joke: Enter little redhaired boy. Clown: What lovely red hair you have. Do mommy and daddy have red hair too? Little Boy: No --- But we do have a milkman with red hair. (audience laughs) Exit boy.} Therefore, implicitly, the self-identified race of the mother is the same race as the infant if, and only if, the mother is monoracial, and the father (either known or unknown) is the identical race as the mother.


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    1. On 2017 Oct 28, Daniel Weiss commented:

      Karter et. al describe a tool to predict the risk of hypoglycemia in persons with Type 2 Diabetes. This tool confirms obvious, well-established clinical observations: sulfonylureas and insulin are associated with an increased risk of hypoglycemia. Three points are worth clarifying.

      First, this tool was developed in the Kaiser Permanente of Northern California health care system where practitioners have a very limited choice of agents for Type 2 Diabetes. In that system and the Veterans Health Administration, the usage of drugs that do not tend to cause hypoglycemia is restricted due to cost. Yet, glucagon-like peptide-1 (GLP-1) receptor agonists have been available since 2005 and the first sodium-glucose cotransporter-2 (SGLT2) inhibitor was approved in 2013. Although less effective, dipeptidyl peptidase-4 (DPP-4) inhibitors have been around since 2007. All these drug classes cost more than sulfonylureas but none put patients at risk for hypoglycemia.

      In large part, because of that risk of hypoglycemia, the American Association of Clinical Endocrinologists algorithm (1) for pharmacotherapy of Type 2 Diabetes judges sulfonylureas as the worst option. Indeed, the annual rate of hypoglycemia was lowest in the Group Health Cooperative patients where sulfonylureas were used less frequently.

      Second, the authors fail to account for the type of insulin prescribed. They lump all insulins together. And they discuss skipping meals as a cause of hypoglycemia. All insulins are not the same. For example, NPH insulin is associated with a greater risk of hypoglycemia than is insulin glargine in head to head trials (2). And the pharmacokinetics of NPH insulin are such that insulin levels often peak when the patient is not eating. Well-designed insulin regimens allow patients to skip meals with no problem.

      Third, in their lengthy discussion on steps to reduce the risk of hypoglycemia, the authors fail to even mention choosing effective agents that do not cause hypoglycemia such as GLP-1 receptor agonists or SGLT-2 inhibitors. And some of these newer agents have now been demonstrated to reduce cardiovascular events and mortality.

      The authors focus on population approaches, not the best care for the individual patient in the exam room.

      Conflict of Interest Disclosures: This commenter receives clinical research funding and speaker honoraria from multiple pharmaceutical companies that market medication for diabetes.

      1. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2017 Executive Summary. Endocr Pract. 2017;23(2):207-238.
      2. Riddle MC, Rosenstock J, Gerich J, Insulin Glargine Study I. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11):3080-3086.


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    1. On 2017 Apr 22, Alessandro Rasman commented:

      Aldo Bruno MD, Pietro M. Bavera MD, Aldo d'Alessandro MD, Giampiero Avruscio MD, Pietro Cecconi MD, Massimiliano Farina MD, Raffaello Pagani MD, Pierluigi Stimamiglio MD, Arnaldo Toffon MD and Alessandro Rasman

      We read with interest this study by Zakaria et al. titled "Failure of the vascular hypothesis of multiple sclerosis in a rat model of chronic cerebrospinal venous insufficiency".(1) Unfortunately the authors ligated the external jugular veins of the rats and not the internal jugular veins. Dr, Zamboni's theory on chronic cerebrospinal venous insufficiency is based on the internal jugular veins and not on external jugular veins.(2) Maybe the authors can read the two papers from Dr. Mancini et al. (3) and (4). So, in our opinion the title of this study is absolutely not correct.

      References: 1. Zakaria, Maha MA, et al. "Failure of the vascular hypothesis of multiple sclerosis in a rat model of chronic cerebrospinal venous insufficiency." Folia Neuropathologica 55.1 (2017): 49-59. 2. Zamboni, Paolo, et al. "Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis." Journal of Neurology, Neurosurgery & Psychiatry 80.4 (2009): 392-399. 3. Mancini, Marcello, et al. "Head and neck veins of the mouse. A magnetic resonance, micro computed tomography and high frequency color Doppler ultrasound study." PloS one 10.6 (2015): e0129912. 4. Auletta, Luigi, et al. "Feasibility and safety of two surgical techniques for the development of an animal model of jugular vein occlusion." Experimental Biology and Medicine 242.1 (2017): 22-28.


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    1. On 2017 Mar 03, Ole Jakob Storebø commented:

      In their editorial, Gerlach and colleagues make several critical remarks (Gerlach M, 2017) regarding our Cochrane systematic review on methylphenidate for children and adolescents with attention-deficit hyperactivity disorder (ADHD) (Storebø OJ, 2015). While we thank them for drawing attention to our review we shall here try to explain our findings and standpoints.

      They argue, on the behalf of the World Federation of ADHD and EUNETHYDIS, that the findings from our Cochrane systematic review contrast with previously published systematic reviews and meta-analyses, (National Collaborating Centre for Mental Health (UK), 2009, Faraone SV, 2010, King S, 2006, Van der Oord S, 2008) which all judged the included trials more favorably than we did.

      There are methodological flaws in most of these reviews that could have led to inaccurate estimates of effect. For example, most of these reviews did not publish an a priori protocol (Faraone SV, 2010, King S, 2006, Van der Oord S, 2008), or present data on spontaneous adverse events (Faraone SV, 2010, King S, 2006, Van der Oord S, 2008), nor did they report on adverse events as measured by rating scales (Faraone SV, 2010, King S, 2006, Van der Oord S, 2008), or systematically assess the risk of random errors, risk of bias, and trial quality (Faraone SV, 2010, King S, 2006,Van der Oord S, 2008). King at al. emphasised in the quality assessments for the NICE review that almost all studies did not score very well in the quality assessments and, consequently, results should be interpreted with caution (King S, 2006).

      The authors of this editorial refer to many published critical editorials and they argue that the issues they have raised have not adequately been addressed adequately by us. On closer examination, it is clear that virtually the same criticism has been levelled at us each time by the same group of authors, published in several journal articles, blogs, letters, and comments (Banaschewski T, 2016, BMJ comment,Banaschewski T, 2016, Hoekstra PJ, 2016, Hoekstra PJ, 2016, Romanos M, 2016, Mental Elf blog.

      Each time, we have refuted repeatedly with clear counter-arguments, recalculation of data, and detailed explanations (Storebø OJ, 2016, Storebø OJ, 2016,Storebø OJ, 2016, Pubmed commment, Storebø OJ, 2016, BMJ comments, Responses on Mental Elf, Pubmed comment.

      Our main point is that the very low quality of the evidence makes it impossible to estimate, with any certainty, what the true magnitude of the effect might be.

      It is correct that a post-hoc exclusion of the four trials with co-interventions in both MPH and control groups and the one trial of preschool children changes the standardised mean difference effect size from 0.77 to 0.89. However, even if the effect size increases upon excluding these trials, the overall risk of bias and quality of the evidence deems this discussion irrelevant. As mentioned above, we have responded several times to this group of authors Storebø OJ, 2016, Storebø OJ, 2016,< PMID: 27138912, Pubmed commment, Storebø OJ, 2016, BMJ comments, Responses on Mental Elf, Pubmed comment.

      We did not exclude any trials for the use of the cross-over design, as these were included in a separate analysis. The use of end-of-period data in cross-over trials is problematic due to the risk for “carry-over effect” (Cox DJ, 2008) and “unit of analysis errors” (http://www.cochrane-handbook.org). In addition, we tested for the risk of “carry-over effect”, by comparing trials with first period data to trials with end-of-period data in a subgroup analysis. This showed no significant subgroup difference, but this analysis has sparse data and one can therefore not rule out this risk. Even with no statistical difference in our subgroup analysis comparing parallel group trials to end-of-period data in cross-over trials, there was high heterogeneity. This means that the risk of “unit of analysis error” and “carry-over effect” is uncertain, and could be real. The aspect about our bias assessment have been raised earlier by these authors and others affiliated to the EUNETHYDIS. In fact, we see nothing new here. There is considerable evidence that trials sponsored by industry overestimate benefits and underestimate harms (Flacco ME, 2015, Lathyris DN, 2010, Kelly RE Jr, 2006). Moreover, the AMSTAR tool for methodological quality assessment of systematic reviews includes funding and conflicts of interest as a domain (http://amstar.ca/). The Cochrane Bias Methods Group (BMG) is currently working on including vested interests in the upcoming version of the Cochrane Risk of Bias tool.

      The aspect about whether teachers can detect well known adverse events of methylphenidate have also been raised earlier by these authors and others affiliated to the EUNETHYDIS (Banaschewski T, 2016, BMJ comment,Banaschewski T, 2016, Hoekstra PJ, 2016, Hoekstra PJ, 2016, Romanos M, 2016, Mental Elf blog.). We have continued to argue that teachers can detect the well-known adverse events of methylphenidate, such as the loss of appetite and disturbed sleep. We highlighted this in our review (Storebø OJ, 2015) and have answered this point in several replies to these authors (Storebø OJ, 2016, Storebø OJ, 2016,Storebø OJ, 2016, Pubmed commment, Storebø OJ, 2016, BMJ comments, Responses on Mental Elf, Pubmed comment. The well-known adverse events of “loss of appetite” and “disturbed sleep” are easily observable by teachers as uneaten food left on lunch plates, yawning, general tiredness, and weight loss.

      We have considered the persistent, repeated criticism by these authors seriously, but no evidence was provided to justify changing our conclusions regarding the very low quality of evidence of methylphenidate trials, which makes the true estimate of the methylphenidate effect unknowable. This is a methodological rather than a clinical or philosophical issue.<br> We had no preconceptions of the findings of this review and followed the published protocol; therefore, any proposed manipulations of the data proposed by this group of authors would be in contradiction to the accepted methods of high-quality meta-analyses. As we have repeatedly responded clearly to the criticism of these authors, and it is unlikely that their view of our (transparent) work is going to change, we propose to agree to disagree.

      Finally, we do not agree that the recent analysis from registries provides convincing evidence on the long-term benefits of methylphenidate due to multiple limitations of this type of kind of study, albeit that interesting perspectives are provided. They require further study to be regarded as reliable.

      Ole Jakob Storebø, Morris Zwi, Helle B. Krogh, Erik Simonsen, Carlos Renato Maia, Christian Gluud


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    1. On 2016 Oct 26, Lydia Maniatis commented:

      Natural scenes

      The use of “natural scene statistics” is popular in current vision science and directly linked to its conceptual confusion.

      In the words of the authors, “Biological systems evolve to exploit the statistical relationships in natural scenes….”

      I want to first address the authors’ use of the term “natural scenes” and its implications, and move on to the problem of the validity and implications of the above quote in a subsequent comment.

      “Natural scenes” is a very broad category, even broader given that the authors include in it man-made environments. In order to be valid on their own terms, the “statistics” involved – i.e. the correlations between “cues” and physical features of the environment – must hold across very different distances and orientations of the observer to the world, and across very different environments, including scenes involving close-ups of human faces.

      Describing 96 photographs taken of various locations on the University of Texas campus from a height of six feet, a camera perpendicular to the ground, at distances of 2-200 meters as a theoretically meaningful, representative sample of “natural scenes” seems rather flakey. If we include human artifacts, then what count as “non-natural scenes” ?

      The authors themselves are forced to confront (but choose to sidestep) the sampling problem when they note that “previous studies have reported that surfaces near 0° of slant are exceedingly rare in natural scenes (Yang & Purves, 2003), whereas we find significant probability mass near 0° of slant. That is, we find—consistent with intuition—that it is not uncommon to observe surfaces that have zero or near-zero slant in natural scenes (e.g., frontoparallel surfaces straight ahead).”

      (Quite frankly, the authors’ intuition is causing them to confuse cause and effect, since we have a behavioral tendency to orient ourselves to objects so that we are in a fronto-parallel relationship to surfaces rather than in an oblique relationship to them, thus biasing the “statistics” in this respect).

      They produce a speculative, technical and preliminary rationalization for the discrepancy between their distributions and those of Yang and Purves, leaving clarification to “future research.”

      What they don’t consider is the sampling problem. Is there any doubt WHATSOEVER that different “natural scenes” - or different heights, or different angles of view, or different head orientations - will produce very different “prior probabilities”? If this is a problem, it isn’t a technical one.


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    1. On 2017 Jan 05, Alan Roger Santos-Silva commented:

      The spectrum of oral squamous cell carcinoma in young patients

      We read with interest the current narrative review published by Liu et al [1], in Oncotarget. The article itself is interesting, however, they appear to have misunderstood our article [2] because they seem to believe that there was a cause-effect relationship between orthodontic treatment and tongue squamous cell carcinoma (SCC) at young age. This idea might provide anecdotal information about the potential of orthodontic treatment to cause persistent irritation on oral mucosa and lead to oral SCC. Thus, we believe that it is relevant to clarify that the current understanding about the spectrum of oral SCC in young patients points out three well-known groups according to demographic and clinicopathologic features: (1). 40-45 years old patients highly exposed to alcohol and tobacco diagnosed with keratinizing oral cavity SCC; (2). <45 years old patients, predominantly non-smoking males, diagnosed with HPV-related non-keratinizing oropharyngeal SCC; and (3). Younger than 40-year-old patients, mainly non-smoking and non-drinking females diagnosed with keratinizing oral tongue SCC (HPV seems not to be a risk factor in this group) [3-5]. Therefore, chronic inflammation triggered by persistent trauma of the oral mucosa must not be considered an important risk factor in young patients with oral cancer.

      References: 1. Liu X, Gao XL, Liang XH, Tang YL. The etiologic spectrum of head and neck squamous cell carcinoma in young patients. Oncotarget. 2016 Aug 12. doi: 10.18632/oncotarget.11265. [Epub ahead of print]. 2. Santos-Silva AR, Carvalho Andrade MA, Jorge J, Almeida OP, Vargas PA, Lopes MA. Tongue squamous cell carcinoma in young nonsmoking and nondrinking patients: 3 clinical cases of orthodontic interest. Am J Orthod Dentofacial Orthop. 2014; 145: 103-7. 3. Toner M, O'Regan EM. Head and neck squamous cell carcinoma in the young: a spectrum or a distinct group? Part 1. Head Neck Pathol. 2009; 3: 246-248. 4. de Castro Junior G. Curr Opin Oncol. 2016; 28: 193-194. 5.Santos-Silva AR, Ribeiro AC, Soubhia AM, Miyahara GI, Carlos R, Speight PM, Hunter KD, Torres-Rendon A, Vargas PA, Lopes MA. High incidences of DNA ploidy abnormalities in tongue squamous cell carcinoma of young patients: an international collaborative study. Histopathology. 2011; 58: 1127-1135.

      Authors: Alan Roger Santos-Silva [1,2]; Ana Carolina Prado Ribeiro [1,2]; Thais Bianca Brandão [1,2]; Marcio Ajudarte Lopes [1]

      [1] Oral Diagnosis Department, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil. [2] Dental Oncology Service, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

      Correspondence to: Alan Roger Santos-Silva Department of Oral Diagnosis, Piracicaba Dental School, UNICAMP Av. Limeira, 901, Areão, Piracicaba, São Paulo, Brazil, CEP: 13414-903 Telephone: +55 19 2106 5320 alanroger@fop.unicamp.br


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    1. On 2017 Apr 07, Janelia Neural Circuit Computation Journal Club commented:

      Highlight/Summary

      This is one of several recent papers investigating cortical dynamics during head-restrained behaviors in mice using mostly imaging methods. The questions posed were:

      Which brain regions are responsible for sensorimotor transformation? Which region(s) are responsible for maintaining task-relevant information in the delay period between the stimulus and response?

      These questions were definitely not answered. However, the study contains some nice cellular calcium imaging in multiple brain regions in a new type of mouse behavior.

      The behavior is a Go / No Go behavioral paradigm. The S+ and S- stimuli were drifting horizontal and vertical gratings, respectively. The mouse had to withhold licking during a delay epoch. During a subsequent response epoch the mouse responded by licking for a reward on Go trials.

      Strengths

      Perhaps the greatest strength of the paper is that activity was probed in multiple regions in the same behavior (all L2/3 neurons, using two-photon calcium imaging). Activity was measured in primary visual cortex (V1), ‘posterior parietal cortex’ (PPC; 2 mm posterior, 1.7 mm lateral), and fMC. ‘fMC' overlaps sMO in the Allen Reference Atlas, posterior and medial to ALM (distance approximately 1 mm) (Li/Daie et al 2016). This location is analogous to rat 'frontal orienting field’ (Erlich et al 2011) or M2 (Murakami et al 2014). Folks who work on whiskers refer to this area as vibrissal M1, because it corresponds to the part of motor cortex with the lowest threshold for whisker movements.

      In V1, a large fraction (> 50 %) of neurons were active and selective during the sample epoch. One of the more interesting findings is that a substantial fraction of V1 neurons were suppressed during the delay epoch. This could be a mechanism to reduce ‘sensory gain’ and ’distractions' during movement preparation. Interestingly, PPC neurons were task-selective during the sample or response epochs; consistent with previous work in primates (many studies in parietal areas) and rats (Raposo et al 2014), individual neurons multiplexed sensory and movement selectivity. However, there was little activity / selectivity during the delay epoch. This suggests that their sequence-like dynamics in maze tasks (e.g. Harvey et al 2012) might reflect ongoing sensory input and movement in the maze tasks, rather than more cognitive variables. fMC neurons were active and selective during the delay and response epoch, consistent with a role in movement planning and motor control, again consistent with many prior studies in primates, rats (Erlich et al 2011), and mice (Guo/Li et al 2014).

      Weaknesses

      Delayed response or movement tasks have been used for more than forty years to study memory-guided movements and motor preparation. Typically different stimuli predict different movement directions (e.g. saccades, arm movements or lick directions). Previous experiments have shown that activity during the delay epoch predicts specific movements, long before the movement. In this study, Go and No Go trials are fundamentally asymmetric and it is unclear how this behavioral paradigm relates to the literature on movement preparation. What does selectivity during the delay epoch mean? On No Go trials a smart mouse would simply ignore the events post stimulus presentation, making delay activity difficult to interpret.

      The behavioral design also makes the interpretation of the inactivation experiments suspect. The paper includes an analysis of behavior with bilateral photoinhibition (Figure 9). The authors argue for several take-home messages (‘we were able to determine the necessity of sensory, association, and frontal motor cortical regions during each epoch (stimulus, delay, response) of a memory-guided task.'); all of these conclusions come with major caveats.

      1.) Inactivation of both V1 and PPC during the sample epoch abolishes behavior, caused by an increase in false alarm rate and decrease in hit rate (Fig. 9d). The problem is that the optogenetic protocol silenced a large fraction of the brain. The methods are unlikely to have the spatial resolution to specifically inactivate V1 vs PPC. The authors evenly illuminated a 2 mm diameter window with 6.5mW/mm<sup>2</sup> light in VGat-ChR2 mice. This amounts to 20 mW laser power. According to the calibrations performed by Guo / Li et al (2014) in the same type of transgenic mice, this predicts substantial silencing over a radius (!) of 2-3 mm (Guo / Li et al 2014; Figure 2). Photoinhibiting V1 will therefore silence PPC and vice versa. It is therefore expected that silencing V1 and PPC have similar behavioral effects.

      2.) Silencing during the response window abolished the behavioral response (licking). Other labs labs have also observed total suppression of voluntary licking with frontal bilateral inactivation (e.g. Komiyama et al 2010; and unpublished). However, the proximal cause of the behavioral effect is likely silencing of ALM, which is more anterior and lateral to ‘fMC’. ALM projects to premotor structures related to licking. Low intensity activation of ALM, but not more medial and posterior structures such as fMC, triggers rhythmic licking (Li et al 2015) The large photostimulus used here would have silenced ALM as well as fMC.

      3.) Somewhat surprisingly, behavior is perturbed after silencing fMC during the sample (stimulus) and delay epochs. In Guo / i et al 2014, unilateral silencing of frontal cortex during the sample epoch (in this case ALM during a tactile decision task, 2AFC type) did not cause a behavioral effect (although bilateral silencing is likely different; see Li / Daie et al 2016). The behavioral effect in Goard et al 2016 may not be caused by the silencing itself, but by the subsequent rebound activity (an overshoot after silencing; see for example Guo JZ et al eLife 2016; Figure 4—figure supplement 2). Rebound activity is difficult to avoid, but can be minimized by gradually ramping down the photostimulus, a strategy that was not used here. The key indication that rebound was a problem is that behavior degrades almost exclusively via an increase in false alarm rate -- in other words - mice now always lick independent of trial type. Increased activity in ‘fMC’, as expected with rebound, is expected to promote these false alarms. More experiments are needed to make the inactivation experiments solid.


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    1. On 2017 Dec 06, Morten Frisch commented:

      Problems in the qualitative synthesis paper on sexual outcomes following non-medical male circumcision by Shabanzadeh et al

      by Frisch M<sup>1,2</sup> & Earp BD<sup>3</sup>

      <sup>1</sup> Statens Serum Institut, Copenhagen, Denmark <sup>2</sup> Aalborg University, Aalborg, Denmark <sup>3</sup> Hastings Center Bioethics Research Institute, USA

      The comment below was published on the Danish Medical Journal's (Ugeskrift for Læger's) website on July 1, 2016: http://ugeskriftet.dk/files/2016-07-01_commentary_frisch_earp_on_paper_by_shabanzadeh_et_al_dmj_1.pdf

      _____________________________________________________________________________________________________________

      Shabanzadeh et al (1) claim in their title that “Male circumcision does not result in inferior perceived male sexual function.” Yet such a categorical conclusion does not follow from the data and analysis presented in the paper itself. As the authors state, there was “considerable clinical heterogeneity in circumcision indications and procedures, study designs, quality and reporting of results” in the studies they reviewed, which precluded an objective, quantitative assessment. Inadequate follow-up periods of only 1-2 years in the prospective studies imply that their results cannot be generalized beyond that range. In addition, “Risks of observer and selective reporting bias were present in the included studies … only half of the studies included validated questionnaires and some studies reported only parts of questionnaires.”

      There is also a troubling heteronormativity to the authors’ headline claim. As they state: “Most studies focused on the heterosexual practice of intravaginal intercourse and did not take into account other important heterosexual or homosexual practices that comprise male sexual function.” Such practices include, inter alia, styles of masturbation that involve manipulation of the foreskin itself, as well as “docking” among men who have sex with men (MSM), both of which are rendered impossible by circumcision (2). Related to this, a recent Canadian study, not included in the paper by Shabanzadeh et al, found “a large preference toward intact partners for anal intercourse, fellatio, and manual stimulation of his partner’s genitals,” in a small but demographically diverse sample of MSM (3). Against such a backdrop, the authors’ characterization of their paper as “a systematic review” showing a definitive lack of adverse effects of circumcision on perceived male sexual function is unjustified. As Yavchitz et al argue, putting such a conclusive ‘spin’ on findings that are in truth more mixed or equivocal “could bias readers' interpretation of [the] results” (4). Thus, while the literature search performed by Shabanzadeh et al may well have been carried out in a systematic manner, their ‘qualitative synthesis without metaanalysis’ leaves the distinct impression of a partial (in both senses of the word)assessment.

      The authors mention that the rationale for undertaking their analysis was “the debate on non-medical male circumcision [that has been] gaining momentum during the past few years”. But the public controversy surrounding male circumcision has to do with the performance of surgery on underage boys, specifically, in the absence of medical necessity. By contrast, therapeutic circumcisions that cannot be deferred until an age of individual consent are broadly perceived to be ethically uncontroversial, as are voluntary circumcisions performed for whatever reason on adult men, who are free to make such decisions about their own genitals (5). Consequently, studies dealing with either therapeutic or adult circumcisions are irrelevant to the ongoing controversy and should have been excluded by the authors in light of their own aims; such exclusion would have left only a handful of relevant investigations out of the 38 included studies.

      As one of us has noted elsewhere: “the [sexual] effects of adult circumcision, whatever they are, cannot be simply mapped on to neonates” or young children (2). This is because studies assessing sexual outcome variables in adults typically do not account for socially desirable responding (6); they concern men who, by definition, actively desire to undergo the surgery to achieve a perceived benefit, and are therefore likely to be psychologically motivated to regard the result as an improvement overall; and such studies are typically hampered by limited follow-up (as noted above), rarely if ever extending into older age, when sexual problems begin to increase markedly (7). In infant or early childhood circumcision, by contrast, “the unprotected head of the penis has to rub against clothing (etc.) for over a decade before sexual debut. In this latter case … the affected individual has no point of comparison by which to assess his sexual sensation or satisfaction - his foreskin was removed before he could acquire the relevant frame of reference - and thus he will be unable to record any differences” (2).

      The sexual consequences of circumcision are likely to vary from person to person. All-encompassing statements, such as that forming the title of the paper by Shabanzadeh et al, do not reflect this lived reality. Individual differences in sexual outcome variables will be shaped by numerous factors, such as the unique penile anatomy of each male, the type of circumcision and the timing of the procedure, the motivation behind it, the cultural context, whether it was undertaken voluntarily (or otherwise), the man’s subjective feelings about having been circumcised, his underlying psychological profile, and so on (8, 9). Collapsing across all of these factors to draw general conclusions can only serve to obscure such crucial variance (10).

      Therefore, the choice of the authors to include any study looking at sexual outcomes after circumcision, whether in boys or adult males, whether in healthy individuals or in patients with a foreskin problem, whether in Africa or in Western settings, and whether with a follow-up period of decades or only a few months to years is problematic. Such a cacophony of 38 studies, dominated by findings on short-term sexual consequences of voluntary, adult male circumcision has limited relevance, if any, to the authors’ stated research question: how non-therapeutic circumcision in boys affects the sex lives of the adult men they will one day become.

      References

      (1) Shabanzadeh DM, Düring S, Frimodt-Møller C. Male circumcision does not result in inferior perceived male sexual function – a systematic review. Danish Medical Journal 2016; 63: A5245 (http://www.danmedj.dk/portal/page/portal/danmedj.dk/dmj_forside/PAST_ISSUE/2016/D MJ201607/A5245).

      (2) Earp BD. Sex and circumcision. American Journal of Bioethics 2015; 15: 43-5.

      (3) Bossio JA, Pukall CF, Bartley K. You either have it or you don't: the impact of male circumcision status on sexual partners. Can J Hum Sex 2015; 24: 104-19.

      (4) Yavchitz A, Boutron I, Bafeta A, Marroun I, Charles P, Mantz J, Ravaud P. Misrepresentation of randomized controlled trials in press releases and news coverage: a cohort study. PLoS Med 2012; 9, e1001308.

      (5) Darby R. Targeting patients who cannot object? Re-examining the case for nontherapeutic infant circumcision. SAGE Open 2016; 6: 2158244016649219.

      (6) Earp BD. The need to control for socially desirable responding in studies on the sexual effects of male circumcision. PLoS ONE 2015; 10: 1-12.

      (7) Earp BD. Infant circumcision and adult penile sensitivity: implications for sexual experience. Trends in Urology & Men’s Health 2016; in press.

      (8) Goldman R. The psychological impact of circumcision. BJU International 1999; 83: 93-102.

      (9) Boyle GJ, Goldman R, Svoboda JS, Fernandez E. Male circumcision: pain, trauma and psychosexual sequelae. Journal of Health Psychology 2002; 7: 329-343.

      (10) Johnsdotter S. Discourses on sexual pleasure after genital modifications: the fallacy of genital determinism (a response to J. Steven Svoboda). Global Discourse 2013; 3: 256-265.


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    1. On 2016 Jun 17, David Keller commented:

      "Long-Acting Opioids Increase Mortality in Patients With Chronic Noncancer Pain" - erroneous Practice Update headline

      Through no fault of the investigators of this trial, the headline over the Practice Update summary of this study mistakes the association demonstrated in this observational study for causality, which can only be proved by means of a prospective, randomized, head-to-head interventional trial comparing long-acting opioids with other options for treating chronic non-cancer pain. Until such results are available, the headline should read:

      Long-Acting Opioids Are Associated With Increased Mortality in Patients With Chronic Noncancer Pain

      This distinction is important, and is a frequent cause of confusion in writers of headlines about clinical trials. Because serious therapeutic mistakes result from over-valuing observational data, it is important to correct these erroneous headlines. Here is the link to Practice Update, accessed on 6/17/2016, containing the erroneous headline:

      http://www.practiceupdate.com/content/long-acting-opioids-increase-mortality-in-patients-with-chronic-noncancer-pain/40326/55/6/1#commentarea

      The primary-care expert who discusses this study for Practice Update is Peter Lin MD,CCFP, who writes: "Long acting opioids increase death? This is an important question but one that we can’t ethically answer with a study. Imagine getting consent for this study? We are trying to see if these medications would kill you. So we could not ethically randomize patients to long acting opioids versus antiepileptic or antidepressant treatment and see who dies faster." This comment misses the most important question raised, but not answered, in this paper.

      The authors list a number of possible toxicities of opioids, and state that long-acting opioids (LAO's) "are of particular concern because the prolonged drug levels might increase toxicity." This raises the question of whether chronic pain patients experience higher mortality due to the long-acting delivery system itself, and whether an equal daily dose of the same opioid would be safer if taken in divided doses of the immediate-release form. For example, a study comparing the mortality associated with extended-release oxycodone versus immediate-release oxycodone would answer the question of how much of the mortality associated with long-acting opioids in this study was due to the long-acting delivery of opioids versus the opioids themselves. Only by comparing an intrinsically short-acting opioid, such as oxycodone, with its extended-release form, in a head-to-head randomized study, can we isolate and quantify any increased harm of the extended-release delivery system itself. Such a trial would be ethical if the subjects were pain patients who are stable on a short-acting opioid and have been designated as appropriate candidates to switch to the extended-release form. The control group would delay that change for a month, while the intervention group would switch to extended-release immediately. Any difference in harms between these two groups during the first month could then be definitely attributed to the extended-release delivery system itself, because all other variables would be held constant, including the pain medication molecule.

      Only a randomized, controlled, head-to-head trial, such as proposed above, can quantify the harms and benefits caused by the extended-release delivery of an opioid molecule as compared with the same total daily dose of the immediate-release form of the same opioid molecule. Answering this fundamental question is necessary before further comparisons can be interpreted, such as between opioid pain medications with differing intrinsic durations of effect, or comparisons between opioids and nonopioid pain treatments.


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    1. On 2016 Mar 09, John B Buse commented:

      As explained in the paper, the comparison was made to glargine to examine the common clinical scenario of inadequately controlled diabetes treated with basal insulin. Glargine is the most commonly prescribed insulin formulation in the world. There are prior comparisons of IDegLira versus degludec in DUAL-1 (Gough, et al. Lancet Diabetes Endocrinol. 2014 PMID: 25190523) and in DUAL-2 (Buse, et al. Diabetes Care 2014. PMID: 25114296). There are also studies that have compared glargine to degludec head to head, e.g., Rodbard Diabet Med. 2013 PMID: 23952326. Thank you for your comment.


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    1. On 2016 Mar 15, Lionel Christiaen commented:

      In this article, the author presents an extensive account of the extreme diversity of adult anatomies and life histories encountered across the thousands of tunicate species that roam the oceans worldwide, and occupy multitudes of ecological niches. The author then emphasizes that tunicate genomes are markedly more compact and evolve faster than the genomes of their chordate relatives, the cephalochordates and vertebrates. Several recent studies support this notion, and the argument that rapid genome diversification may have fostered tunicate evolution is reasonable. Since the early development of tunicates, in particular ascidians, has been considerably simplified and streamlined in a manner analogous to what is observed in nematodes, the author argues that tunicates must have lost most ancestral genomic, developmental and anatomical features that could inform reconstruction of the evolutionary history of vertebrate traits. We wish to provide alternative interpretations and propose a more inclusive approach to the problems posed by tunicates in building models for the evolution of vertebrates. First, the argument about faster evolutionary rates implies that every part of the genome evolves at similarly faster rates; yet, phylogenomic analyses of concatenated coding sequences unequivocally revealed that tunicates and vertebrates form a monophyletic group referred to as olfactores [1, 2]. Moreover, conserved anatomical features including the notochord, the dorsal neural tube and the pharyngeal gill slits depend upon ancestral regulatory inputs from conserved transcription factors, as noted by the author. These simple examples argue against a complete relaxation of evolutionary constraints on ancestral features in tunicates, especially in ascidians. In other words, high average rates of sequence evolution and profound morphological changes are not incompatible with deep conservation of cellular and molecular mechanisms for embryonic patterning and cell fate specification. Instead, the apparent incompatibility between high rates of genome divergence and the maintenance of ancestral olfactores features over long evolutionary distances hints at the notion of developmental system drift (DSD), whereby mechanistically connected developmental features may be conserved between distantly related species exhibiting extensive divergence of the intervening processes [3]. Ascidians provide an attractive test-bed to study DSD since their early embryos have barely changed in almost half a billion years, despite considerable genomic divergence [4]. This is a lively area of research as illustrated by the 11 tunicate genomes recently made openly available to the worldwide research community [4-6]. We argue that comparative developmental studies are poised to identify additional features conserved between tunicates and vertebrates, such as those recently reported for the neural crest, the cranial placodes and the cardiopharyngeal mesoderm [7-10]. These "islands of conservation" will continue to shed light on the mechanisms of tunicate diversification and the deep evolutionary origins of the vertebrate body plan.

      REFERENCES 1. Delsuc, F., Brinkmann, H., Chourrout, D., and Philippe, H. (2006). Tunicates and not cephalochordates are the closest living relatives of vertebrates. Nature 439, 965-968. 2. Putnam, N.H., Butts, T., Ferrier, D.E., Furlong, R.F., Hellsten, U., Kawashima, T., Robinson-Rechavi, M., Shoguchi, E., Terry, A., Yu, J.K., et al. (2008). The amphioxus genome and the evolution of the chordate karyotype. Nature 453, 1064-1071. 3. True, J.R., and Haag, E.S. (2001). Developmental system drift and flexibility in evolutionary trajectories. Evolution & development 3, 109-119. 4. Stolfi, A., Lowe, E.K., Racioppi, C., Ristoratore, F., Brown, C.T., Swalla, B.J., and Christiaen, L. (2014). Divergent mechanisms regulate conserved cardiopharyngeal development and gene expression in distantly related ascidians. eLife 3, e03728. 5. Voskoboynik, A., Neff, N.F., Sahoo, D., Newman, A.M., Pushkarev, D., Koh, W., Passarelli, B., Fan, H.C., Mantalas, G.L., Palmeri, K.J., et al. (2013). The genome sequence of the colonial chordate, Botryllus schlosseri. eLife 2, e00569. 6. Brozovic, M., Martin, C., Dantec, C., Dauga, D., Mendez, M., Simion, P., Percher, M., Laporte, B., Scornavacca, C., Di Gregorio, A., et al. (2016). ANISEED 2015: a digital framework for the comparative developmental biology of ascidians. Nucleic acids research 44, D808-818. 7. Abitua, P.B., Gainous, T.B., Kaczmarczyk, A.N., Winchell, C.J., Hudson, C., Kamata, K., Nakagawa, M., Tsuda, M., Kusakabe, T.G., and Levine, M. (2015). The pre-vertebrate origins of neurogenic placodes. Nature 524, 462-465. 8. Abitua, P.B., Wagner, E., Navarrete, I.A., and Levine, M. (2012). Identification of a rudimentary neural crest in a non-vertebrate chordate. Nature 492, 104-107. 9. Diogo, R., Kelly, R.G., Christiaen, L., Levine, M., Ziermann, J.M., Molnar, J.L., Noden, D.M., and Tzahor, E. (2015). A new heart for a new head in vertebrate cardiopharyngeal evolution. Nature 520, 466-473. 10. Stolfi, A., Ryan, K., Meinertzhagen, I.A., and Christiaen, L. (2015). Migratory neuronal progenitors arise from the neural plate borders in tunicates. Nature 527, 371-374.


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    1. On 2016 Sep 17, ROBERT COMBES commented:

      Professor Michael Balls and Dr Robert Combes respond to Dr Coral Gartner regarding concerns about possible conflicts of interest.

      We thank Dr Gartner for her comments, and for the opportunity to clarify potential conflicts of interest relating to our paper [1]. This was written by us as independent individuals, free of any commercial influence or funding, and after both of us had ceased having close ties with FRAME. FRAME is a scientific charity that has openly received financial support from the chemical, cosmetic, household product, pharmaceutical and tobacco industries, to enable it to undertake independent research into the development, validation and acceptance of alternatives to animal experiments.<br> Some of this work included the development, characterisation and preliminary assessment of in vitro models of inhalation toxicology. While we are not in a position to say anything about FRAME’S current policy on industrial funding, we must stress that the tobacco industry funding enabled FRAME to investigate ways to replace highly invasive and complex animal experiments with urgently needed alternatives with the potential for producing more-relevant and more-reliable data for assessing human safety.

      As far as personal remuneration is concerned, RDC has acted as an external consultant for the tobacco industry since retiring in 2007 from FRAME. This work was conducted under standard contract research agreements, the last of which terminated over 12 months prior to the writing of our article. The work referred to by Dr Gartner, that was co-authored by RDC with a named individual as lead, relates to research undertaken when this individual and RDC were employed by Inveresk Research International (IRI, now Charles River Laboratories), a contract research establishment. This can be directly verified by opening the authors’ affiliations in PubMed (http://9www.ncbi.nlm.nih.gov/pubmed)for each of the four respective abstracts (PMID: 9491389; PMID: 1600961; PMID: 1396612; and PMID: 7968569). This work was entirely funded by the US Government, as was acknowledged in each of the papers, and also by the inclusion of another co-author, then based at NIEHS (the National Institute of Environmental Health Sciences, Research Triangle Park, USA), who acted as project leader. It should be noted that the lead author of the publications arising from the work conducted at IRI subsequently went to work at BAT, and this might have added to any confusion.

      MB has never been a paid consultant for any industrial company. He was honorary Chairman of the FRAME Trustees from 1981 to 2013, and has been honorary Editor of FRAME’s journal, Alternatives to Laboratory Animals, since 1983. He no longer has any influence on FRAME’s policies on the tobacco industry or on any other issue. None of FRAME’s industrial supporters ever attempted to dictate or limit FRAME’s activities, or influence the circulation and/or publication of the results of any FRAME research. While MB was head of the FRAME Alternatives Laboratory at the University of Nottingham Medical School, no tobacco product, or chemical, other material or product of interest to the tobacco industry was involved in FRAME’s research. He left the University of Nottingham in 1993, to become the first head of the European Commission’s European Centre for the Validation of Alternative Methods, a position from which he retired in 2002. We consider that there is a distinction between the above situation, in which, despite previous links of various kinds with the tobacco industry, we wrote our critique [1](ref) without any form of external influence, and that which we referred to, involving alleged conflicts of interest in the MCDA study. However, while we acknowledge that conflicts of interest and their consequences are complex, we hope that we have taken into account as much relevant information as possible to permit a fair and balanced appraisal of the information on which PHE's policy on electronic cigarettes is based. We consider it crucial that scientific opinions, and the policies which result from them, are based on freely-available evidence of high quality, which has been openly conducted and independently assessed. We know of no such evidence to support PHE’s claim that e-cigarettes are 95% safer than tobacco cigarettes.

      We welcome Dr Gartner’s comment, we hope that others will address the scientific arguments that we have used to justify our position, since, the validity, or otherwise, of these should be unaffected by any conflicts of interest. There is a great deal at stake, including the future well-being of those who have opted for vaping as an alternative to tobacco smoking. We stand by our belief, expressed in a letter published in The Times on 18 February 2016, that “The human respiratory system is a delicate vehicle, on the which the length and quality of our lives depend. For governments and companies to condone, or even suggest, the regular and repeated inhaling of a complex mixture of chemicals with addictive and toxic properties, but without comprehensive data, is irresponsible and could have serious consequences.”

      1. Combes, R D. & Balls, M. On the safety of e-cigarettes: "I can resist anything except temptation". ATLA. (2015) 43, 417-425.


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    1. On 2015 Nov 20, David Keller commented:

      Why the blinding of experimental subjects should be tracked during a study, from start to finish

      I wish to address the points raised by Folmer and Theodoroff in their reply [1] to my letter to the editor of JAMA Otolaryngology [2] concerning issues they encountered with unblinding of subjects in their trial of therapeutic MRI for tinnitus. These points are important to discuss, in order to help future investigators optimize the design of future studies of therapies for tinnitus, which are highly subject to the placebo, nocebo, Pygmalion and other expectation effects.

      First, Folmer and Theodoroff object to my suggestion of asking the experimental subjects after each and every therapy session whether they think they have received active or sham placebo therapy in the trial so far (the "blinding question"). They quote an editorial by Park et al [3] which states that such frequent repetition of the blinding question might increase "non-compliance and dropout" by subjects. Park's statement is made without any supportive data, and appears to be based on pure conjecture, as is his recommendation that subjects be asked the blinding question only at the end of a clinical trial. I offer the following equally plausible conjecture: if you ask a subject the blinding question after each session, it will soon become a familiar part of the experimental routine, and will have no more effect on the subject's behavior than did his informed consent to be randomized to active treatment or placebo in the first place. Moreover, the experimenters will obtain valuable information about the evolution of the subjects' state of mind as the study progresses. We have no such data for the present study, which impairs our ability to interpret the subjects' answers to the blinding question, when it is asked only once at the end of the study.

      Second, Folmer and Theodoroff state that I "misinterpreted" their explanation of why so many of their subjects guessed they had received placebo, even if they had experienced "significant improvement" in their tinnitus score. They object to my characterization of this phenomenon as due to the "smallness of the therapeutic benefit" of their intervention, but my wording summarizes their lengthier explanation, that their subjects had a prior expectation of much greater benefit, so subjects incorrectly guessed they had been randomized to sham therapy even if they exhibited a small but significant benefit from the active treatment. In other words, the "benefit" these subjects experienced was imperceptible to them, truly a distinction without a difference.

      A therapeutic trial hopes for the opposite form of unblinding of subjects, which is when the treatment is so dramatically effective that the subjects who were randomized to active therapy are able to answer the blinding question with 100% accuracy.

      Folmer and Theodoroff state that, in their experience, even if subjects with tinnitus "improve in several ways" due to treatment, some will still be disappointed if their tinnitus is not cured. Do these subjects then answer the blinding question by guessing they received placebo because their benefit was disappointing to them, imperceptible to them, as revenge against the trial itself, or for some other reason? Regardless, if you want to know how well they were blinded, independent of treatment effects and of treatment expectation effects, then you must ask them early in the trial, before treatment expectations have time to take hold. Ask the blinding question early and often. Clinical trials should not be afraid to collect data. Data are good; more data are better.

      References:

      1: Folmer RL, Theodoroff SM. Assessment of Blinding in a Tinnitus Treatment Trial-Reply. JAMA Otolaryngol Head Neck Surg. 2015 Nov 1;141(11):1031-1032. doi: 10.1001/jamaoto.2015.2422. PubMed PMID: 26583514.

      2: Keller DL. Assessment of Blinding in a Tinnitus Treatment Trial. JAMA Otolaryngol Head Neck Surg. 2015 Nov 1;141(11):1031. doi: 10.1001/jamaoto.2015.2425. PubMed PMID: 26583513.

      3: Park J, Bang H, Cañette I. Blinding in clinical trials, time to do it better. Complement Ther Med. 2008 Jun;16(3):121-3. doi: 10.1016/j.ctim.2008.05.001. Epub 2008 May 29. PubMed PMID: 18534323.


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    1. On 2016 Dec 26, Boris Barbour commented:

      In this "perspective", the authors build up the importance of using full electrodiffusion simulations without an electroneutrality constraint to describe current flow and ion distributions within dendritic spines, rather than treating the cytoplasm as an Ohmic conductor. Although an electrodiffusion model is in principle more accurate and may in some cases be necessary, the authors do little to make their case here, because their illustrative model in Fig. 3 is quite divorced from physiological conditions.

      They illustrate the equilibrium spatial distribution of ions within a small and isolated sphere of water, a situation loosely representing the head of a dendritic spine. When electrical interactions between the ions are considered at high concentrations, a highly nonuniform spatial distribution emerges. However, there are both trivial and fundamental problems with this apparently dramatic illustration.

      It is worth fixing some numbers. Empirical measurements of membrane capacitance typically yield values of ~1microF/cm<sup>2.</sup> So the capacitance of a typical spine head with diameter 0.5 microns will be about 10fF. Charging this capacitance to the most extreme membrane potentials observed in neurones (of the order of 100mV) will therefore require about 1fC, a charge that represents about 5000 ions. The volume of such a spine head would be about 70aL (attoLitres) and, assuming a 150mM saline of monovalents, would contain about 600000 each of cations and anions. The authors use a rather oversized spine head compared to this, but the numerical differences will be unimportant to what follows.

      The authors simulate 1000, 100000 and 1000000 charges, but already the second number exceeds the largest net concentration of charges that will occur physiologically.

      The concentrations they report are numerically incorrect at least in Fig. 3b (where the mean concentration should be 40 microM) and in Fig. 3c (where the mean concentration should be 400 microM).

      A true representation of these gradients would include the existing 150mM saline. Thus, for Fig. 3a, the ~100nM gradient would be superimposed upon 150mM, about one part in a million, which may not be that significant.

      Another important problem arises from the fact that the authors only include charges of one sign in their model, while physiological saline contains both cations and anions, in roughly if not exactly equivalent concentrations (we calculated above that the net charge represents of the order of 1% of ions present, and even this number is only made possible by the membrane capacitance). This unrealistic situation is likely to have a very strong influence on the behaviour illustrated, because the existence of ions of the opposite sign would allow electrostatic screening, which the authors have in effect banished from their model by only including a single ionic species.

      The ionic gradients illustrated by the authors arise from collective mutual Coulombic repulsion (note that the submembrane ionic concentration shown is unrelated to the concentrations of charges normally occurring on either side of the membrane capacitance, because the external saline is absent in this model). Such Coulombic forces are usually annihilated over all but the shortest distances and times by electrostatic screening. The habitual approximation considers electrostatic shielding to cause an exponential attenuation of Coulombic interactions with a length constant of the Debye length. In 150mM monovalent saline the Debye length is about 0.6nm (using an approximate formula given on wikipedia), so, even over a fraction of a micron, Coulombic interactions should be attenuated to a cosmic degree and the forces generating the interesting concentration gradients of Fig. 3 are unlikely to operate.

      In conclusion, although I'm not in a position to describe exactly the distribution of net charges in the spine head under physiological conditions in the absence of strict electroneutrality, neither are the authors. However, ignoring electrostatic screening seems to be an extremely unrealistic approximation.


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    1. On 2015 Oct 08, Michael R Blatt commented:

      Dear Lydia:-

      I can see that this is a highly emotionally-charged issue for you, whereas it appears less so for Jaime (though I can fully imagine why it might be otherwise). So, I do think it important to step back for a moment.

      Let me relate another matter to you. This pertains to a case that goes back more than a quarter of a century and took place in a university in the mid-West of the United States. I was peripherally associated with the case, primarily because of my knowledge of the professor involved (a good friend, as it happens, and we remain so still). The professor, let’s call him Fred for now, became embroiled in an argument with his head of institute. The details of the argument are less important than the consequences. Fred was so aggrieved by the way he felt he had been treated, that he became disruptive, aggressive and threatening to other academic staff and students alike. In the end, following disciplinary proceedings, Fred was barred from the institute and took ‘early retirement.’ From my own perspective, I could understand why Fred was aggrieved – I, too, felt that the initial handling of the argument was problematic – but I could also see that his reaction was inappropriate and disproportionate, and that the institute had no choice but to bar him. In effect, Fred was within his rights, but was unwilling to accept responsibility for his actions and their consequences.

      I am not suggesting that there is a parallel here, but I recall the story to point out that there are always two sides to an argument. In Fred’s case, I was close enough to the events that it was easy to see what was going on, from both sides. In Jaime’s case, I have gathered what information I can from RetractionWatch, but I note that the information is presented almost entirely from his perspective. In your insistence that I choose a side, do you really mean to deny me the right to hear both sides of the argument?

      Bests,

      Mike

      p.s. I’ll need to attend to my own day job now, so it may be a few days before I respond to any more comments.


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    2. On 2015 Oct 04, Michael R Blatt commented:

      Dear Dr. da Silva,

      Thank you for your comments. I am happy to discuss thoughtfully on the open forum of PubMed Commons. Like you, I reflected long and hard before writing my piece for precisely the reasons we are entering into this discussion: anonymity, fear, and scientific debate. Several of my closest colleagues expressed their anxieties that putting my head ‘above the social media parapet’ could have negative consequences for them. I, too, had my doubts but felt it important to raise concerns expressed to me by colleagues, young and old, which I share. I am therefore writing both in response to your invitation and generally to some of the comments posted to my editorial. I want to thank Philip Moriarty who I have come to know over the past week and who is much more eloquent than I could ever be, and Leonid Schneider who has shown true grace in stepping back from his initial cynicism to participate in the discussion.

      I agree with your point that we should not fear to associate our names with critical opinion and, like Moriarty, I am dismayed by the lack of appetite to engage in open debate (note my emphasis on names and open). I am also deeply disturbed by the attitude of those who think that scientific critique is a license to ride roughshod into any discussion without once considering the possibility of a wider context or background to the questions at hand. At the most trivial level, it is easy – and cheap – to extract a few lines and twist them to the ridiculous; at the most fundamental, it shows an ignorance of social norms that make constructive debate possible. It’s no wonder that my colleagues were anxious and that there is fear within the community. They fear to engage because they do not want to become targets of the vitriol that pervades anonymous social media. To my mind, this is a sign that the “patient is not well” and I agree fully with the assessments of Moriarty, Schneider and others that our current approach to scientific exchange is deeply flawed in many ways.

      So we come to your concerns: journal publication, PPPR, and anonymity. Here I must respectfully disagree with you on several points. Consider your starting premise, that “the final product, i.e. the published paper [is] the product of a failsafe process that is not meant to be challenged.” Surely, this flies in the face of scientific enquiry and one of the first lessons we all learn as students: to challenge ideas in order to progress understanding. Nor is publication a final product; it’s just the most visible at times. The real product of a body of work lies in its capacity to guide subsequent studies and predict their outcomes. As scientists, we subject our own work, and that of others, to scrutiny that either validates, discounts, or refines their outputs. The scientific literature is riddled with misconceptions, false conclusions, and ideas that failed this so-called ‘test of time’. And so it should be. As scientists, we put our work and ideas out into the community and, as a community, we improve and expand on each body of work. In short, publication is only one small step in the scientific process and always has been.

      Second, let me stress that the purpose of editorial review is to assess a body of research, its scientific soundness, and whether it is of sufficient interest to the community – and, most important to the journal readership – to justify publication. Maintaining ethical standards is, of course, part of this task, but only one part of it. Nor is is the editorial process failsafe. No journal editor is able to catch all errors, innocent or otherwise, although on the whole editors are usually pretty good at identifying problems. I agree that there is a place for post-publication critique, including an element of quality control. I stated as much in my editorial.

      What I cannot abide is PubPeer’s stance on anonymity, and I am angered by their efforts to masquerade as a site for open discussion that reflects the opinions of the scientific community. Both I consider to be fundamentally deceitful. I outlined my reasons in the editorial and these have been reiterated in several posts in response. Anonymity does not ‘level the playing field’; quite the contrary, it embeds inequality in any debate simply because one side is hidden. Furthermore, anonymity opens the door to all kinds of antisocial and nefarious behaviour. You need only read many of the comments posted in response to my editorial to see the innuendo and vitriol that was unleashed towards me as well as towards others posting on the site. Such verbal abuse belongs … well, let’s just say it does not belong in the public domain outside the schoolyard. Call me old-fashioned if you will, but in my book this is unnecessary, grubby and, what’s worse, counterproductive. For most people, the mob mentality behind this kind of behaviour is quite frightening. And like it or not, mob mentality is the framework of vigilantism. Is it any wonder, then, that so many of my colleagues, young and old, are fearful? Is this the kind of ‘scientific debate’, indeed the kind of society, we want to support? I don’t. It seems to me that anonymity in these circumstances is not the solution, but the problem. It is at the root of much that has gone terribly wrong in scientific exchange today.

      I agree that there are some circumstances in which confidentiality (not anonymity!) is necessary to protect the identities of individuals, especially of whistleblowers (I’ll come to this point in a moment). However, the vast majority of posts on PubPeer do not fall in this category, even those which highlight one or more errors in a figure. I maintain that it is possible for a PhD student or postdoc to approach a colleague, even a senior scientist, in order to point out an error, and to do so in a way that is constructive and non-threatening. This is a vital social skill to learn. I shudder to think that, through ‘social’ media, this skill could be lost to the sound bite of a tweet. Like Julian Stirling (cited on PubPeer in several posts), I have no patience with lazy or conflicted thinking, and I welcome critical analysis when presented thoughtfully. I encourage my students and postdocs to question me, and others, all the time and, no surprise, the ones who have done so have also proven most successful when they leave my lab. I think you and others have vastly overstated the dangers of retribution, in part perhaps by conflating scientific debate and error correction with whistleblowing. They are not the same.

      As for misconduct, of course whistleblowers need protection through confidentiality, but not through anonymity. Again, I have set out my reasoning in the editorial and will not reiterate here. Mechanisms are in place to provide confidentiality, in the first instance through the established channels of most journals. I agree, too, that if these fail, then there must be alternative mechanisms that allow legitimate concerns to be addressed effectively. I, for one, support efforts to ensure such alternatives. However, I do not agree that the answer is through a culture of secrecy and hearsay.

      So how do we encourage thoughtful debate? How do we enable quality control and at the same time protect whistleblowers? I don’t pretend to have all the answers, but it is patently clear to me and many others that the answer is not through a so-called post-publication peer review process that is anonymous and, for all intents and purposes, unmoderated. Again, I point you to my editorial and the three challenges I have laid before PubPeer. I believe Stell and his colleagues have a real opportunity to lead the way in raising the tenor of science in this social media age, but they must address these challenges to do so.

      Finally, to your personal critique, I appreciate that you have included reference to your own pieces, as I am sure other readers will too.

      Thank you.

      Mike Blatt


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    1. On 2015 Sep 15, David Keller commented:

      Proposal for a clinical trial to test the safety of a widely-used radionuclide scan

      A recent letter to JAMA Internal Medicine [1], asked whether substantia nigra (SN) neurons weakened by Parkinson disease (PD) may be more sensitive to the adverse effects of ionizing radiation than are healthy mature neurons. Dosimetry safety studies assume that neurons are relatively resistant to damage from ionizing radiation. Radiation safety is, instead, calculated based on exposure of such tissues as the thyroid and the lining of the bladder. If SN neurons in PD are significantly more radiosensitive than healthy neurons, then PD patients might suffer progression of PD caused by the level of ionizing radiation exposure caused by certain diagnostic scans.

      In a widely-used clinical diagnostic brain imaging procedure known as the "DaT scan", a radiopharmaceutical tracer marketed as "DaTscan" (Ioflupane I-123) is injected intravenously, crosses into the brain and binds to dopamine transporters. The tracer emits gamma radiation, thereby allowing for imaging which can help distinguish Parkinsonism from other causes of similar symptoms. According to Table 1 of the DaTscan product information, the highest concentration of injected activity occurs in the striatum, close to the substantia nigra [2]. At the recommended adult dose of DaTscan, the striatum is exposed to 185 MBq x 230 microGray/MBq = 42550 microGray = 42.55 mSv = 4.25 Rad of gamma radiation (1 Sv = 1 Gray = 100 Rad). The nearby SN receives approximately the same exposure, although the exact figure is not specified in the DaTscan product information.

      How damaging is a gamma exposure of about 42.5 mSv to SN neurons already weakened by PD? For comparison, a head CT exposes the entire brain to about 2 mSV uniformly; so the radiation exposure to the striatum caused by a dose of DaTscan is the same as it would receive from 21 brain CT scans [3]. The SN and other nearby basal ganglia presumably receive about the same exposure, although the DaTscan product insert does not specify this important information.

      The clinical effect of this radiation dose on PD patients may be found by conducting an observational study of patients who have been ordered to get a DaTscan by their neurologist. Each patient would be given a thorough UPDRS exam (a detailed PD-focused neurologic exam) prior to being scanned, and at appropriate intervals after scanning. The overall rate of UPDRS score deterioration in the study subjects should be compared with that of matched PD patients who have not undergone scanning. Any significant worsening of UPDRS scores in the intervention group, compared to the control group, would presumably be an adverse effect of the DaTscan radiotracer, and should be investigated further.

      With the increasing use of DaT scans, PD patients should be informed whether their clinical condition, as measured by the UPDRS, will be expected to worsen as a result of these scans, and if so, approximately how much.

      I emailed the above observations to the Commissioner of the FDA recently, and received a reply which failed to address my radiation safety concerns regarding the FDA-approved radiopharmaceutical tracer marketed by General Electric as DaTscan.[4]

      The Code of Federal Regulations Title 21, Section 601.35 (Evaluation of safety of diagnostic radiopharmaceuticals) mandates evaluation of "changes in the physiologic or biochemical function of the target and nontarget tissues". The effect of 42.5 mSv of gamma radiation concentrated on the already diseased neurons in the substantia nigra of patients with Parkinson's disease has not been determined, as is required under the above-cited Federal regulation.

      I urge neurologists and their patients with PD to consider the high concentration of gamma radiation caused by DaTscan and ask, before injecting this tracer, "is this scan really necessary, and how will it substantively alter clinical management?".

      References

      1: Keller DL. Non-neurologists and the Dopamine Transporter Scan. JAMA Intern Med. 2015 Aug 1;175(8):1418. doi: 10.1001/jamainternmed.2015.2497. PubMed PMID: 26236969.

      2: DaTscan drug prescribing information, visited on 9/16/2015:<br> http://us.datscan.com/wp-content/uploads/2014/06/prescribing-information.pdf

      3: M.I.T. online guide to radiation exposure, accessed on 9/20/2015 at:<br> http://news.mit.edu/2011/explained-radioactivity-0328

      4: Email received from FDA pharmacist identified only by the initials "H.P.", 10/15/2015.


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    1. On 2015 Dec 05, David Keller commented:

      Patient-oriented result: response rate to magnetic stimulation was the same as to placebo

      This study of repetitive transcranial magnetic stimulation (rTMS) was designed to test the hypothesis that rTMS would result in a "statistically significantly greater percentage of responders to treatment in an active rTMS group compared with a placebo rTMS group" [1]. A relatively new metric called the Tinnitus Functional Index (TFI) was used to measure response to treatment. The TFI rated 18 of the 32 subjects actively treated with rTMS as responders to treatment (56%), while only 7 of the 32 subjects treated with sham therapy were rated as responders (22%). These two rates differed significantly, which was pre-specified in the Objectives section as defining a successful outcome.

      However, 7 of the 18 treated subjects rated as "responders to therapy" using the TFI scale nevertheless believed they had received sham therapy, implying that they did not perceive any treatment benefit beyond the placebo effect. When a subject states that his treatments seemed like sham therapy, providing only placebo-strength benefit, this is important information. Since it is a direct expression of the subject's assessment of the efficacy of rTMS therapy, it has more validity than a contrived metric like the TFI, from a patient-oriented perspective.

      The data in e-Table 12 indicate that, of the 32 subjects who received active rTMS treatments, only 11 correctly guessed they had received active therapy at the end of the last treatment, which implies that only 11 out of 32 actively-treated subjects (about 34%) noted perceptible improvement in their tinnitus symptoms. Coincidentally, 11 of the 32 placebo-treated subjects (also 34%) guessed that they had received active rTMS therapy, which equals the placebo effect. Thus, active rTMS treatments had the same response rate as sham therapy, equal to the placebo effect of 34%.

      Conclusion: rTMS is no more effective than placebo for treating tinnitus, when assessed by subjects after a full course of treatments, based on their perception of whether they received active or sham therapy. The advantage of this assessment is that it eliminates uncertainty about the accuracy and clinical relevance of the TFI metric, because the assessment of treatment benefit came directly from the subjects themselves.

      Reference

      1: Folmer RL, Theodoroff SM, Casiana L, Shi Y, Griest S, Vachhani J. Repetitive Transcranial Magnetic Stimulation Treatment for Chronic Tinnitus: A Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2015 Aug;141(8):716-22. doi: 10.1001/jamaoto.2015.1219. PubMed PMID: 26181507.


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    1. On 2015 Sep 30, Lydia Maniatis commented:

      This study has very serious problems in terms of both its purpose and its methods.

      Purpose: The authors' guiding question is “how color constancy supports object selection,” an issue they claim is “not understood.” What, exactly, is not understood? If color constancy is achieved, if the percept is clear and the task unambiguous, then what do we hope to gain by having subjects choose a matching surface (out of a limited number of pre-selected options) rather thanfreely adjusting a patch, and then comparing it to a target in order to judge the correspondence between the two? Unless the means of gauging the subjects' perceptual experience is expected to affect the experience itself, then why not choose the most direct, precise, and easy-to-analyze means, rather than a cruder, ambiguous, difficult-to-analyze method deemed to be more “naturalistic”? (The authors themselves acknowledge the crudeness of their method – basically a forced-choice method - in relation to the free-choice “asymmetric matching” method).

      Methods: 1) The authors' use the dimensions “naturalistic” vs “simple” as their independent variables, without explaining what they mean by the terms. The study purports to compare color comparison/selection in a “naturalistic” stimulus vs a “simple” stimulus. The problem with this may be appreciated if we describe the “naturalistic” stimulus, which was actually a series of “simulated naturalistic scenes:” “The target objects were embedded in a multifaceted cube suspended in midair in a room in which the illumination, coming from multiple light sources, varied spatially.” Each facet of the cube contained 49 differently-colored, semi-randomly assigned checks. The illumination on one side was blue or yellow, on the other “standard.” Targets were placed on top of these colored checkerboards. The “simple” stimuli were “flat patches embedded in a textured color background across which simulated illumination varied.” It is not clear why the backgrounds in the “simple” stimulus were not checkerboards matched to those of the “natural” stimuli, or, alternatively, a solid background. Even though the authors state, at one point, that they are controlling for “low-level” features of the stimuli, methodological choices are never clarified beyond the “simple/natural” dichotomy.

      The authors themselves acknowledge the theoretical gap at the heart of this dichotomy: “A systematic characterization of how color constancy varies with the degree of stimulus naturalness is challenging, because a definition of naturalness remains elusive.” So, “Rather than attempting to define dimensions along which naturalness varies, we chose to study two configurations that we judged differed considerably in how natural they appeared.” Despite this vagueness in their chosen dimensions, they qualify the undefined value, “stimulus naturalness,” as a “key factor” in their results (at another point they refer to their stimulus as “nearly naturalistic” and the task as “fairly natural”). The problems here are beyond methodological, they are epistemological – failure to specify conditions in an experimental study means it does not meet the basic demands of the scientific method. Scientists go from nature to the lab in order to control and test potential causal variables; these authors are arguing that going "natural" is a merit - is somehow informative - even if they can't define what they mean by the term.

      2) The authors conclude that “a reasonable degree of color constancy operates effectively in support of object selection.” (Again, why wouldn't it?). The assertion turns the scientific method on its head. This is because the surfaces and illumination were “simulated.” Thus, judgment of whether observers' choices are 'color-constant' or not hinged on assumptions about what the true reflectance of a patch should be judged to be, based on the “simulated” illumination: “To find the reflectance match for each target under a test illuminant, we [derived] a surface reflectance function...using a three-dimensional linear model for surface reflectance...derived from analysis of the spectra of Munsell papers, using the tabulated spectral data reported by Nickerson (1957)...”

      Here's the problem: Let's say I take a black surface, place it on a larger grey surface, and brightly illuminate the smaller surface such that its boundary and the boundary of the illumination precisely coincide. Then, based on my knowledge of the illumination, I declare that a well-functioning lightness constancy mechanism should label the smaller surface “black.” Of course, my subjects would all fail this test. But it will not have been fair test, because observers are required to use the luminance structure of the stimulus to guess at both the reflectance and the illumination of the surfaces; they don't have my inside information about the illumination. If the stimulus itself doesn't support the inference of differential illumination, then the best inference is that illumination is uniform. Similarly, observers (their visual systems) of Radonjic et al's stimuli are called on to make guesses about both the reflectance and the illumination of target surfaces based on stimulus structure (geometric/chromatic). In order for the authors' presumed “correct” answers to constitute a valid test of observers' choices, they would have to provide a specific theory of why these answers constitute the best-guess based on stimulus structure. They would need to explicitly state their assumptions, rather than “cheating” by simply stripping away the “simulated illuminant.” And if they had made and shared any such theoretical assumptions, it would probably be more appropriate to consider observer choices a test of the theory, rather than making the predictions of the theory a test of observer choices. Because if we're studying perception, then the typical observer is never wrong.


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    1. On 2015 Mar 18, Kim D Pruitt commented:

      As the head of NCBI’s RefSeq project I would like to make a clarification on the relevance of the authors' results to RefSeq. The authors refer to the RefSeq dataset and UCSC RefGene dataset as if they are equivalent. However, the RefGene data represents annotation derived from UCSC-generated alignments of approximately 1/3 of the RefSeq data. The analysis presented here is of the UCSC RefGene dataset and not the complete RefSeq set as obtained at NCBI which builds and curates RefSeq. NCBI also provides human genome annotation data that includes the comprehensive RefSeq transcript data set. Details about the annotated location of a given RefSeq transcript at NCBI may differ from that shown in the UCSC RefGene track.

      Therefore, the relevance of this analysis to RefSeq is unclear.


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    1. On 2015 Aug 20, Lydia Maniatis commented:

      The authors here report having “investigated how texture and stereo cues are integrated to perceive 3D slant.” The problem here (as with other literature dealing with the same topic) is with the unqualified references to “texture cues.”

      2D “textures” are composed of 2D shapes, and 2D shape is dispositive when it comes to the perception of slant. If I start with a rectangle (or syncytium of rectangles) and I slant it so that it produces a trapezoidal 2D projection, then this projection will look like a slanted rectangle. If I start with a trapezoid and slant it so that it casts a rectangular 2D projection, then it will look like a fronto-parallel rectangle, not a slanted trapezoid. Perceived slant is a function of the shape of the projection.

      Because shape is the key factor mediating apparent slant, and because textures are composed of shapes, saying that we will study the role of “texture” without specifying and controlling for the effects of the particular shapes of which the texture is composed is like proposing to investigate the role of “food cues” on blood pressure, without caring about what type of food we are employing as our “stimulus.” Such practice ensures the enduring confusion and ambiguity that characterizes slant studies, which often seem to contradict each other.

      This study used “Voronoi” textures. Why? An earlier study (Todd et al, 2010) used textures composed of rectangles orthographically projected. Yet another study referred to by Saunders and Chen used Voronoi textures that were more regular than theirs. Do the authors believe that by using the type of structure the do, in which the cells' shape varies, and which has a particular degree of irregularity, they are controlling for the effects of shape? To continue my previous analogy, this would be like assuming that mixing many foods together will control for the effect of the individual nutrients on blood pressure.

      If we know a variable matters, then we don't control for it by mixing it up its values, we control for it by controlling for it. “Food” in this analogy is obviously not an appropriate level of analysis, and the results will vary with the choice of “food.” The same goes for “texture.” What is left after we subtract shape? At the least, the authors should have provided some rationale for their choice of texture.

      There is no doubt whatsoever that the choice of “texture” affects perceived slant. Erkelens (2013) used a “texture” composed of rectangles under perspective projection and found very good agreement with prediction, and an underestimation at all slants. Saunders and Chen found underestimation at low slants, and not at higher ones. They should explain why this low/high dichotomy should be found in their particular conditions, including their choice of pattern, and not in, e.g., Erkelens'. (Are they suggesting that by using “Voronoi” patterns, they have isolated the role of “texture,” independently of shape, and that their results are more valid?)

      The authors' decision to deal with the potential role of the outline containing their texture by randomly varying this shape reflects the tendency to embed confounds in the data in the hope that they will average out (rather than distort or flatten the results – averaging black and white makes grey) rather than to confront and control for them head on.

      Of course, they found that “texture” cues and disparity cues are somehow integrated (the claim that they are “optimally” integrated is difficult to judge, as it has been preceded by layers of speculation). The basic findings were a sure thing. The specifics of the data are uninterpretable due to lack of control of relevant variables.


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    1. On 2015 Jan 20, Paolo Vineis commented:

      We read Drs. Tomasetti and Vogelstein paper on the strong and positive association between the frequency of stem cell division and the risk of cancer with interest (1). However, their analytical approach was limited and their interpretation of findings was misleading. First, the study was based on a relatively small number of cancer types, most of which are rare, and excluded several common cancer types such as breast, prostate, bladder, and endometrium. Second, the frequency of stem cell division over time or across region is expected to change very little compared to changes in risk of cancer for the various cancer types. For example, during the 20th century in the US, risk for lung cancer increased by more than 50 fold but decreased by about ten-fold for cervix and stomach cancers (2). Liver cancer incidence rates in males (number of newly diagnosed cancer cases per 100,000 males per year) range from 2 in Iceland to almost 100 in Mongolia (3), with even larger variation if we were to consider incidence in high-risk vs. low-risk subgroups of populations. These data suggest that the degree of association between the frequency of stem cell division and the risk of cancer across tissues is unlikely to remain constant over time and across regions. Third, their statement on page 79, first column “we show that these stochastic influences are in fact the major contributors to cancer overall, often more important than either hereditary or external environmental factors” is not supported by the data. They can only say that variations in life time risk of cancer across cancer types could be explained by differences in frequency of stem cell divisions as stated on page 79 of the paper. Fourth, the inclusion of oesophageal and head and neck cancers in the “Replicative” category is questionable, since risk factors are well-known for a large fraction of these cancers. The overall conclusion that a large proportion of cancers would not be preventable is not supported by the analyses contained in the paper.

      Paolo Vineis School of Public Health, Imperial College London, W2 1PG UK. e-mail - p.vineis@imperial.ac.uk Ahmedin Jemal American Cancer Society, Atlanta, GA 30303 USA

      1. Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science. 2015 Jan 2;347(6217):78-81
      2. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2015. CA Cancer J Clin. 2015 Jan 5. doi: 10.3322/caac.21254. [Epub ahead of PRINT
      3. Globocan 2012, International Agency for Reaserch on Cancer. Acessed on January 9, 2015. http://globocan.iarc.fr/Default.aspx


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    2. On 2015 Jan 15, Vladimir Kuznetsov commented:

      One of the main hallmarks of cancer is uncontrolled cell proliferation, ultimately leading to the death of the multicellular organism. The strong link between cell proliferation and cancer risk is well-known[1]. While studying this correlation in various human tissues, the scientists at Johns Hopkins University in the U.S. hypothesize that most of the genomic changes leading to human cancer "occur simply by chance during DNA replication rather than as a result of carcinogenic factors"[2]. According to their hypothesis, the authors observed correlation between the estimates of division rates of normal self-renewing tissue-specific cell population (termed as “normal stem cells”(NSC)) with the estimates of overall lifetime risk of cancers, studied across the USA population. In this comment, I point out that the lack of tissue-specific data quality and its incompleteness, population bias, and oversimplification of modeling can lead to ambiguity in the interpretation of the results and loss of confidence in the dichotomized classification of tissue-specific cancer risks in context of efficiency of 'primary prevention measures'. 1. The cell counts and division rates of NSC in normally slow-proliferative and non-proliferated tissues/cell subpopulation (in liver, brain, gallbladder, thyroid tissue, bone, and pancreas) might not be accurately estimated and extrapolate to CSC. 2. The correlation model does not consider directly the level of variation of the number of NSC divisions due to "random mutations arising during DNA replication in normal non-cancerous stem cells" in individuals. According to the authors, "random mutations arising during DNA replication in normal non-cancerous stem cells” leading eventually to occurrence of cancer stem cells (CSC) and tumors due to “many genomic changes occur simply by chance”, or “bad luck”. However, recent integrative genomics studies of somatic mutation spectra in different tumors defined tissue-associated non-random somatic mutation signatures, mutation clusters with specific sequence context and preferential location of the mutations in certain disease-associated chromosomal regions involved in the initiation and development tissue-origin tumor types and subtypes [3, 4]. 3. The model in [2] assumes that the proliferation rate of NSC in normal tissue and the proliferation rate of CSC are closely correlated, however the assumption may be not true [3]. 4. Based on "extra risk score"(ERS) cluster analysis, the authors provided a classification of the tumors into two classes, referred as R-tumors (occurred at random; relatively smaller ERS) and D-tumors (occurred via additional 'deterministic factors'). However, ERS did not include any additive and multiplicative factors which allow to estimate explicitly the effects of individual covariates and their interactions (for instance see [5]). Thus, clustering model does not allow in principle to estimate the significance of alternative factors due to absence of these covariates in the model risk assessment. 4.Variation of the total number of stem cell divisions during an individual’s lifetime is unknown. Therefore, the model reported in [2] says nothing about variation in the cancer risk between individuals and cannot say that ~70% of cancer cases are just "bad luck" only due to count of the rates of divisions in the limited number of normal stem cells. It was argued, that breast cancer stem cell-like cells arise de novo form non-stem-like tumor cells [3] and this could make cancer cell population more heterogeneous. Such plasticity indicates that the concept of CSC can be essentially different from that of NSC. It makes a linear correlation model proposed in [2] more difficult in context of its mechanistic interpretation.<br> 5.The authors considered the "ovarian cancer germ cell" as a representative precursor (“cell of origin”) of the cancer cells in ovaries. However, according to the literature, “ovarian cancer germ cells” (should be classified as D-tumors) and responsible for only a few percent of ovarian cancer cases. Furthermore, "ovarian cancer” can be mostly represented by some distinct secondary “cell of origin” due to migration (or metastasis) from source tissues/organs [6, 7]. Therefore, the estimations under their model assumptions become inappropriate.<br> 6.The authors used 31 normal tissues. The exclusion of the common cancers (breast, prostate and gastric cancers) and the inclusion of 5 times osteosarcomas (depended samples) could induce essential bias which further complicates result interpretation and ability to extrapolate the results into entire population in the USA. 7.Their analysis was not directly concerned with the variations of population-specific incidences or other environmental causes of cancers. For instance, according to published statistics, oral cancer (OrCa) is a heterogeneous group of cancers arising from different parts of the oral cavity, with well-defined and differentiated predisposing risk factors, prevalence, and treatment outcomes[8-10]. There is a significant difference in the incidence of OrCa in different regions of the world. In contrast with the U.S. population where oral cavity cancer represents only about 3% of occurring malignancies, it accounts for over 30% of all oral cancers in India. Due to these results, it is unlikely that these well-established observations can be explained with the prevalence of “oral cancer stem cells”[2] variations. It was estimated that 91% of OrCa cases in the U.K. are linked to lifestyle factors including smoking (57%), alcohol (30%), and infections (13%)[9]. Such knowledge provides oncologists and patients a real hope for prophylactic efforts and prevention via early detection of the OrCa in a near future[10,11]. However according to the prediction in [2], OrCa was classified as so-called R-tumors, of which “primary prevention measures are not likely to be very effective”[2]. 8. Comparison of Fig2 and Fig S1 in the main text and suppl. file, shows that so-called D class tumors includes 9 cancer types in Fig 2 whereas12 cancer types were represented in Figure S1. In Fig S1, head &neck, melanoma, and gallbladder tumors were included in the D-cluster. Also, for ovarian, testicular, and thyroid cancers which were classified by the authors[2] as R-tumors, the significance of the impact of lifestyle and diet in reducing the cancer risk has been reported[12]. For others such as pancreatic, laryngeal, lip and oral cancers which were also classified as R-tumors, the significance of smoking as significant risk factors has also been established. Therefore, there are several inconsistencies in the results of [2] when compared with current knowledge from the literature. 9.Summary: The classification of the tumors on the R (random) and D (deterministic) classes is based on indirect and unreliable measurements and to a certain extent, even inconsistent with well-established data. Risks of at least several of the R-tumor types of cancer can be significantly reduced by several environmental improvements, diets and prophylactic approaches. Therefore, the conclusion that "primary prevention measures are not likely to be effective..." for tumors arising in organs undergoing origin stem cells and their divisions could be misleading and inappropriate. The predictions of the models based on the U.S. data might not be scalable onto other countries and geographic regions. Direct detection of the NSC and CSC characteristics should be obtained and multivariate probabilistic models of cancer risk prediction should be developed and used.

      References: PMID: 1: 2174724; 2: 25554788; 3: 21854987; 4: 24132290;5: ISBN 978-0-205-45938-4; 6: 24879340; 7: 24265397; 8: 24408568; 9: http://www.cancerresearchuk.org/cancer-info/cancerstats/keyfacts/Allcancerscombined/;10: 16629526; 11: 15936419; 12: 24379012


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    3. On 2015 Jan 05, Vincent Detours commented:

      No one denies that cancer initiation has a stochastic component, but the conclusion that "prevention measure are not likely to be effective" for tumors arising in organs undergoing many stem cell divisions could be dangerously broad if not misleading.

      The paper's investigation is limited to the variation of cancer incidence among organs within a single population. But the incidence of many cancers varies enormously among populations. For example, the incidence of esophagus cancer is 20-30 time higher in China than in the USA and 50-100 higher in subject with a history of Barett esophagus (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769895). Yet, this cancer is considered the result of 'bad luck' and unlikely to benefit from prevention measures (R-group) according to Tomasetti and Vogelstein who consider only the overall incidence in the USA. Their analysis is blind to the population-specific incidences and consequently to many environmental and genetics causes of cancer.

      The variation of cancer incidence among organs spans five orders of magnitudes. Hence, a one or two orders of magnitude difference due to, say, Barett esophagus, would presumably not affect drastically the overall correlation between organ-related incidence and stem cell division. The classification in the 'deterministic' vs. 'replicative' framework proposed in the paper, however, could change dramatically. This is in fact illustrated by a few cancers for which the authors stratify incidence according to etiology, e.g. virus-associated liver and head & neck cancers vs. their non virus-related counterparts and lung cancers of smokers vs. non smokers. Likely the same could have occurred with many other cancers provided a more detailed population stratification.

      Another possibility limiting the authors conclusions is that the total number stem cells divisions in an organ could itself vary from person to person under the influence of non-random genetic and/or environmental factors. A trivial example is age. It is hardly a preventable phenomenon, but other preventable factors could also play a role, tissue injury for example.

      A fully developped and extended version of this comment can be found here: http://biorxiv.org/content/early/2015/08/12/024497.


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    4. On 2015 Jan 03, William Grant commented:

      The paper by Tomasetti and Vogelstein reported that variation in cancer risk among tissues can be explained by the number of stem cell divisions (1). In addition, they divided cancer types into two categories: those more susceptible to environmental factors (D-tumors) and those more susceptible to stochastic effects associated with DNA replication of the tissues' stem cells (R-tumors). The authors concluded that primary prevention measures were not likely to be very effective for R-tumor types of cancer. In this comment, I point out that risk of cancers in this category can be reduced through primary prevention measures.

      One way to reduce risk of many types of cancer is through higher solar UVB exposure. Many types of cancers have been found inversely correlated with indices of solar UVB doses in geographical ecological studies in the United States and several other countries including these types of R-tumor types of cancer:esophageal, gallbladder, ovarian, and pancreatic cancer (2). Also, these R-tumor types of cancer have been found inversely correlated with 25-hydroxyvitamin D [25(OH)D] concentrations in prospective observational studies: chronic lymphocytic leukemia (3), head and neck cancer (4), hepatocellular carcinoma (5), and pancreatic cancer (4). One D-tumor type of cancer has the strongest evidence for beneficial effects of UVB exposure and vitamin D: colorectal cancer.

      The findings with respect to UVB exposure are generally attributed to production of vitamin D. However, they may also include some effects from mechanisms other than vitamin D. For example, in a mouse model experiment on intestinal tumors, considered an R-tumor type of cancer, both UVB exposure and oral vitamin D reduced the progression of the tumors, with UVB being more effective than oral vitamin D at approximately the same 25(OH)D concentrations (6). However, neither approach reduced the incidence rate of intestinal tumors in this mouse model with a genetic propensity for intestinal tumors. The mechanisms whereby vitamin D reduces the risk of cancer include effects on cellular differentiation, progression, and apoptosis (2). Vitamin D also reduces progression of tumors by reducing angiogenesis around tumors, and reduces metastasis as well.

      Another very important risk factor for cancer is diet. In a multi-country ecological study of cancer incidence rates with respect to diet, smoking, latitude, gross domestic product, alcohol consumption, and life expectancy, high animal product consumption was a significant risk factor for three types of R-tumor cancers: ovarian, testicular, and thyroid cancer (7). Smoking was a significant risk factor for these types of R-tumor cancers: laryngeal, lip and oral, and pancreatic cancer. Animal product consumption is a risk factor for cancer in part through increasing insulin-like growth factor-I (IGF-I) (8), which increases growth tumors as shown for small cell lung cancer (9).

      Thus, risk of several of the R-tumor types of cancer can be reduced by several environmental approaches including higher UVB exposure and 25(OH)D concentrations, eating fewer animal products, and not smoking. So "bad luck" can be overcome by "healthy choices".

      References 1. Tomasetti C, Vogelstein B. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015;347:78-81. 2. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993-4023. http://www.mdpi.com/2072-6643/5/10/3993 3. Luczynska A, Kaaks R, Rohrmann S, et al. Plasma 25-hydroxyvitamin D concentration and lymphoma risk: results of the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr. 2013;98:827-38 4. Afzal S, Bojesen SE, Nordestgaard BG. Low plasma 25-hydroxyvitamin D and risk of tobacco-related cancer. Clin Chem. 2013;59:771-80. 5. Fedirko V, Duarte-Salles T, Bamia C, et al. Pre-diagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: A nested case-control study. Hepatology. 2014;60:1222-30. 6. Rebel H, der Spek CD, Salvatori D, et al. UV exposure inhibits intestinal tumour growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet. Int J Cancer. 2015;136:271-7. 7. Grant WB. A multicountry ecological study of cancer incidence rates in 2008 with respect to various risk-modifying factors, Nutrients. 2014;6:163-189. http://www.mdpi.com/2072-6643/6/1/163 8. Larsson SC, Wolk K, Brismar K, Wolk A. Association of diet with serum insulin-like growth factor I in middle-aged and elderly men. Am J Clin Nutr. 2005;81:1163-7. 9. Warshamana-Greene GS, Litz J, Buchdunger E, et al. The insulin-like growth factor-I (IGF-I) receptor kinase inhibitor NVP-ADW742, in combination with STI571, delineates a spectrum of dependence of small cell lung cancer on IGF-I and stem cell factor signaling. Mol Cancer Ther. 2004;3:527-35.

      Disclosure I receive funding from Bio-Tech Pharmacal (Fayetteville, AR) and MediSun Technology (Highland Park, IL).


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