A few days ago I decided to have a closer look at goodreads’ quotes and how that part of the site worked. I have now added a little more than 1000 quotes to my personal quote collection on the site, many (literally hundreds) of which are quotes I have added myself to the goodreads quote library. Most of them are naturally quotes taken from the blog – the quote collection I have here is still far larger than is my goodreads collection, but at least in terms of the ‘better than average quotes’ posted here on the blog I do believe I’ve transferred/duplicated a rather substantial proportion of those quotes to goodreads by now.

Although some aspects of the site’s functionality is nice, I thoroughly dislike other aspects of the way the goodreads site works and handles specific problems. Wikiquote has for a long time been my go-to place for quotes, and it’ll remain so for the foreseeable future, barring any sudden unexpected changes of a profoundly negative nature. A really huge problem I have with the way goodreads handles these things is that if a specific quote contains an error, e.g. is missing a comma or is attributed to the wrong person, you cannot correct the error yourself, even if you know it’s an error and you literally sit there with the book in front of you, and to make matters (much) worse you often cannot even add a new quote with correct attribution; if a new quote you add is ‘sufficiently similar’ to an erroneous/misattributed quote already added to the site, you trying to add a correct quote will only lead to you automatically ‘liking’ the original flawed quote you were annoyed about and the corrected quote you tried to add will not be added. I’m still quite annoyed that one of Marie von Ebner-Eschenbach‘s really nice maxims on goodreads have been attributed by some ignorant £$@! to Jane Austen, but that’s just one of several examples I’ve encountered. There are multiple cases where I have decided not to add a specific quote because I refuse on principle to ‘like’ a quote containing an error, and/but there are also a few cases where I have bit the metaphorical bullet, after some thought, and liked a quote despite it not matching perfectly the version of the quote with which I was myself familiar (this has mostly been in the case of quotes by non-English speaking individuals, where at least some leeway can be argued to exist on account of issues pertaining to translation). I found it somewhat irritating that some really quite notable people seem to not be considered notable on goodreads (notability is a requirement for quotation, and goodreads does not allow anonymous quotes/proverbs etc. in the quotes section); for example I found myself trying in vain to add a quote by a Nobel Prize winner in Physics at some point, but the guy hadn’t written any books added to the site and so when trying to add the name after having written out the quote I realized I couldn’t do that; at least it was not immediately obvious to me how to handle this problem, and so I let it go on account of it being just one quote. Books with multiple authors also cause some problems (one specific one of which I’ve now at least partially figured out how to handle, fortunately), and books with many contributors still pose questions to which I do not know the answer; it doesn’t seem to me like the goodreads site in its current format even enables you theoretically in any way to attribute quotes taken from such books correctly – at least I haven’t found out how to do it.

So all in all I’m not particularly impressed with the site in terms of how it handles quotes, but on the other hand if you’re less interested in adding obscure quotes by people almost nobody alive today have ever heard about than I am, and would rather just like an easy way to collect/manage/remember quotes you happen to like, the site’s probably not really bad at all; it’s very easy to add new quotes to your collection if the quote is already in the goodreads library (it takes a little bit of work if it’s not). You can let my collection be a starting point if you like the sort of quotes I do; I know a few people in the past have said that they liked the quotes I’ve posted on the blog and now you have a quite easy way to just ‘grab’ those of ‘my’ quotes (quotes are posted anonymously on goodreads, so the quotes I have added are no more my quotes than they are yours) you like, and leave the rest.

Below I’ve added the 20 new quotes I usually post in my regular quotes posts, all of which (as far as I have been able to ascertain) have not been posted here before.

i. “Though what we accept be true, it is a prejudice unless we ourselves have considered and understood why and how it is true.” (John Lancaster Spalding)

ii. “However firmly thou holdest to thy opinions, if truth appears on the opposite side, throw down thy arms at once.” (-ll-)

iii. “The ultimate result of shielding men from the effects of folly, is to fill the world with fools.” (Herbert Spencer)

iv. “We often do not see what we do not expect to see.” (Alan Lightman)

v. “The past and future are veiled; but the past wears the widow’s veil; the future, the virgin’s.” (Jean Paul Richter)

vi. “There is no duty we so much underrate as the duty of being happy.” (Robert Louis Stevenson)

vii. “Science may be described as the art of systematic over-simplification — the art of discerning what we may with advantage omit.” (Karl Popper)

viii. “I hold that he who teaches that not reason but love should rule opens up the way for those who rule by hate.” (-ll-)

ix. “You cannot have a rational discussion with a man who prefers shooting you to being convinced by you.” (-ll-)

x. “There is an almost universal tendency, perhaps an inborn tendency, to suspect the good faith of a man who holds opinions that differ from our own opinions.” (-ll-)

xi. “Always remember that it is impossible to speak in such a way that you cannot be misunderstood: there will always be some who misunderstand you.” (-ll-)

xii. “The more we learn about the world, and the deeper our learning, the more conscious, specific, and articulate will be our knowledge of what we do not know, our knowledge of our ignorance.” (-ll-)

xiii. “Methodological rules are for science what rules of law and custom are for conduct.” (Émile Durkheim)

xiv. “Men apt to promise, are apt to forget.” (Thomas Fuller)

xv. “Since people of necessity see things from their own perspective, much of what they say adds up to comforting ideas or outright propaganda for themselves and the groups to which they belong.” (Patricia Crone, Pre-Industrial Societies: Anatomy of the Pre-Modern World)

xvi. “… humans are animals. It would not occur to an ethologist studying ants, lions, wolves or giraffes to argue that ‘ultimately’ it is the animal’s need for food which determines the type of society in which it lives, or its need to reproduce, or its mechanisms of defence against predators, or whatever. On the contrary, he will see the society in question as the outcome of a compromise between a variety of fundamental needs and the environment in which it is set. Precisely the same is true of human societies. […] all attempts to explain human history in terms of a single factor are misguided.” (-ll-)

xvii. “Science doesn’t purvey absolute truth. Science is a mechanism. It’s a way of trying to improve your knowledge of nature. It’s a system for testing your thoughts against the universe and seeing whether they match.” (Isaac Asimov)

xviii. “Where any answer is possible, all answers are meaningless.” (-ll-)

xix. “There are no happy endings in history, only crisis points that pass.” (-ll-)

xx. “To write is to read one’s own self” (Max Frisch)

August 30, 2016 Posted by | books, quotes | Leave a comment


I recently read Nick Middleton’s short publication on this topic and decided it was worth blogging it here. I gave the publication 3 stars on goodreads; you can read my goodreads review of the book here.

In this post I’ll quote a bit from the book and add some details I thought were interesting.

“None of [the] approaches to desert definition is foolproof. All have their advantages and drawbacks. However, each approach delivers […] global map[s] of deserts and semi-deserts that [are] broadly similar […] Roughly, deserts cover about one-quarter of our planet’s land area, and semi-deserts another quarter.”

“High temperatures and a paucity of rainfall are two aspects of climate that many people routinely associate with deserts […] However, desert climates also embrace other extremes. Many arid zones experience freezing temperatures and snowfall is commonplace, particularly in those situated outside the tropics. […] For much of the time, desert skies are cloud-free, meaning deserts receive larger amounts of sunshine than any other natural environment. […] Most of the water vapour in the world’s atmosphere is supplied by evaporation from the oceans, so the more remote a location is from this source the more likely it is that any moisture in the air will have been lost by precipitation before it reaches continental interiors. The deserts of Central Asia illustrate this principle well: most of the moisture in the air is lost before it reaches the heart of the continent […] A clear distinction can be made between deserts in continental interiors and those on their coastal margins when it comes to the range of temperatures experienced. Oceans tend to exert a moderating influence on temperature, reducing extremes, so the greatest ranges of temperature are found far from the sea while coastal deserts experience a much more limited range. […] Freezing temperatures occur particularly in the mid-latitude deserts, but by no means exclusively so. […] snowfall occurs at the Algerian oasis towns of Ouagla and Ghardaia, in the northern Sahara, as often as once every 10 years on average.”

“[One] characteristic of rainfall in deserts is its variability from year to year which in many respects makes annual average statistics seem like nonsense. A very arid desert area may go for several years with no rain at all […]. It may then receive a whole ‘average’ year’s rainfall in just one storm […] Rainfall in deserts is also typically very variable in space as well as time. Hence, desert rainfall is frequently described as being ‘spotty’. This spottiness occurs because desert storms are often convective, raining in a relatively small area, perhaps just a few kilometres across. […] Climates can vary over a wide range of spatial scales […] Changes in temperature, wind, relative humidity, and other elements of climate can be detected over short distances, and this variability on a small scale creates distinctive climates in small areas. These are microclimates, different in some way from the conditions prevailing over the surrounding area as a whole. At the smallest scale, the shade given by an individual plant can be described as a microclimate. Over larger distances, the surface temperature of the sand in a dune will frequently be significantly different from a nearby dry salt lake because of the different properties of the two types of surface. […] Microclimates are important because they exert a critical control over all sorts of phenomena. These include areas suitable for plant and animal communities to develop, the ways in which rocks are broken down, and the speed at which these processes occur.”

“The level of temperature prevailing when precipitation occurs is important for an area’s water balance and its degree of aridity. A rainy season that occurs during the warm summer months, when evaporation is greatest, makes for a climate that is more arid than if precipitation is distributed more evenly throughout the year.”

“The extremely arid conditions of today[‘s Sahara Desert] have prevailed for only a few thousand years. There is lots of evidence to suggest that the Sahara was lush, nearly completely covered with grasses and shrubs, with many lakes that supported antelope, giraffe, elephant, hippopotamus, crocodile, and human populations in regions that today have almost no measurable precipitation. This ‘African Humid Period’ began around 15,000 years ago and came to an end around 10,000 years later. […] Globally, at the height of the most recent glacial period some 18,000 years ago, almost 50% of the land area between 30°N and 30°S was covered by two vast belts of sand, often called ‘sand seas’. Today, about 10% of this area is covered by sand seas. […] Around one-third of the Arabian subcontinent is covered by sandy deserts”.

“Much of the drainage in deserts is internal, as in Central Asia. Their rivers never reach the sea, but take water to interior basins. […] Salt is a common constituent of desert soils. The generally low levels of rainfall means that salts are seldom washed away through soils and therefore tend to accumulate in certain parts of the landscape. Large amounts of common salt (sodium chloride, or halite), which is very soluble in water, are found in some hyper-arid deserts.”

“Many deserts are very rich in rare and unique species thanks to their evolution in relative geographical isolation. Many of these plants and animals have adapted in remarkable ways to deal with the aridity and extremes of temperature. Indeed, some of these adaptations contribute to the apparent lifelessness of deserts simply because a good way to avoid some of the harsh conditions is to hide. Some small creatures spend hot days burrowed beneath the soil surface. In a similar way, certain desert plants spend most of the year and much of their lives dormant, as seeds waiting for the right conditions, brought on by a burst of rainfall. Given that desert rainstorms can be very variable in time and in space, many activities in the desert ecosystem occur only sporadically, as pulses of activity driven by the occasional cloudburst. […] The general scarcity of water is the most important, though by no means the only, environmental challenge faced by desert organisms. Limited supplies of food and nutrients, friable soils, high levels of solar radiation, high daytime temperatures, and the large diurnal temperature range are other challenges posed by desert conditions. These conditions are not always distributed evenly across a desert landscape, and the existence of more benign microenvironments is particularly important for desert plants and animals. Patches of terrain that are more biologically productive than their surroundings occur in even the most arid desert, geographical patterns caused by many factors, not only the simple availability of water.”

A small side note here: The book includes brief coverage of things like crassulacean acid metabolism and related topics covered in much more detail in Beer et al. I’m not going to go into that stuff here as this stuff was in my opinion much better covered in the latter book (some people might disagree, but people who would do that would at least have to admit that the coverage in Beer et al. is/was much more comprehensive than is Middleton’s coverage in this book). There are quite a few other topics included in the book which I did not include coverage of here in the post but I mention this topic in particular in part because I thought it was actually a good example underscoring how this book is very much just a very brief introduction; you can write book chapters, if not books, about some of the topics Middleton devotes a couple of paragraphs to in his coverage, which is but to be expected given the nature and range of coverage of the publication.

Plants aren’t ‘smart’ given any conventional definition of the word, but as I’ve talked about before here on the blog (e.g. here) when you look closer at the way they grow and ‘behave’ over the very long term, some of the things they do are actually at the very least ‘not really all that stupid’:

“The seeds of annuals germinate only when enough water is available to support the entire life cycle. Germinating after just a brief shower could be fatal, so mechanisms have developed for seeds to respond solely when sufficient water is available. Seeds germinate only when their protective seed coats have been broken down, allowing water to enter the seed and growth to begin. The seed coats of many desert species contain chemicals that repel water. These compounds are washed away by large amounts of water, but a short shower will not generate enough to remove all the water-repelling chemicals. Other species have very thick seed coats that are gradually worn away physically by abrasion as moving water knocks the seeds against stones and pebbles.”

What about animals? One thing I learned from this publication is that it turns out that being a mammal will, all else equal, definitely not give you a competitive edge in a hot desert environment:

“The need to conserve water is important to all creatures that live in hot deserts, but for mammals it is particularly crucial. In all environments mammals typically maintain a core body temperature of around 37–38°C, and those inhabiting most non-desert regions face the challenge of keeping their body temperature above the temperature of their environmental surrounds. In hot deserts, where environmental temperatures substantially exceed the body temperature on a regular basis, mammals face the reverse challenge. The only mechanism that will move heat out of an animal’s body against a temperature gradient is the evaporation of water, so maintenance of the core body temperature requires use of the resource that is by definition scarce in drylands.”

Humans? What about them?

“Certain aspects of a traditional mobile lifestyle have changed significantly for some groups of nomadic peoples. Herders in the Gobi desert in Mongolia pursue a way of life that in many ways has changed little since the times of the greatest of all nomadic leaders, Chinggis Khan, 750 years ago. They herd the same animals, eat the same foods, wear the same clothes, and still live in round felt-covered tents, traditional dwellings known in Mongolian as gers. Yet many gers now have a set of solar panels on the roof that powers a car battery, allowing an electric light to extend the day inside the tent. Some also have a television set.” (these remarks incidentally somehow reminded me of this brilliant Gary Larson cartoon)

“People have constructed dams to manage water resources in arid regions for thousands of years. One of the oldest was the Marib dam in Yemen, built about 3,000 years ago. Although this structure was designed to control water from flash floods, rather than for storage, the diverted flow was used to irrigate cropland. […] Although groundwater has been exploited for desert farmland using hand-dug underground channels for a very long time, the discovery of reserves of groundwater much deeper below some deserts has led to agricultural use on much larger scales in recent times. These deep groundwater reserves tend to be non-renewable, having built up during previous climatic periods of greater rainfall. Use of this fossil water has in many areas resulted in its rapid depletion.”

“Significant human impacts are thought to have a very long history in some deserts. One possible explanation for the paucity of rainfall in the interior of Australia is that early humans severely modified the landscape through their use of fire. Aboriginal people have used fire extensively in Central Australia for more than 20,000 years, particularly as an aid to hunting, but also for many other purposes, from clearing passages to producing smoke signals and promoting the growth of preferred plants. The theory suggests that regular burning converted the semi-arid zone’s mosaic of trees, shrubs, and grassland into the desert scrub seen today. This gradual change in the vegetation could have resulted in less moisture from plants reaching the atmosphere and hence the long-term desertification of the continent.” (I had never heard about this theory before, and so I of course have no idea if it’s correct or not – but it’s an interesting idea).

A few wikipedia links of interest:
Karakum Canal.
Atacama Desert.
Salar de Uyuni.
Taklamakan Desert.
Dust Bowl.
Namib Desert.


August 27, 2016 Posted by | anthropology, biology, books, Botany, Geography, Zoology | Leave a comment


i. “The more I write, the more I am convinced that the only way to write a popular story is to split it up into scenes, and have as little stuff between the scenes as possible.” (P. G. Wodehouse, Performing Flea. A long time ago I was working on a blog post covering this book, but I realized I’m probably not going to finish that one so I decided to include some of the quotes from the post here instead. He emphasizes the point made in this quote more than once in his letters, for example he writes in another letter that: “The longer I write, the more I realize the necessity for telling a story as far as possible in scenes, especially at the start.”)

ii. “The principle I always go on in writing a long story is to think of the characters in terms of actors in a play. I say to myself, when I invent a good character for an early scene: ‘If this were a musical comedy we should have to get somebody like Leslie Henson to play this part, and if he found that all he had was a short scene in act one, he would walk out. How, therefore, can I twist the story so as to give him more to do and keep him alive till the fall of the curtain?’ This generally works well and improves the story.” (P. G. Wodehouse, Performing Flea)

iii. “The absolute cast-iron good rule, I’m sure, in writing a story, is to introduce all your characters as early as possible – especially if they are going to play important parts later.” (-ll-)

iv. “I think the success of every novel depends largely on one or two high spots. The thing to do is to say to yourself ‘Which are my big scenes?’ and then get every drop of juice out of them.” (-ll-)

v. “I sometimes wonder if I really am a writer. When I look at the sixty-odd books in the shelf with my name on them, and reflect that ten million of them have been sold, it amazes me that I can have done it. I don’t know anything, and I seem incapable of learning … I feel like I’ve been fooling the public for fifty years.” (-ll-)

vi. “I don’t suppose that anything you say or anything I say will make the slightest damn bit of difference. You need dynamite to dislodge an idea that has got itself firmly rooted in the public mind.” (-ll-)

vii. “The day after graduating from college, I found fifty dollars in the foyer of my Chicago apartment building. The single bill had been folded into eighths and was packed with cocaine. It occurred to me then that if I played my cards right, I might never have to find a job. People lost things all the time. They left class rings on the sinks of public bathrooms and dropped gem-studded earrings at the doors of the opera house. My job was to keep my eyes open and find these things. I didn’t want to become one of those coots who combed the beaches of Lake Michigan with a metal detector, but if I paid attention and used my head, I might never have to work again.
The following afternoon, hung over from cocaine, I found twelve cents and an unopened tin of breath mints. Figuring in my previous fifty dollars, that amounted to an average of twenty-five dollars and six cents per day, which was still a decent wage. The next morning I discovered two pennies and a comb matted with short curly hairs. The day after that I found a peanut. It was then that I started to worry.” (David Sedaris, Naked)

viii. “If she’d had it her way, we would never have known about the cancer. It was our father’s idea to tell us, and she had fought it, agreeing only when he threatened to tell us himself. Our mother worried that once we found out, we would treat her differently, delicately. We might feel obliged to compliment her cooking and laugh at all her jokes, thinking always of the tumor she was trying so hard to forget. And that is exactly what we did. […] We were no longer calling our mother. Now we were picking up the telephone to call our mother with cancer.” (-ll-)

ix. “It was rather annoying to hear how kind she’d been; it entailed putting tiresome qualifications on his dislike for her.” (Kingsley Amis, Lucky Jim)

x. “the most noticeable characteristic of the past, as seen by him, at least, was that there was so much more of it now than formerly, with bits that were longer ago than had once seemed possible.” (Kingsley Amis, The Old Devils)

xi. “Why, you might wonder, should prisoners wear themselves out, working hard, ten years on end, in the camps? You’d think they’d say: No thank you, and that’s that. […] But that didn’t work. To outsmart you they thought up work-teams – but not teams like the ones in freedom, where every man is paid his separate wage. Everything was so arranged in the camp that the prisoners egged one another on. It was like this: either you got a bit extra or you all croaked.” (Aleksandr Solzhenitsyn, One Day in the Life of Ivan Denisovich)

xii. “‘Well, brothers, good-bye,’ said the captain with an embarrassed nod to his team-mates, and followed the guard out.
A few voices shouted: ‘Keep your pecker up.’ But what could you really say to him? They knew the cells, the 104th did, they’d built them. Brick walls, cement floor, no windows, a stove they lit only to melt the ice on the walls and make pools on the floor. You slept on bare boards, and if you’d any teeth left to eat with after all the chattering they’d be doing, they gave you three hundred grammes of bread day after day and hot skilly only on the third, sixth, and ninth.
Ten days. Ten days ‘hard’ in the cells – if you sat them out to the end your health would be ruined for the rest of your life. […] As for those who got fifteen ‘hard’ and sat them out – they went straight into a hole in the cold earth.” (-ll-)

xiii. “Shukhov gazed at the ceiling in silence. Now he didn’t know either whether he wanted freedom or not. At first he’d longed for it. Every night he’d counted the days of his stretch – how many had passed, how many were coming. And then he’d grown bored with counting. And then it became clear that men of his like wouldn’t ever be allowed to return home, that they’d be exiled. And whether his life would be any better there than here – who could tell?
Freedom meant one thing to him – home.
But they wouldn’t let him go home.” (-ll-)

xiv. “You want to know what I do? All right. Some guy comes in with a bandage around his head. We don’t mess about. We’ll soon have that off. He’s got a hole in his head. So what do we do. We stick a nail in it. Get the nail – a good rusty one – from the trash or wherever. And lead him out to the Waiting Room where he’s allowed to linger and holler for a while before we ferry him back to the night. […] Because I am a healer, everything I do heals, somehow. The thing called society is, I believe, insane. In the locker room the steel grilles are pasted with letters that say, Thanks for your kindness for making a tough time much easier to bear, and, If it wasn’t for all of you there at the hospital I don’t know how we would have survived. The doctors read these thankyou notes with tears in their eyes, especially when gratitude is expressed in a childish hand. Not Johnny Young, though. Perhaps he knows, as I do, that the letters are propitiatory. The children (‘7 yrs’) haven’t been here yet. They won’t be so grateful when we’re through.” (Martin Amis, Time’s Arrow.)

xv. “Like all of my friends, she’s a lousy judge of character.” (David Sedaris, Me Talk Pretty One Day)

xvi. “Nobody dreams of the things he already has.” (-ll-)

xvii. “The word phobic has its place when properly used, but lately it’s been declawed by the pompous insistence that most animosity is based upon fear rather than loathing. No credit is given for distinguishing between these two very different emotions. I fear snakes. I hate computers. My hatred is entrenched, and I nourish it daily. I’m comfortable with it, and no community outreach program will change my mind.” (-ll-)

xviii. “Of all the stumbling blocks inherent in learning this language [French], the greatest for me is the principle that each noun has a corresponding sex that affects both its articles and its adjectives. Because it is a female and lays eggs, a chicken is masculine. Vagina is masculine as well, while the word masculinity is feminine. Forced by the grammar to take a stand one way or the other, hermaphrodite is male and indecisiveness female. I spent months searching for some secret code before I realized that common sense has nothing to do with it. Hysteria, psychosis, torture, depression: I was told that if something is unpleasant, it’s probably feminine. This encouraged me, but the theory was blown by such masculine nouns as murder, toothache, and Rollerblade.” (-ll-)

xix. “By the time I reached my thirties, my brain had been strip-mined by a combination of drugs, alcohol, and the chemical solvents used at the refinishing company where I worked. Still, there were moments when, against all reason, I thought I might be a genius. These moments were provoked not by any particular accomplishment but by cocaine and crystal methamphetamine — drugs that allow you to lean over a mirror with a straw up your nose, suck up an entire week’s paycheck, and think, “God, I’m smart.”” (-ll-)

xx. “As youngsters, we participated in all the usual seaside activities — which were fun, until my father got involved and systematically chipped away at our pleasure. Miniature golf was ruined with a lengthy dissertation on impact, trajectory, and wind velocity, and our sand castles were critiqued with stifling lectures on the dynamics of the vaulted ceiling. We enjoyed swimming, until the mystery of tides was explained in such a way that the ocean seemed nothing more than an enormous saltwater toilet, flushing itself on a sad and predictable basis. […] [“]The goal is to better yourself. Meet some intellectuals. Read a book!” After all these years our father has never understood that we, his children, tend to gravitate toward the very people he’s spent his life warning us about.” (-ll-. There were several reasons why I really enjoyed Sedaris’ book, but the fact that here in this book was actually a character who in some respects seemed to find it natural to behave in a manner similar to the way I could see myself behave – in a setting where the behaviour in question might by some people be considered unusual, that is – was definitely one of them. (Though I’m also slightly conflicted here; I don’t like children very much, and there’s no conceivable universe in which I’d ever have six of them; in such a universe ‘I’ would not be ‘me‘. I’d also on a related note be much more inclined to warn children to stay away from ‘intellectuals’, rather than the opposite…)).

August 25, 2016 Posted by | books, quotes | Leave a comment


I was debating whether to blog this book at all, as it’s neither very long nor very good, but I decided it was worth adding a few observations from the book here. You can read my goodreads review of the publication here. Whenever quotes look a bit funny in the coverage below (i.e. when you see things like words in brackets or strangely located ‘[…]’, assume that the reason for this is that I tried to improve upon the occasionally frankly horrible language of some of the contributors to the publication. If you want to know exactly what they wrote, rather than what they presumably meant to write (basic grammar errors due to the authors having trouble with the English language are everywhere in this publication, and although I did choose to do so here I do feel a bit uncomfortable quoting a publication like this one verbatim on my blog), read the book.

I went off on a tangent towards the end of the post and I ended up adding some general remarks about medical cost, insurance and various other topics. So the post may have something of interest even to people who may not be highly interested in any of the stuff covered in the book itself.

“Despite intensive recommendations, [the] influenza vaccination rate in medical staff in Poland ranges from about 20 % in physicians to 10 % in nurses. […] It has been demonstrated that vaccination of health care workers against influenza significantly decreases mortality of elderly people remaining under [long-term care]. […] Vaccinating health care workers also substantially reduces sickness absenteeism, especially in emergency units […] Concerning physicians, vaccination avoidance stemmed from the lack of knowledge of protective value of vaccine (33 %), lack of time to get vaccinated (29 %), and Laziness (24 %). In nurses, these figures amounted to 55 %, 12 %, and 5 %, respectively (Zielonka et al. 2009).”

I just loved the fact that ‘laziness’ was included here as an explanatory variable, but on the other hand the fact that one-third of doctors cited lack of knowledge about the protective value of vaccination as a reason for not getting vaccinated is … well, let’s use the word ‘interesting’. But it gets even better:

“The questions asked and opinions expressed by physicians or nurses on vaccinations showed that their knowledge in this area was far from the current evidence-based medicine recommendations. Nurses, in particular, commonly presented opinions similar to those which can be found in anti-vaccination movements and forums […] The attitude of physicians toward influenza vaccination vary greatly. In many a ward, a majority of physicians were vaccinated (70–80 %). However, in the neurology and intensive care units the proportion of vaccinated physicians amounted only to 20 %. The reason for such a small yield […] was a critical opinion about the effectiveness and safety of vaccination. Similar differences, depending on medical specialty, were observed in Germany (4–71% of vaccines) (Roggendorf et al. 2011) […] It is difficult to explain the fear of influenza vaccination among the staff of intensive care units, since these are exactly the units where many patients with most severe cases of influenza are admitted and often die (Ayscue et al. 2014). In this group of health care workers, high efficiency of influenza vaccination has been clearly demonstrated […] In the present study a strong difference between the proportion of vaccinated physicians (55 %) and nurses (21 %) was demonstrated, which is in line with some data coming from other countries. In the US, 69 % of physicians and 46 % of nurses get a vaccine shot […] and in Germany the respective percentages are 39 % and 17 % […] In China, 21 % of nurses and only 13 % of physicians are vaccinated against influenza (Seale et al. 2010a), and in [South] Korea, 91 % and 68 % respectively (Lee et al. 2008).”

“[A] survey was conducted among Polish (243) and foreign (80) medical students at the Pomeranian Medical University in Szczecin, Poland. […] The survey results reveal that about 40 % of students were regular or occasional smoker[s]. […] 60 % of students declared themselves to be non-smokers, 20 % were occasional smokers, and 20 % were regular smokers”

40 % of medical students in a rather large sample turned out to be smokers. Wow. Yeah, I hadn’t seen that one coming. I’d probably expect a few alcoholics and I would probably not have been surprised about a hypothetical higher-than-average alcohol consumption in a sample like that (they don’t talk about alcohol so I don’t have data on this, I’m just saying I wouldn’t be surprised – after all I do know that doctors are high-risk for suicide), but such a large proportion smoking? That’s unexpected. It probably shouldn’t have been, considering that this is very much in line with the coverage included in Thirlaway & Upton’s book. I include some remarks about their coverage about smoking in my third post about the book here. The important observation of note from that part of the book’s coverage is probably that most smokers want to quit and yet very few manage to actually do it. “Although the majority of smokers want to stop smoking and predict that they will have stopped in twelve months, only 2–3 per cent actually stops permanently a year (Taylor et al. 2006).” If those future Polish doctors know that smoking is bad for them, but they assume that they can just ‘stop in time’ when ‘the time’ comes – well, some of those people are probably in for a nasty surprise (and they should have studied some more, so that they’d known this?).

A prospective study of middle-aged British men […] revealed that the self-assessment of health status was strongly associated with mortality. Men who reported poor health had an eight-fold increase in total mortality compared with those reporting excellent health. Those who assessed their health as poor were manual workers, cigarette smokers, and often heavy drinkers. Half of those with poor health suffered from chest pain on exertion and other chronic diseases. Thus, self-assessment of health status appears to be a good measure of current physical health and risk of death“.

It is estimated that globally 3.1 million people die each year due to chronic obstructive pulmonary disease (COPD). According to the World Health Organization (WHO 2014), the disease was the third leading cause of death worldwide in 2012. [In the next chapter of the book they state that: “COPD is currently the fourth leading cause of death among adult patients globally, and it is projected that it will be the third most common cause of death by 2020.” Whether it’s the third or fourth most common cause of death, it definitely kills a lot of people…] […] Approximately 40–50 % of lifelong smokers will go on to develop COPD […] the number of patients with a primary diagnosis of COPD […] constitutes […] 1.33 % of the total population of Poland. This result is consistent with that obtained during the Polish Spirometry Day in 2011 (Dabrowiecki et al. 2013) when 1.1 % of respondents declared having had a diagnosed COPD, while pulmonary function tests showed objectively the presence of obstruction in 12.3 % of patients.”

Based on numbers like these I feel tempted to conclude that the lungs may be yet another organ in which a substantial proportion of people of advanced age experience low-level organ dysfunction arguably not severe enough to lead to medical intervention. The kidneys are similar, as I also noted when I covered Longmore et al.‘s text.

“Generally, the costs of treatment of patients with COPD are highly variable […] estimates suggest […] that the costs of treatment of moderate stages of COPD may be 3–4-fold higher in comparison with the mild form of the disease, and in the severe form they reach up to 6–10 times the basic cost […] every second person with COPD is of working age […] Admission rates for COPD patients differ as much as 10-fold between European countries (European Lung White Book 2013).”

“In the EU, the costs of respiratory diseases are estimated at 6 % of the budget allocated to health care. Of this amount, 56 % is allocated for the treatment of COPD patients. […] Studies show that one per ten Poles over 30 year of age have COPD symptoms. Each year, around 4 % of all hospitalizations are due to COPD. […] One of the most important parameters regarding pharmacoeconomics is the hospitalization rate […] a high number of hospitalizations due to COPD exacerbations in Poland dramatically increase direct medical costs.”

I bolded the quote above because I knew this but had never seen it stated quite as clearly as it’s stated here, and I may be tempted to quote that one later on. Hospitalizations are often really expensive compared to drugs people who are not hospitalized take for their various health conditions, for example you can probably buy a year’s worth of anti-diabetic drugs, or more, for the costs of just one hospital admission due to drug mis-dosing. Before you get the idea that this might have ‘obvious implications’ for how ‘one’ should structure medical insurance arrangements in terms of copay structures etc., do however keep in mind that the picture here is really confusing:


Here’s the link, with more details – the key observation is that: “There is no consistency […] in the direction of change in costs resulting from changes in compliance”. That’s not diabetes, that’s ‘stuff in general’.

It would be neat if you could e.g. tell a story about how high costs of a drug always lead to non-compliance, which lead to increased hospitalization rates, which lead to higher costs than if the drugs had been subsidized. That would be a very strong case for subsidization. Or it would be neat if you could say that it doesn’t matter whether you subsidize a drug or not, because the costs of drugs are irrelevant in terms of usage patterns – people are told to take one pill every day by their doctor, and by golly that’s what they’re doing, regardless of what those pills cost. I know someone personally who wrote a PhD thesis about a drug where that clearly wasn’t the case, and the price elasticity was supposed to be ‘theoretically low’ in that case, so that one’s obviously out ‘in general’, but the point is that people have looked at this stuff, a lot. I’m assuming you might be able to spot a dynamic like this in some situations, and different dynamics in the case of other drugs. It gets even better when you include complicating phenomena like cost-switching; perhaps the guy/organization responsible for potentially subsidizing the drug is not the same guy(/-…) as the guy who’s supposed to pay for the medical admissions (this depends on the insurance structure/setup). But that’s not always the case, and the decision as to who pays for what is not necessarily a given; it may depend e.g. on health care provider preferences, and those preferences may themselves depend upon a lot of things unrelated to patient preferences or -incentives. A big question even in the relatively simple situation where the financial structure is – for these purposes at least – simple, is also the extent to which relevant costs are even measured, and/or how they’re measured (if a guy dies due to a binding budget constraint resulting in no treatment for a health condition that would have been treatable with a drug, is that outcome supposed to be ‘very cheap’ (he didn’t pay anything for  drugs, so there were no medical outlays) or very expensive (he could have worked for another two decades if he’d been treated, and those productivity losses need to be included in the calculation somehow; to focus solely on medical outlays is thus to miss the point)? An important analytical point here is that if you don’t explicitly make those deaths/productivity losses expensive, they are going to look very cheap, because the default option will always be to have them go unrecorded and untallied.

A problem not discussed in the coverage was incidentally the extent to which survey results pertaining to the cost of vaccination are worth much. You ask doctors why they didn’t get vaccinated, and they tell you it’s because it’s too expensive. Well, how many of them would you have expected to tell you they did not get vaccinated because the vaccines were too cheap? This is more about providing people with a perceived socially acceptable out than it is about finding stuff out about their actual reasons for behaving the way they do. If the price of vaccination does not vary across communities it’s difficult to estimate the price elasticity, true (if it does, you probably got an elasticity estimate right there), but using survey information to implicitly assess the extent to which the price is too high? Allow the vaccination price to vary next year/change it/etc. (or even simpler/cheaper, if those data exist; look at price variation which happened in the past and observe how the demand varied), and see if/how the doctors and nurses respond. That’s how you do this, you don’t ask people. Asking people is also actually sort of risky; I’m pretty sure a smart doctor could make an argument that if you want doctors to get vaccinated you should pay them for getting the shot – after all, getting vaccinated is unpleasant, and as mentioned there are positive externalities here in terms of improved patient outcomes, which might translate into specific patients not dying, which is probably a big deal, for those patients at least. The smart doctor wouldn’t necessarily be wrong; if the price of vaccination was ‘sufficiently low’, i.e. a ‘large’ negative number (‘if you get vaccinated, we give you $10.000’), I’m pretty sure coverage rates would go up a lot. That doesn’t make it a good idea. (Or a bad idea per se, for that matter – it depends upon the shape of the implicit social welfare function we’re playing around with. Though I must add – so that any smart doctors potentially reading along here don’t get any ideas – that a ‘large’ negative price of vaccination for health care workers is a bad idea if a cheaper option which achieves the same outcome is potentially available to the decision makers in question, which seems highly likely to me. For example vaccination rates of medical staff would also go up a lot if regular vaccinations were made an explicit condition of their employment, the refusal of which would lead to termination of their employment… There would be implicit costs of such a scheme, in terms of staff selection effects, but if you’re comparing solely those options and you’re the guy who makes the financial decisions..?)

August 22, 2016 Posted by | books, economics, medicine | Leave a comment

Random Stuff

i. On the youtube channel of the Institute for Advanced Studies there has been a lot of activity over the last week or two (far more than 100 new lectures have been uploaded, and it seems new uploads are still being added at this point), and I’ve been watching a few of the recently uploaded astrophysics lectures. They’re quite technical, but you can watch them and follow enough of the content to have an enjoyable time despite not understanding everything:

This is a good lecture, very interesting. One major point made early on: “the take-away message is that the most common planet in the galaxy, at least at shorter periods, are planets for which there is no analogue in the solar system. The most common kind of planet in the galaxy is a planet with a radius of two Earth radii.” Another big take-away message is that small planets seem to be quite common (as noted in the conclusions, “16% of Sun-like stars have an Earth-sized planet”).

Of the lectures included in this post this was the one I liked the least; there are too many (‘obstructive’) questions/interactions between lecturer and attendants along the way, and the interactions/questions are difficult to hear/understand. If you consider watching both this lecture and the lecture below, I would say that it would probably be wise to watch the lecture below this one before you watch this one; I concluded that in retrospect some of the observations made early on in the lecture below would have been useful to know about before watching this lecture. (The first half of the lecture below was incidentally to me somewhat easier to follow than was the second half, but especially the first half hour of it is really quite good, despite the bad start (which one can always blame on Microsoft…)).

ii. Words I’ve encountered recently (…or ‘recently’ – it’s been a while since I last posted one of these lists): Divagationsperiphrasis, reedy, architravesettpedipalp, tout, togs, edentulous, moue, tatty, tearaway, prorogue, piscine, fillip, sop, panniers, auxology, roister, prepossessing, cantle, catamite, couth, ordure, biddy, recrudescence, parvenu, scupper, husting, hackle, expatiate, affray, tatterdemalion, eructation, coppice, dekko, scull, fulmination, pollarding, grotty, secateurs, bumf (I must admit that I like this word – it seems fitting, somehow, to use that word for this concept…), durophagy, randy, (brief note to self: Advise people having children who ask me about suggestions for how to name them against using this name (or variants such as Randi), it does not seem like a great idea), effete, apricity, sororal, bint, coition, abaft, eaves, gadabout, lugubriously, retroussé, landlubber, deliquescence, antimacassar, inanition.

iii. “The point of rigour is not to destroy all intuition; instead, it should be used to destroy bad intuition while clarifying and elevating good intuition. It is only with a combination of both rigorous formalism and good intuition that one can tackle complex mathematical problems; one needs the former to correctly deal with the fine details, and the latter to correctly deal with the big picture. Without one or the other, you will spend a lot of time blundering around in the dark (which can be instructive, but is highly inefficient). So once you are fully comfortable with rigorous mathematical thinking, you should revisit your intuitions on the subject and use your new thinking skills to test and refine these intuitions rather than discard them. One way to do this is to ask yourself dumb questions; another is to relearn your field.” (Terry Tao, There’s more to mathematics than rigour and proofs)

iv. A century of trends in adult human height. A figure from the paper (Figure 3 – Change in adult height between the 1896 and 1996 birth cohorts):


(Click to view full size. WordPress seems to have changed the way you add images to a blog post – if this one is even so annoyingly large, I apologize, I have tried to minimize it while still retaining detail, but the original file is huge). An observation from the paper:

“Men were taller than women in every country, on average by ~11 cm in the 1896 birth cohort and ~12 cm in the 1996 birth cohort […]. In the 1896 birth cohort, the male-female height gap in countries where average height was low was slightly larger than in taller nations. In other words, at the turn of the 20th century, men seem to have had a relative advantage over women in undernourished compared to better-nourished populations.”

I haven’t studied the paper in any detail but intend to do so at a later point in time.

v. I found this paper, on Exercise and Glucose Metabolism in Persons with Diabetes Mellitus, interesting in part because I’ve been very surprised a few times by offhand online statements made by diabetic athletes, who had observed that their blood glucose really didn’t drop all that fast during exercise. Rapid and annoyingly large drops in blood glucose during exercise have been a really consistent feature of my own life with diabetes during adulthood. It seems that there may be big inter-individual differences in terms of the effects of exercise on glucose in diabetics. From the paper:

“Typically, prolonged moderate-intensity aerobic exercise (i.e., 30–70% of one’s VO2max) causes a reduction in glucose concentrations because of a failure in circulating insulin levels to decrease at the onset of exercise.12 During this type of physical activity, glucose utilization may be as high as 1.5 g/min in adolescents with type 1 diabetes13 and exceed 2.0 g/min in adults with type 1 diabetes,14 an amount that quickly lowers circulating glucose levels. Persons with type 1 diabetes have large interindividual differences in blood glucose responses to exercise, although some intraindividual reproducibility exists.15 The wide ranging glycemic responses among individuals appears to be related to differences in pre-exercise blood glucose concentrations, the level of circulating counterregulatory hormones and the type/duration of the activity.2

August 13, 2016 Posted by | astronomy, demographics, diabetes, language, Lectures, mathematics, Physics, random stuff | Leave a comment

Diabetes and the Metabolic Syndrome in Mental Health (I)

As I stated in my goodreads review, ‘If you’re a schizophrenic and/or you have a strong interest in e.g. the metabolic effects of various anti-psychotics, the book is a must-read’. If that’s not true, it’s a different matter. One reason why I didn’t give the book a higher rating is that many of the numbers in there are quite dated, which is a bit annoying because it means you might feel somewhat uncertain about how valid the estimates included still are at this point.

As pointed out in my coverage of the human drug metabolism text there are a lot of things that can influence the way that drugs are metabolized, and this text includes some details about a specific topic which may help to illustrate what I meant by stating in that post that people ‘self-experimenting’ may be taking on risks they may not be aware of. Now, diabetics who need insulin injections are taking a drug with a narrow therapeutic index, meaning that even small deviations from the optimal dose may have serious repercussions. A lot of things influence what is actually the optimal dose in a specific setting; food (“food is like a drug to a person with diabetes”, as pointed out in Matthew Neal’s endocrinology text, which is yet another text I, alas, have yet to cover here), sleep patterns, exercise (sometimes there may be an impact even days after you’ve exercised), stress, etc. all play a role, and even well-educated diabetics may not know all the details.

A lot of drugs also affect glucose metabolism and insulin sensitivity, one of the best known drug types of this nature probably being the corticosteroids because of their widespread use in a variety of disorders, including autoimmune disorders which tend to be more common in autoimmune forms of diabetes (mainly type 1). However many other types of drugs can also influence blood glucose, and on the topic of antidepressants and antipsychotics we actually know some stuff about these things and about how various medications influence glucose levels; it’s not a big coincidence that people have looked at this, they’ve done that because it has become clear that “[m]any medications, in particular psychotropics, including antidepressants, antipsychotics, and mood stabilizers, are associated with elevations in blood pressure, weight gain, dyslipidemias, and/or impaired glucose homeostasis.” (p. 49). Which may translate into an increased risk of type 2 diabetes, and impaired glucose control in diabetics. Incidentally the authors of this text observes in the text that: “Our research group was among the first in the field to identify a possible link between the development of obesity, diabetes, and other metabolic derangements (e.g., lipid abnormalities) and the use of newer, second-generation antipsychotic medications.” Did the people who took these drugs before this research was done/completed know that their medications might increase their risk of developing diabetes? No, because the people prescribing it didn’t know, nor did the people who developed the drugs. Some probably still don’t know, including some of the medical people prescribing these medications. But the knowledge is out there now, and the effect size is in the case of some drugs argued to be large enough to be clinically relevant. In the context of a ‘self-experimentation’-angle the example is also interesting because the negative effect in question here is significantly delayed; type 2 diabetes takes time to develop, and this is an undesirable outcome which you’re not going to spot the way you might link a headache the next day to a specific drug you just started out with (another example of a delayed adverse event is incidentally cancer). You’re not going to spot dyslipidemia unless you keep track of your lipid levels on your own or e.g. develop xanthomas as a consequence of it, leading you to consult a physician. It helps a lot if you have proper research protocols and large n studies with sufficient power when you want to discover things like this, and when you want to determine whether an association like this is ‘just an association’ or if the link is actually causal (and then clarifying what we actually mean by that, and whether the causal link is also clinically relevant and/or for whom it might be clinically relevant). Presumably many people taking all kinds of medical drugs these days are taking on risks which might in a similar manner be ‘hidden from view’ as was the risk of diabetes in people taking second-generation antipsychotics in the near-past; over time epidemiological studies may pick up on some of these risks, but many will probably remain hidden from view on account of the amount of complexity involved. Even if a drug ‘works’ as intended in the context of the target variable in question, you can get into a lot of trouble if you only focus on the target variable (“if a drug has no side effects, then it is unlikely to work“). People working in drug development know this.

The book has a lot of blog-worthy stuff so I decided to include some quotes in the coverage below. The quotes are from the first half of the book, and this part of the coverage actually doesn’t talk much about the effects of drugs; it mainly deals with epidemiology and cost estimates. I thus decided to save the ‘drug coverage’ to a later post. It should perhaps be noted that some of the things I’d hoped to learn from Ru-Band Lu et al.’s book (blog coverage here) was actually included in this one, which was nice.

“Those with mental illness are at higher risk and are more likely to suffer the severe consequences of comorbid medical illness. Adherence to treatment is often more difficult, and other factors such as psychoneuroendocrine interactions may complicate already problematic treatments. Additionally, psychiatric medications themselves often have severe side effects and can interact with other medications, rendering treatment of the mental illness more complicated. Diabetes is one example of a comorbid medical illness that is seen at a higher rate in people with mental illness.”

“Depression rates have been studied and are increased in type 1 and type 2 diabetes. In a meta-analysis, Barnard et al. reviewed 14 trials in which patients with type 1 diabetes were surveyed for rates of depression.16 […] subjects with type 1 diabetes had a 12.0% rate of depression compared with a rate of 3.4% in those without diabetes. In noncontrolled trials, they found an even higher rate of depression in patients with type 1 diabetes (13.4%). However, despite these overall findings, in trials that were considered of an adequate design, and with a substantially rigorous depression screening method (i.e., use of structured clinical interview rather than patient reported surveys), the rates were not statistically significantly increased (odds ratio [OR] 2.36, 95% confidence interval [CI] 0.69–5.4) but had such substantial variation that it was not sufficient to draw a conclusion regarding type 1 diabetes. […] When it comes to rates of depression, type 2 diabetes has been studied more extensively than type 1 diabetes. Anderson et al. compiled a large metaanalysis, looking at 42 studies involving more than 21,000 subjects to assess rates of depression among patients with type 1 versus type 2 diabetes mellitus.18 Regardless of how depression was measured, type 1 diabetes was associated with lower rates of depression than type 2 diabetes. […] Depression was significantly increased in both type 1 and type 2 diabetes, with increased ORs for subjects with type 1 (OR = 2.9, 95% CI 1.6 –5.5, […] p=0.0003) and type 2 disease (OR = 2.9, 95% CI 2.3–3.7, […] p = 0.0001) compared with controls. Overall, with multiple factors controlled for, the risk of depression in people with diabetes was approximately twofold. In another large meta-analysis, Ali et al. looked at more than 51,000 subjects in ten different studies to assess rates of depression in type 2 diabetes mellitus. […] the OR for comorbid depression among the diabetic patients studied was higher for men than for women, indicating that although women with diabetes have an overall increased prevalence of depression (23.8 vs. 12.8%, p = 0.0001), men with diabetes have an increased risk of developing depression (men: OR = 1.9, 95% CI = 1.7–2.1 vs. women: OR = 1.3, 95% CI = 1.2–1.4). […] Research has shown that youths 12–17 years of age with type 1 diabetes had double the risk of depression compared with a teenage population without diabetes.21 This amounted to nearly 15% of children meeting the criteria for depression.

As many as two-thirds of patients with diabetes and major depression have been ill with depression for more than 2 years.44 […] Depression has been linked to decreased adherence to self-care regimens (exercise, diet, and cessation of smoking) in patients with diabetes, as well as to the use of diabetes control medications […] Patients with diabetes and depression are twice as likely to have three or more cardiac risk factors such as smoking, obesity, sedentary lifestyle, or A1c > 8.0% compared with patients with diabetes alone.47 […] The costs for individuals with both major depression and diabetes are 4.5 times greater than for those with diabetes alone.53

“A 2004 cross-sectional and longitudinal study of data from the Health and Retirement Study demonstrated that the cumulative risk of incident disability over an 8-year period was 21.3% for individuals with diabetes versus 9.3% for those without diabetes. This study examined a cohort of adults ranging in age from 51 to 61 years from 1992 through 2000.”

Although people with diabetes comprise just slightly more than 4% of the U.S. population,3 19% of every dollar spent on health care (including hospitalizations, outpatient and physician visits, ambulance services, nursing home care, home health care, hospice, and medication/glucose control agents) is incurred by individuals with diabetes” (As I noted in the margin, these are old numbers, and prevalence in particular is definitely higher today than it was when that chapter was written, so diabetics’ proportion of the total cost is likely even higher today than it was when that chapter was written. As observed multiple times previously on this blog, most of these costs are unrelated to the costs of insulin treatment and oral anti-diabetics like metformin, and indirect costs make out a quite substantial proportion of the total costs).

In 1997, only 8% of the population with a medical claim of diabetes was treated for diabetes alone. Other conditions influenced health care spending, with 13.8% of the population with one other condition, 11.2% with two comorbidities, and 67% with three or more related conditions.6 Patients with diabetes who suffer from comorbid conditions related to diabetes have a greater impact on health services compared with those patients who do not have comorbid conditions. […] Overall, comorbid conditions and complications are responsible for 75% of total medical expenditures for diabetes.” (Again, these are old numbers)

“Heart disease and stroke are the largest contributors to mortality for individuals with diabetes; these two conditions are responsible for 65% of deaths. Death rates from heart disease in adults with diabetes are two to four times higher than in adults without diabetes. […] Adults with diabetes are more than twice as likely to have multiple diagnoses related to macrovascular disease compared to patients without diabetes […] Although the prevalence of cardiovascular disease increases with age for both diabetics and nondiabetics, adults with diabetes have a significantly higher rate of disease. […] The management of macrovascular disease, such as heart attacks and strokes, represents the largest factor driving medical service use and related costs, accounting for 52% of costs to treat diabetes over a lifetime. The average costs of treating macrovascular disease are $24,330 of a total of $47,240 per person (in year 2000 dollars) over the course of a lifetime.17 Moreover, macrovascular disease is an important determinant of cost at an earlier time than other complications, accounting for 85% of the cumulative costs during the first 5 years following diagnosis and 77% over the initial decade. [Be careful here: This is completely driven by type 2 diabetics; a 10-year old newly diagnosed type 1 diabetic does not develop heart disease in the first decade of disease – type 1s are also at high risk of cardiovascular disease, but the time profile here is completely different] […] Cardiovascular disease in the presence of diabetes affects not only cost but also the allocation of health care resources. Average annual individual costs attributed to the treatment of diabetes with cardiovascular disease were $10,172. Almost 51% of costs were for inpatient hospitalizations, 28% were for outpatient care, and 21% were for pharmaceuticals and related supplies. In comparison, the average annual costs for adults with diabetes and without cardiovascular disease were $4,402 for management and treatment of diabetes. Only 31.2% of costs were for inpatient hospitalizations, 40.3% were for outpatient care, and 28.6% were for pharmaceuticals.16

Of individuals with diabetes, 2% to 3% develop a foot ulcer during any given year. The lifetime incidence rate of lower extremity ulcers is 15% in the diabetic population.20 […] The rate of amputation in individuals with diabetes is ten times higher than in those without diabetes.5 Diabetic lower-extremity ulcers are responsible for 92,000 amputations each year,21 accounting for more than 60% of all nontraumatic amputations.5 The 10-year cumulative incidence of lower-extremity amputation is 7% in adults older than 30 years of age who are diagnosed with diabetes.22 […] Following amputation, the 5-year survival rate is 27%.23 […] The majority of annual costs associated with treating diabetic peripheral neuropathy are associated with treatment of ulcers […] Overall, inpatient hospitalization is a major driver of cost, accounting for 77% of expenditures associated with individual episodes of lower-extremity ulcers.24

By 2003, diabetes accounted for 37% of individuals being treated for renal disease in the United States. […] Diabetes is the leading cause of kidney failure, accounting for 44% of all newly diagnosed cases. […] The amount of direct medical costs for ESRD attributed to diabetes is substantial. The total adjusted costs in a 24-month period were 76% higher among ESRD patients with diabetes compared with those without diabetes. […] Nearly one half of the costs of ESRD are due to diabetes.27” [How much did these numbers change since the book was written? I’m not sure, but these estimates do provide some sort of a starting point, which is why I decided to include the numbers even though I assume some of them may have changed since the publication of the book]

Every percentage point decrease in A1c levels reduces the risk of microvascular complications such as retinopathy, neuropathy, and nephropathy by 40%.5 However, the trend is for A1c to drift upward at an average of 0.15% per year, increasing the risk of complications and costs.17 […] A1c levels also affect the cost of specific complications associated with diabetes. Increasing levels affect overall cost and escalate more dramatically when comorbidities are present. A1c along with cardiovascular disease, hypertension, and depression are significant independent predictors of health care
costs in adults with diabetes.”

August 10, 2016 Posted by | books, diabetes, economics, medicine, Pharmacology | Leave a comment

Human Drug Metabolism (II)

My first post covering Coleman’s excellent book can be found here, and here you can read my goodreads review of the book; I think it makes sense to read those things before reading this post, if you have not already done that. As I believe I’ve previously mentioned (?) most non-fiction books I read, including those I do not blog, usually get a goodreads review, and actually I’m much more active on goodreads these days than I am on this blog. I have considered cross-posting goodreads reviews here on the blog, but I decided it might be best to just keep these things separate for the time being. I might change my mind about this, though; I don’t like how inactive the blog has become during the last few months, and goodreads reviews I’ve already written take almost no work to cross-post, so this would be an easy way to at least get some ‘activity’ here.

The book includes a lot of information that really pretty much everybody would be likely to benefit from knowing (how many people for example live their entire lives without consuming any alcohol, tobacco, or medical drugs? If you’ve ever consumed any of these things, the book has material of relevance included in the coverage…). I repeat myself here, but  some of the general observations included in the following seem to me to be important takeaways from the book: Drugs work (sometimes very) differently in different people, they interact with different things, including innocuous things like what you eat and drink and whether you exercise or not; drugs may interact with each other, in a very confusing variety of ways; some drugs are metabolized differently in people who have taken the drug for a while (‘induction’), compared to how the drug might be metabolized in someone who’s not taken the drug before (drug-naïve), and sometimes the ability to metabolize the drug faster/more efficiently may be lost (inhibition) because of a third factor, such as e.g. another drug or a dietary factor, which can be very dangerous (an improved ability to metabolize the drug because of habituation may also be lost due to non-consumption of the drug for some time, leading to a ‘reset’ of the metabolic pathway of relevance, an important factor in an abuse context where this can lead to overdose); there are huge racial and genetic differences in terms of how specific drugs are metabolized; the consequences of getting too much of a specific drug (toxicity) tend to be foreseeably different from the consequences of getting not enough of a drug (drug failure); efficient metabolism of a drug may depend upon the body’s ability not just to transform the xenobiotic compound into something useful, but also the ability to get rid of sometimes really quite toxic metabolites which might be created along the way as the body tries to get rid of that thing you just injected/ingested/etc. Many people don’t consider herbal remedies to be ‘real drugs’ and so neglect to tell their medical practitioner that they’re taking them/have recently stopped taking them, despite some of these having the potential to cause quite serious drug interactions (even if nothing is taken but herbal remedies; St. John’s Wort + kava kava = acute hepatitis? As noted in the book, “One point important to emphasize, is that assuming various herbal remedies do contain active and potent substituents, there is virtually nothing known clinically about what effects mixing herbal remedies might have, in terms of pharmacology and toxicity. This area is unfortunately left for patients to discover for themselves”).

This book is not ‘the whole story’ about drug metabolism and related stuff, it just scratches the surface, but the coverage serves to make it clear to you just how much stuff is to be found ‘below the surface’, and this is something I really like about the book. It makes you appreciate how little you know and how complex this stuff is. People write 500+ page textbooks like this one simply about CYP subtypes (I came across a different 1000+ page textbook also about a CYP subtype while reading the book so I know this one is hardly unique, but unfortunately I did not bookmark the book and I didn’t find the book after a brief search for it – but take my word for it, those books are out there…) and alcohol metabolism, they write 700 page textbooks about the side effects of psychiatric drugs (not the intended effects, that is – the side effects!) they write 800 page textbooks about aspirin and related drugs and about how drugs affect the liver… I know that in some circles it’s somewhat common for people to ‘experiment’ with various drugs and substances, illicit or otherwise; I also assume that most people who do this sort of thing have little idea what they’re actually doing and are likely taking a lot of risks the very existence of which they’re likely not aware of. Simply because there’s just so much stuff you need to know to even have a proper concept of what you’re doing when you’re dealing with how the human body works and how it responds to foreign substances we might choose to introduce into it. It might be that they wouldn’t care even if they knew because you’re probably rather low in risk aversion if you engage in that sort of experimentation in the first place (I incidentally am highly risk averse), but I do find it curious.

I have added some observations from the middle of the book below.

“Although there is growing awareness of the clinical problems posed by P-gp [P-glycoprotein] inhibition on drug bioavailability and toxicity, until recently it was very difficult to generalize and predict which classes of drug might be inhibitors of P-gp. […] There are dozens of drugs which are known inhibitors of P-gp […] it is often difficult to establish what contribution cellular transport systems make to bioavailability. Indeed, it is emerging that one of the reasons for the very wide variety of drug bioavailability in modern medicine could be the sheer number of possible inhibitors and substrates that exist for P-gp in the diet, such as a number of natural products like the flavonols, which can be as potent as cyclosporine or verapamil as P-gp inhibitors. Natural dietary inhibitors have advantages in their general lack of toxicity, but the basic problem of a lack of predictability in their effects on P-gp substrates remains. Since no two people’s diets are identical, the impact of P-gp modulation on drug absorption could be simply too complex to unravel.”

“the objectives of metabolizing systems could be summed up thus:
• To terminate the pharmacological effect of the molecule.
• Make the molecule so water-soluble that it cannot escape clearance, preferably by more than one route to absolutely guarantee its removal.
These objectives could be accomplished by:
• Changing the molecular shape so it no longer binds to its receptors.
• Changing the molecular lipophilicity to hydrophilicity to ensure high water solubility.
• Making the molecule larger and heavier, so it can be eliminated in bile as well as urine.
• Efflux pump systems, which ensure that a highly water-soluble metabolite actually leaves the cell to enter the bloodstream, before it is excreted in bile and urine. […]
CYP-mediated metabolism can increase hydrophilicity, but it does not always increase it enough and it certainly does not make the molecule any bigger and heavier, indeed, sometimes the molecule becomes lighter […] CYP-mediated metabolism does not always alter the pharmacological effects of the drug either […] However, CYPs do perform two essential tasks: the initial destabilization of the molecule, creating a ‘handle’ on it. […] CYPs also ‘unmask’ groups that could be more reactive for further metabolism. […] CYP-mediated preparation can make the molecule vulnerable to the attachment of a very water-soluble and plentiful agent to the drug or steroid, which accomplishes the objectives of metabolism. This is achieved through the attachment of a modified glucose molecule (glucuronidation), or a soluble salt such as a sulphate (sulphation) [see also this] to the prepared site. Both adducts usually make the drug into a stable, heavier and water-soluble ex-drug. […] with many drugs, their stability and lipophilicity mean that their clearance must take more than one metabolic operation to make them water-soluble.”

PXR [Pregnane X receptor], CAR [constitutive androstane receptor] and FXR [Farnesoid X receptor] are […] part of the process whereby the liver can sense whether its own metabolic capacity and physical size is sufficient to respond to homeostatic demands. Hence, alongside various growth factors, the NRs [nuclear receptors] facilitate the amazing process whereby the liver regenerates itself after areas of the organ are removed or damaged. […] As CYPs, UGTs [Glucuronosyltransferases], other biotransforming systems and efflux transporters are meeting the same xenobiotic or endobiotic stimuli in different tissues and degrees of exposure, it is logical that the […] receptor systems integrate and coordinate their responses. […] These multi-receptor mechanisms enable levels of induction to be customized for individual tissues to deal with different chemical threats. Essentially, according to diet, chemical and drug exposure, each individual will possess a unique expression array of UGTs and CYPs which will be constantly fine-tuned throughout life.”

“Sulphonation is accomplished by a set of enzyme systems known as sulphotransferases (SULTs) and they are found in most tissues to varying degrees of activity. […] The general aim of sulphonation is to make the substrate more water-soluble and usually less active pharmacologically. Sulphonated molecules are more readily eliminated in bile and urine. […] All SULTs are subject to genetic polymorphisms, with a high degree of individual variation in their expression and catalytic activities […] Regarding classification of the superfamily of SULTs, it is assumed that 47 per cent amino acid sequence homology is indicative of same family members and 60 per cent homology for subfamily members. To date, there are 47 mammalian SULT isoforms so far discovered, which are derived from ten human sulphotransferase gene families […] knowledge of the role of NRs and AhR [Aryl hydrocarbon receptor] in human SULT expression has progressed in animals but not really in humans. This is partly due to the fact that rodent SULT profiles are quite different to ours […] Many studies have been carried out in rodents, which have produced rather contradictory results […] It seems that whilst SULTs in general are not as responsive to inducers as CYPs and UGTs, their basal expression is much higher, although interindividual expression does vary considerably and this may have severe toxicological consequences, in terms of xenobiotic toxicity and carcinogenicity. There is also some evidence that diet is a strong influence on individual SULT profiles.”

“One of the main problems with the oxidation of various molecules by CYP enzymes is that they are often destabilized and sometimes form highly reactive products. […] CYPs occasionally form metabolites so reactive that they immediately destroy the enzyme by reacting with it, changing its structure and, therefore, its function. […] The most dangerous forms of reactive species are those that evade UGTs and SULT enzymes, or are inadvertently created by conjugation processes. These species escape into the cytosol and even into the nucleus, where potentially carcinogenic events may result. […] CYPs are not the only source of reactive species generated within cells. Around 75 per cent of our food intake is directed at maintaining our body temperature and a great deal of energy must be liberated from the food to accomplish this. Cells derive the vast majority of their energy through oxidative phosphorylation and this takes place in […] the mitochondria. […] In cells almost all the oxygen we breathe is consumed in oxidative phosphorylation, forming ATP, heat and reactive oxidant species in the mitochondria that could cause severe damage to the structure and function of the cell if they were allowed to escape. So all cells, particularly hepatocytes, have evolved a separate system to accommodate such reactive toxic products and this is based on a three amino acid (cysteine, glycine and glutamate) thiol known as glutathione, or GSH. Thiols in general are extremely effective at reducing and thus ‘quenching’ highly reactive, electrophilic species. […] if cells are depleted of GSH by blocking its synthesis (by using buthionine sulphoxime), cell death follows and the organism itself will die in a few days, due to uncontrolled activity of endogenous radicals. […] If GSH levels are not maintained in the cell over a long period of time, the cell wears out more quickly; for example, diabetic complications and HIV infection are linked with poor GSH maintenance.” [I did not know this…]

“There are several enzymes that promote and catalyze the reaction of GSH with potential toxins to ensure that reactive species are actively dealt with, rather than just passive GSH-mediated reduction. Probably the most important from the standpoint of drug metabolism are the GSH-S-transferases [‘GSTs’, which] are the key cellular defence against electrophilic agents formed from endogenous or xenobiotic oxidative metabolism. […] The GSTs are found in humans in several major classes. […] The classes contain several subfamilies […] These enzymes are polymorphic […] and their individual expression ranges from complete absence in some isoforms to overabundance as a response to anticancer therapy. […] The upregulation of GST is a serious problem within cancer therapeutics and resistance to a range of drugs including melphalan and doxorubicin is linked with GST detoxification. Much research has been directed at inhibitors of GST isoforms to reverse or even prevent the development of resistance to anti-neoplastic agents. Unfortunately this strategy has not been successful”

“once xenobiotics have been converted into low-toxicity, higher-molecular-weight and high-water-solubility metabolites by the combination of CYPs, UGTs, SULTs and GSTs, this appears at first sight to be ‘mission accomplished’. However, these conjugates must be transported against a concentration gradient out of the cell into the interstitial space between cells. Then they will enter the capillary system and thence to the main bloodstream and filtration by the kidneys. The biggest hurdle is the transport out of the cell, which is a tall order, as once a highly water-soluble entity has been created, it will effectively be ‘ion-trapped’ in the cell, as the cell membrane is highly lipophilic and is an effective barrier to the exit as well as entry of most hydrophilic molecules. […] failure to remove the hydrophilic products of conjugation reactions [from the cells] can lead to:
• toxicity of conjugates to various cell components;
• hydrolysis of conjugates back to the original reactive species;
• inhibition of conjugating enzymes.
If the cell can manage to transport them out, then they should be excreted in urine or bile and detoxification can proceed at a maximal rate. […] Consequently, an impressive array of multi-purpose membrane bound transport carrier systems has evolved which can actively remove hydrophilic metabolites and many other low molecular weight drugs and toxins from cells. The relatively recent […] term of Phase III metabolism has been applied to the study of this essential arm of the detoxification process. […] The main thrust of research into efflux transporters has been directed at the ABC-type transporters [this link actually has quite a bit of content, unlike some of the other wiki articles on these topics], of which there are 48 genes that code of a variety of ATP-powered pumps.”

“it is clear that the whole process of detection, metabolism and elimination of endobiotic and xenobiotic agents is minutely coordinated and is responsive to changes in load in individual tissues. The CYPs, UGTs, MRPs [Multidrug Resistance Proteins] and P-gp are all tightly regulated through the NR system of PXR, CAR, FXE, PPAR α, LXR etc, as well as the AhR receptor system [does it even make sense to keep adding links here? I’m not sure it does…]. Some enzyme/pump processes are closely linked, such as CYP3A4 and P-gp, as inducers powerfully increase both systems capacity. The reactive species protection ‘arm’ of biotransformation is also controlled through a separate but almost certainly ‘cross-talking’ Nrf2/Keap1 system which coordinates not only the interception of reactive species by GSTs, but also the supply of their GSH substrate, UGTs and the MRPs. This latter coordination is particularly relevant in resistance to cancer chemotherapy and happens because overexpression of any one entity alone cannot rid the cell of the toxin. […] The MRPs, GSH production and GST/UGT activity must be induced in concert. […] much of the integration and coordination of detoxification processes remains to be uncovered”.

Chapter 7, about ‘factors affecting drug metabolism’, has some very interesting stuff, but I think this post is quite long enough as it is. I might talk about that stuff in detail later on, but I make no promises.

August 9, 2016 Posted by | books, medicine, Pharmacology | Leave a comment