“A study of 42 adults with AS diagnoses living in the community found that 40 % of subjects had considered committing suicide at some time in the past, and 15 % of respondents reported that they had made at least one attempt to kill themselves (Balfe & Tantam, 2010)”
“The most relevant study was conducted in 2013. It compared 791 children with autism to non-austistic depressed children and typical children. The findings favored a 28-fold increase in suicide behavior in the autism sample compared to the typical children; 10.9 % of children with autism had suicidal ideation and 7.2 % had made attempts”
“…a large proportion of persons with ASD, over 50% in some studies, […] suffer from depression, and we have reports that suicidal ideation is one of the common depressive symptoms leading to this diagnosis.”
“Clinical samples suggest that suicide occurs more frequently in high functioning autism” (Suicide in Autism Spectrum Disorder)
“Compared to those in the general population, individuals with type 1 diabetes (in a British study) had 11 times the suicide rate” (Insulin Overdose Among Patients With Diabetes: A Readily Available Means of Suicide)
“40% of the [diabetic] patients reported that they had felt tired of living and thought that life was not worth living during the last 12 months, and 23% patients admitted to having thought of ending their own life.” (Quality of Life and Suicide Risk in Patients With Diabetes Mellitus)
“The research reviewed indicated that patients with DM-1 are at an increased risk for suicide, although no clear consensus exists regarding the level of the increased risk. […] Our findings support the recommendation that a suicide risk assessment of patients with DM-1 should be part of the routine clinical assessment. The assessment of patients at risk should consist of the evaluation of current and previous suicidal behaviors (both suicidal ideation and attempted suicide).” (Suicide risk in type 1 diabetes mellitus: A systematic review)
“In terms of rates of 1-year prevalence we found that 3.1 % (confidence interval [CI] at 95% = 2.5-3.7) of the sample reported serious thoughts of suicide […] We found significant associations between suicide ideation on the one hand and living alone (OR = 2.5), having no friends (OR = 23) and feeling alone very often (OR= 10.5) on the other hand. […] Twenty-one percent of the individuals who […] felt lonely very often, reported having thought seriously about suicide, in contrast with 2.5% of those who did not.” (from Loneliness in Relation to Suicide Ideation and Parasuicide: A Population-Wide Study)
I’m a depressed, friendless (to the long-term readers with a good memory: she at the end got tired of my dissatisfactory behaviour and told me, kindly, to get lost and stop bothering her, and I had no difficulty understanding her decision, which I have thus respected. Incidentally I should probably note that my conceptual model of friendship has changed since I wrote that post, at least partly as a result of increased knowledge about these topics), lonely, (supposedly ‘high-functioning’) autistic type 1 diabetic. Relatedly, I live in a place people describe this way: “I’ve never been in a country with such a sharp dichotomy between stranger and friend, or one that was so coldly unfriendly to strangers.”
Below I have posted a list of the 156 books I read to completion in 2016, as well as links to blog posts covering the books and reviews of the books which I’ve written on goodreads. At the bottom of the post I have also added the 7 books I did not finish this year, as well as some related links and comments. The post you read now is unlikely to be the final edition of this post, as I’ll continue to add links and comments to the post also in 2017 if/when I blog or review books mentioned below.
As I also mentioned earlier in the year, I have been reading a lot of fiction this year and not enough non-fiction. Regarding the ‘technical aspects’ of the list below, as usual the letters ‘f’ and ‘nf.’ in the parentheses correspond to ‘fiction’ and ‘non-fiction’, respectively, whereas the ‘m’ category covers ‘miscellaneous’ books. The numbers in the parentheses correspond to the goodreads ratings I thought the books deserved.
I did a brief count of the books on the list and concluded that the list includes 30 books categorized as non-fiction, 20 books in the miscellaneous category, and 106 books categorized as fiction. As usual non-fiction works published by Springer make up a substantial proportion of the non-fiction books I read (20 %), with another 20 % accounted for by Oxford University Press, Princeton University Press and Wiley/Wiley-Blackwell. Some of the authors in the fiction category have also featured on the lists previously (Christie, Wodehouse, Bryson), but other names are new – new names include: Dick Francis (39 books), Tom Sharpe (16 books), David Sedaris (7 books), Mario Puzo (4 books), Gerard Durrell (3 books), and Connie Willis (3 books).
I shared my ‘year in books’ on goodreads, and that link includes a few summary stats as well as cover images of the books (annoyingly a large-ish proportion of the non-fiction books have not added cover pictures, but it’s even so a neat visualization tool). With 156 books finished this year I read almost exactly 3 books per week on average, and the goodreads tools also tell me that I read 47.281 pages during the year. As I don’t believe goodreads includes the page counts of partially read books in that tool, this is probably a slight underestimate but it’s in that neighbourhood anyway; this corresponds to ~130 pages per day on average (129,5) throughout the year, or roughly 900 pages per week. The average length of the books I finished was 309 pages, again according to goodreads.
Since I started blogging, I have published roughly 500 posts about books I’ve read – I actually realized while writing this post that the next post I publish on this site categorized under ‘books’ will be post number 500 in that category. As should be obvious from the list below, as a rule I do not cover fiction books on this blog, aside from in the context of quote posts where I may occasionally include a few quotes from books I’ve read (I decided early on not to include links to such posts on lists like these, as that would be too much work). In the context of quotes I should probably add here to readers not already aware of this that I recently decided to move/copy a large number of quotes from this site to goodreads, and that I now update my goodreads quote collection more frequently than I do the quote collection on this blog; at this point, my quote collection on goodreads includes 1347 quotes. For a few more details about this aspect of the goodreads site, see incidentally this post.
Both Dick Francis and Connie Willis were introduced to me by the SSC commentariat and this link includes a lot of other author recommendations which might be of interest to you. I should perhaps also note before moving on to the list that I have recently added a not-insignificant number of books to my list of favourite books on goodreads. I have (retrospectively) slightly modified my implicit selection criteria for adding books to the list; previously if a book had taught me a lot but I did not give it a five star rating or I figured it wasn’t at least very close to perfect, it wasn’t going to get anywhere near my list of favourite books. I figured recently that perhaps I should also include on the list books which had taught me a lot, books that had changed my way of looking at the world, even if they were not very close to perfect in most respects. I’m still not quite sure what is the best categorization approach, but as of now the list includes some books which did not feature on the list in the near past and I figured I might mention the list explicitly here also because people perusing a list like the one below are presumably in part doing it because they’re looking for good books to read, and my inclusion of a book on that list can still at least be taken to be a qualified recommendation of the book.
1. 4.50 from Paddington (4, f). Agatha Christie.
3. Hickory Dickory Dock (3, f). Agatha Christie.
6. A Caribbean Mystery (3, f). Agatha Christie.
7. A Rulebook for Arguments (Hackett Student Handbooks) (1, nf. Hackett Publishing). Very short goodreads review here.
8. The Clocks (2, f). Agatha Christie.
15. By the Pricking of My Thumbs (2, f). Agatha Christie.
16. The Godfather (4, f). Mario Puzo.
21. A Few Quick Ones (3, f). P. G. Wodehouse.
22. Ice in the Bedroom (4, f). P. G. Wodehouse.
24. The Secret of Chimneys (2, f). Agatha Christie.
26. Something Fishy (3, f). P. G. Wodehouse.
27. Do Butlers Burgle Banks? (3,f). P.G. Wodehouse.
28. The Mirror Crack’d from Side to Side (1, f). Agatha Christie. Boring story, almost didn’t finish it.
29. Frozen Assets (4, f). P. G. Wodehouse.
30. A Cooperative Species: Human Reciprocity and Its Evolution (5, nf. Princeton University Press). Goodreads review here. Blog coverage here.
31. If I Were You (4, f). P. G. Wodehouse.
32. On the Shortness of Life (nf.). Seneca the Younger.
33. Barmy in Wonderland (3, f). P. G. Wodehouse.
38. Company for Henry (4, f). P. G. Wodehouse.
39. Bachelors Anonymous (5, f). P. G. Wodehouse. A short book, but very funny.
40. The Second World War (5, nf.) Winston Churchill. Very long, the book is a thousand pages long abridgement of 6 different volumes written by Churchill. Blog coverage here, here, here, and here. I added this book to my list of favourite books on goodreads.
41. The Old Reliable (3, f). P. G. Wodehouse.
42. Performing Flea (4, m). P. G. Wodehouse, William Townend.
45. The Road to Little Dribbling: Adventures of an American in Britain (3, m). Bill Bryson.
46. Bryson’s Dictionary of Troublesome Words: A Writer’s Guide to Getting It Right (3, nf.). Bill Bryson. Goodreads review here.
48. Shakespeare: The World as Stage (2, m). Bill Bryson.
50. The Sicilian (3, f). Mario Puzo.
53. Pre-Industrial Societies: Anatomy of the Pre-Modern World (5, nf. Oneworld Publications). Goodreads review here. I added this book to my list of favourite books on goodreads.
56. Aunts Aren’t Gentlemen (3, f). P. G. Wodehouse.
57. What If?: Serious Scientific Answers to Absurd Hypothetical Questions (2, m. Randall Munroe). Short goodreads review here.
61. Wilt In Nowhere (3, f). Tom Sharpe.
63. Monstrous Regiment (3, f). Terry Pratchett.
67. Vintage Stuff (2, f). Tom Sharpe.
70. Suicide Prevention and New Technologies: Evidence Based Practice (1, nf. Palgrave Macmillan). Long(-ish) goodreads review here.
72. Diabetes and the Metabolic Syndrome in Mental Health (2, nf. Lippincott Williams & Wilkins). Goodreads review here. Blog coverage here and here.
77. The Great Pursuit (3, f). Tom Sharpe.
78. Riotous Assembly (4, f). Tom Sharpe.
79. Indecent Exposure (3, f). Tom Sharpe.
87. Naked (3, m). David Sedaris.
91. When You Are Engulfed in Flames (3, m). David Sedaris.
93. Poor Richard’s Almanack (m). Benjamin Franklin.
97. The Garden of the Gods (3, m). Gerard Durrell.
100. The Thirteen Problems (2, f). Agatha Christie.
101. Dead Cert (4, f). Dick Francis.
102. Nerve (3, f). Dick Francis.
103. For Kicks (3, f). Dick Francis.
104. Odds Against (3, f). Dick Francis.
108. Blood Sport (3, f). Dick Francis.
110. Forfeit (2, f). Dick Francis.
117. High Stakes (4, f). Dick Francis.
118. In the Frame (3, f). Dick Francis.
119. Knockdown (3, f). Dick Francis.
121. Managing Diabetic Nephropathies in Clinical Practice (4, nf. Springer). Very short goodreads review here. Blog coverage here.
129. Proof (2, f). Dick Francis.
130. Break In (3, f). Dick Francis.
131. Integrated Diabetes Care: A Multidisciplinary Approach (4, nf. Springer). Goodreads review here. Blog coverage here and here.
136. Longshot (4, f). Dick Francis.
141. Decider (3, f). Dick Francis.
142. Essential Microbiology and Hygiene for Food Professionals (2, nf. CRC Press). Short goodreads review here.
143. Wild Horses (2, f). Dick Francis.
144. Come to Grief (4, f). Dick Francis.
145. To the Hilt (2, f). Dick Francis.
147. Second Wind (2, f). Dick Francis.
149. Under Orders (4, f). Dick Francis.
Books I did not finish:
Raising Steam (?, f). Terry Pratchett. These days I mostly use Pratchett’s books as a treat, the few remaining books in the Discworld series which I have yet to read I consider to be books which I feel that I have to make myself deserve to be allowed to read. I started out reading this book because I felt terrible at the time, but I decided after having read a hundred pages or so that I had not in fact deserved to read the book, and so I put it away again. Unlike the two books above I do not consider this book to be bad, that’s not why I didn’t finish it.
Anna Karenina (?, f). Tolstoy. As I pointed out in my short review, “so far (I stopped around page 140) it’s been a story about miserable Russians, and I can’t read that kind of stuff right now.” Again, I would not say this book is bad, but I could not read that kind of stuff at the time.
The Language Instinct: How the Mind Creates Language (nf., Harper Perennial Modern Classics). Pinker’s book may be one of the last popular science books I’ll read, at least for a while – I find that I simply can’t read this kind of book anymore (which is annoying, because I also bought Jonathan Haidt’s The Righteous Mind this year, and I worry that I’ll never be able to read that book, despite the content being at least somewhat interesting, simply on account of the way the book is likely to be written). As I noted while reading the book, “I’ve realized by now that I’ve probably at this point grown to strongly dislike reading popular science books. I’ve disliked other PS books I’ve read in the semi-near past as well, but I always figured I had specific reasons for disliking a particular book. At this point it seems like it’s a general thing. I don’t like these books any more. Too imprecise language, claims are consistently way too strong, etc., etc..” My reading experience of Pinker’s book was definitely not improved by the fact that I have read textbooks on topics closely related to those covered in the book in the past (Eysenck and Keane, Snowling et al.).
Physiology at a Glance (?, Wiley-Blackwell). ‘Too much work, considering the pay-off’, would probably be the short version of why I didn’t finish this one – but this should not be taken as an indication that the book is bad. Despite the words ‘at a glance’ in the title, each short chapter (2 pages) in this book roughly matches the amount of material usually covered in an academic lecture (this is the general structure of the ‘at a glance books’), which means that the book takes quite a bit more work than the limited page count might indicate. The fact that I knew many of the things covered didn’t mean that the book was much faster to read than it otherwise might have been; it still took a lot of time and effort to digest the material. I’m sure there’s some stuff in the book which I don’t know and stuff I’ve forgot, and I did learn some new stuff from the chapters I did read, so I’m conflicted about whether or not to pick it up again later – it may be worth it at some point. However back when I was reading it I decided in the end to just put the book away and read something else instead. If you’re looking for a dense and to-the-point introduction to physiology/anatomy, I’m sure you could do a lot worse than this book.
100 Endgames You Must Know: Vital Lessons for Every Chess Player (?, nf. New in Chess). If I just wanted to be able to say that I had ‘read’ this book, I would have finished it a long time ago, but this is not the sort of book you just ‘read’. The positions covered need to be studied and analyzed in detail, the positions need to be played out, perhaps reviewed (depending on how ambitious you are about your chess). I’m more than half-way through (p. 140 or so), but I rarely feel like working on this stuff as it’s more fun to play chess than to systematically improve your chess in the manner you’ll do if you work on the material covered in this book. It’s a great endgame book, but it takes a lot of work.
Here’s my first post about the book, which I recently finished – here’s my goodreads review. I added the book to my list of favourite books on goodreads, it’s a great textbook. Below some observations from the first few chapters of the book.
“Several studies report T1D [type 1 diabetes] incidence numbers of 0.1–36.8/100,000 subjects worldwide (2). Above the age of 15 years ketoacidosis at presentation occurs on average in 10% of the population; in children ketoacidosis at presentation is more frequent (3, 4). Overall, publications report a male predominance (1.8 male/female ratio) and a seasonal pattern with higher incidence in November through March in European countries. Worldwide, the incidence of T1D is higher in more developed countries […] After asthma, T1D is a leading cause of chronic disease in children. […] twin studies show a low concordant prevalence of T1D of only 30–55%. […] Diabetes mellitus type 1 may be sporadic or associated with other autoimmune diseases […] The latter has been classified as autoimmune polyglandular syndrome type II (APS-II). APS-II is a polygenic disorder with a female preponderance which typically occurs between the ages of 20 and 40 years […] In clinical practice, anti-thyroxine peroxidase (TPO) positive hypothyroidism is the most frequent concomitant autoimmune disease in type 1 diabetic patients, therefore all type 1 diabetic patients should annually be screened for the presence of anti-TPO antibodies. Other frequently associated disorders are atrophic gastritis leading to vitamin B12 deficiency (pernicious anemia) and vitiligo. […] The normal human pancreas contains a superfluous amount of β-cells. In T1D, β-cell destruction therefore remains asymptomatic until a critical β-cell reserve is left. This destructive process takes months to years […] Only in a minority of type 1 diabetic patients does the disease begin with diabetic ketoacidosis, the majority presents with a milder course that may be mistaken as type 2 diabetes (7).”
“Insulin is the main regulator of glucose metabolism by stimulating glucose uptake in tissues and glycogen storage in liver and muscle and by inhibiting gluconeogenesis in the liver (11). Moreover, insulin is a growth factor for cells and cell differentiation, and acting as anabolic hormone insulin stimulates lipogenesis and protein synthesis. Glucagon is the counterpart of insulin and is secreted by the α-cells in the pancreatic islets in an inversely proportional quantity to the insulin concentration. Glucagon, being a catabolic hormone, stimulates glycolysis and gluconeogenesis in the liver as well as lipolysis and uptake of amino acids in the liver. Epinephrine and norepinephrine have comparable catabolic effects […] T1D patients lose the glucagon response to hypoglycemia after several years, when all β-cells are destructed […] The risk of hypoglycemia increases with improved glycemic control, autonomic neuropathy, longer duration of diabetes, and the presence of long-term complications (17) […] Long-term complications are prevalent in any population of type 1 diabetic patients with increasing prevalence and severity in relation to disease duration […] The pathogenesis of diabetic complications is multifactorial, complicated, and not yet fully elucidated.”
“Cataract is much more frequent in patients with diabetes and tends to become clinically significant at a younger age. Glaucoma is markedly increased in diabetes too.” (I was unaware of this).
“T1D should be considered as an independent risk factor for atherosclerosis […] An older study shows that the cumulative mortality of coronary heart disease in T1D was 35% by the age 55 (34). In comparison, the Framingham Heart Study showed a cardiovascular mortality of 8% of men and 4% of women without diabetes, respectively. […] Atherosclerosis is basically a systemic disease. Patients with one clinically apparent localization are at risk for other manifestations. […] Musculoskeletal disease in diabetes is best viewed as a systemic disorder with involvement of connective tissue. Potential pathophysiological mechanisms that play a role are glycosylation of collagen, abnormal cross-linking of collagen, and increased collagen hydration […] Dupuytren’s disease […] may be observed in up to 42% of adults with diabetes mellitus, typically in patients with long-standing T1D. Dupuytren’s is characterized by thickening of the palmar fascia due to fibrosis with nodule formation and contracture, leading to flexion contractures of the digits, most commonly affecting the fourth and fifth digits. […] Foot problems in diabetes are common and comprise ulceration, infection, and gangrene […] The lifetime risk of a foot ulcer for diabetic patients is about 15% (42). […] Wound depth is an important determinant of outcome (46, 47). Deep ulcers with cellulitis or abscess formation often involve osteomyelitis. […] Radiologic changes occur late in the course of osteomyelitis and negative radiographs certainly do not exclude it.”
“Education of people with diabetes is a comprehensive task and involves teamwork by a team that comprises at least a nurse educator, a dietician, and a physician. It is, however, essential that individuals with diabetes assume an active role in their care themselves, since appropriate self-care behavior is the cornerstone of the treatment of diabetes.” (for much more on these topics, see Simmons et al.)
“The International Diabetes Federation estimates that more than 245 million people around the world have diabetes (4). This total is expected to rise to 380 million within 20 years. Each year a further 7 million people develop diabetes. Diabetes, mostly type 2 diabetes (T2D), now affects 5.9% of the world’s adult population with almost 80% of the total in developing countries. […] According to […] 2007 prevalence data […] [a]lmost 25% of the population aged 60 years and older had diabetes in 2007. […] It has been projected that one in three Americans born in 2000 will develop diabetes, with the highest estimated lifetime risk among Latinos (males, 45.4% and females, 52.5%) (6). A rise in obesity rates is to blame for much of the increase in T2D (7). Nearly two-thirds of American adults are overweight or obese (8). [my bold, US]
“In the natural history of progression to diabetes, β-cells initially increase insulin secretion in response to insulin resistance and, for a period of time, are able to effectively maintain glucose levels below the diabetic range. However, when β-cell function begins to decline, insulin production is inadequate to overcome the insulin resistance, and blood glucose levels rise. […] Insulin resistance, once established, remains relatively stable over time. […] progression of T2D is a result of worsening β-cell function with pre-existing insulin resistance.”
“Lifestyle modification (i.e., weight loss through diet and increased physical activity) has proven effective in reducing incident T2D in high-risk groups. The Da Qing Study (China) randomly allocated 33 clinics (557 persons with IGT) to 1 of 4 study conditions: control, diet, exercise, or diet plus exercise (23). Compared with the control group, the incidence of diabetes was reduced in the three intervention groups by 31, 46, and 42%, respectively […] The Finnish Diabetes Prevention Study evaluated 522 obese persons with IGT randomly allocated on an individual basis to a control group or a lifestyle intervention group […] During the trial, the incidence of diabetes was reduced by 58% in the lifestyle group compared with the control group. The US Diabetes Prevention Program is the largest trial of primary prevention of diabetes to date and was conducted at 27 clinical centers with 3,234 overweight and obese participants with IGT randomly allocated to 1 of 3 study conditions: control, use of metformin, or intensive lifestyle intervention […] Over 3 years, the incidence of diabetes was reduced by 31% in the metformin group and by 58% in the lifestyle group; the latter value is identical to that observed in the Finnish Study. […] Metformin is recommended as first choice for pharmacologic treatment [of type 2 diabetes] and has good efficacy to lower HbA1c […] However, most patients will eventually require treatment with combinations of oral medications with different mechanisms of action simultaneously in order to attain adequate glycemic control.”
CVD [cardiovascular disease, US] is the cause of 65% of deaths in patients with T2D (31). Epidemiologic studies have shown that the risk of a myocardial infarction (MI) or CVD death in a diabetic individual with no prior history of CVD is comparable to that of an individual who has had a previous MI (32, 33). […] Stroke is the second leading cause of long-term disability in high-income countries and the second leading cause of death worldwide. […] Stroke incidence is highly age-dependent. The median stroke incidence in persons between 15 and 49 years of age is 10 per 100,000 per year, whereas this is 2,000 per 100,000 for persons aged 85 years or older. […] In Western communities, about 80% of strokes are caused by focal cerebral ischemia, secondary to arterial occlusion, 15% by intracerebral hemorrhage, and 5% by subarachnoid hemorrhage (2). […] Patients with ischemic stroke usually present with focal neurological deficit of sudden onset. […] Common deficits include dysphasia, dysarthria, hemianopia, weakness, ataxia, sensory loss, and cognitive disorders such as spatial neglect […] Mild-to-moderate headache is an accompanying symptom in about a quarter of all patients with ischemic stroke […] The risk of symptomatic intracranial hemorrhage after thrombolysis is higher with more severe strokes and higher age (21). [worth keeping in mind when in the ‘I-am-angry-and-need-someone-to-blame-for-the-death-of-individual-X-phase’ – if the individual died as a result of the treatment, the prognosis was probably never very good to start with..] […] Thirty-day case fatality rates for ischemic stroke in Western communities generally range between 10 and 17% (2). Stroke outcome strongly depends not only on age and comorbidity, but also on the type and cause of the infarct. Early case fatality can be as low as 2.5% in patients with lacunar infarcts (7) and as high as 78% in patients with space-occupying hemispheric infarction (8).”
“In the previous 20 years, ten thousands of patients with acute ischemic stroke have participated in hundreds of clinical trials of putative neuroprotective therapies. Despite this enormous effort, there is no evidence of benefit of a single neuroprotective agent in humans, whereas over 500 have been effective in animal models […] the failure of neuroprotective agents in the clinic may […] be explained by the fact that most neuroprotectants inhibit only a single step in the broad cascade of events that lead to cell death (9). Currently, there is no rationale for the use of any neuroprotective medication in patients with acute ischemic stroke.”
“Between 5 and 10% of patients with ischemic stroke suffer from epileptic seizures in the first week and about 3% within the first 24 h […] Post-stroke seizures are not associated with a higher mortality […] About 1 out of every 11 patient with an early epileptic seizure develops epilepsy within 10 years after stroke onset (51) […] In the first 12 h after stroke onset, plasma glucose concentrations are elevated in up to 68% of patients, of whom more than half are not known to have diabetes mellitus (53). An initially high blood glucose concentration in patients with acute stroke is a predictor of poor outcome (53, 54). […] Acute stroke is associated with a blood pressure higher than 170/110 mmHg in about two thirds of patients. Blood pressure falls spontaneously in the majority of patients during the first week after stroke. High blood pressure during the acute phase of stroke has been associated with a poor outcome (56). It is unclear how blood pressure should be managed during the acute phase of ischemic stroke. […] routine lowering of the blood pressure is not recommended in the first week after stroke, except for extremely elevated values on repeated measurements […] Urinary incontinence affects up to 60% of stroke patients admitted to hospital, with 25% still having problems on hospital discharge, and around 15% remaining incontinent at 1 year. […] Between 22 and 43% of patients develop fever or subfebrile temperatures during the first days after stroke […] High body temperature in the first days after stroke is associated with poor outcome (42, 67). There is currently no evidence from randomized trials to support the routine lowering of body temperature above 37◦C.”
i. “To be good and lead a good life means to give to others more than one takes from them.” (Leo Tolstoy)
ii. “If you tell the truth, you don’t have to remember anything.” (Mark Twain)
iii. “When we cannot obtain a thing, we comfort ourselves with the reassuring thought that it is not worth nearly as much as we believed.” (Max Scheler)
iv. “Few persons are prevented from thinking themselves right by the reflection that, if they be right, the rest of the world is wrong.” (Arthur James Balfour)
v. “Misery loves company, but company does not reciprocate.” (Addison Mizner)
vi. “It is characteristic of the unlearned that they are forever proposing something which is old, and because it has recently come to their own attention, supposing it to be new.” (Calvin Coolidge)
vii. “To be wicked is never excusable, but there is some merit in knowing that you are; the most irreparable of vices is to do evil from stupidity.” (Charles Baudelaire)
viii. “A demagogue is a person with whom we disagree as to which gang should mismanage the country.” (Donald Robert Perry Marquis)
ix. “The usual judgments are judgments of interest and they tell us less about the nature of the person judged than about the interest of the one who judges.” (Constantin Brunner)
x. “Men are forever doing two things at the same time: acting egoistically and talking moralistically.” (-ll-)
xi. “I’m not young enough to know everything.” (J. M. Barrie)
xii. “History repeats itself. That’s one of the things wrong with history.” (Clarence Darrow)
xiii. “People hate the man who is a constant drain on their sympathy.” (E. W. Howe)
xiv. “Abusing the prosperous in order to curry the favor of the envious, is an old game that still works better than it should.” (-ll-)
xv. “The world is full of people whose notion of a satisfactory future is, in fact, a return to an idealised past.” (Robertson Davies)
xvi. “When a man talks with absolute sincerity and freedom he goes on a voyage of discovery. The whole company has shares in the enterprise.” (John Jay Chapman)
xvii. “Be less curious about people and more curious about ideas.” (Marie Curie)
xviii. “Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.” (-ll-)
xix. “If people were always kind and obedient to those who are cruel and unjust; the wicked people would have it all their own way: they would never feel afraid, and so they would never alter, but would grow worse and worse. When we are struck at without a reason, we should strike back again very hard; I am sure we should — so hard as to teach the person who struck us never to do it again.” (Charlotte Brontë)
xx. “Truth disdains the aid of the law for its defence – it will stand upon its own merit.” (John Leland)
I recently learned that the probability that I have brain-damage as a result of my diabetes is higher than I thought it was.
I first took note of the fact that there might be a link between diabetes and brain development some years ago, but this is a topic I knew very little about before reading the book I’m currently reading. Below I have added some relevant quotes from chapters 10 and 11 of the book:
“Cognitive decrements [in adults with type 1 diabetes] are limited to only some cognitive domains and can best be characterised as a slowing of mental speed and a diminished mental flexibility, whereas learning and memory are generally spared. […] the cognitive decrements are mild in magnitude […] and seem neither to be progressive over time, nor to be substantially worse in older adults. […] neuroimaging studies […] suggest that type 1 diabetic patients have relatively subtle reductions in brain volume but these structural changes may be more pronounced in patients with an early disease onset.”
“With the rise of the subspecialty area ‘medical neuropsychology’ […] it has become apparent that many medical conditions may […] affect the structure and function of the central nervous system (CNS). Diabetes mellitus has received much attention in that regard, and there is now an extensive literature demonstrating that adults with type 1 diabetes have an elevated risk of CNS anomalies. This literature is no longer limited to small cross-sectional studies in relatively selected populations of young adults with type 1 diabetes, but now includes studies that investigated the pattern and magnitude of neuropsychological decrements and the associated neuroradiological changes in much more detail, with more sensitive measurements, in both younger and older patients.”
“Compared to non-diabetic controls, the type 1 diabetic group [in a meta-analysis including 33 studies] demonstrated a significant overall lowered performance, as well as impairment in the cognitive domains intelligence, implicit memory, speed of information processing, psychomotor efficiency, visual and sustained attention, cognitive flexibility, and visual perception. There was no difference in explicit memory, motor speed, selective attention, or language function. […] These results strongly support the hypothesis that there is a relationship between cognitive dysfunction and type 1 diabetes. Clearly, there is a modest, but statistically significant, lowered cognitive performance in patients with type 1 diabetes compared to non-diabetic controls. The pattern of cognitive findings does not suggest decline in all cognitive domains, but is characterised by a slowing of mental speed and a diminished mental flexibility. Patients with type 1 diabetes seem to be less able to flexibly apply acquired knowledge in a new situation. […] In all, the cognitive problems we see in type 1 diabetes mimics the patterns of cognitive ageing. […] One of the problems with much of this research is that it is conducted in patients who are seen in specialised medical centres where care is very good. Other aspects of population selection may also have affected the results. Persons who participate in research projects that include a detailed work-up at a hospital tend to be less affected than persons who refuse participation. Possibly, specific studies that recruit type 1 adults from the community, with individuals being in poorer health, would result in greater cognitive deficits”.
“[N]eurocognitive research suggests that type 1 diabetes is primarily associated with psychomotor slowing and reductions in mental efficiency. This pattern is more consistent with damage to the brain’s white matter than with grey-matter abnormalities. […] A very large neuroimaging literature indicates that adults with either type 1 or type 2 diabetes manifest structural changes in a number of brain regions […]. MRI changes in the brain of patients with type 1 diabetes are relatively subtle. In terms of effect sizes, these are at best large enough to distinguish the patient group from the control group, but not large enough to classify an individual subject as being patient or control.”
“[T]he subtle cognitive decrements in speed of information processing and mental flexibility found in diabetic patients are not merely caused by acute metabolic derangements or psychological factors, but point to end-organ damage in the central nervous system. Although some uncertainty remains about the exact pathogenesis, several mechanisms through which diabetes may affect the brain have now been identified […] The issue whether or not repeated episodes of severe hypoglycaemia result in permanent mild cognitive impairment has been debated extensively in the literature. […] The meta-analysis on the effect of type 1 diabetes on cognition (1) does not support the idea that there are important negative effects from recurrent episodes of severe hypoglycaemia on cognitive functioning, and large prospective studies did not confirm the earlier observations […] there is no evidence for a linear relationship between recurrent episodes of hypoglycaemia and permanent brain dysfunction in adults. […] Cerebral microvascular pathology in diabetes may result in a decrease of regional cerebral blood flow and an alteration in cerebral metabolism, which could partly explain the occurrence of cognitive impairments. It could be hypothesised that vascular pathology disrupts white-matter integrity in a way that is akin to what one sees in peripheral neuropathy and as such could perhaps affect the integrity of neurotransmitter systems and as a consequence limits cognitive efficiency. These effects are likely to occur diffusely across the brain. Indeed, this is in line with MRI findings and other reports.”
“[An] important issue is the interaction between different disease variables. In particular, patients with diabetes onset before the age of 5 […] and patients with advanced microangiopathy might be more sensitive to the effects of hypoglycaemic episodes or elevated HbA1c levels. […] decrements in cognitive function have been observed as early as 2 years after the diagnosis (63). It is important to consider the possibility that the developing brain is more vulnerable to the effect of diabetes […] Diabetes has a marked effect on brain function and structure in children and adolescents. As a group, diabetic children are more likely to perform more poorly than their nondiabetic peers in the classroom and earn lower scores on measures of academic achievement and verbal intelligence. Specialized neuropsychological testing reveals evidence of dysfunction in a variety of cognitive domains, including sustained attention, visuoperceptual skills, and psychomotor speed. Children diagnosed early in life – before 7 years of age – appear to be most vulnerable, showing impairments on virtually all types of cognitive tests, with learning and memory skills being particularly affected. Results from neurophysiological, cerebrovascular, and neuroimaging studies also show evidence of CNS anomalies. Earlier research attributed diabetes-associated brain dysfunction to episodes of recurrent hypoglycemia, but more recent studies have generally failed to find strong support for that view.”
“[M]ethodological issues notwithstanding, extant research on diabetic children’s brain function has identified a number of themes […]. All other things being equal, children diagnosed with type 1 diabetes early in life – within the first 5–7 years of age – have the greatest risk of manifesting neurocognitive dysfunction, the magnitude of which is greater than that seen in children with a later onset of diabetes. The development of brain dysfunction seems to occur within a relatively brief period of time, often appearing within the first 2–3 years following diagnosis. It is not limited to performance on neuropsychological tests, but is manifested on a wide range of electrophysiological measures as marked neural slowing. Somewhat surprisingly, the magnitude of these effects does not seem to worsen appreciably with increasing duration of diabetes – at least through early adulthood. […] As a group, diabetic children earn somewhat lower grades in school as compared to their nondiabetic classmates, are more likely to fail or repeat a grade, perform more poorly on formal tests of academic achievement, and have lower IQ scores, particularly on tests of verbal intelligence.”
“The most compelling evidence for a link between diabetes and poorer school outcomes has been provided by a Swedish population-based register study involving 5,159 children who developed diabetes between July 1997 and July 2000 and 1,330,968 nondiabetic children […] Those who developed diabetes very early in life (diagnosis before 2 years of age) had a significantly increased risk of not completing school as compared to either diabetic patients diagnosed after that age or to the reference population. Small, albeit statistically reliable between-group differences were noted in school marks, with diabetic children, regardless of age at diagnosis, consistently earning somewhat lower grades. Of note is their finding that the diabetic sample had a significantly lower likelihood of getting a high mark (passed with distinction or excellence) in two subjects and was less likely to take more advanced courses. The authors conclude that despite universal access to active diabetes care, diabetic children – particularly those with a very early disease onset – had a greatly increased risk of somewhat lower educational achievement […] Similar results have been reported by a number of smaller studies […] in the prospective Melbourne Royal Children’s Hospital (RCH) cohort study (22), […] only 68% of [the] diabetic sample completed 12 years of school, as compared to 85% of the nondiabetic comparison group […] Children with diabetes, especially those with an earlier onset, have also been found to require more remedial educational services and to be more likely to repeat a grade (25–28), to earn lower school grades over time (29), to experience somewhat greater school absenteeism (28, 30–32), to have a two to threefold increase in rates of depression (33– 35), and to manifest more externalizing behavior problems (25).”
“Children with diabetes have a greatly increased risk of manifesting mild neurocognitive dysfunction. This is an incontrovertible fact that has emerged from a large body of research conducted over the past 60 years […]. There is, however, less agreement about the details. […] On standardized tests of academic achievement, diabetic children generally perform somewhat worse than their healthy peers […] Performance on measures of verbal intelligence – particularly those that assess vocabulary knowledge and general information about the world – is frequently compromised in diabetic children (9, 14, 26, 40) and in adults (41) with a childhood onset of diabetes. The few studies that have followed subjects over time have noted that verbal IQ scores tend to decline as the duration of diabetes increases (13, 15, 29). These effects appear to be more pronounced in boys and in those children with an earlier onset of diabetes. Whether this phenomenon is a marker of cognitive decline or whether it reflects a delay in cognitive development cannot yet be determined […] it is possible, but remains unproven, that psychosocial processes (e.g., school absence, depression, distress, externalizing problems) (42), and/or multiple and prolonged periods of classroom inattention and reduced motivation secondary to acute and prolonged episodes of hypoglycemia (43–45) may be contributing to the poor academic outcomes characteristic of children with diabetes. Although it may seem more reasonable to attribute poorer school performance and lower IQ scores to diabetes-associated disruption of specific neurocognitive processes (e.g., attention, learning, memory) secondary to brain dysfunction, there is little compelling evidence to support that possibility at the present time.”
“Children and adults who develop diabetes within the first 5–7 years of life may show moderate cognitive dysfunction that can affect all cognitive domains, although the specific pattern varies, depending both on the cognitive domain assessed and on the child’s age at assessment. Data from a recent meta-analysis of 19 pediatric studies have indicated that effect sizes tend to range between ∼ 0.4 and 0.5 for measures of learning, memory, and attention, but are lower for other cognitive domains (47). For the younger child with an early onset of diabetes, decrements are particularly pronounced on visuospatial tasks that require copying complex designs, solving jigsaw puzzles, or using multi-colored blocks to reproduce designs, with girls more likely to earn lower scores than boys (8). By adolescence and early adulthood, gender differences are less apparent and deficits occur on measures of attention, mental efficiency, learning, memory, eye–hand coordination, and “executive functioning” (13, 26, 40, 48–50). Not only do children with an early onset of diabetes often – but not invariably – score lower than healthy comparison subjects, but a subset earn scores that fall into the “clinically impaired” range […]. According to one estimate, the prevalence of clinically significant impairment is approximately four times higher in those diagnosed within the first 6 years of life as compared to either those diagnosed after that age or to nondiabetic peers (25 vs. 6%) (49). Nevertheless, it is important to keep in mind that not all early onset diabetic children show cognitive dysfunction, and not all tests within a particular cognitive domain differentiate diabetic from nondiabetic subjects.”
“Slowed neural activity, measured at rest by electroencephalogram (EEG) and in response to sensory stimuli, is common in children with diabetes. On tests of auditory- or visual-evoked potentials (AEP; VEP), children and adolescents with more than a 2-year history of diabetes show significant slowing […] EEG recordings have also demonstrated abnormalities in diabetic adolescents in very good metabolic control. […] EEG abnormalities have also been associated with childhood diabetes. One large study noted that 26% of their diabetic subjects had abnormal EEG recordings, as compared to 7% of healthy controls […] diabetic children with EEG abnormalities recorded at diagnosis may be more likely to experience a seizure or coma (i.e., a severe hypoglycemic event) when blood glucose levels subsequently fall […] This intriguing possibility – that seizures occur in some diabetic children during hypoglycemia because of the presence of pre-existing brain dysfunction – requires further study.”
“A very large body of research on adults with diabetes now demonstrates that the risk of developing a wide range of neurocognitive changes – poorer cognitive function, slower neural functioning, abnormalities in cerebral blood flow and brain metabolites, and reductions or alterations in gray and white-brain matter – is associated with chronically elevated blood glucose values […] Taken together, the limited animal research on this topic […] provides quite compelling support for the view that even relatively brief bouts of chronically elevated blood glucose values can induce structural and functional changes to the brain. […] [One pathophysiological model proposed is] the “diathesis” or vulnerability model […] According to this model, in the very young child diagnosed with diabetes, chronically elevated blood glucose levels interfere with normal brain maturation at a time when those neurodevelopmental processes are particularly labile, as they are during the first 5–7 years of life […]. The resulting alterations in brain organization that occur during this “sensitive period” will not only lead to delayed cognitive development and lasting cognitive dysfunction, but may also induce a predisposition or diathesis that increases the individual’s sensitivity to subsequent insults to the brain, as could be initiated by the prolonged neuroglycopenia that occurs during an episode of hypoglycemia. Data from most, but not all, research are consistent with that view. […] Research is only now beginning to focus on plausible pathophysiological mechanisms.”
After having read these chapters, I’m now sort-of-kind-of wondering to which extent my autism was/is also at least partly diabetes-mediated. There’s no evidence linking autism and diabetes presented in the chapters, but you do start to wonder even so – the central nervous system is complicated.. If diabetes did play a role there, that would probably be an argument for not considering potential diabetes-mediated brain changes in me as ‘minor’ despite my somewhat higher than average IQ (just to be clear, a high observed IQ in an individual does not preclude the possibility that diabetes had a negative IQ-effect – we don’t observe the counterfactual – but a high observed IQ does make a potential IQ-lowering effect less likely to have happened, all else equal).
Some stuff from the chapters dealing with the UK:
“we now know that reducing the HbA1c too far and fast in some patients can be harmful . This is a particularly important issue, where primary care is paid through the Quality Outcomes Framework (QoF), a general practice “pay for performance” programme . A major item within QoF, is the proportion of patients below HbA1c criteria: such reporting is not linked to rates of hypoglycaemia, ambulance call outs or hospitalisation, i.e., a practice could receive a high payment through achieving the QoF target, but with a high hospitalisation/ambulance callout rate.”
“nationwide audit data for England 2009–2010 showed that […] targets for HbA1c (≤7.5%/58.5 mmol/mol), blood pressure (BP) (<140/80 mmHg) and total cholesterol (<4.0 mmol/l) were achieved in only 67 %, 69% and 41 % of people with T2D.”
One thing that is perhaps worth noting here before moving any further is that the fact that you have actual data on this stuff is in itself indicative of an at least reasonable standard of care, compared to many places; in a lot of countries you just don’t have data on this kind of stuff, and it seems highly unlikely to me that the default assumption should be that things are going great in places where you do not have data on this kind of thing. Denmark also, incidentally, has a similar audit system, the results of which I’ve discussed in some detail before here on the blog).
“Our local audit data shows that approximately 85–90 % of patients with diabetes are managed by GPs and practice nurses in Coventry and Warwickshire. Only a small proportion of newly diagnosed patients with T2D (typically around 5–10 %) who attend the DESMOND (Diabetes Education and Self-Management for Ongoing and Newly Diagnosed) education programme come into contact with some aspect of the specialist services . […] Payment by results (PBR) has […] actively, albeit indirectly, disincentivised primary care to seek opinion from specialist services . […] Large volumes of data are collected by various services ranging between primary care, local laboratory facilities, ambulance services, hospital clinics (of varying specialties), retinal screening services and several allied healthcare professionals. However, the majority of these systems are not unified and therefore result in duplication of data collection and lack of data utilisation beyond the purpose of collection. This can result in missed opportunities, delayed communication, inability to use electronic solutions (prompts, alerts, algorithms etc.), inefficient use of resources and patient fatigue (repeated testing but no apparent benefit). Thus, in the majority of the regions in England, the delivery of diabetes care is disjointed and lacks integration. Each service collects and utilises data for their own “narrow” purpose, which could be used in a holistic way […] Potential consequences of the introduction of multiple service providers are fragmentation of care, reductions in continuity of care and propagation of a reluctance to refer on to a more specialist service . […] There are calls for more integration and less fragmentation in health-care , yet so far, the major integration projects in England have revealed negligible, if any, benefits [25, 32]. […] to provide high quality care and reduce the cost burden of diabetes, any integrated diabetes care models must prioritise prevention and early aggressive intervention over downstream interventions (secondary and tertiary prevention).”
“It is estimated that 99 % of diabetes care is self-management […] people with diabetes spend approximately only 3 h a year with healthcare professionals (versus 8757 h of self-management)” [this is a funny way of looking at things, which I’d never really considered before.]
“In a traditional model of diabetes care the rigid divide between primary and specialist care is exacerbated by the provision of funding. For example the tariff system used in England, to pay for activity in specialist care, can create incentives for one part of the system to “hold on” to patients who might be better treated elsewhere. This system was originally introduced to incentivise providers to increase elective activity and reduce waiting times. Whilst it has been effective for improving access to planned care, it is not so well suited to achieving the continuity of care needed to facilitate integrated care .”
“Currently in the UK there is a miss-match between what the healthcare policies require and what the workforce is actually being trained for. […] For true integrated care in diabetes and the other long term condition specialties to work, the education and training needs for both general practitioners and hospital specialists need to be more closely aligned.”
The chapter on Germany (Baden-Württemberg):
“An analysis of the Robert Koch-Institute (RKI) from 2012 shows that more than 50 % of German people over 65 years suffer from at least one chronic disease, approximately 50 % suffer from two to four chronic diseases, and over a quarter suffer from five or more diseases . […] Currently the public sector covers the majority (77 %) of health expenditures in Germany […] An estimated number of 56.3 million people are living with diabetes in Europe . […] The mean age of the T2DM-cohort [from Kinzigtal, Germany] in 2013 was 71.2 years and 53.5 % were women. In 2013 the top 5 co-morbidities of patients with T2DM were essential hypertension (78.3 %), dyslipidaemia (50.5 %), disorders of refraction and accommodation (38.2 %), back pain (33.8 %) and obesity (33.3 %). […] T2DM in Kinzigtal was associated with mean expenditure of 5,935.70 € per person in 2013 (not necessarily only for diabetes care ) including 40 % from inpatient stays, 24 % from drug prescriptions, 19 % from physician remuneration in ambulatory care and the rest from remedies and adjuvants (e.g., insulin pen systems, wheelchairs, physiotherapy, etc.), work incapacity or rehabilitation.”
“Zhang et al.  […] reported that globally, 12 % of health expenditures […] per person were spent on diabetes in 2010. The expenditure varies by region, age group, gender, and country’s income level.”
“Over the years many approaches [have been] introduced to improve the quality and continuity of care for chronic diseases. […] the Dutch minister of health approved, in 2007, the introduction of bundled-care (known is the Netherlands as a ‘chain-of-care’) approach for integrated chronic care, with special attention to diabetes. […] With a bundled payment approach – or episode-based payment – multiple providers are reimbursed a single sum of money for all services related to an episode of care (e.g., hospitalisation, including a period of post-acute care). This is in contrast to a reimbursement for each individual service (fee-for-service), and it is expected that this will reduce the volume of services provided and consequently lead to a reduction in spending. Since in a fee-for-service system the reimbursement is directly related to the volume of services provided, there is little incentive to reduce unnecessary care. The bundled payment approach promotes [in theory… – US] a more efficient use of services  […] As far as efficiency […] is concerned, after 3 years of evaluation, several changes in care processes have been observed, including task substitution from GPs to practice nurses and increased coordination of care [31, 36], thus improving process costs. However, Elissen et al.  concluded that the evidence relating to changes in process and outcome indicators, remains open to doubt, and only modest improvements were shown in most indicators. […] Overall, while the Dutch approach to integrated care, using a bundled payment system with a mixed payer approach, has created a limited improvement in integration, there is no evidence that the approach has reduced morbidity and premature mortality: and it has come at an increased cost.”
“In 2013 Sweden spent the equivalent of 4,904 USD per capita on health [OECD average: 3,453 USD], with 84 % of the expenditure coming from public sources [OECD average: 73 %]. […] Similarly high proportions [of public spending] can be found in the Netherlands (88 %), Norway (85 %) and Denmark (84 %) . […] Sweden’s quality registers, for tracking the quality of care that patients receive and the corresponding outcomes for several conditions, are among the most developed across the OECD . Yet, the coordination of care for patients with complex needs is less good. Only one in six patients had contact with a physician or specialist nurse after discharge from hospital for stroke, again with substantial variation across counties. Fewer than half of patients with type 1 diabetes […] have their blood pressure adequately controlled, with a considerable variation (from 26 % to 68 %) across counties . […] at 260 admissions per 100,000 people aged over 80, avoidable hospital admissions for uncontrolled diabetes in Sweden’s elderly population are the sixth highest in the OECD, and about 1.5 times higher than in Denmark.”
“Waiting times [in Sweden] have long been a cause of dissatisfaction . In an OECD ranking of 2011, Sweden was rated second worst . […] Sweden introduced a health-care guarantee in 2005 [guaranteeing fast access in some specific contexts]. […] Most patients who appeal under the health-care guarantee and [are] prioritised in the “queue” ha[ve] acute conditions rather than medical problems as a consequence of an underlying chronic disease. Patients waiting for a hip replacement or a cataract surgery are cured after surgery and no life-long follow-up is needed. When such patients are prioritised, the long-term care for patients with chronic diseases is “crowded out,” lowering their priority and risking worse outcomes. The health-care guarantee can therefore lead to longer intervals between checkups, with difficulties in accessing health care if their pre-existing condition has deteriorated.”
“Within each region / county council the care of patients with diabetes is divided. Patients with type 1 diabetes get their care at specialist clinics in hospitals and the majority of patients with type 2 diabetes in primary care . Patients with type 2 diabetes who have severe complications are referred to the Diabetes Clinics at the hospital. Approximately 10 % of all patients with type 2 continue their care at the hospital clinics. They are almost always on insulin in high doses often in combination with oral agents but despite massive medication many of these patients have difficulties to achieve metabolic balance. Patients with advanced complications such as foot ulcers, macroangiopathic manifestations and treatment with dialysis are also treated at the hospitals.”
Do keep in mind here that even if only 10% of type 2 patients are treated in a hospital setting, type 2 patients may still make up perhaps half or more of the diabetes patients treated in a hospital setting; type 2 prevalence is much, much higher than type 1 prevalence. Also, in view of such treatment- and referral patterns the default assumption when doing comparative subgroup analyses should always be that the outcomes of type 2 patients treated in a hospital setting should be expected to be much worse than the outcomes of type 2 patients treated in general practice; they’re in much poorer health than the diabetics treated in general practice, or they wouldn’t be treated in a hospital setting in the first place. A related point is that regardless of how great the hospitals are at treating the type 2 patients (maybe in some contexts there isn’t actually much of a difference in outcomes between these patients and type 2 patients treated in general practice, even though you’d expect there to be one?), that option will usually not be scalable. Also, it’s to be expected that these patients are more expensive than the default type 2 patient treated by his GP [and they definitely are: “Only if severe complications arise [in the context of a type 2 patient] is the care shifted to specialised clinics in hospitals. […] these patients have the most expensive care due to costly treatment of for example foot ulcers and renal insufficiency”]; again, they’re sicker and need more comprehensive care. They would need it even if they did not get it in a hospital setting, and there are costs associated with under-treatment as well.
“About 90 % of the children [with diabetes in Sweden] are classified as having Type 1 diabetes based on positive autoantibodies and a few percent receive a diagnosis of “Maturity Onset Diabetes of the Young” (MODY) . Type 2 diabetes among children is very rare in Sweden.”
Lastly, some observations from the final chapter:
“The paradox that we are dealing with is that in spite of health professionals wanting the best for their patients on a patient by patient basis, the way that individuals and institutions are organised and paid, directly influences the clinical decisions that are made. […] Naturally, optimising personal care and the provider/purchaser-commissioner budget may be aligned, but this is where diabetes poses substantial problems from a health system point of view: The majority of adverse diabetes outcomes […] are many years in the future, so a system based on this year’s budget will often not prioritise the future […] Even for these adverse “diabetes” outcomes, other clinical factors contribute to the end result. […] attribution to diabetes may not be so obvious to those seeking ways to minimise expenditure.”
[I incidentally tried to get this point across in a recent discussion on SSC, but I’m not actually sure the point was understood, presumably because I did not explain it sufficiently clearly or go into enough detail. It is my general impression, on a related note, that many people who would like to cut down on the sort of implicit public subsidization of unhealthy behaviours that most developed economies to some extent engage in these days do not understand well enough the sort of problems that e.g. the various attribution problems and how to optimize ‘post-diagnosis care’ (even if what you want to optimize is the cost minimization function…) cause in specific contexts. As I hope my comments indicate in that thread, I don’t think these sorts of issues can be ignored or dealt with in some very simple manner – and I’m tempted to say that if you think they can, you don’t know enough about these topics. I say that as one of those people who would like people who engage in risky behaviours to pay a larger (health) risk premium than they currently do].
[Continued from above, …problems from a health system point of view:]
“Payment for ambulatory diabetes care , which is essentially the preventative part of diabetes care, usually sits in a different budget to the inpatient budget where the big expenses are. […] good evidence for reducing hospitalisation through diabetes integrated care is limited […] There is ample evidence [11, 12] where clinicians own, and profit from, other services (e.g., laboratory, radiology), that referral rates are increased, often inappropriately […] Under the English NHS, the converse exists, where GPs, either holding health budgets, or receiving payments for maintaining health budgets , reduce their referrals to more specialist care. While this may be appropriate in many cases, it may result in delays and avoidance of referrals, even when specialist care is likely to be of benefit. [this would be the under-treatment I was talking about above…] […] There is a mantra that fragmentation of care and reductions in continuity of care are likely to harm the quality of care , but hard evidence is difficult to obtain.”
“The problems outlined above, suggest that any health system that fails to take account of the need to integrate the payment system from both an immediate and long term perspective, must be at greater risk of their diabetes integration attempts failing and/or being unsustainable. […] There are clearly a number of common factors and several that differ between successful and less successful models. […] Success in these models is usually described in terms of hospitalisation (including, e.g., DKA, amputation, cardiovascular disease events, hypoglycaemia, eye disease, renal disease, all cause), metabolic outcomes (e.g., HbA1c ), health costs and access to complex care. Some have described patient related outcomes, quality of life and other staff satisfaction, but the methodology and biases have often not been open to scrutiny. There are some methodological issues that suggest that many of those with positive results may be illusory and reflect the pre-existing landscape and/or wider changes, particular to that locality. […] The reported “success” of intermediate diabetes clinics run by English General Practitioners with a Special Interest led to extension of the model to other areas. This was finally tested in a randomised controlled trial […] and shown to be a more costly model with no real benefit for patients or the system. Similarly in East Cambs and Fenland, the 1 year results suggested major reductions in hospitalisation and costs in practices participating fully in the integrated care initiative, compared with those who “engaged” later . However, once the trends in neighbouring areas and among those without diabetes were accounted for, it became clear that the benefits originally reported were actually due to wider hospitalisation reductions, not just in those with diabetes. Studies of hospitalisation /hospital costs that do not compare with rates in the non-diabetic population need to be interpreted with caution.”
“Kaiser Permanente is often described as a great diabetes success story in the USA due to its higher than peer levels of, e.g., HbA1c testing . However, in the 2015 HEDIS data, levels of testing, metabolic control achieved and complication rates show quality metrics lower than the English NHS, in spite of the problems with the latter . Furthermore, HbA1c rates above 9 % remain at approximately 20 %, in Southern California  or 19 % in Northern California , a level much higher than that in the UK […] Similarly, the Super Six model […] has been lauded as a success, as a result of reductions in patients with, e.g., amputations. However, these complications were in the bottom quartile of performance for these outcomes in England  and hence improvement would be expected with the additional diabetes resources invested into the area. Amputation rates remain higher than the national average […] Studies showing improvement from a low baseline do not necessarily provide a best practice model, but perhaps a change from a system that required improvement. […] Several projects report improvements in HbA1c […] improvements in HbA1c, without reports of hypoglycaemia rates and weight gain, may be associated with worse outcomes as suggested from the ACCORD trial .”
My list of quotes on goodreads now includes 1333 quotes; these days I update that list much more often than I update my quote collection here on the blog.
i. “The graveyards are full of people the world could not do without.” (Elbert Hubbard)
ii. “The greatest mistake you can make in life is to be continually fearing you will make one.” (-ll-)
iii. “Do not dump your woes upon people — keep the sad story of your life to yourself. Troubles grow by recounting them.” (-ll-)
iv. “One of the first essentials in securing a good-natured equanimity is not to expect too much of the people amongst whom you dwell.” (William Osler)
v. “L’originalité consiste à essayer de faire comme tout le monde sans y parvenir.” (Raymond Radiguet. I decided to just post the original here because I didn’t like the English translation of the quote on wikiquotes)
vi. “Life is short, even for those who live a long time, and we must live for the few who know and appreciate us, who judge and absolve us, and for whom we have the same affection and indulgence. The rest I look upon as a mere crowd, lively or sad, loyal or corrupt, from whom there is nothing to be expected but fleeting emotions, either pleasant or unpleasant, which leave no trace behind them. We ought to hate very rarely, as it is too fatiguing; remain indifferent to a great deal, forgive often and never forget.” (Sarah Bernhardt)
vii. “There are no foolish questions and no man becomes a fool until he has stopped asking questions.” (Charles Proteus Steinmetz)
viii. “When it is useful to them, men can believe a theory of which they know nothing more than its name.” (Vilfredo Pareto)
ix. “Opinions upon moral questions are more often the expression of strongly felt expediency than of careful ethical reasoning; and the opinions so formed by one generation become the conscientious convictions or the sacred instincts of the next.” (Robert Gascoyne-Cecil)
x. “The commonest error in politics is sticking to the carcass of dead policies.” (-ll-)
xi. “If man knew how women pass the time when they are alone, they’d never marry.” (William Sydney Porter)
xii. “I often say that when you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind; it may be the beginning of knowledge, but you have scarcely, in your thoughts, advanced to the stage of science, whatever the matter may be.” (William Thomson, 1st Baron Kelvin)
xiii. “I know that I am honest and sincere in my desire to do well; but the question is whether I know enough to accomplish what I desire.” (Grover Cleveland)
xiv. “A fine quotation is a diamond on the finger of a man of wit, and a pebble in the hand of a fool.” (Joseph Roux)
xv. “There are men who are willing to marry a woman they do not care about merely because she is admired by other men. Such a relation exists between many men and their thoughts.” (Otto Weininger)
xvi. “Great inventions are never, and great discoveries are seldom, the work of any one mind. Every great invention is really an aggregation of minor inventions, or the final step of a progression. It is not usually a creation, but a growth, as truly so as is the growth of the trees in the forest.” (Robert Henry Thurston)
xvii. “Conscience is, in most men, an anticipation of the opinions of others.” (Henry Taylor)
xviii. “There is no error so monstrous that it fails to find defenders among the ablest men.” (John Emerich Edward Dalberg-Acton)
xix. “Originality consists in thinking for yourself, not in thinking differently from other people.” (James Fitzjames Stephen)
xx. “Does there, I wonder, exist a being who has read all, or approximately all, that the person of average culture is supposed to have read, and that not to have read is a social sin? If such a being does exist, surely he is an old, a very old man.” (Arnold Bennett)
“as we age, we observe a greater heterogeneity of ability and health. The variation in, say, walking speed is far greater in a group of 70 year olds, than in a group on 20 year olds. This makes the study of ageing and the factors driving that heterogeneity of health and functional ability in old age vital. […] The study of the immune system across the lifespan has demonstrated that as we age the immune system undergoes a decline in function, termed immunosenescence. […] the decline in function is not universal across all aspects of the immune system, and neither is the magnitude of functional loss similar between individuals. The theory of inflammageing, which represents a chronic low grade inflammatory state in older people, has been described as a major consequence of immunosenescence, though lifestyle factors such as reduced physical activity and increased adiposity also play a major role […] In poor health, older people accumulate disease, described as multimorbidity. This in turn means traditional single system based health care becomes less valid as each system affected by disease impacts on other systems. This leads some older people to be at greater risk of adverse events such as disability and death. The syndrome of this increased vulnerability is described as frailty, and increasing fundamental evidence is emerging that suggests immunosenescence and inflammageing may underpin frailty […] Thus frailty is seen as one clinical manifestation of immunosenescence.”
The above quotes are from the book‘s preface. I gave it 3 stars on goodreads. I should probably, considering that this topic is mentioned in the preface, mention explicitly that the book doesn’t actually go into a lot of details about the downsides of ‘traditional single system based health care’; the book is mainly about immunology and related topics, and although it provides coverage of intervention studies etc., it doesn’t really provide detailed coverage about issues like the optimization of organizational structures/systems analysis etc.. The book I was currently reading while I started out writing this post – Integrated Diabetes Care – A Multidisciplinary Approach (blog coverage here) – is incidentally pretty much exclusively devoted to providing coverage of these sorts of topics (and it did a fine job).
If you have never read any sort of immunology text before the book will probably be unreadable to you – “It is aimed at fundamental scientists and clinicians with an interest in ageing or the immune system.” In my coverage below I have not made any efforts towards picking out quotes which would be particularly easy for the average reader to read and understand; this is another way of saying that the post is mainly written for my own benefit, perhaps even more so than is usually the case, not for the benefit of potential readers reading along here.
“Physiological ageing is associated with significant re-modelling of the immune system. Termed immunosenescence, age-related changes have been described in the composition, phenotype and function of both the innate and adaptive arms of the immune system. […] Neutrophils are the most abundant leukocyte in circulation […] The first step in neutrophil anti-microbial defence is their extravasation from the bloodstream and migration to the site of infection. Whilst age appears to have no effect upon the speed at which neutrophils migrate towards chemotactic signals in vitro , the directional accuracy of neutrophil migration to inflammatory agonists […] as well as bacterial peptides […] is significantly reduced . […] neutrophils from older adults clearly exhibit defects in several key defensive mechanisms, namely chemotaxis […], phagocytosis of opsonised pathogens […] and NET formation […]. Given this near global impairment in neutrophil function, alterations to a generic signalling element rather than defects in molecules specific to each anti-microbial defence strategy is likely to explain the aberrations in neutrophil function that occur with age. In support of this idea, ageing in rodents is associated with a significant increase in neutrophil membrane fluidity, which coincides with a marked reduction in neutrophil function […] ageing results in a reduction in NK cell production and proliferation […] Numerous studies have examined the impact of age […], with the general consensus that at the single cell level, NK cell cytotoxicity (NKCC) is reduced with age […] retrospective and prospective studies have reported relationships between low NK cell activity in older adults and (1) a past history of severe infection, (2) an increased risk of future infection, (3) a reduced probability of surviving infectious episodes and (4) infectious morbidity [49–51]. Related to this increased risk of infection, reduced NKCC prior to and following influenza vaccination in older adults has been shown to be associated with reduced protective anti-hemagglutinin titres, worsened health status and an increased incidence of respiratory tract infection […] Whilst age has no effect upon the frequency or absolute number of monocytes [54, 55], the composition of the monocyte pool is markedly different in older adults, who present with an increased frequency of non-classical and intermediate monocytes, and fewer classical monocytes when compared to their younger counterparts”.
“Via their secretion of growth factors, pro-inflammatory cytokines, and proteases, senescent cells compromise tissue homeostasis and function, and their presence has been causally implicated in the development of such age-associated conditions as sarcopenia and cataracts . Several studies have demonstrated a role for innate immune cells in the recognition and clearance of senescent cells […] ageing is associated with a low-grade systemic up-regulation of circulating inflammatory mediators […] Results from longitudinal-based studies suggest inflammageing is deleterious to human health with studies in older cohorts demonstrating that low-grade increases in the circulating levels of TNF-α , IL-6 […] and CRP  are associated with both all-cause […] and cause-specific […] mortality. Furthermore, inflammageing is a predictor of frailty  and is considered a major factor in the development of several age-related pathologies, such as atherosclerosis , Alzheimer’s disease  and sarcopenia .”
“Persistent viral infections, reduced vaccination responses, increased autoimmunity, and a rise in inflammatory syndromes all typify immune ageing. […] These changes can be in part attributed to the accumulation of highly differentiated senescent T cells, characterised by their decreased proliferative capacity and the activation of senescence signaling pathways, together with alterations in the functional competence of regulatory cells, allowing inflammation to go unchecked. […] Immune senescence results from defects in different leukocyte populations, however the dysfunction is most profound in T cells [6, 7]. The responses of T cells from aged individuals are typically slower and of a lower magnitude than those of young individuals […] while not all equally affected by age, the overall T cell number does decline dramatically as a result of thymic atrophy […] T cell differentiation is a highly complex process controlled not only by costimulation but also by the strength and duration of T cell receptor (TCR) signalling . Nearly all TCR signalling pathways have been found altered during ageing […] two phenotypically distinct subsets of B cells […] have been demonstrated to exert immunosuppressive functions. The frequency and function of both these Breg subsets declines with age”.
“The immune impairments in patients with chronic hyperglycemia resemble those seen during ageing, namely poor control of infections and reduced vaccination response .” [This is hardly surprising. ‘Hyperglycemia -> accelerated ageing’ seems generally to be a good (over-)simplified model in many contexts. To give another illustrative example from Czernik & Fowlkes text, “approximately 4–6 years of diabetes exposure in some children may be sufficient to increase skin AGEs to levels that would naturally accumulate only after ~25 years of chronological aging”].
“The term “immunosenescence” is commonly taken to mean age-associated changes in immune parameters hypothesized to contribute to increased susceptibility and severity of the older adult to infectious disease, autoimmunity and cancer. In humans, it is characterized by lower numbers and frequencies of naïve T and B cells and higher numbers and frequencies of late-differentiated T cells, especially CD8+ T cells, in the peripheral blood. […] Low numbers of naïve cells render the aged highly susceptible to pathogens to which they have not been previously exposed, but are not otherwise associated with an “immune risk profile” predicting earlier mortality. […] many of the changes, or most often, differences, in immune parameters of the older adult relative to the young have not actually been shown to be detrimental. The realization that compensatory changes may be developing over time is gaining ground […] Several studies have now shown that lower percentages and absolute numbers of naïve CD8+ T cells are seen in all older subjects whereas the accumulation of very large numbers of CD8+ late-stage differentiated memory cells is seen in a majority but not in all older adults . The major difference between this majority of subjects with such accumulations of memory cells and those without is that the former are infected with human herpesvirus 5 (Cytomegalovirus, CMV). Nevertheless, the question of whether CMV is associated with immunosenescence remains so far uncertain as no causal relationship has been unequivocally established . Because changes are seen rapidly after primary infection in transplant patients  and infants , it is highly likely that CMV does drive the accumulation of CD8+ late-stage memory cells, but the relationship of this to senescence remains unclear. […] In CMV-seropositive people, especially older people, a remarkably high fraction of circulating CD8+ T lymphocytes is often found to be specific for CMV. However, although the proportion of naïve CD8+ T cells is lower in the old than the young whether or not they are CMV-infected, the gross accumulation of late-stage differentiated CD8+ T cells only occurs in CMV-seropositive individuals […] It is not clear whether this is adaptive or pathological […] The total CMV-specific T-cell response in seropositive subjects constitutes on average approximately 10 % of both the CD4+ and CD8+ memory compartments, and can be far greater in older people. […] there are some published data suggesting that that in young humans or young mice, CMV may improve immune responses to some antigens and to influenza virus, probably by way of increased pro-inflammatory responses […] observations suggest that the effect of CMV on the immune system may be highly dependent also on an individuals’ age and circumstances, and that what is viewed as ageing is in fact later collateral damage from immune reactivity that was beneficial in earlier life [47, 48]. This is saying nothing more than that the same immune pathology that always accompanies immune responses to acute viruses is also caused by CMV, but over a chronic time scale and usually subclinical. […] data suggest that the remodeling of the T-cell compartment in the presence of a latent infection with CMV represents a crucial adaptation of the immune system towards the chronic challenge of lifelong CMV.”
The authors take issue with using the term ‘senescence’ to describe some of the changes discussed above, because this term by definition should be employed only in the context of changes that are demonstrably deleterious to health. It should be kept in mind in this context that insufficient immunological protection against CMV in old age could easily be much worse than the secondary inflammatory effects, harmful though these may well be; CMV in the context of AIDS, organ transplantation (“CMV is the most common and single most important viral infection in solid organ transplant recipients” – medscape) and other disease states involving compromised immune systems can be really bad news (“Disease caused by human herpesviruses tends to be relatively mild and self-limited in immunocompetent persons, although severe and quite unusual disease can be seen with immunosuppression.” Holmes et al.)
“The role of CMV in the etiology of […] age-associated diseases is currently under intensive investigation […] in one powerful study, the impact of CMV infection on mortality was investigated in a cohort of 511 individuals aged at least 65 years at entry, who were then followed up for 18 years. Infection with CMV was associated with an increased mortality rate in healthy older individuals due to an excess of vascular deaths. It was estimated that those elderly who were CMV- seropositive at the beginning of the study had a near 4-year reduction in lifespan compared to those who were CMV-seronegative, a striking result with major implications for public health . Other data, such as those from the large US NHANES-III survey, have shown that CMV seropositivity together with higher than median levels of the inflammatory marker CRP correlate with a significantly lower 10-year survival rate of individuals who were mostly middle-aged at the start of the study . Further evidence comes from a recently published Newcastle 85+ study of the immune parameters of 751 octogenarians investigated for their power to predict survival during a 65-month follow-up. It was documented that CMV-seropositivity was associated with increased 6-year cardiovascular mortality or death from stroke and myocardial infarction. It was therefore concluded that CMV-seropositivity is linked to a higher incidence of coronary heart disease in octogenarians and that senescence in both the CD4+ and CD8+ T-cell compartments is a predictor of overall cardiovascular mortality”.
“The incidence and severity of many infections are increased in older adults. Influenza causes approximately 36,000 deaths and more than 100,000 hospitalizations in the USA every year […] Vaccine uptake differs tremendously between European countries with more than 70 % of the older population being vaccinated against influenza in The Netherlands and the United Kingdom, but below 10 % in Poland, Latvia and Estonia during the 2012–2013 season […] several systematic reviews and meta-analyses have estimated the clinical efficacy and/or effectiveness of a given influenza vaccine, taking into consideration not only randomized trials, but also cohort and case-control studies. It can be concluded that protection is lower in the old than in young adults […] [in one study including “[m]ore than 84,000 pneumococcal vaccine-naïve persons above 65 years of age”] the effect of age on vaccine efficacy was studied and the statistical model showed a decline of vaccine efficacy for vaccine-type CAP and IPD [Invasive Pneumococcal Disease] from 65 % (95 % CI 38–81) in 65-year old subjects, to 40 % (95 % CI 17–56) in 75-year old subjects […] The most effective measure to prevent infectious disease is vaccination. […] Over the last 20–30 years tremendous progress has been achieved in developing novel/improved vaccines for children, but a lot of work still needs to be done to optimize vaccines for the elderly.”
The book provides a good overview of studies and clinical trials which have attempted to improve the coordination of diabetes treatment in specific areas. The book covers research from all over the world – the UK, the US, Hong Kong, South Africa, Germany, Netherlands, Sweden, Australia. The language of the publication is quite good, considering the number of non-native English speaking contributors. An at least basic understanding of medical statistics is probably required for one to properly read and understand this book in full.
The book is quite good if you want to understand how people have tried to improve (mainly type 2) diabetes treatment ‘from an organizational point of view’ (the main focus here is not on new treatment options, but on how to optimize care delivery and make the various care providers involved work better together, in a way that improves outcomes for patients (at an acceptable cost?), which is to a large extent an organizational problem), but it’s actually also probably quite a nice book if you simply want to know more about how diabetes treatment systems differ across countries; the contributors don’t assume that the readers know how e.g. the Swedish approach to diabetes care differs from that of e.g. Pennsylvania, so many chapters contain interesting details on how specific countries/health care providers handle specific aspects of e.g. care delivery or finance.
What people mean by ‘integrated care’ varies a bit depending on whom you ask (patients and service providers may emphasize different dimensions when thinking about these topics), as should also be clear from the quotes below; however I assumed it might be a good idea to start out the post with the quote above, so that people who might have no idea what ‘integrated diabetes care’ is did not start out reading the post completely in the dark. In short, a big problem in health service delivery contexts is that care provision is often fragmented and uncoordinated, for many reasons. Ideally you might like doctors working in general practice to collaborate smoothly and efficiently with hospital staff and various other specialists involved in diabetes care (…and perhaps also with social services and mental health care providers…), but that kind of coordination often doesn’t happen, leading to what may well be sub-optimal care provision. Collaboration and a ‘desirable’ (whatever that might mean) level of coordination between service providers doesn’t happen automatically; it takes money, effort and a lot of other things (that the book covers in some detail…) to make it happen – and so often it doesn’t happen, at least there’s a lot of room for improvement even in places where things work comparatively well. Some quotes from the book on these topics:
“it is clear that in general, wherever you are in the world, service delivery is now fragmented . Such fragmentation is a manifestation of organisational and financial barriers, which divide providers at the boundaries of primary and secondary care, physical and mental health care, and between health and social care. Diverse specific organisational and professional cultures, and differences in terms of governance and accountability also contribute to this fragmentation . […] Many of these deficiencies are caused by organisational problems (barriers, silo thinking, accountability for budgets) and are often to the detriment of all of those involved: patients, providers and funders – in extreme cases – leading to lose-lose-lose-situations […] There is some evidence that integrated care does improve the quality of patient care and leads to improved health or patient satisfaction [10, 11], but evidence of economic benefits remain an issue for further research . Failure to improve integration and coordination of services along a “care continuum” can result in suboptimal outcomes (health and cost), such as potentially preventable hospitalisation, avoidable death, medication errors and adverse drug events [3, 12, 13].”
“Integrated care is often described as a continuum [10, 24], actually depicting the degree of integration. This degree can range from linkage, to coordination and integration , or segregation (absence of any cooperation) to full integration , in which the integrated organisation is responsible for the full continuum of care responsible for the full continuum of care […] this classification of integration degree can be expanded by introducing a second dimension, i.e., the user needs. User need should be defined by criteria, like stability and severity of condition, duration of illness (chronic condition), service needed and capacity for self-direction (autonomy). Accordingly, a low level of need will not require a fully integrated system, then [10, 24] […] Kaiser Permanente is a good example of what has been described as a “fully integrated system. […] A key element of Kaiser Permanente’s approach to chronic care is the categorisation of their chronically ill patients into three groups based on their degree of need“.
It may be a useful simplification to think along the lines of: ‘Higher degree of need = a higher level of integration becomes desirable/necessary. Disease complexity is closely related to degree of need.’ Some related observations from the book:
“Diabetes is a condition in which longstanding hyperglycaemia damages arteries (causing macrovascular, e.g., ischaemic heart, peripheral and cerebrovascular disease, and microvascular disease, e.g., retinopathy, nephropathy), peripheral nerves (causing neuropathy), and other structures such as skin (causing cheiroarthropathy) and the lens (causing cataracts). Different degrees of macrovascular, neuropathic and cutaneous complications lead to the “diabetic foot.” A proportion of patients, particularly with type 2 diabetes have metabolic syndrome including central adiposity, dyslipidaemia, hypertension and non alcoholic fatty liver disease. Glucose management can have severe side effects, particularly hypoglycaemia and weight gain. Under-treatment is not only associated with long term complications but infections, vascular events and increased hospitalisation. Absence of treatment in type 1 diabetes can rapidly lead to diabetic keto-acidosis and death. Diabetes doubles the risk for depression, and on the other hand, depression may increase the risk for hyperglycaemia and finally for complications of diabetes . Essentially, diabetes affects every part of the body once complications set in, and the crux of diabetes management is to normalise (as much as possible) the blood glucose and manage any associated risk factors, thereby preventing complications and maintaining the highest quality of life. […] glucose management requires minute by minute, day by day management addressing the complexity of diabetes, including clinical and behavioural issues. While other conditions also have the patient as therapist, diabetes requires a fully empowered patient with all of the skills, knowledge and motivation every hour of the waking day. A patient that is fully engaged in self-management, and has support systems, is empowered to manage their diabetes and will likely experience better outcomes compared with those who do not have access to this support. […] in diabetes, the boundaries between primary care and secondary care are blurred. Diabetes specialist services, although secondary care, can provide primary care, and there are GPs, diabetes educators, and other ancillary providers who can provide a level of specialist care.”
In short, diabetes is a complex disease – it’s one of those diseases where a significant degree of care integration is likely to be necessary in order to achieve even close to optimal outcomes. A little more on these topics:
“The unique challenge to providers is to satisfy two specific demands in diabetes care. The first is to anticipate and recognize the onset of complications through comprehensive diabetes care, which demands meticulous attention to a large number of process-of-care measures at each visit. The second, arguably greater challenge for providers is to forestall the development of complications through effective diabetes care, which demands mastery over many different skills in a variety of distinct fields in order to achieve performance goals covering multiple facets of management. Individually and collectively, these dual challenges constitute a virtually unsustainable burden for providers. That is because (a) completing all the mandated process measures for comprehensive care requires far more time than is traditionally available in a single patient visit; and (b) most providers do not themselves possess skills in all the ancillary disciplines essential for effective care […] Diabetes presents patients with similarly unique dual challenges in mastering diabetes self-management with self-awareness, self-empowerment and self-confidence. Comprehensive Diabetes Self-Management demands the acquisition of a variety of skills in order to fulfil a multitude of tasks in many different areas of daily life. Effective Diabetes Self-Management, on the other hand, demands constant vigilance, consistent discipline and persistent attention over a lifetime, without respite, to nutritional self-discipline, monitoring blood glucose levels, and adherence to anti-diabetic medication use. Together, they constitute a burden that most patients find difficult to sustain even with expert assistance, and all-but-impossible without it.”
“Care coordination achieves critical importance for diabetes, in particular, because of the need for management at many different levels and locations. At the most basic level, the symptomatic management of acute hypo- and hyperglycaemia often devolves to the PCP [primary care provider], even when a specialist oversees more advanced strategies for glycaemic management. At another level, the wide variety of chronic complications requires input from many different specialists, whereas hospitalizations for acute emergencies often fall to hospitalists and critical care specialists. Thus, diabetes care is fraught with the potential for sometimes conflicting, even contradictory management strategies, making care coordination mandatory for success.”
“Many of the problems surrounding the provision of adequate person-centred care for those with diabetes revolve around the pressures of clinical practice and a lack of time. Good diabetes management requires attention to a number of clinical parameters
1. (Near) Normalization of blood glucose
2. Control of co-morbidities and risk factors
3. Attainment of normal growth and development
4. Prevention of Acute Complications
5. Screening for Chronic Complications
To fit all this and a holistic, patient-centred collaborative approach into a busy general practice, the servicing doctor and other team members must understand that diabetes cannot be “dealt with” coincidently during a patient consultation for an acute condition.”
“Implementation of the team model requires sharing of tasks and responsibilities that have traditionally been the purview of the physician. The term “team care” has traditionally been used to indicate a group of health-care professionals such as physicians, nurses, pharmacists, or social workers, who work together in caring for a group of patients. In a 2006 systematic review of 66 trials testing 11 strategies for improving glycaemic control for patients with diabetes, only team care and case management showed a significant impact on reducing HbA1c levels .”
Moving on, I found the chapter about Hong Kong interesting, for several reasons. The quality of Scandinavian health registries are probably widely known in the epidemiological community, but I was not aware of Hong Kong’s quality of diabetes data, and data management strategies, which seems to be high. Nor was I aware of some of the things they’ve discovered while analyzing those data. A few quotes from that part of the coverage:
“Given the volume of patients in the clinics, the team’s earliest work from the HKDR [Hong Kong Diabetes Registry, US] prioritized the development of prediction models, to allow for more efficient, data-driven risk stratification of patients. After accruing data for a decade on over 7000 patients, the team established 5-year probabilities for major diabetes-related complications as defined by the International Code for Diseases retrieved from the CMS [Clinical Management System, US]. These included end stage renal disease , stroke , coronary heart disease , heart failure , and mortality . These risk equations have a 70–90 % sensitivity and specificity of predicting outcomes based on the parameters collected in the registry.”
“The lifelong commitments to medication adherence and lifestyle modification make diabetes self-management both physically and emotionally taxing. The psychological burdens result from insulin injection, self-monitoring of blood glucose, dietary restriction, as well as fear of complications, which may significantly increase negative emotions in patients with diabetes. Depression, anxiety, and distress are prevalent mental afflictions found in patients with diabetes […] the prevalence of depression was 18.3 % in Hong Kong Chinese patients with type 2 diabetes. Furthermore, depression was associated with poor glycaemic control and self-reported hypoglycaemia, in part due to poor adherence […] a prospective study involving 7835 patients with type 2 diabetes without cardiovascular disease (CVD) at baseline […] found that [a]fter adjusting for conventional risk factors, depression was independently associated with a two to threefold increase in the risk of incident CVD .”
“Diabetes has been associated with increased cancer risk, but the underlying mechanism is poorly understood. The linkage between the longitudinal clinical data within the HKDR and the cancer outcome data in the CMS has provided important observational findings to help elucidate these connections. Detailed pharmacoepidemiological analyses revealed attenuated cancer risk in patients treated with insulin and oral anti-diabetic drugs compared with non-users of these drugs”
“Among the many challenges of patient self-management, lack of education and empowerment are the two most cited barriers . Sufficient knowledge is unquestionably important in self-care, especially in people with low health literacy and limited access to diabetes education. Several systematic reviews [have] showed that self-management education with comprehensive lifestyle interventions improved glycaemic and cardiovascular risk factor control [60–62].”
“Clinical trials are expensive because of the detail and depth of data required on each patient, which often require separate databases to be developed outside of the usual-care electronic medical records or paper-based chart systems. These databases must be built, managed, and maintained from scratch every time, often requiring double-entry of data by research staff. The JADE [Joint Asia Diabetes Evaluation] programme provides a more efficient means of collecting the key clinical variables in its comprehensive assessments, and allows researchers to add new fields as necessary for research purposes. This obviates the need for redundant entry into non-clinical systems, as the JADE programme is simultaneously a clinical care tool and prospective database. […] A large number of trials fail because of inadequate recruitment . The JADE programme has allowed for ready identification of eligible clinical trial participants because of its detailed clinical database. […] One of the greatest challenges in clinical trials is maintaining the contact between researchers and patients over many years. […] JADE facilitates long-term contact with the patient, as part of routine periodic follow-up. This also allows researchers to evaluate longer term outcomes than many previous trials, given the great expense in maintaining databases for the tracking of longitudinal outcomes.”
Lastly, some stuff on cost and related matters from the book:
“Diabetes imposes a massive economic burden on all healthcare systems, accounting for 11 % of total global healthcare expenditure on adults in 2013.”
“Often, designated service providers institute managed care programmes to standardize and control care rendered in a safe and cost-effective manner. However, many of these programmes concentrate on cost-savings rather than patient service utilization and improved clinical outcomes. [this part of the coverage is from South Africa, but these kinds of approaches are definitely not limited to SA – US] […] While these approaches may save some costs in the short-term, Managed Care Programmes which do not address patient outcomes nor reduce long term complications, ignore the fact that that the majority of the costs for treating diabetes, even in the medium term, are due to the treatment of acute and chronic complications and for inpatient hospital care . Additionally, it is well established that poor long-term clinical outcomes increase the cost burden of managing the patient with diabetes by up to 250 %. […] overall, the costs of medication, including insulin, accounts for just 7 % of all healthcare costs related to diabetes [this number varies across countries, I’ve seen estimates of 15% in the past – and as does the out-pocket share of that cost – but the costs of medications constitute a relatively small proportion of the total costs of diabetes everywhere you look, regardless of health care system and prevalence. If you include indirect costs as well, which you should, this becomes even more obvious – US]”
“[A] study of the Economic Costs of Diabetes in the U.S. in 2012  showed that for people with diabetes, hospital inpatient care accounted for 43 % of the total medical cost of diabetes.”
“There is some evidence of a positive impact of integrated care programmes on the quality of patient care [10, 34]. There is also a cautious appraisal that warns that “Even in well-performing care groups, it is likely to take years before cost savings become visible” […]. Based on a literature review from 1996 to 2004 Ouwens et al.  found out that integrated care programmes seemed to have positive effects on the quality of care. […] because of the variation in definitions of integrated care programmes and the components used cover a broad spectrum, the results should be interpreted with caution. […] In their systematic review of the effectiveness of integrated care Ouwens et al.  could report on only seven (about 54 %) reviews which had included an economic analysis. Four of them showed financial advantages. In their study Powell Davies et al.  found that less than 20 % of studies that measured economic outcomes found a significant positive result. Similarly, de Bruin et al.  evaluated the impact of disease management programmes on health-care expenditures for patients with diabetes, depression, heart failure or chronic obstructive pulmonary disease (COPD). Thirteen studies of 21 showed cost savings, but the results were not statistically significant, or not actually tested for significance. […] well-designed economic evaluation studies of integrated care approaches are needed, in particular in order to support decision-making on the long-term financing of these programmes [30, 39]. Savings from integrated care are only a “hope” as long as there is no carefully designed economic analysis with a kind of full-cost accounting.”
“The cost-effectiveness of integrated care for patients with diabetes depends on the model of integrated care used, the system in which it is used, and the time-horizon chosen . Models of cost benefit for using health coaching interventions for patients with poorly controlled diabetes have generally found a benefit in reducing HbA1c levels, but at the cost of paying for the added cost of health coaching which is not offset in the short term by savings from emergency department visits and hospitalizations […] An important question in assessing the cost of integrated care is whether it needs to be cost-saving or cost-neutral to be adopted, or is it enough to increase quality-adjusted life years (QALYs) at a “reasonable” cost (usually pegged at between $30,000 and $60,000 per QALY saved). Most integrated care programmes for patients with diabetes that have been evaluated for cost-effectiveness would meet this more liberal criterion […] In practice, integrated care programmes for patients with diabetes are often part of generalized programmes of care for patients with other chronic medical conditions, making the allocation of costs and savings with respect to integrated care for diabetes difficult to estimate. At this point, integrated care for patients with diabetes appears to be a widely accepted goal. The question becomes: which model of integrated care is most effective at reasonable cost? Answering this question depends both on what costs are included and what outcomes are measured; the answers may vary among different patient populations and different care systems.”
i. “You can no more make someone tell the truth than you can force someone to love you.” (Philip Roth, Portnoy’s Complaint)
ii. “Every generation laughs at the old fashions, but follows religiously the new.” (Henry David Thoreau, Walden)
iii. “Nature is our kindest friend and best critic in experimental science if we only allow her intimations to fall unbiased on our minds.” (Michael Faraday)
iv. “If you stroke a cat, it will purr; and, as inevitably, if you praise a man, a sweet expression of delight will appear on his face; and even though the praise is a palpable lie, it will be welcome, if the matter is one on which he prides himself.” (Schopenhauer)
v. “Nature answers only when she is questioned.” (Friedrich Gustav Jakob Henle)
vi. “Tyranny and despotism can be exercised by many, more rigorously, more vigorously, and more severely, than by one.” (Andrew Johnson)
vii. “It is hardly in human nature that a man should quite accurately gauge the limits of his own insight; but it is the duty of those who profit by his work to consider carefully where he may have been carried beyond it.” (William Kingdon Clifford, The Ethics of Belief)
viii. “Between two evils, choose neither; between two goods, choose both.” (Tryon Edwards, A Dictionary of Thoughts)
ix. “Any act often repeated soon forms a habit: and habit allowed, steadily gains in strength. — At first it may be but as the spider’s web, easily broken through, but if not resisted it soon binds us with chains of steel.” (-ll-)
x. “The prejudiced and obstinate man does not so much hold opinions, as his opinions hold him.” (-ll-)
xi. “We should be as careful of the books we read, as of the company we keep. The dead very often have more power than the living.” (-ll-)
xii. “Right actions for the future are the best apologies for wrong ones in the past – the best evidence of regret for them that we can offer, or the world receive.” (-ll-)
xiii. “It remains a lesson to all time, that goodness, though the indispensable adjunct to knowledge, is no substitute for it; that when conscience undertakes to dictate beyond its province, the result is only the more monstrous.” (James Anthony Froude)
xiv. “I ask no one who may read this book to accept my views. I ask him to think for himself.” (Henry George, Social Problems)
xv. “The bitterest tears shed over graves are for words left unsaid and deeds left undone.” (Harriet Beecher Stowe)
xvi. “The greater the interest involved in a truth the more careful, self-distrustful, and patient should be the inquiry.” (-ll-)
xvii. “To a person uninstructed in natural history, his country or sea-side stroll is a walk through a gallery filled with wonderful works of art, nine-tenths of which have their faces turned to the wall.” (Thomas Henry Huxley)
xviii. “I can assure you that there is the greatest practical benefit in making a few failures early in life. You learn that which is of inestimable importance — that there are a great many people in the world who are just as clever as you are.” (-ll-)
xix. “Whoever is not in the possession of leisure can hardly be said to possess independence.” (Herman Melville)
xx. “Truth does not need to borrow garments from falsehood.” (José Rizal)
i. Fire works a little differently than people imagine. A great ask-science comment. See also AugustusFink-nottle’s comment in the same thread.
iii. I was very conflicted about whether to link to this because I haven’t actually spent any time looking at it myself so I don’t know if it’s any good, but according to somebody (?) who linked to it on SSC the people behind this stuff have academic backgrounds in evolutionary biology, which is something at least (whether you think this is a good thing or not will probably depend greatly on your opinion of evolutionary biologists, but I’ve definitely learned a lot more about human mating patterns, partner interaction patterns, etc. from evolutionary biologists than I have from personal experience, so I’m probably in the ‘they-sometimes-have-interesting-ideas-about-these-topics-and-those-ideas-may-not-be-terrible’-camp). I figure these guys are much more application-oriented than were some of the previous sources I’ve read on related topics, such as e.g. Kappeler et al. I add the link mostly so that if I in five years time have a stroke that obliterates most of my decision-making skills, causing me to decide that entering the dating market might be a good idea, I’ll have some idea where it might make sense to start.
“Are stereotypes accurate or inaccurate? We summarize evidence that stereotype accuracy is one of the largest and most replicable findings in social psychology. We address controversies in this literature, including the long-standing and continuing but unjustified emphasis on stereotype inaccuracy, how to define and assess stereotype accuracy, and whether stereotypic (vs. individuating) information can be used rationally in person perception. We conclude with suggestions for building theory and for future directions of stereotype (in)accuracy research.”
A few quotes from the paper:
“Demographic stereotypes are accurate. Research has consistently shown moderate to high levels of correspondence accuracy for demographic (e.g., race/ethnicity, gender) stereotypes […]. Nearly all accuracy correlations for consensual stereotypes about race/ethnicity and gender exceed .50 (compared to only 5% of social psychological findings; Richard, Bond, & Stokes-Zoota, 2003).[…] Rather than being based in cultural myths, the shared component of stereotypes is often highly accurate. This pattern cannot be easily explained by motivational or social-constructionist theories of stereotypes and probably reflects a “wisdom of crowds” effect […] personal stereotypes are also quite accurate, with correspondence accuracy for roughly half exceeding r =.50.”
“We found 34 published studies of racial-, ethnic-, and gender-stereotype accuracy. Although not every study examined discrepancy scores, when they did, a plurality or majority of all consensual stereotype judgments were accurate. […] In these 34 studies, when stereotypes were inaccurate, there was more evidence of underestimating than overestimating actual demographic group differences […] Research assessing the accuracy of miscellaneous other stereotypes (e.g., about occupations, college majors, sororities, etc.) has generally found accuracy levels comparable to those for demographic stereotypes”
“A common claim […] is that even though many stereotypes accurately capture group means, they are still not accurate because group means cannot describe every individual group member. […] If people were rational, they would use stereotypes to judge individual targets when they lack information about targets’ unique personal characteristics (i.e., individuating information), when the stereotype itself is highly diagnostic (i.e., highly informative regarding the judgment), and when available individuating information is ambiguous or incompletely useful. People’s judgments robustly conform to rational predictions. In the rare situations in which a stereotype is highly diagnostic, people rely on it (e.g., Crawford, Jussim, Madon, Cain, & Stevens, 2011). When highly diagnostic individuating information is available, people overwhelmingly rely on it (Kunda & Thagard, 1996; effect size averaging r = .70). Stereotype biases average no higher than r = .10 ( Jussim, 2012) but reach r = .25 in the absence of individuating information (Kunda & Thagard, 1996). The more diagnostic individuating information people have, the less they stereotype (Crawford et al., 2011; Krueger & Rothbart, 1988). Thus, people do not indiscriminately apply their stereotypes to all individual members of stereotyped groups.” (Funder incidentally talked about this stuff as well in his book Personality Judgment).
One thing worth mentioning in the context of stereotypes is that if you look at stuff like crime data – which sadly not many people do – and you stratify based on stuff like country of origin, then the sub-group differences you observe tend to be very large. Some of the differences you observe between subgroups are not in the order of something like 10%, which is probably the sort of difference which could easily be ignored without major consequences; some subgroup differences can easily be in the order of one or two orders of magnitude. The differences are in some contexts so large as to basically make it downright idiotic to assume there are no differences – it doesn’t make sense, it’s frankly a stupid thing to do. To give an example, in Germany the probability that a random person, about whom you know nothing, has been a suspect in a thievery case is 22% if that random person happens to be of Algerian extraction, whereas it’s only 0,27% if you’re dealing with an immigrant from China. Roughly one in 13 of those Algerians have also been involved in a case of ‘body (bodily?) harm’, which is the case for less than one in 400 of the Chinese immigrants.
v. Assessing Immigrant Integration in Sweden after the May 2013 Riots. Some data from the article:
“Today, about one-fifth of Sweden’s population has an immigrant background, defined as those who were either born abroad or born in Sweden to two immigrant parents. The foreign born comprised 15.4 percent of the Swedish population in 2012, up from 11.3 percent in 2000 and 9.2 percent in 1990 […] Of the estimated 331,975 asylum applicants registered in EU countries in 2012, 43,865 (or 13 percent) were in Sweden. […] More than half of these applications were from Syrians, Somalis, Afghanis, Serbians, and Eritreans. […] One town of about 80,000 people, Södertälje, since the mid-2000s has taken in more Iraqi refugees than the United States and Canada combined.”
“Coupled with […] macroeconomic changes, the largely humanitarian nature of immigrant arrivals since the 1970s has posed challenges of labor market integration for Sweden, as refugees often arrive with low levels of education and transferable skills […] high unemployment rates have disproportionately affected immigrant communities in Sweden. In 2009-10, Sweden had the highest gap between native and immigrant employment rates among OECD countries. Approximately 63 percent of immigrants were employed compared to 76 percent of the native-born population. This 13 percentage-point gap is significantly greater than the OECD average […] Explanations for the gap include less work experience and domestic formal qualifications such as language skills among immigrants […] Among recent immigrants, defined as those who have been in the country for less than five years, the employment rate differed from that of the native born by more than 27 percentage points. In 2011, the Swedish newspaper Dagens Nyheter reported that 35 percent of the unemployed registered at the Swedish Public Employment Service were foreign born, up from 22 percent in 2005.”
“As immigrant populations have grown, Sweden has experienced a persistent level of segregation — among the highest in Western Europe. In 2008, 60 percent of native Swedes lived in areas where the majority of the population was also Swedish, and 20 percent lived in areas that were virtually 100 percent Swedish. In contrast, 20 percent of Sweden’s foreign born lived in areas where more than 40 percent of the population was also foreign born.”
vi. Book recommendations. Or rather, author recommendations. A while back I asked ‘the people of SSC’ if they knew of any fiction authors I hadn’t read yet which were both funny and easy to read. I got a lot of good suggestions, and the roughly 20 Dick Francis novels I’ve read during the fall I’ve read as a consequence of that thread.
“On the basis of an original survey among native Christians and Muslims of Turkish and Moroccan origin in Germany, France, the Netherlands, Belgium, Austria and Sweden, this paper investigates four research questions comparing native Christians to Muslim immigrants: (1) the extent of religious fundamentalism; (2) its socio-economic determinants; (3) whether it can be distinguished from other indicators of religiosity; and (4) its relationship to hostility towards out-groups (homosexuals, Jews, the West, and Muslims). The results indicate that religious fundamentalist attitudes are much more widespread among Sunnite Muslims than among native Christians, even after controlling for the different demographic and socio-economic compositions of these groups. […] Fundamentalist believers […] show very high levels of out-group hostility, especially among Muslims.”
ix. Portal: Dinosaurs. It would have been so incredibly awesome to have had access to this kind of stuff back when I was a child. The portal includes links to articles with names like ‘Bone Wars‘ – what’s not to like? Again, awesome!
x. “you can’t determine if something is truly random from observations alone. You can only determine if something is not truly random.” (link) An important insight well expressed.
xi. Chessprogramming. If you’re interested in having a look at how chess programs work, this is a neat resource. The wiki contains lots of links with information on specific sub-topics of interest. Also chess-related: The World Championship match between Carlsen and Karjakin has started. To the extent that I’ll be following the live coverage, I’ll be following Svidler et al.’s coverage on chess24. Robin van Kampen and Eric Hansen – both 2600+ elo GMs – did quite well yesterday, in my opinion.
xii. Justified by More Than Logos Alone (Razib Khan).
“Very few are Roman Catholic because they have read Aquinas’ Five Ways. Rather, they are Roman Catholic, in order of necessity, because God aligns with their deep intuitions, basic cognitive needs in terms of cosmological coherency, and because the church serves as an avenue for socialization and repetitive ritual which binds individuals to the greater whole. People do not believe in Catholicism as often as they are born Catholics, and the Catholic religion is rather well fitted to a range of predispositions to the typical human.”
“The use of biomarkers in basic and clinical research has become routine in many areas of medicine. They are accepted as molecular signatures that have been well characterized and repeatedly shown to be capable of predicting relevant disease states or clinical outcomes. In Role of Biomarkers in Medicine, expert researchers in their individual field have reviewed many biomarkers or potential biomarkers in various types of diseases. The topics address numerous aspects of medicine, demonstrating the current conceptual status of biomarkers as clinical tools and as surrogate endpoints in clinical research.”
The above quote is from the preface of the book. Here’s my goodreads review. I have read about biomarkers before – for previous posts on this topic, see this link. I added the link in part because the coverage provided in this book is in my opinion generally of a somewhat lower quality than is the coverage that has been provided in some of the other books I’ve read on these topics. However the fact that the book is not amazing should probably not keep me from sharing some observations of interest from the book, which I have done in this post.
“we suggest more precise studies to establish the exact role of this hormone […] additional studies are necessary […] there are conflicting results […] require further investigation […] more intervention studies with long-term follow-up are required. […] further studies need to be conducted […] further research is needed“ (There are a lot of comments like these in the book, I figured I should include a few in my coverage…)
“Cancer biomarkers (CB) are biomolecules produced either by the tumor cells or by other cells of the body in response to the tumor, and CB could be used as screening/early detection tool of cancer, diagnostic, prognostic, or predictor for the overall outcome of a patient. Moreover, cancer biomarkers may identify subpopulations of patients who are most likely to respond to a given therapy […] Unfortunately, […] only very few CB have been approved by the FDA as diagnostic or prognostic cancer markers […] 25 years ago, the clinical usefulness of CB was limited to be an effective tool for patient’s prognosis, surveillance, and therapy monitoring. […] CB have [since] been reported to be used also for screening of general population or risk groups, for differential diagnosis, and for clinical staging or stratification of cancer patients. Additionally, CB are used to estimate tumor burden and to substitute for a clinical endpoint and/or to measure clinical benefit, harm or lack of benefit, or harm [4, 18, 30]. Among commonly utilized biomarkers in clinical practice are PSA, AFP, CA125, and CEA.”
“Bladder cancer (BC) is the second most common malignancy in the urologic field. Preoperative predictive biomarkers of cancer progression and prognosis are imperative for optimizing […] treatment for patients with BC. […] Approximately 75–85% of BC cases are diagnosed as nonmuscle-invasive bladder cancer (NMIBC) […] NMIBC has a tendency to recur (50–70%) and may progress (10–20%) to a higher grade and/or muscle-invasive BC (MIBC) in time, which can lead to high cancer-specific mortality . Histological tumor grade is one of the clinical factors associated with outcomes of patients with NMIBC. High-grade NMIBC generally exhibits more aggressive behavior than low-grade NMIBC, and it increases the risk of a poorer prognosis […] Cystoscopy and urine cytology are commonly used techniques for the diagnosis and surveillance of BC. Cystoscopy can identify […] most papillary and solid lesions, but this is highly invasive […] urine cytology is limited by examiner experience and low sensitivity. For these reasons, some tumor markers have been investigated […], but their sensitivity and specificity are limited  and they are unable to predict the clinical outcome of BC patients. […] Numerous efforts have been made to identify tumor markers. […] However, a serum marker that can serve as a reliable detection marker for BC has yet to be identified.”
“Endometrial cancer (EmCa) is the most common type of gynecological cancer. EmCa is the fourth most common cancer in the United States, which has been linked to increased incidence of obesity. […] there are no reliable biomarker tests for early detection of EmCa and treatment effectiveness. […] Approximately 75% of women with EmCa are postmenopausal; the most common symptom is postmenopausal bleeding […] Approximately 15% of women diagnosed with EmCa are younger than 50 years of age, while 5% are diagnosed before the age of 40 . […] Roughly, half of the EmCa cases are linked to obesity. Obese women are four times more likely to develop EmCa when compared to normal weight women […] Obese individuals oftentimes exhibit resistance to leptin and show high levels of the adipokine in blood, which is known as leptin resistance […] prolonged exposure of leptin damages the hypothalamus causing it to become insensitive to the effects of leptin […] Evidence shows that leptin is an important pro-inflammatory, pro-angiogenic, and mitogenic factor for cancer. Leptin produced by cancer cells acts in an autocrine and paracrine manner to promote tumor cell proliferation, migration and invasion, pro-inflammation, and angiogenesis [58, 70]. High levels of leptin […] are associated with metastasis and decreased survival rates in breast cancer patients . […] Metabolic syndrome including obesity, hypertension, insulin resistance, diabetes, and dyslipidemia increase the risk of developing multiple malignancies, particularly EmCa . Younger women diagnosed with EmCa are usually obese, and their carcinomas show a well-differentiated histology .”
“Normally, tumor suppressor genes act to inhibit or arrest cell proliferation and tumor development . However; when mutated, tumor suppressors become inactive, thus permitting tumor growth. For example, mutations in p53 have been determined in various cancers such as breast, colon, lung, endometrium, leukemias, and carcinomas of many tissues. These p53 mutations are found in approximately 50% of all cancers . Roughly 10–20% of endometrial carcinomas exhibit p53 mutations . […] overexpression of mutated tumor suppressor p53 has been associated with Type II EmCa (poor histologic grade, non-endometrioid histology, advanced stage, and poor survival).”
“Increasing data indicate that oxidative stress is involved in the development of DR [diabetic retinopathy] [16–19]. The retina has a high content of polyunsaturated fatty acids and has the highest oxygen uptake and glucose oxidation relative to any other tissue. This phenomenon renders the retina more susceptible to oxidative stress . […] Since long-term exposure to oxidative stress is strongly implicated in the pathogenesis of diabetic complications, polymorphic genes of detoxifying enzymes may be involved in the development of DR. […] A meta-analysis comprising 17 studies, including type 1 and type 2 diabetic patients from different ethnic origins, implied that the C (Ala) allele of the C47T polymorphism in the MnSOD gene had a significant protective effect against microvascular complications (DR and diabetic nephropathy) […] In the development of DR, superoxide levels are elevated in the retina, antioxidant defense system is compromised, MnSOD is inhibited, and mitochondria are swollen and dysfunctional [77,87–90]. Overexpression of MnSOD protects [against] diabetes-induced mitochondrial damage and the development of DR [19,91].”
“Continuous high level of blood glucose in diabetes damages micro and macro blood vessels throughout the body by altering the endothelial cell lining of the blood vessels […] Diabetes threatens vision, and patients with diabetes develop cataracts at an earlier age and are nearly twice as likely to get glaucoma compared to non-diabetic[s] . More than 75% of patients who have had diabetes mellitus for more than 20 years will develop diabetic retinopathy (DR) . […] DR is a slow progressive retinal disease and occurs as a consequence of longstanding accumulated functional and structural impairment of the retina by diabetes. It is a multifactorial condition arising from the complex interplay between biochemical and metabolic abnormalities occurring in all cells of the retina. DR has been classically regarded as a microangiopathy of the retina, involving changes in the vascular wall leading to capillary occlusion and thereby retinal ischemia and leakage. And more recently, the neural defects in the retina are also being appreciated […]. Recently, various clinical investigators [have detected] neuronal dysfunction at very early stages of diabetes and numerous abnormalities in the retina can be identified even before the vascular pathology appears [76, 77], thus suggesting a direct effect of diabetes on the neural retina. […] An emerging issue in DR research is the focus on the mechanistic link between chronic low-grade inflammation and angiogenesis. Recent evidence has revealed that extracellular high-mobility group box-1 (HMGB1) protein acts as a potent proinflammatory cytokine that triggers inflammation and recruits leukocytes to the site of tissue damage, and exhibits angiogenic effects. The expression of HMGB1 is upregulated in epiretinal membranes and vitreous fluid from patients with proliferative DR and in the diabetic retina. […] HMGB1 may be a potential biomarker [for diabetic retinopathy] […] early blockade of HMGB1 may be an effective strategy to prevent the progression of DR.”
“High blood pressure is one of the leading risk factors for global mortality and is estimated to have caused 9.4 million deaths in 2010. A meta‐analysis which includes 1 million individuals has indicated that death from both CHD [coronary heart disease] and stroke increase progressively and linearly from BP levels as low as 115 mmHg systolic and 75 mmHg diastolic upwards . The WHO [has] pointed out that a “reduction in systolic blood pressure of 10 mmHg is associated with a 22% reduction in coronary heart disease, 41% reduction in stroke in randomized trials, and a 41–46% reduction in cardiometabolic mortality in epidemiological studies” .”
“Several reproducible studies have ascertained that individuals with autism demonstrate an abnormal brain 5-HT system […] peripheral alterations in the 5-HT system may be an important marker of central abnormalities in autism. […] In a recent study, Carminati et al.  tested the therapeutic efficacy of venlafaxine, an antidepressant drug that inhibits the reuptake of 5-HT, and [found] that venlafaxine at a low dose [resulted in] a substantial improvement in repetitive behaviors, restricted interests, social impairment, communication, and language. Venlafaxine probably acts via serotonergic mechanisms […] OT [Oxytocin]-related studies in autism have repeatedly reported lower blood OT level in autistic patients compared to age- and gender-matched control subjects […] autistic patients demonstrate an altered neuroinflammatory response throughout their lives; they also show increased astrocyte and microglia inflammatory response in the cortex and the cerebellum [47, 48].”
“Due to the high complexity of the [water supply] systems, and the innumerable possible points of contaminant insertion, complete prevention of all possible terror attacks (chemical, biological, or radiological) on modern drinking water supplying systems […] seems to be an impossible goal. For example, in the USA there are about 170,000 water systems, with about 8,100 very large systems that serve 90% of the population who get water from a community water system […] The prevailing approach to the problem of drinking water contamination is based on the implementation of surveillance measures and technologies for “risk reduction” such as improvement of physical security measures of critical assets (high-potential vulnerability to attacks), [and] installation of online contaminant monitoring systems (OCMS) with capabilities to detect and warn in real time on relevant contaminants, as part of standard operating procedures for quality control (QC) and supervisory control and data acquisition (SCADA) systems. […] Despite the impressive technical progress in online water monitoring technologies […] detection with complete certainty of pollutants is expensive, and remains problematic.”
“A key component of early warning systems is the availability of a mathematical model for predicting the transport and fate of the spill or contaminant so that downstream utilities can be warned. […] Simulation tools (i.e. well-calibrated hydraulic and water quality models) can be linked to SCADA real-time databases allowing for continuous, high-speed modeling of the pressure, flow, and water quality conditions throughout the water distribution network. Such models provide the operator with computed system status data within the distribution network. These “virtual sensors” complement the measured data. Anomalies between measured and modeled data are automatically observed, and computed values that exceed predetermined alarm thresholds are automatically flagged by the SCADA system.”
“Any given tap receives water, which arrives though a number of pipes in the supply network, the transport route, and ultimately comes from a source […] in order to achieve maximum supply security in case of pipe failures or unusual demand patterns (e.g. fire flows) water supply networks are generally designed as complicated, looped systems, where each tap typically can receive water from several sources and intermediate storage facilities. This means that the water from any given tap can arrive through several different routes and can be a mixture of water from several sources. The routes and sources for a given tap can vary over time […] A model can show: *Which sources (well-fields, reservoirs, and tanks) contribute to the supply of which parts of the city? *Where does the water come from (percentage distribution) at any specific location in the system (any given tap or pipe)? *How long has the water been traveling in the pipe system, before it reaches a specific location?
One way to reduce the risk – and simplify the response to incidents – is by compartmentalizing the water supply system. If each tap receives water from one and only one reservoir pollution of one reservoir will affect one well-defined and relatively smaller part of the city. Compartmentalizing the water supply system will reduce the spreading of toxic substances. On the flip side, it may increase the concentration of the toxic substance. It is also likely to have a negative impact on the supply of water for fire flow and on the robustness of the water supply network in case of failures of pipes or other elements.”
An important point in the context of that part of the coverage is that if you want online (i.e. continuous, all-the-time) monitoring of drinking water, well, that’s going to be expensive regardless of how precisely you’re going to go about doing it. Another related problem is that it’s actually not really a simple matter to figure out what it even makes sense to test for when you’re analyzing the water (you can’t test for ‘everything’ all the time, and so the leading approach in monitoring systems employed today is according to the authors based on the idea of using ‘surrogate parameters’ which may be particularly informative about any significant changes in the quality of the drinking water taking place.
“After the collapse of the Soviet Union, the countries of the South Caucasus gained their independence. However, they faced problems associated with national and transboundary water management. Transboundary water management remains one of the key issues leading to conflict in the region today. The scarcity of water especially in downstream areas is a major problem […] The fresh surface water resources of the South Caucasus mainly consist of runoff from the Kura–Araz River basins. […] Being a water-poor region, water supply over the Azerbaijan Republic territory totals about 100,000 m³/km2, which amounts to an average of about 1,000 m³ of water per person per year. Accordingly, Azerbaijan Republic occupies one of the lowest рlaces in the world in water availability. Water resources of the Republic are distributed very irregularly over administrative districts.”
Water provision [in Azerbaijan] […] is carried out by means of active hydrotechnical constructions, which are old-fashioned and many water intake facilities and treatment systems cannot operate during high flooding, water turbidity, and extreme pollution. […] Tap water satisfies [the] needs of only 50% of the population, and some areas experience lack of drinking water. Due to the lack of water supply networks and deteriorated conditions of those existing, about half of the water is lost within the distribution system. […] The sewage system of the city of Baku covers only 70% of its territory and only about half of sewage is treated […] Owing to rapid growth of turbidity of Kura (and its inflows) during high water the water treatment facilities are rendered inoperable thus causing failures in the water supply of the population of the city of Baku. Such situations mainly take place in autumn and spring on the average 3–5 times a year for 1–2 days. In the system of centralized water supply of the city of Baku about 300 emergency cases occur annually […] Practically nobody works with the population to promote efficient water use practices.”
Bakris et al.‘s text on this topic is the first book I’ve read specifically devoted to the topic of DN. As I pointed out on goodreads, “this is a well-written and interesting work which despite the low page count cover quite a bit of ground. A well-sourced and to-the-point primer on these topics.” Below I have added a few observations from the book.
“Diabetic nephropathy (DN), also known as diabetic kidney disease (DKD), is one of the most important long-term complications of diabetes and the most common cause of endstage renal disease (ESRD) worldwide. DKD […] is defined as structural and functional renal damage manifested as clinically detected albuminuria in the presence of normal or abnormal glomerular filtration rate (GFR). […] Patients with DKD […] account for one-third of patients demanding renal transplantation. […] in the United States, Medicare expenditure on treating ESRD is approximately US $33 billion (as of 2010), which accounts for 8–9 % of the total annual health-care budget […] According to the United States Renal Data System […], the incidence of ESRD requiring RRT [in 2012] was 114,813 patients, with 44 % due to DKD . A registry report from Japan revealed a nearly identical relative incidence, with 44.2 % of the patients with ESRD caused by diabetes”
Be careful not to confuse incidence and prevalence here; the proportion of diabetics diagnosed with ESDR in any given year is almost certainly higher than the proportion of people with ESDR who have diabetes, because diabetics with kidney failure die at a higher rate than do other people with kidney failure. This problem/fact tends to make some questions hard to answer; to give an example, how large a share of the total costs that diabetics contribute to the whole kidney disease component of medical costs seems to me to be far from an easy question to answer, because you in some sense are not really making an apples-to-apples comparison, and a lot might well depend on the chosen discount rate and how to address the excess mortality in the diabetes sample; and even ‘simply’ adding up medical outlays for the diabetes- and non-diabetes samples would require a lot of data (which may not be available) and work. You definitely cannot just combine the estimates provided above, and assume that the 44% incidence translates into 44% of people with ESDR having diabetes; it’s not clear in the text where the ‘one-third of patients’ number above comes from, but if that’s also US data then it should be obvious from the difference between these numbers that there’s a lot of excess mortality here in the diabetes sample (I have included specific data from the publication on these topics below). The book also talks about the fact that the type of dialysis used in a case of kidney failure will to some extent depend on the health status of the patient, and that diabetes is a significant variable in that context; this means that the available/tolerable treatment options for the kidney disease component may not be the same in the case of a diabetic and a case of a patient with, say, lupus nephritis, and it also means that the patient groups most likely are not ‘equally sick’, so basing cost estimates on cost averages might lead to misleading results if severity of disease and (true) treatment costs are related, as they usually are.
“A recent analysis revealed an estimated diabetes prevalence of 12–14 % among adults in the United States […] In the age group ≥65 years, this amounts to more than 20 %”.
It should be emphasized in the context of the above numbers that the prevalence of DKD is highly variable across countries/populations – the authors also include in the book the observation that: “Over a period of 20 years, 32 studies from 16 countries revealed a prevalence ranging from 11 to 83 % of patients with diabetes”. Some more prevalence data:
“DKD affects about 30 % of patients with type 1 diabetes and 25–40 % of the patients with type 2 diabetes. […] The global prevalence of micro- and macroalbuminuria is estimated at 39 % and 10 %, respectively […] (NHANES III) […] reported a prevalence of 35 % (microalbuminuria) and 6 % (macroalbuminuria) in patients with T2DM aged ≥40 years . In another study, this was reported to be 43 % and 12 %, respectively, in a Japanese population . According to the European Diabetes (EURODIAB) Prospective Complications Study Group, in patients with T1DM, the incidence of microalbuminuria was 12.6 % (over 7.3 years) . This prevalence was further estimated at 33 % in an 18-year follow-up study in Denmark […] In the United Kingdom Prospective Diabetes Study (UKPDS), proteinuria [had] a peak incidence after around 15–20 years after diabetes diagnosis.”
I won’t cover the pathophysiology parts in too much detail here, but a few new things I learned does need to be mentioned:
“A natural history of DKD was first described in the 1970s by Danish physicians . It was characterized by a long silent period without overt clinical signs and symptoms of nephropathy and progression through various stages, starting from hyperfiltration, microalbuminuria, macroalbuminuria, and overt renal failure to ESRD. Microalbuminuria (30–300 mg/day of albumin in urine) is a sign of early DKD, whereas macroalbuminuria (>300 mg/day) represents DKD progression. [I knew this stuff. The stuff that follows below was however something I did not know:]
However, this ‘classical’ natural evolution of urinary albumin excretion and change in GFR is not present in many patients with diabetes, especially those with type 2 diabetes . These patients can have reduction or disappearance of proteinuria over time or can develop even overt renal disease in the absence of proteinuria [30, 35]. […] In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) of patients with T2DM, 45.2 % of participants developed albuminuria, and 29 % developed renal impairment over a 15-year follow-up period . Of those patients who developed renal impairment, 61 % did not have albuminuria beforehand, and 39 % never developed albuminuria during the study. Of the patients that developed albuminuria, only 24 % subsequently developed renal impairment during the study. A significant degree of discordance between development of albuminuria and renal impairment is apparent . These data, thus, do not support the classical paradigm of albuminuria always preceding renal impairment in the progression of DKD. […] renal hyperfiltration and rapid GFR decline are considered stronger predictors of nephropathy progression in type 1 diabetes than presence of albuminuria . The annual eGFR loss in patients with DKD is >3 mL/min/1.73 m2 or 3.3 % per year.”
As for the last part about renal hyperfiltration, they however also note later in the coverage in a different chapter that “recent long-term prospective surveys cast doubt on the validity of glomerular hyperfiltration being predictive of renal outcome in patients with type 1 diabetes”. Various factors mentioned in the coverage – some of which are very hard to avoid and some of which are actually diabetes-specific – contribute to measurement error, which may be part of the explanation for the sub-optimal performance of the prognostic markers employed.
An important observation I think I have mentioned before here on the blog is that diabetic nephropathy is not just bad because people who develop this complication may ultimately develop kidney failure, but is also bad because diabetics may die before they even do that; diabetics with even moderate stages of nephropathy have high mortality from cardiovascular disease, so if you only consider diabetics who actually develop kidney failure you may miss some of the significant adverse health effects of this complication; it might be argued that doing this would be a bit like analyzing the health outcomes of smokers while only tallying the cancer cases, and ignoring e.g. the smoking-associated excess deaths from cardiovascular disease. Some observations from the book on this topic:
“Comorbid DM and DKD are associated with high cardiovascular morbidity and mortality. The risk of cardiovascular disease is disproportionately higher in patients with DKD than patients with DM who do not have kidney disease . The incident dialysis rate might even be higher after adjusting for patients dying from cardiovascular disease before reaching ESRD stage . The United States Renal Data System (USRDS) data shows that elderly patients with a triad of DM, chronic kidney disease (CKD), and heart failure have a fivefold higher chance of death than progression to CKD and ESRD . The 5-year survival rate for diabetic patients with ESRD is estimated at 20 % […] This is higher than the mortality rate for many solid cancers (including prostate, breast, or renal cell cancer). […] CVD accounts for more than half of deaths of patients undergoing dialysis […] the 5-year survival rate is much lower in diabetic versus nondiabetic patients undergoing hemodialysis […] Adler et al. tested whether HbA1c levels were associated with death in adults with diabetes starting HD or peritoneal dialysis . Of 3157 patients observed for a median time of 2.7 years, 1688 died. [this example provided, I thought, a neat indication of what sort of data you end up with when you look at samples with a 20% 5-year survival rate] […] Despite modern therapies […] most patients continue to show progressive renal damage. This outcome suggests that the key pathogenic mechanisms involved in the induction and progression of DN remain, at least in part, active and unmodified by the presently available therapies.” (my emphasis)
The link between blood glucose (Hba1c) and risk of microvascular complications such as DN is strong and well-documented, but Hba1c does not explain everything:
“Only a subset of individuals living with diabetes […] develop DN, and studies have shown that this is not just due to poor blood glucose control [50–54]. DN appears to cluster in families […] Several consortia have investigated genetic risk factors […] Genetic risk factors for DN appear to differ between patients with type 1 and type 2 diabetes […] The pathogenesis of DN is complex and has not yet been completely elucidated […] [It] is multifactorial, including both genetic and environmental factors […]. Hyperglycemia affects patients carrying candidate genes associated with susceptibility to DN and results in metabolic and hemodynamic alterations. Hyperglycemia alters vasoactive regulators of glomerular arteriolar tone and causes glomerular hyperfiltration. Production of AGEs and oxidative stress interacts with various cytokines such as TGF-β and angiotensin II to cause kidney damage. Additionally, oxidative stress can cause endothelial dysfunction and systemic hypertension. Inflammatory pathways are also activated and interact with the other pathways to cause kidney damage.”
“An early clinical sign of DN is moderately increased urinary albumin excretion, referred to as microalbuminuria […] microalbuminuria has been shown to be closely associated with an increased risk of cardiovascular morbidity and mortality [and] is [thus] not only a biomarker for the early diagnosis of DN but also an important therapeutic target […] Moderately increased urinary albumin excretion that progresses to severely increased albuminuria is referred to as macroalbuminuria […] Severely increased albuminuria is defined as an ACR≥300 mg/g Cr; it leads to a decline in renal function, which is defined in terms of the GFR  and generally progresses to ESRD 6–8 years after the onset of overt proteinuria […] patients with type 1 diabetes are markedly younger than type 2 patients. The latter usually develop ESRD in their mid-fifties to mid-sixties. According to a small but carefully conducted study, both type 1 and type 2 patients take an average of 77–81 months from the stage of producing macroproteinuria with near-normal renal function to developing ESRD .”
“Patients with diabetes and kidney disease are at increased risk of hypoglycemia due to decreased clearance of some of the medications used to treat diabetes such as insulin, as well as impairment of renal gluconeogenesis from having a lower kidney mass. As the kidney is responsible for about 30–80 % of insulin removal, reduced kidney function is associated with a prolonged insulin half-life and a decrease in insulin requirements as estimated glomerular filtration rate (eGFR) decline […] Metformin [a first-line drug for treating type 2 diabetes, US] should be avoided in patients with an eGFR < 30 mL/min /1.73 m2. It is recommended that metformin is stopped in the presence of situations that are associated with hypoxia or an acute decline in kidney function such as sepsis/shock, hypotension, acute myocardial infarction, and use of radiographic contrast or other nephrotoxic agents […] The ideal medication regimen is based on the specific needs of the patient and physician experience and should be individualized, especially as renal function changes. […] Lower HbA1c levels are associated with higher risks of hypoglycemia so the HbA1c target should be individualized […] Whereas patients with mild renal insufficiency can receive most antihyperglycemic treatments without any concern, patients with CKD stage 3a and, in particular, with CKD stages 3b, 4, and 5 often require treatment adjustments according to the degree of renal insufficiency […] Higher HbA1c targets should be considered for those with shortened life expectancies, a known history of severe hypoglycemia or hypoglycemia unawareness, CKD, and children.”
“In cases where avoidance of development of DKD has failed, the second approach is slowing disease progression. The most important therapeutic issues at this stage are control of hypertension and hyperglycemia. […] Hypertension is present in up to 85 % of patients with DN/ DKD, depending on the duration and stage (e.g., higher in more progressive cases). […] In a recent meta-analysis, the efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease was analyzed […] In total, 157 studies comprising 43,256 participants, mostly with type 2 diabetes and CKD, were included in the network meta-analysis. No drug regimen was found to be more effective than placebo for reducing all-cause mortality. […] DKD is accompanied by abnormalities in lipid metabolism related to decline in kidney function. The association between higher low-density lipoprotein cholesterol (LDL-C) and risk of myocardial infarction is weaker for people with lower baseline eGFR, despite higher absolute risk of myocardial infarction . Thus, increased LDL-C seems to be less useful as a marker of coronary risk among people with CKD than in the general population.”
“An analysis of the USRDS data revealed an RR of 0.27 (95 % CI, 0.24–0.30) 18 months after transplantation in patients with diabetes in comparison to patients on dialysis on a transplant waiting list . The gain in projected years of life with transplantation amounted to 11 years in patients with DKD in comparison to patients without transplantation.”
i. “You will never find time for anything. If you want time, you must make it.” (Charles Buxton)
ii. “When we meet a fact which contradicts a prevailing theory, we must accept the fact and abandon the theory, even when the theory is supported by great names and generally accepted.” (Claude Bernard)
iii. “The cheapest sort of pride is national pride; for if a man is proud of his own nation, it argues that he has no qualities of his own of which he can be proud; otherwise he would not have recourse to those which he shares with so many millions of his fellowmen. The man who is endowed with important personal qualities will be only too ready to see clearly in what respects his own nation falls short, since their failings will be constantly before his eyes. But every miserable fool who has nothing at all of which he can be proud adopts, as a last resource, pride in the nation to which he belongs; he is ready and glad to defend all its faults and follies tooth and nail, thus reimbursing himself for his own inferiority.” (Schopenhauer)
iv. “… whoever attributes no merit to himself because he really has none is not modest, but merely honest.” (-ll-)
v. “It is the possession of a great heart or a great head, and not the mere fame of it, which is worth having, and conducive to happiness. Not fame, but that which deserves to be famous, is what a man should hold in esteem.” (-ll-)
vi. “It is not knowledge, but the act of learning, not the possession of but the act of getting there, which grants the greatest enjoyment.” (Gauss)
vii. “People may flatter themselves just as much by thinking that their faults are always present to other people’s minds, as if they believe that the world is always contemplating their individual charms and virtues.” (Elizabeth Gaskell)
viii. “Fools have a habit of believing that everything written by a famous author is admirable.” (Voltaire)
ix. “One always speaks badly when one has nothing to say.” (-ll-)
x. “He who dares not offend cannot be honest.” (Thomas Paine)
xi. “False opinions are like false money, struck first of all by guilty men and thereafter circulated by honest people who perpetuate the crime without knowing what they are doing.” (Joseph de Maistre)
xii. “Learning is not attained by chance, it must be sought for with ardor and attended to with diligence.” (Abigail Adams)
xiii. “It is not easy to be wise for all times, not even for the present much less for the future; and those who judge the past must recollect that, when it was the present the present was future” (Gouverneur Morris)
xiv. “Praise — actual personal praise — oftener frets and embarrasses than it encourages. It is too small when too near.” (Letitia Elizabeth Landon)
xv. “Everybody is seldom to be believed. “They say” is not proof that they know.” (Samuel Laman Blanchard)
xvi. “Useless laws weaken the necessary laws.” (Montesquieu)
xvii. “Not to be loved is a misfortune, but it is an insult to be loved no longer.” (-ll-)
xviii. “Pithy sentences are like sharp nails which force truth upon our memory.” (Denis Diderot)
xix. “One may demand of me that I should seek truth, but not that I should find it.” (-ll-)
xx. “It is bad policy to fear the resentment of an enemy.” (Ethan Allen)
I didn’t think much of this book (here’s my goodreads review), but I did learn some new things from reading it. Some of the coverage in the book overlapped a little bit with stuff I’d read before, e.g. coverage provided in publications such as Rodricks and Fong and Alibek, but I read those books in 2013 and 2014 respectively (so I’ve already forgot a great deal) and most of the stuff in the book was new stuff. Below I’ve added a few observations and data from the first half of the publication.
“Mediterranean basin demands for water are high. Today, the region uses around 300 billion cubic meters per year. Two thirds of Mediterranean countries now use over 500 m³ per year per inhabitant mainly because of heavy use of irrigation. But these per capita demands are irregular and vary across a wide range – from a little over 100 to more than 1,000 m³ per year. Globally, demand has doubled since the beginning of the 20th century and increased by 60% over the last 25 years. […] the Middle East ecosystems […] populate some 6% of the world population, but have only some 1% of its renewable fresh water. […] Seasonality of both supply and demand due to tourism […] aggravate water resource problems. During the summer months, water shortages become more frequent. Distribution networks left unused during the winter period face overload pressures in the summer. On the other hand, designing the system with excess capability to satisfy tourism-related summer peak demands raises construction and maintenance costs significantly.”
“There are over 30,000 km of mains within London and over 30% of these are over 150 years old, they serve 7.5 million people with 2,500 million liters of water a day.”
“A major flooding of the Seine River would have tremendous consequences and would impact very significantly the daily life of the 10 million people living in the Parisian area. A deep study of the impacts of such a catastrophic natural hazard has recently been initiated by the French authorities. […] The rise of the water level in the Seine during the last two major floods occurred slowly over several weeks which may explain their low number of fatalities: 50 deaths in 1658 and only one death in 1910. The damage and destruction to buildings and infrastructure, and the resulting effect on economic activity were, however, of major proportions […] Dams have been constructed on the rivers upstream from Paris, but their capacity to stock water is only 830 million cubic meters, which would be insufficient when compared to the volume of 4 billion cubic meters of water produced by a big flood. […] The drinkable water supply system in Paris, as well as that of the sewer network, is still constrained by the decisions and orientations taken during the second half of the 19th century during the large public works projects realized under Napoleon III. […] two of the three water plants which treat river water and supply half of Paris with drinkable water existed in 1910. Water treatment technology has radically changed, but the production sites have remained the same. New reservoirs for potable water have been added, but the principles of distribution have not changed […] The average drinking water production in Paris is 615,000 m³/day.”
They note in the chapter from which the above quotes are taken that a flood comparable to that which took place in 1910 would in 2005 have resulted in 20% of the surface of Paris being flooded, and 600.000 people being without electricity, among other things. The water distribution system currently in place would also be unable to deal with the load, however a plan for how to deal with this problem in an emergency setting does exist. In that context it’s perhaps worth noting that Paris is hardly unique in terms of the structure of the distribution system – elsewhere in the book it is observed that: “The water infrastructure developed in Europe during the 19th century and still applied, is almost completely based on options of centralized systems: huge supply and disposal networks with few, but large waterworks and sewage treatment plants.” Having both centralized and decentralized systems working at the same time/in the same area tends to increase costs, but may also lower risk; it’s observed in the book during the coverage of an Indonesian case-study that in that region the centralized service provider may take a long time to repair broken water pipes, which is … not very nice if you live in a tropical climate and prefer to have drinking water available to you.
“Water resources management challenges differ enormously in Romania, depending on the type of human settlement. The spectrum of settlement types stretches from the very low-density scattered single dwellings found in rural areas, through villages and small towns, to the much more dense and crowded cities. […] Water resources management will always face the challenge of balancing the needs of different water users. This is the case both in large urban or relatively small rural communities. The water needs of the agricultural production, energy and industrial sectors are often in competition. […] Romania’s water resources are relatively poor and unequally distributed in time and space […] There is a vast differential between urban and rural settlements when it comes to centralized drinking water systems; all the 263 municipalities and towns have such systems, while only 17% of rural communities benefit from this service. […] In Braila and Harghita counties, no village has a sewage network, and Giurgiu and Ialomita counties have only one a piece each. Around 47 of the largest cities which do not have wastewater treatment plants (Bucharest, Braila, Craiova, Turnu Severin Tulcea, etc.) produce ∼20 m³/s of wastewater, which is directly discharged untreated into surface water.”
“There is a difference in quality between water from centralized and decentralized supply systems [in the Ukraine (and likely elsewhere as well)]. Water quality in decentralized systems is the worst (some 30% of samples fail to meet standards, compared to 5.7% in the centralized supply). […] The Sanitary epidemiological stations draw random samples from 1,139 municipal, 6,899 departmental, and 8,179 rural pipes, and from 158,254 points of decentralized water supply, including 152,440 wells, 996 springs, and 4,818 artesian wells. […] From the first day following the accident at Chernobyl Nuclear Power Plant (ChNPP), one of the most serious problems was to prevent general contamination of the Dnieper water system and to guarantee safe water consumption for people living in the affected zone. The water protection and development of monitoring programs for the affected water bodies were among the most important post-accident countermeasures taken by the Government Bodies in Ukraine. […] To solve the water quality problem for Kiev, an emergency water intake at the Desna River was constructed within a very short period. […] During 1986 and the early months of 1987, over 130 special filtration dams […] with sorbing screens containing zeolite (klinoptilolite) were installed for detaining radionuclides while letting the water through. […] After the spring flood of 1987, the construction of new dams was terminated and the decision was made to destroy most of the existing dams. It was found that the 90Sr concentration reduction by the dams studied was insignificant […] Although some countermeasures and cleanup activities applied to radionuclides sources on catchments proved to have positive effects, many other actions were evaluated as ineffective and even useless. […] The most effective measures to reduce radioactivity in drinking water are those, which operate at the water treatment and distribution stage.“
“Diversification and redundancy are important technical features to make infrastructure systems less vulnerable to natural and social (man-made) hazards. […] risk management does not only encompass strategies to avoid the occurrence of certain events which might lead to damages or catastrophes, but also strategies of adaptation to limit damages.”
“The loss of potable water supply typically leads to waterborne diseases, such as typhus and cholera.”
“Water velocity in a water supply system is about 1 m³\s. Therefore, time is a primordial factor in contamination spread along the system. In order to minimize the damage caused by contamination of water, it is essential to act with maximum speed to achieve minimum spread of the contaminant”
I have quoted from the book before, but I decided that this book deserves to be blogged in more detail. I’m close to finishing the book at this point (it’s definitely taken longer than it should have), and I’ll probably give it 5 stars on goodreads; I might also add it to my list of favourite books on the site. In this post I’ve added some quotes and ideas from the book, and a few comments. Before going any further I should note that it’s frankly impossible to cover anywhere near all the ideas covered in the book here on the blog, so if you’re even remotely interested in these kinds of things you really should pick up a copy of the book and read all of it.
“I believe that something crucial has been missing from all of the great debates of history, among philosophers, politicians, theologians, and thinkers from other and diverse backgrounds, on the issues of morality, ethics, justice, right and wrong. […] those who have tried to analyze morality have failed to treat the human traits that underlie moral behavior as outcomes of evolution […] for many conflicts of interest, compromises and enforceable contracts represent the only real solutions. Appeals to morality, I will argue, are simply the invoking of such compromises and contracts in particular ways. […] the process of natural selection that has given rise to all forms of life, including humans, operates such that success has always been relative. One consequence is that organisms resulting from the long-term cumulative effects of selection are expected to resist efforts to reveal their interests fully to others, and also efforts to place limits on their striving or to decide for them when their interests are being “fully” satisfied. These are all reasons why we should expect no “terminus” – ever – to debates on moral and ethical issues.” (these comments I also included in the quotes post to which I link at the beginning, but I thought it was worth including them in this post as well even so – US).
“I am convinced that biology can never offer […] easy or direct answers to the questions of what is right and wrong. I explicitly reject the attitude that whatever biology tells us is so is also what ought to be (David Hume’s so-called “naturalistic fallacy”) […] there are within biology no magic solutions to moral problems. […] Knowledge of the human background in organic evolution can [however] provide a deeper self-understanding by an increasing proportion of the world’s population; self-understanding that I believe can contribute to answering the serious questions of social living.”
“If there had been no recent discoveries in biology that provided new ways of looking at the concept of moral systems, then I would be optimistic indeed to believe that I could say much that is new. But there have been such discoveries. […] The central point in these writings [Hamilton, Williams, Trivers, Cavalli-Sforza, Feldman, Dawkins, Wilson, etc. – US] […] is that natural selection has apparently been maximizing the survival by reproduction of genes, as they have been defined by evolutionists, and that, with respect to the activities of individuals, this includes effects on copies of their genes, even copies located in other individuals. In other words, we are evidently evolved not only to aid the genetic materials in our own bodies, by creating and assisting descendants, but also to assist, by nepotism, copies of our genes that reside in collateral (nondescendant) relatives. […] ethics, morality, human conduct, and the human psyche are to be understood only if societies are seen as collections of individuals seeking their own self-interests […] In some respects these ideas run contrary to what people have believed and been taught about morality and human values: I suspect that nearly all humans believe it is a normal part of the functioning of every human individual now and then to assist someone else in the realization of that person’s own interests to the actual net expense of those of the altruist. What [the above-mentioned writings] tells us is that, despite our intuitions, there is not a shred of evidence to support this view of beneficence, and a great deal of convincing theory suggests that any such view will eventually be judged false. This implies that we will have to start all over again to describe and understand ourselves, in terms alien to our intuitions […] It is […] a goal of this book to contribute to this redescription and new understanding, and especially to discuss why our intuitions should have misinformed us.”
“Social behavior evolves as a succession of ploys and counterploys, and for humans these ploys are used, not only among individuals within social groups, but between and among small and large groups of up to hundreds of millions of individuals. The value of an evolutionary approach to human sociality is thus not to determine the limits of our actions so that we can abide by them. Rather, it is to examine our life strategies so that we can change them when we wish, as a result of understanding them. […] my use of the word biology in no way implies that moral systems have some kind of explicit genetic background, are genetically determined, or cannot be altered by adjusting the social environment. […] I mean simply to suggest that if we wish to understand those aspects of our behavior commonly regarded as involving morality or ethics, it will help to reconsider our behavior as a product of evolution by natural selection. The principal reason for this suggestion is that natural selection operates according to general principles which make its effects highly predictive, even with respect to traits and circumstances that have not yet been analyzed […] I am interested […] not in determining what is moral and immoral, in the sense of what people ought to be doing, but in elucidating the natural history of ethics and morality – in discovering how and why humans initiated and developed the ideas we have about right and wrong.”
I should perhaps mention here that sort-of-kind-of related stuff is covered in Aureli et al. (see e.g. this link), and that some parts of that book will probably make you understand Alexander’s ideas a lot better even if perhaps he didn’t read those specific authors – mainly because it gets a lot easier to imagine the sort of mechanisms which might be at play here if you’ve read this sort of literature. Here’s one relevant quote from the coverage of that book, which also deals with the question Alexander discusses above, and in a lot more detail throughout his book, namely ‘where our morality comes from?’
“we make two fundamental assertions regarding the evolution of morality: (1) there are specific types of behavior demonstrated by both human and nonhuman primates that hint at a shared evolutionary background to morality; and (2) there are theoretical and actual connections between morality and conflict resolution in both nonhuman primates and human development. […] the transition from nonmoral or premoral to moral is more gradual than commonly assumed. No magic point appears in either evolutionary history or human development at which morality suddenly comes into existence. In both early childhood and in animals closely related to us, we can recognize behaviors (and, in the case of children, judgments) that are essential building blocks of the morality of the human adult. […] the decision making and emotions underlying moral judgments are generated within the individual rather than being simply imposed by society. They are a product of evolution, an integrated part of the human genetic makeup, that makes the child construct a moral perspective through interactions with other members of its species. […] Much research has shown that children acquire morality through a social-cognitive process; children make connections between acts and consequences. Through a gradual process, children develop concepts of justice, fairness, and equality, and they apply these concepts to concrete everyday situations […] we assert that emotions such as empathy and sympathy provide an experiential basis by which children construct moral judgments. Emotional reactions from others, such as distress or crying, provide experiential information that children use to judge whether an act is right or wrong […] when a child hits another child, a crying response provides emotional information about the nature of the act, and this information enables the child, in part, to determine whether and why the transgression is wrong. Therefore, recognizing signs of distress in another person may be a basic requirement of the moral judgment process. The fact that responses to distress in another have been documented both in infancy and in the nonhuman primate literature provides initial support for the idea that these types of moral-like experiences are common to children and nonhuman primates.”
Alexander’s coverage is quite different from that found in Aureli et al.,, but some of the contributors to the latter work deal with similar questions to the ones in which he’s interested, using approaches not employed in Alexander’s book – so this is another place to look if you’re interested in these topics. Margalit’s The Emergence of Norms is also worth mentioning. Part of the reason why I mention these books here is incidentally that they’re not talked about in Alexander’s coverage (for very natural reasons, I should add, in the case of the former book at least; Natural Conflict Resolution was published more than a decade after Alexander wrote his book…).
“In the hierarchy of explanatory principles governing the traits of living organisms, evolutionary reductionism – the development of principles from the evolutionary process – tends to subsume all other kinds. Proximate-cause reductionism (or reduction by dissection) sometimes advances our understanding of the whole phenomena. […] When evolutionary reduction becomes trivial in the study of life it is for a reason different from incompleteness; rather, it is because the breadth of the generalization distances it too significantly from the particular problem that may be at hand. […] the greatest weakness of reduction by generalization is not that it is likely to be trivial but that errors are probable through unjustified leaps from hypothesis to conclusion […] Critics such as Gould and Lewontin […] do not discuss the facts that (a) all students of human behavior (not just those who take evolution into account) run the risk of leaping unwarrantedly from hypothesis to conclusion and (b) just-so stories were no less prevalent and hypothesis-testing no more prevalent in studies of human behavior before evolutionary biologists began to participate. […] I believe that failure by biologists and others to distinguish proximate- or partial-cause and evolutionary- or ultimate-cause reductionism […] is in some part responsible for the current chasm between the social and the biological sciences and the resistance to so-called biological approaches to understanding humans. […] Both approaches are essential to progress in biology and the social sciences, and it would be helpful if their relationship, and that of their respective practitioners, were not seen as adversarial.”
“Humans are not accustomed to dealing with their own strategies of life as if they had been tuned by natural selection. […] People are not generally aware of what their lifetimes have been evolved to accomplish, and, even if they are roughly aware of this, they do not easily accept that their everyday activities are in any sense means to that end. […] The theory of lifetimes most widely accepted among biologists is that individuals have evolved to maximize the likelihood of survival of not themselves, but their genes, and that they do this by reproducing and tending in various ways offspring and other carriers of their own genes […] In this theory, survival of the individual – and its growth, development, and learning – are proximate mechanisms of reproductive success, which is a proximate mechanism of genic survival. Only the genes have evolved to survive. […] To say that we are evolved to serve the interests of our genes in no way suggests that we are obliged to serve them. […] Evolution is surely most deterministic for those still unaware of it. If this argument is correct, it may be the first to carry us from is to ought, i.e., if we desire to be the conscious masters of our own fates, and if conscious effort in that direction is the most likely vehicle of survival and happiness, then we ought to study evolution.”
“People are sometimes comfortable with the notion that certain activities can be labeled as “purely cultural” because they also believe that there are behaviors that can be labeled “purely genetic.” Neither is true: the environment contributes to the expression of all behaviors, and culture is best described as part of the environment.”
“Happiness and its anticipation are […] proximate mechanisms that lead us to perform and repeat acts that in the environments of history, at least, would have led to greater reproductive success.”
“The remarkable difference between the patterns of senescence in semelparous (one-time breeding) and iteroparous (repeat-breeding) organisms is probably one of the best simple demonstrations of the central significance of reproduction in the individual’s lifetime. How, otherwise, could we explain the fact that those who reproduce but once, like salmon and soybeans, tend to die suddenly right afterward, while those like ourselves who have residual reproductive possibilities after the initial reproductive act decline or senesce gradually? […] once an organism has completed all possibilities of reproducing (through both offspring production and assistance, and helping other relatives), then selection can no longer affect its survival: any physiological or other breakdown that destroys it may persist and even spread if it is genetically linked to a trait that is expressed earlier and is reproductively beneficial. […] selection continually works against senescence, but is just never able to defeat it entirely. […] senescence leads to a generalized deterioration rather than one owing to a single effect or a few effects […] In the course of working against senescence, selection will tend to remove, one by one, the most frequent sources of mortality as a result of senescence. Whenever a single cause of mortality, such as a particular malfunction of any vital organ, becomes the predominant cause of mortality, then selection will more effectively reduce the significance of that particular defect (meaning those who lack it will outreproduce) until some other achieves greater relative significance. […] the result will be that all organs and systems will tend to deteriorate together. […] The point is that as we age, and as senescence proceeds, large numbers of potential sources of mortality tend to lurk ever more malevolently just “below the surface,” so that, unfortunately, the odds are very high against any dramatic lengthening of the maximum human lifetime through technology. […] natural selection maximizes the likelihood of genetic survival, which is incompatible with eliminating senescence. […] Senescence, and the finiteness of lifetimes, have evolved as incidental effects […] Organisms compete for genetic survival and the winners (in evolutionary terms) are those who sacrifice their phenotypes (selves) earlier when this results in greater reproduction.”
“altruism appears to diminish with decreasing degree of relatedness in sexual species whenever it is studied – in humans as well as nonhuman species”
“In the pages that follow we advance two propositions.
First, people cooperate not only for self-interested reasons but also because they are genuinely concerned about the well-being of others, try to uphold social norms, and value behaving ethically for its own sake. People punish those who exploit the cooperative behavior of others for the same reasons. Contributing to the success of a joint project for the benefit of one’s group, even at a personal cost, evokes feelings of satisfaction, pride, even elation. Failing to do so is often a source of shame or guilt.
Second, we came to have these “moral sentiments” because our ancestors lived in environments, both natural and socially constructed, in which groups of individuals who were predisposed to cooperate and uphold ethical norms tended to survive and expand relative to other groups, thereby allowing these prosocial motivations to proliferate. The first proposition concerns proximate motivations for prosocial behavior, the second addresses the distant evolutionary origins and ongoing perpetuation of these cooperative dispositions.”
Here’s my goodreads review of the book – I gave the book five stars on goodreads. In the post I have included some illustrative quotes below, but really you should read all of it if you find this sort of stuff interesting and you’re not mathematically illiterate (and as the authors note early on, they have given the way they present their ideas some thought: “We have presented technical material in verbal as well as mathematical form wherever possible, and avoided mathematical formulations entirely where that was possible without sacrificing clarity.” Even so, the book is somewhat dense and it takes some work to get through).
“In short, humans became the cooperative species that we are because cooperation was highly beneficial to the members of groups that practiced it, and we were able to construct social institutions that minimized the disadvantages of those with social preferences in competition with fellow group members, while heightening the group-level advantages associated with the high levels of cooperation that these social preferences allowed. These institutions proliferated because the groups that adopted them secured high levels of within-group cooperation, which in turn favored the groups’ survival as a biological and cultural entity in the face of environmental, military and other challenges.”
“The regulation of social interactions by group-level institutions plays no less a role than altruistic individual motives in understanding how this cooperative species came to be. Institutions affect the rewards and penalties associated with particular behaviors, often favoring the adoption of cooperative actions over others, so that even the self-regarding are often induced to act in the interest of the group. […] the individual motives and group-level institutions that account for cooperation among humans include not only the most elevated, including a concern for others, fair-mindedness, and democratic accountability of leaders, but also the most wicked, such as vengeance, racism, religious bigotry, and hostility toward outsiders.”
“Optimizing models are commonly used to describe behavior not because they mimic the cognitive processes of the actors, which they rarely do, but because they capture important influences on individual behavior in a succinct and analytically tractable way.”
“Culture is an evolutionary force in its own right, not simply an effect of the interaction of genes and natural environments. […] human preferences and beliefs are the product of a dynamic whereby genes affect cultural evolution and culture affects genetic evolution, the two being tightly intertwined in the evolution of our species. [I have of course talked about gene-culture coevolution before here on the blog and I don’t like to repeat myself, but this idea/notion really is unknown to many people who should know better, and so is perhaps worth repeating here even so – US] […] The idea of treating culture as a form of epigenetic transmission was pioneered by Cavalli-Sforza and Feldman (1973), Karl Popper (1979), and Richard Dawkins, who coined the term “meme” […] to represent an integral unit of information that could be transmitted phenotypically. There quickly followed several major contributions to a biological approach to culture, all based on the notion that culture, like genes, could evolve through replication (intergenerational transmission), mutation, and selection […] Richard Dawkins added a second fundamental mechanism of epigenetic information transmission in The Extended Phenotype (1982), noting that organisms can directly transmit environmental artifacts to the next generation […] Creating a fitness-relevant aspect of an environment and stably transmitting this environment across generations, known as niche construction, is a widespread form of epigenetic transmission […] niche construction gives rise to what might be called a gene-environment coevolutionary process, since a genetically induced environmental regularity becomes the basis for genetic selection, and genetic mutations that give rise to mutant niches will tend to survive if they are fitness enhancing for their constructors. […] Human cultures, along with the institutional structures they support, are instances of niche construction”.
“while genetic transmission of information plays a central role in our account, the genetics of non-pathological social behavior is for the most part unknown. […] No “gene for cooperation” has been discovered. Nor is it likely that one will ever be found, for the idea of a one-to-one mapping between genes and behavior is unlikely given what is now known about gene expression, and is implausible in light of the complexity and cultural variation of cooperative behaviors. […] an explanation of the evolution of human cooperation must hinge on the empirical evidence. The question is not “Which model works?” They all work, if mathematical coherence is the bar. The question we are asking is about something that actually happened in the human past. Thus we measure the empirical plausibility of alternative explanations against the conditions under which early humans lived during the Pleistocene, roughly 1.6 million years before the present, until the advent of agriculture beginning about 12,000 years ago, and especially the last 100 or so millennia of this period.”
“in small-scale societies punishment can be highly effective even when it takes the form of ridicule or gossip and it inflicts no material costs on its targets. […] People are sensitive to others’ evaluation of their moral worth or intentions and will cooperate in social dilemmas when the punishment for free-riding takes the form of criticism by peers rather than a reduction in material payoffs. […] People punish not only those who have hurt them, but also those who hurt others. […] even self-regarding individuals may engage in third-party punishment if they believe that this will induce other-regarding individuals to behave favorably toward them. […] recent experimental results are consistent with the view that the social preferences that become salient in a population depend critically on the manner in which a people’s institutions and livelihood frame social interactions and shape the process of social learning. An expected result, confirmed by a growing body of international comparative evidence, is substantial cross-cultural differences in the nature and extent of social preferences.”
“In experimental and natural settings, people often behave differently toward others, depending on the organizational, linguistic, ethnic, and religious groups to which they belong. People choose to associate with others who are similar to themselves in some salient respect […] Among the salient characteristics on which this choice operates are racial and ethnic identification, and religion […] Conversely, people often seek to avoid interactions with those who are different from themselves. […] Those who condition their behavior on the group membership of the other may do this because group membership is thought to provide information about the other’s likely behavior. Or group membership may matter because people would like to help or to interact with members of some groups more than others. In the first case the actor’s beliefs are involved. In the second case, group-sensitive preferences are at work. […] a series of experiments by Toshio Yamagishi and his associates […] show that experimental subjects’ allocations favor in-group members not because of altruistic sentiments toward those who are similar to themselves, but because they expected reciprocation from in-groupers and not from out-groupers. […] taking account of ethnic, racial and other characteristics of those with whom one interacts appears to be a quite common human trait. We seem quite attuned to noticing and treating as salient the ascriptive markers of group difference. For example, Americans of European and African origin are better at recognizing faces of their own ancestral group, and faces of their own group induce greater activation in the part of the brain associated with face recognition.” (my bold)
“The most parsimonious and compelling proximate explanation of behavior in the ultimatum game, public goods game, and other social dilemma experiments is that people think that cooperating is the right thing to do and enjoy doing it, and that they dislike unfair treatment and enjoy punishing those who violate norms of fairness. […] Recent studies of brain functioning provide some support for this hedonic view of cooperative behavior.“
“Differential group success […] plays a central role in the evolution of human behaviors and institutions, members of less successful groups copying the more successful or being eliminated by them. […] the speed of an evolutionary process is proportional to the differences on which it works […] reduction in within-group differences slows down the selection against altruistic individuals. Insider biases and individual preferences to interact with like individuals lead to large between-group differences in behavior and, to a lesser but not negligible extent, in genotypes too […] insider biases result in frequent between-group conflicts as well as high levels of positive assortment in interactions both within and between groups. […] All of these aspects of human social life enhance the force of between-group selection relative to within-group selection.” (my bold)
“The fact that helping behaviors are […] motivated by [a] wide range of proximate motives, from maternal love, to enlightened self-interest, to solidarity with one’s coethnics or conationals, is consistent with our view that in all likelihood each of the mechanisms […] has played a significant role in human evolution, the importance of each depending on the forms of cooperation under consideration and the ecological and social conditions under which ancestral humans interacted. […] what can be known or reasonably conjectured from genetic, archaeological and other data about [the] ancestral human conditions suggests that neither helping close family members nor reciprocal altruism provides an adequate account of the emergence of [our] cooperative species. […] multi-level selection models based on gene culture coevolution [however] contribute substantially to a convincing explanation.”
As mentioned, if you find this kind of stuff interesting you should strongly consider reading the book.
“Data from animal studies in one country are usually comparable with that of another, provided the animal species and strain are the same. This provides a consistent picture of the basic pharmacological and toxicological actions of a candidate drug in a living organism […] it has been obvious since animal testing began that there would be large differences in the way a drug might perform in man compared with animal species […]. Unfortunately, there is no experimental model yet designed that can not only consider human biochemistry and physiology, but also the effects of age, smoking, legal and illegal drug usage, gender, diet, environment, disease and finally genetic variation. Indeed, many clinical studies have revealed enormous differences in drug clearance and pharmacological effect even in age, sex and ethnically matched individuals. In effect, this means that the first year or so of a drug’s clinical life is a vast, but monitored experiment, involving hundreds of thousands of patients and there is no guarantee of success.”
“Most biotransformational polymorphisms that might potentially cause a problem clinically are due to an inability of those with defective enzymes to remove the drug from the system. Drug failure can occur if the agent is administered as a pro-drug and requires some metabolic conversion to an active metabolite. Drug accumulation can lead to unpleasant side effects and loss of patient tolerance for the agent. […] Overall, there are a large number of factors that can influence drug metabolism, either by increasing clearance to cause drug failure, or by preventing clearance to lead to toxicity. In the real world, it is often impossible to delineate the different conflicting factors which result in net changes in drug clearance which cause a drug to fall out of, or climb above, the therapeutic window. It may only be possible clinically in many cases to try to change what appears to be the major cause to bring about a resolution of the situation to restore curative and non-toxic drug levels.”
“Most population studies of human polymorphisms list the allelic frequency, that is, how many of an ethnic group contain the alleles in question. […] The actual haplotypes in the population, that is, which individuals express which combinations of alleles, are not the same as the population allelic frequency. […] If an SNP or a combination of SNPs is a fairly mild defect in the enzyme when it is homozygously expressed, then the heterozygotes will show little impairment and the polymorphism may be clinically irrelevant. With other SNPs, the enzyme produced may be completely non-functional. Homozygotes will be virtually unable to clear the drug and heterozygotes will show impairment also. There are also smaller populations of UMs, or ultra rapid metabolizers which may have a feature of their enzyme which either makes it super efficient or expressed in abnormally high amounts. […] Phenotyping will group patients in very broad EMs [extensive metabolizers], IMs [intermediate metabolizers] or PM [poor metabolizers] categories, but will be unable to distinguish between heterozygous and homozygous EMs. Although genotyping may be very helpful in dosage estimation in the initiation of therapy, there is no substitute for the normal process of therapeutic monitoring, which is effectively phenotyping the individual in the real world in terms of maximizing response and minimizing toxicity.”
“it is clear that there is a vast amount of genetic variation across humanity in terms of biotransformational capability and so the idea that in therapeutics, ‘one size fits all’ is not only outdated, but fabulously naïve. […] Unfortunately, detecting and responding successfully to human biotransformational polymorphisms has proved to be extremely problematic. In terms of polymorphism detection, this area is a classic illustration of how the exploration of the human genome with powerful molecular biological tools may unearth many apparently marked polymorphic defects that may not necessarily translate into a measurable clinical impact in terms of efficacy and toxicity. In reality, many more scientists have the opportunity to discover and publish such polymorphisms in vitro, than there are clinical scientists, resources and indeed cooperative volunteers or patients in sufficient quantity to determine practical clinical relevance.”
“the CYP3A group (chromosome 7) metabolize around half of all drugs […] variation in the metabolism of CYP3A substrates […] can be up to ten-fold in terms of drug clearances and up to 90-fold in liver protein expression. […] It is likely that the full extent of the variation in CYP3A4 is still to be discovered […] While it is thought that CYP3A4 is not subject to an obvious major polymorphism, CYP3A5 definitely is. […] *3/*3 individuals form no serviceable CYP3A5. Functional CYP3A5 is found in around 20 per cent of Caucasians, half of Chinese/Japanese, 70 per cent of Hispanics and more than 80 per cent of African Americans.”
“A particularly dangerous polymorphism clinically was identified in the 1980s for one of the methyltransferases. The endogenous role of S-methylating thiopurine S-methyltransferase (TPMT) is not that clear, but […] [t]hese drugs are […] effective in some childhood leukaemias […] TPMT highlights the genotyping/phenotyping issue mentioned earlier in the management of patients with polymorphisms. Genotyping will reveal the level of TPMT expression that should be expected in the otherwise healthy patient. However, there are many factors which impact day-to-day TPMT expression during thiopurine therapy. […] Hence, what might be predicted from a genotype test may bear little resemblance to how the enzyme is performing on a particular day in a treatment cycle. So clinically, it is preferred to test actual TPMT activity.”
“Understanding of sulphonation and its roles in endogenous as well as xenobiotic metabolism is not as advanced compared with that of CYPs; however, the role of SULTs in the activation of carcinogens is becoming more apparent. One of the major influences on SULT activity is their polymorphic nature; in the case of one of the most important toxicologically relevant SULTs, SULT1A1, this isoform exists as three variants, SULT1A1*1 (wild-type), SULT1A1*2 and SULT1A1*3. The *1 variant allele is found in the majority of Caucasians (around 65 per cent), whilst the *2 variant differs only in the exchange of one amino acid for another. This single amino acid change has profound effects on the stability and catalytic activity of the isoform. The *2 variant is found in approximately 32 per cent of Caucasians and catalytically faulty […] About 9 in 10 Chinese people have the *1 allele and about 8 per cent have allele *2. About half of African-Americans have *1 and a third have *2. Interestingly, there is a *3 which is rare in most races but accounts for more than 22 per cent of African Americans. There is also considerable variation in SULT2A1 and SULT2B1, which are the major hydroxysteroid sulphators in the body, which may have implications for sex steroid and cholesterol handling. […] from the cancer-risk viewpoint, a highly active SULT1A1 *1 is usually an advantage in that it usually removes reactive species rapidly as stable sulphates. With some agents it is problematic as certain carcinogens such as acetylfluorene are indirectly activated to reactive species by SULTs. In addition, protective dietary flavonoids […] are also rapidly cleared by SULT1A1 *1, so there is a combination of production of toxins and loss of protective dietary agents. In terms of carcinogenesis risk, SULT1A1*2 could be a liability as potentially damaging substrates such as electrophilic toxins cannot be cleared rapidly. However, in some circumstances the *2 allele can be rather protective as […] it also allows protective agents [to] remain in tissues for longer periods. The combinations are endless and so it is often extremely difficult to predict risks of carcinogenicity for individuals and toxin exposures.”
“GSTs are polymorphic and much research has been directed at linking increased predisposition to cytotoxicity and carcinogenicity with defective GST phenotypes. Active wild-type GSTMu-1 is found in around 60 per cent of Caucasians, but a non-functional version of the isoform is found in the remainder. […] GST-M1 null (non-functional alleles) can predispose to risks of prostate abnormalities and GST Pi is subject to several SNPs and many attempts have been made to link these SNPs with the consequences of failure to detoxify reactive species, such as the risk of lung cancer. […] Carcinogenesis may be due to a complex mix of factors, where different enzyme expression and activities may combine with particular reactive species from specific parent xenobiotics that lead to DNA damage only in certain individuals. Resolving specific risk factors may be extremely difficult in such circumstances. […] in cancer chemotherapy, there is evidence that the presence of GST-M1 and GST-T1 null (non-functional) alleles predisposes children to a six-fold higher level of adverse events usually seen with antineoplastic drugs, such as bone marrow damage, nephrotoxicity and neurotoxicity.”
“The effects of age on drug clearance and metabolism have been known since the 1950s, but they have been extensively investigated in the last 20 or so years. It is now generally accepted that at the extremes of life, neonatal and geriatric, drug clearance can be significantly different from the rest of humanity. In general, neonates, i.e. those less than four weeks old, cannot clear certain agents due to immaturity of drug metabolizing systems. Those over retirement age cannot clear the drugs due to loss of efficiency in their metabolizing systems. Either way, the net result can be toxicity due to drug accumulation. […] It seems that the inability of older people to clear drugs is not necessarily related to the efficacy of their CYP-mediated oxidations, which are often not much different from that of younger individuals. Studies with the major CYPs in vitro have revealed that CYP2D6 is unaffected by age, as are most other CYPs, with the exception of CYP1A2, which does decline in activity in the elderly. […] In general, there is little significant change in the inducibility in most CYPs, or in the capability of conjugation systems in vitro. […] there are significant changes in the liver itself, as it decreases in mass and its blood flow is reduced as we age. This occurs at the rate of around 0.5–1.5 per cent per year, so by the time we hit 60–70, we may have up to a 40 per cent decline in liver blood flow compared with a 30-year-old. Other factors include gradual decline in renal function, increased fat deposits and reduction in gut blood flow, which affects absorption. […] The problem arises that the drug’s bioavailability increases due to lack of first-pass clearance; this means that from a standard dose, blood levels can be considerably higher than would be expected in a 40-year-old. This can be a serious problem in drugs with a narrow TI, such as antiarrhythmics. In addition, average doses of warfarin required to provide therapeutic anticoagulation in the elderly are less than half those required for younger people. The person’s lifelong smoking and drinking habits, as well as older individuals ’ sometimes erratic diet also complicate this situation. Among the drugs cleared more slowly in older people are antipsychotics, paracetamol, antidepressants, benzodiazepines, warfarin, beta-blockers and indomethicin.”
“Thousands of polyphenols are found in plants, vegetables, fruit, as well as tea, coffee, wine and fruit juices. […] Flavonoids such as quercetin and fisetin are excellent substrates for COMT, so competitively inhibiting the metabolism of endogenous catecholamine and catechol oestrogens. Quercetin and other polyphenols are found in various foods such as soy (genestein) and they are potent inhibitors of SULT1A1 which sulphate endogenous oestrogens, so potentiating the effects of oestrogens in the body. Many of these flavonoids and isoflavonoids are manufactured and sold as cancer preventative agents; however, it is more likely that their elevation of oestrogen levels may have the opposite effect in the long term. It is also likely that various polyphenols influence other endogenous substrates of sulphotransferases, such as thyroid hormones and various catecholamines. It is gradually becoming apparent that polyphenols can induce UGTs, indeed; it would be surprising if they did not. […] Overall, it is likely that there are a large number of polyphenols that are potent modulators of CYPs and conjugative enzymes. […] It is clear that diet can substantially modulate biotransformation […] As to the effects on prescription drugs, […] abrupt changes in a person’s diet may significantly alter the clearance of drugs and lead to loss of efficacy or toxicity.”
“In general, experimental or ‘probe’ drugs […] which are used to study the activities of a number of CYPs, are metabolized more quickly by women than men. This is allowing for differences in weight, fat distribution (body mass index) and volume of distribution […] It appears that CYP expression is linked to growth hormone (GH) and about the same amount is secreted over 24 hours in both sexes. In animals the pattern of release of the hormone is crucial to the effects on the CYPs; in females, GH is secreted in small but more or less continuous pulses, while males secrete large pulses, then periods of no secretion. The system is thought to be similar in humans. […] Little is known of the effects of the menopause and hormone replacement, where steroid metabolism changes dramatically. It is highly likely that these events could have profound effects on female drug clearance. […] females in general are more susceptible to drug adverse reactions than males, especially hepatotoxic effects.”
“For those chronically dependent on ethanol their CYP2E1 levels can be ten-fold higher than non-drinkers and they would clear CYP2E1 substrates extremely quickly if they chose to be sober for a period of time. This may lead to the accumulation of metabolites of the substrates. It is apparent that alcoholics who are sober can suffer paracetamol (acetaminophen)-induced liver toxicity at overdoses of around half that of non-drinkers, which is due to CYP2E1 induction. […] the vast variation in ADH [alcohol dehydrogenase] catalytic activity across the human race is mainly due to just a few SNPs that profoundly change the efficiency of the isoforms. ADH1B/*1 is the most effective variant and is the ADH wild-type […] Part of a ‘successful’ career as an alcoholic depends possessing the ADH1B/*1 isoform. The other defective isoforms are found in low frequencies in alcoholics and cirrhotics. […] in the vast majority of individuals, whatever their variant of ADH, they are able to process acetaldehyde to acetate and water, as the consequences of failing to do this are severe. With ALDH, the wild-type and gold standard is ALDH2*1/*1, which has the highest activity of all these isoforms and is the second essential component for an alcoholic career. […] the variant ALDH2*1/*2 has less than a quarter of the wild-type’s capacity and is found predominantly in Eastern races. The variant ALDH2*2/*2 is completely useless and renders the individuals very sensitive to acetaldehyde poisoning, although the toxin is removed eventually by ALDH1A1 which does not seem to be affected by polymorphisms. In a survey of 1300 Japanese alcoholics, there was nobody at all with the ALDH2*2/*2 variant. […] Women are much more vulnerable to ethanol damage and on average die in half the time it generally takes for a male alcoholic to drink himself to death. Women drink much less than men also – one study indicated that a group of women consumed about 14,000 drinks to induce cirrhosis, whilst men required more than 44,000 to achieve the same effect. Ethanol distributes in total body water only, so in women their greater fat content means that blood ethanol levels are higher than men of similar weight and age.“