Neurology Grand Rounds – Typical and Atypical Diabetic Neuropathy

The lecture is not particularly easy to follow if you’re not a neurologist, and/but I assume even neurologists might have difficulties with Liewluck’s (? the second guy’s…) contribution because that guy’s English pronunciation is not great. But if you’re the sort of person who watches neurology lectures online it’s well worth watching.

Said noted in his book on these topics that: “In general pharmacological treatments will not cause anywhere near complete pain relief: “For patients receiving pharmacological treatment, the average pain reduction is about 20-30%, and only 20-35% of patients will achieve at least a 50% pain reduction with available drugs. […] often only partial pain relief from neuropathic pain can be expected, and […] sensory deficits are unlikely to respond to treatment.” Treatment of neuropathic pain is often a trial-and-error process.”

These guys make an even stronger point than Said did: Diabetics who develop painful neuropathies do not get rid of the pain even with treatment – the pain can be managed, but it’s permanent in (…almost? …a few young type 1 diabetics, maybe? But the 60-year old neurologist had never encountered one of those, so odds are against you being one of the lucky ones…) every single case. This of course has some consequences for how patients should be managed – for example you want to devote some time and effort to managing expectations, so people don’t get/have unrealistic ideas about what the treatments which are available may actually accomplish. Another aspect related to this is which sort of treatment options to consider in such a setting, as also noted in the lecture – tolerance development is for example an easily foreseeable problem with opiate treatment which is likely to cause problems down the line if not addressed (but as I pointed out a few years ago, my impression is that: “‘it may not work particularly well in the long run, and there are a lot of side-effects’ is a better argument against [chronic opioid treatment] than the potential for addiction”).

June 23, 2017 Posted by | Medicine, Diabetes, Lectures, Pharmacology, Neurology | Leave a comment


Here’s what I wrote about the book on goodreads:

“I think the author was trying to do too much with this book. He covers a very large number of topics, but unfortunately the book is not easy to read because he covers in a few pages topics which other authors write entire books about. If he’d covered fewer topics in greater detail I think the end result would have been better. Despite having watched a large number of lectures on related topics and read academic texts about some of the topics covered in the book, I found the book far from easy to read, certainly compared to other physics books in this series (the books about nuclear physics and particle physics are both significantly easier to read, in my opinion). The author sometimes seemed to me to have difficulties understanding how large the potential knowledge gap between him and the reader of the book might be.

Worth reading if you know some stuff already and you’re willing to put in a bit of work, but don’t expect too much from the coverage.”

I gave the book two stars on goodreads.

I decided early on while reading the book that the only way I was going to cover this book at all here would be by posting a link-heavy post. I have added some quotes as well, but most of what’s going on in this book I’ll only cover by adding some relevant links to wiki articles dealing with these topics – as the link collection below should illustrate, although the subtitle of the book is ‘A Very Short Introduction’ it actually covers a great deal of ground (…too much ground, that’s part of the problem, as indicated above…). There are a lot of links because it’s just that kind of book.

First, a few quotes from the book:

“In thinking about the structure of an accretion disc it is helpful to imagine that it comprises a large number of solid rings, each of which spins as if each of its particles were in orbit around the central mass […] The speed of a circular orbit of radius r around a compact mass such as the Sun or a black hole is proportional to 1/r, so the speed increases inwards. It follows that there is shear within an accretion disc: each rotating ring slides past the ring just outside it, and, in the presence of any friction or viscosity within the fluid, each ring twists or torques the ring just outside it in the direction of rotation, trying to get it to rotate faster.

Torque is to angular momentum what force is to linear momentum: the quantity that sets its rate of change. Just as Newton’s laws yield that force is equal to rate of change of momentum, the rate of change of a body’s angular momentum is equal to the torque on the body. Hence the existence of the torque from smaller rings to bigger rings implies an outward transport of angular momentum through the accretion disc. When the disc is in a steady state this outward transport of angular momentum by viscosity is balanced by an inward transport of angular momentum by gas as it spirals inwards through the disc, carrying its angular momentum with it.”

“The differential equations that govern the motion of the planets are easily written down, and astronomical observations furnish the initial conditions to great precision. But with this precision we can predict the configuration of the planets only up to ∼ 40 Myr into the future — if the initial conditions are varied within the observational uncertainties, the predictions for 50 or 60 Myr later differ quite significantly. If you want to obtain predictions for 60 Myr that are comparable in precision to those we have for 40 Myr in the future, you require initial conditions that are 100 times more precise: for example, you require the current positions of the planets to within an error of 15m. If you want comparable predictions 60.15Myr in the future, you have to know the current positions to within 15mm.”

“An important feature of the solutions to the differential equations of the solar system is that after some variable, say the eccentricity of Mercury’s orbit, has fluctuated in a narrow range for millions of years, it will suddenly shift to a completely different range. This behaviour reflects the importance of resonances for the dynamics of the system: at some moment a resonant condition becomes satisfied and the flow of energy within the system changes because a small disturbance can accumulate over thousands or millions of cycles into a large effect. If we start the integrations from a configuration that differs ever so little from the previous configuration, the resonant condition will fail to be satisfied, or be satisfied much earlier or later, and the solutions will look quite different.”

“In Chapter 4 we saw that the physics of accretion discs around stars and black holes is all about the outward transport of angular momentum, and that moving angular momentum outwards heats a disc. Outward transport of angular momentum is similarly important for galactic discs. […] in a gaseous accretion disc angular momentum is primarily transported by the magnetic field. In a stellar disc, this job has to be done by the gravitational field because stars only interact gravitationally. Spiral structure provides the gravitational field needed to transport angular momentum outwards.

In addition to carrying angular momentum out through the stellar disc, spiral arms regularly shock interstellar gas, causing it to become denser, and a fraction of it to collapse into new stars. For this reason, spiral structure is most easily traced in the distribution of young stars, especially massive, luminous stars, because all massive stars are young. […] Spiral arms are waves of enhanced star density that propagate through a stellar disc rather as sound waves propagate through air. Like sound waves they carry energy, and this energy is eventually converted from the ordered form it takes in the wave to the kinetic energy of randomly moving stars. That is, spiral arms heat the stellar disc.”

“[I]f you take any reasonably representative group of galaxies, from the group’s luminosity, you can deduce the quantity of ordinary matter it should contain. This quantity proves to be roughly ten times the amount of ordinary matter that’s in the galaxies. So most ordinary matter must lie between the galaxies rather than within them.”

“The nature of a galaxy is largely determined by three numbers: its luminosity, its bulge-to-disc ratio, and the ratio of its mass of cold gas to the mass in stars. Since stars form from cold gas, this last ratio determines how youthful the galaxy’s stellar population is.

A youthful stellar population contains massive stars, which are short-lived, luminous, and blue […] An old stellar population contains only low-mass, faint, and red stars. Moreover, the spatial distribution of young stars can be very lumpy because the stars have not had time to be spread around the system […] a galaxy with a young stellar population looks very different from one with an old population: it is more lumpy/streaky, bluer, and has a higher luminosity than a galaxy of similar stellar mass with an old stellar population.”


Accretion disk.
Supermassive black hole.
Magnetorotational instability.
Astrophysical jet.
Herbig–Haro object.
SS 433.
Cygnus A.
Collimated light.
Light curve.
Lyman-alpha line.
Balmer series.
Star formation.
Stellar evolution.
Black-body radiation.
Helium flash.
White dwarf (featured article).
Planetary nebula.
Solar transition region.
Carbon detonation.
X-ray binary.
Inverse Compton scattering.
Quasi-periodic oscillation.
Urbain Le Verrier.
Perturbation theory.
Elliptic orbit.
Axial precession.
Orbital resonance.
Jupiter trojan (featured article).
Late Heavy Bombardment.
Lorentz factor.
Radio galaxy.
Gamma-ray burst (featured article).
Cosmic ray.
Hulse–Taylor binary.
Special relativity.
Lorentz covariance.
Lorentz transformation.
Relativistic Doppler effect.
Superluminal motion.
Fermi acceleration.
Shock waves in astrophysics.
Ram pressure.
Synchrotron radiation.
General relativity (featured article).
Gravitational redshift.
Gravitational lens.
Fermat’s principle.
SBS 0957+561.
Strong gravitational lensing/Weak gravitational lensing.
Gravitational microlensing.
Shapiro delay.
Gravitational wave.
Dark matter.
Dwarf spheroidal galaxy.
Luminosity function.
Lenticular galaxy.
Spiral galaxy.
Disc galaxy.
Elliptical galaxy.
Stellar dynamics.
Constant of motion.
Bulge (astronomy).
Interacting galaxy.
Coma cluster.
Galaxy cluster.
Anemic galaxy.
Decoupling (cosmology).

June 20, 2017 Posted by | Astronomy, Books, Physics | Leave a comment


(The Pestallozzi quotes below are from The Education of Man, a short and poor aphorism collection I can not possibly recommend despite the inclusion of quotes from it in this post.)

i. “Only a good conscience always gives man the courage to handle his affairs straightforwardly, openly and without evasion.” (Johann Heinrich Pestalozzi)

ii. “An intimate relationship in its full power is always a source of human wisdom and strength in relationships less intimate.” (-ll-)

iii. “Whoever is unwilling to help himself can be helped by no one.” (-ll-)

iv. “He who has filled his pockets in the service of injustice will have little good to say on behalf of justice.” (-ll-)

v. “It is Man’s fate that no one knows the truth alone; we all possess it, but it is divided up among us. He who learns from one man only, will never learn what the others know.” (-ll-)

vi. “No scoundrel is so wicked that he cannot at some point truthfully reprove some honest man” (-ll-)

vii. “The man too keenly aware of his good reputation is likely to have a bad one.” (-ll-)

viii. “Many words make an excuse anything but convincing.” (-ll-)

ix. “Fashions are usually seen in their true perspective only when they have gone out of fashion.” (-ll-)

x. “A thing that nobody looks for is seldom found.” (-ll-)

xi. “Many discoveries must have been stillborn or smothered at birth. We know only those which survived.” (William Ian Beardmore Beveridge)

xii. “Time is the most valuable thing a man can spend.” (Theophrastus)

xiii. “The only man who makes no mistakes is the man who never does anything.” (Theodore Roosevelt)

xiv. “It is hard to fail, but it is worse never to have tried to succeed.” (-ll-)

xv. “From their appearance in the Triassic until the end of the Creta­ceous, a span of 140 million years, mam­mals remained small and inconspicuous while all the ecological roles of large ter­restrial herbivores and carnivores were monopolized by dinosaurs; mammals did not begin to radiate and produce large species until after the dinosaurs had al­ready become extinct at the end of the Cretaceous. One is forced to conclude that dinosaurs were competitively su­perior to mammals as large land vertebrates.” (Robert T. Bakker)

xvi. “Plants and plant-eaters co-evolved. And plants aren’t the passive partners in the chain of terrestrial life. […] A birch tree doesn’t feel cosmic fulfillment when a moose munches its leaves; the tree species, in fact, evolves to fight the moose, to keep the animal’s munching lips away from vulnerable young leaves and twigs. In the final analysis, the merciless hand of natural selection will favor the birch genes that make the tree less and less palatable to the moose in generation after generation. No plant species could survive for long by offering itself as unprotected fodder.” (-ll-)

xvii. “… if you look at crocodiles today, they aren’t really representative of what the lineage of crocodiles look like. Crocodiles are represented by about 23 species, plus or minus a couple. Along that lineage the more primitive members weren’t aquatic. A lot of them were bipedal, a lot of them looked like little dinosaurs. Some were armored, others had no teeth. They were all fully terrestrial. So this is just the last vestige of that radiation that we’re seeing. And the ancestor of both dinosaurs and crocodiles would have, to the untrained eye, looked much more like a dinosaur.” (Mark Norell)

xviii. “If we are to understand the interactions of a large number of agents, we must first be able to describe the capabilities of individual agents.” (John Henry Holland)

xix. “Evolution continually innovates, but at each level it conserves the elements that are recombined to yield the innovations.” (-ll-)

xx. “Model building is the art of selecting those aspects of a process that are relevant to the question being asked. […] High science depends on this art.” (-ll-)

June 19, 2017 Posted by | Biology, Books, Botany, Evolutionary biology, Paleontology, Quotes/aphorisms | Leave a comment

A few papers

i. To Conform or to Maintain Self-Consistency? Hikikomori Risk in Japan and the Deviation From Seeking Harmony.

A couple of data points and observations from the paper:

“There is an increasing number of youth in Japan who are dropping out of society and isolating themselves in their bedrooms from years to decades at a time. According to Japan’s Ministry of Health, Labor and Welfare’s first official 2003 guidelines on this culture-bound syndrome, hikikomori (social isolation syndrome) has the following specific diagnostic criteria: (1) no motivation to participate in school or work; (2) no signs of schizophrenia or any other known psychopathologies; and (3) persistence of social withdrawal for at least six months.”

“One obvious dilemma in studying hikikomori is that most of those suffering from hikikomori, by definition, do not seek treatment. More importantly, social isolation itself is not even a symptom of any of the DSM diagnosis often assigned to an individual afflicted with hikikomori […] The motivation for isolating oneself among a hikikomori is simply to avoid possible social interactions with others who might know or judge them (Zielenziger, 2006).”

“Saito’s (2010) and Sakai and colleagues’ (2011) data suggest that 10% to 15% of the hikikomori population suffer from an autism spectrum disorder. […] in the first epidemiological study conducted on hikikomori that was as close to a nation-wide random sample as possible, Koyama and colleagues (2010) conducted a face-to-face household survey, including a structured diagnostic interview, by randomly picking households and interviewing 4,134 individuals. They confirmed a hikikomori lifetime prevalence rate of 1.2% in their nationwide sample. Among these hikikomori individuals, the researchers found that only half suffered from a DSM-IV diagnosis. However, and more importantly, there was no particular diagnosis that was systematically associated with hikikomori. […] the researchers concluded that any DSM diagnosis was an epiphenomenon to hikikomori at best and that hikikomori is rather a “psychopathology characterized by impaired motivation” p. 72).”

ii. Does the ‘hikikomori’ syndrome of social withdrawal exist outside Japan?: A preliminary international investigation.


To explore whether the ‘hikikomori’ syndrome (social withdrawal) described in Japan exists in other countries, and if so, how patients with the syndrome are diagnosed and treated.


Two hikikomori case vignettes were sent to psychiatrists in Australia, Bangladesh, India, Iran, Japan, Korea, Taiwan, Thailand and the USA. Participants rated the syndrome’s prevalence in their country, etiology, diagnosis, suicide risk, and treatment.


Out of 247 responses to the questionnaire (123 from Japan and 124 from other countries), 239 were enrolled in the analysis. Respondents’ felt the hikikomori syndrome is seen in all countries examined and especially in urban areas. Biopsychosocial, cultural, and environmental factors were all listed as probable causes of hikikomori, and differences among countries were not significant. Japanese psychiatrists suggested treatment in outpatient wards and some did not think that psychiatric treatment is necessary. Psychiatrists in other countries opted for more active treatment such as hospitalization.


Patients with the hikikomori syndrome are perceived as occurring across a variety of cultures by psychiatrists in multiple countries. Our results provide a rational basis for study of the existence and epidemiology of hikikomori in clinical or community populations in international settings.”

“Our results extend rather than clarify the debate over diagnosis of hikikomori. In our survey, a variety of diagnoses, such as psychosis, depression anxiety and personality disorders, were proffered. Opinions as to whether hikikomori cases can be diagnosed using ICD-10/DSV-IV criteria differed depending on the participants’ countries and the cases’ age of onset. […] a recent epidemiological survey in Japan reported approximately a fifty-fifty split between hikikomori who had experienced a psychiatric disorder and had not [14]. These data and other studies that have not been able to diagnose all cases of hikikomori may suggest the existence of ‘primary hikikomori’ that is not an expression of any other psychiatric disorder [28,8,9,5,29]. In order to clarify differences between ‘primary hikikomori’ (social withdrawal not associated with any underlying psychiatric disorder) and ‘secondary hikikomori’ (social withdrawal caused by an established psychiatric disorder), further epidemiological and psychopathological studies are needed. […] Even if all hikikomori cases prove to be within some kind of psychiatric disorders, it is valuable to continue to focus on the hikikomori phenomenon because of its associated morbidity, similar to how suicidality is examined in various fields of psychiatry [30]. Reducing the burden of hikikomori symptoms, regardless of what psychiatric disorders patients may have, may provide a worthwhile improvement in their quality of life, and this suggests another direction of future hikikomori research.”

“Our case vignette survey indicates that the hikikomori syndrome, previously thought to exist only in Japan, is perceived by psychiatrists to exist in many other countries. It is particularly perceived as occurring in urban areas and might be associated with rapid global sociocultural changes. There is no consensus among psychiatrists within or across countries about the causes, diagnosis and therapeutic interventions for hikikomori yet.”

iii. Hikikomori: clinical and psychopathological issues (review). A poor paper, but it did have a little bit of data of interest:

“The prevalence of hikikomori is difficult to assess […]. In Japan, more than one million cases have been estimated by experts, but there is no population-based study to confirm these data (9). […] In 2008, Kiyota et al. summarized 3 population-based studies involving 12 cities and 3951 subjects, highlighting that a percentage comprised between 0.9% and 3.8% of the sample had an hikikomori history in anamnesis (11). The typical hikikomori patient is male (4:1 male-to-female ratio) […] females constitute a minor fraction of the reported cases, and usually their period of social isolation is limited.”

iv. Interpreting results of ethanol analysis in postmortem specimens: A review of the literature.

A few observations from the paper:

“A person’s blood-alcohol concentration (BAC) and state of inebriation at the time of death is not always easy to establish owing to various postmortem artifacts. The possibility of alcohol being produced in the body after death, e.g. via microbial contamination and fermentation is a recurring issue in routine casework. If ethanol remains unabsorbed in the stomach at the time of death, this raises the possibility of continued local diffusion into surrounding tissues and central blood after death. Skull trauma often renders a person unconscious for several hours before death, during which time the BAC continues to decrease owing to metabolism in the liver. Under these circumstances blood from an intracerebral or subdural clot is a useful specimen for determination of ethanol. Bodies recovered from water are particular problematic to deal with owing to possible dilution of body fluids, decomposition, and enhanced risk of microbial synthesis of ethanol. […] Alcoholics often die at home with zero or low BAC and nothing more remarkable at autopsy than a fatty liver. Increasing evidence suggests that such deaths might be caused by a pronounced ketoacidosis.”

“The concentrations of ethanol measured in blood drawn from different sampling sites tend to vary much more than expected from inherent variations in the analytical methods used [49]. Studies have shown that concentrations of ethanol and other drugs determined in heart blood are generally higher than in blood from a peripheral vein although in any individual case there are likely to be considerable variations [50–53].”

“The BAC necessary to cause death is often an open question and much depends on the person’s age, drinking experience and degree of tolerance development [78]. The speed of drinking plays a role in alcohol toxicity as does the kind of beverage consumed […] Drunkenness and hypothermia represent a dangerous combination and deaths tend to occur at a lower BAC when people are exposed to cold, such as, when an alcoholic sleeps outdoors in the winter months [78]. Drinking large amounts of alcohol to produce stupor and unconsciousness combined with positional asphyxia or inhalation of vomit are common causes of death in intoxicated individuals who die of suffocation [81–83]. The toxicity of ethanol is often considerably enhanced by the concomitant use of other drugs with their site of action in the brain, especially opiates, propoxyphene, antidepressants and some sedative hypnotics [84]. […] It seems reasonable to assume that the BAC at autopsy will almost always be lower than the maximum BAC reached during a drinking binge, owing to metabolism of ethanol taking place up until the moment of death [85–87]. During the time after discontinuation of drinking until death, the BAC might decrease appreciably depending on the speed of alcohol elimination from blood, which in heavy drinkers could exceed 20 or 30 mg/100 mL per h (0.02 or 0.03 g% per h) [88].”

“When the supply of oxygen to the body ends, the integrity of cell membranes and tissue compartments gradually disintegrate through the action of various digestive enzymes. This reflects the process of autolysis (self digestion) resulting in a softening and liquefaction of the tissue (freezing the body prevents autolysis). During this process, bacteria from the bowel invade the surrounding tissue and vascular system and the rate of infiltration depends on many factors including the ambient temperature, position of the body and whether death was caused by bacterial infection. Glucose concentrations increase in blood after death and this sugar is probably the simplest substrate for microbial synthesis of ethanol [20,68]. […] Extensive trauma to a body […] increases the potential for spread of bacteria and heightens the risk of ethanol production after death [217]. Blood-ethanol concentrations as high as 190 mg/100 mL have been reported in postmortem blood after particularly traumatic events such as explosions and when no evidence existed to support ingestion of ethanol before the disaster [218].”

v. Interventions based on the Theory of Mind cognitive model for autism spectrum disorder (ASD) (Cochrane review).

“The ‘Theory of Mind’ (ToM) model suggests that people with autism spectrum disorder (ASD) have a profound difficulty understanding the minds of other people – their emotions, feelings, beliefs, and thoughts. As an explanation for some of the characteristic social and communication behaviours of people with ASD, this model has had a significant influence on research and practice. It implies that successful interventions to teach ToM could, in turn, have far-reaching effects on behaviours and outcome.”

“Twenty-two randomised trials were included in the review (N = 695). Studies were highly variable in their country of origin, sample size, participant age, intervention delivery type, and outcome measures. Risk of bias was variable across categories. There were very few studies for which there was adequate blinding of participants and personnel, and some were also judged at high risk of bias in blinding of outcome assessors. There was also evidence of some bias in sequence generation and allocation concealment.”

“Studies were grouped into four main categories according to intervention target/primary outcome measure. These were: emotion recognition studies, joint attention and social communication studies, imitation studies, and studies teaching ToM itself. […] There was very low quality evidence of a positive effect on measures of communication based on individual results from three studies. There was low quality evidence from 11 studies reporting mixed results of interventions on measures of social interaction, very low quality evidence from four studies reporting mixed results on measures of general communication, and very low quality evidence from four studies reporting mixed results on measures of ToM ability. […] While there is some evidence that ToM, or a precursor skill, can be taught to people with ASD, there is little evidence of maintenance of that skill, generalisation to other settings, or developmental effects on related skills. Furthermore, inconsistency in findings and measurement means that evidence has been graded of ‘very low’ or ‘low’ quality and we cannot be confident that suggestions of positive effects will be sustained as high-quality evidence accumulates. Further longitudinal designs and larger samples are needed to help elucidate both the efficacy of ToM-linked interventions and the explanatory value of the ToM model itself.”

vi. Risk of Psychiatric and Neurodevelopmental Disorders Among Siblings of Probands With Autism Spectrum Disorders.

“The Finnish Prenatal Study of Autism and Autism Spectrum Disorders used a population-based cohort that included children born from January 1, 1987, to December 31, 2005, who received a diagnosis of ASD by December 31, 2007. Each case was individually matched to 4 control participants by sex and date and place of birth. […] Among the 3578 cases with ASD (2841 boys [79.4%]) and 11 775 controls (9345 boys [79.4%]), 1319 cases (36.9%) and 2052 controls (17.4%) had at least 1 sibling diagnosed with any psychiatric or neurodevelopmental disorder (adjusted RR, 2.5; 95% CI, 2.3-2.6).”

Conclusions and Relevance Psychiatric and neurodevelopmental disorders cluster among siblings of probands with ASD. For etiologic research, these findings provide further evidence that several psychiatric and neurodevelopmental disorders have common risk factors.”

vii. Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child (Cochrane review).

“Accumulating evidence suggests an association between prenatal exposure to antiepileptic drugs (AEDs) and increased risk of both physical anomalies and neurodevelopmental impairment. Neurodevelopmental impairment is characterised by either a specific deficit or a constellation of deficits across cognitive, motor and social skills and can be transient or continuous into adulthood. It is of paramount importance that these potential risks are identified, minimised and communicated clearly to women with epilepsy.”

“Twenty-two prospective cohort studies were included and six registry based studies. Study quality varied. […] the IQ of children exposed to VPA [sodium valproate] (n = 112) was significantly lower than for those exposed to CBZ [carbamazepine] (n = 191) (MD [mean difference] 8.69, 95% CI 5.51 to 11.87, P < 0.00001). […] IQ was significantly lower for children exposed to VPA (n = 74) versus LTG [lamotrigine] (n = 84) (MD -10.80, 95% CI -14.42 to -7.17, P < 0.00001). DQ [developmental quotient] was higher in children exposed to PHT (n = 80) versus VPA (n = 108) (MD 7.04, 95% CI 0.44 to 13.65, P = 0.04). Similarly IQ was higher in children exposed to PHT (n = 45) versus VPA (n = 61) (MD 9.25, 95% CI 4.78 to 13.72, P < 0.0001). A dose effect for VPA was reported in six studies, with higher doses (800 to 1000 mg daily or above) associated with a poorer cognitive outcome in the child. We identified no convincing evidence of a dose effect for CBZ, PHT or LTG. Studies not included in the meta-analysis were reported narratively, the majority of which supported the findings of the meta-analyses.”

“The most important finding is the reduction in IQ in the VPA exposed group, which are sufficient to affect education and occupational outcomes in later life. However, for some women VPA is the most effective drug at controlling seizures. Informed treatment decisions require detailed counselling about these risks at treatment initiation and at pre-conceptual counselling. We have insufficient data about newer AEDs, some of which are commonly prescribed, and further research is required. Most women with epilepsy should continue their medication during pregnancy as uncontrolled seizures also carries a maternal risk.”

Do take note of the effect sizes reported here. To take an example, the difference between being treated with valproate and lamotrigine might equal 10 IQ points in the child – these are huge effects.

June 11, 2017 Posted by | Medicine, Neurology, Pharmacology, Psychiatry, Psychology, Studies | Leave a comment

Harnessing phenotypic heterogeneity to design better therapies

Unlike many of the IAS lectures I’ve recently blogged this one is a new lecture – it was uploaded earlier this week. I have to say that I was very surprised – and disappointed – that the treatment strategy discussed in the lecture had not already been analyzed in a lot of detail and been implemented in clinical practice for some time. Why would you not expect the composition of cancer cell subtypes in the tumour microenvironment to change when you start treatment – in any setting where a subgroup of cancer cells has a different level of responsiveness to treatment than ‘the average’, that would to me seem to be the expected outcome. And concepts such as drug holidays and dose adjustments as treatment responses to evolving drug resistance/treatment failure seem like such obvious approaches to try out here (…the immunologists dealing with HIV infection have been studying such things for decades). I guess ‘better late than never’.

A few papers mentioned/discussed in the lecture:

Impact of Metabolic Heterogeneity on Tumor Growth, Invasion, and Treatment Outcomes.
Adaptive vs continuous cancer therapy: Exploiting space and trade-offs in drug scheduling.
Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer.

June 11, 2017 Posted by | Cancer/oncology, Genetics, Immunology, Lectures, Mathematics, Medicine, Studies | Leave a comment

Computer Science

I have enjoyed the physics books I’ve recently read in the ‘…A very short introduction’-series by Oxford University Press, so I figured it might make sense to investigate whether the series also has some decent coverage of other areas of research. I must however admit that I didn’t think too much of Dasgupta’s book. I think the author was given a very tough task. Having an author write a decent short book on a reasonably well-defined sub-topic of physics makes sense, whereas having him write the same sort of short and decent book about the entire field of ‘physics’ is a different matter. In some sense something analogous to this was what Dasgupta had been asked to do(/had undertaken to do?). Of course computer science is a relatively new field so arguably the analogy doesn’t completely hold; even if you cover every major topic in computer science there might still be significantly less ground to cover here than there would be, had he been required to cover everything from Newton (…Copernicus? Eudoxus of Cnidus? Gan De?) to modern developments in M-theory, but the main point stands; the field is much too large for a book like this to do more than perhaps very carefully scratch the surfaces of a few relevant subfields, making the author’s entire endeavour exceedingly difficult to pull off successfully. I noted while reading the book that document searches for ‘graph theory’ and ‘discrete mathematics’ yielded zero results, and I assume that many major topics/areas of relevance are simply not mentioned at all, which to be fair is but to be expected considering the format of the book. The book could have been a lot worse, but it wasn’t all that great – I ended up giving it two stars on goodreads.

My coverage of the book here on the blog will be relatively lazy: I’ll only include links in this post, not quotes from the book – I looked up a lot of links to coverage of relevant concepts and topics also covered in the book while reading it, and I have added many of these links below. The links should give you some idea of which sort of topics are covered in the publication.

Church–Turing thesis.
Turing machine.
Automata theory.
Donald Knuth.
Procedural knowledge.
Machine code.
Infix notation.
Polish notation.
Time complexity.
Linear search.
Big O notation.
Computational complexity theory.
P versus NP problem.
Programming language.
Assembly language.
Hardware description language.
Data type (computer science).
Statement (computer science).
Instruction cycle.
Assignment (computer science).
Computer architecture.
Control unit.
Computer memory.
Memory buffer register.
Cache (computing).
Parallel computing (featured article).
Instruction pipelining.
Amdahl’s law.
FCFS algorithm.
Exact algorithm.
Artificial intelligence.
Means-ends analysis.

June 8, 2017 Posted by | Books, Computer science | Leave a comment

Cosmology: Recent Results and Future Prospects

This is another old lecture from my bookmarks. I’m reasonably certain the main reason why I did not blog this earlier is that it’s a rather general and not very detailed overview lecture, so it doesn’t actually contain a lot of new stuff. Hubble’s work, the discovery of the cosmic microwave background, properties of the early universe and how it evolved, discussion of the cosmological constant, dark matter and dark energy, some recent observational results – most of the stuff he talks about should be familiar territory to people interested in the field. Before I watched the lecture I had expected it to include a lot more ‘recent results’ and ‘future prospects’ than were actually included; a big part of the lecture is just an overview of what we’ve learned since the 1930es.

June 7, 2017 Posted by | Astronomy, Lectures, Physics | Leave a comment

Nuclear physics

Below I have posted a few observations from the book, as well as a number of links to coverage of other topics mentioned/covered in the book. It’s a good book, the level of coverage is very decent considering the format of the publication.

“Electrons are held in place, remote from the nucleus, by the electrical attraction of opposite charges, electrons being negatively and the atomic nucleus positively charged. A temperature of a few thousand degrees is sufficient to break this attraction completely and liberate all of the electrons from within atoms. Even room temperature can be enough to release one or two; the ease with which electrons can be moved from one atom to another is the source of chemistry, biology, and life.”

“Quantum mechanics explains the behaviour of electrons in atoms, and of nucleons in nuclei. In an atom, electrons cannot go just where they please, but are restricted like someone on a ladder who can only step on individual rungs. When an electron drops from a rung with high energy to one that is lower down, the excess energy is carried away by a photon of light. The spectrum of these photons reveals the pattern of energy levels within the atom. Similar constraints apply to nucleons in nuclei. Nuclei in excited states, with one or more protons or neutrons on a high rung, also give up energy by emitting photons. The main difference between what happens to atomic electrons relative to atomic nuclei is the nature of the radiated light. In the former the light may be in the visible spectrum, whose photons have relatively low energy, whereas in the case of nuclei the light consists of X-rays and gamma rays, whose photons have energies that are millions of times greater. This is the origin of gamma radioactivity.”

“[A]ll particles that feel the strong interaction are made of quarks. […] Quarks that form nuclear particles come in two flavours, known as up (u) or down (d), with electrical charges that are fractions, +2/3 or −1/3 respectively, of a proton’s charge. Thus uud forms a proton and ddu a neutron. In addition to electrical charge, quarks possess another form of charge, known as colour. This is the fundamental source of the strong nuclear force. Whereas electric charge occurs in some positive or negative numerical amount, for colour charge there are three distinct varieties of each. These are referred to as red, green, or blue, by analogy with colours, but are just names and have no deeper significance. […] colour charge and electric charge obey very similar rules. For example, analogous to the behaviour of electric charge, colour charges of the same colour repel, whereas different colours can attract […]. A proton or neutron is thus formed when three quarks, each with a different colour, mutually attract one another. In this configuration the colour forces have neutralized, analogous to the way that positive and negative charges neutralize within an atom.”

“The relativistic quantum theory of colour is known as quantum chromodynamics (QCD). It is similar in spirit to quantum electrodynamics (QED). QED implies that the electromagnetic force is transmitted by the exchange of massless photons; by analogy, in QCD the force between quarks, within nucleons, is due to the exchange of massless gluons.”

“In a nutshell, the quarks in heavy nuclei are found to have, on average, slightly lower momenta than in isolated protons or neutrons. In spatial terms, this equates with the interpretation that individual quarks are, on average, less confined than in free nucleons. […] The overall conclusion is that the quarks are more liberated in nuclei when in a region of relatively high density. […] This interpretation of the microstructure of atomic nuclei suggests that nuclei are more than simply individual nucleons bound by the strong force. There is a tendency, under extreme pressure or density, for them to merge, their constituent quarks freed to flow more liberally. […] This freeing of quarks is a liberation of colour charges, and in theory should happen for gluons also. Thus, it is a precursor of what is hypothesized to occur within atomic nuclei under conditions of extreme temperature and pressure […] atoms are unable to survive at high temperatures and pressure, as in the sun for example, and their constituent electric charges—electrons and protons—flow independently as electrically charged gases. This is a state of matter known as plasma. Analogously, under even more extreme conditions, the coloured quarks are unable to configure into individual neutrons and protons. Instead, the quarks and gluons are theorized to flow freely as a quark–gluon plasma (QGP).”

“The mass of a nucleus is not simply the sum of the masses of its constituent nucleons. […] some energy is taken up to bind the nucleus together. This ‘binding energy’ is the difference between the mass of the nucleus and its constituents. […] The larger the binding energy, the greater is the propensity for the nucleus to be stable. Its actual stability is often determined by the relative size of the binding energy of the nucleus to that of its near neighbours in the periodic table of elements, or of other isotopes of the original elemental nucleus. As nature seeks stability by minimizing energy, a nucleus will seek to lower the total mass, or equivalently, to increase the binding energy. […] An effective guide to stability, and the pattern of radioactive decays, is given by the semi-empirical mass formula (SEMF).”

“For light nuclei the binding energy grows with A [the mass of the nucleus – US] until electrostatic repulsion takes over in large nuclei. […] At large values of Z [# of protons – US], the penalty of electrostatic charge, which extends throughout the nucleus, requires further neutrons to add to the short range attraction in compensation. Eventually, for Z > 82, the amount of electrostatic repulsion is so large that nuclei cannot remain stable, even when they have large numbers of neutrons. […] All nuclei heavier than lead are radioactive.”

“Three minutes after the big bang, the material universe consisted primarily of the following: 75% protons; 24% helium nuclei; a small number of deuterons; traces of lithium, beryllium, and boron, and free electrons. […] 300,000 years later, the ambient temperature had fallen below 10,000 degrees, that is similar to or cooler than the outer regions of our sun today. At these energies the negatively charged electrons were at last able to be held fast by electrical attraction to the positively charged atomic nuclei whereby they combined to form neutral atoms. Electromagnetic radiation was set free and the universe became transparent as light could roam unhindered across space.
The big bang did not create the elements necessary for life, such as carbon, however. Carbon is the next lightest element after boron, but its synthesis presented an insuperable barrier in the very early universe. The huge stability of alpha particles frustrates attempts to make carbon by collisions between any pair of lighter isotopes. […] Thus no carbon or heavier isotopes were formed during big bang nucleosynthesis. Their synthesis would require the emergence of stars.”

“In the heat of the big bang, quarks and gluons swarmed independently in quark–gluon plasma. Inside the sun, relatively cool, they form protons but the temperature is nonetheless too high for atoms to survive. Thus inside the sun, electrons and protons swarm independently as electrical plasma. It is primarily protons that fuel the sun today. […] Protons can bump into one another and initiate a set of nuclear processes that eventually converts four of them into helium-4 […] As the energy mc² locked into a single helium-4 nucleus is less than that in the original four protons, the excess is released into the surroundings, some of it eventually providing warmth here on earth. […] because the sun produces these reactions continuously over aeons, unlike big bang nucleosynthesis, which lasted mere minutes, unstable isotopes, such as tritium, play no role in solar nucleosynthesis.”

“Although individual antiparticles are regularly produced from the energy in collisions between cosmic rays, or in accelerator laboratories such as at CERN, there is no evidence for antimatter in bulk in the universe at large. […] To date, all the evidence is that the universe at large is made of matter to the exclusion of antimatter. […] One of the great mysteries in physics is how the symmetry between matter and antimatter was disturbed.”

Some links:

Nuclear physics.
Alpha decay/beta decay/gamma radiation.
Positron emission.
Rutherford model.
Bohr model.
Nuclear fission.
X-ray crystallography.
EMC effect.
Magic number.
Cosmic ray spallation.
Asymptotic giant branch.
CNO cycle.
Transuranium elements.
Island of stability.
Transfermium Wars.
Nuclear drip line.
Halo nucleus.
Lambda baryon.
Quark star.
Radiation therapy.
Rutherford backscattering spectrometry.
Particle-induced X-ray emission.

June 5, 2017 Posted by | Books, Physics | Leave a comment

A few papers

i. Quality of life of adolescents with autism spectrum disorders: comparison to adolescents with diabetes.

“The goals of our study were to clarify the consequences of autistic disorder without mental retardation on […] adolescents’ daily lives, and to consider them in comparison with the impact of a chronic somatic disease (diabetes) […] Scores for adolescents with ASD were significantly lower than those of the control and the diabetic adolescents, especially for friendships, leisure time, and affective and sexual relationships. On the other hand, better scores were obtained for the relationships with parents and teachers and for self-image. […] For subjects with autistic spectrum disorders and without mental retardation, impairment of quality of life is significant in adolescence and young adulthood. Such adolescents are dissatisfied with their relationships, although they often have real motivation to succeed with them.”

As someone who has both conditions, that paper was quite interesting. A follow-up question of some personal interest to me would of course be this: How do the scores/outcomes of these two groups compare to the scores of the people who have both conditions simultaneously? This question is likely almost impossible to answer in any confident manner, certainly if the conditions are not strongly dependent (unlikely), considering the power issues; global prevalence of autism is around 0.6% (link), and although type 1 prevalence is highly variable across countries, the variation just means that in some countries almost nobody gets it whereas in other countries it’s just rare; prevalence varies from 0.5 per 100.000 to 60 per 100.000 children aged 0-15 years. Assuming independence, if you look at combinations of the sort of conditions which affect one in a hundred people with those affecting one in a thousand, you’ll need on average in the order of 100.000 people to pick up just one individual with both of the conditions of interest. It’s bothersome to even try to find people like that, and good luck doing any sort of sensible statistics on that kind of sample. Of course type 1 diabetes prevalence increases with age in a way that autism does not because people continue to be diagnosed with it into late adulthood, whereas most autistics are diagnosed as children, so this makes the rarity of the condition less of a problem in adult samples, but if you’re looking at outcomes it’s arguable whether it makes sense to not differentiate between someone diagnosed with type 1 diabetes as a 35 year old and someone diagnosed as a 5 year old (are these really comparable diseases, and which outcomes are you interested in?). At least that is the case for developed societies where people with type 1 diabetes have high life expectancies; in less developed societies there may be stronger linkage between incidence and prevalence because of high mortality in the patient group (because people who get type 1 diabetes in such countries may not live very long because of inadequate medical care, which means there’s a smaller disconnect between how many new people get the disease during each time period and how many people in total have the disease than is the case for places where the mortality rates are lower). You always need to be careful about distinguishing between incidence and prevalence when dealing with conditions like T1DM with potential high mortality rates in settings where people have limited access to medical care because differential cross-country mortality patterns may be important.

ii. Exercise for depression (Cochrane review).


Depression is a common and important cause of morbidity and mortality worldwide. Depression is commonly treated with antidepressants and/or psychological therapy, but some people may prefer alternative approaches such as exercise. There are a number of theoretical reasons why exercise may improve depression. This is an update of an earlier review first published in 2009.


To determine the effectiveness of exercise in the treatment of depression in adults compared with no treatment or a comparator intervention. […]

Selection criteria 

Randomised controlled trials in which exercise (defined according to American College of Sports Medicine criteria) was compared to standard treatment, no treatment or a placebo treatment, pharmacological treatment, psychological treatment or other active treatment in adults (aged 18 and over) with depression, as defined by trial authors. We included cluster trials and those that randomised individuals. We excluded trials of postnatal depression.

Thirty-nine trials (2326 participants) fulfilled our inclusion criteria, of which 37 provided data for meta-analyses. There were multiple sources of bias in many of the trials; randomisation was adequately concealed in 14 studies, 15 used intention-to-treat analyses and 12 used blinded outcome assessors.For the 35 trials (1356 participants) comparing exercise with no treatment or a control intervention, the pooled SMD for the primary outcome of depression at the end of treatment was -0.62 (95% confidence interval (CI) -0.81 to -0.42), indicating a moderate clinical effect. There was moderate heterogeneity (I² = 63%).

When we included only the six trials (464 participants) with adequate allocation concealment, intention-to-treat analysis and blinded outcome assessment, the pooled SMD for this outcome was not statistically significant (-0.18, 95% CI -0.47 to 0.11). Pooled data from the eight trials (377 participants) providing long-term follow-up data on mood found a small effect in favour of exercise (SMD -0.33, 95% CI -0.63 to -0.03). […]

Authors’ conclusions

Exercise is moderately more effective than a control intervention for reducing symptoms of depression, but analysis of methodologically robust trials only shows a smaller effect in favour of exercise. When compared to psychological or pharmacological therapies, exercise appears to be no more effective, though this conclusion is based on a few small trials.”

iii. Risk factors for suicide in individuals with depression: A systematic review.

“The search strategy identified 3374 papers for potential inclusion. Of these, 155 were retrieved for a detailed evaluation. Thirty-two articles fulfilled the detailed eligibility criteria. […] Nineteen studies (28 publications) were included. Factors significantly associated with suicide were: male gender (OR = 1.76, 95% CI = 1.08–2.86), family history of psychiatric disorder (OR = 1.41, 95% CI= 1.00–1.97), previous attempted suicide (OR = 4.84, 95% CI = 3.26–7.20), more severe depression (OR = 2.20, 95% CI = 1.05–4.60), hopelessness (OR = 2.20, 95% CI = 1.49–3.23) and comorbid disorders, including anxiety (OR = 1.59, 95% CI = 1.03–2.45) and misuse of alcohol and drugs (OR = 2.17, 95% CI = 1.77–2.66).
Limitations: There were fewer studies than suspected. Interdependence between risk factors could not be examined.”

iv. Cognitive behaviour therapy for social anxiety in autism spectrum disorder: a systematic review.

“Individuals who have autism spectrum disorders (ASD) commonly experience anxiety about social interaction and social situations. Cognitive behaviour therapy (CBT) is a recommended treatment for social anxiety (SA) in the non-ASD population. Therapy typically comprises cognitive interventions, imagery-based work and for some individuals, behavioural interventions. Whether these are useful for the ASD population is unclear. Therefore, we undertook a systematic review to summarise research about CBT for SA in ASD.”

I mostly include this review here to highlight how reviews aren’t everything – I like them, but you can’t do reviews when a field hasn’t been studied. This is definitely the case here. The review was sort of funny, but also depressing. So much work for so little insight. Here’s the gist of it:

“Using a priori criteria, we searched for English-language peer-reviewed empirical studies in five databases. The search yielded 1364 results. Titles, abstracts and relevant publications were independently screened by two reviewers. Findings: Four single case studies met the review inclusion criteria; data were synthesised narratively. Participants (three adults and one child) were diagnosed with ASD and social anxiety disorder.”

You search the scientific literature systematically, you find more than a thousand results, and you carefully evaluate which ones of them should be included in this kind of study …and what you end up with is 4 individual case studies…

(I won’t go into the results of the study as they’re pretty much worthless.)

v. Immigrant Labor Market Integration across Admission Classes.

“We examine patterns of labor market integration across immigrant groups. The study draws on Norwegian longitudinal administrative data covering labor earnings and social insurance claims over a 25‐year period and presents a comprehensive picture of immigrant‐native employment and social insurance differentials by admission class and by years since entry.”

Some quotes from the paper:

“A recent study using 2011 administrative data from Sweden finds an average employment gap to natives of 30 percentage points for humanitarian migrants (refugees) and 26 percentage point for family immigrants (Luik et al., 2016).”

“A considerable fraction of the immigrants leaves the country after just a few years. […] this is particularly the case for immigrants from the old EU and for students and work-related immigrants from developing countries. For these groups, fewer than 50 percent remain in the country 5 years after entry. For refugees and family migrants, the picture is very different, and around 80 percent appear to have settled permanently in the country. Immigrants from the new EU have a settlement pattern somewhere in between, with approximately 70 percent settled on a permanent basis. An implication of such differential outmigration patterns is that the long-term labor market performance of refugees and family immigrants is of particular economic and fiscal importance. […] the varying rates of immigrant inflows and outflows by admission class, along with other demographic trends, have changed the composition of the adult (25‐66) population between 1990 and 2015. In this population segment, the overall immigrant share increased from 4.9 percent in 1990 to 18.7 percent in 2015 — an increase by a factor of 3.8 over 25 years. […] Following the 2004 EU enlargement, the fraction of immigrants in Norway has increased by a steady rate of approximately one percentage point per year.”

“The trends in population and employment shares varies considerably across admission classes, with employment shares of refugees and family immigrants lagging their growth in population shares. […] In 2014, refugees and family immigrants accounted for 12.8 percent of social insurance claims, compared to 5.7 percent of employment (and 7.7 percent of the adult population). In contrast, the two EU groups made up 9.3 percent of employment (and 8.8 percent of the adult population) but only 3.6 percent of social insurance claimants. Although these patterns do illuminate the immediate (short‐term) fiscal impacts of immigration at each particular point in time, they are heavily influenced by each year’s immigrant composition – in terms of age, years since migration, and admission classes – and therefore provide little information about long‐term consequences and impacts of fiscal sustainability. To assess the latter, we need to focus on longer‐term integration in the Norwegian labor market.”

Which they then proceed to do in the paper. From the results of those analyses:

“For immigrant men, the sample average share in employment (i.e., whose main source of income is work) ranges from 58 percent for refugees to 89 percent for EU immigrants, with family migrants somewhere between (around 80 percent). The average shares with social insurance as the main source of income ranges from only four percent for EU immigrants to as much as 38 percent for refugees. The corresponding shares for native men are 87 percent in employment and 12 percent with social insurance as their main income source. For women, the average shares in employment vary from 46 percent for refugees to 85 percent for new EU immigrants, whereas the average shares in social insurance vary from five percent for new EU immigrants to 42 percent for refugees. The corresponding rates for native women are 80 percent in employment and 17 percent with social insurance as their main source of income.”

“The profiles estimated for refugees are particularly striking. For men, we find that the native‐immigrant employment gap reaches its minimum value at 20 percentage points after five to six years of residence. The gap then starts to increase quite sharply again, and reaches 30 percentage points after 15 years. This development is mirrored by a corresponding increase in social insurance dependency. For female refugees, the employment differential reaches its minimum of 30 percentage points after 5‐9 years of residence. The subsequent decline is less dramatic than what we observe for men, but the differential stands at 35 percentage points 15 years after admission. […] The employment difference between refugees from Bosnia and Somalia is fully 22.2 percentage points for men and 37.7 points for women. […] For immigrants from the old EU, the employment differential is slightly in favor of immigrants regardless of years since migration, and the social insurance differentials remain consistently negative. In other words, employment of old EU immigrants is almost indistinguishable from that of natives, and they are less likely to claim social insurance benefits.”

vi. Glucose Peaks and the Risk of Dementia and 20-Year Cognitive Decline.

“Hemoglobin A1c (HbA1c), a measure of average blood glucose level, is associated with the risk of dementia and cognitive impairment. However, the role of glycemic variability or glucose excursions in this association is unclear. We examined the association of glucose peaks in midlife, as determined by the measurement of 1,5-anhydroglucitol (1,5-AG) level, with the risk of dementia and 20-year cognitive decline.”

“Nearly 13,000 participants from the Atherosclerosis Risk in Communities (ARIC) study were examined. […] Over a median time of 21 years, dementia developed in 1,105 participants. Among persons with diabetes, each 5 μg/mL decrease in 1,5-AG increased the estimated risk of dementia by 16% (hazard ratio 1.16, P = 0.032). For cognitive decline among participants with diabetes and HbA1c <7% (53 mmol/mol), those with glucose peaks had a 0.19 greater z score decline over 20 years (P = 0.162) compared with those without peaks. Among participants with diabetes and HbA1c ≥7% (53 mmol/mol), those with glucose peaks had a 0.38 greater z score decline compared with persons without glucose peaks (P < 0.001). We found no significant associations in persons without diabetes.

CONCLUSIONS Among participants with diabetes, glucose peaks are a risk factor for cognitive decline and dementia. Targeting glucose peaks, in addition to average glycemia, may be an important avenue for prevention.”

vii. Gaze direction detection in autism spectrum disorder.

“Detecting where our partners direct their gaze is an important aspect of social interaction. An atypical gaze processing has been reported in autism. However, it remains controversial whether children and adults with autism spectrum disorder interpret indirect gaze direction with typical accuracy. This study investigated whether the detection of gaze direction toward an object is less accurate in autism spectrum disorder. Individuals with autism spectrum disorder (n = 33) and intelligence quotients–matched and age-matched controls (n = 38) were asked to watch a series of synthetic faces looking at objects, and decide which of two objects was looked at. The angle formed by the two possible targets and the face varied following an adaptive procedure, in order to determine individual thresholds. We found that gaze direction detection was less accurate in autism spectrum disorder than in control participants. Our results suggest that the precision of gaze following may be one of the altered processes underlying social interaction difficulties in autism spectrum disorder.”

“Where people look at informs us about what they know, want, or attend to. Atypical or altered detection of gaze direction might thus lead to impoverished acquisition of social information and social interaction. Alternatively, it has been suggested that abnormal monitoring of inner states […], or the lack of social motivation […], would explain the reduced tendency to follow conspecific gaze in individuals with ASD. Either way, a lower tendency to look at the eyes and to follow the gaze would provide fewer opportunities to practice GDD [gaze direction detection – US] ability. Thus, impaired GDD might either play a causal role in atypical social interaction, or conversely be a consequence of it. Exploring GDD earlier in development might help disentangle this issue.”

June 1, 2017 Posted by | Diabetes, Economics, Epidemiology, Medicine, Neurology, Psychiatry, Psychology, Studies | Leave a comment


Orthoepy. Elucubrate. Lachrymatory. Ephectic. Palilogy. Sempiternal. Anadrome. Entelechy. Paracosm. Amerce. Syndactyly. Ustulation. Darrein. Mesority. Busker. Philematology. Episiotomy. Codger. Dacite. Obliviality.

Vermiculate. Temeritous. Buckler. Gormless. Vaginismus. Twerp. Décolletage. Wimple. Buccal. Anadromous/catadromous. Seraglio. Theriomorphic. Hypogeum. Sempervirent. Chinwag. Belonephobia/aichmophobia. Blepharospasm. Vigesimal. Eonism. Grandisonant.

Tiddly. Dactylography. Fulgurous. Oppilate. Xerophagy. Ostler. Skeuomorph. Lubricity. Yclept.
Dyspareunia. Sthenic. Magnalium. Vigil. Sejunction. Tonology. Tussle. Radix. Natatory. Obsidional.

Quillet. Elutriate. Runnel. Energumen. Mullered. Aquatint. Wyvern. Undine. Hectograph.
Traction engine. Custrel. Ochlagogy. Saturnalia. Querent. Tucket. Custrel. Sanguinolent. Abaisse. Clavis. Scenester.

Stonker. Ramus. Anfractuous. Scrumptious. Ctenoid. Enfleurage. Lamina. Worsted. Schlemiel. Erubescent. Clachan. Vinew. Dottle. Armlet. Kernel. Quitclaim. Avulsion. Dehisce. Zephyr. Kenning.

May 30, 2017 Posted by | language | Leave a comment


i. “Fools hate knowledge.” (Joseph Heller)

ii. “Most people like to believe something is or is not true. Great scientists tolerate ambiguity very well. They believe the theory enough to go ahead; they doubt it enough to notice the errors and faults so they can step forward and create the new replacement theory. If you believe too much you’ll never notice the flaws; if you doubt too much you won’t get started. It requires a lovely balance.” (Richard Hamming)

iii. “It is not easy to become an educated person.” (-ll-)

iv. “The world attributes its misfortunes to the schemes and plottings of the very evil and powerful. I think stupidity is underestimated.” (Adolfo Bioy Casares)

v. “Life’s hard. To be in peace with oneself, one must speak the truth. To be in peace with others, one must lie.” (-ll-)

vi. “An information retrieval system will tend not to be used whenever it is more painful and troublesome for a customer to have information than for him not to have it… Where an information retrieval system tends not to be used, a more capable information retrieval system may tend to be used even less.” (Calvin Mooers)

vii. “I believe that there are very few scientists who deliberately falsify their work, cheat on their colleagues, or steal from their students. On the other hand, I am afraid that a great many scientists deceive themselves from time to time in their treatment of data, gloss over problems involving systematic errors, or understate the contributions of others. These are the ‘honest mistakes’ of science. The scientific equivalent of the ‘little white lie’ of social discourse. The scientific community has no way to protect itself from sloppy or deceptive literature except to learn whose work is suspect as unreliable.” (Lewis M. Branscomb. Related link.)

viii. “Scientists lie, especially if the result reinforces what they want to be true. Contemporary scientists strongly trend in a certain ideological direction, and so there’s a blizzard of false results pointing in that direction. The replication crisis produces correlated noise.” (A slightly different take on this issue, I figured I should include both quotes here… This quote is by Gregory Cochran)

ix. “The young always have the same problem — how to rebel and conform at the same time. They have now solved this problem by defying their elders and copying each other.” (Quentin Crisp)

x. “Even a monotonously undeviating path of self-examination does not necessarily lead to self-knowledge. I stumble towards my grave confused and hurt and hungry.” (-ll-)

xi. “There is no substitute for the comfort supplied by the utterly taken-for-granted relationship.” (Iris Murdoch)

xii. “Bereavement is a darkness impenetrable to the imagination of the unbereaved.” (-ll-)

xiii. “Serious reflexion about one’s own character will often induce a curious sense of emptiness; and if one knows another person well, one may sometimes intuit a similar void in him. (This is one of the strange privileges of friendship.)” (-ll-)

xiv. “An ignorant doctor is the aide-de-camp of death.” (Avicenna)

xv. “The universal aptitude for ineptitude makes any human accomplishment an incredible miracle.” (John Stapp)

xvi. “Forget whatever should be forgotten, so that you can remember what should be remembered.” (Bing Xin)

xvii. “War has been with us ever since the dawn of civilization. Nothing has been more constant in history than war.” (Robert Aumann)

xviii. “A fundamental value in the scientific outlook is concern with the best available map of reality. The scientist will always seek a description of events which enables him to predict most by assuming least.” (Anatol Rapoport)

xix. “There may be occasions when it is best to behave irrationally, but whether there are should be decided rationally.” (Irving J. Good)

xx. “Why should I worry about dying? It’s not going to happen in my lifetime!” (Raymond Smullyan)

May 28, 2017 Posted by | Quotes/aphorisms | Leave a comment

A few diabetes papers of interest

i. Cost-Effectiveness of Prevention and Treatment of the Diabetic Foot.

“A risk-based Markov model was developed to simulate the onset and progression of diabetic foot disease in patients with newly diagnosed type 2 diabetes managed with care according to guidelines for their lifetime. Mean survival time, quality of life, foot complications, and costs were the outcome measures assessed. Current care was the reference comparison. Data from Dutch studies on the epidemiology of diabetic foot disease, health care use, and costs, complemented with information from international studies, were used to feed the model.

RESULTS—Compared with current care, guideline-based care resulted in improved life expectancy, gain of quality-adjusted life-years (QALYs), and reduced incidence of foot complications. The lifetime costs of management of the diabetic foot following guideline-based care resulted in a cost per QALY gained of <$25,000, even for levels of preventive foot care as low as 10%. The cost-effectiveness varied sharply, depending on the level of foot ulcer reduction attained.

CONCLUSIONS—Management of the diabetic foot according to guideline-based care improves survival, reduces diabetic foot complications, and is cost-effective and even cost saving compared with standard care.”

I won’t go too deeply into the model setup and the results but some of the data they used to feed the model were actually somewhat interesting in their own right, and I have added some of these data below, along with some of the model results.

“It is estimated that 80% of LEAs [lower extremity amputations] are preceded by foot ulcers. Accordingly, it has been demonstrated that preventing the development of foot ulcers in patients with diabetes reduces the frequency of LEAs by 49–85% (6).”

“An annual ulcer incidence rate of 2.1% and an amputation incidence rate of 0.6% were among the reference country-specific parameters derived from this study and adopted in the model.”

“The health outcomes results of the cohort following standard care were comparable to figures reported for diabetic patients in the Netherlands. […] In the 10,000 patients followed until death, a total of 1,780 ulcer episodes occurred, corresponding to a cumulative ulcer incidence of 17.8% and an annual ulcer incidence of 2.2% (mean annual ulcer incidence for the Netherlands is 2.1%) (17). The number of amputations observed was 362 (250 major and 112 minor), corresponding to a cumulative incidence of 3.6% and an annual incidence of 0.4% (mean annual amputation incidence reported for the Netherlands is 0.6%) (17).”

“Cornerstones of guidelines-based care are intensive glycemic control (IGC) and optimal foot care (OFC). Although health benefits and economic efficiency of intensive blood glucose control (8) and foot care programs (914) have been individually reported, the health and economic outcomes and the cost-effectiveness of both interventions have not been determined. […] OFC according to guidelines includes professional protective foot care, education of patients and staff, regular inspection of the feet, identification of the high-risk patient, treatment of nonulcerative lesions, and a multidisciplinary approach to established foot ulcers. […] All cohorts of patients simulated for the different scenarios of guidelines care resulted in improved life expectancy, QALYs gained, and reduced incidence of foot ulcers and LEA compared with standard care. The largest effects on these outcomes were obtained when patients received IGC + OFC. When comparing the independent health effects of the two guidelines strategies, OFC resulted in a greater reduction in ulcer and amputation rates than IGC. Moreover, patients who received IGC + OFC showed approximately the same LEA incidence as patients who received OFC alone. The LEA decrease obtained was proportional to the level of foot ulcer reduction attained.”

“The mean total lifetime costs of a patient under either of the three guidelines care scenarios ranged from $4,088 to $4,386. For patients receiving IGC + OFC, these costs resulted in <$25,000 per QALY gained (relative to standard care). For patients receiving IGC alone, the ICER [here’s a relevant link – US] obtained was $32,057 per QALY gained, and for those receiving OFC alone, this ICER ranged from $12,169 to $220,100 per QALY gained, depending on the level of ulcer reduction attained. […] Increasing the effectiveness of preventive foot care in patients under OFC and IGC + OFC resulted in more QALYs gained, lower costs, and a more favorable ICER. The results of the simulations for the combined scenario (IGC + OFC) were rather insensitive to changes in utility weights and costing parameters. Similar results were obtained for parameter variations in the other two scenarios (IGC and OFC separately).”

“The results of this study suggest that IGC + OFC reduces foot ulcers and amputations and leads to an improvement in life expectancy. Greater health benefits are obtained with higher levels of foot ulcer prevention. Although care according to guidelines increases health costs, the cost per QALY gained is <$25,000, even for levels of preventive foot care as low as 10%. ICERs of this order are cost-effective according to the stratification of interventions for diabetes recently proposed (32). […] IGC falls into the category of a possibly cost-effective intervention in the management of the diabetic foot. Although it does not produce significant reduction in foot ulcers and LEA, its effectiveness resides in the slowing of neuropathy progression rates.

Extrapolating our results to a practical situation, if IGC + OFC was to be given to all diabetic patients in the Netherlands, with the aim of reducing LEA by 50% (St. Vincent’s declaration), the cost per QALY gained would be $12,165 and the cost for managing diabetic ulcers and amputations would decrease by 53 and 58%, respectively. From a policy perspective, this is clearly cost-effective and cost saving compared with current care.”

ii. Early Glycemic Control, Age at Onset, and Development of Microvascular Complications in Childhood-Onset Type 1 Diabetes.

“The aim of this work was to study the impact of glycemic control (HbA1c) early in disease and age at onset on the occurrence of incipient diabetic nephropathy (MA) and background retinopathy (RP) in childhood-onset type 1 diabetes.

RESEARCH DESIGN AND METHODS—All children, diagnosed at 0–14 years in a geographically defined area in northern Sweden between 1981 and 1992, were identified using the Swedish Childhood Diabetes Registry. From 1981, a nationwide childhood diabetes care program was implemented recommending intensified insulin treatment. HbA1c and urinary albumin excretion were analyzed, and fundus photography was performed regularly. Retrospective data on all 94 patients were retrieved from medical records and laboratory reports.

RESULTS—During the follow-up period, with a mean duration of 12 ± 4 years (range 5–19), 17 patients (18%) developed MA, 45 patients (48%) developed RP, and 52% had either or both complications. A Cox proportional hazard regression, modeling duration to occurrence of MA or RP, showed that glycemic control (reflected by mean HbA1c) during the follow-up was significantly associated with both MA and RP when adjusted for sex, birth weight, age at onset, and tobacco use as potential confounders. Mean HbA1c during the first 5 years of diabetes was a near-significant determinant for development of MA (hazard ratio 1.41, P = 0.083) and a significant determinant of RP (1.32, P = 0.036). The age at onset of diabetes significantly influenced the risk of developing RP (1.11, P = 0.021). Thus, in a Kaplan-Meier analysis, onset of diabetes before the age of 5 years, compared with the age-groups 5–11 and >11 years, showed a longer time to occurrence of RP (P = 0.015), but no clear tendency was seen for MA, perhaps due to lower statistical power.

CONCLUSIONS—Despite modern insulin treatment, >50% of patients with childhood-onset type 1 diabetes developed detectable diabetes complications after ∼12 years of diabetes. Inadequate glycemic control, also during the first 5 years of diabetes, seems to accelerate time to occurrence, whereas a young age at onset of diabetes seems to prolong the time to development of microvascular complications. […] The present study and other studies (15,54) indicate that children with an onset of diabetes before the age of 5 years may have a prolonged time to development of microvascular complications. Thus, the youngest age-groups, who are most sensitive to hypoglycemia with regard to risk of persistent brain damage, may have a relative protection during childhood or a longer time to development of complications.”

It’s important to note that although some people reading the study may think this is all ancient history (people diagnosed in the 80es?), to a lot of people it really isn’t. The study is of great personal interest to me, as I was diagnosed in ’87; if it had been a Danish study rather than a Swedish one I might well have been included in the analysis.

Another note to add in the context of the above coverage is that unlike what the authors of the paper seem to think/imply, hypoglycemia may not be the only relevant variable of interest in the context of the effect of childhood diabetes on brain development, where early diagnosis has been observed to tend to lead to less favourable outcomes – other variables which may be important include DKA episodes and perhaps also chronic hyperglycemia during early childhood. See this post for more stuff on these topics.

Some more stuff from the paper:

“The annual incidence of type 1 diabetes in northern Sweden in children 0–14 years of age is now ∼31/100,000. During the time period 1981–1992, there has been an increase in the annual incidence from 19 to 31/100,000 in northern Sweden. This is similar to the rest of Sweden […]. Seventeen (18%) of the 94 patients fulfilled the criteria for MA during the follow-up period. None of the patients developed overt nephropathy, elevated serum creatinine, or had signs of any other kidney disorder, e.g., hematuria, during the follow-up period. […] The mean time to diagnosis of MA was 9 ± 3 years (range 4–15) from diabetes onset. Forty-five (48%) of the 94 patients fulfilled the criteria for RP during the follow-up period. None of the patients developed proliferative retinopathy or were treated with photocoagulation. The mean time to diagnosis of RP was 11 ± 4 years (range 4–19) from onset of diabetes. Of the 45 patients with RP, 13 (29%) had concomitant MA, and thus 13 (76.5%) of the 17 patients with MA had concomitant RP. […] Altogether, among the 94 patients, 32 (34%) had isolated RP, 4 (4%) had isolated MA, and 13 (14%) had combined RP and MA. Thus, 49 (52%) patients had either one or both complications and, hence, 45 (48%) had neither of these complications.”

“When modeling MA as a function of glycemic level up to the onset of MA or during the entire follow-up period, adjusting for sex, birth weight, age at onset of diabetes, and tobacco use, only glycemic control had a significant effect. An increase in hazard ratio (HR) of 83% per one percentage unit increase in mean HbA1c was seen. […] The increase in HR of developing RP for each percentage unit rise in HbA1c during the entire follow-up period was 43% and in the early period 32%. […] Age at onset of diabetes was a weak but significant independent determinant for the development of RP in all regression models (P = 0.015, P = 0.018, and P = 0.010, respectively). […] Despite that this study was relatively small and had a retrospective design, we were able to show that the glycemic level already during the first 5 years may be an important predictor of later development of both MA and RP. This is in accordance with previous prospective follow-up studies (16,30).”

“Previously, male sex, smoking, and low birth weight have been shown to be risk factors for the development of nephropathy and retinopathy (6,4549). However, in this rather small retrospective study with a limited follow-up time, we could not confirm these associations”. This may just be because of lack of power, it’s a relatively small study. Again, this is/was of personal interest to me; two of those three risk factors apply to me, and neither of those risk factors are modifiable.

iii. Eighteen Years of Fair Glycemic Control Preserves Cardiac Autonomic Function in Type 1 Diabetes.

“Reduced cardiovascular autonomic function is associated with increased mortality in both type 1 and type 2 diabetes (14). Poor glycemic control plays an important role in the development and progression of diabetic cardiac autonomic dysfunction (57). […] Diabetic cardiovascular autonomic neuropathy (CAN) can be defined as impaired function of the peripheral autonomic nervous system. Exercise intolerance, resting tachycardia, and silent myocardial ischemia may be early signs of cardiac autonomic dysfunction (9).The most frequent finding in subclinical and symptomatic CAN is reduced heart rate variability (HRV) (10). […] No other studies have followed type 1 diabetic patients on intensive insulin treatment during ≥14-year periods and documented cardiac autonomic dysfunction. We evaluated the association between 18 years’ mean HbA1c and cardiac autonomic function in a group of type 1 diabetic patients with 30 years of disease duration.”

“A total of 39 patients with type 1 diabetes were followed during 18 years, and HbA1c was measured yearly. At 18 years follow-up heart rate variability (HRV) measurements were used to assess cardiac autonomic function. Standard cardiac autonomic tests during normal breathing, deep breathing, the Valsalva maneuver, and the tilt test were performed. Maximal heart rate increase during exercise electrocardiogram and minimal heart rate during sleep were also used to describe cardiac autonomic function.

RESULTS—We present the results for patients with mean HbA1c <8.4% (two lowest HbA1c tertiles) compared with those with HbA1c ≥8.4% (highest HbA1c tertile). All of the cardiac autonomic tests were significantly different in the high- and the low-HbA1c groups, and the most favorable scores for all tests were seen in the low-HbA1c group. In the low-HbA1c group, the HRV was 40% during deep breathing, and in the high-HbA1c group, the HRV was 19.9% (P = 0.005). Minimal heart rate at night was significantly lower in the low-HbA1c groups than in the high-HbA1c group (P = 0.039). With maximal exercise, the increase in heart rate was significantly higher in the low-HbA1c group compared with the high-HbA1c group (P = 0.001).

CONCLUSIONS—Mean HbA1c during 18 years was associated with cardiac autonomic function. Cardiac autonomic function was preserved with HbA1c <8.4%, whereas cardiac autonomic dysfunction was impaired in the group with HbA1c ≥8.4%. […] The study underlines the importance of good glycemic control and demonstrates that good long-term glycemic control is associated with preserved cardiac autonomic function, whereas a lack of good glycemic control is associated with cardiac autonomic dysfunction.”

These results are from Norway (Oslo), and again they seem relevant to me personally (‘from a statistical point of view’) – I’ve had diabetes for about as long as the people they included in the study.

iv. The Mental Health Comorbidities of Diabetes.

“Individuals living with type 1 or type 2 diabetes are at increased risk for depression, anxiety, and eating disorder diagnoses. Mental health comorbidities of diabetes compromise adherence to treatment and thus increase the risk for serious short- and long-term complications […] Young adults with type 1 diabetes are especially at risk for poor physical and mental health outcomes and premature mortality. […] we summarize the prevalence and consequences of mental health problems for patients with type 1 or type 2 diabetes and suggest strategies for identifying and treating patients with diabetes and mental health comorbidities.”

“Major advances in the past 2 decades have improved understanding of the biological basis for the relationship between depression and diabetes.2 A bidirectional relationship might exist between type 2 diabetes and depression: just as type 2 diabetes increases the risk for onset of major depression, a major depressive disorder signals increased risk for on set of type 2 diabetes.2 Moreover, diabetes distress is now recognized as an entity separate from major depressive disorder.2 Diabetes distress occurs because virtually all of diabetes care involves self-management behavior—requiring balance of a complex set of behavioral tasks by the person and family, 24 hours a day, without “vacation” days. […] Living with diabetes is associated with a broad range of diabetes-related distresses, such as feeling over-whelmed with the diabetes regimen; being concerned about the future and the possibility of serious complications; and feeling guilty when management is going poorly. This disease burden and emotional distress in individuals with type 1 or type 2 diabetes, even at levels of severity below the threshold for a psychiatric diagnosis of depression or anxiety, are associated with poor adherence to treatment, poor glycemic control, higher rates of diabetes complications, and impaired quality of life. […] Depression in the context of diabetes is […] associated with poor self-care with respect to diabetes treatment […] Depression among individuals with diabetes is also associated with increased health care use and expenditures, irrespective of age, sex, race/ethnicity, and health insurance status.3

“Women with type 1 diabetes have a 2-fold increased risk for developing an eating disorder and a 1.9-fold increased risk for developing subthreshold eating disorders than women without diabetes.6 Less is known about eating disorders in boys and men with diabetes. Disturbed eating behaviors in women with type 1 diabetes include binge eating and caloric purging through insulin restriction, with rates of these disturbed eating behaviors reported to occur in 31% to 40% of women with type 1 diabetes aged between 15 and 30 years.6 […] disordered eating behaviors persist and worsen over time. Women with type 1 diabetes and eating disorders have poorer glycemic control, with higher rates of hospitalizations and retinopathy, neuropathy, and premature death compared with similarly aged women with type 1 diabetes without eating disorders.6 […] few diabetes clinics provide mental health screening or integrate mental/behavioral health services in diabetes clinical care.4 It is neither practical nor affordable to use standardized psychiatric diagnostic interviews to diagnose mental health comorbidities in individuals with diabetes. Brief paper-and-pencil self-report measures such as the Beck Depression Inventory […] that screen for depressive symptoms are practical in diabetes clinical settings, but their use remains rare.”

The paper does not mention this, but it is important to note that there are multiple plausible biological pathways which might help to explain bidirectional linkage between depression and type 2 diabetes. Physiological ‘stress’ (think: inflammation) is likely to be an important factor, and so are the typical physiological responses to some of the pharmacological treatments used to treat depression (…as well as other mental health conditions); multiple drugs used in psychiatry, including tricyclic antidepressants, cause weight gain and have proven diabetogenic effects – I’ve covered these topics before here on the blog. I’ve incidentally also covered other topics touched briefly upon in the paper – here’s for example a more comprehensive post about screening for depression in the diabetes context, and here’s a post with some information about how one might go about screening for eating disorders; skin signs are important. I was a bit annoyed that the author of the above paper did not mention this, as observing whether or not Russell’s sign – which is a very reliable indicator of eating disorder – is present or not is easier/cheaper/faster than performing any kind of even semi-valid depression screen.

v. Diabetes, Depression, and Quality of Life. This last one covers topics related to the topics covered in the paper above.

“The study consisted of a representative population sample of individuals aged ≥15 years living in South Australia comprising 3,010 personal interviews conducted by trained health interviewers. The prevalence of depression in those suffering doctor-diagnosed diabetes and comparative effects of diabetic status and depression on quality-of-life dimensions were measured.

RESULTS—The prevalence of depression in the diabetic population was 24% compared with 17% in the nondiabetic population. Those with diabetes and depression experienced an impact with a large effect size on every dimension of the Short Form Health-Related Quality-of-Life Questionnaire (SF-36) as compared with those who suffered diabetes and who were not depressed. A supplementary analysis comparing both depressed diabetic and depressed nondiabetic groups showed there were statistically significant differences in the quality-of-life effects between the two depressed populations in the physical and mental component summaries of the SF-36.

CONCLUSIONS—Depression for those with diabetes is an important comorbidity that requires careful management because of its severe impact on quality of life.”

I felt slightly curious about the setup after having read this, because representative population samples of individuals should not in my opinion yield depression rates of either 17% nor 24%. Rates that high suggest to me that the depression criteria used in the paper are a bit ‘laxer’/more inclusive than what you see in some other contexts when reading this sort of literature – to give an example of what I mean, the depression screening post I link to above noted that clinical or major depression occurred in 11.4% of people with diabetes, compared to a non-diabetic prevalence of 5%. There’s a long way from 11% to 24% and from 5% to 17%. Another potential explanation for such a high depression rate could of course also be some sort of selection bias at the data acquisition stage, but that’s obviously not the case here. However 3000 interviews is a lot of interviews, so let’s read on…

“Several studies have assessed the impact of depression in diabetes in terms of the individual’s functional ability or quality of life (3,4,13). Brown et al. (13) examined preference-based time tradeoff utility values associated with diabetes and showed that those with diabetes were willing to trade a significant proportion of their remaining life in return for a diabetes-free health state.”

“Depression was assessed using the mood module of the Primary Care Evaluation of Mental Disorders questionnaire. This has been validated to provide estimates of mental disorder comparable with those found using structured and longer diagnostic interview schedules (16). The mental disorders examined in the questionnaire included major depressive disorder, dysthymia, minor depressive disorder, and bipolar disorder. [So yes, the depression criteria used in this study are definitely more inclusive than depression criteria including only people with MDD] […] The Short Form Health-Related Quality-of-Life Questionnaire (SF-36) was also included to assess the quality of life of the different population groups with and without diabetes. […] Five groups were examined: the overall population without diabetes and without depression; the overall diabetic population; the depression-only population; the diabetic population without depression; and the diabetic population with depression.”

“Of the population sample, 205 (6.8%) were classified as having major depression, 130 (4.3%) had minor depression, 105 (3.5%) had partial remission of major depression, 79 (2.6%) had dysthymia, and 5 (0.2%) had bipolar disorder (depressed phase). No depressive syndrome was detected in 2,486 (82.6%) respondents. The population point prevalence of doctor-diagnosed diabetes in this survey was 5.2% (95% CI 4.6–6.0). The prevalence of depression in the diabetic population was 23.6% (22.1–25.1) compared with 17.1% (15.8–18.4) in the nondiabetic population. This difference approached statistical significance (P = 0.06). […] There [was] a clear difference in the quality-of-life scores for the diabetic and depression group when compared with the diabetic group without depression […] Overall, the highest quality-of-life scores are experienced by those without diabetes and depression and the lowest by those with diabetes and depression. […] the standard scores of those with no diabetes have quality-of-life status comparable with the population mean or slightly better. At the other extreme those with diabetes and depression experience the most severe comparative impact on quality-of-life for every dimension. Between these two extremes, diabetes overall and the diabetes without depression groups have a moderate-to-severe impact on the physical functioning, role limitations (physical), and general health scales […] The results of the two-factor ANOVA showed that the interaction term was significant only for the PCS [Physical Component Score – US] scale, indicating a greater than additive effect of diabetes and depression on the physical health dimension.”

“[T]here was a significant interaction between diabetes and depression on the PCS but not on the MCS [Mental Component Score. Do note in this context that the no-interaction result is far from certain, because as they observe: “it may simply be sample size that has not allowed us to observe a greater than additive effect in the MCS scale. Although there was no significant interaction between diabetes and depression and the MCS scale, we did observe increases on the effect size for the mental health dimensions”]. One explanation for this finding might be that depression can influence physical outcomes, such as recovery from myocardial infarction, survival with malignancy, and propensity to infection. Various mechanisms have been proposed for this, including changes to the immune system (24). Other possibilities are that depression in diabetes may affect the capacity to maintain medication vigilance, maintain a good diet, and maintain other lifestyle factors, such as smoking and exercise, all of which are likely possible pathways for a greater than additive effect. Whatever the mechanism involved, these data indicate that the addition of depression to diabetes has a severe impact on quality of life, and this needs to be managed in clinical practice.”

May 25, 2017 Posted by | Cardiology, Diabetes, Medicine, Nephrology, Neurology, Papers, Personal, Pharmacology, Psychiatry, Psychology | Leave a comment

Extraordinary Physics with Millisecond Pulsars

A few related links:
Millisecond pulsar.
PSR J0348+0432.
Pulsar timing array.
Detection of Gravitational Waves using Pulsar Timing (paper).
The strong equivalence principle.
European Pulsar Timing Array.
Parkes Observatory.
Gravitational wave.
Gravitational waves from binary supermassive black holes missing in pulsar observations (paper – it’s been a long time since I watched the lecture, but in my bookmarks I noted that some of the stuff included in this publication was covered in the lecture).

May 24, 2017 Posted by | Astronomy, Lectures, Papers, Physics | Leave a comment

Imported Plant Diseases

I found myself debating whether or not I should read Lewis, Petrovskii, and Potts’ text The Mathematics Behind Biological Invasions a while back, but at the time I in the end decided that it would simply be too much work to justify the potential payoff – so instead of reading the book, I decided to just watch the above lecture and leave it at that. This lecture is definitely a very poor textbook substitute, and I was strongly debating whether or not to blog it because it just isn’t very good; the level of coverage is very low. Which is sad, because some of the diseases discussed in the lecture – like e.g. wheat leaf rust – are really important and worth knowing about. One of the important points made in the lecture is that in the context of potential epidemics, it can be difficult to know when and how to intervene because of the uncertainty involved; early action may be the more efficient choice in terms of resource use, but the earlier you intervene, the less certain will be the intervention payoff and the less you’ll know about stuff like transmission patterns (…would outbreak X ever really have spread very wide if we had not intervened? We don’t observe the counterfactual…). Such aspects of course are not only relevant to plant-diseases, and the lecture also contains other basic insights from epidemiology which apply to other types of disease – but if you’ve ever opened a basic epidemiology text you’ll know all these things already.

May 22, 2017 Posted by | Biology, Botany, Ecology, Epidemiology, Lectures | Leave a comment

Out of this World: A history of Structure in the Universe

This lecture is much less technical than were the last couple of lectures I posted, and if I remember correctly it’s aimed at a general audience (…the sort of ‘general audience’ that attends IAS lectures, but even so…). The lecture itself is quite short, only roughly 35 minutes long, but there’s a long Q&A session afterwards.

May 21, 2017 Posted by | Astronomy, Lectures, Physics | Leave a comment


Sciolism, amative, hypocorism, leiotrichouslatitudinariancircumlocutionary, daedal, ceruse, wimple, doyen, fuscous, jorum, groupuscule, gelid, hadal, palfrey, malum, cachou, fellmonger, susurrus.

Zeteticeirenicon, dystocia, vicereine, brachiation, odalisque, daglock, galumph, plantain, insufflation, marquetry, névé, samite, pangram, whisk, hamiform, addeem, oeillade, daggle, teratophilia.

Boffin, paraph, girandole, stramineouscusp, telishment, lenition, paludous, phoresy, foramen, zymurgy, pinion, clusivity, gnomon, enallage, zymogram, autopoiesis, bradyseism, appurtenant, dealation.

Peen, chamfer, siphonapterology, onomastics, stridulate, whinging, irrorate, amnion, pectination, sturt, anthelminthic, arrhinia, aprosopia, viscidity, periotic, constat, muffler, ostosis, petrichor, scelidate.

Thalassochorykex, engastration, braw, urbicolous, armillary, clanger, crith, enteron, mullion, quag, hooch, enounce, congé, bdelygmia, catenative, falx, cotyledon, egret, pericyte.

May 20, 2017 Posted by | language | Leave a comment

The Mathematical Challenge of Large Networks

This is another one of the aforementioned lectures I watched a while ago, but had never got around to blogging:

If I had to watch this one again, I’d probably skip most of the second half; it contains highly technical coverage of topics in graph theory, and it was very difficult for me to follow (but I did watch it to the end, just out of curiosity).

The lecturer has put up a ~500 page publication on these and related topics, which is available here, so if you want to know more that’s an obvious place to go have a look. A few other relevant links to stuff mentioned/covered in the lecture:
Szemerédi regularity lemma.
Turán’s theorem.
Quantum graph.

May 19, 2017 Posted by | Computer science, Lectures, Mathematics, Statistics | Leave a comment

Hydrodynamical Simulations of Galaxy Formation: Progress, Pitfalls, and Promises

“This calculation was relatively expensive, about 19 million CPU hours were spent on it.”


Posts including only one lecture is a recent innovation here on the blog as I have in the past bundled lectures so that a lecture post would include at least 2 or 3 lectures, but I am starting to come around to the idea that these new types of posts are a good idea. I have been going over some old lectures I’ve watched in the past recently, and it turns out that there are quite a few lectures I never got around to blogging; I have mentioned before how the 3 lectures per post format was likely suboptimal, in the sense that they tended to lead to lectures never being covered e.g. because of the long time lag between watching a lecture and blogging it (in the case of book blogging I tend to be much more likely to spend my time covering books I read recently, rather than books I read a while ago, and the same dynamic goes for lectures), and I think this impression is now confirmed.

As some of the lectures I’ll be covering in posts like these in the future are lectures I watched a long time ago my coverage will probably be limited to the actual lectures and the comments I wrote down when I first watched the lecture in question. I don’t want to add a few big lecture posts to just get rid of the backlog, mostly because this blog is obviously not nearly as active as it used to be, and adding single-lecture posts dropwise is an easy (…low-effort) and convenient way for me to keep the blog at least somewhat active. What I wrote down in my comments about the lecture above when I watched it, aside from the quote above, is that considering the very high-level physics included it was sort of surprising to me that the lecture was not so technical as to not be worth watching – but it wasn’t. You’ll certainly not understand all of it, but it’s interesting stuff.

May 18, 2017 Posted by | Astronomy, Lectures, Physics | Leave a comment

A few diabetes papers of interest

i. Association Between Blood Pressure and Adverse Renal Events in Type 1 Diabetes.

“The Joint National Committee and American Diabetes Association guidelines currently recommend a blood pressure (BP) target of <140/90 mmHg for all adults with diabetes, regardless of type (13). However, evidence used to support this recommendation is primarily based on data from trials of type 2 diabetes (46). The relationship between BP and adverse outcomes in type 1 and type 2 diabetes may differ, given that the type 1 diabetes population is typically much younger at disease onset, hypertension is less frequently present at diagnosis (3), and the basis for the pathophysiology and disease complications may differ between the two populations.

Prior prospective cohort studies (7,8) of patients with type 1 diabetes suggested that lower BP levels (<110–120/70–80 mmHg) at baseline entry were associated with a lower risk of adverse renal outcomes, including incident microalbuminuria. In one trial of antihypertensive treatment in type 1 diabetes (9), assignment to a lower mean arterial pressure (MAP) target of <92 mmHg (corresponding to ∼125/75 mmHg) led to a significant reduction in proteinuria compared with a MAP target of 100–107 mmHg (corresponding to ∼130–140/85–90 mmHg). Thus, it is possible that lower BP (<120/80 mmHg) reduces the risk of important renal outcomes, such as proteinuria, in patients with type 1 diabetes and may provide a synergistic benefit with intensive glycemic control on renal outcomes (1012). However, fewer studies have examined the association between BP levels over time and the risk of more advanced renal outcomes, such as stage III chronic kidney disease (CKD) or end-stage renal disease (ESRD)”.

“The primary objective of this study was to determine whether there is an association between lower BP levels and the risk of more advanced diabetic nephropathy, defined as macroalbuminuria or stage III CKD, within a background of different glycemic control strategies […] We included 1,441 participants with type 1 diabetes between the ages of 13 and 39 years who had previously been randomized to receive intensive versus conventional glycemic control in the Diabetes Control and Complications Trial (DCCT). The exposures of interest were time-updated systolic BP (SBP) and diastolic BP (DBP) categories. Outcomes included macroalbuminuria (>300 mg/24 h) or stage III chronic kidney disease (CKD) […] During a median follow-up time of 24 years, there were 84 cases of stage III CKD and 169 cases of macroalbuminuria. In adjusted models, SBP in the 2 (95% CI 1.05–1.21), and a 1.04 times higher risk of ESRD (95% CI 0.77–1.41) in adjusted Cox models. Every 10 mmHg increase in DBP was associated with a 1.17 times higher risk of microalbuminuria (95% CI 1.03–1.32), a 1.15 times higher risk of eGFR decline to 2 (95% CI 1.04–1.29), and a 0.80 times higher risk of ESRD (95% CI 0.47–1.38) in adjusted models. […] Because these data are observational, they cannot prove causation. It remains possible that subtle kidney disease may lead to early elevations in BP, and we cannot rule out the potential for reverse causation in our findings. However, we note similar trends in our data even when imposing a 7-year lag between BP and CKD ascertainment.”

CONCLUSIONS A lower BP (<120/70 mmHg) was associated with a substantially lower risk of adverse renal outcomes, regardless of the prior assigned glycemic control strategy. Interventional trials may be useful to help determine whether the currently recommended BP target of 140/90 mmHg may be too high for optimal renal protection in type 1 diabetes.”

It’s important to keep in mind when interpreting these results that endpoints like ESRD and stage III CKD are not the only relevant outcomes in this setting; even mild-stage kidney disease in diabetics significantly increase the risk of death from cardiovascular disease, and a substantial proportion of patients may die from cardiovascular disease before reaching a late-stage kidney disease endpoint (here’s a relevant link).

Identifying Causes for Excess Mortality in Patients With Diabetes: Closer but Not There Yet.

“A number of epidemiological studies have quantified the risk of death among patients with diabetes and assessed the causes of death (26), with highly varying results […] Overall, the studies to date have confirmed that diabetes is associated with an increased risk of all-cause mortality, but the magnitude of this excess risk is highly variable, with the relative risk ranging from 1.15 to 3.15. Nevertheless, all studies agree that mortality is mainly attributable to cardiovascular causes (26). On the other hand, studies of cancer-related death have generally been lacking despite the diabetes–cancer association and a number of plausible biological mechanisms identified to explain this link (8,9). In fact, studies assessing the specific causes of noncardiovascular death in diabetes have been sparse. […] In this issue of Diabetes Care, Baena-Díez et al. (10) report on an observational study of the association between diabetes and cause-specific death. This study involved 55,292 individuals from 12 Spanish population cohorts with no prior history of cardiovascular disease, aged 35 to 79 years, with a 10-year follow-up. […] This study found that individuals with diabetes compared with those without diabetes had a higher risk of cardiovascular death, cancer death, and noncardiovascular noncancer death with similar estimates obtained using the two statistical approaches. […] Baena-Díez et al. (10) showed that individuals with diabetes have an approximately threefold increased risk of cardiovascular mortality, which is much higher than what has been reported by recent studies (5,6). While this may be due to the lack of adjustment for important confounders in this study, there remains uncertainty regarding the magnitude of this increase.”

“[A]ll studies of excess mortality associated with diabetes, including the current one, have produced highly variable results. The reasons may be methodological. For instance, it may be that because of the wide range of age in these studies, comparing the rates of death between the patients with diabetes and those without diabetes using a measure based on the ratio of the rates may be misleading because the ratio can vary by age [it almost certainly does vary by age, US]. Instead, a measure based on the difference in rates may be more appropriate (16). Another issue relates to the fact that the studies include patients with longstanding diabetes of variable duration, resulting in so-called prevalent cohorts that can result in muddled mortality estimates since these are necessarily based on a mix of patients at different stages of disease (17). Thus, a paradigm change may be in order for future observational studies of diabetes and mortality, in the way they are both designed and analyzed. With respect to cancer, such studies will also need to tease out the independent contribution of antidiabetes treatments on cancer incidence and mortality (1820). It is thus clear that the quantification of the excess mortality associated with diabetes per se will need more accurate tools.”

iii. Risk of Cause-Specific Death in Individuals With Diabetes: A Competing Risks Analysis. This is the paper some of the results of which were discussed above. I’ll just include the highlights here:

RESULTS We included 55,292 individuals (15.6% with diabetes and overall mortality of 9.1%). The adjusted hazard ratios showed that diabetes increased mortality risk: 1) cardiovascular death, CSH = 2.03 (95% CI 1.63–2.52) and PSH = 1.99 (1.60–2.49) in men; and CSH = 2.28 (1.75–2.97) and PSH = 2.23 (1.70–2.91) in women; 2) cancer death, CSH = 1.37 (1.13–1.67) and PSH = 1.35 (1.10–1.65) in men; and CSH = 1.68 (1.29–2.20) and PSH = 1.66 (1.25–2.19) in women; and 3) noncardiovascular noncancer death, CSH = 1.53 (1.23–1.91) and PSH = 1.50 (1.20–1.89) in men; and CSH = 1.89 (1.43–2.48) and PSH = 1.84 (1.39–2.45) in women. In all instances, the cumulative mortality function was significantly higher in individuals with diabetes.

CONCLUSIONS Diabetes is associated with premature death from cardiovascular disease, cancer, and noncardiovascular noncancer causes.”


Diabetes is associated with premature death from cardiovascular diseases (coronary heart disease, stroke, and heart failure), several cancers (liver, colorectal, and lung), and other diseases (chronic obstructive pulmonary disease and liver and kidney disease). In addition, the cause-specific cumulative mortality for cardiovascular, cancer, and noncardiovascular noncancer causes was significantly higher in individuals with diabetes, compared with the general population. The dual analysis with CSH and PSH methods provides a comprehensive view of mortality dynamics in the population with diabetes. This approach identifies the individuals with diabetes as a vulnerable population for several causes of death aside from the traditionally reported cardiovascular death.”

iv. Disability-Free Life-Years Lost Among Adults Aged ≥50 Years With and Without Diabetes.

RESEARCH DESIGN AND METHODS Adults (n = 20,008) aged 50 years and older were followed from 1998 to 2012 in the Health and Retirement Study, a prospective biannual survey of a nationally representative sample of adults. Diabetes and disability status (defined by mobility loss, difficulty with instrumental activities of daily living [IADL], and/or difficulty with activities of daily living [ADL]) were self-reported. We estimated incidence of disability, remission to nondisability, and mortality. We developed a discrete-time Markov simulation model with a 1-year transition cycle to predict and compare lifetime disability-related outcomes between people with and without diabetes. Data represent the U.S. population in 1998.

RESULTS From age 50 years, adults with diabetes died 4.6 years earlier, developed disability 6–7 years earlier, and spent about 1–2 more years in a disabled state than adults without diabetes. With increasing baseline age, diabetes was associated with significant (P < 0.05) reductions in the number of total and disability-free life-years, but the absolute difference in years between those with and without diabetes was less than at younger baseline age. Men with diabetes spent about twice as many of their remaining years disabled (20–24% of remaining life across the three disability definitions) as men without diabetes (12–16% of remaining life across the three disability definitions). Similar associations between diabetes status and disability-free and disabled years were observed among women.

CONCLUSIONS Diabetes is associated with a substantial reduction in nondisabled years, to a greater extent than the reduction of longevity. […] Using a large, nationally representative cohort of Americans aged 50 years and older, we found that diabetes is associated with a substantial deterioration of nondisabled years and that this is a greater number of years than the loss of longevity associated with diabetes. On average, a middle-aged adult with diabetes has an onset of disability 6–7 years earlier than one without diabetes, spends 1–2 more years with disability, and loses 7 years of disability-free life to the condition. Although other nationally representative studies have reported large reductions in complications (9) and mortality among the population with diabetes in recent decades (1), these studies, akin to our results, suggest that diabetes continues to have a substantial impact on morbidity and quality of remaining years of life.”

v. Association Between Use of Lipid-Lowering Therapy and Cardiovascular Diseases and Death in Individuals With Type 1 Diabetes.

“People with type 1 diabetes have a documented shorter life expectancy than the general population without diabetes (1). Cardiovascular disease (CVD) is the main cause of the excess morbidity and mortality, and despite advances in management and therapy, individuals with type 1 diabetes have a markedly elevated risk of cardiovascular events and death compared with the general population (2).

Lipid-lowering treatment with hydroxymethylglutaryl-CoA reductase inhibitors (statins) prevents major cardiovascular events and death in a broad spectrum of patients (3,4). […] We hypothesized that primary prevention with lipid-lowering therapy (LLT) can reduce the incidence of cardiovascular morbidity and mortality in individuals with type 1 diabetes. The aim of the study was to examine this in a nationwide longitudinal cohort study of patients with no history of CVD. […] A total of 24,230 individuals included in 2006–2008 NDR with type 1 diabetes without a history of CVD were followed until 31 December 2012; 18,843 were untreated and 5,387 treated with LLT [Lipid-Lowering Therapy] (97% statins). The mean follow-up was 6.0 years. […] Hazard ratios (HRs) for treated versus untreated were as follows: cardiovascular death 0.60 (95% CI 0.50–0.72), all-cause death 0.56 (0.48–0.64), fatal/nonfatal stroke 0.56 (0.46–0.70), fatal/nonfatal acute myocardial infarction 0.78 (0.66–0.92), fatal/nonfatal coronary heart disease 0.85 (0.74–0.97), and fatal/nonfatal CVD 0.77 (0.69–0.87).

CONCLUSIONS This observational study shows that LLT is associated with 22–44% reduction in the risk of CVD and cardiovascular death among individuals with type 1 diabetes without history of CVD and underlines the importance of primary prevention with LLT to reduce cardiovascular risk in type 1 diabetes.”

vi. Prognostic Classification Factors Associated With Development of Multiple Autoantibodies, Dysglycemia, and Type 1 Diabetes—A Recursive Partitioning Analysis.

“In many prognostic factor studies, multivariate analyses using the Cox proportional hazards model are applied to identify independent prognostic factors. However, the coefficient estimates derived from the Cox proportional hazards model may be biased as a result of violating assumptions of independence. […] RPA [Recursive Partitioning Analysis] classification is a useful tool that could prioritize the prognostic factors and divide the subjects into distinctive groups. RPA has an advantage over the proportional hazards model in identifying prognostic factors because it does not require risk factor independence and, as a nonparametric technique, makes no requirement on the underlying distributions of the variables considered. Hence, it relies on fewer modeling assumptions. Also, because the method is designed to divide subjects into groups based on the length of survival, it defines groupings for risk classification, whereas Cox regression models do not. Moreover, there is no need to explicitly include covariate interactions because of the recursive splitting structure of tree model construction.”

“This is the first study that characterizes the risk factors associated with the transition from one preclinical stage to the next following a recommended staging classification system (9). The tree-structured prediction model reveals that the risk parameters are not the same across each transition. […] Based on the RPA classification, the subjects at younger age and with higher GAD65Ab [an important biomarker in the context of autoimmune forms of diabetes, US – here’s a relevant link] titer are at higher risk for progression to multiple positive autoantibodies from a single autoantibody (seroconversion). Approximately 70% of subjects with a single autoantibody were positive for GAD65Ab, much higher than for insulin autoantibody (24%) and IA-2A [here’s a relevant link – US] (5%). Our study results are consistent with those of others (2224) in that seroconversion is age related. Previous studies in infants and children at an early age have shown that progression from single to two or more autoantibodies occurs more commonly in children 25). The subjects ≤16 years of age had almost triple the 5-year risk compared with subjects >16 years of age at the same GAD65Ab titer level. Hence, not all individuals with a single islet autoantibody can be thought of as being at low risk for disease progression.”

“This is the first study that identifies the risk factors associated with the timing of transitions from one preclinical stage to the next in the development of T1D. Based on RPA risk parameters, we identify the characteristics of groups with similar 5-year risks for advancing to the next preclinical stage. It is clear that individuals with one or more autoantibodies or with dysglycemia are not homogeneous with regard to the risk of disease progression. Also, there are differences in risk factors at each stage that are associated with increased risk of progression. The potential benefit of identifying these groups allows for a more informed discussion of diabetes risk and the selective enrollment of individuals into clinical trials whose risk more appropriately matches the potential benefit of an experimental intervention. Since the risk levels in these groups are substantial, their definition makes possible the design of more efficient trials with target sample sizes that are feasible, opening up the field of prevention to additional at-risk cohorts. […] Our results support the evidence that autoantibody titers are strong predictors at each transition leading to T1D development. The risk of the development of multiple autoantibodies was significantly increased when the GAD65Ab titer level was elevated, and the risk of the development of dysglycemia was increased when the IA-2A titer level increased. These indicate that better risk prediction on the timing of transitions can be obtained by evaluating autoantibody titers. The results also suggest that an autoantibody titer should be carefully considered in planning prevention trials for T1D in addition to the number of positive autoantibodies and the type of autoantibody.”

May 17, 2017 Posted by | Diabetes, Immunology, Medicine, Nephrology, Statistics, Studies | Leave a comment

Today’s Landscape of Pharmaceutical Research in Cancer

It’s been a while since I watched this lecture so I don’t remember the details very well, but I usually add notes in my bookmarks when I watch lectures so that I know what details to include in my comments here on the blog, and I have added the details from the bookmark notes below.

It is a short lecture, the lecture itself lasts only roughly 30 minutes; it doesn’t really start until roughly the 9 minutes and 30 seconds mark, and it finishes around the 44 min mark (the rest is Q&A – I skipped some of the introduction, but watched the Q&A). The lecture is not very technical, I think the content is perfectly understandable also to people without a medical background. One data point from the lecture which I thought worth including in these comments is this: According to Sigal, “roughly 30 per cent of the biopharmaceutical industry’s portfolio … is focused on research in oncology.”

May 17, 2017 Posted by | Cancer/oncology, Immunology, Lectures, Medicine, Pharmacology | Leave a comment