Econstudentlog

Promoting the unknown…

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(I am grateful for you sharing this wonderful piece, SpewReeky!)

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November 1, 2019 Posted by | Music | Leave a comment

Quotes

i. “Experience is a dim lamp, which only lights the one who bears it.” (Louis-Ferdinand Céline)

ii. “The house of delusions is cheap to build, but draughty to live in, and ready at any instant to fall.” (A. E. Housman)

iii. “Three minutes’ thought would suffice to find this out; but thought is irksome and three minutes is a long time.” (-ll-)

iv. “Do not do an immoral thing for moral reasons!” (Thomas Hardy)

v. “The value of old age depends upon the person who reaches it. To some men of early performance it is useless. To others, who are late to develop, it just enables them to finish the job.” (-ll-)

vi. “Dying young is rarely worth it.” (James Thompson)

vii. “I have never thought there was much to be said in favor of dragging on long after all one’s friends were dead.” (Murasaki Shikibu)

viii. “A typical part of culture/social norms is the idea that it is very bad if people (have to) lie about X, should tell the truth about Y, should lie about Z and should not even believe A.

If you have internalized the surrounding (sub)culture and/or fit the (sub)culture so these restrictions don’t feel stifling, then you aren’t so much free, but rather: compatible. I think that most people have a hard time noticing restrictions that they are very comfortable with.

If you travel to a different (sub)culture that you are not compatible with and that feels oppressive to you, you will typically find people who don’t consider those restrictions to be stifling, but consider yours to be.” (Aapje, here)

ix. “I had a deprived childhood, you see. I had lots of other kids to play with and my parents bought me outdoor toys and refused to ill-treat me, so it never occurred to me to seek solitary consolation with a good book.” (Terry Pratchett)

x. “The destruction of the natural world is not the result of global capitalism, industrialisation, ‘Western civilisation’ or any flaw in human institutions. It is a consequence of the evolutionary success of an exceptionally rapacious primate. Throughout all of history and prehistory, human advance has coincided with ecological devastation.” (John Gray)

xi. “A lover who promises eternal fidelity is more likely to be believed if he believes his promise himself; he is no more likely to keep the promise.” (-ll-)

xii. “As commonly practised, philosophy is the attempt to find good reasons for conventional beliefs. In Kant’s time the creed of conventional people was Christian, now it is humanist. Nor are these two faiths so different from one another. Over the past 200 years, philosophy has shaken off Christian faith. It has not given up Christianity’s cardinal error — the belief that humans are radically different from all other animals.” (-ll-)

xiii. “There is no more consensus on what justice means than there is on the character of the good. If anything, there is less. Among the virtues, justice is one of the most shaped by convention. For that reason it is among the most changeable.” (-ll-)

xiv. “My friends are much more dangerous than my enemies. These latter – with infinite subtlety – spin webs to keep me out of places where I hate to go, – and tell stories of me to people whom it would be vanity and vexation to meet; – and they help me so much by their unconscious aid that I almost love them.” (Yakumo Koizumi)

xv. “He was too much concerned with his own perfection ever to think of admiring any one else.” (Max Beerbohm)

xvi. “The Socratic manner is not a game at which two can play.” (-ll-)

xvii. “Death cancels all engagements.” (-ll-)

xviii. “A crowd, proportionately to its size, magnifies all that in its units pertains to the emotions, and diminishes all that in them pertains to thought.” (-ll-)

xix. “Keeping up with the Joneses was a full-time job with my mother and father. It was not until many years later when I lived alone that I realized how much cheaper it was to drag the Joneses down to my level.” (Quentin Crisp)

xx. “Health consists of having the same diseases as one’s neighbours.” (-ll-)

October 24, 2019 Posted by | Quotes/aphorisms | Leave a comment

Designing Fast and Robust Learning Algorithms – Yu Cheng

Some links related to the lecture’s coverage:

Recommender system.
Collaborative filtering.
Matrix completion.
Non-Convex Matrix Completion Against a Semi-Random Adversary (Cheng & Ge, 2018).
Singular value decomposition.
Spectral graph theory.
Spectral Sparsification of Graphs (Spielman & Teng).
Cut (graph theory).
Split (graph theory).
Robust statistics.
Being Robust (in High Dimensions) Can Be Practical (Diakonikolas et al).
High-Dimensional Robust Mean Estimation in Nearly-Linear Time (Cheng, Diakonikolas and Ge).

October 13, 2019 Posted by | Computer science, Lectures, Mathematics, Statistics | Leave a comment

Data science (I?)

I’m not sure if I’ll actually blog this book in detail – I might, later on, but for now I’ll just cover it extremely lazily, by adding links to topics covered which I figured I wanted to include in this post.

The book is ‘okay’ – it’ll both allow (relatively) non-technical (management) people to at least begin to understand what sort of tasks the more technical guys are spending time on (and how to prioritize regarding critical resources, and engage with the nerds!), and it might also give the data guys a few more tools that they’ll be able to use when confronted with a specific issue. I really liked the book’s emphasis on conceptualizing data as a strategic asset. On the other hand I imagine some parts of the book will often be close to painful to read for people who have spent at least a few semesters dealing with stats-related topics in the past: This is the sort of book which is also at least in part written for people who might not be completely clear on what a statistical hypothesis test is, which discusses text mining without at any point in the coverage even mentioning the existence of regular expressions, and which discusses causal evaluation without mentioning topics like IV estimation.

Although there are some major gaps in the coverage the level of coverage is however not really all that bad; I hope to refer to at least some of the more technical material included in the book in my work in the future, but it’s not clear at this point how relevant this stuff’ll actually end up being long-term.

Links (…in random order, I did not have the book in front of me as I was writing this post so this is just a collection of links/topics I could recall being potentially worth including here):

Training, validation, and test sets
Cross-validation (statistics)
Statistical classification
Tree model
Decision tree pruning
Random forest
Naive Bayes classifier
Bigram
n-gram
Data mining
Zipf’s law (not covered, but relevant to some parts of the coverage)
Nearest neighbor search
K-nearest_neighbors_algorithm
Cluster analysis
Jaccard index
Bias–variance tradeoff
Hierarchical clustering
Dendrogram
Boosting (machine learning)
Ensemble learning
Feature (machine learning)
Feature selection
Curse of dimensionality
Regularization (mathematics)
Overfitting
Association rule learning
Labeled data
Dimensionality reduction
Supervised_learning/Unsupervised learning
Model selection
Rubin causal model (not covered, but relevant to some parts of the coverage)
Regression discontinuity design (-ll-)
Lift (data mining)
Receiver operating characteristic
Stepwise regression
Grid search (hyperparameter optimization).

October 4, 2019 Posted by | Books, Mathematics, Statistics | Leave a comment

A few diabetes papers of interest

i. Real-World Costs of Continuous Insulin Pump Therapy and Multiple Daily Injections for Type 1 Diabetes: A Population-Based and Propensity-Matched Cohort From the Swedish National Diabetes Register.

“Continuous subcutaneous insulin infusion, or insulin pump, therapy for individuals with type 1 diabetes has increased gradually since the 1980s. Yet, a Cochrane review concluded in 2010 that although some evidence indicates that insulin pumps improve glycemic control compared with standard multiple daily injection (MDI) therapy, insufficient evidence exists regarding mortality, morbidity, and costs (1). A systematic review of cost-effectiveness studies summarized comparisons of insulin pump and MDI therapy using model analyses to describe the expected impact on long-term costs, development of complications, and quality of life (2). Five of the studies reported long-term discounted incremental costs of insulin pumps of $20,000–$40,000, whereas two studies reported lower and one higher additional costs for insulin pump therapy. However, real-world data on health care and societal costs of insulin pump therapy compared with MDI therapy are scarce. […] Data from the Swedish National Diabetes Register (NDR) have shown a lower incidence of some cardiovascular events and all-cause mortality for individuals with type 1 diabetes on insulin pump therapy in 2005–2012 (5). Registration of insulin pump therapy started in 2002 in the NDR, and use of pump therapy among individuals with type 1 diabetes increased from 10% in 2002 to 22% in 2015 (6). A relevant research question from a health care planning perspective is whether real-world data match earlier model-based predictions for differences in resource use and costs. We investigated from a societal perspective costs of continuous insulin pump and MDI therapy in clinical practice for individuals with type 1 diabetes using the NDR and a 9-year observational panel from national health and socioeconomic data registers.”

“The final analysis set included data in 2005–2013 for 14,238 individuals with type 1 diabetes, of whom 4,991 had insulin pump therapy (598 individuals switched to pump therapy in 2005 or later after original inclusion as control subjects with MDI). We had 73,920 person-years of observation with a mean follow-up of 5 years per subject. […] The distribution of annual costs was left-skewed with a tail of observations with high costs, although the most person-years incurred costs corresponding to typical insulin therapy and up to two regular follow-up appointments […] The difference in the annual total cost between the therapy groups was $3,923 (95% CI $3,703–$4,143). […] The difference in annual medication costs, including disposables, was $3,600, indicating that they contributed significantly to overall annual cost differences. Pump users had more outpatient appointments (3.8 vs. 3.5 per year; P < 0.001) and were less likely to have person-years without use of outpatient or inpatient care (9% vs. 12% of person-years). Even with a median duration of diabetes of 21 years at baseline, the mean cost per patient-year of cardiovascular comorbidities and diabetic complications was low because of the overall low rates of events. […] Total annual costs increased with age for both insulin therapies, and pump therapy was associated with higher costs across age-groups. However, the cost increments for insulin pump therapy decreased with age (differences ranging from 56% for those 18–27 years of age to 44% for those ≥48 years [reference: MDI 18–27 years]). Total costs were higher for women but decreased with years of education and disposable income. […] The level of HbA1c at baseline affected the differences in average annual cost between study groups: the smallest difference ($2,300) was observed for individuals with HbA1c ≥8.6% (≥70 mmol/mol) and the greatest difference for individuals with HbA1c 6.5–8.5% (48–69 mmol/mol) at baseline [pump $12,824 vs. MDI $8,083; P < 0.001, US].”

“The study cohort was young (mean baseline age 34 years) with relatively few diabetic complications in both study groups. For instance, 1.5% of person-years had a cardiovascular event, and 5% had at least one health care contact with a cardiovascular diagnosis.

Observational studies provide a better indication of what is achieved in daily medical practice than randomized controlled studies (12). The strength of this observational study is the size and completeness of the study population, with virtually all adults with type 1 diabetes in Sweden included, longitudinal national register data, and a matching technique that accounts for time-variant variables, including diabetes duration, diabetes-related conditions and comorbidities, and demographic and socioeconomic factors. With the use of time-varying propensity scores, we allowed selected MDI control subjects to switch to pump therapy rather than to condition their eligibility or noneligibility on a future therapeutic change. The plentiful data allowed us to match two control subjects to each pump user to account for the variance in cost variables and enabled extensive subgroup and sensitivity analyses.”

“We observed only a few deaths (n = 353 [2.5% main analysis sample], no difference pump vs. MDI [OR 0.98 (95% CI 0.79–1.23)]) and similar rates of cardiovascular disease for pump and MDI in this study, except for borderline significantly fewer events with angina in the pump group. A heterogeneous distribution of events was found across nontreatment characteristics: ∼70% of all cardiovascular events occurred among individuals 48 years of age or older, and >90% of the events occurred among individuals with diabetes duration ≥20 years at baseline.

A lack of comparable calculations of total costs of diabetes treatment has been published to date, but cost-effectiveness studies of pump and MDI therapy have predicted long-term costs for the two treatment methods. Roze et al. (2) performed a meta-review of model-based studies that compared pump therapy and MDI, concluding that pump therapy can be cost effective. Published models have identified change in HbA1c and reduction in number of hypoglycemic events as important drivers of costs. A Swedish health technology assessment review in 2013 did not find evidence for differences in severe hypoglycemia between pump therapy and MDI but identified indications of lower HbA1c (13). […] Subgroup analyses by age indicated that the value of improved prevention may take time to manifest. Approximately one-quarter of additional annual costs for individuals with type 1 diabetes age ≥48 years (∼25% of the cohort) could be prevented with insulin pump therapy.

Whether insulin pump therapy is cost efficient ultimately depends on therapeutic effects beyond resource use and costs as well as on how much the payer is prepared to invest in additional quality-adjusted life-years (QALYs). If the payer’s cost-effectiveness threshold is $50,000 per QALY gained, treatment needs to provide an average annual additional 0.1 QALY or, on the basis of the subgroup analyses, gains in the range of 0.06–0.12 QALY. Similarly, with a threshold of $100,000, the required gain in annual QALYs would have to be between 0.03 and 0.06. The average cost difference between insulin therapies in this study and a 20-year time horizon roughly correspond to a discounted (3%) lifetime cost difference of $62,000. The corresponding cost for a 40-year time horizon is $95,000. Previous model-based cost-effectiveness analyses have reported expected discounted QALY gains for a lifetime in the range of 0.46–1.06 QALYs, whereas the estimates of the increase in discounted lifetime costs varied (2).”

ii. Cumulative Risk of End-Stage Renal Disease Among Patients With Type 2 Diabetes: A Nationwide Inception Cohort Study.

“One of the most devastating complications of diabetes is chronic kidney disease. Relative to the general population, persons with diabetes have a 5- to 13-fold risk of end-stage renal disease (ESRD) (46). ESRD extensively increases risk of death among patients with diabetes (79), and diabetes is the most common cause of ESRD in most industrialized countries (10); a study of 18 European countries showed that type 2 diabetes was the most frequent renal disease leading to initiation of renal replacement therapy (11).

Most earlier studies of the incidence of ESRD in diabetes have used prevalence cohorts, which means that patients have not been followed since their diabetes diagnosis. Patients with all types of diabetes typically have been included, and the incidence rate of ESRD has been 1–9 per 1,000 patient-years (4,1214), with larger estimates among African Americans and those with a longer duration of diabetes. Notably, a prevalence cohort study from Italy including only patients with type 2 diabetes showed that only 10 of 1,408 patients developed ESRD over a 10-year follow-up (15). To our knowledge, only two inception cohort studies have addressed the incidence of ESRD. The UK Prospective Diabetes Study followed 5,097 patients with newly diagnosed type 2 diabetes, only 14 of whom required renal replacement therapy during the median follow-up of 10.4 years (16). However, the cumulative risk was not computed, and any subgroup analyses would not have been possible because of the small number of patients who developed ESRD. A population-based study from Saskatchewan, Canada, included 90,429 incident cases of diabetes among the adult study population, and the results showed an almost threefold risk of ESRD among indigenous patients (17). Among nonindigenous patients, the cumulative incidence of ESRD was ∼1–2% at 20 years since the diabetes diagnosis.

We and others have estimated the cumulative risk of ESRD in inception cohorts of patients with type 1 diabetes (1821). Although type 2 diabetes is a major cause of ESRD, cumulative risk of ESRD after type 2 diabetes has been diagnosed is not well known. Here, we present the cumulative risk of ESRD during a 24-year follow-up of a nationwide population-based cohort of 421,429 patients newly diagnosed with type 2 diabetes in 1990–2011.”

“Of 421,429 patients diagnosed with type 2 diabetes in 1990–2011, 1,516 developed ESRD and 150,524 died before the end of 2013. The total number of patient-years of type 2 diabetes was 3,458,797 […]. The median follow-up was 6.82 years. A sex difference was found for age distribution: 70% of women and 55% of men were 60 years or older when type 2 diabetes was diagnosed. […] The cumulative risk of ESRD was 0.29% at 10 years and 0.74% at 20 years since the diagnosis of type 2 diabetes. […] Men had a 93% higher risk of ESRD than women. […] this male predominance is a common finding for all causes of ESRD (10). […] As an alternative analysis, the incidence rate of ESRD was calculated among all prevalent cases of type 2 diabetes in the time periods 1990–1999 and 2000–2011, thus including patients who were diagnosed with type 2 diabetes before 1990 but who contributed patient-years in 1990–2013 […]. During a total of 4,345,251 patient-years, 2,127 patients developed ESRD, resulting in an incidence rate of 0.49 per 1,000 patient-years (95% CI 0.47–0.51). The incidence rate was higher among men (0.66 [95% CI 0.63–0.70]) than among women (0.33 [95% CI 0.31–0.35]) and in 2000–2013 (0.53 [95% CI 0.51–0.56]) than in 1990–1999 (0.37 [95% CI 0.34–0.41]). The incidence rate of ESRD had increased most among men older than 70 years. For both men and women, the incidence rate of ESRD peaked among those aged 60–79 years.”

“Among patients diagnosed with type 2 diabetes between 1990 and 2011, the cumulative risk of death was 34% at 10 years and 64% at 20 years since the diagnosis of diabetes. […] Patients aged 70–79 years when diabetes was diagnosed had an eightfold risk of death during the follow-up compared with those aged 40–49 years. When calculating HR for death, occurrence of ESRD was included in the multivariable model as a time-dependent variable […], and ESRD increased the risk of death 4.2-fold during follow-up. […] In the interaction analysis, sex modified the effects of age and ESRD on HR for death. Among men, ESRD increased risk of death 3.8-fold and among women, 5.6-fold. Age (70–79 vs. 40–49 years) showed an HR for death of 7.4 among men and 9.8 among women. Also, a statistically significant interaction occurred between age and ESRD during follow-up, showing a weaker association between ESRD and risk of death among those aged 70 years or older (HR 3) than among those younger than 60 years (HR 5).”

“Our study shows that risk of ESRD is small among people with type 2 diabetes. This may seem unexpected, because a substantial proportion of patients are entering early stages of chronic kidney disease, with 25% of patients having microalbuminuria and 5% having macroalbuminuria 10 years after their diabetes diagnosis (16). These early stages of kidney disease are associated with increased premature mortality; this contributes to the fact that relatively few patients develop ESRD, as death is a common competing risk event. However, diabetes is the most common cause of ESRD in most industrialized countries, and because of a high and increasing prevalence of diabetes among the general population, a considerable absolute number of patients with type 2 diabetes need dialysis therapy (10,11). Our findings are important for clinicians who inform patients with type 2 diabetes about the associated risks and complications. […] Notably, people diagnosed with type 2 diabetes at an older age have a lower risk of ESRD and a higher risk of death than those diagnosed at a younger age. The cumulative risk of ESRD and death has decreased since the early 1990s among people with type 2 diabetes.”

iii. Impact of Age of Onset, Puberty, and Glycemic Control Followed From Diagnosis on Incidence of Retinopathy in Type 1 Diabetes: The VISS Study.

“In a population-based observational study, HbA1c for 451 patients diagnosed with diabetes before 35 years of age during 1983–1987 in southeast Sweden was followed for up to 18–24 years from diagnosis. Long-term mean weighted HbA1c (wHbA1c) was calculated. Retinopathy was evaluated by fundus photography and analyzed in relation to wHbA1c levels.”

RESULTS Lower wHbA1c, diabetes onset ≤5 years of age, and diabetes onset before puberty, but not sex, were associated with longer time to appearance of simplex retinopathy. Proliferative retinopathy was associated only with wHbA1c. The time to first appearance of any retinopathy decreased with increasing wHbA1c. Lower wHbA1c after ≤5 years’ diabetes duration was associated with later onset of simplex retinopathy but not proliferative retinopathy. With time, most patients developed simplex retinopathy, except for those of the category wHbA1c ≤50 mmol/mol (6.7%), for which 20 of 36 patients were without any retinopathy at the end of the follow-up in contrast to none of 49 with wHbA1c >80 mmol/mol (9.5%). […] At the end of the follow-up only 54 patients (12.5%) had no signs of retinopathy and 145 (33.6%) had slight simplex, 175 (40.5%) moderate simplex, and 57 (13.2%) proliferative retinopathy.”

CONCLUSIONS Onset at ≤5 years of age and lower wHbA1c the first 5 years after diagnosis are associated with longer duration before development of simplex retinopathy. There is a strong positive association between long-term mean HbA1c measured from diagnosis and up to 20 years and appearance of both simplex and proliferative retinopathy.”

“Complete avoidance of retinopathy in patients with type 1 diabetes evidently requires a very tight glycemic control, which is very difficult to achieve with the treatment tools available today and is also dangerous because of the risk of severe hypoglycemia (27). […] In clinical practice, it is of great importance to find the balance between the risk of potentially dangerous hypoglycemic events and quality of life and the risk of severe microvascular complications to be able to recommend an evidence-based optimal level of HbA1c both in the short-term and in the long-term. The observation that wHbA1c before and during puberty did not influence the prevalence of proliferative retinopathy at 20 years’ diabetes duration is of clinical importance in the setting of targets for glycemic control in young children for whom severe hypoglycemia might be especially dangerous.

Simplex retinopathy is not sight threatening, even if advanced simplex retinopathy is a risk factor for proliferative retinopathy (13). However, simplex retinopathy may regress, and in our study simplex retinopathy regressed in a group of patients with mean wHbA1c 7.0% (SD 0.7%) (53 [8] mmol/mol). Proliferative retinopathy is clinically more relevant and should be avoided. We previously showed that the threshold for proliferative retinopathy is higher than for simplex retinopathy (28). Proliferative retinopathy did not occur in this material in patients with wHbA1c <7.6% (60 mmol/mol), which indicates what should be an important goal for glycemic control. This is in close agreement with the position statement for type 1 diabetes in children and adolescents recently issued by the American Diabetes Association recommending an HbA1c target of <7.5% (58 mmol/mol) (31).

In summary, after 20 years of diabetes duration, there is a strong positive association between long-term mean wHbA1c followed from diagnosis and appearance of both simplex and proliferative retinopathy. Diabetes onset at <5 years of age and lower wHbA1c the first 5 years after diagnosis are associated with longer duration before development of simplex retinopathy but not proliferative retinopathy. Proliferative retinopathy does not appear in patients with wHbA1c <7.6% (60 mmol/mol).”

iv. Association of Diabetes and Glycated Hemoglobin With the Risk of Intracerebral Hemorrhage: A Population-Based Cohort Study.

“Spontaneous intracerebral hemorrhage (ICH) is a devastating condition accounting for 10–15% of all stroke cases. It is associated with a dismal prognosis, as only 38% of affected patients survive the first year (1).

Type 2 diabetes affects more than 415 million adults worldwide and is a well-known contributor to cardiovascular morbidity, cognitive decline, and all-cause mortality (2). Although diabetes is an independent risk factor for ischemic stroke (3), as yet there is no conclusive evidence for the association between diabetes and ICH, as previous studies showed conflicting results (48). […] We sought to determine 1) the association of diabetes and ICH and 2) the relationship between HbA1c levels and ICH in a large nationwide population-based cohort. […] We sought to determine 1) the association of diabetes and ICH and 2) the relationship between HbA1c levels and ICH in a large nationwide population-based cohort.”

Do keep in mind in the following that although the link between hemorrhagic stroke and diabetes is somewhat unclear (…for example: “in the Copenhagen Stroke Registry, hemorrhagic stroke was even six times less frequent in diabetic patients than in non-diabetic subjects (102). […] However, in another prospective population-based study DM was associated with an increased risk of primary intracerebral hemorrhage (103).”), the link between ischemic stroke and diabetes is strong and well-established – see the link for more details.

“This study is based on data from the computerized database of Clalit Health Services (CHS), which provides inclusive health care for more than half of the Israeli population. […] 313,130 patients had a preexisting diagnosis of diabetes and 1,167,585 individuals were without diabetes. Patients with diabetes had to have at least one test result for HbA1c in the 2 years before cohort entry (n = 297,486). Cohort participants (n = 1,465,071) were followed-up until reaching the study outcome (ICH), death, loss to follow-up, or end of follow-up at 31 December 2017 — whichever came first. […] The outcome of interest was ICH, defined as primary discharge diagnosis with ICH (ICD-9 code 431). […] Overall 4,170 patients had incident ICH during a mean (SD) follow-up of 7.3 (1.8) years and 10,730,915 person-years, reflecting an ICH crude incidence rate of 38.8 per 100,000 person-years. […] The strongest risk factors for ICH were prior ICH, prior stroke/transient ischemic attack (TIA), use of anticoagulation, hypertension, alcohol abuse, male sex, Arab ethnicity, chronic liver disease, and older age.”

“Because of the large number of potential confounders, we performed adjustment for a disease risk score (DRS), a summary measure of disease probability. The DRS was estimated using a Cox proportional hazards regression model for ICH outcome that included most clinically relevant ICH risk factors and other clinical covariates likely to be correlated with ICH […]. In comparison with conventional multivariate analyses, adjustment for the single variable DRS increases the efficiency of the analyses (16,17). It has been shown than the DRS and propensity score methods had comparable performance and that DRS has an advantage when multiple comparison groups are studied (16,17). […] The crude incidence rate of ICH was 78.9 per 100,000 person-years among patients with diabetes and 29.4 per 100,000 person-years among patients without diabetes (crude HR 2.69 [95% CI 2.53–2.87]) (Table 2). Diabetes remained significantly associated with ICH after adjustment for DRS (1.36 [1.27–1.45]). […] The results were unchanged after exclusion of new cases of diabetes and after censoring at the time of new diabetes diagnosis occurring during follow-up: DRS-adjusted HR 1.37 (95% CI 1.28–1.46) and 1.38 (1.29–1.47), respectively. […] The risk of ICH was directly associated with diabetes duration. Compared with the group without diabetes, the DRS-adjusted HR was 1.23 (95% CI 1.12–1.35) and 1.44 (1.34–1.56) for diabetes duration ≤5 years and >5 years, respectively. The corresponding HRs with adjustment for propensity score were 1.27 (1.15–1.41) and 1.65 (1.50–1.80), respectively […] HbA1c was significantly associated with ICH among patients with diabetes: adjusted HR 1.14 (95% CI 1.10–1.17) for each 1% increase in HbA1c […] HbA1c appears to have a nonlinear J-shaped relationship with ICH (Pnonlinearity = 0.0186), with the lowest risk observed at HbA1c of 6.5% (48 mmol/mol). […] The risk of ICH among patients with HbA1c of 6.5–6.7% (48–50 mmol/mol) was comparable with the risk in patients without diabetes, suggesting that albeit having diabetes, patients with good, but not extreme, diabetes control do not appear to have excess risk of ICH compared with patients without diabetes.”

“To date, the exact mechanisms underlying the association between diabetes, HbA1c, and ICH remain unknown. […] In summary, our study suggests that diabetes is associated with increased risk of ICH that is directly associated with diabetes duration. ICH and HbA1c appear to have a J-shaped relationship, suggesting that both poor control as well as extreme intensive diabetes control might be associated with increased risk.”

v. Nonproteinuric Versus Proteinuric Phenotypes in Diabetic Kidney Disease: A Propensity Score–Matched Analysis of a Nationwide, Biopsy-Based Cohort Study.

“Mainly based on the analysis of the data from patients with type 1 diabetes, in the clinical course of diabetic kidney disease it has long been considered that an increase of albuminuria, from normoalbuminuria (urine albumin-to-creatinine ratio ratio [UACR] <30 mg/g) to microalbuminuria (UACR 30–299 mg/g) to macroalbuminuria (UACR ≥300 mg/g), precedes the progression of renal decline (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) (13). Morphological changes known as nodular glomerular sclerosis (Kimmelstiel-Wilson nodule) have also been observed in patients with diabetes and loss of renal function (4,5). Therefore, patients with diabetes and reduced renal function are deemed to have overt proteinuria with nodular glomerular sclerosis. Recently, however, cumulative evidence from several cross-sectional studies revealed that a proportion of patients with type 2 diabetes develop progression of renal decline without proteinuria (macroalbuminuria) or even without microalbuminuria, suggesting the existence of a nonproteinuric phenotype of diabetic kidney disease defined as eGFR <60 mL/min/1.73 m2 and UACR <300 mg/g (611). Despite increasing attention, few clinical trials and longitudinal studies in type 2 diabetes include individuals without proteinuria or individuals with biopsy-proven diabetic kidney disease, and therefore their clinicopathological characteristics, renal prognosis, and all-cause mortality are very limited.

Similar to the U.S. and most countries in Europe, Japan has been suffering from the expanding trend in the continued increase of the prevalence of diabetic kidney disease that leads to end-stage renal disease (ESRD) and high mortality (1215). Commissioned by the Ministry of Health, Labour and Welfare and the Japan Agency for Medical Research and Development with a goal of better understanding and halting the pandemic of diabetic kidney disease, we established a nationwide biopsy-based cohort of diabetic kidney disease with followed-up data, including ESRD and death ascertainment. Using this nationwide cohort and propensity score–matching methods, we aimed to investigate clinicopathological characteristics, renal prognosis, and mortality in patients with the nonproteinuric phenotype of diabetic kidney disease compared with patients with the classical proteinuric phenotype of diabetic kidney disease.”

“This is a retrospective study of patients who underwent clinical renal biopsy performed from 1 January 1985 to 31 December 2016 and had a pathological diagnosis of diabetic kidney disease at [one of] 18 hospitals in Japan […] 895 patients underwent clinical renal biopsy and had a pathological diagnosis of diabetic kidney disease in our cohort […]. We identified 526 who had an eGFR <60 mL/min/1.73 m2 at the time of biopsy. Among them, 88 had nonproteinuric diabetic kidney disease (UACR <300 mg/g), and 438 had proteinuric diabetic kidney disease (UACR ≥300 mg/g) at baseline. After propensity score matching, the nonproteinuric diabetic kidney disease group comprised 82 patients and the proteinuric diabetic kidney disease group comprised 164 patients […] In propensity score–matched cohorts, the blood pressure in patients with nonproteinuric diabetic kidney disease was better controlled compared with patients with proteinuric diabetic kidney disease, although patients with nonproteinuric diabetic kidney disease were less prescribed RAAS blockade. Patients with nonproteinuric diabetic kidney disease had lower total cholesterol levels and higher hemoglobin levels. For pathological characteristics, there was a difference in classification assignment for diabetic kidney disease between the nonproteinuric diabetic kidney disease group and proteinuric diabetic kidney disease group. […] Compared with the proteinuric diabetic kidney disease group, the nonproteinuric diabetic kidney disease group had less severe interstitial and vascular lesions. […] In a multivariable logistic regression model, older age, lower systolic blood pressure, higher hemoglobin level, and higher HbA1c were significantly associated with a higher odds of nonproteinuric diabetic kidney disease.”

“After a median follow-up of 1.8 years (IQR 0.9–3.7) from the date of renal biopsy, 297 (56%) of the 526 patients had renal events. The 5-year CKD progression-free survival was 33.2% (95% CI 28.4–38.2%) for all patients, 86.9% (95% CI 73.1–93.9%) for the nonproteinuric diabetic kidney disease group, and 24.5% (95% CI 19.8–29.5%) for the proteinuric diabetic kidney disease group (log-rank test P < 0.001) […]. The same trend was seen in the propensity score–matched cohort: After a median follow-up of 1.9 years (IQR 0.9–5.0) from the date of renal biopsy, 124 (50%) of the 246 matched patients had renal events. The 5-year CKD progression-free survival was 46.4% (95% CI 38.7–53.6%) for all patients, 86.6% (95% CI 72.5–93.8%) for the nonproteinuric diabetic kidney disease group, and 30.3% (95% CI 22.4–38.6%) for the proteinuric diabetic kidney disease group (log-rank test P < 0.001) […]. Similarly, for the secondary outcome (all-cause mortality), after a median follow-up of 2.7 years (IQR 1.1–5.7) from the date of renal biopsy, 55 (10%) of the 526 patients had death events. The 5-year death-free survival was 89.7% (95% CI 85.6–92.7%) for all patients, 98.4% (95% CI 89.1–99.8%) for the nonproteinuric diabetic kidney disease group, and 87.5% (95% CI 82.5–91.2%) for the proteinuric diabetic kidney disease group (log-rank test P < 0.001) […]. The same trend was seen in the propensity matched cohort: After a median follow-up of 3.1 years (IQR 1.3–7.0) from the date of renal biopsy, 35 (14%) of the 246 matched patients had death events. The 5-year death-free survival was 88.2% (95% CI 82.0–92.3%) for all patients, 98.3% (95% CI 88.7–99.8%) for the nonproteinuric diabetic kidney disease group, and 82.6% (95% CI 73.6–88.8%) for the proteinuric diabetic kidney disease group (log-rank test P = 0.005) […] The overall CKD progression incidence was significantly lower in the nonproteinuric diabetic kidney disease group (30 [95% CI 18–50] per 1,000 person-years) than in the proteinuric diabetic kidney disease group (231 [95% CI 191–278] per 1,000 person-years; crude HR 0.15 [95% CI 0.08–0.26]). After adjustment for age, sex, known duration of diabetes, and baseline eGFR, the risk of CKD progression remained lower in the nonproteinuric diabetic kidney disease cohort than in the proteinuric diabetic kidney disease cohort (adjusted HR 0.13 [95% CI 0.08–0.24]). The risk of CKD progression was consistently lower in the nonproteinuric diabetic kidney disease group than in the proteinuric diabetic kidney disease group when stratified by potential confounders such as age, sex, obesity, retinopathy, smoking status, use of RAAS blockade, hypertension, dyslipidemia, poor glycemic control, lower eGFR, and pathological findings.”

“In conclusion, in propensity score–matched cohorts of biopsy-proven nonproteinuric diabetic kidney disease and proteinuric diabetic kidney disease, patients with nonproteinuric diabetic kidney disease had lower blood pressure with less frequent typical pathological lesions and were at lower risk of CKD progression and all-cause mortality. Further studies are warranted to confirm these findings in other cohorts.”

vi. Single herbal medicine for diabetic retinopathy (Cochrane).

“Diabetic retinopathy is one of the major causes of blindness and the number of cases has risen in recent years. Herbal medicine has been used to treat diabetes and its complications including diabetic retinopathy for thousands of years around the world. However, common practice is not always evidence‐based. Evidence is needed to help people with diabetic retinopathy or doctors to make judicious judgements about using herbal medicine as treatment.”

“We included 10 studies involving 754 participants, of which nine were conducted in China and one in Poland. In all studies, participants in both groups received conventional treatment for diabetic retinopathy which included maintaining blood glucose and lipids using medicines and keeping a stable diabetic diet. In three studies, the comparator group also received an additional potentially active comparator in the form of a vasoprotective drug. The single herbs or extracts included Ruscus extract tablet, Sanqi Tongshu capsule, tetramethylpyrazine injection, Xueshuantong injection, Puerarin injection and Xuesaitong injection. The Sanqi Tongshu capsule, Xueshuantong injection and Xuesaitong injection were all made from the extract of Radix Notoginseng (San qi) and the main ingredient was sanchinoside. The risk of bias was high in all included studies mainly due to lack of masking (blinding). None of the studies reported the primary outcome of this review, progression of retinopathy.

Combined analysis of herbal interventions suggested that people who took these herbs in combination with conventional treatment may have been more likely to gain 2 or more lines of visual acuity compared to people who did not take these herbs when compared to conventional intervention alone at the end of treatment (RR 1.26, 95% CI 1.08 to 1.48; 5 trials, 541 participants; low‐certainty evidence). Subgroup analyses based on the different single herbs found no evidence for different effects of different herbs, but the power of this analysis was low. […]

Authors’ conclusions

No conclusions could be drawn about the effect of any single herb or herbal extract on diabetic retinopathy from the current available evidence. It was difficult to exclude the placebo effect as a possible explanation for observed differences due to the lack of placebo control in the included studies. Further adequately designed trials are needed to establish the evidence.”

 

September 25, 2019 Posted by | Diabetes, Epidemiology, Health Economics, Medicine, Nephrology, Ophthalmology, Studies | Leave a comment

Links and random stuff

i. Pulmonary Aspects of Exercise and Sports.

“Although the lungs are a critical component of exercise performance, their response to exercise and other environmental stresses is often overlooked when evaluating pulmonary performance during high workloads. Exercise can produce capillary leakage, particularly when left atrial pressure increases related to left ventricular (LV) systolic or diastolic failure. Diastolic LV dysfunction that results in elevated left atrial pressure during exercise is particularly likely to result in pulmonary edema and capillary hemorrhage. Data from race horses, endurance athletes, and triathletes support the concept that the lungs can react to exercise and immersion stress with pulmonary edema and pulmonary hemorrhage. Immersion in water by swimmers and divers can also increase stress on pulmonary capillaries and result in pulmonary edema.”

“Zavorsksy et al. studied individuals under several different workloads and performed lung imaging to document the presence or absence of lung edema. Radiographic image readers were blinded to the exposures and reported visual evidence of lung fluid. In individuals undergoing a diagnostic graded exercise test, no evidence of lung edema was noted. However, 15% of individuals who ran on a treadmill at 70% of maximum capacity for 2 hours demonstrated evidence of pulmonary edema, as did 65% of those who ran at maximum capacity for 7 minutes. Similar findings were noted in female athletes. Pingitore et al. examined 48 athletes before and after completing an iron man triathlon. They used ultrasound to detect lung edema and reported the incidence of ultrasound lung comets. None of the athletes had evidence of lung edema before the event, while 75% showed evidence of pulmonary edema immediately post-race, and 42% had persistent findings of pulmonary edema 12 hours post-race. Their data and several case reports have demonstrated that extreme exercise can result in pulmonary edema”

Conclusions

Sports and recreational participation can result in lung injury caused by high pulmonary pressures and increased blood volume that raises intracapillary pressure and results in capillary rupture with subsequent pulmonary edema and hemorrhage. High-intensity exercise can result in accumulation of pulmonary fluid and evidence of pulmonary edema. Competitive swimming can result in both pulmonary edema related to fluid shifts into the thorax from immersion and elevated LV end diastolic pressure related to diastolic dysfunction, particularly in the presence of high-intensity exercise. […] The most important approach to many of these disorders is prevention. […] Prevention strategies include avoiding extreme exercise, avoiding over hydration, and assuring that inspiratory resistance is minimized.”

ii. Some interesting thoughts on journalism and journalists from a recent SSC Open Thread by user ‘Well’ (quotes from multiple comments). His/her thoughts seem to line up well with my own views on these topics, and one of the reasons why I don’t follow the news is that my own answer to the first question posed below is quite briefly that, ‘…well, I don’t’:

“I think a more fundamental problem is the irrational expectation that newsmedia are supposed to be a reliable source of information in the first place. Why do we grant them this make-believe power?

The English and Acting majors who got together to put on the shows in which they pose as disinterested arbiters of truth use lots of smoke and mirror techniques to appear authoritative: they open their programs with regal fanfare, they wear fancy suits, they make sure to talk or write in a way that mimics the disinterestedness of scholarly expertise, they appear with spinning globes or dozens of screens behind them as if they’re omniscient, they adorn their publications in fancy black-letter typefaces and give them names like “Sentinel” and “Observer” and “Inquirer” and “Plain Dealer”, they invented for themselves the title of “journalists” as if they take part in some kind of peer review process… But why do these silly tricks work? […] what makes the press “the press” is the little game of make-believe we play where an English or Acting major puts on a suit, talks with a funny cadence in his voice, sits in a movie set that looks like God’s Control Room, or writes in a certain format, using pseudo-academic language and symbols, and calls himself a “journalist” and we all pretend this person is somehow qualified to tell us what is going on in the world.

Even when the “journalist” is saying things we agree with, why do we participate in this ridiculous charade? […] I’m not against punditry or people putting together a platform to talk about things that happen. I’m against people with few skills other than “good storyteller” or “good writer” doing this while painting themselves as “can be trusted to tell you everything you need to know about anything”. […] Inasumuch as what I’m doing can be called “defending” them, I’d “defend” them not because they are providing us with valuable facts (ha!) but because they don’t owe us facts, or anything coherent, in the first place. It’s not like they’re some kind of official facts-providing service. They just put on clothes to look like one.”

iii. Chatham house rule.

iv. Sex Determination: Why So Many Ways of Doing It?

“Sexual reproduction is an ancient feature of life on earth, and the familiar X and Y chromosomes in humans and other model species have led to the impression that sex determination mechanisms are old and conserved. In fact, males and females are determined by diverse mechanisms that evolve rapidly in many taxa. Yet this diversity in primary sex-determining signals is coupled with conserved molecular pathways that trigger male or female development. Conflicting selection on different parts of the genome and on the two sexes may drive many of these transitions, but few systems with rapid turnover of sex determination mechanisms have been rigorously studied. Here we survey our current understanding of how and why sex determination evolves in animals and plants and identify important gaps in our knowledge that present exciting research opportunities to characterize the evolutionary forces and molecular pathways underlying the evolution of sex determination.”

v. So Good They Can’t Ignore You.

“Cal Newport’s 2012 book So Good They Can’t Ignore You is a career strategy book designed around four ideas.

The first idea is that ‘follow your passion’ is terrible career advice, and people who say this should be shot don’t know what they’re talking about. […] The second idea is that instead of believing in the passion hypothesis, you should adopt what Newport calls the ‘craftsman mindset’. The craftsman mindset is that you should focus on gaining rare and valuable skills, since this is what leads to good career outcomes.

The third idea is that autonomy is the most important component of a ‘dream’ job. Newport argues that when choosing between two jobs, there are compelling reasons to ‘always’ pick the one with higher autonomy over the one with lower autonomy.

The fourth idea is that having a ‘mission’ or a ‘higher purpose’ in your job is probably a good idea, and is really nice if you can find it. […] the book structure is basically: ‘following your passion is bad, instead go for Mastery[,] Autonomy and Purpose — the trio of things that have been proven to motivate knowledge workers’.” […]

“Newport argues that applying deliberate practice to your chosen skill market is your best shot at becoming ‘so good they can’t ignore you’. The key is to stretch — you want to practice skills that are just above your current skill level, so that you experience discomfort — but not too much discomfort that you’ll give up.” […]

“Newport thinks that if your job has one or more of the following qualities, you should leave your job in favour of another where you can build career capital:

  • Your job presents few opportunities to distinguish yourself by developing relevant skills that are rare and valuable.
  • Your job focuses on something you think is useless or perhaps even actively bad for the world.
  • Your job forces you to work with people you really dislike.

If you’re in a job with any of these traits, your ability to gain rare and valuable skills would be hampered. So it’s best to get out.”

vi. Structural brain imaging correlates of general intelligence in UK Biobank.

“The association between brain volume and intelligence has been one of the most regularly-studied—though still controversial—questions in cognitive neuroscience research. The conclusion of multiple previous meta-analyses is that the relation between these two quantities is positive and highly replicable, though modest (Gignac & Bates, 2017; McDaniel, 2005; Pietschnig, Penke, Wicherts, Zeiler, & Voracek, 2015), yet its magnitude remains the subject of debate. The most recent meta-analysis, which included a total sample size of 8036 participants with measures of both brain volume and intelligence, estimated the correlation at r = 0.24 (Pietschnig et al., 2015). A more recent re-analysis of the meta-analytic data, only including healthy adult samples (N = 1758), found a correlation of r = 0.31 (Gignac & Bates, 2017). Furthermore, the correlation increased as a function of intelligence measurement quality: studies with better-quality intelligence tests—for instance, those including multiple measures and a longer testing time—tended to produce even higher correlations with brain volume (up to 0.39). […] Here, we report an analysis of data from a large, single sample with high-quality MRI measurements and four diverse cognitive tests. […] We judge that the large N, study homogeneity, and diversity of cognitive tests relative to previous large scale analyses provides important new evidence on the size of the brain structure-intelligence correlation. By investigating the relations between general intelligence and characteristics of many specific regions and subregions of the brain in this large single sample, we substantially exceed the scope of previous meta-analytic work in this area. […]

“We used a large sample from UK Biobank (N = 29,004, age range = 44–81 years). […] This preregistered study provides a large single sample analysis of the global and regional brain correlates of a latent factor of general intelligence. Our study design avoids issues of publication bias and inconsistent cognitive measurement to which meta-analyses are susceptible, and also provides a latent measure of intelligence which compares favourably with previous single-indicator studies of this type. We estimate the correlation between total brain volume and intelligence to be r = 0.276, which applies to both males and females. Multiple global tissue measures account for around double the variance in g in older participants, relative to those in middle age. Finally, we find that associations with intelligence were strongest in frontal, insula, anterior and medial temporal, lateral occipital and paracingulate cortices, alongside subcortical volumes (especially the thalamus) and the microstructure of the thalamic radiations, association pathways and forceps minor.”

vii. Another IQ study: Low IQ as a predictor of unsuccessful educational and occupational achievement: A register-based study of 1,098,742 men in Denmark 1968–2016.

“Intelligence test score is a well-established predictor of educational and occupational achievement worldwide […]. Longitudinal studies typically report cor-relation coefficients of 0.5–0.6 between intelligence and educational achievement as assessed by educational level or school grades […], correlation coefficients of 0.4–0.5 between intelligence and occupational level […] and cor-relation coefficients of 0.2–0.4 between intelligence and income […]. Although the above-mentioned associations are well-established, low intelligence still seems to be an overlooked problem among young people struggling to complete an education or gain a foothold in the labour market […] Due to contextual differences with regard to educational system and flexibility and security on the labour market as well as educational and labour market policies, the role of intelligence in predicting unsuccessful educational and occupational courses may vary among countries. As Denmark has free admittance to education at all levels, state financed student grants for all students, and a relatively high support of students with special educational needs, intelligence might be expected to play a larger role – as socioeconomic factors might be of less importance – with regard to educational and occupational achievement compared with countries outside Scandinavia. The aim of this study was therefore to investigate the role of IQ in predicting a wide range of indicators of unsuccessful educational and occupational achievement among young people born across five decades in Denmark.”

“Individuals who differed in IQ score were found to differ with regard to all indicators of unsuccessful educational and occupational achievement such that low IQ was associated with a higher proportion of unsuccessful educational and occupational achievement. For example, among the 12.1% of our study population who left lower secondary school without receiving a certificate, 39.7% had an IQ < 80 and 23.1% had an IQ of 80–89, although these individuals only accounted for 7.8% and 13.1% of the total study population. The main analyses showed that IQ was inversely associated with all indicators of unsuccessful educational and occupational achievement in young adulthood after adjustment for covariates […] With regard to unsuccessful educational achievement, […] the probabilities of no school leaving certificate, no youth education at age 25, and no vocational qualification at age 30 decreased with increasing IQ in a cubic relation, suggesting essentially no or only weak associations at superior IQ levels. IQ had the strongest influence on the probability of no school leaving certificate. Although the probabilities of the three outcome indicators were almost the same among individuals with extremely low IQ, the probability of no school leaving certificate approached zero among individuals with an IQ of 100 or above whereas the probabilities of no youth education at age 25 and no vocational qualification at age 30 remained notably higher. […] individuals with an IQ of 70 had a median gross income of 301,347 DKK, individuals with an IQ of 100 had a median gross income of 331,854, and individuals with an IQ of 130 had a median gross income of 363,089 DKK – in the beginning of June 2018 corresponding to about 47,856 USD, 52,701 USD, and 57,662 USD, respectively. […] The results showed that among individuals undergoing education, low IQ was associated with a higher hazard rate of passing to employment, unemployment, sickness benefits receipt and welfare benefits receipt […]. This indicates that individuals with low IQ tend to leave the educational system to find employment at a younger age than individuals with high IQ, but that this early leave from the educational system often is associated with a transition into unemployment, sickness benefits receipt and welfare benefits receipt.”

Fig 1

Conclusions
This study of 1,098,742 Danish men followed in national registers from 1968 to 2016 found that low IQ was a strong and consistent predictor of 10 indicators of unsuccessful educational and occupational achievement in young adulthood. Overall, it seemed that IQ had the strongest influence on the risk of unsuccessful educational achievement and on the risk of disability pension, and that the influence of IQ on educational achievement was strongest in the early educational career and decreased over time. At the community level our findings suggest that intelligence should be considered when planning interventions to reduce the rates of early school leaving and the unemployment rates and at the individual level our findings suggest that assessment of intelligence may provide crucial information for the counselling of poor-functioning schoolchildren and adolescents with regard to both the immediate educational goals and the more distant work-related future.”

September 15, 2019 Posted by | Biology, IQ, Medicine, Psychology, Studies | Leave a comment

Dyslexia (I)

A few years back I started out on another publication edited by the same author, the Wiley-Blackwell publication The Science of Reading: A Handbook. That book is dense and in the end I decided it wasn’t worth it to finish it – but I also learned from reading it that Snowling, the author of this book, probably knows her stuff. This book only covers a limited range of the literature on reading, but an interesting one.

I have added some quotes and links from the first chapters of the book below.

“Literacy difficulties, when they are not caused by lack of education, are known as dyslexia. Dyslexia can be defined as a problem with learning which primarily affects the development of reading accuracy and fluency and spelling skills. Dyslexia frequently occurs together with other difficulties, such as problems in attention, organization, and motor skills (movement) but these are not in and of themselves indicators of dyslexia. […] at the core of the problem is a difficulty in decoding words for reading and encoding them for spelling. Fluency in these processes is never achieved. […] children with specific reading difficulties show a poor response to reading instruction […] ‘response to intervention’ has been proposed as a better way of identifying likely dyslexic difficulties than measured reading skills. […] To this day, there is tension between the medical model of ‘dyslexia’ and the understanding of ‘specific learning difficulties’ in educational circles. The nub of the problem for the concept of dyslexia is that, unlike measles or chicken pox, it is not a disorder with a clear diagnostic profile. Rather, reading skills are distributed normally in the population […] dyslexia is like high blood pressure, there is no precise cut-off between high blood pressure and ‘normal’ blood pressure, but if high blood pressure remains untreated, the risk of complications is high. Hence, a diagnosis of ‘hypertension’ is warranted […] this book will show that there is remarkable agreement among researchers regarding the risk factors for poor reading and a growing number of evidence-based interventions: dyslexia definitely exists and we can do a great deal to ameliorate its effects”.

“An obvious though not often acknowledged fact is that literacy builds on a foundation of spoken language—indeed, an assumption of all education systems is that, when a child starts school, their spoken language is sufficient to support reading development. […] many children start school with considerable knowledge about books: they know that print runs from left to right (at least if you are reading English) and that you read from the front to the back of the book; and they are familiar with at least some letter names or sounds. At a basic level, reading involves translating printed symbols into pronunciations—a task referred to as decoding, which requires mapping across modalities from vision (written forms) to audition (spoken sounds). Beyond knowing letters, the beginning reader has to discover how printed words relate to spoken words and a major aim of reading instruction is to help the learner to ‘crack’ this code. To decode in English (and other alphabetic languages) requires learning about ‘grapheme–phoneme’ correspondences—literally the way in which letters or letter combinations relate to the speech sounds of spoken words: this is not a trivial task. When children use language naturally, they have only implicit knowledge of the words they use and they do not pay attention to their sounds; but this is precisely what they need to do in order to learn to decode. Indeed, they have to become ‘aware’ that words can be broken down into constituent parts like the syllable […] and that, in turn, syllables can be segmented into phonemes […]. Phonemes are the smallest sounds which differentiate words; for example, ‘pit’ and ‘bit’ differ by a single phoneme [b]-[p] (in fact, both are referred to as ‘stop consonants’ and they differ only by a single phonemic feature, namely the timing of the voicing onset of the consonant). In the English writing system, phonemes are the units which are coded in the grapheme-correspondences that make up the orthographic code.”

“The term ‘phoneme awareness‘ refers to the ability to reflect on and manipulate the speech sounds in words. It is a metalinguistic skill (a skill requiring conscious control of language) which develops after the ability to segment words into syllables and into rhyming parts […]. There has been controversy over whether phoneme awareness is a cause or a consequence of learning to read. […] In general, letters are easier to learn (being concrete) than phoneme awareness is to acquire (being an abstract skill). […] The acquisition of ‘phoneme awareness’ is a critical step in the development of decoding skills. A typical reader who possesses both letter knowledge and phoneme awareness can readily ‘sound out’ letters and blend the sounds together to read words or even meaningless but pronounceable letter strings (nonwords); conversely, they can split up words (segment them) into sounds for spelling. When these building blocks are in place, a child has developed ‘alphabetic competence’ and the task of becoming a reader can begin properly. […[ Another factor which is important in promoting reading fluency is the size of a child’s vocabulary. […] children with poor oral language skills, specifically limited semantic knowledge of words, [have e.g. been shown to have] particular difficulty in reading irregular words. […] Essentially, reading is a ‘big data’ problem—the task of learning involves extracting the statistical relationships between spelling (orthography) and sound (phonology) and using these to develop an algorithm for reading which is continually refined as further words are encountered.”

“It is commonly believed that spelling is simply the reverse of reading. It is not. As a consequence, learning to read does not always bring with it spelling proficiency. One reason is that the correspondences between letters and sounds used for reading (grapheme–phoneme correspondences) are not just the same as the sound-to-letter rules used for writing (phoneme–grapheme correspondences). Indeed, in English, the correspondences used in reading are generally more consistent than those used in spelling […] many of the early spelling errors children make replicate errors observed in speech development […] Children with dyslexia often struggle to spell words phonetically […] The relationship between phoneme awareness and letter knowledge at age 4 and phonological accuracy of spelling attempts at age 5 has been studied longitudinally with the aim of understanding individual differences in children’s spelling skills. As expected, these two components of alphabetic knowledge predicted the phonological accuracy of children’s early spelling. In turn, children’s phonological spelling accuracy along with their reading skill at this early stage predicted their spelling proficiency after three years in school. The findings suggest that the ability to transcode phonologically provides a foundation for the development of orthographic representations for spelling but this alone is not enough—information acquired from reading experience is required to ensure spellings are conventionally correct. […] for spelling as for reading, practice is important.”

“Irrespective of the language, reading involves mapping between the visual symbols of words and their phonological forms. What differs between languages is the nature of the symbols and the phonological units. Indeed, the mappings which need to be created are at different levels of ‘grain size’ in different languages (fine-grained in alphabets which connect letters and sounds like German or Italian, and more coarse-grained in logographic systems like Chinese that map between characters and syllabic units). Languages also differ in the complexity of their morphology and how this maps to the orthography. Among the alphabetic languages, English is the least regular, particularly for spelling; the most regular is Finnish with a completely transparent system of mappings between letters and phonemes […]. The term ‘orthographic depth’ is used to describe the level of regularity which is observed between languages — English is opaque (or deep), followed by Danish and French which also contain many irregularities, while Spanish and Italian rank among the more regular, transparent (or shallow) orthographies. Over the years, there has been much discussion as to whether children learning to read English have a particularly tough task and there is frequent speculation that dyslexia is more prevalent in English than in other languages. There is no evidence that this is the case. But what is clear is that it takes longer to become a fluent reader of English than of a more transparent language […] There are reasons other than orthographic consistency which make languages easier or harder to learn. One of these is the number of symbols in the writing system: the European languages have fewer than 35 while others have as many as 2,500. For readers of languages with extensive symbolic systems like Chinese, which has more than 2,000 characters, learning can be expected to continue through the middle and high school years. The visual-spatial complexity of the symbols may add further to the burden of learning. […] when there are more symbols in a writing system, the learning demands increase. […] Languages also differ importantly in the ways they represent phonology and meaning.”

“Given the many differences between languages and writing systems, there is remarkable similarity between the predictors of individual differences in reading across languages. The ELDEL study showed that for children reading alphabetic languages there are three significant predictors of growth in reading in the early years of schooling. These are letter knowledge, phoneme awareness, and rapid naming (a test in which the names of colours or objects have to be produced as quickly as possible in response to a random array of such items). Researchers have shown that a similar set of skills predict reading in Chinese […] However, there are also additional predictors that are language-specific. […] visual memory and visuo-spatial skills are stronger predictors of learning to read in a visually complex writing system, such as Chinese or Kannada, than they are for English. Moreover, there is emerging evidence of reciprocal relations – that learning to read in a complex orthography hones visuo-spatial abilities just as phoneme awareness improves as English children learn to read.”

“Children differ in the rate at which they learn to read and spell and children with dyslexia are typically the slowest to do so, assuming standard instruction for all. Indeed, it is clear from the outset that they have more difficulty in learning letters (by name or by sound) than their peers. As we have seen, letter knowledge is a crucial component of alphabetic competence and also offers a way into spelling. So for the dyslexic child with poor letter knowledge, learning to read and spell is compromised from the outset. In addition, there is a great deal of evidence that children with dyslexia have problems with phonological aspects of language from an early age and specifically, acquiring phonological awareness. […] The result is usually a significant problem in decoding—in fact, poor decoding is the hallmark of dyslexia, the signature of which is a nonword reading deficit. In the absence of remediation, this decoding difficulty persists and for many reading becomes something to be avoided. […] the most common pattern of reading deficit in dyslexia is an inability to read ‘new’ or unfamiliar words in the face of better developed word-reading skills — sometimes referred to as ‘phonological dyslexia’. […] Spelling poses a significant challenge to children with dyslexia. This seems inevitable, given their problems with phoneme awareness and decoding. The early spelling attempts of children with dyslexia are typically not phonetic in the way that their peers’ attempts are; rather, they are often difficult to decipher and best described as bizarre. […] errors continue to reflect profound difficulties in representing the sounds of words […] most people with dyslexia continue to show poor spelling through development and there is a very high correlation between (poor) spelling in the teenage years and (poor) spelling in middle age. […] While poor decoding can be a barrier to reading comprehension, many children and adults with dyslexia can read with adequate understanding when this is required but it takes them considerable time to do so, and they tend to avoid writing when it is possible to do so.”

Links:

Phonics.
History of dyslexia research. Samuel Orton. Rudolf Berlin. Anna Gillingham. Orton-Gillingham(-Stillman) approach. Thomas Richard Miles.
Seidenberg & McClelland’s triangle model.
“The Simple View of Reading”.
The lexical quality hypothesis (Perfetti & Hart). Matthew effect.
ELDEL project.
Diacritical mark.
Hiragana.
Phonetic radicals.
Morphogram.

September 15, 2019 Posted by | Books, Language, Psychology | Leave a comment

Words

Many of the words below I encountered while reading the books One of our Thursdays is missing, The secret of our success, Bowling alone, Thief of Time, and The Major Works of Samuel Johnson.

Damson. Greengage. Ingle. Marchioness. Tuberose. Flue. Titushky. Cowling. Soteriology. Piazza. Rake-off. Rusk. Babbittry. Aeolipile. SpallationLeister. Weir. Puffin. Omnipercipient. Shiv.

Vociferation. Ebriety. Playbill. Surtout. Outvie. Copiousness. Animadvert. Vendible. Silvicolous. Leveret. Novitiate. Commodious. Appellative. Preterite. Apostasize. Commixture. Sepulture. Desiccative. Siccity. Philology.

Incivism. Prorogation. Metonym. Apologue. Altricial(ity). Palilalia. Macaroon. Compositionality. Alloparental. Pizzle. Cholo. Epizeuxis. Cursorial. Misprision. Terrestriality. Pranny. Epistrophe. Analepsis. Corvid. Zorbing.

Polyptoton. Antanaclasis. Kern. Scrumtrulescent. Cotillion. Confute. Pinner. Declension. Piscatory. Jointure. Vulnerary. Subtilize. Sublunary. Ebullition. Affright. Exorbitance. Impost. Judicature. Fulminate. Cogency.

September 7, 2019 Posted by | Books, Language | Leave a comment

Quotes

i. “The advantage of living is not measured by length, but by use; some men have lived long, and lived little; attend to it while you are in it. It lies in your will, not in the number of years, for you to have lived enough.” (Michel de Montaigne)

ii. “All of the days go toward death and the last one arrives there.” (-ll-)

iii. “Nothing is so firmly believed as that which we least know.” (-ll-) (Variant: “Men are most apt to believe what they least understand.”)

iv. “The plague of man is boasting of his knowledge.” (-ll-)

v. “Saying is one thing and doing is another.” (-ll-)

vi. “Let no man be ashamed to speak what he is not ashamed to think.” (-ll-)

vii. “Few men have been admired by their own households.” (-ll-)

viii. “There is no wish more natural than the wish to know.” (-ll-)

ix. “It is not without good reason said, that he who has not a good memory should never take upon him the trade of lying.” (-ll-)

x. “Religion abhors the competition for truth. Science can’t live without it.” (Scott Atran, In gods we trust)

xi. “Imagination and intelligence enter into our existence in the part of servants of the primary instincts.” (Albert Einstein, Out of My Later Years (1950)), as quoted in Scott Atran’s In Gods we trust)

xii. “…yes, we are smart, but not because we stand on the shoulders of giants or are giants ourselves. We stand on the shoulders of a very large pyramid of hobbits. The hobbits do get a bit taller as the pyramid ascends, but it’s still the number of hobbits, not the height of particular hobbits, that’s allowing us to see farther.” (Joseph Heinrich, The Secret of Our Success)

xiii. “Underlying these failures is the assumption that we, as humans, all perceive the world similarly, want the same things, pursue these things based on our beliefs (the “facts” about the world), and process new information and experience in the same way. We already know all these assumptions are wrong. […] Different societies possess quite different social norms, institutions, languages, and technologies, and consequently they possess different ways of reasoning, mental heuristics, motivations, and emotional reactions. […] Culture, social norms, and institutions all shape our brains, biology, and hormones, as well as our perceptions, motivations, and judgments. We can’t pick our underlying cultural perceptions and motivations any more than we can suddenly speak a new language.” (-ll-)

xiv. “One of the debates in this literature involves opposing “innate” and “learned” in explaining our abilities and behaviors. [However,] much behavior is both 100% innate and 100% learned. For example, humans have clearly evolved to walk on two legs, and it’s one of our species’ behavioral signatures. Yet we also clearly learn to walk. […] showing that something is learned only tells us about the developmental process but not about whether it was favored by natural selection acting on genes.” (-ll-)

xv. “People always talk about the body as a beautiful well-oiled machine. But sometimes the body communicates with itself by messages written with radioactive ink on asbestos-laced paper, in the hopes that it’s killing itself slightly more slowly than it’s killing anyone who tries to send it fake messages. Honestly it is a miracle anybody manages to stay alive at all.” (Scott Alexander)

xvi. “It is better to be hated for what you are than to be loved for what you are not.” (André Gide)

xvii. “No matter how full a reservoir of maxims one may possess, and no matter how good one’s sentiments may be, if one have not taken advantage of every concrete opportunity to act, one’s character may remain entirely unaffected for the better.” (William James, Principles of Psychology)

xviii. “It is the duty of every man to endeavour that something may be added by his industry to the hereditary aggregate of knowledge and happiness. To add much can indeed be the lot of few, but to add something, however little, every one may hope” (Samuel Johnson, The Major Works of Samuel Johnson)

xix. ” …we should always wish to preserve the dignity of virtue by adorning her with graces which wickedness cannot assume.” (-ll-)

xx. “Let pain deserved without complaint be borne.” (“Leniter ex merito quicquid patiare ferendum est”) (Ovid, as quoted in -ll-)

 

August 20, 2019 Posted by | Anthropology, Books, culture, Quotes/aphorisms | Leave a comment

A few diabetes papers of interest

i. Identical and Nonidentical Twins: Risk and Factors Involved in Development of Islet Autoimmunity and Type 1 Diabetes.

Some observations from the paper:

“Type 1 diabetes is preceded by the presence of preclinical, persistent islet autoantibodies (1). Autoantibodies against insulin (IAA) (2), GAD (GADA), insulinoma-associated antigen 2 (IA-2A) (3), and/or zinc transporter 8 (ZnT8A) (4) are typically present prior to development of symptomatic hyperglycemia and progression to clinical disease. These autoantibodies may develop many years before onset of type 1 diabetes, and increasing autoantibody number and titers have been associated with increased risk of progression to disease (57).

Identical twins have an increased risk of progression of islet autoimmunity and type 1 diabetes after one twin is diagnosed, although reported rates have been highly variable (30–70%) (811). This risk is increased if the proband twin develops diabetes at a young age (12). Concordance rates for type 1 diabetes in monozygotic twins with long-term follow-up is >50% (13). Risk for development of islet autoimmunity and type 1 diabetes for nonidentical twins is thought to be similar to non-twin siblings (risk of 6–10% for diabetes) (14). Full siblings who inherit both high-risk HLA (HLA DQA1*05:01 DR3/4*0302) haplotypes identical to their proband sibling with type 1 diabetes have a much higher risk for development of diabetes than those who share only one or zero haplotypes (55% vs. 5% by 12 years of age, respectively; P = 0.03) (15). Despite sharing both HLA haplotypes with their proband, siblings without the HLA DQA1*05:01 DR3/4*0302 genotype had only a 25% risk for type 1 diabetes by 12 years of age (15).”

“The TrialNet Pathway to Prevention Study (previously the TrialNet Natural History Study; 16) has been screening relatives of patients with type 1 diabetes since 2004 and follows these subjects with serial autoantibody testing for the development of islet autoantibodies and type 1 diabetes. The study offers longitudinal monitoring for autoantibody-positive subjects through HbA1c testing and oral glucose tolerance tests (OGTTs).”

“The purpose of this study was to evaluate the prevalence of islet autoantibodies and analyze a logistic regression model to test the effects of genetic factors and common twin environment on the presence or absence of islet autoantibodies in identical twins, nonidentical twins, and full siblings screened in the TrialNet Pathway to Prevention Study. In addition, this study analyzed the presence of islet autoantibodies (GADA, IA-2A, and IAA) and risk of type 1 diabetes over time in identical twins, nonidentical twins, and full siblings followed in the TrialNet Pathway to Prevention Study. […] A total of 48,051 sibling subjects were initially screened (288 identical twins, 630 nonidentical twins, and 47,133 full siblings). Of these, 48,026 had an initial screening visit with GADA, IA2A, and IAA results (287 identical twins, 630 nonidentical twins, and 47,109 full siblings). A total of 17,226 participants (157 identical twins, 283 nonidentical twins and 16,786 full siblings) were followed for a median of 2.1 years (25th percentile 1.1 year and 75th percentile 4.0 years), with follow-up defined as at least ≥12 months follow-up after initial screening visit.”

“At the initial screening visit, GADA was present in 20.2% of identical twins (58 out of 287), 5.6% of nonidentical twins (35 out of 630), and 4.7% of full siblings (2,205 out of 47,109) (P < 0.0001). Additionally, IA-2A was present primarily in identical twins (9.4%; 27 out of 287) and less so in nonidentical twins (3.3%; 21 out of 630) and full siblings (2.2%; 1,042 out of 47,109) (P = 0.0001). Nearly 12% of identical twins (34 out of 287) were positive for IAA at initial screen, whereas 4.6% of nonidentical twins (29 out of 630) and 2.5% of full siblings (1,152 out of 47,109) were initially IAA positive (P < 0.0001).”

“At 3 years of follow-up, the risk for development of GADA was 16% for identical twins, 5% for nonidentical twins, and 4% for full siblings (P < 0.0001) (Fig. 1A). The risk for development of IA-2A by 3 years of follow-up was 7% for identical twins, 4% for nonidentical twins, and 2% for full siblings (P = 0.0005) (Fig. 1B). At 3 years of follow-up, the risk of development of IAA was 10% for identical twins, 5% for nonidentical twins, and 4% for full siblings (P = 0.006) […] In initially autoantibody-negative subjects, 1.5% of identical twins, 0% of nonidentical twins, and 0.5% of full siblings progressed to diabetes at 3 years of follow-up (P = 0.18) […] For initially single autoantibody–positive subjects, at 3 years of follow-up, 69% of identical twins, 13% of nonidentical twins, and 12% of full siblings developed type 1 diabetes (P < 0.0001) […] Subjects who were positive for multiple autoantibodies at screening had a higher risk of developing type 1 diabetes at 3 years of follow-up with 69% of identical twins, 72% of nonidentical twins, and 47% of full siblings developing type 1 diabetes (P = 0.079)”

“Because TrialNet is not a birth cohort and the median age at screening visit was 11 years overall, this study would not capture subjects who had initial seroconversion at a young age and then progressed through the intermediate stage of multiple antibody positivity before developing diabetes.”

“This study of >48,000 siblings of patients with type 1 diabetes shows that at initial screening, identical twins were more likely to have at least one positive autoantibody and be positive for GADA, IA-2A, and IAA than either nonidentical twins or full siblings. […] risk for development of type 1 diabetes at 3 years of follow-up was high for both single and multiple autoantibody–positive identical twins (62–69%) and multiple autoantibody–positive nonidentical twins (72%) compared with 47% for initially multiple autoantibody–positive full siblings and 12–13% for initially single autoantibody–positive nonidentical twins and full siblings. To our knowledge, this is the largest prediagnosis study to evaluate the effects of genetic factors and common twin environment on the presence or absence of islet autoantibodies.

In this study, younger age, male sex, and genetic factors were significantly associated with expression of IA-2A, IAA, more than one autoantibody, and more than two autoantibodies, whereas only genetic factors were significant for GADA. An influence of common twin environment (E) was not seen. […] Previous studies have shown that identical twin siblings of patients with type 1 diabetes have a higher concordance rate for development of type 1 diabetes compared with nonidentical twins, although reported rates for identical twins have been highly variable (30–70%) […]. Studies from various countries (Australia, Denmark, Finland, Great Britain, and U.S.) have reported concordance rates for nonidentical twins ∼5–15% […]. Concordance rates have been higher when the proband was diagnosed at a younger age (8), which may explain the variability in these reported rates. In this study, autoantibody-negative nonidentical and identical twins had a low risk of type 1 diabetes by 3 years of follow-up. In contrast, once twins developed autoantibodies, risk for type 1 diabetes was high for multiple autoantibody nonidentical twins and both single and multiple autoantibody identical twins.”

ii. A Type 1 Diabetes Genetic Risk Score Can Identify Patients With GAD65 Autoantibody–Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy.

This is another paper in the ‘‘ segment from the February edition of Diabetes Care – multiple other papers on related topics were also included in that edition, so if you’re interested in the genetics of diabetes it may be worth checking out.

Some observations from the paper:

“Type 2 diabetes is a progressive disease due to a gradual reduction in the capacity of the pancreatic islet cells (β-cells) to produce insulin (1). The clinical course of this progression is highly variable, with some patients progressing very rapidly to requiring insulin treatment, whereas others can be successfully treated with lifestyle changes or oral agents for many years (1,2). Being able to identify patients likely to rapidly progress may have clinical utility in prioritization monitoring and treatment escalation and in choice of therapy.

It has previously been shown that many patients with clinical features of type 2 diabetes have positive GAD65 autoantibodies (GADA) and that the presence of this autoantibody is associated with faster progression to insulin (3,4). This is often termed latent autoimmune diabetes in adults (LADA) (5,6). However, the predictive value of GADA testing is limited in a population with clinical type 2 diabetes, with many GADA-positive patients not requiring insulin treatment for many years (4,7). Previous research has suggested that genetic variants in the HLA region associated with type 1 diabetes are associated with more rapid progression to insulin in patients with clinically defined type 2 diabetes and positive GADA (8).

We have recently developed a type 1 diabetes genetic risk score (T1D GRS), which provides an inexpensive ($70 in our local clinical laboratory and <$20 where DNA has been previously extracted), integrated assessment of a person’s genetic susceptibility to type 1 diabetes (9). The score is composed of 30 type 1 diabetes risk variants weighted for effect size and aids discrimination of type 1 diabetes from type 2 diabetes. […] We aimed to determine if the T1D GRS could predict rapid progression to insulin (within 5 years of diagnosis) over and above GADA testing in patients with a clinical diagnosis of type 2 diabetes treated without insulin at diagnosis.”

“We examined the relationship between GADA, T1D GRS, and progression to insulin therapy using survival analysis in 8,608 participants with clinical type 2 diabetes initially treated without insulin therapy. […] In this large study of participants with a clinical diagnosis of type 2 diabetes, we have found that type 1 genetic susceptibility alters the clinical implications of a positive GADA when predicting rapid time to insulin. GADA-positive participants with high T1D GRS were more likely to require insulin within 5 years of diagnosis, with 48% progressing to insulin in this time in contrast to only 18% in participants with low T1D GRS. The T1D GRS was independent of and additive to participant’s age of diagnosis and BMI. However, T1D GRS was not associated with rapid insulin requirement in participants who were GADA negative.”

“Our findings have clear implications for clinical practice. The T1D GRS represents a novel clinical test that can be used to enhance the prognostic value of GADA testing. For predicting future insulin requirement in patients with apparent type 2 diabetes who are GADA positive, T1D GRS may be clinically useful and can be used as an additional test in the screening process. However, in patients with type 2 diabetes who are GADA negative, there is no benefit gained from genetic testing. This is unsurprising, as the prevalence of underlying autoimmunity in patients with a clinical phenotype of type 2 diabetes who are GADA negative is likely to be extremely low; therefore, most GADA-negative participants with high T1D GRS will have nonautoimmune diabetes. The use of this two-step testing approach may facilitate a precision medicine approach to patients with apparent type 2 diabetes; patients who are likely to progress rapidly are identified for targeted management, which may include increased monitoring, early therapy intensification, and/or interventions aimed at slowing progression (36,37).

The costs of analyzing the T1D GRS are relatively modest and may fall further, as genetic testing is rapidly becoming less expensive (38). […] In conclusion, a T1D GRS alters the clinical implications of a positive GADA test in patients with clinical type 2 diabetes and is independent of and additive to clinical features. This therefore represents a novel test for identifying patients with rapid progression in this population.”

iii. Retinopathy and RAAS Activation: Results From the Canadian Study of Longevity in Type 1 Diabetes.

“Diabetic retinopathy is the most common cause of preventable blindness in individuals ages 20–74 years and is the most common vascular complication in type 1 and type 2 diabetes (13). On the basis of increasing severity, diabetic retinopathy is classified into nonproliferative diabetic retinopathy (NPDR), defined in early stages by the presence of microaneurysms, retinal vascular closure, and alteration, or proliferative diabetic retinopathy (PDR), defined by the growth of new aberrant blood vessels (neovascularization) susceptible to hemorrhage, leakage, and fibrosis (4). Diabetic macular edema (DME) can be present at any stage of retinopathy and is characterized by increased vascular permeability leading to retinal thickening.

Important risk factors for the development of retinopathy continue to be chronic hyperglycemia, hyperlipidemia, hypertension, and diabetes duration (5,6). Given the systemic nature of these risk factors, cooccurrence of retinopathy with other vascular complications is common in patients with diabetes.”

“A key pathway implicated in diabetes-related small-vessel disease is overactivation of neurohormones. Activation of the neurohormonal renin-angiotensin-aldosterone system (RAAS) pathway predominates in diabetes in response to hyperglycemia and sodium retention. The RAAS plays a pivotal role in regulating systemic BP through vasoconstriction and fluid-electrolyte homeostasis. At the tissue level, angiotensin II (ANGII), the principal mediator of the RAAS, is implicated in fibrosis, oxidative stress, endothelial damage, thrombosis, inflammation, and vascular remodeling. Of note, systemic RAAS blockers reduce the risk of progression of eye disease but not DKD [Diabetic Kidney Disease, US] in adults with type 1 diabetes with normoalbuminuria (12).

Several longitudinal epidemiologic studies of diabetic retinopathy have been completed in type 1 diabetes; however, few have studied the relationships between eye, nerve, and renal complications and the influence of RAAS activation after prolonged duration (≥50 years) in adults with type 1 diabetes. As a result, less is known about mechanisms that persist in diabetes-related microvascular complications after long-standing diabetes. Accordingly, in this cross-sectional analysis from the Canadian Study of Longevity in Type 1 Diabetes involving adults with type 1 diabetes for ≥50 years, our aims were to phenotype retinopathy stage and determine associations between the presence of retinopathy and other vascular complications. In addition, we examined the relationship between retinopathy stage and renal and systemic hemodynamic function, including arterial stiffness, at baseline and dynamically after RAAS activation with an infusion of exogenous ANGII.”

“Of the 75 participants, 12 (16%) had NDR [no diabetic retinopathy], 24 (32%) had NPDR, and 39 (52%) had PDR […]. At baseline, those with NDR had lower mean HbA1c compared with those with NPDR and PDR (7.4 ± 0.7% and 7.5 ± 0.9%, respectively; P for trend = 0.019). Of note, those with more severe eye disease (PDR) had lower systolic and diastolic BP values but a significantly higher urine albumin-to-creatine ratio (UACR) […] compared with those with less severe eye disease (NPDR) or with NDR despite higher use of RAAS inhibitors among those with PDR compared with NPDR or NDR. History of cardiovascular and peripheral vascular disease history was significantly higher in participants with PDR (33.3%) than in those with NPDR (8.3%) or NDR (0%). Diabetic sensory polyneuropathy was prevalent across all groups irrespective of retinopathy status but was numerically higher in the PDR group (95%) than in the NPDR (86%) or NDR (75%) groups. No significant differences were observed in retinal thickness across the three groups.”

One quick note: This was mainly an eye study, but some of the other figures here are well worth taking note of. 3 out of 4 people in the supposedly low-risk group without eye complications had sensory polyneuropathy after 50 years of diabetes.

Conclusions

Hyperglycemia contributes to the pathogenesis of diabetic retinopathy through multiple interactive pathways, including increased production of advanced glycation end products, IGF-I, vascular endothelial growth factor, endothelin, nitric oxide, oxidative damage, and proinflammatory cytokines (2933). Overactivation of the RAAS in response to hyperglycemia also is implicated in the pathogenesis of diabetes-related complications in the retina, nerves, and kidney and is an important therapeutic target in type 1 diabetes. Despite what is known about these underlying pathogenic mechanisms in the early development of diabetes-related complications, whether the same mechanisms are active in the setting of long-standing type 1 diabetes is not known. […] In this study, we observed that participants with PDR were more likely to be taking RAAS inhibitors, to have a higher frequency of cardiovascular or peripheral vascular disease, and to have higher UACR levels, likely reflecting the higher overall risk profile of this group. Although it is not possible to determine why some patients in this cohort developed PDR while others did not after similar durations of type 1 diabetes, it seems unlikely that glycemic control alone is sufficient to fully explain the observed between-group differences and differing vascular risk profiles. Whereas the NDR group had significantly lower mean HbA1c levels than the NPDR and PDR groups, differences between participants with NPDR and those with PDR were modest. Accordingly, other factors, such as differences in vascular function, neurohormones, growth factors, genetics, and lifestyle, may play a role in determining retinopathy severity at the individual level.

The association between retinopathy and risk for DKD is well established in diabetes (34). In the setting of type 2 diabetes, patients with high levels of UACR have twice the risk of developing diabetic retinopathy than those with normal UACR levels. For example, Rodríguez-Poncelas et al. (35) demonstrated that impaired renal function is linked with increased diabetic retinopathy risk. Consistent with these studies and others, the PDR group in this Canadian Study of Longevity in Type 1 Diabetes demonstrated significantly higher UACR, which is associated with an increased risk of DKD progression, illustrating that the interaction between eye and kidney disease progression also may exist in patients with long-standing type 1 diabetes. […] In conclusion, retinopathy was prevalent after prolonged type 1 diabetes duration, and retinopathy severity associated with several measures of neuropathy and with higher UACR. Differential exaggerated responses to RAAS activation in the peripheral vasculature of the PDR group highlights that even in the absence of DKD, neurohormonal abnormalities are likely still operant, and perhaps accentuated, in patients with PDR even after long-standing type 1 diabetes duration.”

iv. Clinical and MRI Features of Cerebral Small-Vessel Disease in Type 1 Diabetes.

“Type 1 diabetes is associated with a fivefold increased risk of stroke (1), with cerebral small-vessel disease (SVD) as the most common etiology (2). Cerebral SVD in type 1 diabetes, however, remains scarcely investigated and is challenging to study in vivo per se owing to the size of affected vasculature (3); instead, MRI signs of SVD are studied. In this study, we aimed to assess the prevalence of cerebral SVD in subjects with type 1 diabetes compared with healthy control subjects and to characterize diabetes-related variables associated with SVD in stroke-free people with type 1 diabetes.”

RESEARCH DESIGN AND METHODS This substudy was cross-sectional in design and included 191 participants with type 1 diabetes and median age 40.0 years (interquartile range 33.0–45.1) and 30 healthy age- and sex-matched control subjects. All participants underwent clinical investigation and brain MRIs, assessed for cerebral SVD.

RESULTS Cerebral SVD was more common in participants with type 1 diabetes than in healthy control subjects: any marker 35% vs. 10% (P = 0.005), cerebral microbleeds (CMBs) 24% vs. 3.3% (P = 0.008), white matter hyperintensities 17% vs. 6.7% (P = 0.182), and lacunes 2.1% vs. 0% (P = 1.000). Presence of CMBs was independently associated with systolic blood pressure (odds ratio 1.03 [95% CI 1.00–1.05], P = 0.035).”

Conclusions

Cerebral SVD is more common in participants with type 1 diabetes than in healthy control subjects. CMBs especially are more prevalent and are independently associated with hypertension. Our results indicate that cerebral SVD starts early in type 1 diabetes but is not explained solely by diabetes-related vascular risk factors or the generalized microvascular disease that takes place in diabetes (7).

There are only small-scale studies on cerebral SVD, especially CMBs, in type 1 diabetes. Compared with the current study, one study with similar diabetes characteristics (i.e., diabetes duration, glycemic control, and blood pressure levels) as in the current study, but lacking a control population, showed a higher prevalence of WMHs, with more than half of the participants affected, but similar prevalence of lacunes and lower prevalence of CMBs (8). In another study, including 67 participants with type 1 diabetes and 33 control subjects, there was no difference in WMH prevalence but a higher prevalence of CMBs in participants with type 1 diabetes and retinopathy compared with control subjects (9). […] In type 1 diabetes, albuminuria and systolic blood pressure independently increase the risk for both ischemic and hemorrhagic stroke (12). […] We conclude that cerebral SVD is more common in subjects with type 1 diabetes than in healthy control subjects. Future studies will focus on longitudinal development of SVD in type 1 diabetes and the associations with brain health and cognition.”

v. The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study).

“In the U.S., an estimated 1.4 million adults are newly diagnosed with diabetes every year and present an important intervention opportunity for health care systems. In patients newly diagnosed with type 2 diabetes, the benefits of maintaining an HbA1c <7.0% (<53 mmol/mol) are well established. The UK Prospective Diabetes Study (UKPDS) found that a mean HbA1c of 7.0% (53 mmol/mol) lowers the risk of diabetes-related end points by 12–32% compared with a mean HbA1c of 7.9% (63 mmol/mol) (1,2). Long-term observational follow-up of this trial revealed that this early glycemic control has durable effects: Reductions in microvascular events persisted, reductions in cardiovascular events and mortality were observed 10 years after the trial ended, and HbA1c values converged (1). Similar findings were observed in the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes (24). These posttrial observations have been called legacy effects (also metabolic memory) (5), and they suggest the importance of early glycemic control for the prevention of future complications of diabetes. Although these clinical trial long-term follow-up studies demonstrated legacy effects, whether legacy effects exist in real-world populations, how soon after diabetes diagnosis legacy effects may begin, or for what level of glycemic control legacy effects may exist are not known.

In a previous retrospective cohort study, we found that patients with newly diagnosed diabetes and an initial 10-year HbA1c trajectory that was unstable (i.e., changed substantially over time) had an increased risk for future microvascular events, even after adjusting for HbA1c exposure (6). In the same cohort population, this study evaluates associations between the duration and intensity of glycemic control immediately after diagnosis and the long-term incidence of future diabetic complications and mortality. We hypothesized that a glycemic legacy effect exists in real-world populations, begins as early as the 1st year after diabetes diagnosis, and depends on the level of glycemic exposure.”

RESEARCH DESIGN AND METHODS This cohort study of managed care patients with newly diagnosed type 2 diabetes and 10 years of survival (1997–2013, average follow-up 13.0 years, N = 34,737) examined associations between HbA1c <6.5% (<48 mmol/mol), 6.5% to <7.0% (48 to <53 mmol/mol), 7.0% to <8.0% (53 to <64 mmol/mol), 8.0% to <9.0% (64 to <75 mmol/mol), or ≥9.0% (≥75 mmol/mol) for various periods of early exposure (0–1, 0–2, 0–3, 0–4, 0–5, 0–6, and 0–7 years) and incident future microvascular (end-stage renal disease, advanced eye disease, amputation) and macrovascular (stroke, heart disease/failure, vascular disease) events and death, adjusting for demographics, risk factors, comorbidities, and later HbA1c.

RESULTS Compared with HbA1c <6.5% (<48 mmol/mol) for the 0-to-1-year early exposure period, HbA1c levels ≥6.5% (≥48 mmol/mol) were associated with increased microvascular and macrovascular events (e.g., HbA1c 6.5% to <7.0% [48 to <53 mmol/mol] microvascular: hazard ratio 1.204 [95% CI 1.063–1.365]), and HbA1c levels ≥7.0% (≥53 mmol/mol) were associated with increased mortality (e.g., HbA1c 7.0% to <8.0% [53 to <64 mmol/mol]: 1.290 [1.104–1.507]). Longer periods of exposure to HbA1c levels ≥8.0% (≥64 mmol/mol) were associated with increasing microvascular event and mortality risk.

CONCLUSIONS Among patients with newly diagnosed diabetes and 10 years of survival, HbA1c levels ≥6.5% (≥48 mmol/mol) for the 1st year after diagnosis were associated with worse outcomes. Immediate, intensive treatment for newly diagnosed patients may be necessary to avoid irremediable long-term risk for diabetic complications and mortality.”

Do note that the effect sizes here are very large and this stuff seems really quite important. Judging from the results of this study, if you’re newly diagnosed and you only obtain a HbA1c of say, 7.3% in the first year, that may translate into a close to 30% increased risk of death more than 10 years into the future, compared to a scenario of an HbA1c of 6.3%. People who did not get their HbA1c measured within the first 3 months after diagnosis had a more than 20% increased risk of mortality during the study period. This seems like critical stuff to get right.

vi. Event Rates and Risk Factors for the Development of Diabetic Ketoacidosis in Adult Patients With Type 1 Diabetes: Analysis From the DPV Registry Based on 46,966 Patients.

“Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus (T1DM) that results from absolute insulin deficiency and is marked by acidosis, ketosis, and hyperglycemia (1). Therefore, prevention of DKA is one goal in T1DM care, but recent data indicate increased incidence (2).

For adult patients, only limited data are available on rates and risk factors for development of DKA, and this complication remains epidemiologically poorly characterized. The Diabetes Prospective Follow-up Registry (DPV) has followed patients with diabetes from 1995. Data for this study were collected from 2000 to 2016. Inclusion criteria were diagnosis of T1DM, age at diabetes onset ≥6 months, patient age at follow-up ≥18 years, and diabetes duration ≥1 year to exclude DKA at manifestation. […] In total, 46,966 patients were included in this study (average age 38.5 years [median 21.2], 47.6% female). The median HbA1c was 7.7% (61 mmol/mol), median diabetes duration was 13.6 years, and 58.3% of the patients were treated in large diabetes centers.

On average, 2.5 DKA-related hospital admissions per 100 patient-years (PY) were observed (95% CI 2.1–3.0). The rate was highest in patients aged 18–30 years (4.03/100 PY) and gradually declined with increasing age […] No significant differences between males (2.46/100 PY) and females (2.59/100 PY) were found […] Patients with HbA1c levels <7% (53 mmol/mol) had significantly fewer DKA admissions than patients with HbA1c ≥9% (75 mmol/mol) (0.88/100 PY vs. 6.04/100 PY; P < 0.001)”

“Regarding therapy, use of an insulin pump (continuous subcutaneous insulin infusion [CSII]) was not associated with higher DKA rates […], while patients aged 31–50 years on CSII showed lower rates than patients using multiple daily injections (2.21 vs. 3.12/100 PY; adjusted P < 0.05) […]. Treatment in a large center was associated with lower DKA-related hospital admissions […] In both adults and children, poor metabolic control was the strongest predictor of hospital admission due to DKA. […] In conclusion, the results of this study identify patients with T1DM at risk for DKA (high HbA1c, diabetes duration 5–10 years, migrants, age 30 years and younger) in real-life diabetes care. These at-risk individuals may need specific attention since structured diabetes education has been demonstrated to specifically reduce and prevent this acute complication.”

August 13, 2019 Posted by | Cardiology, Diabetes, Genetics, Immunology, Medicine, Molecular biology, Nephrology, Neurology, Ophthalmology, Studies | Leave a comment

Neutron Stars – Victoria Kaspi

I’ve read Springer books – well, a book – about pulsars in the past and this is certainly not the first post here on this blog covering these topics, yet I definitely found this lecture hard to follow. It’s highly technical, but occasionally quite interesting.

Some links related to the lecture coverage:

Coherence time.
Coherence (physics).
Pulsar timing and its applications (Manchester 2018).
NE2001. I. A new model for the galactic distribution of free electrons and its fluctuations (Cordes and Lazio).
Pulsar Timing.
Supplementary parameters in the parameterized post-Keplerian formalism.
Shapiro time delay.
Fonseca et al. 2014.
Hulse–Taylor binary.
PSR J0737−3039.
Spin–orbit coupling.
Tests of general relativity – Binary pulsars.
Relativistic Spin Precession in the Double Pulsar (Breton et al. 2008).
PSR J1614−2230.
PSR J0348+0432.
Scalar–tensor theory.
A Massive Pulsar in a Compact Relativistic Binary (Antoniadis et al. 2013).
The strong equivalence principle.
Nordtvedt effect.
PSR J0337+1715.
A millisecond pulsar in a stellar triple system (Ransom, Archibald et al. 2014).
Millisecond pulsar (recycled pulsar).
A comprehensive study of binary compact objects as gravitational wave sources: Evolutionary channels, rates, and physical properties (Belczynski et al. 2002).
Relativistic binary pulsars with black-hole companions (Pfahl et al. 2005).
Pulsar timing array.
PALFA (Pulsar Arecibo L-band Feed Array) Survey.
Green Bank North Celestial Cap (GBNCC) Survey.

August 6, 2019 Posted by | Astronomy, Lectures, Physics, Studies | Leave a comment

The Shapes of Spaces and the Nuclear Force

This one was in my opinion a great lecture which I enjoyed watching. It covers some quite high-level mathematics and physics and some of the ways in which these two fields intersected in a specific historical research context; however it does so in a way that will enable many people outside of the fields involved to be able to follow the narrative reasonably easily.

Some links related to the lecture coverage:

Topological space.
Topological invariant.
Topological isomorphism.
Dimension of a mathematical space.
Metrically topologically complete space.
Genus (mathematics).
Quotient space (topology).
Will we ever classify simply-connected smooth 4-manifolds? (Stern, 2005).
Nuclear force.
Coulomb’s law.
Maxwell’s equations.
Commutative property.
Abelian group.
Non-abelian group.
Yang–Mills theory.
Soliton.
Instanton.
Michael Atiyah.
Donaldson theory.
Michael Freedman.
Topological (quantum) field theory.
Edward Witten.
Effective field theory.
Seiberg–Witten invariants.
“Theoretical mathematics”: toward a cultural synthesis of mathematics and theoretical physics (Jaffe & Quinn, 1993).
Responses to “Theoretical mathematics: toward a cultural synthesis of mathematics and theoretical physics (Atiyah et al, 1994).

July 31, 2019 Posted by | Lectures, Mathematics, Physics | Leave a comment

Learning Phylogeny Through Simple Statistical Genetics

From a brief skim I concluded that a lot of the stuff Patterson talks about in this lecture, particularly in terms of the concepts and methods part (…which, as he also alludes to in his introduction, makes up a substantial proportion of the talk), is included/covered in this Ancient Admixture in Human History paper he coauthored, so if you’re either curious to know more, or perhaps just wondering what the talk might be about, it’s probably worth checking it out. In the latter case I would also recommend perhaps just watching the first few minutes of the talk; he provides a very informative outline of the talk in the first four and a half minutes of the video.

A few other links of relevance:

Martingale (probability theory).
GitHub – DReichLab/AdmixTools.
Human Genome Diversity Project.
Jackknife resampling.
Ancient North Eurasian.
Upper Palaeolithic Siberian genome reveals dual ancestry of Native Americans (Raghavan et al, 2014).
General theory for stochastic admixture graphs and F-statistics. This one is only very slightly related to the talk; I came across it while looking for stuff about admixture graphs, a topic he does briefly discuss in the lecture.

July 29, 2019 Posted by | Archaeology, Biology, Genetics, Lectures, Molecular biology, Statistics | Leave a comment

Words

Many of the words below are words I encountered while reading the books Lost in a good book, The Eyre Affair, In Gods We Trust: The Evolutionary Landscape of Religion, and The Complete Saki: 144 Collected Novels and Short Stories.

Ergotropic. Trophotropic. Abreaction. Nomological. Triskaidekaphobia. Casuistry. Nonsequitous. Amontillado. Contrail. Nacelle. Potluck. Sizar. Herpetology. Phenology. Fustigate. Tintinnabula. Phoropter. Vexillology. Quondam. Onomastic.

Glossolalia. Scrupulosity. Proclaim. Pablum. Ochlocracy. Probate. Anacyclosis. Anastylosis. Diphyodonty. Pakicetus. Gymnure. Sojourner. Rescission. Illocution. Sylvatic. Diabolist. Lariat. Carcinization. Champerty. Barratry.

Pannus. Vitiate. Svengali. Brevet. Scud. Vermicelli. Couplet. Offertory. Rognon. Mangold. Dissentient. Heller. Desultory. Crinkle. Whitsuntide. Syce. Variegation. Novelette. Wassail. Kith.

Astrakhan. Satrap. Halva. Precipitancy. Hie. Lambkin. Toque. Wapiti. Spiraea. Pleasaunce. Berberis. Goodly. Estaminet. Lyddite. Acclamation. Burgh. Wharfage. Tamarin. Chaffer. Catafalque.

July 22, 2019 Posted by | Books, Language | Leave a comment

A recent perspective on invariant theory

Some time ago I covered here on the blog a lecture with a somewhat technical introduction to invariant theory. Even though I didn’t recommend the lecture, I do recommend that you don’t watch the lecture above without first knowing the sort of stuff that might have been covered in that lecture (for all you know, that is), as well as some other lectures on related topics – to be more specific, to get anything out of this lecture you need some linear algebra, you need graph theory, you need some understanding of group theory, you need to know a little about computational complexity, it’ll probably help if you know a bit about invariant theory already, and surely you need some knowledge of a few other topics I forgot to mention. One of the statements I made about the introductory lecture to which I linked above also applies here: “I had to look up a lot of stuff to just sort-of-kind-of muddle along”.

Below some links to stuff I looked up while watching the lecture:

Algebraically closed field.
Reductive group.
Rational representation.
Group homomorphism.
Morphism of algebraic varieties.
Fixed-point subring.
Graph isomorphism.
Adjacency matrix.
Group action (mathematics).
General linear group.
Special linear group.
Alternating minimization, scaling algorithms, and the null-cone problem from invariant theory. (Bürgisser, Garg, Oliveira, Walter, and Wigderson (2017))
Noether normalization lemma.
Succinct data structure. (This link is actually not directly related to the lecture’s coverage; I came across it by accident while looking for topics he did talk about and I found it interesting, so I decided to include the link here anyway)
Characteristic polynomial.
Matrix similarity.
Monomial.
Associative algebra.
Polynomial degree bounds for matrix semi-invariants (Derksen & Makam, 2015).
Semi-invariant of a quiver.

July 6, 2019 Posted by | Computer science, Lectures, Mathematics | Leave a comment

On the possibility of an instance-based complexity theory

Below some links related to the lecture’s coverage:

Computational complexity theory.
Minimum cut.
2-satisfiability.
3-SAT.
Worst-case complexity.
Average-case complexity.
Max-Cut.
Karp’s 21 NP-complete problems.
Reduction (complexity).
Levin’s Universal search algorithm – Scholarpedia.
Computational indistinguishability.
Circuit complexity.
Adversarial Perturbations of Deep Neural Networks.
Sherrington–Kirkpatrick model.
Equivalence class.
Hopkins (2018).
Planted clique.
SDP (Semidefinite programming).
Jain, Koehler & Risteski (2018): Mean-field approximation, convex hierarchies, and the optimality of correlation rounding: a unified perspective.
Structural operational semantics (SOS).

July 1, 2019 Posted by | Computer science, Lectures | Leave a comment

The pleasure of finding things out (II)

Here’s my first post about the book. In this post I have included a few more quotes from the last half of the book.

“Are physical theories going to keep getting more abstract and mathematical? Could there be today a theorist like Faraday in the early nineteenth century, not mathematically sophisticated but with a very powerful intuition about physics?
Feynman: I’d say the odds are strongly against it. For one thing, you need the math just to understand what’s been done so far. Beyond that, the behavior of subnuclear systems is so strange compared to the ones the brain evolved to deal with that the analysis has to be very abstract: To understand ice, you have to understand things that are themselves very unlike ice. Faraday’s models were mechanical – springs and wires and tense bands in space – and his images were from basic geometry. I think we’ve understood all we can from that point of view; what we’ve found in this century is different enough, obscure enough, that further progress will require a lot of math.”

“There’s a tendency to pomposity in all this, to make it all deep and profound. My son is taking a course in philosophy, and last night we were looking at something by Spinoza – and there was the most childish reasoning! There were all these Attributes, and Substances, all this meaningless chewing around, and we started to laugh. Now, how could we do that? Here’s this great Dutch philosopher, and we’re laughing at him. It’s because there was no excuse for it! In that same period there was Newton, there was Harvey studying the circulation of the blood, there were people with methods of analysis by which progress was being made! You can take every one of Spinoza’s propositions, and take the contrary propositions, and look at the world – and you can’t tell which is right. Sure, people were awed because he had the courage to take on these great questions, but it doesn’t do any good to have the courage if you can’t get anywhere with the question. […] It isn’t the philosophy that gets me, it’s the pomposity. If they’d just laugh at themselves! If they’d just say, “I think it’s like this, but von Leipzig thought it was like that, and he had a good shot at it, too.” If they’d explain that this is their best guess … But so few of them do”.

“The lesson you learn as you grow older in physics is that what we can do is a very small fraction of what there is. Our theories are really very limited.”

“The first principle is that you must not fool yourself – and you are the easiest person to fool. So you have to be very careful about that. After you’ve not fooled yourself, it’s easy not to fool other scientists. You just have to be honest in a conventional way after that.”

“When I was an undergraduate I worked with Professor Wheeler* as a research assistant, and we had worked out together a new theory about how light worked, how the interaction between atoms in different places worked; and it was at that time an apparently interesting theory. So Professor Wigner†, who was in charge of the seminars there [at Princeton], suggested that we give a seminar on it, and Professor Wheeler said that since I was a young man and hadn’t given seminars before, it would be a good opportunity to learn how to do it. So this was the first technical talk that I ever gave. I started to prepare the thing. Then Wigner came to me and said that he thought the work was important enough that he’d made special invitations to the seminar to Professor Pauli, who was a great professor of physics visiting from Zurich; to Professor von Neumann, the world’s greatest mathematician; to Henry Norris Russell, the famous astronomer; and to Albert Einstein, who was living near there. I must have turned absolutely white or something because he said to me, “Now don’t get nervous about it, don’t be worried about it. First of all, if Professor Russell falls asleep, don’t feel bad, because he always falls asleep at lectures. When Professor Pauli nods as you go along, don’t feel good, because he always nods, he has palsy,” and so on. That kind of calmed me down a bit”.

“Well, for the problem of understanding the hadrons and the muons and so on, I can see at the present time no practical applications at all, or virtually none. In the past many people have said that they could see no applications and then later they found applications. Many people would promise under those circumstances that something’s bound to be useful. However, to be honest – I mean he looks foolish; saying there will never be anything useful is obviously a foolish thing to do. So I’m going to be foolish and say these damn things will never have any application, as far as I can tell. I’m too dumb to see it. All right? So why do you do it? Applications aren’t the only thing in the world. It’s interesting in understanding what the world is made of. It’s the same interest, the curiosity of man that makes him build telescopes. What is the use of discovering the age of the universe? Or what are these quasars that are exploding at long distances? I mean what’s the use of all that astronomy? There isn’t any. Nonetheless, it’s interesting. So it’s the same kind of exploration of our world that I’m following and it’s curiosity that I’m satisfying. If human curiosity represents a need, the attempt to satisfy curiosity, then this is practical in the sense that it is that. That’s the way I would look at it at the present time. I would not put out any promise that it would be practical in some economic sense.”

“To science we also bring, besides the experiment, a tremendous amount of human intellectual attempt at generalization. So it’s not merely a collection of all those things which just happen to be true in experiments. It’s not just a collection of facts […] all the principles must be as wide as possible, must be as general as possible, and still be in complete accord with experiment, that’s the challenge. […] Evey one of the concepts of science is on a scale graduated somewhere between, but at neither end of, absolute falsity or absolute truth. It is necessary, I believe, to accept this idea, not only for science, but also for other things; it is of great value to acknowledge ignorance. It is a fact that when we make decisions in our life, we don’t necessarily know that we are making them correctly; we only think that we are doing the best we can – and that is what we should do.”

“In this age of specialization, men who thoroughly know one field are often incompetent to discuss another.”

“I believe that moral questions are outside of the scientific realm. […] The typical human problem, and one whose answer religion aims to supply, is always of the following form: Should I do this? Should we do this? […] To answer this question we can resolve it into two parts: First – If I do this, what will happen? – and second – Do I want that to happen? What would come of it of value – of good? Now a question of the form: If I do this, what will happen? is strictly scientific. […] The technique of it, fundamentally, is: Try it and see. Then you put together a large amount of information from such experiences. All scientists will agree that a question – any question, philosophical or other – which cannot be put into the form that can be tested by experiment (or, in simple terms, that cannot be put into the form: If I do this, what will happen?) is not a scientific question; it is outside the realm of science.”

June 26, 2019 Posted by | Astronomy, Mathematics, Philosophy, Physics, Quotes/aphorisms, Science | Leave a comment

Promoting the unknown…

i.

ii.

iii.

iv.

v.

June 22, 2019 Posted by | Music | Leave a comment

The pleasure of finding things out (I?)

As I put it in my goodreads review of the book, “I felt in good company while reading this book“. Some of the ideas in the book are by now well known, for example some of the interview snippets also included in the book have been added to youtube and have been viewed by hundreds of thousands of people (I added a couple of them to my ‘about’ page some years ago, and they’re still there, these are enjoyable videos to watch and they have aged well!) (the overlap between the book’s text and the sound recordings available is not 100 % for this material, but it’s close enough that I assume these were the same interviews). Others ideas and pieces I would assume to be less well known, for example Feynman’s encounter with Uri Geller in the latter’s hotel room, where he was investigating the latter’s supposed abilities related to mind reading and key bending..

I have added some sample quotes from the book below. It’s a good book, recommended.

“My interest in science is to simply find out about the world, and the more I find out the better it is, like, to find out. […] You see, one thing is, I can live with doubt and uncertainty and not knowing. I think it’s much more interesting to live not knowing than to have answers which might be wrong. I have approximate answers and possible beliefs and different degrees of certainty about different things, but I’m not absolutely sure of anything and there are many things I don’t know anything about […] I don’t have to know an answer, I don’t feel frightened by not knowing things, by being lost in a mysterious universe without having any purpose, which is the way it really is so far as I can tell. It doesn’t frighten me.”

“Some people look at the activity of the brain in action and see that in many respects it surpasses the computer of today, and in many other respects the computer surpasses ourselves. This inspires people to design machines that can do more. What often happens is that an engineer has an idea of how the brain works (in his opinion) and then designs a machine that behaves that way. This new machine may in fact work very well. But, I must warn you that that does not tell us anything about how the brain actually works, nor is it necessary to ever really know that, in order to make a computer very capable. It is not necessary to understand the way birds flap their wings and how the feathers are designed in order to make a flying machine. It is not necessary to understand the lever system in the legs of a cheetah – an animal that runs fast – in order to make an automobile with wheels that goes very fast. It is therefore not necessary to imitate the behavior of Nature in detail in order to engineer a device which can in many respects surpass Nature’s abilities.”

“These ideas and techniques [of scientific investigation] , of course, you all know. I’ll just review them […] The first is the matter of judging evidence – well, the first thing really is, before you begin you must not know the answer. So you begin by being uncertain as to what the answer is. This is very, very important […] The question of doubt and uncertainty is what is necessary to begin; for if you already know the answer there is no need to gather any evidence about it. […] We absolutely must leave room for doubt or there is no progress and there is no learning. There is no learning without having to pose a question. And a question requires doubt. […] Authority may be a hint as to what the truth is, but it is not the source of information. As long as it’s possible, we should disregard authority whenever the observations disagree with it. […] Science is the belief in the ignorance of experts.”

“If we look away from the science and look at the world around us, we find out something rather pitiful: that the environment that we live in is so actively, intensely unscientific. Galileo could say: “I noticed that Jupiter was a ball with moons and not a god in the sky. Tell me, what happened to the astrologers?” Well, they print their results in the newspapers, in the United States at least, in every daily paper every day. Why do we still have astrologers? […] There is always some crazy stuff. There is an infinite amount of crazy stuff, […] the environment is actively, intensely unscientific. There is talk about telepathy still, although it’s dying out. There is faith-healing galore, all over. There is a whole religion of faith-healing. There’s a miracle at Lourdes where healing goes on. Now, it might be true that astrology is right. It might be true that if you go to the dentist on the day that Mars is at right angles to Venus, that it is better than if you go on a different day. It might be true that you can be cured by the miracle of Lourdes. But if it is true it ought to be investigated. Why? To improve it. If it is true then maybe we can find out if the stars do influence life; that we could make the system more powerful by investigating statistically, scientifically judging the evidence objectively, more carefully. If the healing process works at Lourdes, the question is how far from the site of the miracle can the person, who is ill, stand? Have they in fact made a mistake and the back row is really not working? Or is it working so well that there is plenty of room for more people to be arranged near the place of the miracle? Or is it possible, as it is with the saints which have recently been created in the United States–there is a saint who cured leukemia apparently indirectly – that ribbons that are touched to the sheet of the sick person (the ribbon having previously touched some relic of the saint) increase the cure of leukemia–the question is, is it gradually being diluted? You may laugh, but if you believe in the truth of the healing, then you are responsible to investigate it, to improve its efficiency and to make it satisfactory instead of cheating. For example, it may turn out that after a hundred touches it doesn’t work anymore. Now it’s also possible that the results of this investigation have other consequences, namely, that nothing is there.”

“I believe that a scientist looking at nonscientific problems is just as dumb as the next guy – and when he talks about a nonscientific matter, he will sound as naive as anyone untrained in the matter.”

“If we want to solve a problem that we have never solved before, we must leave the door to the unknown ajar.”

“For a successful technology, reality must take precedence over public relations, for nature cannot be fooled.”

“I would like to say a word or two […] about words and definitions, because it is necessary to learn the words. It is not science. That doesn’t mean just because it is not science that we don’t have to teach the words. We are not talking about what to teach; we are talking about what science is. It is not science to know how to change centigrade to Fahrenheit. It’s necessary, but it is not exactly science. […] I finally figured out a way to test whether you have taught an idea or you have only taught a definition. Test it this way: You say, “Without using the new word which you have just learned, try to rephrase what you have just learned in your own language.”

“My father dealt a little bit with energy and used the term after I got a little bit of the idea about it. […] He would say, “It [a toy dog] moves because the sun is shining,” […]. I would say “No. What has that to do with the sun shining? It moved because I wound up the springs.” “And why, my friend, are you able to move to wind up this spring?” “I eat.” “What, my friend, do you eat?” “I eat plants.” “And how do they grow?” “They grow because the sun is shining.” […] The only objection in this particular case was that this was the first lesson. It must certainly come later, telling you what energy is, but not to such a simple question as “What makes a [toy] dog move?” A child should be given a child’s answer. “Open it up; let’s look at it.””

“Now the point of this is that the result of observation, even if I were unable to come to the ultimate conclusion, was a wonderful piece of gold, with a marvelous result. It was something marvelous. Suppose I were told to observe, to make a list, to write down, to do this, to look, and when I wrote my list down, it was filed with 130 other lists in the back of a notebook. I would learn that the result of observation is relatively dull, that nothing much comes of it. I think it is very important – at least it was to me – that if you are going to teach people to make observations, you should show that something wonderful can come from them. […] [During my life] every once in a while there was the gold of a new understanding that I had learned to expect when I was a kid, the result of observation. For I did not learn that observation was not worthwhile. […] The world looks so different after learning science. For example, the trees are made of air, primarily. When they are burned, they go back to air, and in the flaming heat is released the flaming heat of the sun which was bound in to convert the air into trees, and in the ash is the small remnant of the part which did not come from air, that came from the solid earth, instead. These are beautiful things, and the content of science is wonderfully full of them. They are very inspiring, and they can be used to inspire others.”

“Physicists are trying to find out how nature behaves; they may talk carelessly about some “ultimate particle” because that’s the way nature looks at a given moment, but . . . Suppose people are exploring a new continent, OK? They see water coming along the ground, they’ve seen that before, and they call it “rivers.” So they say they’re exploring to find the headwaters, they go upriver, and sure enough, there they are, it’s all going very well. But lo and behold, when they get up far enough they find the whole system’s different: There’s a great big lake, or springs, or the rivers run in a circle. You might say, “Aha! They’ve failed!” but not at all! The real reason they were doing it was to explore the land. If it turned out not to be headwaters, they might be slightly embarrassed at their carelessness in explaining themselves, but no more than that. As long as it looks like the way things are built is wheels within wheels, then you’re looking for the innermost wheel – but it might not be that way, in which case you’re looking for whatever the hell it is that you find!”

 

June 20, 2019 Posted by | Books, Physics, Science | Leave a comment

Quotes

i. “Roughly, religion is a community’s costly and hard-to-fake commitment to a counterfactual and counterintuitive world of supernatural agents who master people’s existential anxieties, such as death and deception.” (Scott Atran)

ii. “The more one accepts what is materially false to be really true, and the more one spends material resources in displays of such acceptance, the more others consider one’s faith deep and one’s commitment sincere.” (-ll-)

iii. “Cultures and religions do not exist apart from the individual minds that constitute them and the environments that constrain them, any more than biological species and varieties exist independently of the individual organisms that compose them and the environments that conform them. They are not well-bounded systems or definite clusters of beliefs, practices, and artifacts, but more or less regular distributions of causally connected thoughts, behaviors, material products, and environmental objects. To naturalistically understand what “cultures” are is to describe and explain the material causes responsible for reliable differences in these distributions.” (-ll-)

iv. “Religions are not adaptations and they have no evolutionary functions as such.” (-ll-)

v. “Mature cognitions of folkpsychology and agency include metarepresentation. This involves the ability to track and build a notion of self over time, to model other minds and worlds, and to represent beliefs about the actual world as being true or false. It also makes lying and deception possible. This threatens any social order. But this same metarepresentational capacity provides the hope and promise of open-ended solutions to problems of moral relativity. It does so by enabling people to conjure up counterintuitive supernatural worlds that cannot be verified or falsified, either logically or empirically. Religious beliefs minimally violate ordinary intuitions about the world, with its inescapable problems, such as death. This frees people to imagine minimally impossible worlds that seem to solve existential dilemmas, including death and deception. […] Religion survives science and secular ideology not because it is prior to or more primitive than science or secular reasoning, but because of what it affectively and collectively secures for people.” (-ll-)

vi. “Don’t worry about people stealing an idea. If it’s original, you will have to ram it down their throats.” (Howard H. Aiken)

vii. “As long as scientists are free to pursue the truth wherever it may lead, there will be a flow of new scientific knowledge to those who can apply it to practical problems.” (Vannevar Bush)

viii. “Scientific progress on a broad front results from the free play of free intellects, working on subjects of their own choice, in the manner dictated by their curiosity for exploration of the unknown.” (-ll-)

ix. “There are some people who imagine that older adults don’t know how to use the internet. My immediate reaction is, “I’ve got news for you, we invented it.”” (Vinton Cerf)

x. “When we are young we are often puzzled by the fact that each person we admire seems to have a different version of what life ought to be, what a good man is, how to live, and so on. If we are especially sensitive it seems more than puzzling, it is disheartening. What most people usually do is follow one person’s ideas and then another’s depending on who looms largest on one’s horizon at the time. The one with the deepest voice, the strongest appearance, the most authority and success, is usually the one who gets our momentary allegiance; and we try to pattern our ideals after him. […] Each person thinks that he has the formula for triumphing over life’s limitations and knows with authority what it means to be a man, and he usually tries to win a following for his particular patent. Today we know that people try so hard to win converts for their point of view because it is more than merely an outlook on life: it is an immortality formula.” (Ernest Becker)

xi. “A human being cannot survive alone and be entirely human.” (Peter Farb)

xii. “The members of a society do not make conscious choices in arriving at a particular way of life. Rather, they make unconscious adaptations. …they know only that a particular choice works, even though it may appear bizarre to an outsider.” (-ll-)

xiii. “To say that the invention “was in the air” or “the times were ripe for it” are just other ways of stating that the inventors did not do the inventing, but that the cultures did.” (-ll-)

xiv. “Culture is best seen not as complexes of concrete behavior patterns — customs, usages, traditions, habit clusters — as has, by and large, been the case up to now, but as a set of control mechanisms — plans, recipes, rules, instructions (what computer engineers call “programs”) — for the governing of behavior.” (Clifford Geertz)

xv. “In the status game […] the working-class child starts out with a handicap and, to the extent that he cares what the middle-class persons think of him or has internalised the dominant middle-class attitudes toward social class position, he may be expected to feel some ‘shame’.” (Albert Cohen)

xvi. “It is nationalism which engenders nations, and not the other way round.” (Ernest Gellner)

xvii. “Doubt is the offspring of knowledge” (William Winwood Reade)

xviii. “Civilization after civilization, it is the same. The world falls to tyranny with a whisper. The frightened are ever keen to bow to a perceived necessity, in the belief that necessity forces conformity, and conformity a certain stability. In a world shaped into conformity, dissidents stand out, are easily branded and dealt with. There is no multitude of perspectives, no dialogue. The victim assumes the face of the tyrant, self-righteous and intransigent, and wars breed like vermin. And people die.” (Steven Erikson)

xix. “Helping myself is even harder than helping others.” (Gerald Weinberg)

xx. “Science is the study of those things that can be reduced to the study of other things. ” (-ll-)

June 15, 2019 Posted by | Quotes/aphorisms | Leave a comment