Sunday, 17 September 2017

Statins are of no value in the elderly


Most (virtually all) episodes of heart attacks (myocardial infarction, MI) and deaths from coronary heart disease (CHD) occur in people above the age of 70 years. This group is generally regarded as "elderly". Conventional wisdom is that CHD  and its most serious manifestation of MI, is "due to cholesterol". However previous Posts have shown the absurdity of this. 

The Framingham study from the USA was a 30 year follow-up of the population of this town in Masachussets. The objective was to investigate the factors that would be associated with early death, specifically death from CHD. The expectation was that the cholesterol level of the blood would be the major factor, but it was not to be.

The conclusion to the major Framingham paper was:


blood cholesterol level is not important

In young men a high blood level of cholesterol predicted a higher death rate, but this was only minimal in young women. In men and women above the age of 50 years, blood level of cholesterol did not predict death from CHD or from "all causes".


Framingham - no effect of cholesterol on survival
Survival of men in Framingham. Note the survival is identical in all cholesterol groups: blood cholesterol did NOT predict survival.

How remarkable that this conclusion did not penetrate medical consciousness. Despite the fact the great majority of deaths from CHD have been in people above the age of 50 years, reducing blood and dietary levels of cholesterol has continued to dominate medical activity.

Statin medications to achieve cholesterol-lowering were introduced in the late 1980s and the result of the first clinical trial was published in 1995. However it was only in the 21st century that statins came into widespread use. The logic was that reducing the cholesterol level of the blood would lead to a reduction of age-adusted deaths from CHD. 

As things have turned out, the small benefit from statins is not related to cholesterol reduction. Although this is clear from the first published trial, such data has been withheld from the publications of subsequent statin trials, and the published conclusion is denied. 

The 20th century epidemic of CHD was coming to an end at the close of the 20th century and so there could only be a low expectation of statin being of any benefit, irrespective of cholesterol.

And this has been shown to be the case.

New study 

A study from the New York University School of Medicinepublished this year, concerned the effect of pravastatin given to 1467 participants over the age of 75 years compared to 1400 controls of the same age. The study concluded that pravastatin gave no advantage. There was no reduction of either deaths or coroanry events in those receiving pravastatin.


JAMA Intern Med. Published online May 22, 2017. doi:10.1001/jamainternmed.2017.1442 


We have seen in a previous Post that a high level of cholesterol appears to give a survival advantage in the elderly, those above the age of 70 years. This is clear from three studies, Honolulu, New Haven (Connecticut USA), and Paris. So why are the elderly given interventions designed to reduce cholesterol?


There is no reason for well people over the age of 70 years (or indeed of any age) to take statins. If such a person has experienced an MI (heart attack) then there might be a marginal advantage to taking a statin, but in the absence of up-to-date trials the evidence for this is far from strong. Benefit from statins is now less likely than undesirable side-effects. 




Sunday, 6 August 2017

Is being overweight really "killing millions"? Or is it good for us? The obesity paradox.



The Organ Grinder - L S Lowry

Dramatic headlines sell newspapers but might misinform the readers. Risks are generally greatly exaggerated and statistics are far from clear. 

A headline in the UK press on June 13th 2017 stated:



(Between normal weight and obesity is called "overweight", that is excess weight short of obesity. It is this that is apparently "killing millions".)

I must say that I have been unaware of millions being killed by anything at present, certainly not by being a bit overweight and not actually obese.

It goes on:
" Nearly two-thirds of adults in Britain weigh too much " 

Do you know – all these two thirds are going to die, and so are their slim fellow-citizens, whose "virtue" of slimness will not give them immortality. Who says that they "weigh too much"? Is it doing them any harm? On what is the standard based? And when was it established?

Another comment:
" Experts say many people failing to understand risks "

Perhaps the experts fail to understand risks. How is it that so many people are living so much longer? This is not disputed. 

Let us look further at the influence of body weight on survival.

Framingham

In previous Posts I have referred to the Framingham study in the USA. The study is  based on a small town in Massachusetts and it was initiated in 1948. It has followed 5209 participants aged between 28 and 62 years, recording the development of illness and death during the past 70 years . It is an observational programme that has collected much useful information. 

I have previously drawn attention to the 40 year study of cholesterol levels of the population. The conclusion reached is that “After the age of 50 years there is no increased overall mortality with either high or low serum cholesterol levels.” Despite its profound importance, this finding never entered collective consciousness. It is the cholesterol truth that has been kept away from the public and the media.

Between 1951 and 2011, 1058 participants in Framingham suffered from a stroke. 

Most episodes of stroke are ischaemic, the result of cerebral infarction, the occlusion of blood supply to part of the brain. This is usually due to narrowing of an artery by the process of atherosclerosis. It is occasionally due an embolus from or via the heart. The other cause of stroke is a cerebral haemorrhage, due to the rupture of an artery, usually from an asymptomatic aneurysm. It is difficult to distinguish the two forms of stroke clinically, but CT scanning will show a haemorrhage. The absence of haemorrhage on CT scan leads to the diagnosis of ischaemic stroke. It is this group that is the subject of a study from Framingham published this year.

The purpose of this particular study was to investigate the influence of body weight on the outcome of stroke. The outcome measure was survival at ten years. In addition to following the outcome of those who had suffered stroke, age-matched controls from Framingham were also followed.

BMI (Body Mass Index)

In the initial presentation of data the subjects were divided into two groups based on BMI, the simple measure of obesity. The two groups were those with BMI less than 25 (normal) and those with BMI 25 or greater (overweight or obese).

BMI is a number based on weight and height: weight Kg / height in metres squared. Between 18 and 25 is regarded as “normal”. "Normal" is arbitrary and thus judgmental. We see from the headline above that two-thirds of UK adults being so defined as overweight is not a statistical normality. 

Effect of BMI on survival


Framingham study shows no effect of BMI on ten year survival
Figure 1: Ten year survival based on BMI (Framingham study)

Figure 1 shows the 10 year survival rates of the control groups, who had not had a stroke. They were divided into those with BMI less than 25 and those with BMI 25 or greater. It can be seen clearly that there is no significant difference. The two survival lines are very close together, indistinguishable. This is an important finding from a large and well-constructed study, but the information appears to have been hidden from public scrutiny.

The main purpose of the study was to investigate the outcome after a stroke, and we can see this in Figure 2.
Framingham study show better survival of obese following stroke
Figure 2: Effect of BMI and stroke on survival

In Figure 2 we see the addition of the survival lines for the people who had experienced a stroke. They are divided into two groups depending on BMI. 

It is not surprising that the life expectancy of those who had a stroke was about half that of  those who had not experienced a stroke, the control group. Having had a stroke is clearly a serious risk indicator of an early death.


Figure 3: Effect of BMI on survival after stroke

Figure 3 show just the stroke survivors. Following a stroke there is a significant difference in the 10 year life expectancy, depending on the BMI. Here we encounter what has been recognised in previous studies and called “the obesity paradox”

The life expectancy is much better in the obese group (BMI 25+, green line) compared to their slimmer counterparts (BMI <25, blue line). This is not what conventional wisdom would have led us to believe.

The study also subdivided the  participants into the sub-categories of:
“normal weight” (BMI less than 25), 
“low overweight” (BMI 25 to less than 27.5), 
“high overweight” (BMI 27.5 to less than 30), 
“low obesity”, (BMI 30 to less than 32.5), 
“high obesity” (BMI 32.5 or greater).

Once again we can first look at the control group, those without stroke, and we can see the results in Figure 4. A low column height is a good thing.
Framingham - survival advantage for the "overweight"
Figure 4: Relative risks of death by obesity group (controls, Framingham)

The normal weight group has death rate at 10 years standardised at 1.0. Low overweight has a similar risk of death. The lowest risk of death is with the high overweight group, a relative risk reduction of 0.78. This is a 20% reduction of risk of death at 10 years. 

Low obesity is little different from normal weight, but high obesity gives a survival disadvantage with a relative risk of 1.21 (21% increased risk of death at 10 years).

These results, taken from a sample of the general population of Framingham, are very interesting: despite what we are told in the headlines at the top of this Post, there are advantages in being overweight, but not if BMI is above 32.5.

Survival after stroke

We can now look at the data for those who had experienced a stroke, shown in Figure 5. Again a low column height is a good thing.
Framingham - obesity and survival after a stroke
Figure 5: Risk of death at 10 years and obesity following stroke (Framingham)

The death rate at 10 years for normal weight individuals is standardised as 1.0. We see a survival advantage in those with low overweight, high overweight, and low obesity – that is with people with BMI between 25 and 32.5. With “low obesity” there is a death risk reduction of almost 40%.

If BMI is greater than 32.5 there is a survival disadvantage, with an increase in risk of death at 10 years of just under 20%.

We have been looking at observations. Explanation is something different and I have no intention of making a guess. There is so much about body weight and its controls that we simply do not understand.

In respect of the survival advantage of overweight and mild obesity, there is no explanation in respect of characteristics of the population groups (see Figure  6). 

Figure 6: Characteristics of Framingham obesity study

For example it is the normal weight group that has the highest proportion of severe strokes. This group also has the highest proportion of smokers. The obese group has the highest incidence of diabetes, as would be expected, but surprisingly the lowest incidence of coronary heart disease. 

The lower risk of death in the overweight groups as shown in Figure 5 cannot be explained by the table in Figure 6 or other factors in the fuller analysis of risk factors.

The lesson from this first-class study study is that moderate obesity appears to give  a survival advantage following a stroke. In the control population obesity does not give a survival disadvantage.

Previous study of BMI and survival

It has been shown but not extensively publicised that BMI and measures of adiposity do not in themselves predict cardiovascular disease. This was published in The Lancet, the work being funded by the British Heart Foundation and the UK Medical Research Council.

I have shown in a previous Post further evidence that mild to moderate obesity does not give a survival disadvantage, but some advantage. The details can be seen in Figure 7.


Figure 7: BMI and death rate
The graph lines indicate risk of death based on BMI for two groups, ages 50 years (green line) and 70 years (blue line). As would be expected the death rates were higher in the 70 year-olds. 

But in both age groups the lowest death rates were in those people with BMI between 20 and 30. There was a gradual increase of death rate as the BMI increased to 45, the point of gross obesity, a dangerous condition. However the death rate rose steeply in the other direction with BMI less than 20. 

The best life expectancy was in those considered to be overweight or mildly obese. Our obsession with thinness should come to an end.

Overweight is an advantage after heart surgery

A recent study from the University of Leicester, UK, was led by Professor Gavin Murphy and its results were published in the European Heart Journal.  The study concerned the early mortality following heart surgery, and it has been given particularly detailed coverage by the academic press.

The study was of 401,227 adults, and a review of 557,720 patients from 13 countries. Average age was 59 years and 27% were women.

Being overweight appears to give a survival advantage after heart surgery
Figure 8: Body weight and risk of death after heart surgery

The results can be seen in Figure 8. The risk of death was highest at 8.5% in the underweight group. It was 4.4% in the "normal" weight group but even lower at 2.7% and 2.8% in the overweight and obese groups. It was very surprisingly low at 3.3% in the obese patients who were considered to be at particularly high risk.

There have been attempts to disregard or explain away these findings but this was not the purpose of the study. Explanation must wait. There are of course attempts to find faults that might invalidate the findings, as we expect all categories of excess weight to be dangerous, but such attempts have not been successful. The research was very well controlled and those with low weight appear to be at the greatest risk.

Conclusion


We can conclude that there is much about body weight that we do not understand. Gross obesity is to be avoided, not only because of death rate but also because of serious morbidity, especially musculoskeletal problems and reduced mobility. 

However we cannot conclude that thinness is to be applauded. At the present time we have two concurrent epidemics. The first is that of long life expectancy, a serious social problem. It is a to a major extent the consequence of the end of the epidemic of coronary heart disease. The other epidemic is allegedly that of obesity. Perhaps this so-called "epidemic" is an important factor leading us to be living longer.

BMI between 20 and 30 seems to be about right, and the evidence is clear.


References:

Journal of the American Heart Association doi: 10.1161/JAHA.116.004721

 2011 Mar 26;377(9771):1085-95. doi: 10.1016/S0140-6736(11)60105-0.

New Scientist 2014; Volume 222, Number 2967, Page 44.


Eur Heart J (2017) 38 (23): 1786-1787. 

DOI:
 










Thursday, 29 June 2017

Atomic Physics in Ancient Greece

Atomic Physics in Ancient Greece

atomic physics in ancient Greece

The first scientific thinking took place 2500 years ago, in ancient Greece.

Mathematics had developed in Babylon at an earlier time and also in Egypt. Records show detailed astronomical recording in Babylon. The great pyramids of Giza were constructed to remarkable mathematical precision. But there no evidence of investigation into the fundamental laws of physics and how the universe functions.

Miletus is the place of the dawn of scientific thinking. It is situated on the west coast of the Kingdom of Lydia, now in Turkey. 






In the 7th century BC Miletus was part of the Persian Empire.

Thales
Thales
Thales (624–546 BC) was a citizen of Lydia and one of the thinkers of Miletus; he is considered to be the first philosopher. His most famous statement is that: 

“We should know more than our parents”.

Anaximander

The most famous pupil of Thales was Anaximander (610–546 BC). He is considered to be the first scientist. He developed the hypothesis of the “apeiron" (ἄπειρον), the primal substance of which everything is formed.

Anaximander
Anaximander thought that the wide variety of substances found in the world must be understood in terms of a single, unitary and simple constituent, which he called the apeiron, the indistinct.

He also suggested that: “The Earth floats in the sky” and that:“The sky continues beneath the Earth”.

Furthermore he proposed that rainwater comes from the evaporation of water from the surface of the Earth. This was a major step forward in understanding the way in which the Earth functions.

He made further suggestions about evolution, recognising that animals and plants evolve and adapt to changes in the environment, and that man must have evolved from other animals. Darwen and Wallace were the next to suggest this, but even now, although evolution is generally accepted, the process leading to humankind is not clear.

Anaximander also proposed the concept of “panspermia”, that life might initially have arrived on Earth from “the heavens”, what today we would call outer space. The idea was presented in the late 20th century by Sir Fred Hoyle and Dr Chandra Wickramasinghe.

The place of Miletus within the Persian Empire made it vulnerable. The years 499–493BC saw the Ionian revolt against Persian rule, the start of the Greco-Persian wars. In revenge, Miletus was destroyed by the Persians.

Miletus and Abdera
The Taking of Miletus is a tragedy written by Phrynincus, and it was performed regularly in Athens in the years following the event.

Leucippus

There was an exodus of the “thinkers” from Miletus to Abdera, on the Aegean coast of Thrace.

Leucippus
One of the exiles was Leucippus, who was born in Miletus in the 5th century and died in Abdera. On his arrival in Abdera, Leucippus founded a scientific and philosophical school, and he wrote The Great Cosmology

Democritus

The most important disciple of Leucippus was Democritus (460–370 BC).

Democritus was born in Abdera. He is regarded as the father of modern science. He apparently wrote many books, all of which have been lost. His ideas predated those of the Enlightenment of the 18th century by more than two thousand years.
Democritus
His most important thought was this: if you were to divide a piece of matter an infinite number of times, what would be left? The logical answer is “nothing”, but as pointed out by Democritus, this cannot be. If you start off with something, you must finish up with something, not nothing. Therefore there must be a point at which matter cannot be further divided.

There is a limit to infinity – there is a finite number of divisions, but a very big number. 

“Any piece of matter is made up of a finite number of discrete pieces which are indivisible, each one having finite size.” (It was Einstein who determined that size)

This led to the concept of the “atom”. “a-” implies a negative, and “tomos” means “cut, slice, divide”. So “atom” meant “cannot be divided, indivisible".

(Tomos bread is sliced bread; tomography, as in CT scan, means digital slicing of the body; tomos, Thomas, indicates twins, divided baby).

From these thoughts Democritus concluded that:

“Just as by combining the letters of the alphabet in different ways we may obtain comedies or tragedies, ridiculous stories or epic poems, so elementary atoms combine to produce the world in its endless variety”.

This is a remarkable vision of the nature of substances and their atomic structure. 

The next remarkable contribution of Democritus was reported by Leucretius. It was based on the rule that “Nothing moves unless pulled or pushed”. Otherwise things remain stationary.

Democritus observed the nature of a sunbeam shining into a deserted and windless room. Within the sunbeam he observed vast numbers of dust particles and puzzled as to why they were in constant movement.

“Observe what happens when sunbeams are admitted into a building and shed light on its shadowy places. You will see a multitude of tiny particles mingling in a multitude of ways in the empty space within the light of the beam, as though contending in everlasting conflict, rushing into battle rank on rank with never a moment’s pause in a rapid sequence of unions and disunions. From this you may picture what it is for the atoms to be perpetually tossed about in the illimitable void.”

“Besides, there is a further reason why you should give your mind to these particles that are seen dancing in a sunbeam: their dancing is an actual indication of underlying movements of matter that are hidden from our sight. There you will see many particles under the impact of invisible blows, changing their course and driven back upon their tracks, this way and that, in all directions. You must understand that they all derive this restlessness from the atoms. It originates with the atoms, which move of themselves. Then those small compound bodies that are least removed from the impetus of the atoms are set in motion by the impact of their invisible blows and in turn cannon against slightly larger bodies. So the movement mounts up from the atoms and gradually emerges to the level of our senses, so that those bodies are in motion that we see in sunbeams, moved by blows that remain invisible.”

Democritus thus suggests that the dust particles move perpetually because of impact by the atoms of the air.

The same process can be observed form the “spontaneous” movement of pollen grains on the surface of water. The next person to suggest that this is the result of collisions by atoms was Albert Einstein, 2500 years later. Einstein used his observations to calculate the size of atoms.

Democritus was an avid observer of nature, observation being the true basis of logic. He stated: “To a wise man, the whole earth is open, because the true country of a virtuous soul is the entire universe.”

Socrates and Plato

Socrates (470/469–399 BC) was rather more utilitarian. Most of his thoughts were reported by Plato (428/427 or 424/423 – 438/437 BC).

Socrates
Plato
 Plato’s Phaedo describes the last days of Socrates and his death by poisoning with hemlock. He quotes Socrates:

“I had expected to be first told that the Earth was flat or round, but also that, afterwards, the reason for the necessity of this shape would be explained to me, starting from the principle of the best, proving to me that the best thing for the Earth is to have this shape.”

“If the Earth is at the centre of the world, then show me how being at the centre is of benefit to the Earth.”

Plato also mentions a further comment of Socrates:

"When ‘physicists’ had explained that the Earth was round, he rebelled because he wanted to know what ‘good’ it was for the Earth to be round; how its roundness would benefit it.”

Zeno (c450 BC)



Zeno was an important philosopher, but little is known about him. He lived in Elea, a town of Greater Greece (Magna Graecia ), now Viela in the Cilento region of southern Italy. 


Elea today

Zeno is famous for "Zeno's Paradox". 

It is similar to the assertion of Democritus concerning the absurdity of the infinite divisibility of matter, and that there must be a finite but very small ultimate and indivisible "atom".

Zeno took the same approach to length and distance: could there be a length that is infinitely small? To discuss this he used the analogy of a race between Achilles and a tortoise. The tortoise was given a 10 metre starting advantage, and the challenge was for Achilles to catch up with the tortoise. The logical argument is that Achilles would never catch up.



The logic went like this: by the time that Achilles covered the ten metres to where the tortoise started, the tortoise would have moved forward a few centimetres. By the time that Achilles have caught up these few centimetres, the tortoise would have moved forward a few more centimetres. By the time that Achilles have caught up these very few centimetres, the tortoise would have moved forward a very few more centimetres. And so it goes on ad infinitum

Achilles would therefore, by logical thought, never catch up with the tortoise, but Zeno recognised the absurdity of this and felt that an infinitely small distance cannot exist, it would no distance. Multiple divisions of length cannot result in no distance. There must be a finite minimum distance.

It was more than 2,000 years later that Max Planck calculated the shortest distance possible, the Planck Length (also known as the Bronšten Length). It is approximately one millionth of a billionth of a billionth of a billionth of a centimetre, 10-33 centimetres. It is very small but finite, a measure of the quantum granularity of space time.

Epicurus
Epicurus
Epicurus (341–270 BC) was a pupil of Democritus. His assertion was “Knowledge in place of ancient myths and religion”. This continues objectivity through careful observation.

Lucretius
Titus Lucretius Carus
Lucretius (99–55 BC) was an influential follower of Epicurus. 

“Religion is ignorance; reason is the torch that brings light.”

“Nature is clamouring for two things only, a body free from pain, a mind released from worry and fear for the enjoyment of pleasurable sensations.”

Lucretius wrote a manuscript De Rera Natura (On the Nature of Things) for the benefit of the Romans, to whom he hoped to bring Epicurean enlightenment.

His greatest personal contribution of natural philosophy within this manuscript is contained in the remarkable and profound quotation:

“It must not be claimed that anyone can sense time by itself apart from the movement of things”

Time is only relative. Without movement there is no time. This also predated Einstein, who re-introduced the assertion that there is no absolute time. It is fundamental to his Special Theory of  Relativity. 

But the assertion of Lucretius that “religion is ignorance” brought him no friends in Rome, and his attempt to bring enlightenment to the Romans was a failure. After the Christianisation of the Roman Empire things became worse. Even as late as the time of the Renaissance the Roman Catholic Church attempted to suppress the words of Lucretius. In the Florentine Synod of December 1516 it prohibited the reading of Lucretius in schools, and in 1551, the Council of Trent banned his work.

Lucretius' manuscript De Rera Natura was lost, but was re-discovered by Poggio Bracciolini in the Benedictine Abbey of Fulda in 1417. An account of the discovery can be found in the fascinating book "The Swerve - how the Renaissance began", by Stephen Greenblatt.

Pythagoras

Pythagoras
Pythagoras (570–495 BC), like Epicurus was born on the island of Samos. His contribution was in the field of mathematics, at that time not obviously related to atomic physics. However now we know the connection between the two: the famous equations of Maxwell and Einstein laid the foundations of 20th century and present day physics.
Einstein equation
We now appreciate that the intuition of Pythagoras was correct: mathematics allows the world to be described and the future to be predicted (for example the occurrence of an eclipse of the sun).

The understanding of atomic physics by the thinkers in Ancient Greece was truly remarkable. They envisaged the atomic structure of matter, the concept of a minimum length or distance, that time is not a constant in the universe, and that laws of physics have a mathematical basis. 

Much of their understanding has probably been lost in the destruction of their written records.