Good evening. Thank you very, very much for this evening's talk.
I appreciate. It's a lovely sunny day outside, but you brought the cold rain and we're in for a treat.
We've got more to love. Yes. Well, talking about fake surgeries and pills and the challenges facing the trial.
Trial trials, they hand over to you. Thank you.
Good evening. So I I'll be talking about control for for bias study design.
So I'm a medic. And also I did the Dphil with Irene Tracey on pain imaging.
So I've spent my dphil and my post-doc is trying to understand why certain
people respond to pain and what happens in their brains after pain treatment.
So you may ask what pain has to do with trial design.
The thing is that pain is very common.
So pain is the main reason patients seek medical attention, and pain accounts for about 22% of all GP consultations.
It's estimated that during the life span, one in four adults in the UK will develop chronic pain condition.
So it's highly likely that in one of your trials you'll have pain as an outcome.
So what's pain? So according to the International Association for the Study of Pain.
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.
What's important about this, the finish physician is the pain is an experience.
It's not just a sensation. It's a subjective experience that's very complex and multidimensional.
So it's got the sensory aspect, emotional aspect, cognitive aspect.
It's influenced by your past memories, your experience,
but also by social and cultural aspect of your brother, but that you have to man up buried, no pain, no gain.
You will behave differently. That people who are brought up and be allowed to express their pain, their pain and seek help.
But in everyday practice and research,
we usually just you say that pain is whatever the experiencing person says it is and it exists whether they say it does.
So we cannot experience other people's pain.
If this guy is in pain, I will not know it.
I cannot measure it in any objective way. The same way I will be able to measure his blood pressure.
The only way for me to ask him whether he is really in pain, whether he's trying to smile, but he's really suffering inside and cannot play his act.
What is to ask? I can use questionnaires, but usually what we do, we use pain scales.
So those are the two most popular pain skills. We've got a visual analogue scale, a numerical rating scale.
So what we are what we do, we ask a patient or a researcher volunteer to rate this complex,
subjective experience on this unique dimensional scale with relative anchors.
But that's what we have and that's what we use. So in the trial, this will be our data.
So we've got a baseline. We ask participants for pain ratings, then we give them treatment and we've got to follow up visits.
And if the treatment works, the pain will go down. Awesome.
If we ask them every day, we may see something like that.
So that's a mean change in their pain score from zero down to improved by two points.
But if we have a group of patients who received a dummy pill, a placebo or placebo pill, we may see something like that.
So despite the fact that those people got just a sugar pill, their pain ratings went down as well.
This is because what we observe as an improvement after treatment is not just
a physiological effect related to the pharmacological properties of the drug.
Some of it is just fluctuations of the symptoms.
People have good days. People have bad days. Some of it is natural history of the disease.
So, for example, lower back pain it will improve upon after a couple of days or weeks for some people.
Some of it is just regression to the mean. So we've recruited our patients where they are really paid are really suffering.
And then when we ask them of the follow up, the next rating may be kind of closer to the actual mean for this person.
Some of it is going prevention. So we want our patients to only take our medication bath.
They may be naughty, they may take paracetamol when they have a bad night, or they may change something about their lifestyle.
Buy a new mattress, go to the gym more often because they're in the trial and what happens in the trial,
behaviour of our participants will change because they know they are being observed and they know they're going to be assessed.
Some of it is due to patient doctor interactions.
So we know there is research that if doctor is really nice, shows empathy, gives a clear diagnosis, nice clear prognosis and a clear treatment plan.
Patients are more likely to improve. Some of it may be just report bias because if the doctor is really nice.
A patient may be slightly less willing to say that the treatment actually doesn't work.
Patient may not want to upset the doctor. And some of it is a placebo effect.
So the thing about placebo effect is that there isn't a very good definition and it's
literally what's not specific to the treatment and what cannot be explained by any of those.
So definition by definition, it's an improvement in clinical symptoms or patients well being in response to placebo manipulations such as
in active substance of a procedure that only simulates an active therapy but itself has no specific effects.
But the thing is, any pill or therapy is actually necessary.
A good, positive consultation may also result in what we will call a placebo effect.
People just don't want to say that. Oh, apples of consultation because it's a placebo effect.
Well, positive consultation as part of a good patient doctor relationship sometimes.
Also, just diagnostic tests result in improvement of symptoms.
So people actually report that they feel better after an EKG or an MRI scan.
So placebo effect is just this improvement that we cannot really explain by the actual specific effect of the treatment.
So this is an experiment done by my colleagues in the previous group.
So they've recruited healthy, pain free volunteers and they said, we are going to use this mode to give you painful stimulus,
and we're also going to give you a very potent opioid and please rein the pain while you are on the drug.
So first there was a baseline, so they gave them the stimulus.
They could you please read the pain for us? And this is a visual analogue scale.
This one is from not two 100 and the participants rated it as 65.
And then without telling the participants, the drug infusion started through the IV line.
But the participants did know and again, they received a painful stimulus and they were asked to give a pain rating and their pain rating went down.
So what they have here, it's a hidden administration of an energy zinc, which we kind of assumed that this is just a pure effect of the drug.
What happened next was a researcher walked into the scanner, said, well, now we are actually starting the experiment.
We are going to turn on the drug. They lied because the drug was already on and this is what happened to the pain rating.
So they went down even more. Nothing has changed except for the information given to the patient.
But because my colleagues were really cheeky then they said, Well, now we are finishing the experiment.
The drug is off. Could you please rate the pain again?
So the participants were expecting no help from the opioids and they were just left there with their pain on their own.
And this is the rating they're gave. So what was really interesting about this experiment is that being told that there is no medication,
not only reversed the positive expectation, but it also reverse some of the effect of the drug.
And this is the placebo effect that we can observe.
So what we have to remember when we use subjective outcomes like pain is that patient patients are really affected by what they believe or well,
they're told about the treatment, and patients believe that drugs are invasive.
So, for example, injection or I.V. drip. Drugs that are new.
So that's why they prefer the novel drug or the experimental drug or medication does expensive.
That's why they, like, run the drugs.
They believe that those types of treatment are more effective and they are kind of biased to give better response after those types of drugs.
The funny thing is that the power of the pill in our culture is so strong that people respond even if they know that this is a placebo.
Because in our culture, we go to a doctor, we get the diagnosis, we get the prognosis and walk out with a prescription.
This is part of the ritual in the Greek culture.
They make gold, a bottle of herbal remedy and the prayer to read.
There is actually a snippet in a Greek text saying that you have to use this herb and say the prayer.
Without the prayer, it will not work. So there is this cultural set up that influences what patients experience.
And this is a trial done by KAPTCHUK in patients with irritable bowel syndrome.
So one group got no treatment. They just had interaction with the clinicians and the research stuff.
And the other group received placebo in an open label manner.
This is placebo. This is a dummy pill. It may have some effect through the mind body interaction, but it has no pharmacological effect.
And still, patients improved much better when they were given placebo than when they were receiving no actual treatment.
And now let's get to the trial design.
So the reason we do a trial is because we want to test efficacy and safety of a treatment in a controlled manner.
So usually what we do, we know a nice cohort of patients here, very handsome and young.
Not always, though. So what would we do? We randomise them into two groups to balance that out.
So we've got men and women different eight different ethnicity, two to kind of balance out everything that may potentially bias our results.
And then we can allocate them to treatment. So we've got interactions with the doctor and the pill and for example, no treatment.
So this design will control for regression to the mean natural history of disease fluctuation,
effect of being in the trial, so effect of being observe.
But as we said, patients want the novel expensive treatment and this group will not get it, which will bias the results.
So what we can do, we can give them placebo.
So the power of pill, it's present in both halves.
But this group will know that actually they are getting a dummy pill and this group is still getting
this novel expensive new drug that will potentially completely change the treatment of this disease.
So that's why we need blinding. So usually what happens, the drug is usually put in external capsule or coated,
so so that it looks the same regardless whether inside is the active drug or a placebo.
What we can do to improve the design even more is blind doctors as well, and we can blind people giving the drug.
So by their behaviour or information they give or the way they give information they do not reveal the allocation to for the patients.
Or we can also blind people who are assessing the outcomes because we know that by the way, people ask questions, oh, by the way they behave.
They may bias patients responses. And also there is so-called Pygmalion effect.
So people who are expecting a certain outcome are more likely to actually see it.
So that's why blinding both patients and assessors and preferentially everybody interacting with a patient throughout the trial is so important.
So we can kind of expand this design even more so we can test new treatable but standard treatment so it doesn't have to be placebo.
We can test with whether one drug is better than another, whether it's safer than a novel, or we can use all three.
So we can compare a new drug to all treatment and do placebo.
And we make the pills identical.
Patients will not know which treatment are they are receiving.
And this is the trial I run as my.
So this was a trial in which Pregabalin pretended to be the new novel Treatment for Pain.
Tramadol was the standard treatment, so the less preferred, potentially worse.
And then there was also a placebo drug. So this is a placebo controlled crossover three period randomised trials with only one group.
So every participant, every patient was their own control.
So everyone received placebo, pregabalin and Tramadol and there was a week of washout between.
So there they came down their normal medication, they received placebo.
Then there were some tablets with increasing dose of the drug.
When the dose was stable, we assessed them, then we gave them a new blister medication.
Then there was first there was placebo to bring down the dose of whatever drug
they were on and then a new medication will start and that was repeated.
So this is a brilliant design because you don't need a control group, you just have to recruit one group, but it's not always feasible.
So for example, with your treatment or surgery,
you cannot really randomise someone to surgery and then say, Well, now we'll cross over to physiotherapy.
It doesn't really work like that. You cannot really reverse surgery. There is such a thing as placebo surgery.
It really exists and this is another trial.
So this is my second post. So this is a three arm surgical trial.
All saw the Cromwell pain.
So some people with age or because of the job they do for example they pain ceiling for a living they develop shoulder pain.
And there was a very common surgery that involves a keyhole access into the joint and the removal,
a bit of a bit of a bone to create more space for the shoulder tendons.
And this is believed to cure the pain.
So as a placebo control, a placebo surgery, those the patients in those in the control group only underwent the diagnostic arthroscopy.
So the scope was put into the joints. A surgeon would take a look but wouldn't do anything.
But a patient could not tell whether actually the anatomy was change or not, so whether they were in the surgical arm or the control arm,
and there was also no treatment arm to control for the natural history of the disease.
And as you can see, we could blind between the surgical or placebo arm,
but people in the non interventional arm knew that they are not getting any surgery and those are the results of the trial.
So this is on the Y axis, it's ox Oxford shoulder score, which is a composite score of pain and function.
And the higher the score, the better the outcome. So you can see that at six, six months, surgery and placebo were better than no intervention.
And at 12 months there was no difference between surgery and placebo and people in the non intervention group had better, worse outcomes.
So we can interpret it that surgery is not better than placebo.
Bob The intervention still seems better than no treatment.
Or if we actually assume that people who did not receive a surgery never met those and some
surgeons never went to the surgical theatre with the machines that go B felt like they missed out.
We could also interpret that as a sea effect and just simply report bias.
But this is a limitation of the trial trials.
Surgical trials with a placebo arm are very rare.
Surgical recipes are about 15% of all are published in the journals, and only a fraction of them actually uses a placebo control.
So many people, when you mentioned placebo control, the thing that is absolutely ridiculous because when they think about surgery,
they think about something like that, something really invasive, performed to save life and absolutely dumb as a last resort.
But this was in the 18th century. Nowadays, many surgical procedures look like that.
They are minimally invasive. We've got antiseptics. We've done it, we've got analgesia, we've got antibiotics.
Surgery is less dangerous. The force performed more often and the indications for surgery have changed.
So now instead of doing surgery just to save lives, we perform surgery to improve function, improve quality of life to help people.
Who experience pay. So, for example, all the pharmacological treatment fail.
So patients are offered surgery. Therefore, outcomes have changed.
So very often we use pain in function and quality of life as an outcome of surgical procedures.
So that's why we may need placebo control in a trial that assesses safety and efficacy of surgery.
But when we discuss placebo control, people ask, Well, but what's the harm to benefit ratio can even do it?
Is it feasible? Because it's not just the pill. You actually have to pretend that you are performing a surgery.
Is there even a placebo effect? Do we really need a control?
And finally, would surgeons be willing to do it? Would they approve of placebo control?
And is it even ethical? So what we've done, that's what we've done.
So we, we've reviewed all published randomised controlled trials on surgical procedures that have a placebo control.
There were no the strict restrictions on conditions.
An intervention had to be invasive, so it had to be a procedure that was believed to be therapeutic by nature of changing anatomy.
So injecting something to deliver a drug without performing surgery to insert a stimulator or modulator was out.
We had we needed a change of anatomy to be the crucial therapeutic element.
A comparator was called either sham or placebo or imitation.
But the key point was that the crucial therapeutic element was omitted.
There were no restrictions on the outcomes. The study had to be a randomised controlled trials.
We searched the Medline and based central but also clinical trials to the Gulf to look for recently completed trials.
And then we looked into references of all D'identifier trials just in case we missed something.
And we searched those databases since the beginning, till November 2013, and then we run the update two years later.
So that's what we found. So most of the interventions trialled in that design were minimally invasive, so nobody really trialled an open surgery.
The most invasive ones were the seminal trials on Parkinson's disease,
in which a hole was drilled in some of the skull to insert foetal cells into the basal ganglia.
Most of those trials used other medications, so there was either L-dopa in the Parkinson's trials, all, for example, if the outcome was pain.
Many patients were given a rescue medication to begin with. So it's not true that people were completely left without any help.
They just received the placebo surgery. Conditions were mostly non-life-threatening.
So osteoarthritis, obesity. There were some trials on bleeding as a fragile viruses performed in the eighties when endoscopy was introduced.
But since then, most of the trials were among life threatening conditions.
Outcomes are mostly subjective pain, function, quality of life.
Those trials were mainly small, with fewer than 100 patients, and the publication spanned from the late fifties to 2015,
with a big spike after 2000, which may be related to popularity of the minimally invasive surgery.
So are those trials risky?
Generally, none of those trials reported any serious adverse events reported to anaesthesia, which was the biggest concerns in all the ethical papers.
So there were many papers discussing those potential risks of placebo controlled surgical trials.
43% of the review trials reported no serious adverse events.
Six Never mentioned serious adverse events. But this is a problem with the reporting of trials, especially surgical trials.
In 51% there were serious adverse events, but in two thirds of them there were in both study arms and in one six there were only in the surgical arm.
Some of them didn't say in which arm they occurred in general, placebo arm, what was safer and associated with fewer and less severe adverse events.
Some of some of those events were directly associated with the crucial surgical element.
So for example, who are patients with endoscopy and ablation?
So there was a change to the wall of the gut and in some of the trials there was a perforation caused by the ablation.
So this is. A direct link between the crucial surgical element and the adverse event.
In many cases, the adverse events were associated with the severity of the condition itself.
So, for example, patients were admitted to hospital because of asthma, fog baths.
All the patients in the trial had severe asthma, so some of them might have been admitted to the hospital anyway.
So that's why it's kind of difficult to make a blanket generalisation.
Are those trials too difficult to complete? So we looked at the strength of limitations, methods, sections and anaesthesia or problems with blinding.
We're not reporters as obstacles in completing any of these trials.
In general, if there was a general anaesthesia.
Blinding was really easy because patients was asleep and they didn't know what was happening.
But in about a quarter of the trials, they've used local anaesthesia,
and in those trials they've used absolutely ingenious methods to blind patients and pretend they're actually doing the real surgery.
So for example, in case of arthroscopy, they pulled my nipple and the limb splash saline, all that.
Use a mechanical razor without the blade to pretend they're actually using devices and performing the surgery.
They were asked to talk over the procedure as if they were really activating the laser, asking for devices.
In the three trials, they actually tried to blind the surgeon.
So those trials included an implant, and the producer of the implant prepared two different applicators,
and one of them actually contained the implant, whereas the other did not.
So the operator, the person actually performing the procedure, did not know whether the charm or the or the surgery.
In other trial, a surgeon would do everything, placed the device, and then a technician would either activated or not.
So the surgeon would not know whether actually the active element was bound or not.
The biggest obstacle and absolutely underestimated by many researchers was recruitment.
On average, 20% of screened patients were randomised.
Only 20%. However, 75% of eligible patients were randomised into the trial and once recruited, the patients tended to stay and complete the trial.
This was quite surprising. So because you are blinding patients and they don't know whether they've received the actual surgery or a placebo surgery,
they tend to stay in the trial. They don't drop out because they're disappointed.
Then look for treatment somewhere else. They tend to stay.
But recruitment was a big obstacle and actually three trials had to be terminated early because the recruitment was as slow as one patient a month.
So they said, sorry, we have to call it the day. We cannot continue the trial because we've run out of funding.
So this is an example of a placebo controlled surgical trial on patients with knee problems.
And you can see that of all 476 patients screened, 286 were not eligible because they either did not have the condition.
All told, they were not eligible for the surgery. Out of 190 who are eligible, 102 declined participation.
Some of them didn't like the idea of a trial. Some didn't like surgery, something like a placebo.
So they refused. So 88 agreed to participate, but 48 were not included because it was a surgical trial.
So there was an additional criterion that they had to have the particular change on the MRI and those who did not were not eligible.
So out of 476 patients screened, only 40 were included in the trial.
And this is the thing. Many people don't realise why when they design a trial that they may not have access to sufficient
number of patients within the time of the that they have to run and complete the trial.
So do we need them? Do we need those placebo controlled trial?
Is there any placebo effect? So in the review trials, there was an improvement in 85% of them in the surgical arm and in the placebo arm in 74%.
So in the majority, there was an improvement, despite the fact that it was only a fake surgery, not the real deal.
Surgery was better than placebo only in 49% of these trials, which means that in over 50% there was surgery was actually not better.
There was improvement only in the surgical arm in Southern Review trials, which was about 30% but important.
Five of the five of these trials used objective outcomes, not pain and function, but actually something measurable in objective way.
A placebo was better than surgery in one trial. No improvement was reported in any arm in six out of 53.
This is part of the forest plot. So there are two a full pages of forest plot and this is, if I can say so, this is done.
Of those difference between the surgery and the placebo arm, we did not calculate a pooled effect because of heterogeneity of the trials.
We we group them by the condition above.
Even within each condition, there were different procedures or different outcomes.
So we simply could not pull them together. But overall, you can see that the effect size is small.
This is a study by a different group also on placebo controlled surgical trials in which
they actually calculated an effect size in the surgical and placebo arm separately.
And if you look at those results, I'll in there will take them.
So there are actually vertical you can see that the effect is generally large,
but very often the difference between the surgical and the placebo arm is rather small.
And this is really surprising because the active procedure here is a surgery.
We are actually changing anatomy and we would expect actually a really large effect and that will be better than a fake surgery.
So what we have here is efficacy paradox.
So we've got a massive response after the real procedure and placebo, but the difference between them is very often non-significant.
So what I was interested in is what's going on in the placebo arm, because all the trials were so heterogeneous,
we analysed only the change in the placebo arm because then it was slightly more comparable because literally you are just comparing fake surgeries.
So this is a meta analysis of responses between the baseline, the follow up in the placebo arm only,
and this included all the review trials with continuous outcomes because we are interested in the magnitude of the effect and the effect of time.
So you can see trials subdivided by the outcome type and there are also all the by
the duration of the follow up from couple of days to two years at the very bottom.
And this is the same here within each subgroup. So you can see that for subjective outcomes there was a large, a significant effect.
And for assessed and objective outcomes, the pooled effect was not significant.
And those whiskers are not confidence intervals, those are prediction intervals.
So from this we can see that there doesn't seem to be a strong effect of time, but there seemed to be a really strong effect of the outcome type.
So what we've done, we've looked only at trials with pain as an outcome.
Okay, fine. Let's make it slightly more heterogeneous. Homogeneous.
Let's look at subgroups. So those are trials only with pain as an outcome assessed as a primary outcome time point.
And you can see big effect this point 70, 78,
huge effect significant for all the trials and stays significant for 24 months and if the outcome is objective.
So those are trials in which weight loss weight was used as an outcome, which is an absolute objective outcome.
You put this step on the scale.
There is a number whether you are happy or unhappy, whether you've been told the good news or bad news, it's just a number.
You can look affected and you can see that the effect was not significant in any of the trials to pull.
The fact is not significant and there seem to be a bit of an effect of time.
So we've done a meta regression.
So this is actually a beta coefficient showed as a forest plot for every factor that was reported in the literature as potentially affected,
affecting the magnitude of placebo response. And there was no effect of time, no effect, no difference whether the outcome was assessed or objective.
There was a large effect of subjective outcomes versus objective.
It didn't matter whether there was a standard or rescue medication.
It didn't matter whether the trial was done in the States or in Europe, and it didn't matter how.
What was the chance of getting the active treatment, whether the RANDOMISATION ratio was 1 to 1 or 3 to 1.
But we've got sports. We can do it even better. So what we've done,
we've actually we've taken every single time point for every review trial with a continuous
outcome and done the analysis across all time points and all visits because some in some trials.
There were multiple follow up visits, and you can see that overall there was a significant placebo effect that seemed rather flat.
It wasn't really what I was expecting,
so I was expecting the placebo effect to decrease with time because you have to remember, this is not a pharmacological trial.
In all those trials, there was only one surgery at the beginning.
And then the only thing we do, we keep following patients up and asking them, Is your pain still better have improved?
Could you please rate it for me? Could you please raise your symptoms?
Because we knew that the type of outcome actually matters.
We've done this analysis by subdividing trials, by the outcome type.
So in red you can see trials with subjective outcome. In blue with assessed.
We have very few trials. That's why the confidence intervals are massive and in green you can see trials with objective outcome.
But because those are trialled mostly on obesity, the effect seems to decrease,
which may be related to the fact that in obesity trials people tend to stick to diet
and lifestyle changes at the beginning and then they slip back to the old habits.
But for subjective outcomes like pain, function and quality of life, there is a big,
highly significant effect that remains highly significant for 12 months.
That's 12 and that's seven visits. So if we don't have a control arm, an effect like that will be interpreted as amazing success of our surgery.
So just to finish up, so we've also asked surgeons what they think about placebo.
So we gave a short survey to hundreds surgical members of the British Alban Shoulder Society at one of their conferences and ask them,
how often do you use operations that you believe may have a significant placebo component?
So surgeons are notorious for not admitting that what they do may not be actually specifically effective.
This is well, this is not surprising because unlike doctors who just give a pill made by a big pharma company,
surgeons actually have to go over and perform the surgery.
So they have to believe they what they do is actually helpful and effective.
So 42% said never. I've never done anything that wasn't directly helpful and effective,
but 21% said really less than once a year, 24% more than once a year and 30% more than once a month.
I do something that I believe may actually be placebo.
So we've asked them what their position concerning the use of placebo and only 4% said it should be always prohibited.
I disagree. It should not be used. I I'm I'm opposed.
But 46% said it should be permitted only in clinical research, but 50% said, well, actually, it should be permitted in a clinical clinical practice.
If research supported or it should be permitted in clinical practice, if experience in the departments supports its efficacy.
So we have to remember that this is what people say, not what people do.
But we were still surprised that the response was quite positive and the main concern that they had was deception.
So surgeons were generally opposed lying to patients or deceiving them in any way.
So as long as we actually disclose that this is a placebo surgery, they were quite okay with the concept.
Finally, ethical issues.
So with Professor Gillian Lesko, we really suggested that actually surgical trials are not that different from pharmacological trials.
So as long as there is an equipoise.
So lack of clear evidence that this treatment is truly effective and really superior than no treatment with physiotherapy, such a trial is justified.
There should be some preliminary, preliminary evidence that the surgery is effective.
So like those trials I mentioned earlier than they've done the placebo controlled surgical trial, and there was no improvement in neither of the arms.
There was really no point doing that.
But if we actually perform a surgery like the shoulder surgery and patients tend to improve, but they also improve after physiotherapy.
So there is some evidence of efficacy, but we don't know whether it's actually due to surgery or placebo.
There was definitely a sense to run the placebo controlled randomised trial.
It's also not no point to run the trial if there is just a small improvement.
So we want things like the shoulder surgery. There are hundreds of thousands of those surgeries performed every year.
The number of surgeries of salt operated patients increased seven times between 2000 and 2010.
So this is something performed very, very often. So if it's not necessary, we save money, we save time, we save NHS resources.
And also instead of sending patients, patients to wait for surgery,
we can just offer them physiotherapy and they'll go get equally effective treatment much sooner.
We definitely propose that harms should be minimised.
And like in the placebo controlled shoulder trial, if there is an option to offer direct benefits to patients in the placebo arm,
for example, like diagnostic arthroscopy or laparoscopy, they should be offered.
And finally, there should be no deception. And I would like to finish with a quote by Kolbe,
who did a placebo controlled trial on the efficacy of increasing blood flow to the heart in the sixties.
So he said that after observing some of the dramatic results afforded by only minor bilateral thoracic scale incision.
So they've actually, to the point, cut one seriously questions how much of the reported clinical improvement after thoracotomy is actually
dependent upon the patient's like reaction to surgery rather than an enhancement of coronary artery,
blood flow or other physiologic alteration? Thank you very much for your attention.