Category Archives: Medicine in general

The most interesting paper I’ve read this year

We all know what the estrogen receptor is and what it does.  It’s a large protein with 3  functional components.  Actually there are several estrogen receptor proteins, but I’m going to discuss just one — Estrogen Receptor alpha (ERalpha).

Here are the components:

a DNA binding domain (which binds to stretches of bases called the Estrogen Response Element (ERE))

a domain which binds estrogen changing the conformation of the third domain which is —

a domain which binds to RNA polymerase II activating it so it transcribes genes into mRNA.

Given the complexity of the hormonal cycles, it is far from surprising that the estrogen receptor controls the levels of 15% of all annotated protein coding genes < Cell vol. 145 pp. 622 – 634 ’11 >.

Given its importance in breast cancer, ERalpha has been intensively studied for years.

Now various regions of proteins have been assigned function, the SH2 domain binds to phosphotyrosine in proteins, SH3 binds to proline rich motifs, RNA Binding Domains (RBDs) bind to (what else?) RNAs.  Each of them has a characteristic sequence of amino acids allowing them to be picked out from DNA sequences.

Enter Cell vol. 184 pp. 5086 – 5088, 5215 – 5229 ’21 where ERalpha was found to bind to over 1,200 messenger RNAs (mRNAs).   It was not supposed to do that as it doesn’t contain any RBDs (well at least the RBDs we knew about — back to the drawing board on that one).  Even more interesting is the fact what most of the mRNAs bound by ERalpha aren’t from the genes whose ERE ERalpha binds.

Life is said to have originated in the RNA world.  We all know about the big 3 important RNAs for the cell, mRNA, ribosomal RNA and transfer RNA.  But just like the water, sewer, power and subway systems under Manhattan, there is another world down there in the cell which doesn’t much get talked about.  These areRNAs, whose primary (and possibly only) function is to interact with other RNAs.

The RNA world is still alive and well in all our cells.  It’s like DOS still out there under Windows, or Unix and its command line under the Apple interface. We studied proteins and DNA because they were (relatively) easy to study.

The papers go on to study how ERalpha RNA binding affects cancer (which it does).

But there are far larger questions the work brings forth.

l. ERalpha is just one nuclear hormone receptor and Estrogen is just one hormone.  Do the nuclear hormone receptor for other hormones also bind RNA? Have we been missing some of their actions inside cells and if so there are mechanisms to exploit?

2. Why stop at nuclear hormone receptors?  ERalpha binds RNA with no RNA binding  domains (RBDs) in sight.  Do other proteins also bind RNAs and if so what does it mean?

Fantastic stuff.  There is a whole world of possibilities opening before our eyes thanks to these papers.

It reminds me of what an anatomy professor told us when we were studying neuroanatomy — ‘unfortunately everything is connected to everything else’.

Cassava Sciences — the clinical reality underneath the stock gyrations.

The stock of Cassava Sciences (symbol SAVA) has undergone some wild gyrations this year.  On 14 September it traded at 41.70, today just two weeks later it is trading in the upper 60s.

The important thing to keep in mind, is that 1 year out on treatment with SAVA’s drug Simufilam 50 patients with mild Alzheimer disease were (as a group) slightly improved.  This is absolutely unprecedented.  The best that previous therapy could accomplish was a slightly slower rate of decline — see ars — for a recent review of other therapy attempts.  So Cassava’s results are unprecedented.   While Alzheimer (and other dementia) patients fluctuate from day to day (like the tides from minute to minute) at the end of a year they are all worse.

These results have not been attacked, unlike their data on the effect of Simufilam on biomarkers which has been criticized by a person of standing — Elizabeth Bik —

But that’s irrelevant and guilt by association at best.  As a clinical neurologist, no one was ever brought to see me because of their biomarkers.

They have released part of their 1 year results —  There is a lot more that I’d like to know, but a press release is not a detailed scientific paper.

What follows is a lot of commentary and speculation about the 1 year data which we haven’t seen yet.

The results concern the first 50 patients to complete one year on the drug.  The dropout rate is stated to be under 10%.  Presumably this includes death, in a cohort (presently at around 200) with a significant mortality.  It would be interesting to know how many patients on entry made it to one year.

As a clinical neurologist I was particularly impressed with part of their data at 9 months.  Here’s a link — keep it handy —

They measured cognitive changes by something called ADAS-Cog — a full description can be found in the following post —

ADAS-Cog score counts errors, so a perfect score would be 0, and a terrible score would be 70.  The range of deficit on entry was 16 – 26 (but possibly on something else called the MMSE) — this is what the 1 year results used.  The 9 month results used ADAS-Cog.  Perhaps they are actually the same thing — I don’t know.

On the link — — look at the diagram titled “Individual Patient Changes in ADAS-Cog (N = 50).

There were 5 patients out of 50 at 9 months with improvements of 11 – 14, which would mean that they were pretty close to normal if their entry score was 16 and 50% improved if their score was 26.  From here out I’m just calling them ‘the 5’.

The 9 month report doesn’t discuss this, and only a clinician would know, but this is the way neurologic patients respond to treatment.  Some do extremely well while others have no effect.  Why?  It’s probably because not really understanding causation, we classify patients clinically (it’s all docs have after all).

I ran a Muscular Dystrophy Clinic for 15 years back in the day.  The Muscular Dystrophy Association was founded by parents of weak kids.  They didn’t know that some weakness was due to the muscle itself (what we’re now calling muscular dystrophy), some was due to disease affected the nerves from the spinal cord to the muscle (what we call a neuropathy now) and others were due to disease of the cells in the spinal cord giving rise to the nerves to the muscle (motor neuron disease).  That all came later.

It is quite presumptuous to say that Alzheimer’s disease is just one thing.  Perhaps the 5 patients doing so very well had it from a different (as yet unknown) cause than the other 45.  Even so such a treatment would be worth having.

So here are a few questions for the folks at Cassava about their data

l. Some 16 different sites were involved in the open label study.  Were all of ‘the 5’  from the same site (doubtful — but if true, perhaps they tested ADAS-Cog differently, casting doubt on these results).

2. What were the ADAS-Cog scores initially on ‘the 5’.

3. What happened to ‘the 5’ in the past 3 months (did they maintain improvement, slide back, or improve further?)

4. We must have lots more people passing the 3, 6, 9 month markers.  Have their results paralleled that of the first 50 reaching the mileposts?   It would be very useful to know if there are now more than 5 with improvements over 10 in ADAS-Cog at 9 months.

The slightly slowing of improvement at 1 year relative to 9 months is typical of neurologic disease.  When L-DOPA was first available in the USA in 1970, some patients because so normal that you couldn’t tell they had Parkinson’s disease, and for a few years, neurologists (myself included) thought we were actually curing the disease.  Of course we weren’t and the underlying pathology of Parkinsonism (death of neurons using dopamine) continued unabated.  The L-DOPA just helped the surviving neurons function more efficiently.  Something similar may be going on with Simufilam and Alzheimer’s.

Now for some blue sky about Simufilam. Just as the gray hair on the head of an 80 year old looks the same under the microscope as one from a prematurely gray 30 year old, the brain changes of Alzheimer’s disease (the senile plaque)  are the same regardless of the age of onset.  Assuming that the senile plaque is in someway related to dementia (despite the lack of effect of therapies trying to remove it) and given that we all accumulate a few as we age, could Simufilam improve cognition in the elderly?   Would it then be intellectual viagra and the blockbuster drug of all blockbuster drugs.


Spot the flaw in this argument — I didn’t

The following sentence appeared in an article in the latest (24 September ’21)  Science.   ” In mid-August, after vaccine efficacy had started to wane and before the effects of boosters had taken hold, 59% of severe patients were fully vaccinated.”

This is far worse than ’started to wane’, given the following sentence from the same article “Israel’s vaccination rate—64% of its population has received at least two doses”

Put the two together (which the article really didn’t do) and you see that at most the vaccine was giving at most 5% protection against severe infection, which is really no protection at all.

The null hypothesis is that the rates of severe COVID19 in the vaccinated and unvaccinated should be the same, and the percentages cited above seems to bear that out.  

What’s wrong?  Something called the Simpson paradox —

Start by assuming 100% of the population vaccinated, then all breakthrough hospitalizations will be in the vaccinated group, which means nothing. The point is that the vaccinated groups of Israeli’s are much different than the unvaccinated.    Note the unstated assumption in the above paragraph in bold type — we’re assuming that vaccination in the Israeli population is a random event.

But of course vaccination was never random.  Those at higher risk (the elderly, the immunodeficient for whatever reason) were vaccinated first.  So there are a lot of them to have breakthroughs, and they will have more breakthroughs because their immune systems aren’t as strong.

“Among Israeli adults under 50, as of Aug. 15, 3.5 million were vaccinated and 1.1 million were not. That’s still a considerable number of vaccine holdouts. Among those 3.5 million vaccinated younger people, just 11 were hospitalized — about three per million. Meanwhile, of the unvaccinated in this age range, 43 were in the hospital, or 39 per million.

Note that hospitalizations of young people for both the vaccinated and unvaccinated are low, because younger people rarely suffer the severest illness from covid-19. (Their immune systems are stronger)l Still, vaccination reduced the rate of hospitalization more than 10-fold in the population under 50.

Now look at the population 50 and older. There are 2.1 million vaccinated Israelis over 50, and 290 were in the hospital Aug. 15. That’s 136 per million, a rate that dwarfs anything younger people are experiencing. And unvaccinated older Israelis? There are very few people in that category: just 186,000. But of that group, 171 were hospitalized — a grievously higher rate of 919 per million. In the older population, vaccinated people were less than one-sixth as likely to be hospitalized as the unvaccinated.”

I thank a friend for pointing out the error of my ways.

Even so only in the under 50 group can vaccination be said to provide > 90% protection against severe infection.  In the over 50 group the protection is 84% — still not bad

We’re not as protected as we thought we were

We all know that the only people hospitalized and dying of COVID-19 are lower forms of animal life such as the rednecked Trumpenproletariat from the deep South.  Here’s the New York Times of less than a month ago —

“Serious coronavirus infections among vaccinated people have been relatively rare since the start of the vaccination campaign, a New York Times analysis of data from 40 states and Washington, D.C., shows. Fully vaccinated people have made up as few as 0.1 percent of and as many as 5 percent of those hospitalized with the virus in those states, and as few as 0.2 percent and as many as 6 percent of those who have died.”

Nothing to worry about up here in Massachusetts where roughly 2/3 of the population have been vaccinated.  Well that’s what I thought until Friday 3 September — when I saw this from the Massachusetts department of public health —

149 of 609 hospitalizations (24%) with COVID19 had been fully vaccinated.  That is far from the protection we had been led to believe.  It could have been worse.  If the vaccination was totally useless,  the fully vaccinated should have made up 66% of the cases.  So there was some protection, but nothing like the New York Times and others were talking about a few weeks ago.


Addendum 26 September — There is a serious flaw in the above argument — for details please see —

So for the elderly, it’s back to restricted social contact and masks.

On a more personal note, I proved Richard Feynman right again.  He famously said ”

“The first principle is that you must not fool yourself — and you are the easiest person to fool.”

Well I certainly did.  I read the following article in the 27 August Science –

It contained the following statement. ” As of 15 August, 514 Israelis were hospitalized with severe or critical COVID-19, a 31% increase from just 4 days earlier. Of the 514, 59% were fully vaccinated.”

I even took notes on the article.  Yet somehow I chose to ignore it.  Why?  Too threatening?  Didn’t fit with what I’d been told?  Kahneman has shown just how irrational, those who call themselves rational turn out to be.  Mea Culpa.

Addendum  7 September —

“The state reported a total of 601 COVID hospitalizations Tuesday 7 September ’21. Data shows that 160 of the 601 hospitalizations are people who were fully vaccinated — about 26% of all COVID hospitalizations. ”

So the data of 3 September referred to earlier are to be believed and likely NOT a statistical fluke as they are essentially the same as today’s.

Cassava Sciences 9 month data is probably better than they realize

My own analysis of the Cassava Sciences 9 month data shows that it is probably even better than they realize.

Here is a link to what they released — keep it handy

I was unable to listen to Lindsay Burn’s presentation at the Alzheimer Association International Conference in July as I wasn’t signed up.  I have been unable to find either a video or a transcript, so perhaps Lindsay did realize what I’m about to say.

Apparently today 25 August there was another bear attack on the company and its data.  I’ve not read it or even seen what the stock did.  In what follows I am assuming that everything they’ve said about their data is true and that their data is what they say it is.

So the other day I had a look at what Cassava released at the time of Lindsay’s talk.

First some background on their study.  It is a report on the first 50 patients who had received Simulfilam for 9 months.  It is very important to understand how they were measuring cognition.  It is something called ADAS-Cog11

Here it is and how it is scored and my source —

The original version of the ADAS-Cog consists of 11 items, including:1

1. Word Recall Task: You are given three chances to recall as many words as possible from a list of 10 words that you were shown. This tests short-term memory.

2. Naming Objects and Fingers: Several real objects are shown to you, such as a flower, pencil and a comb, and you are asked to name them. You then have to state the name of each of the fingers on the hand, such as pinky, thumb, etc. This is similar to the Boston Naming Test in that it tests for naming ability, although the BNT uses pictures instead of real objects, to prompt a reply.

3. Following Commands: You are asked to follow a series of simple but sometimes multi-step directions, such as, “Make a fist” and “Place the pencil on top of the card.”

4. Constructional Praxis: This task involves showing you four different shapes, progressively more difficult such as overlapping rectangles, and then you will be asked to draw each one. Visuospatial abilities become impaired as dementia progresses and this task can help measure these skills.

5. Ideational Praxis: In this section, the test administrator asks you to pretend you have written a letter to yourself, fold it, place it in the envelope, seal the envelope, address it and demonstrate where to place the stamp. (While this task is still appropriate now, this could become less relevant as people write and send fewer letters through the mail.)

6. Orientation: Your orientation is measured by asking you what your first and last name are, the day of the week, date, month, year, season, time of day, and location. This will determine whether you are oriented x 1, 2, 3 or 4.

7. Word Recognition Task: In this section, you are asked to read and try to remember a list of twelve words. You are then presented with those words along with several other words and asked if each word is one that you saw earlier or not. This task is similar to the first task, with the exception that it measures your ability to recognize information, instead of recall it.

8. Remembering Test Directions: Your ability to remember directions without reminders or with a limited amount of reminders is assessed.

9. Spoken Language: The ability to use language to make yourself understood is evaluated throughout the duration of the test.

10. Comprehension: Your ability to understand the meaning of words and language over the course of the test is assessed by the test administrator.

11. Word-Finding Difficulty: Throughout the test, the test administrator assesses your word-finding ability throughout spontaneous conversation.

What the ADAS-Cog Assesses

The ADAS-Cog helps evaluate cognition and differentiates between normal cognitive functioning and impaired cognitive functioning. It is especially useful for determining the extent of cognitive decline and can help evaluate which stage of Alzheimer’s disease a person is in, based on his answers and score. The ADAS-Cog is often used in clinical trials because it can determine incremental improvements or declines in cognitive functioning.2


The test administrator adds up points for the errors in each task of the ADAS-Cog for a total score ranging from 0 to 70. The greater the dysfunction, the greater the score. A score of 70 represents the most severe impairment and 0 represents the least impairment.

The average score of the 50 individuals entering was 17 with a standard deviation of 8, meaning that about 2/3 of the group entering had scores of 9 to 25 and that 96% had scores of 1 to 32 (but I doubt that anyone would have entered the study with a score of 1 — so I’m assuming that the lowest score on entry was 9 and the highest was 25).  Cassava Sciences has this data but I don’t know what it is.

Now follow the link to Individual Patient Changes in ADAS-Cog (N = 50) and you will see 50 dots, some red, some yellow, some green.

Look at the 5 individuals who fall between -10 and – 15 and think about what this means.  -10 means that an individual made 10 fewer errors at 9 months than on entry into the study.  Again, I have no idea what the scores of the 5 were on entry.

So assume the worst and that the 5 all had scores of 25 on entry.  The group still showed a 50% improvement from baseline as they look like they either made 12, 13, or 14 fewer errors.  If you assume that the 5 had the average impairment of 17 on entry, they were nearly normal after 9 months of treatment.  That doesn’t happen in Alzheimer’s and is a tremendous result.   Lindsay may have pointed this out in her talk, but I don’t know although I’ve tried to find out.

Is there another neurologic disease with responses like this.  Yes there is, and I’ve seen it.

I was one of the first neurologists in the USA to use L-DOPA for Parkinsonism.  All patients improved, and I actually saw one or two wheelchair bound Parkinsonians walk again (without going to Lourdes).  They were far from normal, but ever so much better.

However,  treated mildly impaired Parkinsonians became indistinguishable from normal, to the extent that I wondered if I’d misdiagnosed them.

12 to 14 fewer errors is a big deal, an average decrease of 3 errors, not so much, but still unprecedented in Alzheimer’s disease.   Whether this is clinically meaningful is hard to tell.  However, 12 month data on the 50 will be available in the fourth quarter of ’21, and if the group as a whole continues to improve over baseline it will be a very big deal as it will tell us a lot about Alzheimer’s.

Cassava Sciences has all sorts of data we’ve not seen (not that they are hiding it).  Each of the 50 has 4 data points (entry, 3, 6 and 9 months) and it would be interesting to see the actual scores rather than the changes between them in all 50.  Were the 5 patients with the 12 – 14 fewer errors more impaired (high ADAS-Cog11 score in entry) or less.

Was the marked improvement in the 5 slow and steady or sudden?   Ditto for the ones who deteriorated or who got much worse or who slightly improved.

Even if such dramatic improvement is confined to 10% of those receiving therapy it is worth a shot to give it to all.  Immune checkpoint blockade has dramatically helped some patients with cancer  (far from all), yet it is tried in many.

Disclaimer:  My wife and I have known Lindsay since she was a teenager and we were friendly with her parents.  However, everything in this post is on the basis of public information available to anyone (and of course my decades of experience as a clinical neurologist)


Is the end of the pandemic at hand?

6 days ago I published my brother’s idea, that the pandemic may be nearing an end.  That post can be found below the ****

Here is some startling evidence that he might be right.  Today’s (12 August) Nature pp. 175 – 176, notes that new ‘cases’ in the UK defined as a positive test for the viral genome dropped in half from 17 July to 2 August 54,674 to 22,287. That could just be due to fewer people being tested (the total number tested isn’t given in the article).  More to the point, hospitalizations dropped from 836 25 July to 645 1 August.  It isn’t clear if all these numbers are daily or weekly.  Regardless, it is worth noting just how few cases are actually hospitalized ( 836/54674 = 1.5%)

These numbers are those persons deciding or required to be tested.  A random population survey is in order to see how many people now have antibodies to the virus.  Clearly SARS-Cov-2 can spread widely without making most people sick.

It is worth noting that the article doesn’t consider my brother’s idea as a possibility, so it likely originated with him.  If so, Bravo ! ! !

Addendum 19 August — from Nature vol. 596 p. 326 “In a nationwide survey of about 28,000 people (two-thirds of whom were unvaccinated and had therefore acquired immunity from infection) in June and July this year, researchers found that 68% had SARS-CoV-2 antibodies in their blood. This represented a huge increase from the 21% with antibodies, recorded in a similar survey in December 2020 to January 2021, before the second wave.”  This is exactly what my brother was talking about — vaccination by infection. It shows that most infections are survivable — with a population of 1.3 billion, the vast majority of those coming in contact with the pandemic virus are still here.


Sibling rivalry aside, my younger brother thinks that we’re currently in a mass vaccination situation with the pandemic virus.  He does not mean that people are willingly signing up for vaccinations. He says that the Delta virus is so infectious and spreading so quickly, and that most cases are asymptomatic that  the populace is being vaccinated by infection.  If so, those who will die because they weren’t vaccinated will die and those unvaccinated who have been infected but not sick will be immune, so that the populace will achieve herd immunity in a month or two and the pandemic will be over.Fantastic if true.

Cassava Sciences: What happened and what they should do next

The results of 9 months treatment with Sumafilam reported 29 July were exactly what I had hoped for;  namely continued improvement over baseline and over the 3 and 6 month interim results.  Yet the stock tanked that day, and has come back about 50% from the low.  It’s the old sick joke, the operation was a success but the patient was a failure.

I had a few guesses as to what happened in a post I wrote 30 July

” In the past few months, all companies with drugs for Alzheimer’s disease have been fluctuating in price together, and one of them (to remain nameless to protect the innocent) had the temerity to release a 25 day study today on their drug based on 14 patients.  The stock was down 60%.


So Cassava got tarred with this brush.


Another likely reason is that the rise in Cassava was fueled by very small investors.  If you watched the transactions on a day SAVA was soaring, the purchases were rarely over 200.  So many of them were likely buying because others were.  So they sold when others were.  Lemmings anyone?”


My guesses were totally wrong.  What actually happened was a very well timed and very well coordinated bear attack on the price of the stock.


As Lindsay Burns was presenting positive data the morning of July 29th, an article run by a guy with a political science degree attacked her data, using 3 neurologists, all developing other drugs for Alzheimer’s disease. At the same time some 200 Million  dollars worth of sell orders were placed (likely by several hedge funds).  The stock tanked.


Reality has subsequently intruded, as SAVA’s stock has rebounded 50% from the attack.


So what should Cassava do at this point?  Assume, as time passes, that patients continue improve or remain stable (as they already have for 9 months).  Within the next 3 months, and possibly sooner, SAVA will have  1 year results.  If patient cognition continues to show improvement (over 9 months, over baseline), game over.  No one taking care of an Alzheimer patient has ever seen them better off cognitively after a year has passed. .


The bears should not be forewarned as they have been. The 12 month results should released without warning, early in the week, so the bears don’t have the weekend to respond.  It would be an interesting short squeeze.

An experiment of nature

China is unintentionally undertaking an experiment which would never get past an institutional review board.  We are about to see how effective their vaccines from Sinovac and Sinopharm actually are versus the Delta variant of the pandemic virus.

Consider the following two direct quotes from Fortune 5 August,

l. “As of Wednesday, China has recorded nearly 500 cases in the past two weeks across 18 different provinces stemming from an outbreak in the southern Chinese city of Nanjing. The outbreak started after airport workers contracted the Delta variant of COVID-19 while cleaning an airplane arriving from Russia on July 20, ”  From Fortune 5 August,

2. “China has now delivered over 1.7 billion vaccine shots domestically, nearly five times as many as the U.S. The total is enough to fully vaccinate 60% of China’s 1.4 billion citizens, and vaccine coverage of adults in major urban centers like Beijing and Shanghai is over 91% and 85%, respectively.

For its campaign, China has largely relied on inactivated COVID-19 vaccines from private firm Sinovac and state-owned manufacturer Sinopharm.”

There are similar quotes from the BBC and from the South China Morning Post.  Depending on who you read the Delta virus is in 12 – 24 Chinese cities. We are about to find out just how protective the Sinovac and Sinopharm vaccines really are. The results in Beijing and Shanghai where Delta is actually present and vaccination rates are high will be particularly important.

There is one proviso, of course.

The proviso is that the government of China manages information very carefully.  Will we actually told the extent of the spread, hospitalizations and deaths?

Example #1: From the South China Morning Post   —

China flood survivors tell of rising water and last goodbyes as disaster claims at least 25 lives and displaces thousands

  • Passengers were trapped in subway trains in Zhengzhou, some struggling to reach rescuers and others sending what they feared were final words to loved ones
  • Survivors sharing their stories on Weibo are told to remove them to avoid being ‘manipulated by hostile foreign forces’, while photos and videos are deleted

Example #2 :

Zhang was a blogger in Wuhan during the first wave of the epidemic in 2020.  She just described what was going on.

” Zhang Zhan, a 37-year-old former lawyer and citizen journalist who was arrested in May while reporting from Wuhan, has been sentenced to four years in jail.


Zhang was arrested for “picking quarrels and provoking trouble” – an accusation commonly used against dissidents, activists and journalists – with her video and blog reports from the Wuhan lockdown. Last month she was charged with disseminating false information.



My kid brother’s brilliant idea

Sibling rivalry aside, my younger brother thinks that we’re currently in a mass vaccination situation with the pandemic virus.  He does not mean that people are willingly signing up for vaccinations. He says that the Delta virus is so infectious and spreading so quickly, and that most cases are asymptomatic that  the populace is being vaccinated by infection.  If so, those who will die because they weren’t vaccinated will die and those unvaccinated who have been infected but not sick will be immune, so that the populace will achieve herd immunity in a month or two and the pandemic will be over.Fantastic if true.