Saturday, February 20, 2016

Why Johnny can't make drugs any more ... we need better science from government.

I think of In the Pipeline’s Derek Lowe as a small ‘m’ marketarian. He has more confidence in the “invisible hand” of markets than I, but he’s not a believer in Rand’s Market Divine (the market that can do no evil, so long as government snakes are avoided). He combines critiques of big pharma CEOs with a robust defense of antibiotic development process.

Which may explain why he sort-off calls for more government funding of basic research — without quite getting there…

A Terrific Paper on the Problems in Drug Discovery | In the Pipeline

… Jack Scannell and Jim Bosley … “These kinds of improvements should have allowed larger biological and chemical spaces to be searched for therapeutic conjunctions with ever higher reliability and reproducibility, and at lower unit cost … in contrast many results derived with today’s powerful tools appear irreproducible; today’s drug candidates are more likely to fail in clinical trials than those in the 1970s … some now even doubt the economic viability of R&D in much of the drug industry [22] [23].

The contrasts ..between huge gains in input efficiency and quality, on one hand, and a reproducibility crisis and a trend towards uneconomic industrial R&D on the other, are only explicable if powerful headwinds have outweighed the gains [1], or if many of the “gains” have been illusory …

Shaywitz and Taleb wrote something similar about ten years ago (via Hensley, WSJ, emphases mine)…

… The molecular revolution was supposed to enable drug discovery to evolve from chance observation into rational design, yet dwindling pipelines threaten the survival of the pharmaceutical industry,” say consultant David Shaywitz and Nassim Nicholas Taleb, author of “The Black Swan: The Impact of the Highly Improbable.”

“What went wrong?” they ask in the opinion pages of the Financial Times. “The answer, we suggest, is the mismeasure of uncertainty, as academic researchers underestimated the fragility of their scientific knowledge while pharmaceuticals executives overestimated their ability to domesticate scientific research.”

When you get right down to it, Shaywitz and Taleb say, we still don’t understand the causes of most disease. Even when we think we do, because someone found a relevant gene, we’re not very good at turning the knowledge into a treatment. “Spreadsheets are easy; science is hard,” they tell Big Pharma.

I lived through this, including the 2nd failure of the genomic revolution. In retrospect the years from 1945 through the 1970s were a Golden Age of medicine. I did my medical science in 1982; for my generation the Golden Age was a baseline. We thought we understood so much …

By 2008 we all knew we had a problem. I’d been long out of practice and I was having to catchup on 7 years of medicine for my licensing exam. That turned out to be easier than expected. I wrote then about medications…

  1. Lots of new combinations of old drugs, maybe due to co-pay schemes
  2. Many new drugs have suicidal ideation as a side-effect.
  3. Lots of failed immune related drugs re-purposed with limited focal impact on a few disorders.
  4. Probably some improvements in seizure meds. Lots of new Parkinson’s and diabetes meds, but they’ve had limited value. (metformin was a home run, but that was more than 7 years ago).
  5. Really lousy progress in antibiotics; there are fewer useful therapies now than 7 years ago. Actually, fewer every year.
With Lowe’s latest we learn what has come from 8+ years of digging into our research flail (emphases mine):
… this paper is also a great source for what others have had to say about these issues, too (and since it’s in PLoS, it’s open-access). But the heart of the paper is a series of attempts to apply techniques from decision theory/decision analysis to these problems …
… Let’s all say “Alzheimer’s!” together, because I can’t think of a better example of a disease where people use crappy models because that’s all they have. This brings to mind Bernard Munos’ advice that (given the state of the field), drug companies would be better off not going after Alzheimer’s at all until we know more about what we’re doing, because the probability of failure is just too high…
… I’ve long thought that a bad animal model (for example) is much worse than no animal model, and I’m glad to see some quantitative backup for that view. The same principle applies all the way down the process, but the temptation to generate numbers is sometimes just too high, especially if management really wants lots of numbers. So how’s that permeability assay do at predicting which of your compounds will have decent oral absorption? Not so great? Well, at least you got it run on all your compounds…
… there’s no cure for the physical world, either, at least until we get better informed about it, which is not a fast process and does not fit well on most Gantt charts. Interestingly, the paper notes that the post-2012 uptick in drug approvals might be due to concentration on rare diseases and cancers that have a strong genetic signature …
… in drug discovery, we have areas that where our models (in vitro and in vivo) are fairly predictive and areas where they really aren’t…
I think what Lowe is telling us that we need more basic science work because drug development has raced ahead of the science-road it runs on. On the other hand, being a believer in markets and enterprise, he doesn’t quite come out and say that government needs to fund this work, even though he knows pharma won’t.
Or perhaps he has such a low opinion of current US government funded research that he doesn’t think our NIH will help. I see his point.  So we need government, but we need better government science …
It’s a tough one.
But… I just did my board exams again. Seven more years have passed. This time I had to learn more things. Maybe, when we look back, we’ll say that genomics science began to pay dividends around 2010. I think that’s not enough though. If the US is ungovernable, maybe we need to look for others to lead…

See also:

A peculiar finding of a 2010 RSV infection and transient autoimmune diabetes leads to ... nothing.

In March of 2012 we learned that a researcher identified a striking relationship between a RSV (respiratory syncytial virus) respiratory infection and development of transient auto-immune diabetes mellitus. You can read the companion article online, the ’54-year-old male volunteer” was Michael Snyder, one of the researchers.

I came across my old blog post on this today, so I looked to see what we’ve learned since about this peculiar relationship. I did a PubMed literature search on “respiratory syncytial virus” and “diabetes”. I found that 2012 article … and nothing else.

I reviewed the 100 or so subsequent article extracts that cited the 2012 paper. There didn’t seem to be any follow-up research.

Maybe the article was badly mistaken. Or maybe this is related to our post-70s research problem.

Thursday, February 18, 2016

Red Cross Basic Life Support training: avoid the Flash based simulation option

The American Red Cross runs classes in basic life support (CPR/AED). I’m doing the professional course. 

Historically these courses have been quite good, but these days they are sometimes (always?) offered as a combined online training module and a class-based skills portion.

Which would be a good idea — if the module weren’t buggy. It’s a Flash based program, and on my new MacBook Air Flash/Chrome misses trackpad clicks. Not something one would normally notice, but the simulation requires one tap 30 times at a rate of 100-120 taps/minute. When the tap frequency exceeds about 105 clicks get dropped. One can hear the pad click, but the simulation doesn’t respond.

Two counting errors means repeating the simulation. With this bug counting errors are common.

I’ve done one module, the last one left, at least 4 times. Once my wife, watching me, saw it miss 6 of 30 clicks.

Software is hard. Server side software is very hard. It’s expensive to develop, but it’s even more expensive to maintain and revise. We compare software development to building bridges, but really it’s more like building a fancy English garden. Hard to plan, hard to create, but it’s the maintenance that really hurts.

The Red Cross shouldn’t be running this simulation. They can’t afford it. They’re not alone though. The American Board of Family Medicine recently deprecated a very ambitious patient simulation software project. They really needed to do that, but it must have been a hard call. They’d invested a lot of work and money. The reality was, they couldn’t afford the maintenance.

There’s nothing easy about software. We need less of it, done better.

Tip: If you do have to do this, try a mouse instead of the trackpad. I found the glitches distracting and stopped watching the animated hands, but that was a mistake. Click the mouse but count on the hand movement. 

PS. When it comes to abdominal trust vs. back blows for chocking adult/child the downloadable text is internally inconsistent and also inconsistent with the abdominal thrust only simulation…

Update 2/12/2016: Our in-person class had 6 participants. One didn’t realize there was an online portion — I can see missing it, communications and the web site are both confusing. At least one other person had to call support to find the online portion. Everyone had click-count problem; one young person described the simulation as the worst experience of her life (she is young).

As is typical once one person spoke of having problems everyone joined in. It seems I got off lightly.

The logic and consistency errors around foreign body/choking management are well known. The course is scheduled to be rebooted in a month; i hope the simulations will be redone or eliminated. I’d suggest the American Heart Association course instead.

Monday, February 15, 2016

Aspirin, NSAIDs, cell death and the treatment of arthritis and interstitial cystitis

While doing some research on interstitial cystitis Google uncovered an extraordinary claim by the Cleveland Clinic’s Raymond Rackley:

Microsoft Word - Transcript for IC Video.doc

… exposure to TNF−α produces a dysfunctional activation pattern in IC urothelial cells that leads to cellular apoptosis…

Aberrant NF−κB signaling activation may be responsible for the imbalance of apoptotic and survival mechanism of the bladder epithelium that gives rise to the pathogenesis of IC … asking all IC patients to avoid aspirin or aspirins like products such as NSAIDs that block normal NF- B signaling …

I can’t tell when this transcript was created, there’s no date information on the PDF. As of Feb 2016 Rackley has 71 publications, but the only one that might lead in this direction was from 2011. I don’t think there have been any publications out of this particular video presentation.

The claim is extraordinary for two reasons. The first is that interstitial cystitis is a common cause of significant suffering, we have no good treatments (see also), and patients often use NSAIDs or even aspirin (which acidifies urine, for some that might help). If this claim were true those people should all switch to acetaminophen.

The other reason, of course, is that the transcript notes that aspirin and NSAIDS (ibuprofen, etc) have a significant effect on the mechanisms that influence cell death (apoptosis). This is mentioned as though it were common knowledge, but it was a surprise to me. Perhaps it shouldn’t have been, I know here has been a suspicion for at least 10 years that NSAIDs slow tendon injury healing. I’m also aware of epidemiology studies of an inverse association between colon cancer and aspirin use, and recently the USPSTF added colorectal cancer prevention to its draft aspirin use guidelines.

I suppose, in retrospect, if aspirin reduces the risk of colorectal cancer it may well do so by empowering our cellular level anti-cancer controls (vs. say, altering the microbiome). One way to empower those controls is to bias our cellular monitoring systems towards more aggressive cellicide (apoptosis) — and away from healing.

This has occurred to researchers. A search on apoptosis and aspirin returns 181 results starting in 1995 and accelerating in 2008 (NSAIDs) with a flurry of publications in the past few years. So among researchers, the idea that aspirin and NSAIDs shift our cellular systems away from healing and towards apoptosis (for better or worse) is probably not so surprising.

For clinicians however, this is potentially significant. We use aspirin for heart disease of course, but only in modest doses. More importantly, we use NSAIDs extensively for arthritic conditions where we may want more rather than less healing. (Not to mention interstitial cystitis).

It would be good to know how real this effect is. As Emily reminds me it is perilous to extrapolate from basic research to clinical practice. Even so, I would suggest people suffering from interstitial cystitis may want to consider acetominophen, assuming their liver is in good health.

Rebooting medical research - the world needs Canada.

My mother had a bottle of thalidomide on the shelf.

It was her first pregnancy and she was sick. Thalidomide was the hot new treatment for morning sickness. It wasn’t approved in the US, but Canada was ahead of the curve and a keen young obstetrician gave her the meds. 

Being a nurse she was suspicious of physicians, so she never took them and my arms and legs developed normally. I don’t know why thalidomide helped with morning sickness, but it was quite toxic to the developing fetus. 

Thalidomide had a second life though. Over the past 50 years it’s come to be used for a complication of Leprosy, for early multiple myeloma and for a few other conditions. Research has led to development of several related drugs.

It all took a long time though. There’s not much money to be made from off-patent medications, so there’s no funding from drug companies. There’s not a lot of support from traditional government sources either — there’s nothing exciting or sexy about this kind of costly, slow, research. Individual clinicians might do small trials on their own initiative, but unless the results are extremely positive nothing more will come of them. Worse, those small trials are increasingly hard to do in an era of humane and ethical research. Perhaps these are some of the reasons medical process has slowed since the early 1980s.

There are lots of odd drugs out there that have accumulated small research results but languish for lack of further investigation. Cimetidine was popular in the 1980s for ulcer disease, but in it’s off-patent life it’s been used for interstitial cystitis, persistent calcific tendinitis, animal studies of the innate immune system, eosinophilic fasciitis, warts, herpes simplex cold sores and doubtless other unpublished experiments. It probably doesn’t work for warts, but does it work for any of these conditions? We don’t know. There’s no money for the boring and expensive animal model development and clinical trials.

There are many drugs like cimetidine. They show up as “possible treatments” in the extensive literature around diseases we can’t fix. They are shots in the dark often based on biological plausibility, chance observations, and unreplicated animal experiments.

We can do better than this.

And by “we” I mean the world, not the United States. Our peculiar strain of anti-government and anti-science politics makes it hard for the US to play a leadership role in rebooting practical medical research. Other nations are in a better place to lead. Canada, the UK, Germany and the Nordics come to mind, but perhaps also Brazil, Israel, and India.

Canada, the world needs you.

Saturday, February 13, 2016

Heberden's nodes deserve more respect.

Wikipedia has the party line description of these buggers. Emphases mine.

Heberden's node

Heberden’s nodes are hard or bony swellings that can develop in the distal interphalangeal joints (DIP) … They are a sign of osteoarthritis and are caused by formation of osteophytes (calcific spurs) of the articular (joint) cartilage in response to repeated trauma at the joint.

Heberden's nodes typically develop in middle age, beginning either with a chronic swelling of the affected joints or the sudden painful onset of redness, numbness, and loss of manual dexterity. This initial inflammation and pain eventually subsides, and the patient is left with a permanent bony outgrowth that often skews the fingertip sideways.

Heberden's nodes are more common in women than in men, and there seems to be a genetic component involved in predisposition to the condition.

Let’s deconstruct that narrative, looking for internal contradictions.

Here’s one: “Repeated trauma … but sudden onset of redness … inflammation”. Really? Trauma? From what - typing? If it’s repeated trauma, why the sudden inflammatory onset? Hmm.

Here’s another: “calcific spurs”. So why are they “nodes” and not spikes? Why are they rounded, like things that grow from an internal nexus? Why do they grow so quickly? Why don’t they keep growing? Why don’t we call these “Herberden’s tumors”? Why are they universal by age 80?

Lastly, how do they grow so quickly? I’ve seen the become prominent in 2-3 weeks. That’s tumor class growth.

Really, we could be a bit more curious.

See also:

That 1940 article is fascinating, I’ll have to see if I can get the full article. We certainly don’t think of them as associated with breast cancer today.

I’d like to toss a few nodes in a blender and mine the slurry for non-human DNA.

Friday, February 12, 2016

Forget electric or hybrid or mileage. There's only one thing that matters for your next car.

What are the worst things that happen to us directly? (i.e. not things that happen to our kids)

Death and extreme suffering of course. Unfortunately, one is inevitable — and the longer that is delayed the more likely the other. Don’t blame me, I didn’t make this world.

Then there’s accidentally killing someone with a car, most likely a cyclist or pedestrian. That’s got to be in the top 3, maybe top 1. Drive a lot and bad luck or bad judgment may have its way. It feels like something we want to avoid.

Historically we had to minimize driving and/or drive with care. Now though, there’s a third option. Cars are beginning to incorporate pedestrian-collision avoidance systems like Volvo’s Mobileye or Toyota’s Pre-Collision safety [1].

Forget electric or hybrid or mileage or CO2 emissions. What I want most is something to keep me from hurting unarmored people. Until we have fully autonomous cars these warning systems are my best option — especially when they work under low vision conditions like darkness, rain, snow and fog.

So when I buy our next vehicle in 3-5 years this technology will determine what I buy. Only then will I look at electric, hybrid and the rest. Maybe now you’re thinking the same thing — imagine how you’d feel in 2019 if you go without and do hurt or kill someone [3].

We will all have this choice to make in the next few years [2]. 

- fn -

[1] This ConsumerReports review mixes systems that protect drivers with things that protect pedestrians. One I care little about, the other I care a lot about. It’s hard for a car-centric culture to think about the unarmored.

[2] Government action would help greatly - another reason to vote Dem. So would insurance company discounts

[3] Easy to imagine the advertising.

See also

Update 2/17/2016

I’ve been thinking more about what I want, which is detection of unarmored people (and animals), particularly in low visibility conditions. Assuming one can devise a system that can distinguish a bicycle from a fire bush in realtime at a useful distance the challenges are liability, user interface costs, and false positives. I think the liability barrier will require government action — in particular protection against suits for failure to warn. That probably requires a democrat for President (though Trump might do anything.)

The false positive problem rules out sound alerts; they’d become far too annoying. Who wants a warning of cyclist seen a half mile away? (Presumably the car would automatically report passing proximity violations to the authorities :-). We need a subtle but useful visual symbol. The obvious solution is a visible circle that appears on the windshield around the target; but that may require a costly windshield and expensive projection equipment. At the extreme the windshield is simply a display showing the results of enhanced vision systems — so night time appears like an overcast daytime view. That would be a hard sell.

I think one could go a long way, however, by simply placing a strip of lights around the perimeter of the windshield. Then a portion of the strip would light up to bracket targets (often multiple) above, below and to the side. That would be a subtle warning that would work for my needs.

Deep Burning Butt Ache review: Piriformis syndrome, sciatica, deep gluteal syndrome, sacroiliac syndrome, deep buttock syndrome ...

One of the more interesting aspects of being an older physician is that we get to experience first hand problems we’ve treated (or mis-treated) in other people. We learn experiential subspecialties like cancer, pain management, arthritis (yay), hypertension, obesity, heart disease and the like.

My experiential subspecialty is sports medicine, particularly anything related to tendons and, most recently, joints. I owe my experience to a combination of bad genes (thanks Mom) and a need to move. 

Experiential specialties teach even new physicians that the medical knowledge base is weird. It’s not simply that textbook descriptions and treatment plans are incomplete, it’s also that they vary a great deal, both between references and within them. Even books that do some things well may cover other things poorly. If you hang around for a while you also see the same “thing” get new names and explanations, even if the treatments don’t change as much. Insider experience exposes some “well known” disorders as Potemkin villages — on closer inspection they kind of fall apart. (Osteoarthritis? We know almost nothing. There really is something wrong with how we explore disease).

Deep Burning Butt Ache (DBBA) is all of the above. Actually, that’s my term, not the scientific name. It’s sometimes known as “Piriformis syndrome”, “deep gluteal syndrome”, “sciatica” (older name, now obsolete), “sacroiliac syndrome” (less often), and “deep buttock syndrome”. PITA, inevitably.

I’ve had DBBA three times in my life. Once it was related to carrying a wallet in my hip pocket (today it would be a phone). That one cleared up when I moved the wallet, but it still took many months to completely resolve (also typical). A second time was related to inline skating, and only slowly resolved when the season ended. This time it seems to have come from playing ice hockey, but it is a bugger during my broken-arthritic-old-man CrossFit workouts —  especially running, rope jumping, and, weirdly, kipping pull-ups but not squats or box jumps. (There may be a new arthritic component to the problem, but I can’t tell that.)

Having lived with this a few times I think I’m in a good position to do an informed review of the accessible online literature. These references matched my insider experience:

I think with this set of references you know about as much as anyone does - except what the stretches actually look like (see below).  All of the references are pretty recent, that’s because until a few years ago DDBA didn’t “exist”. We used the term “sciatica” to include both disk and bone pressure on the sciatic nerve and what most now call “piriformis syndrome”. Two very different problems with different courses (disk problems often resolve in 6 weeks) and different management (esp. stretching).

The use of “Piriformis Syndrome” came out of the internet community; this may be the first crowd-sourced medical syndrome. In truth we really don’t know that the Piriformis muscle is the root problem; it gets blamed because in many people (muscle anatomy varies) the Piriformis lies on top of the sciatic nerve and the symptoms resemble those caused by known injury to the sciatic nerve. Unfortunately, the muscle is hard to study — there’s too much on top of it. For that reason I prefer terms like “Deep Gluteal Syndrome” or “Deep Buttock Syndrome” or “Deep Burning Butt Ache” (DBBA). Similarly I prefer “shoulder pain syndrome” to “rotator cuff tendonitis”. Humility is a good idea.

I particularly liked Dr. Pribut’s description of the problem (excerpt and emphases mine):

Dr. Pribut on Piriformis Syndrome

Piriformis syndrome is difficult to diagnose and resistant to therapy. The existence of piriformis syndrome has been doubted for years, but with the power of the Internet the reality of this syndrome has finally reached a tipping point. Previously, it was not even considered as a diagnosis, in others it was quickly ruled out. In others the symptoms are ascribed to "sciatica" or some other cause, even if the piriformis is considered as a possible cause. Often the patient has considered the possibility before the physicians, trainers, therapists and others have.

Piriformis syndrome may overlap with a variety of other problems including what McCrory et. al. have called a "deep buttock" syndrome. This includes pain in the buttock region, possibly pain in the hamstrings, occasionally pain in the back of the leg that is difficult to locate.

… Scant information is available on the piriformis syndrome in lay publications, and only a little more in scientific publications. The functioning of the muscle has not been clearly defined and examined in the literature. The location of the muscle does not allow for surface EMG (electromyographical) study. It is quite difficult, if not impossible to place a deep electrode in the muscle for study purposes also.

The anatomical position of the muscle leads one to conclude that it functions in some ways similar to that of the gluteus medius

The sciatic nerve passes immediately below the piriformis muscle

…Like Achilles tendonitis and iliopsoas tendonitis this is a very difficult problem to eliminate…

Dr Pribut, like most medical types, skips over the details of conservative management. We usually outsource that to physical therapy! It’s surprisingly hard to find good descriptions online, this is best I could do (don’t forget - nothing in back pocket!):

  • Roll sore butt over foam roller, can be combined with the cross-over sit stretch as in this picture. (The other exercises on this site don’t make as much sense to me.)
  • Rubber (lacrosse) ball over piriformis/sore spot, roll over it. I have no idea why this seems to help, it sounds crazy. Should make things worse.
  • Google Image Search: Piriformis stretch: I gave up and outsourced to the Google AI. Pretty good set, lots of examples of variations on sitting with one ankle on other knee and leaning forward/pushing down. That’s the fundamental external rotation stretch.
  • ”External” Rotation banded Hip Driver - CrossFit St Paul: this is an aggressive version of the classic sitting leg external rotation piriformis stretch; it’s one of a series of stretches in a single YouTube “lower body mobility” set.

For my personal flavor of DBBA I’m doing several versions of hamstring stretches, seated and freestanding “chair sit" external rotation stretches, leg over leg to chest stretches, foam roller, lacrosse ball, and, my personal favorite, the banded ”External” RotationHip Driver - CrossFit St Paul. After 6-8 weeks of this I’m improved, but a few hours of hockey or running/jumping will set me right back.

Oh, I’m supposed to not do things that make it worse? Well, yes. That time will come. For now though I’m trying something counter-intuitive that I learned from my pretty-much-fixed long-term bad back problem (another experiential subspecialty of mine). I do the problem activity to produce mild to moderate burning discomfort, then I stretch it out, then I go back to the work. After I rest and recover I stretch some more. Experimenting, because we really don’t know much. Anyway, only 8 more hockey games left before it’s mountain biking (knee pain) season …

- fn -

[1]  Filler AG, Haynes J, Jordan SE, et al. Sciatica of non disc origin and piriformis syndrome: diagnosis by magnetic resonance neurography and interventional magnetic resonance imaging with outcome study of resulting treatment. J Neurosurg Spine 2005; 2:99–115.

I haven’t read the article, but looking the tumors they found (very rare in real world) I think they are a referral center …

“Piriformis syndrome: 68%

No diagnosis: 4%

Sciatic tumor: 1.7% (that’s 4 people in 239. I think this is referral center and small sample bias)

Lumbar stenosis: 0.8% (2 people)

Sacroiliac joint inflammation: 0.8% (2 people, surprised no sacroiliac arthritis)

Tumor in lumbosacral plexus: 0.4% (1 person, suspect referral bias.) 

Update 3/19/2016

Eight weeks after new painful burning pain in one butt or the other made me skip a week of CrossFit my piriformis pain is entirely gone. A 1.5 mile run and extended double-under session produced no symptoms at all.

So either the exercises worked or I just needed to run the clock. Eight weeks is actually a fairly short time to fix a tennis-elbow class problem at my age so I will credit the stretches. I had to substitute rowing for running, do burpees without a jump, use bands with my pull-ups, and make a few other accommodations but otherwise CrossFit Saint Paul was fine. It helped that despite our extreme temperatures we didn’t run much in Minnesota’s January and February.

Interestingly something I learned in my back pain days applied here. Once I was pain free with usual activities, I found I had to induce mild to moderate symptoms and then stretch them out in order to improve. So I’d run a bit, stretch both hamstring and piriformis/hip extenders until symptoms were clear, then run a bit more. It’s an approach that’s consistent with a PNBC marketing/research document:

Many, if not most, of our patients initial periods of discomfort as they vigorously exercised a weak and stiff lumbar spine. This discomfort was not unexpected, but it was amazing how many patients had been advised to continuously decrease their activity levels and to let pain guide their activity level. Such patients become conditioned to avoid pain. This causes more deconditioning and more dependence on the health care system…

I remember that aching and controlled discomfort feeling from my 8y ago PNBC therapy. There’s a hard to describe difference between real pain and therapeutic discomfort. I wonder if it’s a general principle in healing many soft tissue injuries … (or, for that matter, fractures…)

Tuesday, February 09, 2016

Medical knowledge diffusion: The osteoarthritis example

For personal reasons I’ve been doing a deep dive into current medical knowledge of osteoarthritis — particularly the relatively early and aggressive diffuse joint condition i’m enjoying.

It’s given me an opportunity to compare what’s in a current Internal Medicine textbook (Harrison’s 18th edition, 2012) vs. a current Rheumatology text (Hochberg, 6th ed, 2015) vs. the medical literature. 

There’s a relatively clear trend. Harrison’s has vestiges of the 1980s and 1990s view of OA, which focused on injury and “wear and tear” and treats OA as thought it is a single disorder. It is cautious about exercise and joint use. There’s no way to slow, much less reverse, disease progression.

Hochberg, the specialist text, deprecates “wear and tear” and focuses on genetics, but inflammation is mostly a secondary response to some relatively unspecified joint process. In this text OA is a “heterogenous disorder”, which is a pedantic way of saying it’s a whole bunch of things that need to be divided up better. Hochberg is keener on exercise. There’s still no way to slow, much less reverse, disease progression.

The literature, of course, is all over the place, but there’s a consensus for dividing OA up into more useful diagnostic categories. In general exercise is encouraged with little caution. There’s a movement to treat some kinds of OA as a primary disorder of the pre-vertebrate ancient innate immune system (vertebrates also have an adaptive immune system). There are experiments now with medications which act on the innate immune system, like H3 blockers. Of course to be effective these would need to start early in what feels to some like a fast moving disease.

Future versions of Hochberg may or may not incorporate the medical literature. Some quite nice studies have sown that the medical research literature is usually misleading or flat out wrong; most physicians are wise to avoid it. I am, however, a bit disappointed that Harrison’s seems to lag behind Hochberg — the authors are drawn from a similar pool of researchers. Maybe it’s simply that Harrison’s 19th edition is due out shortly, the one I read was probably written five years ago.

For a family physician, internist or geriatrician one lesson might be to stop reading the “generalist” textbooks and skip to the specialist textbooks. Harrison’s is famously unreadable, Hochberg is actually an easier slog. This assumes one has online access to both of course, these are very expensive references.

See also

Monday, February 08, 2016

Google deprecated 'security questions' - in May of 2015.

How the heck did I miss this? Why wasn’t it all over my feeds? It’s sad Google actually had write a paper to prove the self-evident, but I guess even within Google there were executives who couldn’t get their head around this (emphases mine)…

Google Online Security Blog: New Research: Some Tough Questions for ‘Security Questions’

… we analyzed hundreds of millions of secret questions and answers that had been used for millions of account recovery claims at Google. We then worked to measure the likelihood that hackers could guess the answers.

Our findings, summarized in a paper that we recently presented at WWW 2015, led us to conclude that secret questions are neither secure nor reliable enough to be used as a standalone account recovery mechanism. That’s because they suffer from a fundamental flaw: their answers are either somewhat secure or easy to remember—but rarely both…

…  37% of people intentionally provide false answers to their questions thinking this will make them harder to guess. However, this ends up backfiring because people choose the same (false) answers, and actually increase the likelihood that an attacker can break in ….

.. the ‘easiest’ question and answer is "What city were you born in?"—users recall this answer more than 79% of the time. The second easiest example is “What is your father’s middle name?”, remembered by users 74% of the time …

… probability that an attacker could get both answers in ten guesses is 1%, but users will recall both answers only 59% of the time … Piling on more secret questions makes it more difficult for users to recover their accounts and is not a good solution …

We’ve only been saying this for 10 years. Yeah, Schneier of course, but really everyone else. Shame on Apple for persisting with this dumbass approach. (FWIW my security question ‘Fake Answers’ are basically unique random passwords - secure but a royal pain to manage.)

For all the flack I give Google, they’ve been doing better over the past 1-2 years. When it comes to security and usability of online resources they are without peer.

Thursday, February 04, 2016

Google and RSS: Not unfolding as anticipated

Google Reader died just 3 years ago. It feels a lot longer, I’m probably thinking of when Google burned Reader Social in favor of their G+ initiative. That was 5 years ago; eons by our reckoning, but things have changed less than we expected.

2013 was a truly bad year, but then Google ran into some G+ problems. Namely we hated it. They’ve since cut G+ into pieces, burned each piece, and scattered the ashes deep beneath the continental plates.

Meanwhile, despite a Feed 101 page that’s unchanged since 2004, Google’s Feedburner still lives. Google’s ancient Blogger Buzz blog is active, indeed blogs continue to be Google’s primary way of talking to the world.

Consider Google Fiber — one of their most critical projects. Today’s public housing announcement has a URL. More — take a look at the sidebar:

 Screen Shot 2016 02 04 at 9 58 43 AM

Ok, so it still has the obsolete G+ link, and Twitter and Facebook get colorful links, but note the old “Feed” link. Still there.

That’s not what we expected three years ago.

There’s more. Gmail has 1 billion active accounts. That’s big, but Google wants to replace it with Inbox. So Inbox is a good guide to Google’s current thinking. Inbox has an RSS (Atom) Feed.

RSS survived the great fire of 2013Media gurus are shocked to learn that RSS still rules the news. RSS is still the only standard for two essential net functions: notification and subscription. RSS is going to last (Feedbin and are my personal clients).

I wonder when Google will incorporate Feed subscription into Inbox.

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