Field of Science

Do hyaluronic acid injections help knee pain? Don't waste your money.

As spring turns into summer, we spend more time outdoors, exercising, gardening, or just walking around. And for many people, more exercise means knee pain. Count me among the afflicted.

Several people, including my orthopedic specialist, have suggested that I try injections of hyaluronic acid to treat my knee pain. Many people swear by it, and even though I looked into this two years ago (and rejected it as ineffective), I thought I would look again. Perhaps the evidence had changed.

It hadn't.

Superficially, these injections sound reasonable. Hyaluronic acid is already inside your knee and helps to lubricate and cushion the joint. Adding more lubricant seems like a good idea; after all, it works for cars, bicycles, door hinges, or any other creaky joint.

But not for knees. Just recently, Anne Rutjes, Peter J√ľni and their colleagues published a very large review of the evidence on knee injections. They looked at 89 trials involving over 12,000 adults and found that in the trials that were properly controlled (blinded), hyaluronic acid injections had either no effect or a “clinically irrelevant effect”; that is, too small a difference to matter to the patient. (They also found five unpublished trials that showed no effect at all; this is a good example of the so-called “file drawer effect”, where studies that don’t have the desired outcome are stashed away in a drawer and never published.)

Rutjes and colleagues also pointed out that there’s a real risk of harm when you inject something deep into the knee joint. To quote their summary for patients (published along with the article),
“Viscosupplementation [injection of hyaluronic acid] may provide little if no pain relief or function improvement in patients with knee osteoarthritis. It also seems to increase the risk for adverse events."
If you don’t believe Rutjes, perhaps you’ll believe the American Academy of Orthopaedic Surgeons (AAOS), who reviewed a large body of evidence and wrote
“We cannot recommend using hyaluronic acid for patients with symptomatic osteoarthritis of the knee. Strength of recommendation: Strong.”
After looking at numerous studies, the AAOS concluded that there was no clinically meaningful benefit from these injections. This document is their official recommendation for physicians.

I was disturbed, though, to find that the AAOS information for patients directly contradicts their own recommendations to clinicians, and suggests that knee injections might work. On their patient-oriented web page, they offer the wishy-washy comment that “hyaluronic acid does seem to have anti-inflammatory and pain-relieving properties … [that] may last for several months,” though “not all patients will have relief of pain.”

What the heck? Are they orthopedists trying to hide the truth from their patients? Why would they do that?

I checked to see if the AAOS patient information was merely out of date, but no, it was reviewed in 2014, and the clinical recommendations appeared in 2013. I have to assume that the authors of the patient information page are not the same doctors who established the official recommendations for clinicians–but it seems unlikely that they are ignorant of their own organizations official guidelines. So why don’t they warn patients that hyaluronic acid injections don’t work? Is it because hyaluronic acid treatments are a significant money-maker for some orthopedists? 

I can hear the response from some doctors already: "In my experience," they say, "this works for some patients." Sorry, but one doctor's experience (or "clinical judgment", as some call it) doesn't trump science. That's why we do experiments, to determine whether or not our subjective impression is correct. In this case, the science is clear.

Incidentally, the Mayo Clinic also fails on this topic. Their site states that hyaluronic acid 
“can be injected into your knee to improve mobility and ease pain. Relief may last as long as six months to a year.” 
They cite no evidence to back this up. Patients looking at either the Mayo site or the AAOS site will be misled into thinking that these injections might be worth a try.

WebMD does a much better job, writing that 
“one study published in Rheumatology found that hyaluronan was no better at reducing joint pain than a placebo injection of salt water. An analysis of seven different studies published in the Journal of Family Practice did not recommend the treatment, since the benefits–if it had any at all–were so slight.”
Note that unlike the Mayo Clinic page,  the WebMD page mentions specific studies and names the journals.

So what does work for knee pain? Physical therapy and exercise to strengthen the muscles around the knee is still the best course, according to the AAOS's clinical guide. Weight loss also helps, by reducing the load on the knee. The only medical intervention that helps is an NSAID pain reliever such as ibuprofen. (See my 2013 article for other treatments that don’t work, including acupuncture (not even close) and glucosamine-condroitin supplements).

As for me, I bought a knee brace even though the AAOS says it doesn’t help. But it feels like it’s helping, and it was cheap. And my knee is definitely feeling better. Why not take advantage of a placebo effect once in a while?

MMR vaccine (still) doesn't cause autism, new study finds

Nope.
We’re still spending vast amounts of time and money trying to counter the ill effects of a discredited, retracted paper from 1998 that claimed to find a link between the MMR (measles, mumps, and rubella) vaccine and autism. Even after the The Lancet retracted the study, and even after the British Medical Council revoked the medical license of its lead author, Andrew Wakefield, many people continue to withhold vaccines from their children because of a fear that somehow, despite all the evidence to the contrary, vaccines might cause autism. Vaccines, I hasten to add, have saved millions of lives and are probably the greatest medical advance of the past two centuries.

Now another study has appeared to add more weight to the evidence about the safely of the MMR vaccine. The new study by Anjali Jain and colleagues, just published in the Journal of the American Medical Association, looked at a huge number of children–95,727–for evidence of any link between autism and the MMR vaccine.

The results were not surprising, to those who have been following the science. To quote the conclusions directly
“Receipt of the MMR vaccine was not associated with increased risk of ASD [autism spectrum disorder], regardless of whether older siblings had ASD. These findings indicate no harmful association between MMR vaccine receipt and ASD even among children already at higher risk for ASD.”
That should settle it, right? But then, dozens of previous studies should have already settled this question. Unfortunately, due to the ongoing activism of anti-vaccine groups such as Age of Autism, (who already attacked this new study) and to conspiracy theorists such as Robert F. Kennedy Jr. (whom I wrote about last summer, and who was campaigning against vaccines in Vermont just last week), misguided claims that vaccines cause autism or neurological problems persist.

Here are the numbers from the new study. The authors compared vaccinated children to unvaccinated children, using a huge database of medical claims that included at least 5 years of followup. (This was an "observational" study, by necessity–it would be unethical to withhold vaccines from children on purpose.) The relative risk for autism in children who had 2 doses of the MMR vaccine (the recommended amount) compared to unvaccinated children was 0.74. In other words, a child was somewhat less likely to be diagnosed with autism if he or she were vaccinated. 

Even more surprising was the relative risk among children who had an older sibling with autism: in this smaller group, children with 2 doses of MMR were just 44% as likely to be diagnosed with autism as unvaccinated children. This statistically significant finding indicates, unexpectedly, that vaccines might actually protect children from autism.

The authors were quick to note that there are other good reasons for this apparent protective effect of vaccines: in particular, if parents of autistic children withheld vaccines from their younger children, this could explain the effect. Why? Because we know that autism has a genetic component, and that if one child has autism, his younger sibling is more likely (because they share many genes) to have autism as well. Jain and colleagues explained that if these parents withheld vaccines–because of fears spread by the anti-vaccine movement–then their children could contribute to the apparently lower rate of autism in children who were vaccinated. The authors couldn’t rule out a protective effect of vaccines, but scientifically it seems unlikely, and they wisely offered an alternative explanation.

So: once again we have a large, carefully conducted study showing that the MMR vaccine does not cause autism, and even finding evidence that vaccinated children have lower rates of autism. Let's hope this study helps to end the anti-vax movement, so that we can soon stop spending time and money trying to refute their long-discredited hypotheses and instead focus on trying to understand the true cause.

DNA testing offers a far better way to detect Down syndrome

The results of a new study offer very good news for expectant parents: a remarkably accurate prenatal genetic test for Down syndrome that requires only a blood sample from the mother.

Expectant parents have a lot to deal with. What can a mom-to-be eat, drink, or do to ensure the health of the baby? There is plenty of advice out there, both good and bad, but one area that has advanced rapidly in recent years is prenatal genetic testing. We now have tests that can identify a small but growing number of genetic disorders early in pregnancy.

Until recently, the only way to test the genetic makeup of a fetus was through amniocentesis ("amnio"), an invasive procedure in which a doctor inserts a long needly directly into the womb and collects a sample of amniotic fluid. This test is not only uncomfortable, but it also carries a small risk of miscarriage. Fortunately, it may soon become completely unnecessary, thanks in part to advances in DNA sequencing.

It turns out that small amounts of fetal DNA are circulating in the mother's blood from a very early point in pregnancy, just 10 weeks along. New technology allows us to take a simple blood sample from the mother and use that to examine the baby's DNA to look for trisomy–the presence of 3 copies of a chromosome rather than two. The new study primarily looked at trisomy 21, which causes Down syndrome, but it also looked at the ability of DNA screening to detect other trisomies.*

The new study by Mary Norton and colleagues, by far the largest of its kind to date, involved almost 19,000 women at 35 locations in 6 different countries, all of whom were undergoing routine prenatal screening. The study compared the standard blood test, the "triple screen", to a new cell-free DNA sequencing (cfDNA) test from Ariosa Diagnostics (recently acquired by Roche). I wrote about a similar study involving 1914 patients last year, which used the same kind of DNA testing. The new study is ten times larger, and the results are even better. All of the participants had both standard screening and DNA testing.

What did they find? First, the number of mothers who had both standard and cfDNA testing was 15,841. (For technical reasons, some of the 19,000 participants didn't get both tests.) Out of all pregnancies, there were a total of 38 fetuses with trisomy 21. Standard screening detected 30 out of 38, while cfDNA detected all 38. Much more impressive–startling, really–was the difference in false positives. The standard screen had 854 false positives, while cfDNA testing only had 9. This is nearly 100 times better.

Or to put it another way: among all the mothers, standard screening reported 884 "positive" results, of which only 30 were correct. Thus if you were a mom who got the standard screen, and you had a positive result, there was only a 3.4% chance that your baby would have Down syndrome. Nearly all of these mothers would probably elect amniocentesis to confirm, and go through the anxiety as well as risk of miscarriage that amnio entails.

The cfDNA test reported only 47 positive results, of which 38 were correct. Thus there was an 81% chance (38/47) that the baby will a positive result would have Down syndrome.

Although the numbers were smaller, cfDNA testing was also far more accurate for detecting trisomy 13 and 18, rarer conditions that cause health problems so severe that most infants die before reaching their first birthday.

With a false positive rate nearly 100 times lower than the standard blood test (9 versus 854 false positives), the superiority of DNA testing for prenatal screening is clear. Let's hope that we can soon replace the older blood tests and spare parents-to-be the anxiety and unnecessary follow-up testing caused by thousands of false positive results under the current standard of care.

*For those who want to understand the technical details, this paper by Sparks et al. (2012) explains the sequencing and statistical methods.




How disruptive are MOOCs? Hopkins launches new genomic data science series.

If you could visit a college classroom a hundred years from now, would you expect it to look just like one of today's classrooms?

I suspect not.

Yet if you walked into almost any college classroom today, you’d see a scene right out of the 19th century: students sitting in a classroom listening to a professor talk. Perhaps the professor is using a laptop to project slides, rather than writing on a chalkboard, but other signs of the 21st century can be hard to find. 

Of course the content today is different, particularly in the sciences–no one even knew what DNA was 200 years ago–but the way we teach has barely changed in the past two centuries.

Well, it’s changing now. The advent of massive, online open courses (MOOCs) is making high-quality content available to millions of people for the first time, and much of it is free. These online courses, even in their infancy, have generated a huge response, revealing the hunger out there for learning. 

Professors too are discovering something: how rewarding it is to reach thousands of students rather than just a handful. And capturing lectures on video allows us to mix and match material, updating just the parts that need changing and re-using the good stuff with relatively little effort. 

Hopkins joined the MOOC revolution last year, with a Data Science series of courses led by Brian Caffo, Jeff Leek, and Roger Peng. This June we’re launching a new specialization on genomic data science, that five of my colleagues and I are teaching. Coursera announced our 6-course specialization just a few days ago; Jeff Leek and Roger Peng produced a teaser video that you can watch here:


The specialization will cover statistics, Python programming, the Bioconductor and Galaxy environments, and more, all designed as a gentle introduction to genomic data science for students, postdocs, or even established scientists who want to start learning the tools behind genomics and “precision medicine.” 

Most of the videos are “in the can” and we’re doing the post-production now, creating the quizzes and projects that go along with the classes. Students can sign up now, but they'll have many chances to take the series. Once it launches, the classes will run every month, forever. (Okay, maybe not forever, but for a while.)

One of the first questions people ask me about MOOCs is, how can you offer all this content for free? Isn’t this a threat to the traditional university model?

You bet it is. But it’s happening, whether universities like it or not. As with other disruptive technologies, MOOCs are likely to change dramatically over the next few years, but they aren’t going away.

We're just learning how to deliver knowledge through MOOCs and we’ll get better at it. Right now MOOCs exist in a separate world from universities, but that’s likely to change. Maybe the experiment will fail, and MOOCs will fade away. Maybe that classroom in the year 2115 will look just like my classroom today. I’m betting it won't.


Ted Cruz is not as smart as Galileo, whatever he claims

Global temperatures for the past 125 years. It's getting hot!
The word in Washington lately is that Senator Ted Cruz–who just announced that he’s running for President–is supposed to be a very smart guy. Some of this comes from Harvard Law professor Alan Dershowitz, who said last year that Cruz was “clearly among the top students” at the prestigious Harvard Law School. Dershowitz is very liberal, while Cruz is very conservative, so one assumes that Dershowitz wouldn't say this if it weren't true.

Perhaps Cruz was an excellent law student. But when it comes to science, Cruz is no whiz kid. On the contrary, he seems to be woefully ignorant. We know this because despite his lack of expertise, he doesn’t hesitate to make sweeping pronouncements about scientific matters.

In just the past week, Cruz has weighed in on two major science issues, and he's been wrong on both. First, in an interview a few days ago with the Texas Tribune, Cruz stated that global warming isn’t happening. This wasn’t the first time he’s made that claim, but this time he threw in what’s known in skeptical circles as the "Galileo gambit," a well-known ploy of conspiracy theorists. He compared his global warming denialism to Galileo thusly:
Today, the global warming alarmists are the equivalent of the flat-Earthers. It used to be [that] it is accepted scientific wisdom the Earth is flat, and this heretic named Galileo was branded a denier.”
Cruz managed to get at least two things wrong in a single sentence here. 

First, Galileo did not become famous for arguing against flat-Earthers: he argued that the Earth revolved around the sun (the heliocentric model of the solar system) rather than the sun revolving around the earth (the geocentric or Ptolemaic model, after the Greek philosopher Ptolemy).

Second, Galileo was not a denialist, nor was he called one. He was not denying a vast array of scientific data to make his point–just the opposite, in fact. The data showed that the Earth and other planets revolved around the sun, and the Catholic church (among other institutions) didn’t want to believe it, and therefore they forced him to recant. The Church didn't call Galileo a "denier."

Cruz's statement is not just wrong: it's also arrogant. Cruz is comparing himself to Galileo, one of the greatest scientists in history, as if he (Cruz) were making a brave scientific stand against a dogmatic opponent. This is the crux of the Galileo gambit: the speaker claims to take a heroic stand against a powerful foe while defending the truth. Sorry, Senator Cruz: you’re no Galileo. Not even a little bit.

And let's not ignore Cruz’s scientific claim: that the Earth isn't getting warmer. Here's one of his quotes:
"And many of the alarmists on global warming, they’ve got a problem cause the science doesn’t back them up. And in particular, satellite data demonstrate for the last 17 years, there’s been zero warming. None whatsoever."
Oh good. Ted Cruz has evaluated the satellite data and figured this out. Who knew that he was not only a lawyer but also a scientist? Real climate scientists–who understand this issue far, far better than Cruz–disagree. For example, NASA and NOAA recently announced that 2014 was the warmest year on record. They also explained that 
“The 10 warmest years in the instrumental record, with the exception of 1998, have now occurred since 2000. This trend continues a long-term warming of the planet, according to an analysis of surface temperature measurements by scientists at NASA’s Goddard Institute of Space Studies.” (See the Figure.)
There’s no mystery about why Cruz and others deny global warming: the oil and coal industries have conducted a vigorous campaign for years now, primarily targeting Republicans, to cast doubt on the science. The reason is simple: fossil-fuel companies are worried that if we take global warming seriously, we might burn less fossil fuel. Their lobbying campaign is working: Cruz has certainly fallen into line.

Meanwhile, coastal areas are fighting rising sea levels, and the Arctic and Antarctic are melting. Lobbying might change the minds of politicians, but the planet doesn't care.

Now let’s look at the second bit of dodgy science that Senator Cruz endorsed this week. He announced his candidacy at Liberty University, a Christian fundamentalist college in Virginia that was founded by Jerry Falwell, an evangelical Southern Baptist minister. Liberty University’s Center for Creation Studies teaches students that the the Earth is only a few thousand years old and that all species were placed here by an all-powerful god, exactly as described in the Bible. Not surprisingly, students and faculty at Liberty University deny the facts of evolution. To a scientist, Cruz's appearance at Liberty University is an in-your-face endorsement of creationism.

I should be clear that Ted Cruz didn’t explicitly embrace creationism and deny evolution when he announced his candidacy, but he did choose Liberty University, and he must know its views about evolution. I wrote to Senator Cruz to see if he believed in young-Earth creationism, or if he believed that species evolved over millions of years, as science has demonstrated. He didn’t reply.

Virtually all of modern biology and medicine has its basis in evolution. No serious scientist disputes that evolution is by far the best explanation for the species around us, and for a thousand other phenomena that scientists study every day. The debate about the fact of evolution is long over. As a scientist, I find it just embarrassing to have prominent U.S. politicians publicly deny evolution.

Actually, I suspect that Ted Cruz isn’t really a creationist. I find it hard to believe that a guy who went to Princeton and Harvard, and apparently did quite well at both schools, can really believe the Earth was created 4,000 years ago. I also wonder if he truly believes that the world's leading climate scientists are just making stuff up about the Earth warming. Maybe he’s just pandering to his right-wing audience and his campaign donors.

Do politicians need to make decisions about science? Of course they do. But science can be incredibly complex and specialized. A good president (or prime minister, or governor) will identify experts–independent ones, without conflicts of interest–and seek their advice. Ted Cruz is no scientist, as his recent comments demonstrate, but I predict he won't be the only U.S. presidential candidate to make misguided remarks about science.

A true fountain-of-youth drug combo?

This is really, really interesting. Can we alleviate the effects of aging by getting rid of "bad" cells in the body?

A new study from the Mayo Clinic and the Scripps Research Institute reports that a novel cocktail of two unrelated drugs 
dramatically slows the aging process—alleviating symptoms of frailty, improving cardiac function and extending a healthy lifespan.” 
The scientists who conducted the study, led by James Kirkland, Laura Niedernhofer, and Paul Robbins, screened 46 different compounds to find ones that would interfere with the ability of senescent cells to survive. The two that seemed to work best were quercetin and dasatinib. They call these drugs "senolytic" for their ability to kill senescent cells.

Old cells are supposed to die and let the body replace them. Most of them do, but some cells become senescent: old geezers who just won’t go away. The problem is, these cells just don’t sit quietly in the living room reading a book. Instead, they make lots of noise, throwing things around that can mess up the living room and make all the other cells miserable. At a molecular level, they secrete enzymes that cause inflammation and other problems, which may explain the relationship between these cells and age-related chronic diseases such as heart disease and osteoporosis. 

This current line of research started about four years ago, when the Mayo Clinic's Jan van Deursen published a study (in mice) showing that if you could selectively destroy senescent cells, the mice had fewer age-related diseases and lived up to 25% longer. Senescent cells, it seems, are definitely a problem.

The challenge is that very few cells are senescent, even in very old people, and it's difficult to destroy these cells without harming all the healthy cells around them. In the new study, Kirkland and his team screened 46 different compounds to find ones that could interfere with what they called “pro-survival” genes in senescent cells. The theory is that the senescent cells have a special ability to survive, and if we can interfere with that ability, the cells will die.

The two compounds they found are very different. Quercetin is a common plant extract, found in a wide variety of fruits and vegetables, especially capers, red onions, plums, and cranberries. Dasatinib, in contrast, is a highly specialized cancer drug made by Bristol-Myers Squibb (NYSE:BMY) and sold under the name Sprycel®. Dasatinib is used to treat CML, a form of leukemia. Quercetin is cheap and easily available, while dasatinib is very expensive and cannot be obtained without a prescription.

The study results were very impressive: after a single dose, mice had improved heart function that lasted up to 7 months. Periodic doses worked too: mice showed improvements in a wide range of age-related symptoms, including bone loss, tremors, grip strength, and overall body condition.

Before everyone runs out and buys a giant bag of red onions (or a quercetin supplement), I should inject a dose of skepticism. Quercetin’s effect on lifespan has been studied before, and it came up short. A study in 2013 by Stephen Spindler and colleagues looked at extracts of blueberry, pomegranate, green tea, black tea, quercetin, and other plants, feeding each of them to mice in a controlled experiment. None of the mice lived longer, and Spindler reported that 
our results do not support the idea that isolated phytonutrient anti-oxidants and anti-inflammatories are potential longevity therapeutics.”

However, the method of delivery for quercetin and dasatinib in the new experiment was different, and the combination of the two might have benefits that quercetin alone does not offer. As Kirkland point out, dasatinib and quercetin “are both approved for use in humans and appear to be relatively safe,” although they then go on to point out a variety of possible side effects, some of them harmful. They end, though, on a remarkably optimistic note: 
If senolytic agents can indeed be brought into clinical application, they could be transformative. With intermittent short treatments, it may eventually become feasible to delay, prevent, alleviate, or even reverse multiple chronic diseases and disabilities as a group, instead of one at a time.”
Of course, results in mice often fail when we try them out in humans–but not always. Let’s hope this drug combination shows the same effects in humans that Kirkland and colleagues observed in mice. None of us are getting any younger.

NIH distorts report showing risk of stroke after chiropractic

Why would an NIH center try to mislead the public about a newly published study that it funded? Last month NIH’s alternative medicine center, NCCIH, highlighted one of its studies with this headline: “Low risk of stroke after chiropractic spinal manipulation in older patients with neck pain, study finds.” 

This sounds reassuring, unless you read the study. It turns out that the risk of stroke was 10% higher in patients who saw a chiropractor compared to those who saw a regular doctor. Yet NIH wants us to believe that the study found no serious risk.

Why ask this question? Because earlier studies showed a small but frightening risk of stroke in younger people (45 and below) after chiropractic, caused by dissection of the vertebral artery. Strokes caused by a tear in this artery are extremely rare, but even a tiny possibility of a fatal stroke after a chiropractic manipulation is alarming. As Forbes writer Larry Husten reported last August, the American Heart Association and the American Stroke Association issued a statement warning that chiropractic neck adjustments might cause strokes. The AHA stated:
  • "Manipulating the neck has been associated with cervical dissection, a type of arterial tear that can lead to stroke.
  • Although a direct cause-and-effect link has not been established between neck manipulation and the risk of stroke, healthcare providers should inform patients of the association before they undergo neck manipulation."
I’ve written about this as well, both at Forbes and in The Atlantic Monthly. The risk is small but the consequences can be extremely serious.

So what's in this new study? The study, led by chiropractor James Whedon at Dartmouth College, was a large-scale survey of Medicare claims involving people aged 66 to 99. Its aim was to answer this question: "what is the probability of stroke following chiropractic spinal manipulation, as compared to a control group of subjects evaluated for neck pain by a primary care physician?" Key findings from the study included these (all from Table 2):

                     Hazard ratio for stroke at 30 days
All patients         1.10 (10% increase)
Patients aged 75-79  1.93 (93% increase)
Patients aged 80-84  2.50 (2.5 times more likely)
Patients over 85     3.59 (over 3.5 times more likely)

This looks bad: for all patients, the risk of stroke was 10% higher if they'd seen a chiropractor versus a regular doctor. In the older patients, the risk of stroke after 30 days was 1.9 to 3.6 times higher than for patients aged 66-69. (All four of these results were reported as statistically significant.) Yet the conclusions of the study–and the NIH press release–make no mention of these findings. The study itself concludes only that 
Among Medicare B beneficiaries aged 66 to 99 years with neck pain, incidence of vertebrobasilar stroke was extremely low. Small differences in risk between patients who saw a chiropractor and those who saw a primary care physician are probably not clinically significant.”
Talk about spin! The study provides no support for the dismissive statement that the increase in risk of stroke after chiropractic is "not clinically significant"; it seems they are trying to downplay their own finding of a statistically significant increase in risk. The NIH’s press release is just as bad: it merely parrots the study's conclusions, opening with the statement that “cervical spine manipulation is unlikely to cause a stroke,” and never mentioning the statistically significant 10% increase in risk or that the study was led by a chiropractor.

Despite the misleading press release, this new study adds to the evidence that chiropractic carries an increased risk of stroke, especially for older patients. As the American Heart Association recommends, patients should be informed of this risk before submitting themselves to a possibly dangerous neck manipulation. And NIH press officers should read the study before issuing a press release.