It’s easy to take for granted today the revolution in non-invasive medicine over the last century. Prior to the 20th century there was no blood testing to monitor health or diagnose disease. The first clinical use of X-rays was in 1896. The only way to peer into the body prior to that was with auscultation – listening to the sound various organs made, like heart sounds, the lungs breathing, and bowel sounds. Substances that came out of the body could also be examined.  A physical examine could sometimes feel what was under the skin, not but deep or beneath bones. There was essentially very little that could be done to non-invasively examine what was happening inside the body. Surgery was the last resort – you had to open up the body and look inside if you needed to see.

Today modern medicine has a long list of options, including using X-rays, magnetic fields, electrical signals, ultrasound, radioisotopes, and tiny cameras to non-invasively or minimally invasively look inside the body. This is all in the last century, a tiny slice of human history. We are also still on the steep part of the curve in terms of increasing our ability to diagnose and treat disease non-invasively. There are frequent incremental advances in the various technologies, and they are adding up over time.

One such incremental advance, which may expand the utility of an entire diagnostic technology, is wearable ultrasound. Ultrasound uses high frequency sound which is projected into the body, usually with a small hand-held probe which is pushed against the skin through a conducting gel. These sound waves bounce back and are picked up by the probe, which sends the information to a computer to construct an image. Anyone in a developed nation who has had a child since 1956 when the technology was first developed is likely familiar with this.  Ultrasound is safe, minimally invasive, and can provide a wealth of useful data. It can examine more than fetuses, but can also look at heart function with sufficient detail to detect how the valves are working. It can examine blood vessels to look for clots, or to see if they are open and how they react to stimuli. Ultrasound can be used to look at other organs, to detect cysts or tumors, and to examine the lungs.

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It is a frustrating reality that much of the cool technology we read about today will not be ready for widespread use for another 20-30 years. And of course not all such technology will pan out – but even when there is a high confidence level that they will, it will likely be decades before they change our lives. The cool technology I read about in popular science magazines in the 1980s didn’t really hit until the 2000s, and the advanced medical technology I learned about in medical school in the early 1990s didn’t mature until recently. So keep that in mind as I discuss this incremental advance in medical millirobots.

A millirobot is literally a millimeter size robot. The challenge of designing robots this small is to pack into that small size significant functionality. One method of getting such small robots to do stuff is origami technology – the robots can change their shape by folding and unfolding. Shape changing can accomplish specific tasks, such as locomotion, or package delivery. The advance here is to allow the millirobot to perform several tasks at once with the same origami feature, therefore packing more functionality into a tiny space.

Here we report a magnetically actuated amphibious origami millirobot that integrates capabilities of spinning-enabled multimodal locomotion, delivery of liquid medicine, and cargo transportation with wireless operation.

These tiny robots can therefore be controlled wirelessly. Further they can move both through liquid and over solid surfaces. And finally, the shape changing can deliver a liquid to a target destination. All of this is accomplished with the same origami feature, allowing for increased function while maintaining a small size.

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The technology of CRISPR (clustered regularly interspaced short palindromic repeat) continues to advance as a rapid pace. A recent study, Cas9/Nickase-induced allelic conversion by homologous chromosome-templated repair in Drosophila somatic cells, provides the potential for a new method of treating certain kinds of genetic diseases. This approach also appears to be safer, with fewer off-site genetic changes, but still has to be tested in humans.

CRISPR works by pairing it with a guide RNA (gRNA) that targets a specific sequence in the DNA, and with a Cas9 endonuclease which will cleave the DNA at the target site. The normal DNA repair machinery will then fix the cut, but there are two basic pathways for this to happen. The first pathway (nonhomologous end joining – NHEJ) blindly reconnects the ends together, creating the potential for the introduction of random mutations at the repair site. This is considered an error-prone repair pathway. The other pathway is homology-directed repair (HDR), which uses the other copy of the DNA as a template, and is therefore much less prone to error. Remember, every cell has two of every somatic chromosome, one from each parent, and therefore two copies of every gene.

The researchers in the current study wanted to know if the HDR pathway could be exploited to not only repair the cleaved DNA but also to make the repaired copy of the gene look like the other copy, the “homologous” gene. Some genetic conditions or traits are dominant and others recessive. A dominant trait will manifest if an organism has only one copy of that trait, which a recessive trait requires that both copies of the gene have the trait. The classic example is eye color (this is an oversimplifcation, but demonstrates the point). Brown eye color is the dominant allele (gene version), while blue is recessive. A person with one brown and one blue allele will have brown eyes (dominant). You need two blue alleles to have blue eyes (recessive).

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Sound can be a powerful form of energy, and is often underappreciated. Remember the weirding modules in Dune, that focused and amplified sound as a weapon? That is not an unrealistic technology. If you are near a powerful explosion, even without being exposed to heat or shrapnel, you can be killed by the pressure wave alone, which can cause significant internal damage.

Sound has also been used for years as a medical tool. You are probably most familiar with ultrasound technology, a non-invasive and safe way to image living tissue in real time. Many parents are familiar with this technology, as it is safe enough to image a growing fetus. But sound can also be used medically to destroy, and this application has many potential advantages.

One such technique is called High-Intensity Focused Ultrasound, or histotripsy. This is the latest approach to using sound to destroy unwanted tissue inside the body. There are older techniques that would use sound wave to heat up tissue and cause thermal damage. Histrotripsy uses a different method, and early research suggests this is a potentially significant step forward. The basics of the technology is the use of two highly focused beams of very short (<50 microseconds) bursts of high intensity sound. Where the beams cross, I am assuming through constructive interference, the intensity is great enough to cause cavitation within the tissue.

Cavitation is negative pressure that will cause a bubble of gases to expand inside the cells. These bubbles then collapse, resulting in significant mechanical stress on the cells that destroy them. Repeated applications of the histotripsy over the same area causes these areas of cavitation to coalesce into one large area filled with “liquified homogenate” – i.e. goo. This process can be targeted by simultaneous ultrasound imaging (the cavities appear bright on ultrasound), which makes the entire setup fairly portable and convenient.

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“Nanotechnology” is one of the buzzwords of our time. It is used the exact same way “space age technology” was used in the last few decades of the 20th century, and to a lesser extent even to today. It creates a marketing halo of advanced cutting-edge technology, but it’s not clear what it actually means. The term has loosely been used to refer to any tech that involves any component that has one dimension which is between 1-100 nanometers (nm). If only one dimension is in this size range then we are dealing with a nanosheet, and if one of the remaining two dimensions is a lot longer than the other this is a nanoribbon. If two dimensions are in the nano range then that is a nanofiber (long) or nanorod (short), and if it’s hollow then a nanotube. If all three dimensions are between 1-100 nm then that is a nanoparticle.  The nanoparticles themselves could be anything. Since many natural substances have features in this size range, it’s easy to invoke the “nanotechnology” buzzword. For this reason synthetic machines that operate on the nanoscale have been dubbed “molecular nanotechnology” to distinguish this from the now overused regular nanotechnology label.

That said, the ability to determine and control features of objects at the nanoscale is incredibly useful, and in many areas of material science is taking our technology to the next level. We are not yet at the point where we can create sophisticated nanomachines to do our bidding at the nanoscale, but that is the long-term goal. In the meantime we are finding lots of uses for nanoparticles, specifically in medicine. It has been argued that biology is nanotechnology, and if we want to interact with biological systems at their most fundamental scale then we need to get down to the nanoscale. One potential application of nanoparticle medicine is to reduce internal bleeding.

Trauma is the number one cause of death in people 45 years of age and younger. Internal bleeding is a major contributor to trauma-related death, because it may be difficult to identify prior to getting to a hospital, and it may be difficult or even impossible to stop the bleeding by applying pressure. In fact there are technical terms for such bleeds, such as noncompressible torso hemorrhage (NCTH). But what if we can help stop the bleeding from the inside?

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Most people I know, whether personally or as my patients, want to take positive steps to improve their health and quality of life. Unfortunately, many people who make a decision to get healthier rely on information in the popular culture and being promoted by the self-help industry. Much of this information is wrong or misleading. When people want to improve their diet, they often tell me they only eat organic whole foods, or perhaps they go paleo or raw if they are really motivated. But these changes are worthless – just expensive distractions.

Older patients concerned about their memory and cognitive function tend to focus on two things, diet and “brain games”. As I have discussed before, brain games basically don’t work. If you play Wordle, you get better at Wordle. That’s it. Diet is a little more complicated, as some people, especially older adults, may be deficient in certain nutrients, particularly B12. Even here people get distracted by the notion of “super foods” or some magical supplement. The reality is, for most people, just have a good well-rounded diet and eat plenty of fruits and vegetables. Vitamin B12, however, largely comes from meat. It is also a difficult vitamin to absorb (it requires a cofactor) and some people have impaired absorption or it wanes as they get older. The solution here is to get regular checkups with your PMD, who will check your B12 level and supplement if necessary. You may even need a B12 shot if your GI absorption is really impaired.

But we haven’t even discussed the factors that have perhaps the greatest effect on the cognitive function of healthy adults. I emphasize healthy, because if someone has a disease that affects their brain function that is a separate issue. Perhaps the most significant single factor affecting memory is healthy adults is sleep. Often sleep gets difficult as we get older for various reasons. People become accustomed to chronically poor sleep, and underestimate its affect on their cognitive function and memory. So step one should always be – fix your sleep. You may be able to do this with improved sleep hygiene, but if this doesn’t fix the problem again you need to see your doctor. You may have a sleep disorder, such as sleep apnea (difficulty breathing when asleep), and this will wreak havoc on your memory. Some people also struggle with anxiety and depression, and this can impair memory and focus. So address those issues as well.

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The Twitterverse is outraged, appropriately, it turns out, that Florida Acting Surgeon General Joseph Ladapo, who is undergoing confirmation hearings, refused to state when asked directly four times, that the COVID vaccines are safe and effective. At first he straight-up dodged the question, saying, “The question is a scientific one.” Uh, yeah, and you’re an MD, PhD with a degree in public health (i.e. a medical scientist) so answer the question. When pushed repeatedly he finally did answer that the vaccines have:

“reasonable effectiveness for the prevention of hospitalization and death” and “relatively low effectiveness for prevention” against transmission over time.

This is not accurate. They have extremely high effectiveness at preventing hospitalization and death. The risk of dying from COVID is 53 times greater for those who are unvaccinated vs those who are fully boosted.  Regarding prevention of transmission, Ladapo is narrowly correct but misleading through selective reporting. Studies show that a fully vaccinated person has a relative risk of 0.32 of passing on the virus compared to an unvaccinated person (so an unvaccinated person who gets COVID is 3 times more likely to pass it on). This is not “low effectiveness”, but the same data does also show that this protection wanes over time, and is mostly gone three months after the second shot. However, this is for vaccinated but not boosted individuals. Other studies show that boosted individuals have a 93% relative reduction in their risk of contracting COVID (even Delta), either symptomatic or asymptomatic, and of course people who never catch the virus cannot pass it on.

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David Bennett, 57, had terminal heart disease. He was bed-ridden and kept alive on a heart machine for the last six weeks, a temporary measure at best. He was deemed too sick for a donor heart transplant, which are in limited supply and given to the patients most likely to benefit from them. Essentially, his options were over and death was imminent and unavoidable. For this reason he was considered a viable candidate for an experimental procedure, and the FDA granted emergency use authorization under its compassionate use guidelines.

On January 7th he received a heart transplant from a pig that had been genetically modified to minimize rejection. This is a true milestone – the first successful transplant of a living organ from a non-human donor into a living human (organ xenotransplantation). The reason for the caveats are the fact that pig valves are routinely transplanted into people, but these valves are fixed and therefore not living tissue. Also, you may remember the girl with the baboon heart, Baby Fae, an infant who received a baboon heart in 1984. She lived for 21 days, but this was not considered a viable procedure, which is why it was not repeated. Also, last year a genetically modified pig kidney was transplanted into a human, but they were brain dead at the time.

It remains to be seen how long David Bennett with survive with his new pig heart. Rejection is still a major issue, and he will need to be on powerful immunosuppressant drugs. There is also a reason he was not considered a good candidate for a human heart transplant. But even if the procedure is moderately successful this would represent a true milestone, our entry into the age of routine organ xenotransplantation with genetically modified organs.

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The COVID-19 pandemic is not done with us yet. We are still in the middle of the delta surge, and while delta will eventually pass, the omicron variant is right on its heels. In the US we just passed the milestone of 800,000 people dead from COVID with over 50 million cases. More Americans died of COVID in 2021 than in 2020, although in 2021 most deaths were among the unvaccinated. The vaccines remain our best defense against this pandemic, which is why it is tragic that there are still holdouts for tribal or ideological reasons. Regardless, it is extremely likely that we will be dealing with COVID through 2022. It is also likely that COVID is now endemic, and while it may fade down to flu-like proportions, we will also very likely have to deal with it for years to come. COVID is also likely not the last respiratory pandemic we will have to deal with this century.

All of this is why masks are still important. We just have to accept the fact that face masks are now an important part of life. At least for the foreseeable future we will need face masks as a layer of protection in health care settings, large indoor crowds, among vulnerable populations, and for anyone who is symptomatic. Walking around in the public maskless, sneezing and coughing from a “cold” is no longer socially acceptable. If you want to avoid the mask in small or outdoor crowds and in gatherings of family and friends, then get fully vaccinated. But even then, there are some situations where masks provide an extra needed layer of protection.

There are at least two important questions relating to mask wearing. The first is – do they really work? The short answer is yes, they do. But obviously there is some complexity here. When worn properly, and in the right setting, masks provide a measurable level of protection from a respiratory infection. They protect you and they protect others. The latest evidence to support this conclusion looked at countries with and without face mask policies. They found:

Average COVID-19 mortality per million was 288.54 in countries without face mask policies and 48.40 in countries with face mask policies.

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Experts knew, and had been warning, that delta was not going to be the last Greek letter to sweep across the world. The World Health Organization (WHO) tracks variants of the SARS-CoV-2 virus which causes COVID-19. They track variants of interest (VOI) which have been identified as potentially problematic, and variants of concern (VOC) which have been demonstrated to have either increased infectivity, increased illness severity, and/or evasion of preventive measures (such as vaccines or masks). These variants are given a Greek letter designation as they are added to the list. What is now called the omicron variant has been added to the list of VOC. Here’s what we know so far.

The virus appears to have originated in South Africa. Fortunately, South Africa has a robust surveillance system and labs that can grow the virus and do a whole-genome sequence. They were therefore able to identify the variant quickly and share their information with the world. This isn’t the first variant to originate in South Africa, which raises the question of why this is the case? Increased surveillance may be part of the answer, but is not able to fully explain why. Some scientists speculate that South Africa’s large population of HIV infected and inadequately treated people provide a fertile breeding ground for new variants.

Variants are caused by mutations in the virus genome, some of which may alter proteins and therefore viral functions. SARS-CoV-2 does not have a particularly high mutation rate, but because we are having a world-wide pandemic there are lots of opportunities for new mutations to occur. It’s possible that when a person has a prolonged infection the viruses in their system are under selective pressure, so any mutation that might partly evade the immune system will be favored. Those with untreated HIV have an impaired immune response. This may be just enough to provide some selective pressure but not enough to fight off the infection, creating a breeding ground for new variants.

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