On balance, these bits tend more to the positive than the negative, including a few positive items about COVID-19. (But then, it seems that most of the news about COVID-19 is on the positive side these days.) We’ll get to COVID at the end of this piece, but first I will report on a recent Lancet article that is not precisely bad news, but definitely of serious concern.

It is this: the number of global deaths directly attributable to antimicrobial resistance is high and on the rise. The Lancet paper puts it at 1.27 million for the year 2019 and predicts that at the current rate it could reach 10 million per year by 2050. (Lancet 2022:399;629-655, “Epidemic of Antimicrobial Resistance”)

As we would expect, Lancet is super-thorough in its methods. The study was conducted in 204 countries and based on 471 million individual case records, and investigated 88 different pathogen-drug combinations. The authors took the trouble to distinguish between what they called “deaths directly attributable to antimicrobial resistance” and those “associated with antimicrobial resistance.” The numbers of the latter were about four times higher.

The most frequent types of infections were, first, lower respiratory infections; second, blood stream infections; and third, intra-abdominal infections. This, I note, is exactly what we would expect. Six pathogens were responsible for most of the deaths in the study. These were Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. One single pathogen-drug combination, methicillin-resistant Staph aureus (MRSA) was the direct cause of more than 100,000 deaths in the study.

The antibiotics most affected by antimicrobial resistance are the fluoroquinolones and the beta-lactams. Again, this is not a surprise. Fluoroquinolones are the class that includes ciprofloxacin, levofloxacin, and any other drug that has –floxacin in its name. The beta-lactams are the penicillin family of drugs, including amoxicillin and all the other –cillins, as well as cephalosporins and carbapenems. These two classes of drugs take up a huge chunk of the pharmacopoeia.

Interestingly, about half-way through the Lancet paper, the authors stop using the term “antimicrobial” and shift to “antibiotic.” That’s because the specific drugs to which pathogens most frequently demonstrate resistance are all antibiotics, and not just antimicrobial. Any substance that kills germs of any kind – alcohol, peroxide, iodine – can be used as an antimicrobial. But pathogens do not develop resistance to those antimicrobials. Drugs that attack viruses are antimicrobials, but because viruses are not always considered to be living things, these drugs are not called antibiotics. Antibiotics specifically target living pathogens, disrupting essential parts of their physiology.

The Lancet paper concluded with five fairly obvious recommendations:

• Infection prevention
• Widespread vaccination
• Reduce exposure to antibiotics unrelated to human disease
• Minimize use of antibiotics when unnecessary
• Invest in research on alternative agents

The first two recommendations would fall under the age-old maxim “An ounce of prevention is worth a pound of cure.” No need to prescribe antibiotics to people that aren’t infected with something.

“Reduce exposure to antibiotics unrelated to human disease” clearly means “stop giving antibiotics to farm animals,” because these antibiotics wind up in the environment, and that plays a big part in exposing germs to the antibiotics so that they develop resistance before they get close to infecting a human.

“Minimize use of antibiotics when unnecessary” is a major challenge. A great deal of antibiotic use is under the term “empiric prescribing.” That means that the patient has symptoms suggestive of a particular illness, and the prescribing physician starts the patient on an antibiotic without having done tests to identify the specific pathogen. This happens all the time. The physician wants to get the patient on a drug as soon as possible, before the symptoms get worse. In a few days, the patient gets better. He/she might have had a bad cold, or possibly the flu. The drug was not necessary.

This scenario takes place frequently with children who have symptoms that might be one of many common pediatric ailments. Parents expect the doctor to give the kid some kind of a pill. Even if the doctor is fairly confident that the child has a common virus, which would not in the least be affected by an antibiotic, there is the possibility that the infection is bacterial, so the doctor prescribes a common antibiotic, with clear instructions that the child finish the course. But after a couple of days, the kid is just fine, and the parents see no reason to keep pushing the pills. So the prescription is unfinished.

But this patient – like just about every single one of us on Planet Earth – does have some pathogens in his/her system. The pathogens are exposed to this antibiotic for a few days. Some of the pathogens die, maybe even most of them. But the ones that survive are ones that have something in their genetic makeup that helps them avoid the effects of the antibiotic. Those pathogens survive – “the survival of the fittest” – and multiply, passing on whatever physiologic characteristics that permitted them to escape the antibiotic. Thus is born a resistant strain.

Should the physician have refrained from prescribing the drug to the patient until the necessary tests results came back? In the long run, if every physician on the planet did that with every patient, antibiotic resistance would likely diminish. However, the consequences for some patients might be considerable. We might then be tallying deaths from delayed antibiotic prescriptions.

Another problem that arises when patients get better and do not take their medication for the full prescribed course is that the pill bottle goes back in the medicine cabinet. Then, when somebody in the household has similar symptom, there’s a temptation to take one of those nifty little pills that knocked the symptom out in a couple of days last time. And so more pathogens develop resistance.

The moral of this story is, “finish the course of treatment.” If we keep hitting those pathogens with the drug, there’s a good chance that we’ll kill them all. As some doctors point out, “dead bugs don’t mutate.”

“Invest in research on alternative agents.” The authors note that government investment in this area of public health has been small in comparison with investment in other areas. In other words, since the pharmaceutical companies are not spending a whole lot of their money on developing new antibiotics targeting resistant pathogens, perhaps the governments need to step in.

Pharmaceutical companies have excellent reasons not to invest huge sums in developing new antibiotics and bringing them to market. The prospects for recovering their investment are not rosy.

Precisely because much antibiotic prescription is empiric – that is, prior to ascertaining the pathogen – and because empiric drug use is more likely to lead to antibiotic resistance, the responsible medical practitioner will refrain from prescribing the new antibiotic that is effective against resistant bacteria unless he/she has evidence of the specific pathogen causing the patient’s illness, and also that the infective pathogen is likely to be antibiotic resistant. New highly effective antibiotics that circumvent resistance tend not to be used empirically, and thus tend to be underprescribed. They are reserved for illnesses where nothing else will work.

This is not a scenario for a big money-making antibiotic.

The Lancet paper, as I mentioned earlier, is very thorough, and its conclusions are of serious concern. Of equal concern is that the recommendations in that paper are so far from original as to be almost clichés. Many knowledgeable people have for decades been urging the livestock industry to quit using antibiotics, with limited success. Similarly, doctors have been lectured about prescribing antibiotics too frequently. But doctors, faced with patients (and their families), tend to favor the treatment of the person facing them in the examining room over the abstract well-being of the population at large. And, yes, it might be a good thing if the research that goes into drug development could somehow be divorced from the profit motive.

Let’s move on to something else. Although I personally lost weight during the COVID-19 siege (no going to restaurants), lots of folks couldn’t keep their hands off the refrigerator door and have experienced added avoirdupois. Another recent Lancet piece evaluated a few of the pharmaceutical agents that offer assistance in shedding those extra pounds.

Which weight-loss drugs are most effective and safe?

This is not news of crucial importance, but some of us are bound to be curious about this subject. The information was in a review of previously published material. Lancet evaluated 14,605 citations in 143 clinical trials, which enrolled 49,810 participants. Overall, they found that all the drugs lowered body weight as compared with lifestyle modification alone – except for levocarnitine (Carnitor, from Sigma Tau Pharmaceuticals), whose primary use is not weight-loss, but compensating for carnitine deficiencies. (Carnitine is a form of fat abundantly present in many kinds of meat, but some people have a problem accessing carnitine even when it is present in their diets.) (Lancet 2022 “Pharmacotherapy for Overweight and Obesity”:399;10321:259-269)

The agent that was most effective in lowering body weight was phentermine-topiramate (Qsmya, from Vivus), which delivered a reduction in weight of about 8%, followed by GLP-1 receptor agonists such as semaglutide (Ozempic, from Novo Nordisk) and delaglutide (Trulicity, from Lilly) with 5% weight reduction.

Several of these drugs were associated with side effects of sufficient severity to lead to discontinuation. Naltrexone-bupropion (Contrave, from Currax), phentermine-topiramate, the GLP-receptor agonists, and orlistat (Xenical, from Roche, and Alli, from GSK)) were all affected by these side effects.

On balance, the Lancet study concluded that semaglutide provided the best trade-off between delivering weight loss and side effects.

Can surgery to remove cataracts help prevent the onset of dementia?

It makes sense that anything we can do to improve our connections with the world will help keep our minds up and running. Hearing aids make it possible for those of us who have become somewhat hearing impaired to keep communicating with others. We can hear and understand what they say. And we can, therefore, respond and keep the conversation going. Or we can at least think about it. The alternative is a vegetative stupor. The same thing might be said of eyesight.

This was confirmed in a just-published study that analyzed the relationship between cataract surgery and the risk of dementia among more than 3,000 older adults with either cataracts or glaucoma. None of these persons had dementia at the start of the study, which was published in JAMA Internal Medicine this February. (JAMA Intern Med 2022;182(2)134-141)

Here’s what they found:

• Compared with persons in this cohort who did not have surgery, the individuals who had cataract surgery had a 29% lower risk of developing dementia.
• This was not the case in the individuals who had surgery for glaucoma. But a crucial difference between those two procedures is that while cataract surgery restores vision, glaucoma surgery has no effect on vision.
• The authors were scrupulously careful about accounting for factors such as differences in underlying health or access to health care. After accounting for those factors, the results were the same.

If persons with untreated cataracts are more likely to become demented, what do we know about the connection between total loss of eyesight and dementia? I did a bit of digging with slim results. There seems to be some credible link between poor vision and dementia, and the cataract study would tend to confirm that. But between total blindness and dementia I found nothing. Doc Gumshoe’s guess (no more than that!) is that total blindness presents a huge challenge to the person, and that this challenge is met, more often than not, by summoning up all other possible resources. Helen Keller did not retreat into a vegetative stupor.

Vitamin D supplements reduce the risk of developing autoimmune diseases

Autoimmune diseases are very common, and while they are mostly not life-threatening, at least in the short term, they affect lives in a number of major ways. The most common autoimmune diseases are rheumatoid arthritis and type 1 diabetes, both of which lead to shortened life spans. Other autoimmune diseases include rheumatic fever, vitiligo, psoriasis, lupus, osteoporosis, Celiac disease, Graves disease, autoimmune thyroid disease, inflammatory bowel disease, and pernicious anemia. The autoimmune factor that plays a part in these diseases varies considerably, but in essence it is an error of mistaken identity on the part of our immune system, which mistakes human cells for hostile invaders and dispatches human immune cells to eliminate these mistaken cells.

The VITAL study that discovered the relationship between vitamin D and autoimmune diseases was initially launched to investigate the possibility that vitamin D might have protective effects against other diseases such as cancer, heart disease, and stroke. The results were published in the British Medical Journal on January 26, 2022. (BMJ. 2022; 376: e066452. doi: 10.1136/bmj-2021-066452)

VITAL was a randomized, double-blind, placebo-controlled study of 25,871 men (age 50 and older) and women (age 55 and older) across the US. Participants were randomized to receive either vitamin D with an omega-3 fatty acid supplement; vitamin D with a placebo; omega-3 fatty acid with a placebo; or placebo only. Prior to the launch of VITAL, investigators determined that they would look at rates of autoimmune diseases in addition to the original outcome measures. This was based on the known effects of vitamin D and omega-3 fatty acids in reducing inflammation.

Among patients who were randomized to receive vitamin D, 123 participants in the treatment group and 155 in the placebo group were diagnosed with confirmed autoimmune diseases, a reduction of 22%. In the omega-3 fatty acid arm, the reduction in autoimmune diseases did not reach statistical significance, but the study did find some evidence of an increased effect after longer duration of supplementation.

“It is exciting to have these new and positive results for nontoxic vitamins and supplements preventing potentially highly morbid diseases,” said senior author Karen Costenbader. “Now, when my patients, colleagues, or friends ask me which vitamins or supplements I’d recommend they take to reduce risk of autoimmune disease, I have new evidence-based recommendations for women age 55 years and older and men 50 years and older. I suggest vitamin D 2000 IU a day and marine omega-3 fatty acids (fish oil), 1000 mg a day — the doses used in VITAL.”

The results of the VITAL study look to be legitimate, and while a 22% reduction in the risk of developing an autoimmune disease doesn’t sound all that major, what it boils down to is that one in five individuals on the VITAL regimen can avoid a troublesome and definitely life-altering disease, using agents that are in no way risky. What the VITAL study did not get into was the mechanism through which vitamin D produced that effect. It would be worth further investigation.

A patient is given a vaccine tailored to prevent the return of cancer

The patient in this case is a UK resident who was first diagnosed with cancer of the head and neck in 2011. The initial treatment, which included facial surgery, reconstruction, and radiation therapy, seemed to have been successful. The cancer disappeared. But it returned in 2016, and then was treated four more times, each time resulting in temporary remission.

The patient has now been treated with a vaccine that directly addresses his genetic characteristics, specifically tailored to train his immune system to recognize the cancer cells and attack them before they have the chance to multiply and spread. In this regard, this cancer vaccine resembles the mRNA vaccines that have been used against the coronavirus that causes COVID-19. However, it differs in that this cancer vaccine is tailored to the patient’s immune system rather than to the characteristics of the invader.

The trial is being conducted by the Clatterbridge Cancer Center, in Liverpool, UK. The vaccine, designated TG4050, is made by Transgene, a biotechnology company based in France, whose focus is on designing and developing targeted immunotherapies for the treatment of cancer.

The Clatterbridge Cancer Center is planning to add more patients to the trial, not only patients with head and neck cancers, but with ovarian cancer.

This is another example of the potential of vaccines enabled by gene editing, whether through CRISPR or other modalities.

Two patients have been in remission for ten years after treatment with CAR T cells

Both of these patients had long-standing chronic lymphocytic leukemia (CLL), a form of cancer that starts in the bone marrow, where blood cells are formed. Cells that would normally become white blood cells (lymphocytes) start to grow out of control as they become cancer cells. These cells subdivide and grow, move into the bloodstream, and invade other parts of the body – the lymph nodes, the liver, and the spleen.

The symptoms of CLL may be slow to emerge, but ultimately leukemia cancer cells disrupt the function of those essential organs and end the life of the patient.

One of these patients was first diagnosed with CLL in 1996, and, as was (and still is) standard, was treated with chemotherapy. As we have discussed, chemotherapy takes advantage of the fact that cancer cells, since they grow and reproduce faster, take in more “nourishment” from the host than normal cells. Thus, if there is a substance that is toxic in the host’s body fluids, the cancer cells take in more of the toxic substance than normal cells, and as a result, may die while the normal cells survive. That’s why chemotherapy generally has unpleasant side effects.

After his CLL recurred, this patient was told that his best option was a bone marrow transplant – a procedure he was reluctant to undergo. As an alternative, he enrolled in a clinical trial in which he would be infused with his own genetically-modified T cells.

These T cells were modified using a chimeric antigen receptor (CAR) that had been constructed using CRISPR techniques. Two forms of T cells were generated in this way – CD4 cells, which are the ones that recognize the cancer cells, and CD8 cells that cause the death of the cancer cell, either through destruction of the cancer cells’ outer coating or by interrupting their reproductive process.

Several weeks after the first infusion of CAR T cells, about 20% of the white blood cells in this patient’s circulatory system were CAR T cells. About a week after that first finding, the patient was told that the treating physicians had not been able to find so much as a single cancer cell in his bone marrow. Now, ten years later, this patient is completely cancer-free, and the prevalence of CAR T CD4 cells has increased to 99.6%, while the prevalence of CAR T CD8 cells has steadily diminished. The implications of this is that the CD4 cells continue to be on the lookout for cancer cells, while the CD8 cells are in decline because there is no work for them to do.

One other patient had a similar outcome – no cancer cells ten years after the original treatment. The successful treatment of those two patients, although unquestionably cause for celebration, was something of an exception in the overall clinical trial, which enrolled a total of 41 patients, most of whom did not fare nearly as well as the two who retained complete remission for ten years . The reasons for these different outcomes are still unclear and will be the subject for further investigation.

What can we take from this experience? Simply put, that a cure for cancer through gene editing is possible. This is only the beginning.

A few COVID-19 updates

Like most of us, I am no longer avidly scanning all possible sources for something new about COVID. However, bits of news keep turning up and I do take notice.

Both the rate of new cases and the death rates have varied enormously between different countries. Take Hong Kong, for example, which had successfully kept COVID-19 infections to a minimum during these past two years, mostly by rigidly enforcing travel restrictions. Since about mid-February of this year, the daily death rate in Hong Kong has skyrocketed – about 4 per 100,000 residents. This compares with fewer than 1 per 100,000 in the US, as well as in Hong Kong’s near neighbors, South Korea, Singapore, and New Zealand. The greater transmissibility of the Omicron variant, as well as Hong Kong’s low vaccination rate, is considered to be the underlying causes of this surge in the death rate.

The new cases rates have also varied hugely, with countries such as the Netherlands experiencing peaks in new daily cases rates in mid-February to more than 600 new cases per 100,000 residents – more than 6 times the daily case rate in other countries like Germany, the UK, and Italy, and more than 10 times the daily case rate in the US. This, despite the vaccination rate in the Netherlands, where 70.9% of the population is fully vaccinated.

The main cause of this disparity is the emergence of a new variant of Omicron – the strain designated BA.2, which spread much faster in Europe than it has – so far, anyway – in the US. But it has arrived and is spreading in the US as well. As of today, 28 March, BA.2 is the likely cause of somewhere between a third and a half of all COVID cases. Overall, new cases in the US have dropped by more than 95%, but the spread of this new variant will likely reverse to some extent that falling new case count.

This increase in new cases will be limited by the fact that about 45% of the US population has already been infected with Omicron, and also by the percentage of the population that has been fully vaccinated and has received boosters. While this percentage is still far from optimal – 44.4%, according to CDC data – it significantly reduces the population that is apt to become infected and require hospitalization.

Booster shots make a major difference

It has taken some time for the data to emerge, but several studies have brought forward evidence that booster shots, especially the Pfizer/BioNTech and Moderna vaccines, trigger the production of a wider variety of antibodies that are also longer-lasting than the antibodies generated by the original two-dose vaccines. The antibodies produced six months after the third dose of a vaccine bind more effectively to the spike proteins of the coronavirus and are more potent neutralizers of the ability of the coronavirus to attach to host cells and produce an infection.

While antibodies recognize and bind to perhaps two or three key parts of that spike protein, the cellular immune system – B cells and T cells – recognize many more parts of the spike protein and last much, much longer. Antibody levels do decrease over time, but B cells and T cells that have been generated in response to earlier versions of coronaviruses have been found as long as 17 years after the initial infection, according to data as of 2020. And memory B cells can quickly trigger the production of specific antibodies that can help prevent infection with the virus that they remember and recognize – as well as calling up the killer T cells to attack the virus.

It is estimated that T cells produced after immunization with four of the current vaccines – Johnson and Johnson and Novavax as well as Pfizer/BioNTech and Moderna – confer approximately 80% protection against the Omicron variants as they do against the earlier versions of SARS-CoV-2. This was confirmed in a study published this January, in which it was demonstrated that T cells generated after vaccination recognized the Omicron spike protein as well as those of the Beta or Delta variants. (Keeton R. “T cell responses to SARS-CoV-2 spike cross-recognize Omicron,” Nature 2022 Jan 31 doi.10.1038/s41586-022004460-3)

It appears that immunity resulting from prior infection with the coronavirus is less consistently effective than immunity conferred through vaccination. Immunity resulting from previous infection can vary for a number of reasons, such as the original dose of the infective virus, and the immune responses mounted by the host. It has also been demonstrated a third dose of vaccine both broadens the effectiveness of the vaccine against variants and also increases the level of effectiveness.

Pfizer is seeking a second booster for older adults

Pfizer/BioNTech announced that they had applied for emergency use authorization for a second booster shot of their vaccine for older adults – that is, over the age of 65. Moderna has also suggested that a second booster would be a good idea for some patients, such as those who are immunocompromised. And many experts have said that eventually, annual shots against the coronavirus would be a good idea – much like annual flu shots.

Opinions on this emanate from all points of the compass. There are those who point out that the key target should be immunization of the most vulnerable, in the US and elsewhere, which is what will not only protect the multitudes from illness and death, but also reduce the breeding pool for dangerous variants. There are those who observe that, while immunity from infection declines as antibodies wane, protection against severe illness and death remains robust. And there are those who dispute the data supporting second boosters or fourth shots mostly comes from Israel, and did not provide evidence about the duration of protection from the second booster. Finally, there is the “who pays” question – Federal funds are running short, and further appropriations are bound to be contentious.

As for Doc Gumshoe, he would get another booster in a jiffy if one was available.

… and, by the way, the latest on the J & J vaccine is pretty good news

It appears that the single-shot Johnson & Johnson vaccine is doing about as well as the Pfizer/BioNTech and Moderna vaccines at preventing serious illness and death. The antibodies produced by the J & J vaccine decline more slowly that the ones generated by the mRNA vaccines, and there are reports that those antibodies become more sophisticated over time – meaning that they recognize more parts of the coronavirus spike protein, due to a biological process called affinity maturation.

This is good news for several reasons – and not just for J & J. For one, the J & J vaccine does not need to be refrigerated. And for another, it’s a single-dose vaccine. These characteristics make it a much more practical vaccine, especially in parts of the developing world, where the logistics of administering the current mRNA vaccines are, to say the least, highly challenging.

All in all, Doc Gumshoe thinks these developments strike a cheerful note.

*****

That’s all, folks! Let me know if there’s anything that you’re curious about in the healthcare/medical field & I will sleuth to the best of my ability. Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers a couple times a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]