A double dose of vexation afflicts me as I once again take up the COVID 19 cudgels. Firstly, I was hoping and expecting that by this time COVID would have receded into the past and no longer be of much concern. Clearly, I was wrong. But secondly, both my wife and I got hit (once again) with the cursed disease. My case was milder than my wife’s; I did not have to take to my bed, but I did get rebound, which was triply vexing because it forced us to miss two concerts which we had been anticipating for months – Handel’s “Rodelinda” and an all-Vivaldi concert, both at Carnegie Hall.

What’s happening on the COVID front?

We seem to be experiencing a slight surge. Data regarding new cases is scarce, probably because most new cases are unreported. The most recent hospitalization data from the CDC reports a 20.4% increase in the period from November 11th to December 30th of this past year. However, compared with previous points in time, the hospitalization rate is fairly low. As of December 25th, there were 4.8 hospitalizations per 100,000 population, compared with 12.8 a year prior to that, and 56.5 hospitalizations per 100,000 population in January of 2022. That’s a big decline in hospitalizations, which is excellent news, but COVID hasn’t gone away.

The COVID adversary keeps changing its spots. Just about a month ago, the latest news was that a variant labeled BA.2.86 was growing rapidly. In late October, it was the cause of about 3% of new cases, but by the end of November it was thought by the CDC to be the cause of about 13% of cases in the Northeast. That’s a CDC estimate. Very few COVID cases are precisely pinned to a specific viral variant. The CDC bases its estimates on analyses of waste water. If 13% of the COVID virus particles in the waste water are the BA.2.86 variant, the CDC assumes that BA.2.86 was the cause of about 13% of the COVID cases in the span of time preceding that analysis.

BA.2.86 is a subvariant of Omicron, which was the dominant COVID variant a couple of years ago. The CDC has stated that BA.2.86 doesn’t appear to be driving increases in infections or hospitalizations, and the CDC and the World Health Organization believe that, compared with other variants, the BA.2.86’s risk to public health is low for severe illness. But on Aug. 21, WHO reclassified BA.2.86 as a “variant of interest” amid global increases. Updated COVID-19 vaccines are expected to increase protection against BA.2.86, the CDC said.

That was the situation at the end of this past November. At that time another subvariant, JN.1 had been detected, but was thought to be rare. That picture changed very quickly. By mid-December, JN.1 was estimated to account for 21% of new cases in the US, and in the Northeast according to the CDC it was the cause of an estimated 32% of the new COVID cases.

Dr Mandy Cohen, the director of the CDC said (on ABC News), “We know that the COVID virus continues to change. And even in the last few weeks, it has changed again. The good news is that, that new change to the virus…one, we can still pick it up with our tests. Two, our treatments are still effective against that change. And importantly, the updated COVID vaccine that you can get right now is still good coverage for those changes – we’ve seen that in the lab.”

And now, a couple of weeks later as I write this, JN.1 is the fastest growing variant and the dominant one. Based on its findings, the CDC estimates the variant is now responsible for between 39% and 50% of all COVID cases, up from the previously reported 15%-29%.

The CDC estimates that JN.1 is strongest in the Northeast U.S. including New Jersey and New York, where it accounts for nearly 57% of cases. In the West (Arizona, California, Nevada), it accounts for about 41%, and in the mid-Atlantic (including Maryland, Pennsylvania, Virginia, and West Virginia), JN.1 accounts for about 39% of cases.

At present, fewer Americans are getting vaccines against COVID-19, flu, and other viruses such as respiratory syncytial virus (RSV), which was previously thought principally to affect children but is now causing illness in adults as well. The CDC last week issued a health advisory to medical caregivers saying that low vaccination rates “could lead to more severe disease and increased healthcare capacity strain in the coming weeks.”

The CDC further stated that “At this time, the spread of JN.1 does not appear to pose additional risks to public health beyond that of other recent variants. CDC is closely monitoring COVID-19 increases domestically and internationally and will communicate if the situation changes.”

New and ongoing COVID hospital admissions, COVID diagnoses in emergency rooms, and the percentage of test results positive for COVID, have risen steadily since November through the week ending December 30. But they remain far, far below the highest rates seen in the peak of the pandemic, according to the CDC. So, yes, the COVID-19 pandemic is waning, but it hasn’t gone away. We’ll keep watching.

Paxlovid – effectiveness versus the rate of rebound

Paxlovid consists of two separate drugs, nirmatrelvir and ritonavir, packaged together. It was granted Emergency Use Authorization in December of 2021, based on clinical trials in which high-risk patients with COVID taking the combination had an 88% reduction in hospitalization or death. At that time, there was little or no data regarding the possible benefit of Paxlovid in vaccinated persons. Just a couple of weeks ago, a study in Annals of Internal Medicine (https://doi.org /10.7326/ M22-2141) based on patients in Mass General Hospital Brigham confirmed that the drug is associated with a 44% reduction in hospitalization or death in a highly vaccinated population of adults over the age of 50.

A closer look at the study elicits a degree of skepticism. In the study population of about 45,000 persons, about 28% were prescribed Paxlovid. These individuals tended to be older, have more comorbidities, and be vaccinated. In this cohort, just 69 patients (0.55%) experienced the composite outcome of hospitalization or death, in comparison with 310 patients (0.97%) who did not experience that outcome. Yes, that comes to a 44% reduction is hospitalization or death in the patient cohort that took Paxlovid, but the actual risks of these outcomes was small, therefore the dimensions of the risk reduction are not quite so impressive.

A larger and more convincing study, conducted by the National Institutes of Health in over a million subjects, reported robust results supporting the effectiveness of Paxlovid in at-risk patients. Of the 1,012,910 COVID-positive patients, 9.7% were treated with Paxlovid. In the 28 days after the study initiation date, participants who were treated with Paxlovid were 26% less likely to be hospitalized. Mortality in participants who received Paxlovid was 73% lower than in participants who were not treated with Paxlovid. The study, not yet peer-reviewed, was posted this past June and has not received much media attention. (https: DOI: 10.1101/2023.05. 26.23290602)

Despite these studies, which, viewed in the context of several other studies, robustly confirm the effectiveness of Paxlovid in preventing the serious consequences of infection with the coronavirus, uptake of the drug has been surprisingly limited. The NIH, evaluating the results of the study described above, suggest that if even half of the eligible patients had taken Paxlovid during the period of the study, about 48,000 deaths would have been prevented. Most people in the US are aware of Paxlovid as a potential treatment option for COVID, but reluctance to take the drug appears to stem from concern in the health-care community regarding potential interactions with other commonly-used drugs. It’s also the case that Paxlovid does effectively prevent the virus from leading to the more serious outcomes – hospitalization and death – but does not alleviate the symptoms of COVID, which perhaps accounts for its diminished utilization.

Another recent study in Annals of Internal Medicine (https://doi.org/ 10.7326/M23-1756) arrived at the concerning conclusion that about one in five persons taking Paxlovid experience a rebound of their COVID infection. Again, looking at the actual numbers to some degree mitigates the concern. The study compared 72 persons taking Paxlovid with 55 persons who were not taking Paxlovid. The members of the cohort taking Paxlovid were older, more likely to be vaccinated, and also more likely to be immunosuppressed. Of this group, 15 participants experienced rebound of the COVID virus, while of the 55 persons not taking Paxlovid, only one experienced viral rebound. The raw numbers suggest that the ratio of viral rebound in Paxlovid-treated patients versus those not treated with Paxlovid was about 20 to 1.

The differences between the two groups are very substantial and, in my opinion, are likely to account for a large part of the difference in the outcomes in turns of viral rebound. This was not a controlled study in which closely matched populations were randomly assigned to active drug or placebo. It should be obvious that the group that was prescribed Paxlovid got the drug because a prescribing physician thought they needed the protection. The group that was not prescribed Paxlovid presumably was at lower risk, or had milder symptoms, suggesting that they had a smaller viral load to start with. About half of the subjects that experienced viral rebound also experienced a return of symptoms. Chances are that rebound was more linked to the size of the viral load and the intensity of symptoms than to an effect of the drug.

What are the prospects?

My perspective is that COVID 19 will be around a long, long time – not necessarily taking a large toll in terms of severe disease and death, but causing illness in many thousands of people every year. We have only to consider the flu, which hit the human race in 1918 as “Spanish flu” and has been around in the intervening years, sometimes more severe, but mostly less so. That pandemic killed almost three-quarters of a million people in the US in 1918 – 1920, when the population was just over 100 million, so the flu fatality rate was quite a bit higher than the COVID fatality rate. COVID cases will likely diminish both in number and severity, but in all likelihood they won’t go away.

A highly sensitive, rapid, and inexpensive test for early detection of deadly cancers

We’re talking here about a new test, not yet available, but highly promising. The test detects a common biomarker for many cancers. It detects the presence of a telltale protein, labeled LINE-1-ORF-1p, in a very small amount of blood. Results emerge in less than two hours, and the test costs about $3 to produce.

The protein, LINE-1-ORF-1p, was first detected by researchers about ten years ago. It is linked to LINE-1, which is a virus-like element that is present in every human cell. LINE-1 tends to replicate abundantly, resulting in a new copy in a new position in the genome. In the presence of cancer, ORF-1p is a protein that LINE-1 produces at high levels, but healthy cells have mechanisms that prevent the production of ORF-1p. Dr John LaCava, co-author of a paper on LINE-1-ORF-1p, said “You shouldn’t find ORF-1p in the bloodstream of a healthy person.” (Taylor, M. S., et al. Cancer Discovery 2023 doi.org/10.1158/2159-8290.CD-23-0313)

The researchers, from Mass General Brigham, Harvard, and the Dana Farber Cancer Institute, analyzed the plasma of 400 healthy people who had donated blood to the Mass General Brigham Biobank. ORF-1p was undetectable in nearly 99% of this cohort. But of the five persons who had the highest level of ORF-1p, the person with the highest level was found, six months later, to have advanced prostate cancer.

ORP-1p levels have been found to be elevated in most forms of cancer, including many of the most common and lethal cancers of the esophagus, colon, lung, breast, prostate, ovaries, uterus, pancreas, and head and neck cancers.

Another potential use of the assay is monitoring how a patient is responding to cancer treatment. If a treatment is effective, the ORF-1p level in the patient’s blood should drop. For example, researchers studied 19 patients being treated for gastroesophageal cancer; in the 13 people who responded to the treatment, levels of ORF-1p fell below the detection limit of the assay.

Dr LaCava suggested that tracking the protein could potentially be incorporated into routine healthcare. “During a healthy time in your life, you could have your ORF-1p levels measured to establish a baseline. Then your doctor would just keep an eye out for any spikes in ORF-1p levels, which could be indicative of a change in your state of health. While there might be some minor ORF-1p fluctuations here and there, a spike would be a cause for a deeper investigation.”

Early detection results in highly significant benefits in terms of treatment and outcomes. Cancers that can be detected early, such as prostate, skin, and breast cancers, have by far the highest survival rates, whereas cancers that are more difficult to detect, such as pancreatic, liver, and ovarian cancer, are at the opposite end of the scale, with the least favorable survival rates. The development of a quick, simple, and inexpensive cancer test that could be included as a standard component of an annual physical examination would likely lead to earlier and more successful treatment for many people. If I may be permitted to state the obvious, spotting and treating the disease in its early stages is vastly preferable to delaying treatment until severe symptoms emerge.

Statins may provide some benefit to persons who do not have elevated cholesterol

The evidence that statins prevent severe cardiovascular events – heart attacks and strokes – in persons with high cholesterol is quite strong. (Doc Gumshoe is aware that there are significant challenges to that statement – the statistical dimension of the benefit from taking statins is not large, and there are side effects that range from the merely disagreeable to serious, but on a population basis, the benefits are considerable).

In particular, the evidence that statins can lower the risk of a second heart attack or stroke in individuals who have already had heart attacks or strokes is very robust. However, some clinicians are not in agreement with the practice of prescribing statins as preventative treatment for persons who have not sustained these cardiovascular events, but are at high risk due to age or other factors, whether or not they have elevated cholesterol.

Recent emerging evidence points to benefits in individuals who do not have elevated levels of low-density lipoprotein cholesterol (LDL-C).

Researchers at the Brigham and Women’s Hospital in Boston, using data from the Veteran’s Affairs Healthcare System, looked at 14,828 individuals with chronic kidney disease. In this cohort, the investigators found that using statins was associated with 9% reduced mortality and a 4% lower risk of heart attack or stroke. The team also looked at a much larger group of older adults without kidney disease, of whom 12% were frail. Among this group of 710,313 people defined as frail, they found that statin therapy was associated with a 39% percent lower risk of mortality and 14% lower risk of a first heart attack or stroke. (Barayev O. JAMA Netw Open. 2023 Dec 1;6(12):e2346373. doi: 10.1001/jamanetworkopen. 2023.)

Somewhat surprisingly, the results of the trial indicated that frailty status did not decrease the benefit from statin treatment – quite the contrary. It may be that the frailest older adults benefit the most from statin treatment.

According to NIH, “Frailty is theoretically defined as a clinically recognizable state of increased vulnerability resulting from aging-associated decline in reserve and function across multiple physiologic systems such that the ability to cope with everyday or acute stressors is comprised.” The factors that are evaluated to define frailty are weight loss, exhaustion, low physical activity, slowness, and weakness.

After traumatic brain injuries, an implant may restore cognitive function

It should be no surprise that our cognitive function is impaired when we experience a traumatic brain injury. Our brains are the machines that do our thinking for us, so when those machines get damaged, all those functions suffer.
A December 4, 2023 paper in Nature Medicine described the restoration of normal thinking in five patients who had experienced these severe brain injuries. (Schiff ND. “Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study.” Nat Med. 2023 Dec;29(12):3162-3174.)

One of these patients was in an automobile accident and had a traumatic brain injury. At that time, she was in her final semester in college and planning to apply to law school. After her brain injury, instead of attending law school she took a job sorting mail, and the injury so affected her cognitive function that she couldn’t effectively do her job. She was unable to read. She said, “I couldn’t remember anything. My left foot dropped, so I’d trip over things all the time. I was always in car accidents. And I had no filter — I’d get pissed off really easily.”

Nearly 20 years later, her parents learned about research being conducted at Stanford about potentially effective treatments for traumatic brain injuries. They contacted the researchers, who implanted a device in her brain, which quickly improved her ability to focus, her memory, and her mood.

She said, “Since the implant I haven’t had any speeding tickets. I don’t trip anymore. I can remember how much money is in my bank account. I wasn’t able to read, but after the implant I bought a book, Where the Crawdads Sing, and loved it and remembered it. And I don’t have that quick temper.”

More than 5 million Americans live with the lasting effects of moderate to severe traumatic brain injury — difficulty focusing, remembering, and making decisions. Though some may recover enough to live independently, their impairments prevent them from returning to school or work and from resuming their social lives.

However, the fact that these patients had emerged from comas and recovered some cognitive function suggested to researchers that the brain systems that support attention and arousal — the ability to stay awake, pay attention to a conversation, and focus on a task — were relatively preserved. These systems connect the thalamus, a relay station deep inside the brain, to points throughout the cortex (the brain’s outer layer) which controls higher cognitive functions. In particular, an area of the thalamus called the central lateral nucleus acts as a hub that regulates many aspects of consciousness. The researchers hoped that precise electrical stimulation of the central lateral nucleus and its connections could reactivate these pathways, essentially turning the lights back up.

The researchers recruited five participants who had experienced traumatic brain injuries (which had taken place three to eighteen years earlier) and had lasting cognitive impairments due to these injuries. The challenge was placing the stimulation device in exactly the right area, which varied from person to person. Each brain is shaped differently to begin with, and the injuries had led to further modifications. The researchers created a virtual model of each brain that allowed them to pinpoint the location and level of stimulation that would activate the central lateral nucleus.

Guided by these models, the researchers surgically implanted the devices in the five participants. After a two-week titration phase to optimize the stimulation, the participants spent 90 days with the device turned on for 12 hours a day. Their progress was measured by a standard test of mental processing speed, called the trail-making test, which involves drawing lines connecting a jumble of letters and numbers. At the end of the 90-day treatment period, the participants had improved their speeds on the test, on average, by 32%, far exceeding the 10% the researchers had aimed for.

For the participants and their families, the improvements were apparent in their daily lives. They resumed activities that had seemed impossible — reading books, watching TV shows, playing video games or finishing a homework assignment. They felt less fatigued and could get through the day without napping.

The therapy was so effective the researchers had trouble completing the last part of their study. They had planned a blinded withdrawal phase, in which half the participants would be randomly selected to have their devices turned off. Two of the patients declined, unwilling to take that chance. Of the three who agreed to participate in the withdrawal phase, one was randomized to have the device turned off. After three weeks without stimulation, that participant performed 34% slower on that trail-making test, described above.

The results of this study were definitely positive and may point to potential future treatment options for persons who experience cognitive impairment due to brain injuries. The number of people who have had traumatic brain injuries, in the US and globally, is very large, and the researchers in this study carefully hold out hopes that further work can lead to development of models and practices that can make therapeutic brain implants widely available treatment options for such persons.

Daily toothbrushing saves lives in hospitalized patients

Those of us who have had knee or hip replacements are keenly aware that oral infections can transmit to other parts of the body and result in severe – and sometimes life-threatening – infections in those knees and hips. Therefore, prior to any dental appointments, we take precautionary antibiotics.

A new study published December 18, 2023 in JAMA Internal Medicine produced data to support the substantial benefit of daily toothbrushing. (doi: 10.1001/ jamainternmed.2023.6638. Online ahead of print.)

The particular data in this new study had to do with hospitalized patients in intensive care units. The overall conclusion was that daily toothbrushing in these patients was associated with a significantly lower incidence of hospital-acquired pneumonia, which is a common and severe threat to hospitalized patients.

Data from 15 trials were analyzed in the study. This included 10,742 patients, of whom 2,033 were in intensive care units. Daily toothbrushing was associated with a 33% lower risk of hospital-acquired pneumonia than in patients who were given oral care without toothbrushing. Significant reduction in pneumonia was particularly associated with daily toothbrushing in patients receiving mechanical ventilation, but not in patients who were not receiving mechanical ventilation. Toothbrushing for patients in the ICU was also associated with fewer days of mechanical ventilation.

The lead author of the study, Dr Michael Klompas of the Harvard Medical School, summed up the results of the study. Here’s what he said:

“The findings from our study emphasize the importance of implementing an oral health routine that includes toothbrushing for hospitalized patients. Our hope is that our study will help catalyze policies and programs to assure that hospitalized patients regularly brush their teeth. If a patient cannot perform the task themselves, we recommend a member of the patient’s care team assist.”

This reminds me of the huge reduction in severe infections that occurred back when surgeons first took the simple precautions of carefully washing their hands before plunging them into the bodies of their patients. Prior to that, surgeons flaunted their filthy gowns in the operating theater, almost as evidence that their profession entailed mucking in blood and body waste – much like football players proudly covered in mud. Improved sanitation won’t be a factor in football, but can obviously make a major difference in the health professions.

*****

Here’s hoping that we won’t be having to focus a lot of attention on the coronavirus and COVID-19 in the coming months. There’s a whole lot more to talk and think about, both positive and (I’m sorry!) negative news. I’ll try to maintain a balance. Today is a freezing cold but bright and sunny day as I write this, and I’m looking forward to Spring! Best to all, stay well, and many thanks for all comments! 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 once or twice 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.]