More Americans are using melatonin supplements, and in bigger doses
Melatonin supplement use jumped dramatically in the past 2 decades, researchers found.
Among U.S. adults, melatonin supplement consumption significantly increased from 1999-2000 to 2017-2018 across all demographic groups, reported Naima Covassin, PhD, of the Mayo Clinic in Rochester, Minnesota, and co-authors in a JAMA research letter.
Melatonin use rose from 0.4% in 1999-2000 to 2.1% in 2017-2018, which corresponded to over 6 million people, the researchers said. The most notable increase was in the last decade, and the prevalence of using higher-dose melatonin (over 5 mg/day) was greater with time.
The findings may raise safety concerns, especially since the actual content of melatonin supplements may be up to 478% higher than the labeled content, the researchers noted.
“Given the increasing popularity in use of exogenous melatonin, our observations support the need for better awareness of safety and effects of melatonin supplements in the public, as well as among medical professionals,” Covassin told MedPage Today.
“Indeed, while melatonin is effective in resetting our circadian clock, and therefore primarily indicated for management of circadian disorders, it has been widely adopted as a non-prescription therapy for sleep promotion,” Covassin said. But the extensive variety of formulations, doses, routes, and timing of supplemental melatonin has meant there’s not much evidence about its clinical efficacy as a sleep aid, she maintained.
Because melatonin is sold as a dietary supplement, it’s not subject to the same regulations and standards applied to drugs, Covassin pointed out. “Therefore, the quality, purity, and dose accuracy of melatonin supplements may not be adequately controlled,” she said.
“Additionally, despite being generally considered safe and well-tolerated, side effects following melatonin supplementation have been reported, especially at high doses and in patients with pre-existing vulnerabilities, and long-term safety data are scarce,” she added.
“There’s actually a lot of evidence to show that melatonin can help people fall asleep faster and have better sleep quality, and it may be even more beneficial for jet lag and addressing sleep timing problems,” observed Michael Grandner, PhD, of the University of Arizona in Tucson, who wasn’t involved with the study. “Accumulating evidence also shows that, in certain doses, it can support a healthy immune system.”
“However, many people don’t really use it correctly,” Grandner told MedPage Today. “It does not generally work to treat insomnia and the dose and timing can be tricky to get right. For example, higher doses are not necessarily more effective.”
The study used data from the 1999-2000 through 2017-2018 cycles of the CDC’s National Health and Nutrition Examination Survey (NHANES) for people ages 20 and older to examine melatonin trends. “Because the recommended dosage of melatonin typically does not exceed 5 mg/d, we additionally evaluated prevalence and trends in use of greater than 5 mg/d of melatonin,” the researchers noted.
Data from 55,021 adults from 10 NHANES cycles were included in the analysis. Mean age of participants was 47.5, and 52% were women.
The overall weighted prevalence of melatonin use rose from 0.4% (95% CI 0.2%-1.0%) in 1999-2000 to 2.1% (95% CI 1.5%-2.9%) in 2017-2018 (P=0.004), with an increase starting in 2009-2010. Trends were similar for both men and women and across age groups.
Before 2005-2006, melatonin use exceeding 5 mg/day was not reported. The prevalence of melatonin use greater than 5 mg/day increased from 0.08% (95% CI 0.02%-0.38%) in 2005-2006 to 0.28% (95% CI 0.13%-0.60%) in 2017-2018 (P=0.005), the researchers found.
The study’s limitations included its reliance on self-reported melatonin use, although supplement containers were verified in nearly all participants, Covassin and colleagues said. In some subgroups, the number of melatonin users was small and stratified data should be interpreted with caution, they acknowledged. “Reliable estimates of trends in melatonin use across racial/ethnic groups cannot be provided,” they added.
Reviewed By Valerie A. Flores, MD, assistant professor, Division of Reproductive Endocrinology & Infertility, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine – Yale New Haven Hospital, New Haven, Connecticut
Endometriosis is a painful disorder that commonly affects the pelvic region but can impact many other body sites as well. An estimated 10% of U.S. girls and women of reproductive age suffer from this under-diagnosed condition.
While endometriosis is generally seen as a disease of adult women, who may not be diagnosed until they are unable to get pregnant and then go for fertility testing, the condition has been found in preadolescent girls. The disease is likely driven by a combination of factors, including genetics, reproductive hormones, and the immune system. Lifestyle and environmental factors may also have an impact.
Once considered to be a disease confined to the female reproductive tract, driven by a woman’s menstrual cycle and associated with severe menstrual pain, endometriosis is now seen as a chronic, systemic, disease that triggers inflammation in different parts of the body – not unlike rheumatoid arthritis. It can affect the nerves to increase a woman’s overall sensitivity to pain and cause scarring, bleeding, and debilitating inflammation at any time of the month and at multiple different locations, including the heart, brain, diaphragm, spleen, kidneys, and lungs.
The classic hallmark of endometriosis has been abnormally severe pain at menstruation. But this normal monthly process should not involve long-lasting excruciating pain or pain that worsens over time, as in endometriosis, noted Margaret Nachtigall, MD, of NYU Langone Health in New York City. “It is certainly reasonable to seek medical attention, especially because there is often a good solution such as a continuous birth control pill, which might be able to alleviate the pain, as well as other good treatment options.”
What Happens in Endometriosis?
Most commonly, the disease has been thought to develop when tissue from the lining of the womb – i.e., the endometrium – escapes from the uterus through the fallopian tubes into the pelvic cavity and continues to grow there.
Implants from this “retrograde menstruation” may then attach to the ovaries, fallopian tubes, or surface of the uterus, as well as the intestines, bladder, rectum, or the space behind the uterus.
Unlike normal menstrual tissue, which leaves the body during a woman’s period, this “ectopic tissue” is trapped in the pelvis with no way to exit. Under the influence of hormones regulating the monthly cycle, this ectopic tissue expands and swells, causing bloating, inflammation, scarring, and pain, which is usually more severe and longer lasting than that of typical monthly cramps
Some affected women have no pain and are diagnosed only during investigation for other diseases or when being evaluated for causes of infertility.
More recently, another source of these external deposits has been identified: immature endometrial stem cells produced in bone marrow and at other sites, which travel to distant locations like the brain, heart, diaphragm, or lungs and grow into endometrial-like tissue, causing inflammation, scarring, and pain wherever they take up residence.
The inflammation may be linked to the way a woman’s immune system functions, since some sufferers have other immune-related conditions such as asthma, eczema, and other allergies or intolerances. Other factors may be the overproduction of estrogen and fatty hormone-like compounds called prostaglandins, which can cause inflammation and muscle cramping.
How Does Endometriosis Cause Infertility?
The pain of endometriosis can interfere with day-to-day activities as well as fertility, since the displaced tissue can cause inflammation, affecting the eggs, or adhesions, making it harder for the sperm and egg to unite. Scarring may block the ovaries and fallopian tubes, and the inflammation can damage the egg and trigger changes in the uterine lining that make it less receptive to implantation of an embryo.
About 30% to 40% of women with endometriosis become infertile. In more advanced disease, endometriomas — cysts formed by endometrial tissue growing in the ovaries — may develop, which can negatively impact the ability to become pregnant.
Early Diagnosis of Endometriosis
It is important to get diagnosed early before the disease progresses. The severity of pain, however, does not always indicate how far the endometriosis extends or what stage of growth it has reached.
Typical Symptoms
Pain in the lower abdomen around the time of menstruation and usually with severe cramps
Painful urination or bowel movements or rectal bleeding during menstruation/cyclically
Pain in the lower abdomen or back at other times, usually cyclic, or unexplained pain at other body sites
Pain during sexual intercourse
Periods that last more than 7 days
Shorter than usual intervals between periods
Fatigue
Gastrointestinal problems such as diarrhea, constipation, and nausea during menstruation
Mood swings and depression
If you have one or more of these symptoms, ask your doctor about getting investigated for endometriosis.
Sometimes surgery may be needed to help with treatment of endometriosis-associated pain.
Risk Factors for Endometriosis
Having a close relative with endometriosis, which suggests an inherited predisposition
Starting menstruation before age 12
Intervals between periods of less than 27 days, leading to more periods per year and thus greater exposure to ovarian hormones
Anatomical abnormalities in the uterus
Allergic conditions such as asthma or eczema
Low body mass index
Asian race
Heavy consumption of red meat
Overcoming Reluctance to Seek Help
Gender-based misconceptions may cause some girls and women to brush off their symptoms as normal and avoid seeking help. No woman who suspects she might have endometriosis should allow female stereotyping to condemn her to decades of pain and possible infertility, Nachtigall stressed. “If an individual’s physician is not going to evaluate for endometriosis, there are many excellent physicians who do regularly see and take care of patients for endometriosis.”
Ask for a referral – or act as your own advocate for getting tested or find someone to advocate for you. The Endometriosis Association can help you find the information and support and connect you with other women who suffer from the condition.
Since the beginning of the COVID-19 pandemic, we have seen a handful of variants of this deadly virus.
To date, the most notable is delta, which was first detected in India in the latter half of 2020. The World Health Organization identified the delta variant as the dominant strain in June 2021.
Said to be much more contagious in comparison to the original strain of COVID-19, this variant caused grave concerns for people all over the world when it came to protecting themselves from it.
Elise Kramer
While it comes as no surprise that COVID-19 can have devastating effects on seemingly every part of the body, optometrists are interested in its direct impact on the eye. It is important to note that the research regarding these details continues to be a work in progress. However, certain information has come to light in the less than 2 years since the pandemic first began.
Ocular symptoms
Prior COVID-19 strains have been shown to cause ocular symptoms; however, there is not yet enough information to link such symptoms to the delta variant. A number of individuals infected with the delta variant have experienced symptoms such as ocular redness and conjunctivitis, but this has not occurred frequently enough to establish a link.
The original strain of COVID-19 produced the following symptoms:
conjunctivitis;
discomfort;
itch;
redness;
blurry vision; and
light sensitivity.
Therefore, it is possible that those infected with the delta variant may suffer from these symptoms as well.
Long-term impact
Toward the beginning of the pandemic, it was not known that COVID-19 could cause lingering effects. However, it has been determined that this is not the case, and patients with “long haul COVID-19” can struggle with a myriad of eye health issues.
In July 2021, the British Journal of Ophthalmology published an article (Biturgen et al.) linking COVID to corneal nerve fiber loss as detected with corneal confocal microscopy.
While the authors noted that continued testing must be done to develop their findings, these initial results are important to eye care professionals with patients who have had any variation of COVID-19.
We are continuing to learn about the long-term impact of this virus and its variants on adults and children. While it may feel as though the world has been in the midst of this pandemic for a long time, the reality is that the first cases of COVID were reported only 2 years ago.
A growing concern among children
Children are also at risk of serious complications from this virus. Multisystem inflammatory syndrome in children (MIS-C) has been identified as one of them. MIS-C has many traits similar to Kawasaki disease.
Although the symptoms associated with MIS-C can vary, ocular redness is one of them. Some patients may mistakenly believe their symptoms are caused by dry eye; however,
if this symptom is paired with stomach issues, headache or chest pain, the child should be tested for COVID-19 as soon as possible.
Continued research
It goes without saying that new COVID variants will continue to be discovered over time. Medical professionals are closely watching the omicron variant to see how this new strain will impact us.
Eye care professionals should stay up-to-date on the research so the health care community can find new and better ways to treat patients.
On January 24, attorney Thomas Renz, a member of the America’s Frontline Doctors (AFLDS) legal team, revealed to a panel that Wuhan coronavirus (Covid-19) “vaccines” are extremely dangerous, despite constant reassurances from the government that they are “safe and effective.”
Three military doctors from the Department of Defense (DoD) who have access to vaccination data that has been withheld from the general public procured the information. They are Lt. Col. Theresa Long, Dr. Samuel Sigoloff and Lt. Colonel Peter Chambers.
“All three have given me this data in declarations that stated this is under penalty of perjury, we intend to submit this to the courts,” Renz said.
What these three whistleblowers showed with the data is that miscarriages have increased by 300 percent over the past year, as have cancers. Neurological problems increased 1,000 percent during the same timeframe.
“Our soldiers are being injured, experimented on, and sometimes possibly killed,” Renz further explained.
Biden regime ignored affidavit warning that covid jabs are killing military servicemen
Lt. Col. Long is a senior U.S. Army flight surgeon with specialized training in infectious diseases. She testified under the Military Whistleblower Protection Act, which protects members who make lawful disclosures of wrongdoing to members of Congress or the Inspector General.
Long told Sen. Ron Johnson (R-Wisc.) that she actually had to ground vaccinated pilots in order to place them under monitoring for symptoms of myocarditis, which include chronic fatigue, so as to avoid them potentially dying from heart failure mid-air.
On Nov. 3, 2021, The Washington Times reported that Long had made “numerous efforts to get senior medical leaders to at the very least inform soldiers of this risk,” only to be ignored.
“The military didn’t even pause their vaccination efforts to rush out the Pfizer and Moderna shots,” she is quoted as saying.
Long initially decided to speak up after the U.S. Centers for Disease Control and Prevention (CDC) announced back in June an “emergency meeting to discuss higher than expected myocarditis in 16 to 24-year-olds.”
Long then filed an affidavit against the Biden regime over its jab mandate for active-duty military personnel, warning that heart side effects could cause pilots to die mid-flight.
Long is directly responsible, by the way, for certifying the fitness of 4,000 flight-ready airmen at the 1st Aviation Brigade in Ft. Rucker, Ala. It is her job, in other words, to be on the lookout for things that could harm them, including covid jabs.
“The vaccines can cause inflamed heart muscles in young men in the age range of most flight-ready pilots and … the Department of Defense has not followed its own protocols by requiring an MRI scan of each airman after vaccination,” the affidavit reads.
“The majority of young new Army aviators are in their early twenties. We know there is a risk of myocarditis with each mRNA vaccination.”
A lawsuit was also filed, but the Biden regime has thus far ignored both the affidavit and that legal filing.
Dr. Peter McCullough backed all this up when he spoke at a second opinion meeting, revealing that myocarditis “is not mild,” and is not something to be balked at as being no big deal.
“When they do an MRI on these individuals with suspected myocarditis, 100 percent are having heart damage,” he explained.
Scientific studies show that around 13 percent of jab-induced myocarditis victims will have permanent heart injury, while 32 percent will never return back to normal.
An embalmer with decades of experience said in a recent interview that for more than a year he has found “long, fibrous blood clots” in the bodies of some deceased people who got a COVID-19 vaccine.
According to a report by The Exposé, board-certified funeral director and embalmer Richard Hirschman revealed his observations in an interview with Dr. Jane Ruby, “a medical professional with expertise in pharmaceutical drug development and over 20 years of experience in regulatory processes for FDA drug approval,” the site reported.
Specifically, Hirschman reports finding “arteries and veins filled with unnatural blood clot combinations” that also contain “strange fibrous materials” that have completely filled up the vascular systems of many people who have died during the pandemic and after vaccines became widely used.
In his interview with Ruby, Hirschman not only reported that he has never seen anything like what he now increasingly finds, but that he has discussed his findings with other embalmers and many of them have encountered the same phenomenon, The Exposé reported.
“Hirschman stated these clots or worm-like structures appear closely to vaccinated blood under a microscope, but he has never seen anything of these sizes before,” the outlet reported, adding that the embalmer states he began encountering the phenomenon of long, stretchy, fibrous clots in November 2020.
Eventually, he reported finding the clots in as many as 50 percent of deceased people he was embalming, but today that figure is closer to 80 percent, the outlet reported, citing Hirschman’s claims in his interview with Ruby.
He also said that he was able to confirm that some of those deceased with these blood clots had indeed received the Covid-19 vaccines, but he could not confirm all of them were vaccinated or what specifically is causing this increase in these usually long blood clots in the circulatory systems of the deceased.
Hirschman added that he has seen an increase in deaths resulting from heart attacks and strokes coming to his table. With increasing numbers of blood clots like these, that is no surprise.
He went on to say that other professionals in his field are becoming “nervous” about what they increasingly are finding as well, especially when they related it to the increasing number of people dying after getting COVID vaccines.
“If this is caused by the vaccine and my gut is telling me it is, I can’t prove that, but if this is caused by the vaccine, imagine the amount of people that will be dying in the future because people cannot live with this kind of substance floating around in their vessels,” he told Ruby.
He went on to say he thinks it is “amazing” how so many people are dying from heart attacks and strokes of late, adding: “If one of these small fibrous tissues gets up into the brain, you’re going to have a stroke.
“If it gets into your heart, it’s going to lead you to a heart attack,” he added.
After first noting an uptick in November 2020 of people he had embalmed with what he termed “worms” in their bloodstream, Hirschman says he began to keep track of the numbers and documented his findings.
In January alone, of the 35 people he has embalmed, he estimated that at least 20 of them had fibrous anomalies in their bloodstream.
“Needless to say, this should be investigated immediately, if not for the respect of the deceased, then to at least rule out if these long, fibrous blood clots are indeed a physiological result of the Covid-19 vaccines,” he told Ruby, adding that if the vaccines are not responsible, obviously something else is occurring.
A new wearable designed at Stanford University is much more accurate at calculating calorie burn than your smartwatch.
A new wearable designed at Stanford University is much more accurate at calculating calorie burn than your smartwatch.
Lexy Savvides
Smartwatches are great tools for keeping track of your activity. They can monitor your heart rate during a workout and track your sleep, and some even help manage workout recovery. But severalstudies show smartwatches and fitness trackers don’t do as good of a job at calculating calorie burn during activity and can be off anywhere between 40% to 80% of your actual energy expenditure.
A new wearable developed at Stanford University claims to be far more accurate. It’s not worn on the wrist — you put it on your leg.
That’s because it measures leg motion, where most of your energy is used during lower body exercises like walking, running, climbing stairs and cycling. It uses two inertial measurement units (IMUs) plus a battery unit and microcontroller worn on the hip. Definitely not as convenient as strapping on a wrist-based smartwatch or tracker, but it’s the first proof of concept developed by Stanford University graduate student Patrick Slade.
Measuring calorie burn accurately is important for a number of reasons, but mainly because it can help people manage their weight. “We want to understand the connection between physical activity and obesity so we can develop new interventions to help people live longer, healthier and more fulfilling lives,” says Steve Collins, associate professor of mechanical engineering at Stanford University, who co-authored the findings with Slade.
Naturally, I wanted to put this system to the test to see if a tracker worn on my leg could really be more accurate at estimating calories burned than one on my wrist.
Stanford graduate student Delaney Miller wearing the leg tracker.Andrew Brodhead
Measuring calorie burn is complex
Most consumer wearables use heart rate and wrist-based motion to calculate calorie burn during activity. But heart rate isn’t directly related to the energy you are expending, says Slade. “Your heart is just pumping blood through your body and has a bunch of different factors that affect it,” he says. “How tired you are, if you had coffee, worked out, this time history makes it really volatile.”
Despite the wires, the tracker didn’t get in the way during my workouts and is lightweight.Lexy Savvides/CNET
Instead, his system breaks down motion into each step, then uses a machine-learning model to calculate energy expenditure. It was tested with over a dozen participants of varying ages and weights and averaged 13% error, compared with 40% to 80% error from consumer wearables.
To test its accuracy for myself, I’ve come to Stanford University’s human performance lab, filled to the brim with a range of sophisticated workout equipment including an antigravity treadmill. But for the purposes of testing out this new wearable, only regular gym machines like a stair climber and exercise bike are needed. I’ll be doing four workouts for 5 minutes each: walking, running, cycling and stair stepping.
Putting on Slade’s system is straightforward. You strap two stretchy bands with the IMUs on your thigh and shin, then wrap a controller and battery around your waist. It feels like I have a small smartphone strapped to my midsection and I don’t even notice the wires running down my legs.
I also put on a lab-grade respirometer to measure my actual energy expenditure. This monitors the carbon dioxide I breathe out and the oxygen I breathe in to give me what Slade calls the “ground truth” reading, or my actual calorie burn. It costs tens of thousands of dollars and weighs about 5 pounds complete with mask and backpack, so it’s not really the best tool for people to use outside the lab.
Finally, I strap a smartwatch to my wrist to get its calorie estimations. After my workouts, we’ll compare results from all three devices.
Once we get a baseline reading from the respirometer, I start working out. I know I’m not going to be setting any pace records with all these tools strapped to my body, but fortunately that doesn’t matter — we’re only tracking energy expenditure.
The results are in — and they’re surprising
After gathering all the data points from each device, Slade walks me through the results. For running, the respirometry device said I burned 87 calories, the leg wearable 66 calories and the smartwatch 52 calories. You can see the rest of the calorie counts per exercise in the video on this page, but across all four workouts, the leg wearable error rate was 14% compared with 58% from the watch on my wrist. Turns out the watch was underestimating my overall calorie burn during each exercise, but Slade tells me it could overestimate for someone else. “People can’t necessarily just scale the smartwatch estimates by a fixed amount to make them accurate for everyone,” he says.
For now, this leg-based system only works for lower-body exercises, but he’s already thinking of ways to make a version that can also take into account upper-body movement like weightlifting. “Maybe using an IMU in your smartwatch to get that arm motion, if you’re doing a rep you could perhaps use the same modeling approach,” he says. The research paper also encourages smartwatch engineers to use its method to improve calorie tracking effectiveness.
You can’t buy this new wearable, but you can make it yourself. All of the instructions and code were made available in the hopes this will help speed up development. Slade is also working on a smaller and lighter version that could be integrated into clothing and maybe even use a smartphone as the controller.
For these sorts of trackers viable, they’ll need to be affordable and small enough to wear all day, so we can track our energy expenditure on a second-by-second basis. “So you can really understand which activities led to the energy expenditure and how intense it was,” Collins tells me. The end goal? By tracking our activity more accurately, wearables will be able to give us personalized insights into how to exercise or manage our weight.
Stanford neuro-oncologist Michelle Monje is studying the link between “chemo brain” and long Covid’s brain fog.STANFORD
Back in the pandemic’s first wave, Michelle Monje was worried about Covid-19’s power to muddle the brain. Seeing the massive inflammatory response to the virus and early signs of what became known as long Covid’s brain fog, she was reminded of “chemo brain,” that mind-numbing side effect cancer patients endure when therapy to burn tumors away also inflames the brain.
Monje’s not a virologist or an epidemiologist. She’s a neuro-oncologist at Stanford who has studied the neurobiological underpinnings of cognitive impairment after cancer therapy for 20 years. But like scientists around the world, for the last two years her research has pivoted to include Covid and its far-reaching impact throughout the body. That includes brain fog, when people can’t do simple math, concentrate for more than a few minutes, or find the right words.
Working with a team that includes Yale virologist Akiko Iwasaki and Mount Sinai Health System’s David Putrino, she discovered that chemo and Covid spark neuro-inflammation in much the same way. Their study, based on mouse experiments and autopsy findings, was recently published as a preprint on the bioRxiv server and it’s been submitted to a peer-reviewed journal (one that does not allow authors to disclose its name before acceptance). But with that caveat, the comparison Monje and her co-authors draw still offers new insight into an often debilitating symptom that up to a third of people with long Covid experience for months or even years after initial infection. And the link raises hopes that a treatment one day could put out the fire in the same hot spots in the brain.
“While the link is not immediately obvious, in light of the roles that neuroinflammation plays in the neurobiology of ‘chemo brain,’ it makes a lot of sense that there would be these similarities with the cognitive impairment after an inflammatory challenge like Covid,” Beth Stevens, an associate professor of neurology at Harvard Medical School and Boston Children’s Hospital, told STAT. In 2012, Stevens discovered that microglia, brain cells ignored since they were first noted in the 1920s, were actually powerful immune cells. She was not involved in Monje’s study, but is familiar with her research.
Understanding the basic biology is a first step toward an effective therapy, Stevens said, both for chemo brain and brain fog after Covid. “Monje and team have been working on therapeutic interventions for cancer therapy-related cognitive impairment for some time, so they can now test those possible therapies for long Covid. There are clear next steps.”
Therapies for chemo brain are a long way off, Monje cautioned, so remedies for long Covid’s brain fog would be too, but these findings could pave the way toward them.
It’s no secret to people like Simone Bowles, a special education teacher’s assistant in Naperville, Ill., that there are no treatments available. She has lived with long Covid and brain fog for almost two years and said she has not found medical care to be helpful. One doctor suggested she take Claritin to see if taste or smell could come back, but it did no good.
The fog has thrown confusion into everyday tasks: She lost her bank card getting gas once. “And I never forget my bank card. Now I’m checking constantly, like, where is this?” she told STAT.
Her sense of taste and smell are still gone, and she deals with fatigue every day. She is devoted to her 9-year-old daughter, she takes heart from people she talks with online in a Black long haulers group, and said her faith in God keeps her going.
“I mean, I get up and go to work because I’ve got to go to work,” she said. “I do have a trip planned just because I’m trying to force myself to get back to doing things. I don’t want to do nothing.”
As Monje set out to analyze chemo brain and long Covid brain fog, her starting point was neuroinflammation and the cognitive impairment it causes. Cancer therapies can lead to persistent activation of microglia, which normally help in brain development and later in maintaining brain health. But these cells can go into overdrive in disease, particularly an immunogenic one like Covid-19, known for sparking cytokine release syndrome and other kinds of inflammatory dysregulation.
“I worried back in the spring of 2020 that we would perhaps see a syndrome very similar to what we see after cancer therapy, that we might start to see a cognitive syndrome characterized by things like impairment in memory, executive function, attention, speed of information processing, multitasking,” Monje told STAT. “And then, you know, within months, reports of exactly that sort of complaint started to emerge.”
It was clear then that severe Covid could harm the brain, causing strokes or in rare cases direct viral infection. But what she wanted to understand was how milder infection and inflammation elsewhere in the body might affect the brain in ways similar to cancer chemotherapy targeting tumors throughout the body.
She knew the commonly used cancer drug methotrexate directly stimulates certain microglia in the brain’s white matter that then turn cells called astrocytes neurotoxic. Together they damage formation of myelin — a sheath around nerves that speeds brain circuit signals — in ways that result in cognitive impairment. Experiments have shown that depleting overactive microglia can reverse this process. Monje set out to understand if a similar physiological process might be at play in long Covid brain fog, and if it might be a potentially reversible one. The goal would be to restore balance between brain cells in order to rescue cognition.
To test this idea, Monje’s team used a model developed by Iwasaki at Yale to infect mice with a mild form of Covid-19 that was limited to the airways. They also studied brain samples taken from nine people who had died of Covid-19. And Putrino, who works with patients in Mount Sinai’s Center for Post-COVID Care, had been collecting serum samples from people suffering from long Covid with or without cognitive impairment. The scientists found high levels of cytokines and chemokines — proteins that regulate immune responses — as well as signs of microglial reactivity in the brain’s white matter that mirror what appears in the brains of people after chemotherapy. One particular chemokine linked to cognitive impairment was higher in people experiencing long Covid’s brain fog than in people whose long Covid didn’t include cognitive symptoms.
Monje wasn’t surprised to find this similarity, but she did find it quite striking. “It was not subtle,” she said. She credits advances made in the fundamental understanding of how neurons and glial cells work with each other to maintain neuronal health and plasticity. “That basic work is going to really hopefully inform the cognitive function after Covid,” she said. “What’s exciting about that is we’re not starting from ground zero.”
At long Covid clinics, which have sprung up in every state but North and South Dakota in the U.S., symptom relief is the mainstay to treat the array of persistent problems spanning the body and mind.
“In rehabilitation medicine, we always have been focused on addressing people’s current symptoms and their impairments and improving their quality of life and getting their functioning back,” said John Baratta, founder and co-director of UNC COVID Recovery Clinic in Chapel Hill, N.C., and a physician who specializes in stroke rehabilitation. “Certainly if a magic drug becomes available in the future that treats whatever the underlying issues are with long Covid, then we would love to have access to that. But until that time, if that time comes, we’ll continue focusing on managing the symptoms and helping people improve as much as they can.”
That can mean a neuropsychiatric evaluation along with cognitive rehabilitation, which uses exercises to help patients with processing speed as well as memory and attention. Sometimes stimulants can help, especially if brain fog and fatigue come together.
What’s next for Monje’s research is to build on the basic science. Questions to answer could include how vaccination affects the inflammatory response to mild Covid, Stevens of Boston Children’s said, and whether early childhood exposure to Covid influences brain development, and could therapies for chemo brain help people recover from Covid’s brain fog.
Monje said it’s too soon to talk about any treatments.
“I don’t want to speculate about what therapies might be useful because I can’t recommend anything we haven’t tested,” she said. “We will be testing potential interventions first in preclinical models and then there will be carefully controlled clinical trials so that we can identify the best and safest. But I wouldn’t want people to think, ‘Oh, I read somewhere that x y z, you know, calms down microglia.’ I’ve seen that happen on Twitter.”
Meanwhile, she suspects because infection with the Omicron variant is milder for vaccinated and boosted people that might limit long Covid. She certainly hopes so. She and most of her family tested positive for Covid-19 after a distressing six-hour plane ride home from holiday celebrations back east.
“I was vaccinated and boosted and incredibly grateful for that because, wow, just having a taste of how bad the disease is — I was pretty sick for a few days,” she said. “But one thing that I am taking some personal solace in are these emerging preprints that suggest that being vaccinated is protective, potentially against long Covid, but that needs to be peer-reviewed. I’m not an epidemiologist, but I’m hopeful that we will find that vaccination changes the neuro immunogenicity of fighting this infection.”
When a resting immune cell that is latently infected with HIV gets reactivated, the cell starts producing HIV virions (red) that bud and release from the cell (blue).NIAID/NIH
Antiretroviral therapy, the standard treatment for HIV, can remove any trace of the virus from the blood, but a hidden reservoir of HIV persists in patients who are in treatment. That means patients are never truly cured and need to be on HIV drugs for the rest of their lives.
Researchers have yet to discover a way to eliminate the virus in its latent stage, but new, early-stage research suggests a landmark cancer drug — pembrolizumab, also known as Keytruda — may be able to help. In a study published Wednesday in Science Translational Medicine, researchers looked at 32 patients that had both cancer and HIV and found that pembrolizumab, which revives the immune system and encourages it to attack tumors, also has the ability to flush HIV out of its hiding spot in immune cells.
“This is an exciting advance,” Adeeba Kamarulzaman, the president of the International AIDS Society, said in a statement. She was not involved in the study. “Being able to stop HIV from hiding is an important part of finding an HIV cure.”
HIV attacks the immune system by infecting white blood cells known as T cells. Without antiretroviral drugs, the virus will proliferate wildly through the body, obliterating the immune system and eventually leading to the patient’s death. There are effective treatments for HIV that can stop the virus from replicating and give the immune system a chance to recover.
“But treatment can’t clear latent virus,” explained Sharon Lewin, an HIV researcher at the University of Melbourne and the senior author on the study. “And you always end up with exhausted T cells.”
These cells weaken the immune system and make it harder for it to fight diseases. Exhausted T cells often make a molecule called PD1, which stands for programmed death 1, a compound that suppresses the immune system and puts immune cells in a state of stupor. At the same time, PD1 can cause HIV to go quiet as well.
“PD1 causes a bit of trouble in HIV,” Lewin said. “It means you have an exhausted immune system that can’t clear [infected] cells, but you basically also silence the virus and put it in a latent form. So, you find a lot of these latent viruses inside cells that express PD1.”
That’s where the pembrolizumab comes in. The drug, first approved by the FDA in 2014 for use against advanced melanoma, binds to PD1 and takes it out of play. In cancer, this revs the immune system up to destroy tumor cells. It’s also made the drug a blockbuster and one of the most effective treatments for a range of cancers. In HIV, it may also help the immune system hunt down the last vestiges of HIV while also disrupting the virus’ ability to hide. “It has the potential to be a double whammy,” Lewin said.
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But testing the drug’s potential in HIV treatment poses challenges, because pembrolizumab and similar cancer immunotherapy drugs can have severe toxic side effects. Boosting the immune system with them is a double-edged sword. They can lead immune cells to kill tumors, but they can also cause the immune system to become overactive and lash out against the body’s healthy tissues, too.
“It’s challenging to give anti-PD1 drugs to people who don’t have cancer. There have been small studies, but they were stopped because of the side effects,” Lewin said.
So Lewin and her collaborators at the Fred Hutchinson Cancer Research Center had to find people who were both on antiretroviral therapy for HIV and were already being treated with pembrolizumab for cancer. They found 32 individuals who fit the bill and tracked levels of HIV in their blood throughout the course of their treatment.
Patients received an infusion of pembrolizumab every three weeks for up to 105 weeks, depending on how they responded to the drug. During that time, researchers regularly collected blood and analyzed it for HIV genetic material.
After the first infusion of pembrolizumab, the team began finding HIV genetic material in the patients’ blood, suggesting the drug was forcing the virus out its sanctuary and making it again vulnerable to the antiretroviral treatment and the body’s natural defenses. But, Lewin added, it wasn’t enough to free the patient of HIV entirely.
“It released the brakes on the virus, and now they’re visible to the immune system,” Lewin said. “But this is just a proof of concept. Anti-PD1 on its own repeatedly didn’t get rid of the reservoir.”
Still, it’s an important step toward finding a cure to HIV, said Steven Deeks, a professor of medicine at the University of California, San Francisco, and an HIV expert who worked on the study with Lewin. For decades, scientists looked for a powerful weapon against the latent reservoir of HIV that can finish the infection off once and for all.
“But we now have this road map saying, ‘OK, let’s try low doses. Let’s try other ways to manipulate the system in the same pathway,’” Deeks said. “And that’s why this is an important advance.”
Experts said far more research is needed to figure out where the road map leads.
“It makes us more enthusiastic about cure efforts, but I would not say we are close,” said Shyam Kottilil, an infectious disease physician and professor at the Institute of Human Virology at the University of Maryland School of Medicine. Kottilil, who was not involved in the research, added that ” major concern is safety of these agents in people with HIV without cancer.”
Because drugs like pembrolizumab can have such severe toxicity, scientists must see if there’s a dose that can effectively do the job without causing severe side effects or death. And more broadly, scientists must still understand whether and how drugs like pembrolizumab might play a role in treating HIV, and find the best way to use these drugs to fully clear the virus from the body.
That work has already started, Lewin said, including a planned study to give a low level of pembrolizumab to patients living with HIV who don’t also have cancer. It’s possible that study might yield better results, too, she said, since the cancer may have interfered with the body’s ability to take full advantage of the drug’s effect on HIV.
“There’s a lot of avenues being tested now,” she said.
Less than two decades into the genomic era in health care, our knowledge about the connections between DNA and human health continues to explode, from the genetic underpinnings of disease to how to use genetics to identify what therapy is best suited to each person. Ultimately genomics will transform the way we understand our health and make most health decisions, from pregnancy to newborn health to childhood disorders, cancer treatment and more.
One of the most dramatic changes is in the world of so-called rare disease. In total, rare diseases are anything but rare. There are thousands of conditions that may individually impact relatively small groups of people but together impact more than 30 million people in the U.S. alone.1
Advances in genetic medicine have made a major contribution to improving diagnosis for these patients
While too many patients still endure a years-long “diagnostic odyssey,” the increasing availability of genetic testing offers hope. Genetic testing has the ability to diagnose thousands of rare conditions, accurately and quickly, and that capability is only growing, with hundreds of new gene-disease relationships identified each year.
Recently the industry has seen gene therapies and other targeted treatments enter the market, offering therapeutic options to patients who previously had none
Today, treatments for rare diseases account for $24 billion or roughly 20 percent of all prescription drug spending and is growing at 12 percent a year.2 But the role of genetics in rare disease treatment does not end at diagnosis, even one that provides a gateway to treatment. Each diagnostic test not only gives an answer to a patient, but also contributes to a treasure trove of data that improves diagnosis for the next patient and can transform how we understand and treat these conditions.
GeneDx – a diagnostic company founded in 2000 by two scientists from the National Institutes of Health (NIH) – has already seen this play out. To date the company has completed more than 300,000 clinical exome sequences, more than anyone else in the industry. Exome sequencing covers all 20,000 genes responsible for proteins in the body and provides the broadest look at the potential genetic causes of health conditions. Only sequencing a person’s entire genome is broader. That experience, coupled with a dataset that includes 2.1 million health descriptions (phenotypes), has allowed the company to accelerate discovery in ways that are impossible without the benefit of large datasets. For example, by plotting symptoms and age at testing across a large cohort, researchers can see the course of disease changing over time, with patients under age two showing very different symptoms than patients at age six. For physicians who see these types of cases infrequently, the conditions may look different when in fact they’re the same. Again and again, a symptomatic, hypothesis-based approach may miss what’s really going on.
Where medicine is heading, then, will begin not with the hypothesis but with the data
Through large datasets of both genomic and clinical information, we will be able to start by asking, “What do the genes say?” Then, “What do the symptoms likely mean?” And finally, “What treatment will help?” It upends diagnosis and treatment in ways that can dramatically improve care. For patients with rare diseases, many of which worsen over time, the sooner a diagnosis and an effective treatment is found, the better the outcome.
Likewise, drug development can be transformed. Large datasets of both genomic and clinical data can drastically speed every phase of the drug development cycle, from identifying novel targets to designing clinical trials to developing the kinds of complementary diagnostics needed to ensure the right patient receives the right therapy at the right time.
The most impactful datasets will be those that are large, deep and structured, combining both genetic and health information
Health systems, payers, diagnostic companies and biopharma companies all have a role to play in creating a framework that will generate the greatest benefit for patients. Improving access to testing, ensuring reimbursement, creating useable datasets, contributing to public data trusts and fostering cross-industry partnerships will all be part of building a new ecosystem to deliver genome-informed health care.
Millions of patients enduring rare diseases have for years had too few options. Given the potential to transform health care for the better, now’s the time to double-down on the transition to a data-driven approach to diagnosis and drug development.
Close your eyes for a few seconds and imagine what a hospital will look like 10 years in the future. If medical robots, artificial intelligence, and other technologies come to mind, you are on the right track. But if you picture these innovations happening in a sprawling hospital campus, think again.
Radical changes afoot in health care philosophy, medical technology, and treatment capability will lead to hospital-quality care being administered outside of hospitals — in primary care and urgent care center and in people’s homes. These changes will create more comfortable conditions for patients, yield better outcomes, and be more affordable.
What’s more, the stress of hospitalization, the presence of antibiotic-resistant microbes, and other issues increase the risk of infection the longer someone is hospitalized. Unless hospitalization is absolutely imperative to receiving proper care, people are almost always better off avoiding a hospital stay.
Health care is shifting to a value-based model
Due to the health risks and economic burdens involved, doctors and insurance companies prefer to keep patients out of hospitals for conditions that are not life-threatening. Payers increasingly financially reward health care providers for delivering high-quality care that keeps their patients healthy at a reasonable cost and relying on inpatient treatment only when absolutely necessary.
But this so-called value-based care ethos has its own challenges. Failing to admit people to the hospital who do need inpatient care can have life-threatening consequences, as can discharging patients too soon. At least one in seven people are readmitted to the hospital within 30 days of being discharged. Clearly, health care providers need a way to deliver value-based care for acute and chronic conditions without compromising patient safety and breaking the bank.
What is the solution? Give patients hospital-quality care without the hospital.
Hospital care is going remote
Before Covid-19, telemedicine was seen by many as a niche service that would remain irrelevant to most patients and health care providers. The pandemic changed that entirely, driving 3,800% growth in telemedicine, now well on its way to $250 billion of market value, according to a report by McKinsey & Company. Video calls and asynchronous texts with health care providers have become commonplace health care modalities for everything from skin rashes to more serious conditions.
Diagnosing health conditions can also be done via devices that are portable, wearable, and affordable, such as the FDA-cleared Apple smartwatch and Owlstone Medical’s cancer-detecting breathalyzers, which are now being tested in clinical trials. As devices like these continue to evolve, early diagnosis and preventive care for conditions such as heart disease, diabetes, and even pancreatic cancer will be done in the home during daily activities instead of in hospitals only after patients experience symptoms. This will save countless lives.
Care after hospital discharge is also now increasingly handled through digital devices. Remote continuous monitoring technology is used to observe breathing and heart rates, blood sugar, and other indicators, identifying early warning signs of relapse for stroke, heart failure, and other serious conditions. Digital health care company KenSci, for example, conducts remote monitoring of chronic obstructive pulmonary disease in people who have been discharged from the hospital. The ability to prevent “bounce back” return hospital visits for conditions like this saves both lives and money, and will soon make post-acute care in clinical settings like long-term hospitals and inpatient nursing facilities the exception rather than the rule.
Hospital care is coming to the home
The most impressive element of the hospital of the future does not involve hospitals at all. Johns Hopkins, Mount Sinai, and other health care organizations will furnish an individual or family with the equipment needed to administer hospital-level care in the home. In this hospital-at-home model, doctors and nurses treat patients through a combination of telemedicine, digital diagnostics, and in-person visits by medics or registered nurses to administer medicine or draw blood, for example.
In addition to the added convenience and comfort, a review of nine hospital-at-home trials shows that people treated with this modality had a 26% lower risk of readmission, a lower need for long-term care, and lower rates of anxiety and depression, all at a cost of up to 38% less than conventional hospital inpatient care.
Obstacles to overcome
Most hospitals today are monolithic facilities made up of multiple buildings and floors where patients are admitted, treated, and monitored until they are well enough to go home. Going forward, nonemergency services will be pushed horizontally to outpatient clinics, patients’ homes, and remote devices. This is reminiscent of what happened to financial services, which migrated from bank tellers to drive-thru windows to far-flung ATMs and then to mobile apps on the smartphones so many people carry that now take care of almost any financial transaction.
Before that can happen to hospital care, however, several things need to change:
Patient records must be migrated from siloed medical records systems and securely into the hands (and phones) of patients themselves.
Payers must complete their shift to value-based care using the Goldilocks principle that incentivizes health care providers to administer just the right amount of care.
Doctors must relearn which patients to admit to the hospital, which ones can receive acute care at home, which ones can be treated by telemedicine, and which ones to discharge.
Work has gone remote. So has banking, grocery shopping, notary services, and pretty much everything else. Hospitalization is next. It won’t be easy, but it will happen. Once health care providers, payers, and regulators catch up with the technology that already exists, the hospitals of tomorrow will expand to the home as they become smaller, more affordable, and better versions of what we have today.
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