Bad Sleep = Bad Health / Chronic Disease

I’ve been using an OURA ring for nearly 3 years now – it’s the best sleep data available to consumers and you can learn a lot about what certain behaviors do to your sleep quality – alcohol, cigars, altering sleep time, eating meals close to bedtime all will mess you up.  It then becomes up to you whether or not that behavior is “worth it.” 

If you’ve been reading my stuff, then you know I believe that sleep is critical.  Sleep is probably more important than anything.  Exercise comes in a close second.  Diet is obviously important, but it pales in comparison – you can eat a tremendous amount of bad stuff, but if you exercise regularly and get enough sleep, you probably get away with it a lot more often than if you don’t sleep or don’t get any exercise.  Yes, it will all catch up with you, but I’m trying to make a point.

So why do we care about sleep?  One major thing to understand is that the brain’s sewer system (the glymphatic system) increases it’s flow by over 40% when you sleep.  We make junk systematically all day long and if we don’t clear it out, we’re in trouble.  And this doesn’t even take into account all the ideas around solidifying memories,  processing experiences, etc.  

Now we have a study that confirms that sleep quality ties directly to development of chronic diseases.  I kind of this qualifies as a “DUH”, but some folks need “proof”. 

If you want to talk about measuring sleep quality, or other health trackers, I’m always happy to have the conversation – because “it depends” which one you should get!  

If you want $40 off an OURA ring – use this link (it’s possible I’ll get a tee shirt, but I think that promotion is long over 😊):

ouraring.com/raf/d120a63065?utm_medium=iac_raf

FROM MEDSCAPE / BY HEIDI SPLETE

Wearable Monitors Confirm Impact of Sleep Patterns on Chronic Disease

Rapid eye movement (REM) sleep, deep sleep, and sleep irregularity were significantly associated with increased risk for a range of chronic diseases, based on a new study of > 6000 individuals. 

"Most of what we think we know about sleep patterns in adults comes from either self-report surveys, which are widely used but have all sorts of problems with over- and under-estimating sleep duration and quality, or single-night sleep studies," said corresponding author Evan L. Brittain, MD, of Vanderbilt University, Nashville, Tennessee, in an interview. 

The single-night study yields the highest quality data but is limited by extrapolating a single night's sleep to represent habitual sleep patterns, which is often not the case, he said. In the current study, published in Nature Medicine, "we had a unique opportunity to understand sleep using a large cohort of individuals using wearable devices that measure sleep duration, quality, and variability. The All of Us Research Program is the first to link wearables data to the electronic health record at scale and allowed us to study long-term, real-world sleep behavior," Brittain said.

The timing of the study is important because the American Heart Association now recognizes sleep as a key component of heart health, and public awareness of the value of sleep is increasing, he added. 

The researchers reviewed objectively measured, longitudinal sleep data from 6785 adults who used commercial wearable devices (Fitbit) linked to electronic health record data in the All of Us Research Program. The median age of the participants was 50.2 years, 71% were women, and 84% self-identified as White individuals. The median period of sleep monitoring was 4.5 years.

REM sleep and deep sleep were inversely associated with the odds of incident heart rhythm and heart rate abnormalities. Each percent increase in REM sleep was associated with a reduced incidence of atrial fibrillation (odds ratio [OR], 0.86), atrial flutter (OR, 0.78), and sinoatrial node dysfunction/bradycardia (OR, 0.72). A higher percentage of deep sleep was associated with reduced odds of atrial fibrillation (OR, 0.87), major depressive disorder (OR, 0.93), and anxiety disorder (OR, 0.94). 

Increased irregular sleep was significantly associated with increased odds of incident obesity (OR, 1.49), hyperlipidemia (OR, 1.39), hypertension (OR, 1.56), as well as major depressive disorder (OR, 1.75), anxiety disorder (OR, 1.55), and bipolar disorder (OR, 2.27). 

The researchers also identified J-shaped associations between average daily sleep duration and hypertension (P for nonlinearity = .003), as well as major depressive disorder and generalized anxiety disorder (both P < .001). 

The study was limited by several factors including the relatively young, White, and female study population. However, the results illustrate how sleep stages, duration and regularity are associated with chronic disease development, and may inform evidence-based recommendations on healthy sleeping habits, the researchers wrote.

Findings Support Need for Sleep Consistency 

"The biggest surprise for me was the impact of sleep variability of health," Brittain told Medscape Medical News. "The more your sleep duration varies, the higher your risk of numerous chronic diseases across the entire spectrum of organ systems. Sleep duration and quality were also important but that was less surprising," he said. 

The clinical implications of the findings are that sleep duration, quality, and variability are all important, Brittain told Medscape Medical News. "To me, the easiest finding to translate into the clinic is the importance of reducing the variability of sleep duration as much as possible," he said. For patients, that means explaining that they need to go to sleep and wake up at roughly the same time night to night, he said. 

"Commercial wearable devices are not perfect compared with research grade devices, but our study showed that they nonetheless collect clinically relevant information," Brittain added. "For patients who own a device, I have adopted the practice of reviewing my patients' sleep and activity data which gives objective insight into behavior that is not always accurate through routine questioning," he said.

As for other limitations, "Our cohort was limited to individuals who already owned a Fitbit; not surprisingly, these individuals differ from a random sample of the community in important ways, both demographic and behavioral, and our findings need to be validated in a more diverse population," said Brittain. 

Looking ahead, "we are interested in using commercial devices as a tool for sleep interventions to test the impact of improving sleep hygiene on chronic disease incidence, severity, and progression," he said.

Device Data Will Evolve to Inform Patient Care

"With the increasing use of commercial wearable devices, it is crucial to identify and understand the data they can collect," said Arianne K. Baldomero, MD, a pulmonologist and assistant professor of medicine at the University of Minnesota, Minneapolis, in an interview. "This study specifically analyzed sleep data from Fitbit devices among participants in the All of Us Research Program to assess sleep patterns and their association with chronic disease risk," said Baldomero, who was not involved in the study. 

The significant relationships between sleep patterns and risk for chronic diseases were not surprising, said Baldomero. The findings of an association between shorter sleep duration and greater sleep irregularity with obesity and sleep apnea validated previous studies in large-scale population surveys, she said. Findings from the current study also reflect data from the literature on sleep duration associated with hypertension, major depressive disorder, and generalized anxiety findings, she added.

"This study reinforces the importance of adequate sleep, typically around 7 hours per night, and suggests that insufficient or poor-quality sleep may be associated with chronic diseases," Baldomero told Medscape Medical News. "Pulmonologists should remain vigilant about sleep-related issues, and consider further investigation and referrals to sleep specialty clinics for patients suspected of having sleep disturbances," she said.

"What remains unclear is whether abnormal sleep patterns are a cause or an effect of chronic diseases," Baldomero noted. "Additionally, it is essential to ensure that these devices accurately capture sleep patterns and continue to validate their data against gold standard measures of sleep disturbances," she said.

HEY - Are you in there? Anybody Home?

When people are unconscious, it’s pretty clear that they are legitimately unresponsive -- they don’t know what’s going on around them.  But what about when someone is in a coma?  Are they still “conscious” but just can’t move?  Should you be holding someone’s hand, talking to them, encouraging them, etc.?  Does that make any difference?

I’ve attached an interesting article detailing how ¼ of coma patients show clear evidence that they know what’s going on around them.  This has profound implications for how they should be cared for and how, as caregivers/supporters, we should interact with these loved ones if they should unfortunately be stuck in a coma.  Be aware that everything that you say or do in earshot of this patient may be heard – and remembered!

Realize that this does not apply to patients that might be considered brain-dead – there is no electrical activity in those cases.  In coma cases there is still brain activity, but no conscious activity. 

FROM MEDPAGE TODAY / BY JUDY GEORGE

One in Four Brain Injury Patients Who Appear Unresponsive Respond Covertly

— Functional MRI and EEG detect awareness in coma or vegetative states

Key Takeaways

• One in four severe brain injury patients had cognitive-motor dissociation detected on EEG or fMRI.

• Despite appearing unresponsive, these patients repeatedly showed covert consciousness.

• Younger age, longer time since injury, and brain trauma were associated with cognitive-motor dissociation.

Cognitive-motor dissociation -- a phenomenon that occurs when patients who appear unresponsive perform cognitive tasks that can be detected on functional MRI (fMRI) or electroencephalography (EEG) -- occurred in one in four people with severe brain injury, a prospective cohort study found.

The study evaluated 241 unresponsive patients with brain injury who were given verbal commands -- to imagine playing tennis, or to imagine opening and closing their hand, for example.

Of these, 60 patients (25%) repeatedly showed brain activation on fMRI or EEG indicating they were covertly following instructions, reported Nicholas Schiff, MD, of Weill Cornell Medicine in New York City, and co-authors in the New England Journal of Medicine.

Cognitive-motor dissociation was associated with younger age, longer time since injury, and brain trauma as an etiologic factor. In total, 11 patients with cognitive-motor dissociation were assessed with fMRI only, 13 were assessed with EEG only, and 36 with both techniques.

"This research shows that a substantial fraction of apparently unresponsive, severely brain-injured persons are aware and can engage in sustained cognitive activity," Schiff told MedPage Today. "These findings importantly point to the need to establish infrastructure to evaluate patients and to begin efforts to test possible therapies to help them."

Persons with cognitive-motor dissociation have cognitive abilities that exceed their motor abilities, Schiff noted. "They show a sharp dissociation with a high level of retained cognitive ability and limited or no motor responses," he said.

Earlier work reported that cognitive-motor dissociation occurred in 15% to 20% of brain-injured patients who seemed unresponsive. One study suggested that detecting it soon after injury may predict recovery.

"The percentage of participants with cognitive motor dissociation is 5 to 10 percentage points higher in our study than in previous studies," Schiff and co-authors pointed out.

"This finding may be due to our multimodal approach, which classified the participants who underwent assessment with both techniques on the basis of responses on either fMRI or EEG," they wrote. "The percentage of participants with cognitive motor dissociation may have been even higher if all the participants had been assessed with both imaging techniques."

Schiff and colleagues evaluated 353 adults with disorders of consciousness at six sites from 2006 to 2023. Some sites recruited participants from intensive care units soon after severe brain injury trauma, stroke, or cardiac arrest; others included participants who had brain injury years ago.

The researchers conducted behavioral assessments using the Coma Recovery Scale-Revised (CRS-R). They divided participants into two groups based on whether responses to verbal commands or intelligible speech were observed during CRS-R evaluations.

Participants had a median age of about 38. The median time between brain injury and CRS-R assessment was 7.9 months; 25% of participants had a CRS-R evaluation within 28 days after injury. Brain trauma was an etiologic factor in 50% of cases.

Overall, 241 patients had a behavioral diagnosis of coma, vegetative state, or minimally conscious state-minus (i.e., they showed signs of awareness but not responses to commands or intelligible verbal output). The other 112 patients had observable responses to verbal commands.

In the group with observable response to verbal commands, fMRI or EEG detected covert responses in only 43 of 112 patients (38%).

"The paradigms used in studies of task-based fMRI and EEG may require more cognitive resources (e.g., short-term memory, selective attention, and mental persistence) than in typical command-following trials performed at the bedside," Schiff and co-authors suggested. "Although this hypothesis has not been proven, it is supported by our finding that responses on fMRI and EEG were detected in only 38% of the participants with an observable response to commands at the bedside."

American Academy of Neurology guidelines note that the natural history of disorders of consciousness is not well-defined and prognosis can be challenging. Recently, a propensity score analysis led by co-author Yelena Bodien, PhD, of Mass General Brigham in Boston, suggested that some patients with severe traumatic brain injury who had life support withdrawn may have survived and achieved at least partial independence.

"Our team's recent studies suggest there is a benefit to waiting before decisions are made to withdraw life support, because some patients may be more conscious than they appear, and patients with even the most severe injuries may recover and regain independence," Bodien told MedPage Today. "Our papers highlight the need for improved access to advanced testing, like with fMRI, long-term monitoring of recovery, and evidence-based medical guidelines so doctors do not have to rely on their past experiences to establish prognosis."

Survival bias may have influenced outcomes in this study, Schiff and colleagues said. Participating sites used heterogeneous strategies to acquire, analyze, and interpret fMRI and EEG data, they acknowledged.

"Our findings may therefore not be generalizable across all centers," the researchers wrote. "Large-scale validation studies are needed to improve data acquisition and analysis for clinical translation."

Skin Cancer Protection -- Is the FDA too slow (again)? As usual, it depends.

Many people have had complaints about the FDA’s regulatory processes.  Examples of “too fast” can be directed at numerous surgical products, like joint replacements and even cardiac tools, but also the recent challenges related to COVID vaccinations.  “Too slow” used to be attached (back in the day) to HIV-related treatments, but now one that could hit home to people you know – sunscreen protective agents.  As stated in the article, 2 Americans die every hour from skin cancer, with more skin cancers diagnosed than all other cancers combined.  Seems like we should take this seriously.

Meanwhile, in the US, we’re using old sunscreen agents for decades, most of which have never been fully tested.  That’s not to safe they’re unsafe – they have just been used starting before the tests were even initiated.  But any newer products are required to be fully tested before approval.  So agents that have been used worldwide (excluding the US) for over a decade are still not approved, and thus not sold here.  And people keep getting skin cancer…

I guess there isn’t a strong enough skin cancer lobby – not as sexy as breast cancer, I guess.  But one of the issues, I think, is that these products are non-prescription, so as a consumer product there are different hoops to jump through.  Plus, you can’t charge $10,000 a tube like you can for a drug.  

Supposedly we’re on track to have superior sun protection by 2025.  In the meantime – hats, sleeves, umbrellas, and lots of the old sunscreen.  Remember, 5 sunburns doubles your risk of melanoma, the deadliest form of skin cancer.

FROM NBC NEWS / BY MICHAEL SCATURRO

What's keeping the U.S. from allowing better sunscreens?

Products sold in Europe, Japan and South Korea offer more protection from the sun. In the U.S., the key ingredients aren't FDA-approved.

When dermatologist Dr. Adewole “Ade” Adamson sees people spritzing sunscreen as if it’s cologne at the pool where he lives in Austin, Texas, he wants to intervene. “My wife says I shouldn’t,” he said, “even though most people rarely use enough sunscreen.”

At issue is not just whether people are using enough sunscreen, but what ingredients are in it.

The Food and Drug Administration’s ability to approve the chemical filters in sunscreens that are sold in countries such as Japan, South Korea, and France is hamstrung by a 1938 U.S. law that requires sunscreens to be tested on animals and classified as drugs, rather than as cosmetics as they are in much of the world. So Americans are not likely to get those better sunscreens — which block the ultraviolet rays that can cause skin cancer and lead to wrinkles — in time for this summer, or even the next.

Sunscreen makers say that requirement is unfair because companies including BASF Corp. and L’Oréal, which make the newer sunscreen chemicals, submitted safety data on sunscreen chemicals to the European Union authorities some 20 years ago.

Steven Goldberg, a retired vice president of BASF, said companies are wary of the FDA process because of the cost and their fear that additional animal testing could ignite a consumer backlash in the European Union, which bans animal testing of cosmetics, including sunscreen. The companies are asking Congress to change the testing requirements before they take steps to enter the U.S. marketplace.

In a rare example of bipartisanship last summer, Sen. Mike Lee (R-Utah) thanked Rep. Alexandria Ocasio-Cortez (D-N.Y.) for urging the FDA to speed up approvals of new, more effective sunscreen ingredients. Now a bipartisan bill is pending in the House that would require the FDA to allow non-animal testing.

“It goes back to sunscreens being classified as over-the-counter drugs,” said Carl D’Ruiz, a senior manager at DSM-Firmenich, a Switzerland-based maker of sunscreen chemicals. “It’s really about giving the U.S. consumer something that the rest of the world has. People aren’t dying from using sunscreen. They’re dying from melanoma.”

Every hour, at least two people die of skin cancer in the United States. Skin cancer is the most common cancer in America, and 6.1 million adults are treated each year for basal cell and squamous cell carcinomas, according to the Centers for Disease Control and Prevention. The nation’s second-most-common cancer, breast cancer, is diagnosed about 300,000 times annually, though it is far more deadly.

Though skin cancer treatment success rates are excellent, 1 in 5 Americans will develop skin cancer by age 70. The disease has cost the health care system $8.9 billion a year, according to CDC researchers. One study found that the annual cost of treating skin cancer in the United States more than doubled from 2002 to 2011, while the average annual cost for all other cancers increased by just 25%. And unlike many other cancers, most forms of skin cancer can largely be prevented — by using sunscreens and taking other precautions.

But a heavy dose of misinformation has permeated the sunscreen debate, and some people question the safety of sunscreens sold in the United States, which they deride as “chemical” sunscreens. These sunscreen opponents prefer “physical” or “mineral” sunscreens, such as zinc oxide, even though all sunscreen ingredients are chemicals.

“It’s an artificial categorization,” said E. Dennis Bashaw, a retired FDA official who ran the agency’s clinical pharmacology division that studies sunscreens.

Innisfree's Daily UV Defense Sunscreen, made in South Korea, is sold in the U.S. and doesn't contain bemotrizinol.Chelsea Stahl and Elise Wrabetz / NBC News

Still, such concerns were partly fed by the FDA itself after it published a study that said some sunscreen ingredients had been found in trace amounts in human bloodstreams. When the FDA said in 2019, and then again two years later, that older sunscreen ingredients needed to be studied more to see if they were safe, sunscreen opponents saw an opening, said Nadim Shaath, president of Alpha Research & Development, which imports chemicals used in cosmetics.

“That’s why we have extreme groups and people who aren’t well informed thinking that something penetrating the skin is the end of the world,” Shaath said. “Anything you put on your skin or eat is absorbed.”

Adamson, the Austin dermatologist, said some sunscreen ingredients have been used for 30 years without any population-level evidence that they have harmed anyone. “The issue for me isn’t the safety of the sunscreens we have,” he said. “It’s that some of the chemical sunscreens aren’t as broad spectrum as they could be, meaning they do not block UVA as well. This could be alleviated by the FDA allowing new ingredients.”

Ultraviolet radiation falls between X-rays and visible light on the electromagnetic spectrum. Most of the UV rays that people come in contact with are UVA rays that can penetrate the middle layer of the skin and that cause up to 90% of skin aging, along with a smaller amount of UVB rays that are responsible for sunburns.

The sun protection factor, or SPF, rating on American sunscreen bottles denotes only a sunscreen’s ability to block UVB rays. Although American sunscreens labeled “broad spectrum” should, in theory, block UVA light, some studies have shown that they fail to meet the European Union’s higher UVA-blocking standards.

“It looks like a number of these newer chemicals have a better safety profile in addition to better UVA protection,” said David Andrews, deputy director of Environmental Working Group, a nonprofit that researches the ingredients in consumer products. “We have asked the FDA to consider allowing market access.”

The FDA defends its review process and its call for tests of the sunscreens sold in American stores as a way to ensure the safety of products that many people use daily, rather than just a few times a year at the beach.

“Many Americans today rely on sunscreens as a key part of their skin cancer prevention strategy, which makes satisfactory evidence of both safety and effectiveness of these products critical for public health,” Cherie Duvall-Jones, an FDA spokesperson, wrote in an email.

D’Ruiz’s company, DSM-Firmenich, is the only one currently seeking to have a new over-the-counter sunscreen ingredient approved in the United States. The company has spent the past 20 years trying to gain approval for bemotrizinol, a process D’Ruiz said has cost $18 million and has advanced fitfully, despite attempts by Congress in 2014 and 2020 to speed along applications for new UV filters.

Bemotrizinol is the bedrock ingredient in nearly all European and Asian sunscreens, including those by the South Korean brand Beauty of Joseon and Bioré, a Japanese brand.

D’Ruiz said bemotrizinol could secure FDA approval by the end of 2025. If it does, he said, bemotrizinol would be the most vetted and safest sunscreen ingredient on the market, outperforming even the safety profiles of zinc oxide and titanium dioxide.

As Congress and the FDA debate, many Americans have taken to importing their own sunscreens from Asia or Europe, despite the risk of fake products.

“The sunscreen issue has gotten people to see that you can be unsafe if you’re too slow,” said Alex Tabarrok, a professor of economics at George Mason University. “The FDA is just incredibly slow. They’ve been looking at this now literally for 40 years. Congress has ordered them to do it, and they still haven’t done it.”

Avoiding a Heart Attack -- Timing CAN BE Everything!

When am I supposed to take my blood pressure pill if I want to avoid a heart attack?  Well…. Are you a night-owl or a morning lark?  It matters – and it seems to matter A LOT!

Night owls (up late in the morning and to bed late in the evening) should take their pills at night – 34% lower risk of heart attack hospitalization.  What’s crazy, though, is that if those people take their medication in the morning – there’s a 62% INCREASED risk of the same. The reverse is mostly true for the morning larks – better risk for pills in the morning and worse risk for pills at night.  So, oddly enough – IT DEPENDS on who you are and recommendations need to be tailored to the individual.  

There’s more in the article – Chronotherapy is the whole concept to timing for one’s specific circadian rhythm or body clock.  Lots more yet to learn.

FROM MEDSCAPE INTERNAL MEDICINE / BY SARI HARRAR

Chronotherapy: Why Timing Drugs to Our Body Clocks May Work

Do drugs work better if taken by the clock?

A new analysis published in this month's issue of The Lancet journal's eClinicalMedicine suggests: Yes, they do — if you consider the patient's individual body clock. The study is the first to find that timing blood pressure drugs to a person's personal "chronotype" — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or "chronotherapy" — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

"We are really just at the beginning of an exciting new way of looking at patient care," said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München's Institute for Diabetes and Cancer focuses on metabolic physiology. Dyar is co-lead author of the new blood pressure analysis.

"Chronotherapy is a rapidly growing field," he said, "and I suspect we are soon going to see more and more studies focused on 'personalized chronotherapy,' not only in hypertension but also potentially in other clinical areas."

The 'Missing Piece' in Chronotherapy Research

Blood pressure drugs have long been chronotherapy's battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so "take at bedtime" has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

"We did this study thinking nocturnal blood pressure tablets might be better," said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study. "But there was no difference for heart attacks, strokes, or vascular death."

So, the researchers then looked at participants' chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise "night owls" or early-to-bed, early-to-rise "morning larks."

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for "owls" who took their drugs at bedtime. By contrast, owls' heart attack risk was at least 62% higher with morning doses. For "larks," the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine's success.

"Our 'internal personal time' appears to be an important variable to consider when dosing antihypertensives," said lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine, who conceived the study. "Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven't considered the internal time of individual people. I think that is the missing piece."

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. "We started it late in the original TIME study," MacDonald said. "You could argue we were reporting on those who survived long enough to get into the analysis." More research is needed, they concluded.

Looking Beyond Blood Pressure

What about the rest of the body? "Almost all the cells of our body contain 'circadian clocks' that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles," said Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that synching a drug with a person's body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

"The sweet spot in our data was somewhere around late morning to late afternoon," said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the Division of Pulmonary and Critical Care Medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

"Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking," the researchers noted. But "prospective randomized trials are needed to establish recommendations for optimal circadian timing."

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren't healthcare providers adding time of day to more prescriptions? "What's missing is more reliable data," Dyar said.

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn't well-controlled. Dyar and Pigazzani said night-time blood pressure drugs may be helpful for people with a "late chronotype." Of course, patients shouldn't change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants' chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves "morning types" or "evening types." (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Pigazzani said. "However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension."

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Haspel said. But the most important thing is getting vaccinated. "If you can only get one in the evening, it's still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups."

Statins for Atrial Fibrillation? Not just cholesterol?

Hey – one more stuck in my outbox.  

Nobody wants to take medications they don’t have to.  Many of my patients are especially concerned about taking statins (cholesterol meds like Lipitor/atorvastatin or Crestor/rosuvastatin to name a couple) fearing side effects or other issues, not to mention whether or not it’s actually benefiting them.  This is an active conversation with all of my folks, really regardless of what meds they might be taking.

Now a study came out supporting the idea that those with atrial fibrillation would benefit from taking a cholesterol lowering drug.  How does that make sense?

One needs to understand that lowering cholesterol (mainly the large LDL portion) is only one thing that the HMG CoA Reductase Inhibitors (yeah, that’s really what a Statin is) does.  That effect takes weeks.  But it’s long been known that statins can have benefit within 3 days.  Turns out that statins stabilize the blood vessel walls, making heart attacks are that much harder to happen.  We take advantage of this fact in patients with Long COVID as well, since micro-clots seem to be at the heart of a lot of the LC problems and this activity keeps that process slowed.  

As usual, the body does more than one thing with one process.  That’s why drugs can be problematic, but sometimes those “side effects” can translate into a real “up” side – think Viagra 😉.

FROM MEDSCAPE INTERNAL MEDICINE / BY DANIEL M. KELLER PhD

Statins Tied to Lower Stroke Risk in Atrial Fibrillation

Among patients with atrial fibrillation (AF), initiation of statins soon after diagnosis was protective against stroke and related vascular events, and longer duration of use was associated with greater protection, a new cohort study shows.

Statin use was associated with lower risks of ischemic stroke or systemic embolism, hemorrhagic stroke, and transient ischemic attack (TIA), regardless of whether patients were also taking anticoagulant medications.

Lead author Jiayi Huang, a PhD student at Hong Kong University at Shenzhen Hospital, Shenzhen, China, concluded that the study's findings support the use of statins to prevent stroke for patients with new-onset AF.

"The findings have important clinical implications, particularly given that in atrial fibrillation, patients' ischemic strokes are often fatal or disabling and have a high risk of recurrence," she said.

The results were presented in a moderated poster session at the European Heart Rhythm Association (EHRA) 2023 in Barcelona and are available online.

Widely Prescribed

Anticoagulant drugs are prescribed to lower the fivefold increased risk of stroke among individuals with AF compared with those without AF, but the therapy does not eliminate the higher risk, Huang explained. And although statins are widely prescribed to reduce the likelihood of myocardial infarction and stroke, "the benefit of statins for stroke prevention in patients with atrial fibrillation has been unclear," she said.

Huang and colleagues analyzed data from 51,472 patients newly diagnosed with AF between 2010 and 2018. The population was divided into statin users (n = 11,866), defined as patients who had taken statins for at least 19 consecutive days in the first year after AF diagnosis, and statin nonusers (n = 39,606), based on whether they were prescribed statin therapy after their first diagnosis of AF.

The median age of the cohort was 74.9 years, and 47.7% were women. The investigators used statistical methods to balance baseline covariates between the two groups.

The primary outcomes were ischemic stroke or systemic embolism, hemorrhagic stroke, and TIA. Median follow-up was 5.1 years.

Statin use was associated with a significantly lower risk of all outcomes compared with nonuse. Statin users had a 17% reduced risk of ischemic stroke or systemic embolism, a 7% reduced risk of hemorrhagic stroke, and a 15% rate of reduced risk of TIA, Huang reported.

Are Benzoyl Peroxide Acne treatments safe?

Benzoyl peroxide is a stalwart acne treatment for many years.  But is it safe?  There’s been some recent studies calling this into question.

Let’s take a trip in the time machine back to my days in college chemistry lab.  We used pure benzoyl peroxide as a free radical initiator for plastics polymerization.  Huh?  The point here is that it makes free radicals, which are, by nature somewhat destructive (in lab you needed to portion the benzoyl peroxide with a paper spatula because if it contacted a static electric charge – like if you used a metal spatula – you risked literally blowing up the lab!).  This inflammatory response is helpful in causing the acne-related bacteria to “explode” on their own.  

So what’s the problem?  Benzoyl peroxide (as I’ve already suggested) is pretty unstable.  When benzoyl peroxide degrades, it ends up, at least in part, as benzene, a highly toxic, carcinogenic compound. Recent testing suggests that’s exactly what’s happening to several acne products (800 times higher levels than the FDA says is ok).  

What we don’t know is what does this really mean in terms of outcomes.  Says, it’s concentrated, but how much is really getting to the patient?  Benzene is volatile, so when you open the tube, it leaks into the air – is the problem inhalation (there is some risk there)?  Is the amount you’re using for acne enough to actually make a difference?  Is it a consequence of persistent exposure (do you need to use it for years)?  Lots of questions, not many answers.

Bottom line for me is if there are no alternatives, it’s hard to believe that benzoyl peroxide is going to substantially increase your risks compared to all the other terrible stuff we’re being exposed to everyday already. 

FROM MEDSCAPE INTERNAL MEDICINE / BY KATHLEEN DOHENY

Benzoyl Peroxide in Acne Products: Debates, Uncertainty Over Safety

Nine days after the independent laboratory Valisure petitioned the US Food and Drug Administration (FDA) to recall acne products with benzoyl peroxide (BP) because of the lab's findings of extremely high levels of the carcinogen benzene, it published another report in Environmental Health Perspectives (EHP) on March 14, also warning about BP acne products.

The bottom line was the same: The laboratory, based in New Haven, Connecticut, said its analyses raise substantial concerns about the safety of BP-containing acne products currently on the market.

The lab's results showed that the products can form over 800 times the conditionally restricted FDA concentration limit of 2 parts per million (ppm) of benzene, with both prescription and over-the-counter products affected.

"This is a problem of degradation, not contamination," David Light, CEO and founder of Valisure, said in a telephone interview. BP can decompose into benzene, and exposure to benzene has been linked with a higher risk for leukemia and other blood cancers, according to the American Cancer Society.

In the wake of the findings, however, debate has erupted over the method and approach used by Valisure to test these products, with critics and companies contending that more "real-world" use data are needed. And the US Pharmacopeia (USP) is asking for full transparency about the testing methods.

In a March 8 statement, USP said the petition indicated that modified USP methods were used in the study, noting that "if changes are made to a USP method, complete validation data is necessary to demonstrate that a product meets USP standards."

However, Valisure contended that drug products need to demonstrate stability over the entire life cycle, from shipment to continued use, emphasizing that constitutes the best "real-world" approach. It also defended the methodology it used.

The reports have led to a state of uncertainty about the use of BP products.

"Right now, we have more unknowns than anything else," John Barbieri, MD, MBA, assistant professor of dermatology at Harvard Medical School and director of the Advanced Acne Therapeutics Clinic at Brigham and Women's Hospital, Boston, Massachusetts, said in a video posted on X and YouTube, summarizing the findings released by Valisure on March 6 and 14. He was not involved in the Valisure research.

In a telephone interview, Barbieri said the report "needs to be taken seriously," but he also believed the Valisure report is lacking information about testing under "real-world" conditions. He is calling for more information and more transparency about the data. What's clear, Barbieri told Medscape Medical News, is that the findings about high benzene levels are not a manufacturing error. "It's something to do with the molecule itself."

Valisure's Analyses

Valisure performed an initial analysis, using a method called gas chromatography-mass spectrometry, which is the FDA-preferred method for detecting benzene, Light said. It tested 175 acne products, 99 containing BP and 76 with other ingredients, such as salicylic acid. All the products without BP had no detectable benzene or values below 2 ppm, the FDA concentration limit for benzene.

Of the 99 BP products, 94 contained benzene without any elevated temperature incubation, according to Valisure. Using 50 °C (122 °F, the accepted pharmaceutical stability testing temperature) on 66 products, Valisure detected over 1500 ppm of benzene in two products, over 100 ppm in 17 products, and over 10 ppm in 42 products over an 18-day period.

The analysis confirmed, Valisure said in a press release and the petition, that a substantial amount of benzene can form in a BP product and leak outside the packaging into surrounding air.

The EHP paper, which includes authors from Valisure, reported that researchers took single lots of seven branded BP products, namely, Equate Beauty 2.5% BP cleansers, Neutrogena 10% BP cleanser, CVS Health 10% BP face wash, Walgreens 10% BP cream, Clean & Clear 10% cleanser, Equate Beauty 10% BP acne wash, and Proactiv 2.5% BP cleanser.

Using testing that involved gas chromatography-mass spectrometry, benzene was detected in all the BP products samples tested, and levels increased during incubation at body and shelf-life performance temperatures to more than 2 ppm. The authors concluded that the study "raises substantial concerns" about the safety of BP products currently on the market.

Methodology Debates

Two days after Valisure released its analysis on March 6, the USP reviewed the citizen's petition filed by Valisure and called for more transparency around the testing methods.

"The petition referenced USP and indicated that modified USP methods and procedures were used in the study. The presence of unsafe levels of benzene should be taken seriously," the statement said. The USP statement also noted that the Valisure analysis used modified USP methods and said that "if changes are made to a USP method, complete validation data is necessary to demonstrate that a product meets USP standards."

In its statement, USP took issue with a practice known as accelerated thermal degradation, which it said Valisure used. USP said the approach involves raising the storage temperature of a product to higher than the temperature indicated on the label for the purpose of simulating degradation over a longer period. While the approach may be acceptable, USP said, the temperatures chosen may not be what is expected to happen to the products.

In response, Light of Valisure referenced guidance issued in August, 2020, from the FDA, stating that the method it used in the BP analysis can be used to detect impurities in hand sanitizers, including benzene. (In 2021, Valisure detected high levels of benzene in some hand sanitizers and asked the FDA to take action.)

Company Response

Among the companies that took issue with the report was Reckitt, which makes Clearasil, which contains BP. In a statement, the company said, in part: "The products and their ingredients are stable over the storage conditions described on their packaging which represent all reasonable and foreseeable conditions." It said the findings presented by Valisure reflect "unrealistic scenarios rather than real-world conditions."

The Personal Care Products Council, a national trade association that represents cosmetic and personal care product manufacturers, also took issue with the findings and the approach used to evaluate the products.

FDA and the Citizen's Petition

The FDA accepted the petition, Light said, and gave it a docket number. "We'll hopefully hear more soon" because the FDA is required to respond to a citizen's petition within 180 days, he said.

"We generally don't comment on pending citizens' petitions," an FDA spokesperson said in an email. "When we respond, we will respond directly to the petitioner and post the response in the designated agency public docket."

Valisure's Patent Application

Light and others have applied for a patent on methods of producing shelf-stable formulations to prevent degradation of BP to benzene.

"We saw the problem long before we had any sort of application," Light said. The issue has been "known for decades."

Role of BP Products for Acne

In the midst of uncertainty, "the first discussion is, do we want to use it?" Barbieri said in the interview. Some patients may want to avoid it altogether, until more data are available, including more verification of the findings, while others may be comfortable accepting the potential risk, he said.

"Benzoyl peroxide is one of our foundational acne treatments," Barbieri said. In the American Academy of Dermatology updated guidelines on acne, published in January, 2024, strong recommendations were made for BP products, as well as topical retinoids, topical antibiotics, and oral doxycycline.

"When you take away BP, there's no substitute for it," Barbieri said. And if patients don't get improvement with topicals, oral medications might be needed, and "these all have their own risks."

In the Interim

Until more information is available, Barbieri is advising patients not to store the products at high temperatures or for a long time. Don't keep the products past their expiration date, and perhaps keep products for a shorter time, "something like a month," he said.

Those living in a hot climate might consider storing the products in the refrigerator, he said.

"We need more data from Valisure, from other groups that confirm their findings, and we need to hear from the FDA," Barbieri said. "There's a lot of uncertainty right now. But it's important not to overreact."

Chronic Fatigue/Fibromyalgia/Weird Pain/Swelling? LDN Can Work

If you’ve never heard of LDN either you’re lucky because you don’t possibly need it, or unlucky because you do.  LDN stands for Low Dose Naltrexone, a drug used primarily for addiction and alcoholism, but typically dosed 50-100 mg a day.  Low Dose is between 1 and 5 mg/day and it works differently at that dosage range.  

At high dose it blocks the opiate receptor, making a “high” impossible, thus effective as an anti-addiction treatment.  What’s really cool is that at low doses it has an anti-inflammatory effect on the microglial cells (the brain and spinal cord’s inflammation managing cells), thus having a positive impact on “cooling” central nervous system pain, so can be very effective in patients with conditions like fibromyalgia or chronic fatigue syndrome.  

Recently a study came out that said there was no difference between those treated and placebo.  The details, of course, are important – dose of the LDN was a little higher than most; it didn’t show pain improvement, but patients had significantly better brain function – so, it didn’t work??!?  That’s what the accompanying commentary from the article said, but most are not buying it.  

I’ve had multiple patients with generalized achiness, pain, swelling, etc with no clear causes, and nothing else obviously off who have responded quite well to LDN.  Some have had near complete resolution of their issues.  As far as I’m concerned, anyone in these categories, it’s worth a shot.  

The point?  There’s lots of headlines that get the details all wrong.  I may not read every word, but I make sure I read enough of them the get the details right!

FROM MEDSCAPE INTERNAL MEDICINE / BY MIRIAM E. TUCKER

Low-Dose Naltrexone Researcher Disputes Fibromyalgia Study Negativity

Neuroinflammation expert Jarred Younger, PhD, disputes a recent study commentary calling for clinicians to stop prescribing low-dose naltrexone for people with fibromyalgia.

Naltrexone is a nonselective µ-opioid receptor antagonist approved by the US Food and Drug Administration (FDA) at doses of 50-100 mg/day to treat opioid and alcohol dependence. Lower doses, typically 1-5 mg, can produce an analgesic effect via antagonism of receptors on microglial cells that lead to neuroinflammation. The low-dose version, available at compounding pharmacies, is not FDA-approved, but for many years it has been used off-label to treat fibromyalgia and related conditions.

Results from earlier small clinical trials have conflicted, but two conducted by Younger using doses of 4.5 mg/day showed benefit in reducing pain and other fibromyalgia symptoms. However, a new study from Denmark on 6 mg low-dose naltrexone versus placebo among 99 women with fibromyalgia demonstrated no significant difference in the primary outcome of change in pain intensity from baseline to 12 weeks.

On the other hand, there was a significant improvement in memory, and there were no differences in adverse events or safety, the authors reported in Lancet Rheumatology.

Nonetheless, an accompanying commentary called the study a "resoundingly negative trial" and advised that while off-label use of low-dose naltrexone could continue for patients already taking it, clinicians should not initiate it for patients who have not previously used it, pending additional data.

Younger, director of the Neuroinflammation, Pain and Fatigue Laboratory at the University of Alabama, Birmingham, was speaking on December 13, 2023, at a National Institutes of Health meeting about myalgic encephalomyelitis/chronic fatigue syndrome about the potential use of low-dose naltrexone for that patient population. He had checked the literature in preparation for his talk and saw the new study, which had just been published December 5, 2023. 

During his talk, Younger said, "It looks like the study was very well done, and all the decisions made sense to me, so I don't doubt the quality of their data or the statistics."

But as for the commentary, he said, "I strongly disagree, and I believe the physicians at this conference strongly disagree with that as well. I know plenty of physicians who would say that is not good advice because this drug is so helpful for so many people."

Indeed, Anthony L. Komaroff, MD, who heard Younger's talk but hadn't seen the new study, told Medscape Medical News that he is a "fan" of low-dose naltrexone based on his own experience with one patient who had a "clearly beneficial response" and that of other clinicians he's spoken with about it. "My colleagues say it doesn't work for everyone because the disease is so heterogeneous…but it definitely works for some patients."

Younger noted that the proportion of people in the Danish study who reported a clinically significant, that is 30% reduction, in pain scores was 45% versus 28% with placebo, not far from the 50% he found in his studies. "If they'd had 40 to 60 more people, they would have had statistically significant difference," Younger said.

Indeed, the authors themselves pointed this out in their discussion, noting, "Our study was not powered to detect a significant difference regarding responder indices…Subgroups of patients with fibromyalgia might respond differently to low-dose naltrexone treatment, and we intend to conduct a responder analysis based on levels of inflammatory biomarkers and specific biomarkers of glial activation, hypothesising that an inflammatory subgroup might benefit from the treatment. Results will be published in subsequent papers."

The commentary authors responded to that, saying that they "appreciate" the intention to conduct that subgroup analysis, but that it is "probable that the current sample size will preclude robust statistical comparisons but could be a step to generate hypotheses."

Those authors noted that a systematic review has described both pro-inflammatory (tumor necrosis factor, interleukin [IL]-6, and IL-8) and anti-inflammatory (IL-10) cytokines as peripheral inflammatory biomarkers in patients with fibromyalgia. "The specific peripheral biomarkers of glial activation are yet to be identified. The neuroinflammation hypothesis of fibromyalgia could be supported if a reduction of central nervous system inflammation would predict improvement of fibromyalgia symptoms. Subsequent work in this area is eagerly awaited."

In the meantime, Younger said, "I do not think this should stop us from looking at low-dose naltrexone [or that] we shouldn't try it. I've talked to over a thousand people over the last 10 years. It would be a very bad thing to give up on low-dose naltrexone now."

Could your arthritic knee be destroying brain cells?

Well, yeah, could be.  Not really a big surprise – inflammation associated with knee arthritis (chronic knee pain) shows accelerated brain cell aging.  Not a surprise because we know that inflammation is the route of all bad things… though it’s a necessary part of normal function as well.  Controlled inflammation (i.e. regular exercise) is good for you.  Uncontrolled inflammation is bad for you.  This article talks about a single specific gene, but there are a multitude of genes that impact inflammation.  We look at these – managing the response to inflammation with this guidance can be both very helpful and likely has more long-term impact than we probably even know.  

Opportunities for better health abound – Limitless Healing is our tagline!

FROM MEDSCAPE INTERNAL MEDICINE / BY MEGAN BROOKS

Chronic Pain Linked to Accelerated Brain Aging

The consequences of chronic musculoskeletal pain (CMP) may extend well beyond physical discomfort, potentially leading to faster aging of the brain, new research showed.

Using structural MRI data from more than 9000 adults with knee osteoarthritis (KOA) from the UK Biobank, investigators developed a brain age model to compare an individual's brain age with their chronological age. Those with KOA showed a much faster rate of brain aging than healthy individuals.

The acceleration in brain aging was largely driven by the hippocampus and predicted memory decline and incident dementia during follow-up. Researchers identified a gene highly expressed in glial cells as a possible genetic factor for accelerated brain aging.

"We demonstrate the accelerated brain aging and cognitive decline in chronic musculoskeletal pain, in particular knee osteoarthritis, and provide a neural marker for early detection and intervention," co-first author Jiao Liu, PhD candidate, Chinese Academy of Sciences, Beijing, China, told Medscape Medical News.

"We are interested to know how to slow down the aging brain in chronic musculoskeletal pain patients. Proper exercise and lifestyle may reduce the risk," Liu said.

Common Condition

CMP affects more than 40% of the world's population and has been shown to have a harmful impact on cognitive function, although the exact mechanisms remain unclear. Prior research suggests that inflammatory markers associated with brain aging are higher in patients with CMP, suggesting a link between brain aging and CMP.

To investigate further, researchers explored patterns of brain aging in healthy cohorts and cohorts with four common types of CMP — chronic knee pain, chronic back pain, chronic neck pain, and chronic hip pain.

Using their brain age model, investigators observed significantly increased brain aging, or "predicted age difference," only in individuals with KOA (P < .001). The observation was validated in an independent dataset (P = .020), suggesting a pattern of brain aging acceleration specific to KOA.

This acceleration was primarily driven by key brain regions involved in cognitive processing, including hippocampus and orbitofrontal cortex, and was correlated with longitudinal memory decline and dementia risk.

These data also suggest that the SLC39A8 gene, which is highly expressed in glial cells, might be a key genetic factor underpinning this acceleration.

"We not only revealed the specificity of accelerated brain aging in knee osteoarthritis patients, but importantly, we also provided longitudinal evidence suggesting the ability of our brain aging marker to predict future memory decline and increased dementia risk," corresponding author Yiheng Tu, PhD, also with Chinese Academy of Sciences, Beijing, China, said in a news release.

A Future Treatment Target?

Commenting on this research for Medscape Medical News, Shaheen Lakhan, MD, PhD, neurologist, and researcher based in Miami, Florida, noted that in this study, people with KOA showed signs of "faster brain aging on scans. Think of it as your brain wearing a disguise, appearing older than its actual years," Lakhan said.

"Inflammation, a key player in osteoarthritis, might be playing a double agent, wreaking havoc not just on your joints but potentially on your memory too. Researchers even identified a specific gene linked to both knee pain and faster brain aging, hinting at a potential target for future treatments," he added.

"Importantly, the increased risk of cognitive decline and dementia associated with chronic pain is likely one of many factors, and probably not a very high one on its own," Lakhan noted.

The "good news," said Lakhan, is that there are many "well-established ways to keep your brain sharp. Regular exercise, a healthy diet, and staying mentally stimulated are all proven strategies to reduce dementia risk. Think of chronic pain management as another tool you can add to your brain health toolbox."

Good way to get unhealthy-- Eat late and eat fast

A very good summary article of lots of little tidbits about eating and issues.  

Eating fast leads to a bunch of problems.  While eating slow leads to lower calories for those not-so-heavy, it may not make any difference if you’re already obese.  But eating late (evening or lots later in the day) has substantially increased risks of weight gain.  Even time restricted eating is better if you make your eating window earlier in the day.

The article even suggests a truly radical concept:  Eat only if you are hungry, don’t if you’re not!  RADICAL!

FROM MEDSCAPE INTERNAL MEDICINE / by john watson

Speedy Eating and Late-Night Meals May Take a Toll on Health

You are what you eat, as the adage goes. But a growing body of evidence indicates that it's not just what and how much you eat that influence your health. How fast and when you eat also play a role.

Research now indicates that these two factors may affect the risk for gastrointestinal problems, obesity, and type 2 diabetes (T2D). Because meal timing and speed of consumption are modifiable, they present new opportunities to change patient behavior to help prevent and perhaps address these conditions.

Not So Fast

Most people are well acquainted with the short-term gastrointestinal effects of eating too quickly, which include indigestion, gas, bloating, and nausea. But regularly eating too fast can cause long-term consequences.

Obtaining a sense of fullness is key to staving off overeating and excess caloric intake. However, it takes approximately 20 minutes for the stomach to alert the brain to feelings of fullness. Eat too quickly and the fullness signaling might not set in until you've consumed more calories than intended. Research links this habit to excess body weight.

The practice also can lead to gastrointestinal diseases over the long term because overeating causes food to remain in the stomach longer, thus prolonging the time that the gastric mucosa is exposed to gastric acids.

A study of 10,893 adults in Korea reported that those with the fastest eating speed (< 5 min/meal) had a 1.7 times greater likelihood of endoscopic erosive gastritis than those with the slowest times (≥ 15 min/meal). Faster eating also was linked to increased risk for functional dyspepsia in a study involving 89 young-adult female military cadets in Korea with relatively controlled eating patterns.

On the extreme end of the spectrum, researchers who performed an assessment of a competitive speed eater speculated that the observed physiological accommodation required for the role (expanding the stomach to form a large flaccid sac) makes speed eaters vulnerable to morbid obesity, gastroparesis, intractable nausea and vomiting, and the need for gastrectomy.

The risk for metabolic changes and eventual development of T2D also appear to be linked to how quickly food is consumed.

Two clinical studies conducted in Japan — a cohort study of 2050 male factory workers and a nationwide study with 197,825 participants — identified a significant association between faster eating and T2D and insulin resistance. A case-control study involving 234 patients with new onset T2D and 468 controls from Lithuania linked faster eating to a greater than twofold risk for T2D. And a Chinese cross-sectional study of 7972 adults indicated that faster eating significantly increased the risk for metabolic syndrome, elevated blood pressure, and central obesity in adults.

Various hypotheses have been proposed to explain why fast eating may upset metabolic processes, including a delayed sense of fullness contributing to spiking postprandial glucose levels, lack of time for mastication causing higher glucose concentrations, and the triggering of specific cytokines (eg, interleukin-1 beta and interleukin-6) that lead to insulin resistance. It is also possible that the association is the result of people who eat quickly having relatively higher body weights, which translates to a higher risk for T2D.

However, there's an opportunity in the association of rapid meal consumption with gastrointestinal and metabolic diseases, as people can slow the speed at which they eat so they feel full before they overeat.

A 2019 study in which 21 participants were instructed to eat a 600-kcal meal at a "normal" or "slow" pace (6 minutes or 24 minutes) found that the latter group reported feeling fuller while consuming fewer calories.

This approach may not work for all patients, however. There's evidence to suggest that tactics to slow down eating may not limit the energy intake of those who are already overweight or obese.

Patients with obesity may physiologically differ in their processing of food, according to Michael Camilleri, MD, consultant in the Division of Gastroenterology and Hepatology at Mayo Clinic in Rochester, Minnesota.

"We have demonstrated that about 20%-25% of people with obesity actually have rapid gastric emptying," he told Medscape Medical News. "As a result, they don't feel full after they eat a meal and that might impact the total volume of food that they eat before they really feel full."

The Ideal Time to Eat

It's not only the speed at which individuals eat that may influence outcomes but when they take their meals. Research indicates that eating earlier in the day to align meals with the body's circadian rhythms in metabolism offers health benefits.

"The focus would be to eat a meal that syncs during those daytime hours," Collin Popp, PhD, MS, RD, a research scientist at the NYU Grossman School of Medicine in New York, told Medscape Medical News. "I typically suggest patients have their largest meal in the morning, whether that's a large or medium-sized breakfast, or a big lunch."

A recent cross-sectional study of 2050 participants found that having the largest meal at lunch protected against obesity (odds ratio [OR], 0.71), whereas having it at dinner increased the risk for obesity (OR, 1.67) and led to higher body mass index.

Consuming the majority of calories in meals earlier in the day may have metabolic health benefits, as well.

A 2015 randomized controlled trial involving 18 adults with obesity and T2D found that eating a high-energy breakfast and a low-energy dinner leads to reduced hyperglycemia throughout the day compared with eating a low-energy breakfast and a high-energy dinner.

Time-restricted eating (TRE), a form of intermittent fasting, also can improve metabolic health depending on the time of day.

A 2023 meta-analysis found that TRE was more effective at reducing fasting glucose levels in participants who were overweight and obese if done earlier rather than later in the day. Similarly, a 2022 study involving 82 healthy patients without diabetes or obesity found that early TRE was more effective than mid-day TRE at improving insulin sensitivity and that it improved fasting glucose and reduced total body mass and adiposity, while mid-day TRE did not.

A study that analyzed the effects of TRE in eight adult men with overweight and prediabetes found "better insulin resistance when the window of food consumption was earlier in the day," noted endocrinologist Beverly Tchang, MD, an assistant professor of clinical medicine at Weill Cornell Medicine with a focus on obesity medication.

Patients May Benefit From Behavioral Interventions

Patients potentially negatively affected by eating too quickly or at late hours may benefit from adopting behavioral interventions to address these tendencies. To determine if a patient is a candidate for such interventions, Popp recommends starting with a simple conversation.

"When I first meet patients, I always ask them to describe to me a typical day for how they eat — when they're eating, what they're eating, the food quality, who are they with — to see if there's social aspects to it. Then try and make the recommendations based on that," said Popp, whose work focuses on biobehavioral interventions for the treatment and prevention of obesity, T2D, and other cardiometabolic outcomes.

Tchang said she encourages her patients to be mindful of hunger and fullness cues.

"Eat if you're hungry; don't force yourself to eat if you're not hungry," she said. "If you're not sure whether you're hungry or not, speak to a doctor because this points to an abnormality in your appetite-regulation system, which can be helped with GLP-1 [glucagon-like peptide 1] receptor agonists."

Adjusting what patients eat can help them improve their meal timing.

"For example, we know that a high-fiber diet or a diet that has a large amount of fat in it tends to empty from the stomach slower," Camilleri said. "That might give a sensation of fullness that lasts longer and that might prevent, for instance, the ingestion of the next meal."

Those trying to eat more slowly are advised to seek out foods that are hard in texture and minimally processed.

A study involving 50 patients with healthy weights found that hard foods are consumed more slowly than soft foods and that energy intake is lowest with hard, minimally processed foods. Combining hard-textured foods with explicit instructions to reduce eating speed has also been shown to be an effective strategy. For those inclined to seek out technology-based solution, evidence suggests that a self-monitoring wearable device can slow the eating rate.

Although the evidence is mounting that the timing and duration of meals have an impact on certain chronic diseases, clinicians should remember that these two factors are far from the most important contributors, Popp said.

"We also have to consider total caloric intake, food quality, sleep, alcohol use, smoking, and physical activity," he said. "Meal timing should be considered as under the umbrella of health that is important for a lot of folks."

That's not Teen Spirit... That's an upcoming trauma reaction

It doesn’t Smell(s) Like Teen Spirit --  but it does smell like an upcoming PTSD episode.  At least that’s what a couple of highly trained dogs would tell you.  

This article is a testament to the creativity and ingenuity of some folks who are willing to experiment with innate talents.  Dogs have crazy sensitive noses, and people smell funny at times.  Turns out that you can have dogs differentiate certain chemicals (VOCs – volatile organic compounds), and identify people who are (in this case) experiencing a trauma reaction (think PTSD flashback).  What’s really interesting is the presumed difference between the dog’s sensitivities – one to shame, the other to anxiety.  

Anyway, I thought this is a cool thing that points to some interesting possibilities.  VOC sensors are getting pretty sophisticated, so maybe there’ll be a device that one could wear to detect the buildup of these chemicals to signal the individual so they could avoid disaster.

Just thinking out loud…

FROM MEDSCAPE INTERNAL MEDICINE / BY PAULINE ANDERSON

Dogs Able to Sniff Out PTSD, Other Trauma, in Human Breath

Dogs can detect stress-related compounds in the breath of people experiencing early signs of trauma, including those with posttraumatic stress disorder (PTSD), a new proof-of-concept study suggested.

The research provides evidence that some service dogs with PTSD can be trained to detect episodes of pending distress through a person's breath and perhaps prompt the individual to use coping skills to manage the episode.

"Ours is the first study to demonstrate that at least some dogs can detect putative stress-related volatile organic compounds in human breath that are associated with PTSD symptoms," study author Laura Kiiroja, PhD candidate, Department of Psychology and Neuroscience, Faculty of Science, Dalhousie University, Halifax, Nova Scotia, Canada, told Medscape Medical News.

The study was published online on March 28, 2024, in Frontiers of Allergy.

Heightened Sense of Smell

The lifetime prevalence of PTSD is about 8% in the general population, but data show it can reach 23% in veterans. In addition, many more trauma-exposed individuals experience subthreshold symptoms.

Research is investigating the application of dogs' sense of smell, which is up to 100,000 times more sensitive than humans', to detect cancers, viruses, parasites, hypoglycemia, and seizures in humans.

There is also some evidence that dogs can detect putative stress-related volatile organic compounds (VOCs) such as isoprene and monoterpenes from the human body through urine, sweat, and breath, with the greatest success achieved with breath.

The new study included 26 mostly civilian "donors" (mean age, 31 years; 18 females) who had experienced various types of trauma but had no severe mental illness. More than 50% met the criteria for PTSD.

Participants were recruited from a study examining neurocognitive mechanisms underlying the potential links between trauma and cannabis use. However, participants in the dog study abstained from using cannabis for at least 12 hours prior to the study experiments.

Breath Donors

Breath samples were collected via disposable medical-grade face masks at baseline and during ensuing experiments. In total, 40 breath sample sets were collected.

Two female companion dogs — Ivy, a red golden retriever, and Callie, a German shepherd/Belgian Malinois mix — were trained to identify target odors from the samples.

The animals were tested to determine whether they were able to discriminate between breath samples collected from these same "breath donors" during a relatively relaxed state and during induced stress testing which is known as the alternative forced choice discrimination test.

The dogs' ability to discern trauma cues from breath samples of various individuals was tested by presenting one sample (baseline or trauma cue) at a time. The researchers used signal detection theory to evaluate the sensitivity and specificity of dogs in detecting human stress VOCs.

Investigators found the dogs had about a 90% accuracy rate across all sample sets in the discrimination experiment and 74% and 81% accuracy for Ivy and Callie, respectively, in the detection experiment.

"Our study contributed to the evidence showing that not only are dogs able to detect some physical health conditions in humans but also that some mental health conditions alter the released VOCs in a way that is detectable by dogs," Kiiroja said.

Emotion Detectors

At baseline and during each cue exposure, donors reported their affect using the Positive and Negative Affect Schedule. Ivy's performance correlated with the donors' self-reported anxiety, and Callie's performance correlated with the donors' self-reported shame.

Based on these correlations, the researchers speculate Ivy detected VOCs that likely originated from the sympathetic-adrenomedullary axis, which involves adrenaline and noradrenaline.

VOCs detected by Callie likely originated in the hypothalamus-pituitary-adrenal axis, which involves cortisol and corticosterone. These two endocrine subsystems play a major role in reestablishing homeostasis in response to a stressor.

The results suggest some service dogs could alert to upcoming intrusion and hyperarousal symptoms even before physical signs manifest and before the person is even aware of the situation, said Kiiroja.

"This would enable earlier distraction and reminders to use skills learned in psychotherapy; this would have a better likelihood of increasing the efficacy of these skills and preventing further escalation of the arousal," she said.

Most breath samples likely included both early and late stress VOCs, as the breath donors wore the trauma mask for a relatively long time, the authors noted. Future studies should test dogs' olfactory acuity on samples collected minutes after the trauma cue, they added.

Another limitation is that all donors were regular cannabis users, so the results may not generalize to others. However, the fact the dogs demonstrated their detection ability even with cannabis users makes the proof-of-concept "more stringent," Kiiroja said.

The goal of the study was to see if some dogs are capable of detecting stress VOCs from people with trauma histories in response to trauma cues, so the small number of dogs in the study isn't a limitation, the authors noted.

'Wonderful Work'

Commenting on the findings, Elspeth Ritchie, MD, chair of psychiatry, MedStar Washington Hospital Center, Washington, DC, described the research as "wonderful work." Ritchie, who was not a part of this study, has also studied PTSD supports dogs.

The study is yet another illustration of the "amazing things dogs can do…not just for veterans but for people with mental illness." They can be a source of comfort and help people manage their anxiety.

Training PTSD service dogs can be expensive, with some well-accredited organizations charging about $50,000 for an animal, Ritchie said. Training a dog to detect VOCs could also be costly, she added.

Although such research has increased in recent years, it's unclear how it would be applied in practice. Identifying funding for this sort of study and designing trials would also be challenging, Ritchie added.

"The idea is good, but when you try to operationalize it, it gets tricky," she said.

The fact that all donors in the study used cannabis is a confounding factor and raises the question of what else might confound the results, Ritchie added.

Ritchie emphasized that although ideally veterans would learn to recognize the onset of stress symptoms themselves, a dog could serve as a valuable companion in this process. "That's precisely why this research should progress," she said.