The study, published online in Clinical Infectious Diseases, underscores the extraordinary effect of these newer antivirals, which have been shown to cure hepatitis C in 98 percent of patients who take them. Patients are said to be cured when the virus is no longer detectable in their blood.

“The findings of our study show that curing hepatitis C not only gets rid of the virus, it also improves the overall health of patients,” said Stuart Gordon, M.D., Director of the Division of Hepatology at Henry Ford and the study’s lead author. “This is consistent with our earlier studies that showed effective treatment of hepatitis C also reduces the risk of patients developing other health conditions like diabetes, kidney disease, stroke and heart attacks.”

According to federal data, at least 2.4 million people are living with hepatitis C in the United States and most don’t know they have the virus. As a result, they are at risk for life threatening liver disease and cancer. Rates of new liver cancer cases have increased 38 percent from 2003 to 2012.

The Henry Ford-led study was conducted in collaboration with researchers from Geisinger Health System, Kaiser Permanente in Hawaii and Oregon and Centers for Disease Control and Prevention. They comprise the Chronic Hepatitis Cohort Study, which has been collecting and analyzing data drawn from the four health systems to assess the impact of hepatitis C and B on the U.S. population.

This observational study is believed to be the first to examine healthcare utilization involving hepatitis C patients with and without advanced liver disease and treated with the direct-acting antivirals, or DAAs.

Researchers analyzed data of 6,100 patients — half who were treated with DAAs and half who were not.

The antivirals are taken orally once a day for eight to 12 weeks. Side effects are mild, if any. The medications stop the hepatitis C virus from multiplying in the body and can prevent long-term complications like liver damage.

Key findings of the study:

• Patients treated with DAAs had lower rates of hospitalization and shorter stays for liver and non-liver related health issues compared to those who did not receive DAAs.
• Patients treated with DAAs had fewer visits to the Emergency Department for liver disease related issues compared to those who did not receive DAAs.

Researchers did not quantify the potential cost savings as part of the study.

Still, Dr. Gordon said the projected cost savings would be substantial. People being cured of hepatitis C leads to less incidence of chronic medical issues associated with the disease, he said.

“There are tangible downstream benefits from these antiviral treatments,” he said. “If you’re cured of the virus, your overall health will get better and you’re less likely to be hospitalized for some other health condition.”

A one-time universal screening for hepatitis C is recommended for all adults ages 18 and older including pregnant women during each pregnancy. Regular hepatitis C testing is recommended for people with ongoing risk factors such as drug use with needles, on dialysis and those born between 1945 and 1965.

Last year, Michigan lifted restrictions that prevented some people from getting access to antiviral treatment. “Given the remarkable effectiveness and benefits of these DAAs, everyone with hepatitis C should get treated and treated soon,” Dr. Gordon said.

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This discovery, described in a paper published Feb. 15 in Proceedings of the National Academy of Sciences, represents an important step in the effort to develop anti-viral drugs to fight off infections.

“This paper is about trying to understand the mechanism that makes these RNA escape degradation,” says senior author Mandy Muller, assistant professor of microbiology. “The next step is to figure out if we can manipulate this to our advantage.”

In the Muller Lab, student researchers work with Muller studying how Kaposi sarcoma-associated herpesvirus (KSHV) hides for years inside the human body before seeking to gain control over human gene expression to complete the viral infection. At that point, people with a weakened immune system may develop Kaposi sarcoma cancer lesions in the mouth, skin or other organs.

The researchers use genome-wide sequencing, post-transcriptional sequencing and molecular biology to examine how the human cell or the virus knows how to prevent degradation.

“Viruses are very smart, that’s what I love to say,” Muller says. “They have lots of strategies to stick around, and they don’t do a lot of damage for a very long time, because that’s one way to hide from the immune system.

“But then, at some point — many, many years later — they reactivate. The way they do this is by triggering a massive RNA degradation event where the virus will wipe out the mRNA from the cell. That means the human system can no longer express the proteins that it needs to express, and that means also that a lot of resources are suddenly available for the virus.”

How and why some RNA are able to escape the viral degradation are questions Muller’s team — including lead author and graduate student Daniel Macveigh-Fierro and co-authors and undergraduates Angelina Cicerchia, Ashley Cadorette and Vasudha Sharma — has been investigating.

“We show that RNA that escape have a chemical tag on them — a post-transcriptional modification — that makes them different from the others,” Muller explains. “By having this tag, M⁶A, they can recruit proteins that protect them from degradation.”

Muller has been studying KSHV since she was an undergraduate in her native France, and her mission continues.

“We know you need this protein to protect the RNA from degradation, but we still don’t know how that physically stops the degradation, so that’s what we’re going to look at now,” she says.

Ultimately, understanding the mechanisms and pathways involved in KSHV infection may lead to the development of RNA therapeutics to treat viral diseases.

“By identifying the determinants of what makes an mRNA either resistant or susceptible to viral-induced decay, we could use those findings to our advantage to better design anti-viral drugs and reshape the outcome of infection,” Muller says.

The research was supported by a $1.9 million Maximizing Investigators’ Research Award (MIRA) to Muller in 2020 from the NIH’s National Institute for General Medical Sciences.

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“The common assumption is that the older we get, the more slowly we react to external stimuli. If that were so, mental speed would be fastest at the age of about twenty and would then decline with increasing age,” says Dr von Krause, a researcher in the Quantitative Research Methods department headed by Prof. Dr Andreas Voß at Heidelberg University’s Institute of Psychology. In order to verify this theory, the researchers reevaluated data from a large-scale American study on implicit biases. In the online experiment with over a million participants, subjects had to press a button to sort pictures of people into the categories “white” or “black” and words into the categories “good” or “bad.” According to Dr von Krause, the content focus was of minor importance in the Heidelberg study. Instead, the researchers used the large batch of data as an example of a response-time task to measure the duration of cognitive decisions.

When evaluating the data, Dr von Krause and his colleagues noted that, on average, the response times of the test subjects rose with increasing age. However, with the aid of a mathematical model, they were able to show that this phenomenon was not due to changes in mental speed. “Instead, we think that older test subjects are mainly slower because they reply more cautiously and concentrate more on avoiding mistakes,” Mischa von Krause explains. At the same time, motor execution speed slows down during the course of adult life: older participants in the experiment needed longer to press the appropriate key after they had found the right answer.

Another finding of the study was that average information processing speed only progressively declined with participants over the age of 60. “It looks as though, in the course of our life, we don’t need to fear any substantial losses of mental speed — particularly not in the course of a typical working life,” says Mischa von Krause. “Generally speaking, we should also note that the test subjects in all age groups included individuals with high and low mental speeds. Our results relate to the average trend.”

The German Research Foundation (DFG) funded the research work in the context of the research training group for doctoral students “Statistical Modelling in Psychology” (GRK 2277). The results were published in the journal Nature Human Behaviour.

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The low-cost jelly-like materials, developed by researchers at the University of Cambridge, can sense strain, temperature and humidity. And unlike earlier self-healing robots, they can also partially repair themselves at room temperature.

The results are reported in the journal NPG Asia Materials.

Soft sensing technologies could transform robotics, tactile interfaces and wearable devices, among other applications. However, most soft sensing technologies aren’t durable and consume high amounts of energy.

“Incorporating soft sensors into robotics allows us to get a lot more information from them, like how strain on our muscles allows our brains to get information about the state of our bodies,” said David Hardman from Cambridge’s Department of Engineering, the paper’s first author.

As part of the EU-funded SHERO project, Hardman and his colleagues have been working to develop soft sensing, self-healing materials for robotic hands and arms. These materials can detect when they are damaged, take the necessary steps to temporarily heal themselves and then resume work — all without the need for human interaction.

“We’ve been working with self-healing materials for several years, but now we’re looking into faster and cheaper ways to make self-healing robots,” said co-author Dr Thomas George-Thuruthel, also from the Department of Engineering.

Earlier versions of the self-healing robots needed to be heated in order to heal, but the Cambridge researchers are now developing materials that can heal at room temperature, which would make them more useful for real-world applications.

“We started with a stretchy, gelatine-based material which is cheap, biodegradable and biocompatible and carried out different tests on how to incorporate sensors into the material by adding in lots of conductive components,” said Hardman.

The researchers found that printing sensors containing sodium chloride — salt — instead of carbon ink resulted in a material with the properties they were looking for. Since salt is soluble in the water-filled hydrogel, it provides a uniform channel for ionic conduction — the movement of ions.

When measuring the electrical resistance of the printed materials, the researchers found that changes in strain resulted in a highly linear response, which they could use to calculate the deformations of the material. Adding salt also enabled sensing of stretches of more than three times the sensor’s original length, so that the material can be incorporated into flexible and stretchable robotic devices.

The self-healing materials are cheap and easy to make, either by 3D printing or casting. They are preferable to many existing alternatives since they show long-term strength and stability without drying out, and they are made entirely from widely available, food-safe, materials.

“It’s a really good sensor considering how cheap and easy it is to make,” said George-Thuruthel. “We could make a whole robot out of gelatine and print the sensors wherever we need them.”

The self-healing hydrogels bond well with a range of different materials, meaning they can easily be incorporated with other types of robotics. For example, much of the research in the Bio-Inspired Robotics Laboratory, where the researchers are based, is focused on the development of artificial hands. Although this material is a proof-of-concept, if developed further, it could be incorporated into artificial skins and custom-made wearable and biodegradable sensors.

This work was supported by the Self-HEaling soft RObotics (SHERO) project, funded under the Future and Emerging Technologies (FET) programme of the European Commission.

Take-home exposures — toxic contaminants that are unintentionally brought from the workplace into the home, exposing children and other family members — are a documented public health hazard, but the majority of research and interventions have focused on take-home exposure to lead. Much less is known about take-home exposures to other harmful metals.

Now, a new study led by a Boston University School of Public Health (BUSPH) researcher provides evidence that construction workers, in particular, are at high risk of inadvertently tracking a host of other toxic metals into their homes. The study identifies and measures the highest number of metals — 30 — in construction workers’ homes, to date.

Published in the journal Environmental Research, the findings reveal that, in addition to lead, construction workers had higher levels of arsenic, chromium, copper, manganese, nickel, and tin dust in their homes, compared to workers in janitorial and auto repair occupations. The study also found that overlapping sociodemographic, work, and home-related factors can affect metal concentrations in the dust of workers’ homes.

This new data underscores the need for more proactive and preventative measures that reduce these harmful exposures at construction sites.

“Given the lack of policies and trainings in place to stop this contamination in high-exposure workplaces such as construction sites, it is inevitable that these toxic metals will migrate to the homes, families, and communities of exposed workers,” says study lead and corresponding author Dr. Diana Ceballos, an assistant professor of environmental health and director of the Exposure Biology Research Laboratory at BUSPH. “Many professions are exposed to toxic metals at work, but construction workers have a more difficult job implementing safe practices when leaving the worksite because of the type of transient outdoor environments where they work, and the lack of training on these topics.”

To better understand the sources and predictors of take-home exposure of metals dust, Ceballos and colleagues from BUSPH and Harvard T.H. Chan School of Public Health recruited 27 Greater Boston workers to participate in this pilot study from 2018-2019, focusing primarily on construction workers, but also including janitorial and auto repair workers. To assess the metal concentrations in workers’ homes, the researchers visited the homes and collected dust vacuum samples, issued questionnaires to the workers about work and home-related practices that could affect exposure, and made other home observations.

The researchers found that higher concentrations of cadmium, chromium, copper, manganese, and nickel were associated with a range of sociodemographic and work- and home-related factors, including lower education, working in construction, not having a work locker to store clothes, mixing work and personal items, not having a place to launder clothes, not washing hands after work, and not changing clothes after work.

Further compounding the issue, Ceballos says, is that many construction workers live in disadvantages communities or substandard housing that may already contain toxic metals.

“Given the complexity of these issues, we need interventions on all fronts — not only policies, but also resources and education for these families,” she says.

Small fish occur at very low abundances in the 200-600 m deep Atlantic water layer of the Amundsen Basin as shown by the unique hydroacoustic dataset collected by the EFICA Consortium that showed a “deep scattering layer” (DSL) consisting of zooplanktion and fish along a 3170 km long track of the MOSAiC expedition.

Therefore, it was a big surprise when suddenly four larger fish were caught at 350-400 meters of depth. An even bigger surprise to the research team was that three of the fish were Atlantic cod, a predatory species that is not supposed to live this far north and, being a coastal fish, not in an four kilometers deep ocean basin more than 500 kilometers away from any coastline. With a deep-sea camera deployed underneath the sea ice, the scientists also discovered that Atlantic armhook squid and Atlantic lanternfish occur much further north than previously known.

The Atlantic cod originated from Norwegian spawning grounds, and had lived in Arctic water temperature (-1 to 2 ^oC) for up to six years laboratory analyses showed. The fish preferred the Atlantic water layer, a slightly warmer water mass (0-2 ^oC) that reaches far into the Arctic basin in-beteen the surface and deeper water layers which are below 0 ^oC.

“So, even if the Atlantic cod does not have its own central Arctic stock, this research shows that it can survive. A small number of individuals seem to find enough food to stay healthy for a longer time,” says Pauline Snoeijs Leijonmalm, coordinator of the EFICA Consortium and professor in marine ecology at Stockholm University.

New insights in the functioning of the pelagic food web

The study thus adds a new trophic level to the pelagic food web of the central Arctic ecosystem — that of large predatory fish and squid. Together with the smaller fishes in the DSL, continuous immigration of larger Atlantic fish contributes to potential food for mammals since seals and walrus can dive down to the Atlantic water layer.

“The availability of small and even some larger fish in the Atlantic water layer could explain why seals, walrus and polar bear can be found even at the North Pole. Both fish and mammals are very few, but they are there,” says biologist Dr. Hauke Flores, Alfred Wegener Institute.

The new study also found that diel vertical migration of the DSL is absent during the polar night, half a year of continuous darkness (DSL at 100-250 m), and the polar day, half a year of continuous light (DSL at 300-500 m). This implies that the carbon flux from shallower to deeper water through daily vertical migration of the DSL is hampered in the Central Arctic Ocean compared to all other oceans.

“During the short productive season of the polar day the DSL will remain in the deeper part of the Atlantic water layer 24 hours per day, even when the sea ice disappears, because this process is regulated by the availability of light” says Pauline Snoeijs Leijonmalm.

No harvestable fish stocks

Based on their scientific results, the authors of the new paper in Science Advances conclude that — at least in the Eurasian Basin — there are no harvestable fish stocks today or in the near future.

“This was expected because the Central Arctic Ocean has very low nutrient concentrations and very low biological productivity. Even if more Atlantic fish and their prey would be advected with the water inflow from the Atlantic Ocean, the capacity of the Central Arctic Ocean ecosystem to support larger fish stocks is without doubt rather limited,” says Pauline Snoeijs Leijonmalm.

Pauline Snoeijs Leijonmalm stresses that it is of great importance that this fragile but fully functional ecosystem will receive robust international protection similar to Antarctica.

International agreement prevents commercial fishing

Global warming strikes the Artic region harder than the rest of the globe and climate models predict that the opening up of the Central Arctic Ocean for non-ice-breaking vessels is just a matter of decades. Since most of the area consists of high seas — international waters outside national jurisdictions — possible future human activities here are debated at national and international political levels.

“Usually, exploitation of newly accessible natural resources tends to precede scientific research and management measures, and internationally shared fish stocks in high seas are especially prone to overexploitation,” says Pauline Snoeijs Leijonmalm.

Taking a precautionary approach, Canada, China, Greenland (Kingdom of Denmark), Iceland, Japan, Norway, Russia, South-Korea, the USA and the European Union negotiated the Agreement to Prevent Unregulated High Seas Fisheries in the Central Arctic Ocean (CAO) that entered into force on 25 June 2021. The ten partners of the Agreement will soon be launching a large Joint Scientific Research and Monitoring Program to collect new fish and ecosystem data in the Central Arctic Ocean. The EU has already started this work by financing the EFICA Consortium’s ecosystem research on the MOSAiC expedition (2019-2020), and the Synoptic Arctic Survey expedition with the Swedish icebreaker Oden (2021). The new paper in Science Advances is the first scientific paper presenting new field data in the context of the agreement.

“This agreement prevents any commercial fishing for at least 16 years to come, and puts “science first,” warranting scientific assessments of the status and distribution of possible fish stocks in the Central Arctic Ocean and the ecosystem supporting them — a wise political decision and a good start towards full protection,” says Pauline Snoeijs Leijonmalm.

For the first time, the Magness lab used entire human GI tracts from three organ donors to show how cell types differ across all regions of the intestines, to shed light on cellular functions, and to show gene expression differences between these cells and between individuals.

This work, published in Cellular and Molecular Gastroenterology and Hepatology, opens the door to exploring the many facets of gut health in a much more precise manner at greater resolution than ever before.

“Our lab showed it’s possible to learn about each cell type’s function in important processes, such as nutrient absorption, protection from parasites, and the production of mucus and hormones that regulate eating behavior and gut motility,” said Magness, associate professor in the Joint UNC-NC State Department of Biomedical Engineering and senior author of the paper. “We also learned how the gut lining might interact with the environment through receptors and sensors, and how drugs could interact with different cell types.”

The Sensitive Gut

Think of a typical pharmaceutical commercial voiceover when the voice actor pleasantly recites possible side effects, such as diarrhea, vomiting, intestinal bleeding, and other unpleasant collateral damage. Well, the Magness lab is attempting to understand why those side effects happen, down to the level of individual cells, their functions, their locations, and their genes.

For this research, the Magness lab focused on the epithelium: the single-cell thick layer separating the inside of the intestines and colon from everything else. Like other cell populations and the microbiota, the epithelium is incredibly important to human health, and for years scientists have been exploring it. But until now, researchers could only take tiny biopsies the size of grains of rice from a few parts of the digestive tract, usually from the colon or limited regions of the small intestine.

“Such exploration would be like looking at the United States from space but only investigating what’s going on in Massachusetts, Oklahoma, and California,” Magness said. “To really learn about the country, we’d want to see everything.”

Magness leaned on co-first authors, postdoctoral fellow Joseph Burclaff, PhD, and graduate student, Jarrett Bliton, both trainees in the Magness lab.

“Not only do we want to identify where the cells are located, but we want to know exactly which cell types do what, and why,” Burclaff said. “So, staying with the map analogy, we don’t want to just say, ‘oh, there’s North Carolina’. We want to know where to get the best barbecue. We want a ground level view to know as much as possible.”

In the past, researchers would mash up those rice-sized biopsies to identify all epithelial cell types and learn some general features of these cells. Magness’s approach was to sample thousands of individual cells from every part of the lower digestive tract (small intestine and colon) to create an atlas and then study the potential roles of these cells through the genes that each cell expresses. Knowing all of this would deepen scientific knowledge about the gut epithelium and hopefully encourage other scientists to explore each cell’s function in biology, in disease, and in the unfortunate scenario of pharmaceutical side effects.

To do such a deep individual cell dive, Magness needed two things: better technology and the entire digestive tracts of humans.

The Biology of Data

UNC-Chapel Hill acquired state-of-the-art RNA sequencing technology several years ago for the creation of the Advanced Analytics Core Facility through the UNC Center for Gastrointestinal Disease and Biology, which developed the scientific and intellectual heft — research faculty, staff, postdocs, and students — to use state-of-the-art equipment.

The Magness Group acquired human digestive tracts through a research agreement with organ donor services at HonorBridge. When intestines are harvested for transplant and if they are not claimed by higher-priority groups, HonorBridge staff coordinates with the Magness Group to donate the transplant-grade organs for research.

Six to eight hours after harvest, the Magness lab receives intact intestinal tracts, each about 15 to 30 feet long. They remove the epithelial layer, which is one long connected piece of tissue despite being only one cell thick. Then the researchers use enzymes to break down the epithelium into individual cells. For this study, they repeated this for organs from three separate donors.

Using sequencing technology to characterize gene expression, the Magness group first extracts RNA from each cell while keeping each cell separate, and then they run single-cell sequencing, which takes a snapshot of which genes each intestinal cell is expressing and how much.

“The picture we get from each cell is a mosaic of all the different types of genes the cells make and this complement of genes creates a ‘signature’ to tell us what kind of cell it is and potentially what it is doing,” Magness said. “Is it a stem cell or a mucous cell or a hormone-producing cell or an immune-signaling cell?

Burclaff added, “We were able to see the differences in cell types throughout the entire digestive tracts, and we can see different gene expression levels in the same cell types from three different people. We can see the different sets of genes turned on or off in individual cells. This is how, for instance, we might begin to understand why some people form toxicity to certain foods or drugs and some people don’t.”

A major problem with this kind of research is the sheer amount of data produced. The single cell sequencing picks up about 11,000 ‘reads’, or individual samples of gene products in just one cell, and in many thousands of individual cells, each with different combinations of the 20,000-plus human genes that are turned on or off. This creates almost 140,000,000 data points for all the 12,590 cells in the study that have to be put into a visualizable format so that scientists can make sense of the vast amount of information.

“The human brain can only comprehend two dimensions, three is challenging,” Magness said. “Add time, and it’s even trickier to comprehend what a single cell is up to. The amount of data our experiments produced was basically millions of dimensions all at once.”

Bliton devised computational techniques to filter the data to produce a manageable data set that included cell populations from all portions of the GI tract. Then, based on what Magness and other researchers had already learned of each cell type, Bliton could computationally identify each cell type from each region. He then plotted these data in a manner that humans can understand and interpret.

Reining in the immense data allowed the scientists to learn a lot about each cell type. Consider the tuft cell, discovered 40 years ago and so named because they look as if they have tufts of hair on their surface. Turns out these tuft cells express similar genes as those on taste buds on the tongue. Other researchers discovered that these tuft cells sensed worm infections and sent signals to the immune system to begin waging war. The Magness lab showed that tuft cells exhibit a set of genes thought to be important for sensing and “tasting” other kinds of intestinal content so it can signal the immune system if need be. This would represent a much broader function than sensing if there’s a parasite in your gut or not.

“Not only did we describe every single cell type and every single gene they express individually, but we also looked at potential functions,” Burclaff said. “If you look at intestinal mucus, which is a complex mixture that protects the cells, we show which cells express various mucin proteins, how much, and in which regions of the digestive tract. We looked at where specific enzymes that digest food are expressed. We looked at cells with anti-inflammatory gene expression and synapse genes where the gut is probably connected to nerves so it can talk to the rest of the body. We looked at aquaporins, proteins involved in transferring water through the intestinal membrane.”

What the Magness group found was a whole new level of variation in potential functions that had not previously been appreciated through mashing up biopsy samples.

The researchers explored all epithelial receptors — the cell surface proteins used to communicate with other cells and molecules and with the environment of the gut. Magness and colleagues could see which receptors were expressed the most and in which cell types, painting a new picture of how cells might interact with gut contents such as nutrients, microbes, toxins, and drugs.

“As far as we know, we’re the first to do this kind of analysis across the length of the human gut from three full donors,” Bliton said. “We can look at each cell type and predict which pharmaceuticals might affect which cell type individually.”

For instance, there’s a class of drugs to treat inflammatory bowel disease; they’re designed to hit specific targets, certain immune cells that trigger inflammation. But the Magness lab learned that some epithelial cells express the same genes as those in the immune cells that are intended to be the target. This finding indicates there could be “off-target” effects in epithelial cells that are not intended and could lead to side-effects.

“This was not known,” Burclaff said. “Lots of drugs have bad GI side effects. And it could be because the drugs are affecting individual cells along the entire length of the GI tract. We show where these receptors are most expressed and in which cell types.”

This kind of knowledge is just one outcome from the Magness lab’s initial study.

“We want the scientific, medical, and pharmaceutical community to use what we’ve found,” Magness said. “We adopted an analytic approach to methodically address each cell type, produce easy-to-read and accessible spreadsheets for most scientists, and show several examples of what we can be discovered with this kind of high resolution, precision approach.”

Funding for this research came from the National Institutes of Health, the Katherine E. Bullard Charitable Trust, the Crohn’s and Colitis Foundation, and the University Cancer Research Fund at UNC-Chapel Hill.

Aside from the aforementioned researchers, other authors are Keith Breau, Meryem Ok, Ismael Gomez-Martinez, Jolene Ranek, Aadra Bhatt, Jeremy Purvis, and John Woosley, all at UNC-Chapel Hill.

Duchenne primarily affects males and is usually diagnosed by age 4. While a variety of therapies can slow progression and extend life expectancy, the disease has no cure yet. Those born with Duchenne seldom live beyond their mid-20s.

In 2017, researchers learned that weekly doses of prednisone, a widely prescribed steroid, appear to provide better support for weakening muscles compared to daily doses while also reducing the significant side effects induced by daily intake. Now, a new study reports that the time of day for providing the drug may be crucial to the effectiveness of such treatments.

Detailed findings, based on mouse models, were published online Feb. 18, 2022, in Science Advances. Mattia Quattrocelli, PhD, a researcher with the Heart Institute at Cincinnati Children’s, is the study’s corresponding author. Co-authors included lab team members Michelle Wintzinger and Karen Miz of Cincinnati Children’s and Northwestern University researchers Daniel Levine, PhD, Clara Peek, PhD, Joseph Bass, MD, PhD, and Elizabeth McNally, MD.

The findings represent another advance in the growing field of chronopharmacology, which examines how medications work in sync — or in conflict — with the circadian rhythms of our bodies. A number of important findings in this field have been led by experts at Cincinnati Children’s, which recently launched the country’s only clinic dedicated to childhood circadian sleep disorders.

Confirming a clear time-based influence for the use of prednisone among Duchenne patients very likely will help improve outcomes for affected children, but it also raises questions about the time of day for other uses of the steroid. More than 2.5 million Americans use prednisone and similar drugs to manage inflammation for conditions ranging from allergy treatment to preventing organ transplant rejection.

“Our internal clock system is quite complex. Not only do we have our central circadian rhythm dictated by a special region in our brain, but all our tissues — for instance, muscle — have their own internal molecular clock constantly ticking,” Quattrocelli says. “We are beginning to learn much more about the importance of the timing of drug administrations for their effects in our tissues.”

“In this study, we have focused on the interaction between the muscle clock and drug-activated molecules. But it will require considerably more research to determine how these findings may extend beyond the specific use of prednisone that we studied,” he says.

Potential tool for precision dosing

In mice, the researchers found that once-weekly prednisone doses administered at the start of the light period (approximately 7 am) promoted muscle function. The team observed that the treatment boosted nutrient utilization and strengthened mitochondrial bioenergetics in muscle. It also increased endurance and improved muscle mass and muscle force. However, these responses were lost when dosing occurred in the dark period.

With mice being primarily nocturnal, their circadian clocks vary considerably from humans, so the specific time of day that achieves the most beneficial effect would be different for humans than for mice. However, Quattrocelli and colleagues report that many of the time-based mechanisms involving muscle cell activity are conserved between mice and humans, which suggests that timing also will matter for treating people with muscle diseases.

If confirmed in future human studies, the findings suggest that precision drug timing may maximize the drug benefits while avoiding side effects that may be more likely when a drug is given at the wrong time of day. That might help improve efficacy of treatment and possibly quality of life for a range of muscle conditions, from muscular dystrophy to aging to metabolic stress.

More study needed to explore implications

This study focused exclusively on prednisone and muscle tissue. The time-based effectiveness of other synthetic glucocorticoids, such as dexamethasone and vamorolone (currently in trial for Duchenne muscular dystrophy (NCT03439670)) remain to be determined.

Another pilot clinical trial with once-weekly prednisone in non-Duchenne forms of muscular dystrophy is ongoing at Northwestern University (NCT04054375). This trial is adapting the time of drug intake based on the new findings reported here.

Patients were instructed to take the drug in the evening after their last meal (between 7-9 pm) in a first attempt to mirror the positive findings found in mice. “Results from the trial are still pending and hopefully will inform our refinement of chronopharmacology approaches for muscular dystrophies and other conditions,” Quattrocelli says.

Aside from differing drug characteristics, various tissues have their own internal clocks. So more research will be needed to determine if the day vs. night effects of prednisone also apply when treating conditions affecting other organ tissues. Notably, most uses of prednisone are related to controlling inflammation, often in immune conditions rather than muscle diseases. Time of day studies for treating immune conditions have only just begun.

“Every tissue of our body has an internal clock and this work reports on the fact that we can exploit the internal clock of muscle to interact with time-specific drug dosing to boost the positive effects of the drug on energy and function. However, more studies are required to precisely translate these findings to humans,” Quattrocelli says. “Besides the obvious difference that mice are nocturnal animals while humans are mainly diurnal, we must consider many factors that will inevitably affect chronopharmacology in our population. For instance, people have far more complex patterns of eating, working, playing and sleeping compared to mice. All these differences would need further exploration to translate mouse-based learning to human medical care.”

About this study

Funding sources for this work included the National Institutes of Health (AR052646, HL061322, DK121875, HL158531), a Trustee Award from Cincinnati Children’s, and a Heart Institute Translational Grant. Quattrocelli and McNally also are listed as inventors on a related patent application filed by Northwestern University.