SCOTUS mifepristone ruling procedural not substantive: analyst

 STORY: The justices, in a brief order, granted emergency requests by the Justice Department and the pill's manufacturer Danco Laboratories to put on hold an April 7 preliminary injunction issued by U.S. District Judge Matthew Kacsmaryk in Texas. The judge's order would have greatly limited the availability of mifepristone while litigation proceeds in a challenge by anti-abortion groups to the pill's federal regulatory approval.

The Food and Drug Administration (FDA), the U.S. agency that signs off on the safety of food products, drugs, and medical devices, approved mifepristone in 2000. The challengers contend that the FDA illegally approved mifepristone and then removed critical safeguards on what they call a dangerous drug.

"If the FDA is ignoring the science and harming women... whatever your position is on on the life issue, we should care about that," Kirk said.

The current case now returns to the New Orleans-based 5th U.S. Circuit Court of Appeals, which is set to hear arguments on May 17. The losing side after the 5th Circuit rules could appeal the case back to the Supreme Court.

Mifepristone is taken with another drug called Misoprostol to perform medication abortion, which accounts for more than half of all U.S. abortions. The drug has other uses including management of miscarriages.

Anti-abortion medical associations led by the Texas-based Alliance for Hippocratic Medicine sued the U.S. Food and Drug Administration last year in federal court in Amarillo, Texas, claiming the agency approved mifepristone for abortion in 2000 using an unlawful process and did not adequately consider the drug's safety. They asked U.S. District Judge Matthew Kacsmaryk, who is presiding over the lawsuit, to revoke the drug's approval, effectively pulling it off the market.

The FDA, along with mainstream U.S. medical associations, strongly disputes the claims. Danco intervened in the case to defend its drug.

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Russia advising citizens to avoid traveling to Canada, citing attacks

 Russia is advising citizens to avoid travel to Canada, citing what it calls numerous cases of discrimination against Russians, including physical violence, its foreign ministry said on Saturday.

Canada is one of the most vocal backers of Ukraine in the war against Moscow's forces and has imposed sanctions on hundreds of Russian officials and companies as well as wide-scale trade bans.

"Due to the numerous instances of discrimination against Russian citizens ... in Canada, including physical violence, we recommend you refrain from traveling to this country for the purposes of tourism, education, and in the context of business relations," the Russian foreign ministry said in an advisory.

"If you are already in Canada, we urge you to be vigilant, especially in public places."

The advisory, dated April 20, was posted on the ministry's main Telegram channel on Saturday. The Canadian foreign ministry was not immediately available for comment.

Shortly after the war started last year, Canada advised citizens to avoid all travel to Russia.

Russia last week imposed sanctions on 333 Canadian officials and public figures, including prominent Olympians, in what it said was a tit-for-tat response to Canadian restrictions on Moscow and support for Ukraine.

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Belarus units complete training on Russian tactical nuclear missile systems

 Units from Belarus returned home from Russia on Saturday after training on how to use the Iskander tactical missile system to launch nuclear weapons, the Belarusian defence ministry said.

It made the announcement exactly four weeks after President Vladimir Putin said Russia would station tactical nuclear weapons in neighbouring Belarus, sending a warning to NATO over its military support for Ukraine.

In early February, Belarus said its armed forces were in autonomous control of Iskander mobile guided missile systems that Russia had already provided.

But when the units were sent to Russia on April 4 for additional training, Minsk made clear their sessions would include study of "the maintenance and use of tactical nuclear warheads of the Iskander missile defense system".

Those units returned to Belarus on Saturday, the defence ministry said on Telegram.

Russia has not given a clear timetable for moving tactical nuclear weapons to Belarus, but Putin said the construction of storage facilities should be complete by the start of July.

It will be the first deployment of part of Russia's nuclear arsenal outside its borders since the collapse of the Soviet Union in 1991.

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Too much insulin can be as dangerous as too little

 Just over a century has passed since the discovery of insulin, a time period during which the therapeutic powers of the hormone have broadened and refined. Insulin is an essential treatment for type 1 diabetes and often for type 2 diabetes, as well. Roughly 8.4 million Americans use insulin, according to the American Diabetes Association.

One hundred years of research have greatly advanced medical and biochemical understanding of how insulin works and what happens when it is lacking, but the reverse, how potentially fatal insulin hyper-responsiveness is prevented, has remained a persistent mystery.

In a new study, published in the April 20, 2023 online edition of Cell Metabolism, a team of scientists at the University of California San Diego School of Medicine, with colleagues elsewhere, describe a key player in the defense mechanism that safeguards us against excessive insulin in the body.

"Although insulin is one of the most essential hormones, whose insufficiency can result in death, too much insulin can also be deadly," said senior study author Michael Karin, Ph.D., Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine.

"While our body finely tunes insulin production, patients who are treated with insulin or drugs that stimulate insulin secretion often experience hypoglycemia, a condition that if gone unrecognized and untreated can result in seizures, coma and even death, which collectively define a condition called insulin shock."

Hypoglycemia (low blood sugar) is a significant cause of death among persons with diabetes.

In the new study, Karin, first author Li Gu, Ph.D., a postdoctoral scholar in Karin's lab, and colleagues describe "the body's natural defense or safety valve" that reduces the risk of insulin shock.

That valve is a metabolic enzyme called fructose-1,6-bisphosphate phosphatase or FBP1, which acts to control gluconeogenesis, a process in which the liver synthesizes glucose (the primary source of energy used by cells and tissues) during sleep and secretes it to maintain steady supply of glucose in the bloodstream.

Some antidiabetic drugs, such as metformin, inhibit gluconeogenesis but without apparent ill effect. Children born with a rare, genetic disorder in which they do not produce sufficient FBP1 can also remain healthy and live long lives.

But in other cases, when the body is starved for glucose or carbohydrates, an FBP1 deficiency can result in severe hypoglycemia. Without a glucose infusion, convulsions, coma and possibly death can ensue.

Compounding and confounding the problem, FPB1 deficiency combined with glucose starvation produces adverse effects unrelated to gluconeogenesis, such as an enlarged, fatty liver, mild liver damage and elevated blood lipids or fats.

To better understand the roles of FBP1, researchers created a mouse model with liver specific FBP1 deficiency, accurately mimicking the human condition. Like FBP1-deficient children, the mice appeared normal and healthy until fasted, which quickly resulted in the severe hypoglycemia and the liver abnormalities and hyperlipidemia described above.

Gu and her colleagues discovered that FBP1 had multiple roles. Beyond playing a part in the conversion of fructose to glucose, FBP1 had a second non-enzymatic but critical function: It inhibited the protein kinase AKT, which is the primary conduit of insulin activity.

"Basically, FBP1 keeps AKT in check and guards against insulin hyper-responsiveness, hypoglycemic shock and acute fatty liver disease," said first author Gu.

Working with Yahui Zhu, a vising scientist from Chongqing University in China and second author of the study, Gu developed a peptide (a string of amino acids) derived from FBP1 that disrupted the association of FBP1 with AKT and another protein that inactivates AKT.

"This peptide works like an insulin mimetic, activating AKT," said Karin. "When injected into mice that have been rendered insulin resistant, a highly common pre-diabetic condition, due to prolonged consumption of high-fat diet, the peptide (nicknamed E7) can reverse insulin resistance and restore normal glycemic control."

Karin said the researchers would like to further develop E7 as a clinically useful alternative to insulin "because we have every reason to believe that it is unlikely to cause insulin shock."

More information: Li Gu et al, Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness, Cell Metabolism (2023). DOI: 10.1016/j.cmet.2023.03.021

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Alcohol-related liver disease soared in nearly all states during the pandemic

 Alcohol consumption increased substantially across the United States during the COVID-19 pandemic, but the impact was greatest among American Indian and Alaska Native (AIAN) populations, where deaths from alcohol-associated liver disease were six times those of white people, according to a study by Massachusetts General Hospital (MGH), a founding member of Mass General Brigham (MGB). The disproportionately high mortality rate reflects not just the pandemic, but a systemic failure of supportive health care and lack of critical resources for AIAN populations which demand urgent action by public policy leaders, the researchers reported in a study published in JAMA Health Forum.

"Even before the pandemic we saw a steady increase in alcohol consumption in this country, and continue to experience high levels of alcohol-associated liver disease exacerbated by COVID-19," says senior author Jagpreet Chhatwal, Ph.D., associate professor of Radiology, Harvard Medical School and director of the Institute for Technology Assessment at MGH. "Our examination of all racial or ethnic groups showed that none are more vulnerable than American Indian and Alaska Native. While alcohol consumption is known to be lower among these groups compared to others, studies have shown that people who engage in any level of drinking are more likely to become excessive in their habit."

Alcohol-associated liver disease (ALD) is characterized by progressive deterioration of the liver and loss of function, and is now the leading indication for liver transplant in the United States. The rate of ALD grew nationally by 43 percent from 2009 to 2015, accounting for more than $5 billion in direct healthcare costs in 2015 alone. At the height of the pandemic, deaths from ALD increased by 23 percent in just one year. Drawing on the CDC's WONDER Multiple Cause of Death database, Mass General researchers learned that ALD mortality rose in nearly every state from 2019 to 2020, with the greatest mortality rates occurring in Wyoming, South Dakota and New Mexico—states with some of the highest concentrations of AIAN populations.

As for actionable measures, the study cites the need for significantly higher levels of preventive healthcare and resource allocation to agencies like the Indian Health Service (IHS), the U.S. Department of Health and Human Services agency charged with providing comprehensive health services to the approximately 2.6 million American Indians and Alaska Natives in 574 federally recognized tribes in 37 states.

"Based on our findings, strong action needs to be taken at the public policy level to increase awareness among American Indians and Alaska Natives of the alarming mortality rates from alcohol-associated liver disease, and to implement universal alcohol screening and preventive health programs," says Neeti Kulkarni, a research analyst at the MGH Institute for Technology Assessment, and lead author of the study. "It's critical for the states and federal government to recognize and responsibly address this problem before it spirals into a major health crisis for our country."

Chhatwal points out that alcohol consumption hasn't shown any signs of decline even as the pandemic has receded. "It's no coincidence that in 2021, life expectancy in this country dropped to its lowest level since 1996, with ALD being the top reason after COVID-19 and unintentional injuries," he says. "Alcohol-associated liver disease among all ethnicities continues to represent a serous burden on our nation's healthcare system, and the problem will only intensify if we don't take meaningful steps to address it now."

More information: Neeti S. Kulkarni et al, Alcohol-Associated Liver Disease Mortality Rates by Race Before and During the COVID-19 Pandemic in the US, JAMA Health Forum (2023). DOI: 10.1001/jamahealthforum.2023.0527

https://medicalxpress.com/news/2023-04-alcohol-related-liver-disease-soared-states.html

Engineering team develops multifunctional tendon-mimetic hydrogels

 Repairing or replacing injured tendons or similar load-bearing tissues represents one of the major challenges in clinical medicine. Natural tendons are water-rich tissues exhibiting outstanding mechanical strength and durability. Their mechanical properties originate from sophisticated microscale structures involving stiff collagen fibrils aligned in parallel and interlaced with soft water-retaining biopolymers.

Over the past decades, researchers have been trying to use synthetic hydrogels, a class of water-rich materials involving polymer networks, to replicate the structures and properties of natural tendons. It remains difficult since synthetic hydrogels are usually weak and brittle. Resolving this mismatch would enable critical applications in tissue repair, biomedical robots, implantable devices, and many other technologies.

A research team led by Dr. Lizhi Xu of the Department of Mechanical Engineering in the Faculty of Engineering at the University of Hong Kong (HKU) has developed a new type of tendon-mimetic hydrogel with outstanding mechanical properties matching those of natural tendons combined with multifunctionalities for biomedical applications.

The research was published in Science Advances, in an article entitled "Multifunctional tendon-mimetic hydrogels." The research was also featured in Nature as a Research Highlight.

In this study, aramid nanofibers derived from Kevlar, a polymer material used in bullet-proof vests and helmets, were mixed with polyvinyl alcohol, another synthetic polymer, for the construction of tendon-mimetic hydrogels. With tensile stress applied during the fabrication process, aramid nanofibers aligned with each other according to the direction of stretching, leading to an anisotropic network mimicking the structural features of natural tendons.

The interactions between the stiff nanofibers and soft polymers further confer high mechanical toughness on the composites. This hydrogel consists of 60% water while showing an excellent Young's modulus of ~1 GPa and strength of ~80 MPa, outperforming other synthetic hydrogels by orders of magnitude. The surface of the hydrogels can be further functionalised for directing the behaviors of cells or integrating with soft bioelectronic sensors.

"We developed a biomimetic materials platform for advanced biomedical applications. The materials building blocks captured many structural features of natural tendons, leading to amazing properties that are inaccessible with other synthetic hydrogels," said Dr. Xu, adding that "these hydrogels are not only mechanically strong but also functionalised with bioactive molecules and soft electronic sensors, providing critical capabilities for tissue repair and implantable medical devices."

More information: Mingze Sun et al, Multifunctional tendon-mimetic hydrogels, Science Advances (2023). DOI: 10.1126/sciadv.ade6973

Nature Research Highlight: www.nature.com/articles/d41586-023-00492-5

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New injectable cell therapy could resolve osteoarthritis

 Wake Forest Institute for Regenerative Medicine (WFIRM) scientists have created a promising injectable cell therapy to treat osteoarthritis that both reduces inflammation and also regenerates articular cartilage.

Recently identified by the Food and Drug Administration as a public health crisis, osteoarthritis affects more than 520 million people worldwide who deal with pain and inflammation. Osteoarthritis is typically induced by mechanical or traumatic stress in the joint, leading to damaged cartilage that cannot be repaired naturally.

"Without better understanding of what drives the initiation and progression of osteoarthritis, effective treatment has been limited," said lead author Johanna Bolander of WFIRM. "Initially, we studied what goes wrong in osteoarthritic joints, compared these processes to functional environments, and used this information to develop an immunotherapy cell treatment."

Osteoarthritis is a disease of the joint system. The joint includes a synovial membrane—a connective tissue that lines the inner surface of the joint. The membrane functions to protect the joint and secretes a lubricating fluid filled with cell elements needed to maintain a healthy environment and to provide friction free movement.

In healthy joints when an injury occurs, the body recruits an army of inflammatory cells and sends them to the injury site to contribute to cleaning of the damaged tissues. In the osteoarthritic joint, however, a traumatic injury leads to inflammation of the synovial membrane and cartilage damage.

"With time, the inflammation worsens, leading to degradation of the cartilage lining the joint bones and chronic inflammation in the surrounding tissues. For patients, this causes severe pain, swelling and often limits daily activities," said co-author Gary Poehling, MD, an orthopedic surgeon at Atrium Health Wake Forest Baptist.

For this study, published in Science Advances, the journal of the American Association for the Advancement of Science, the research team set out to investigate what is taking place in the osteoarthritic joint environment that keeps the healing process from happening.

"We evaluated whether the cell population present in the joint fluid environment lacked the capability to contribute to functional tissue repair, or if there is something in the environment that impairs their ability to do so," said Gustavo Moviglia, Ph.D., a WFIRM researcher.

The team isolated cells from the joint fluid of osteoarthritic patients, separated the cells from the fluid and investigated them alone, but also in the presence of the autologous fluid. Separated from the fluid, they saw that the cells had the ability to undergo processes required for functional tissue repair. When they added a small percentage of the fluid back into the cell culture assay, the cells' abilities were impaired—they couldn't do their job—suggesting that the specific osteoarthritic environment stops them.

Based on these findings and what is known about functional tissue repair, a cell therapy was designed that can overcome the inflammatory environment and also regenerate cartilage.

"Cartilage activated immune cells that target inflammation, combined with progenitor cells aid tissue regeneration," said Anthony Atala, MD, senior author and director of WFIRM. "It's really a dynamic communication between these two cell populations that are crucial for the efficacy of the treatment."

The combination of cells leads to simultaneous treatment of several of the aspects involved in osteoarthritis: synovial inflammation, cartilage degradation, subchondral bone sclerosis and innervation of pain sensory neurons.

The therapy was tested in a pre-clinical model and was found to have the ability to reverse cartilage damage in the synovial membrane and diminish the inflammation as well. To evaluate clinical efficacy, a compassionate use study was conducted in nine patients with confirmed osteoarthritis who each received one or two injections. Efficacy was evaluated through scoring of pain and functional living, MRI scans pre- and post-treatment and a biopsy from one patient was obtained.

Once treated, the patients experienced improved quality of life, ability to participate in recreational activities, and reduced pain. Additionally, MRI studies confirmed cartilage regeneration. Additional clinical studies are required to evaluate the outcome in a larger patient population as well as to evaluate potential differences in patients in specific subgroups.

More information: Johanna Bolander, The Synovial Environment Steers Cartilage Deterioration and Regeneration, Science Advances (2023). DOI: 10.1126/sciadv.ade4645. www.science.org/doi/10.1126/sciadv.ade4645

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