New study documents increasing frequency, cost, and severity of gunshot wounds

The rise in firearm violence has coincided with an increase in the severity of injuries firearms inflict as well as the cost of operations to treat those injuries; policy makers must be more aggressive in addressing violence to curb these trends, researchers report in a large national study of gunshot wounds that appears as an “article in press” on the Journal of the American College of Surgeons website ahead of print.

“Taken together, our findings suggest that gun violence has increased in numbers, at least for the sector that meets surgical criteria, and that these injuries result in a substantial financial burden in addition to the obvious psychosocial burden and other downstream effects,” said lead study author Peyman Benharash, MD, MS, with the Cardiovascular Outcomes Research Laboratories and an associate professor-in-residence of surgery and bioengineering at the David Geffen School of Medicine at the University of California Los Angeles. “We hope that our findings are able to better inform policy in terms of violence prevention as well as reimbursement to hospitals, which are often in underserved regions, that care for these patients.”

The study authors note that gun violence overall carries an annual cost to the U.S. health care system of $170 billion, with $16 billion for operations alone. The researchers used the National Inpatient Sample (NIS) to identify all hospital admissions for gunshot wounds (GSW) from 2005 through 2016. The researchers did not look at all adult GSW victims admitted to the hospital, estimated at 322,599, but only at the 262,098 victims who required at least one major operation.

Dr. Benharash explained the rationale for the study. “We’re now seeing a lot more on the impact of gun violence,” he said. “In the past, gun violence was never really discussed in the open; it was thought to only affect a certain population. However, now we know that it affects everyone. In the hopes of trying to reduce it at a systemic level from top to bottom, we’re reporting, as surgeons, how gun violence in the patients that we treat has changed over the last decade.”

The costs for hospitalizations, measured as median costs adjusted for gross domestic product, increased more than 27 percent over the 12-year study period, from $15,100 to $19,200 (p<0.001). The amount of time these patients spent in the hospital—a major cost driver—also increased from an average of 7.1 days to 12.6 days (p<0.001). The percentage of fatalities declined, from 8.6 percent in 2005 to 7.6 percent in 2016, despite an annual increase in overall admissions for GSW-related operations, from 19,832 in 2005 to 23,480 in 2016. The severity of these injuries, based on billing codes, increased slightly over that period, with predicted survival decreasing from 81 to 79 percent (P<0.001). The authors used a non-parametric test for trends to judge the significance of temporal changes in their analysis.

The cost analysis categorized operations by type and three different cost ranges: low, medium and high, with average costs of $7,400, $17,200, and $58,800, respectively. “We found that compared with those who were not operated on, patients having head-neck, vascular, and gastrointestinal operations had increased odds of being in the high-cost tertile,” Dr. Benharash said. “Being in the Western United States was also a predictor [of being in the high-cost tertile], as was being of Black race and having insurance by Medicaid. So there are certainly disparities that are socioeconomic in origin as well.”

For example, the study found that while 3.4 percent of all patients had operations for head and neck injuries, these operations were disproportionately represented in the low- and high-cost ranges, accounting for only 0.81 percent of the former but 7.1 percent of the latter. “Gunshot wounds to the neck, for example, can be very costly because they can affect many delicate structures as compared with lower extremities, and these patients often require extensive hospitalization and a greater number of procedures,” Dr. Benharash said.

The finding that costs in the West were higher is also important, Dr. Benharash noted, because it’s in line with what other studies have reported with other specialties. “It’s very important for policy makers and health services researchers to evaluate the disparities in cost,” he said.

The improved survival of GSW patients is a function of improvements in trauma transport from the field, better prehospital resuscitation, and improved techniques, patient management and adjunct therapies once they get to the hospital, Dr. Benharash said. “It appears that patients are reaching surgery more often because of reduced mortality before they get to the hospital,” he said.

The study also attributed these improvements in survival to efforts by the American College of Surgeon’s Committee on Trauma, including the Advanced Trauma Life Support curriculum and Stop the Bleed campaign. The latter trains the public in techniques to stop life-threatening bleeding in everyday emergencies.

But those improvements don’t obviate the need for addressing the underlying problem, Dr. Benharash noted. “It’s very important to put it in perspective that this entity is quite economically burdensome,” he said. “If you’re looking at prevention vs. treating a gunshot wound from an economic standpoint, it would make sense to invest in anti-violence interventions that can reduce assaults that are often preventable.”

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New test better predicts which babies will develop type 1 diabetes

A new approach to predicting which babies will develop type 1 diabetes moves a step closer to routine testing for newborns which could avoid life-threatening complications.

Scientists at seven international sites have followed 7,798 children at high risk of developing type 1 diabetes from birth, over nine years, in The Environmental Determinants of Diabetes in the Young (TEDDY) Study. The TEDDY Study is a large international study funded primarily by the US National Institutes of Health and U.S. Centers for Disease Control, as well as by the charity JDRF.

In research published in Nature Medicine, scientists at the University of Exeter and the Pacific Northwest Research Institute in Seattle used the TEDDY data to develop a method of combining multiple factors that could influence whether a child is likely to develop type 1 diabetes. The combined risk score approach incorporates genetics, clinical factors such as family history of diabetes, and their count of islet autoantibodies—biomarkers known to be implicated in type 1 diabetes.

The research team found that the new combined approach dramatically improved prediction of which children would develop type 1 diabetes, potentially allowing better diabetes risk counseling of families. Most importantly, the new approach doubled the efficiency of programs to screen newborns to prevent the potentially deadly condition of ketoacidosis, a consequence of type 1 diabetes in which insulin deficiency causes the blood to become too acidic. Identifying which children are at highest risk will also benefit clinical trials on drugs that are showing promise in preventing the condition.

Dr. Lauric Ferrat at the University of Exeter Medical School, said: “At the moment, 40 per cent of children who are diagnosed with type 1 diabetes have the severe complication of ketoacidosis. For the very young this is life-threatening, resulting in long intensive hospitalizations and in some cases even paralysis or death. Using our new combined approach to identify which babies will develop diabetes can prevent these tragedies, and ensure children are on the right treatment pathway earlier in life, meaning better health.”

Professor William Hagopian of the Pacific Northwest Research Institute, said: “We’re really excited by these findings. They suggest that the routine heel prick testing of babies done at birth, could go a long way towards preventing early sickness as well as predicting which children will get type 1 diabetes years later. We’re now putting this to the test in a trial in Washington State. We hope it will ultimately be used internationally to identify the condition as early as possible, and to power efforts to prevent the disease.”

Researchers believe the combined approach can also be rolled out to predict the onset of other diseases with a strong genetic component that are identifiable in childhood, such as celiac disease.

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Sperm don’t swim anything like we thought they did, new study finds

Under a microscope, human sperm seem to swim like wiggling eels, tails gyrating to and fro as they seek an egg to fertilize. 

But now, new 3D microscopy and high-speed video reveal that sperm don’t swim in this simple, symmetrical motion at all. Instead, they move with a rollicking spin that compensates for the fact that their tails actually beat only to one side. 

“It’s almost like if you’re a swimmer, but you could only wiggle your leg to one side,” said study author Hermes Gadêlha, a mathematician at the University of Bristol in the U.K. “If you did this in a swimming pool and you only did this to one side, you would always swim in circles. … Nature in its wisdom came [up] with a very complex, ingenious way to go forward.” 

Strange swimmers

The first person to observe human sperm close up was Antonie van Leeuwenhoek, a Dutch scientist known as the father of microbiology. In 1677, van Leeuwenhoek turned his newly developed microscope toward his own semen, seeing for the first time that the fluid was filled with tiny, wiggling cells. 

Under a 2D microscope, it was clear that the sperm were propelled by tails, which seemed to wiggle side-to-side as the sperm head rotated. For the next 343 years, this was the understanding of how human sperm moved. 

“[M]any scientists have postulated that there is likely to be a very important 3D element to how the sperm tail moves, but to date we have not had the technology to reliably make such measurements,” said Allan Pacey, a professor of andrology at the University of Sheffield in England, who was not involved in the research. 

The new research is thus a “significant step forward,” Pacey wrote in an email to Live Science. 

Gadêlha and his colleagues at the Universidad Nacional Autónoma de México started the research out of “blue-sky exploration,” Gadêlha said. Using microscopy techniques that allow for imaging in three dimensions and a high-speed camera that can capture 55,000 frames per second, they recorded human sperm swimming on a microscope slide. 

“What we found was something utterly surprising, because it completely broke with our belief system,” Gadêlha told Live Science. 

The sperm tails weren’t wiggling, whip-like, side-to-side. Instead, they could only beat in one direction. In order to wring forward motion out of this asymmetrical tail movement, the sperm head rotated with a jittery motion at the same time that the tail rotated.The head rotation and the tail are actually two separate movements controlled by two different cellular mechanisms, Gadêlha said. But when they combine, the result is something like a spinning otter or a rotating drill bit. Over the course of a 360-degree rotation, the one-side tail movement evens out, adding up to forward propulsion.

“The sperm is not even swimming, the sperm is drilling into the fluid,” Gadêlha said. 

The researchers published their findings today (July 31) in the journal Science Advances.

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Asymmetry and fertility

In technical terms, how the sperm moves is called precession, meaning it rotates around an axis, but that axis of rotation is changing. The planets do this in their rotational journeys around the sun, but a more familiar example might be a spinning top, which wobbles and dances about the floor as it rotates on its tip. 

“It’s important to note that on their journey to the egg that sperm will swim through a much more complex environment than the drop of fluid in which they were observed for this study,” Pacey said. “In the woman’s body, they will have to swim in narrow channels of very sticky fluid in the cervix, walls of undulating cells in the fallopian tubes, as well have to cope with muscular contractions and fluid being pushed along (by the wafting tops of cells called cilia) in the opposite direction to where they want to go. However, if they are indeed able to drill their way forward, I can now see in much better clarity how sperm might cope with this assault course in order to reach the egg and be able to get inside it,” Pacey said

Sperm motility, or ability to move, is one of the key metrics fertility doctors look at when assessing male fertility, Gadêlha said. The rolling of the sperm’s head isn’t currently considered in any of these metrics, but it’s possible that further study could reveal certain defects that disrupt this rotation, and thus stymy the sperm’s movement. 

Fertility clinics use 2D microscopy, and more work is needed to find out if 3D microscopy could benefit their analysis, Pacey said. 

“Certainly, any 3D approach would have to be quick, cheap and automated to have any clinical value,” he said. “But regardless of this, this paper is certainly a step in the right direction.”

Originally published in Live Science.

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New motion capture screening technology could slow progression of arthritis

Most people don’t think about their thumbs very often. But for people living with advancing arthritis, the simplest thumb movements—from grasping a cup to sending a text message—can be painful and incredibly challenging.

That’s why Michigan State University researchers set out to see if they could use motion capture technology to screen for differences between healthy hand movements and those in patients with osteoarthritis, or OA. This method could potentially detect arthritis earlier, possibly delaying and preventing the loss of thumb function. In turn, that could save arthritis patients from surgery and even being forced into assisted living.

The team’s research is published in Clinical Biomechanics.

“Our work suggests that three-dimensional motion tasks may be able to identify OA-associated motion deficits earlier than the two-dimensional motion tasks typically used in a clinical setting,” said Amber Vocelle, co-author on the research and a DO/Ph.D. student in the College of Osteopathic Medicine. “By identifying the disease earlier, we can treat OA earlier in the disease process.”

According to Vocelle, therapists and clinicians traditionally use goniometers, simple two-dimensional measurement tools, along with basic movements to screen for reduced hand function due to OA. But the results can vary depending on who’s doing the measuring, making it hard to track reliably over time.

“There are pieces of information that aren’t being gathered right now that could be useful for early prediction of OA of the thumb, or setting up thresholds to define when people should consider doing therapy before they’re in severe pain,” said Tamara Reid Bush, an associate professor of mechanical engineering in the College of Engineering who also worked on the research.

In contrast, motion capture technology records precise, objective measurements in three dimensions.

Both Bush and Vocelle, along with Gail Shafer, an assistant professor in the College of Human Medicine, put markers on participants’ hands, which were then monitored by motion capture technology as they went through a series of three-dimensional thumb movements. Differences between healthy and OA-diagnosed patients were observed.

The thumb isn’t usually looked at in isolation with reference to OA, but this research may be changing that.

“Thumbs aren’t just important for people playing the piano or knitting for fun. Almost everything you do on a daily basis involves the thumb in some way, shape or form,” Bush added.

Forthcoming research from the trio will look at how a six-week thumb exercise protocol impacted the ability to generate forces with the thumb. The researchers observed an increase in thumb strength in just two weeks.

So where could this go next? One avenue would be to develop tools for conducting these three-dimensional measurements in-clinic without the need for laboratory-grade motion capture devices. That would give therapists the ability to not only evaluate more complex movement patterns for earlier diagnosis, but also measure the impact of treatment for better outcomes.

This type of collaboration between research specialties can be difficult to pull off, but Vocelle’s rotations as part of her DO/Ph.D. program presented a meaningful opportunity for integration. The three combined Vocelle’s clinical knowledge, Shafer’s rehabilitation expertise, and Bush’s deep understanding of biomechanics to offer a fresh perspective on a long-standing clinical problem.

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Ever heard of a surgical assistant? Meet a new boost to your medical bills

Izzy Benasso was playing a casual game of tennis with her father on a summer Saturday when she felt her knee pop. She had torn a meniscus, one of the friction-reducing pads in the knee, locking it in place at a 45-degree angle.

Although she suspected she had torn something, the 21-year-old senior at the University of Colorado in Boulder had to endure an anxious weekend in July 2019 until she could get an MRI that Monday.

“It was kind of emotional for her,” said her father, Steve Benasso. “Just sitting there thinking about all the things she wasn’t going to be able to do.”

At the UCHealth Steadman Hawkins Clinic Denver, the MRI confirmed the tear, and she was scheduled for surgery on Thursday. Her father, who works in human resources, told her exactly what to ask the clinic regarding her insurance coverage.

Steve had double-checked that the hospital; the surgeon, Dr. James Genuario; and Genuario’s clinic were in her Cigna health plan’s network.

“We were pretty conscious going into it,” he said.

Isabel met with Genuario’s physician assistant on Wednesday, and the following day underwent a successful meniscus repair operation.

“I had already gotten a ski pass at that point,” she said. “So that was depressing.” But she was heartened to hear that with time and rehab she would get back to her active lifestyle.

Then the letter arrived, portending of bills to come.

The Patient: Izzy Benasso, a 21-year-old college student covered by her mother’s Cigna health plan.

The Total Bill: $96,377 for the surgery was billed by the hospital, Sky Ridge Medical Center in Lone Tree, Colorado, part of HealthONE, a division of the for-profit hospital chain HCA. It accepted a $3,216.60 payment from the insurance company, as well as $357.40 from the Benassos, as payment in full. The surgical assistant billed separately for $1,167.

Service Provider: Eric Griffith, a surgical assistant who works as an independent contractor.

Medical Service: Outpatient arthroscopic meniscus repair surgery.

What Gives: The Benassos had stumbled into a growing trend in health care: third-party surgical assistants who aren’t part of a hospital staff or a surgeon’s practice. They tend to stay out-of-network with health plans, either accepting what a health plan will pay them or billing the patient directly. That, in turn, is leading to many surprise bills.

Even before any other medical bills showed up, Izzy received a notice from someone whose name she didn’t recognize.

“I’m writing this letter as a courtesy to remind you of my presence during your surgery,” the letter read.

It came from Eric Griffith, a Denver-based surgical assistant. He went on to write that he had submitted a claim to her health plan requesting payment for his services, but that it was too early to know whether the plan would cover his fee. It didn’t talk dollars and cents.

Steve Benasso said he was perplexed by the letter’s meaning, adding: “We had never read or heard of anything like that before.”

Surgical assistants serve as an extra set of hands for surgeons, allowing them to concentrate on the technical aspects of the surgery. Oftentimes other surgeons or physician assistants—or, in teaching hospitals, medical residents or surgical fellows—fill that role at no extra charge. But some doctors rely on certified surgical assistants, who generally have an undergraduate science degree, complete a 12- to 24-month training program, and then pass a certification exam.

Surgeons generally decide when they need surgical assistants, although the Centers for Medicare & Medicaid Services maintains lists of procedures for which a surgical assistant can and cannot bill. Meniscus repair is on the list of allowed procedures.

A Sky Ridge spokesperson said that it is the responsibility of the surgeon to preauthorize the use and payment of a surgical assistant during outpatient surgery, and that HealthOne hospitals do not hire surgical assistants. Neither the assistant nor the surgeon works directly for the hospital. UC School of Medicine, the surgeon’s employer, declined requests for comment from Genuario.

Karen Ludwig, executive director of the Association of Surgical Assistants, estimates that 75% of certified surgical assistants are employed by hospitals, while the rest are independent contractors or work for surgical assistant groups.

“We’re seeing more of the third parties,” said Dr. Karan Chhabra, a surgeon and health policy researcher at the University of Michigan Medical School. “This is an emerging area of business.”

And it can be lucrative: Some of the larger surgical assistant companies are backed by private equity investment. Private equity firms often target segments of the health care system where patients have little choice in who provides their care. Indeed, under anesthesia for surgery, patients are often unaware the assistants are in the operating room. The private equity business models include keeping such helpers out-of-network so they can bill patients for larger amounts than they could negotiate from insurance companies.

Surgical assistants counter that many insurance plans are unwilling to contract with them.

“They’re not interested,” said Luis Aragon, a Chicago-area surgical assistant and managing director of American Surgical Professionals, a private equity-backed group in Houston.

Chhabra and his colleagues at the University of Michigan recently found that 1 in 5 privately insured patients undergoing surgery by in-network doctors at in-network facilities still receive a surprise out-of-network bill. Of those, 37% are from surgical assistants, tied with anesthesiologists as the most frequent offenders. The researchers found 13% of arthroscopic meniscal repairs resulted in surprise bills, at an average of $1,591 per bill.

Colorado has surprise billing protections for consumers like the Benassos who have state-regulated health plans. But state protections don’t apply to the 61% of American workers who have self-funded employer plans. Colorado Consumer Health Initiative, which helps consumers dispute surprise bills, has seen a lot of cases involving surgical assistants, said Adam Fox, director of strategic engagement.

Resolution: Initially, the Benassos ignored the missive. Izzy didn’t recall meeting Griffith or being told a surgical assistant would be involved in her case.

But a month and a half later, when Steve logged on to check his daughter’s explanation of benefits, he saw that Griffith had billed the plan for $1,167. Cigna had not paid any of it.

Realizing then that the assistant was likely out-of-network, Steve sent him a letter saying “we had no intention of paying.”

Griffith declined to comment on the specifics of the Benasso case but said he sends letters to every patient so no one is surprised when he submits a claim.

“With all the different people talking to you in pre-op, and the stress of surgery, even if we do meet, they may forget who I was or that I was even there,” he said. “So the intention of the letter is just to say, ‘Hey, I was part of your surgery.'”

After KHN inquired, Cigna officials reviewed the case and Genuario’s operative report, determined that the services of an assistant surgeon were appropriate for the procedure and approved Griffith’s claim. Because Griffith was an out-of-network provider, Cigna applied his fee to Benasso’s $2,000 outpatient deductible. The Benassos have not received a bill for that fee.

Griffith says insurers often require more information before determining whether to pay for a surgical assistant’s services. If the plan pays anything, he accepts that as payment in full. If the plan pays nothing, Griffith usually bills the patient.

The Takeaway: As hospitals across the country restart elective surgeries, patients should be aware of this common pitfall.

Chhabra said he’s hearing more anecdotal reports about insurance plans simply not paying for surgical assistants, which leaves the patient stuck with the bill.

Chhabra said patients should ask their surgeons before surgery whether an assistant will be involved and whether that assistant is in-network.

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New study reveals older adults coped with pandemic best

Adults aged 60 and up have fared better emotionally compared to younger adults (18-39) and middle-aged adults (40-59) amid the COVID-19 pandemic, according to new UBC research published recently in the Journal of Gerontology: Psychological Sciences.

Based on daily diary data collected between mid-March and mid-April of this year, the researchers found that older adults experienced greater emotional well-being and felt less stressed and threatened by the pandemic.

“Our findings provide new evidence that older adults are emotionally resilient despite public discourse often portraying their vulnerability. We also found that younger adults are at greater risk for loneliness and psychological distress during the pandemic,” says Patrick Klaiber, the study’s lead author and a graduate student in the UBC department of psychology.

For the study, the researchers analyzed data from 776 participants aged 18-91, who lived in Canada and the U.S. and completed daily surveys for one week about their stressors, positive events and their emotional well-being during the first several weeks of the pandemic. The time period was selected as it was likely to be the period of greatest disruption and uncertainty as local, provincial and state governments began issuing stay-at-home orders.

Klaiber says the difference in reported stress levels may be a result of age-related stressors and how well the different age groups respond to stress.

“Younger and middle-aged adults are faced with family- and work-related challenges, such as working from home, homeschooling children and unemployment,” says Klaiber. “They are also more likely to experience different types of ongoing non-pandemic stressors than older adults, such as interpersonal conflicts.”

Klaiber adds, “While older adults are faced with stressors such as higher rates of disease contraction, severe complications and mortality from COVID-19, they also possess more coping skills to deal with stress as they are older and wiser.”

The study also reveals older and middle-aged adults experienced more daily positive events—such as remote positive social interactions—in 75 per cent of their daily surveys, which helped increase positive emotions compared to younger adults.

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New Zealand military to control borders after virus bungle

New Zealand Prime Minister Jacinda Ardern ordered the military to oversee the country’s border controls Wednesday after a bungle that allowed two people with the coronavirus to leave quarantine.

A 24-day run with no new cases was broken Tuesday when it emerged two women who recently arrived from Britain were allowed out of quarantine early without being tested for the virus, even though one had mild symptoms.

The pair were eventually swabbed and proved to be infected, but only after they made a 650-kilometre (400-mile) road trip from Auckland to Wellington to see a dying relative.

Ardern said it was “absolutely nonsensical” they were not tested earlier and border controls clearly needed to be tightened to prevent similar failures.

She said Assistant Chief of Defence Digby Webb had been appointed to oversee border quarantine operations and was being given access to military personnel and logistical expertise.

“My view is that we need the rigour, we need the confidence, we need the discipline that the military can provide,” Ardern told reporters.

Health Minister David Clark acknowledged widespread anger at the blunder. Kiwis endured a stringent seven-week lockdown to eliminate the virus in the country which has recorded only 1,156 cases and 22 deaths in a population of five million.

“New Zealanders have made great sacrifices to make it to this point,” he told Radio New Zealand.

“Our system has performed incredibly well as a whole in New Zealand. We have eliminated COVID-19 but I want this fixed straight away.”

‘Envy of the world’

The South Pacific nation last week scrapped domestic social distancing measures while maintaining strong border controls.

The changes have heralded a return to near-normality, with sports matches played in front of sold-out stadiums, nightclubs open and thousands gathering for events such as Black Lives Matter Protests without restrictions.

Clark said it was unacceptable that mistakes at the border, which is now seen as the frontline in the fight against COVID-19, could put such gains at risk.

“We’re the envy of the world in many ways and we want to continue being the envy of the world,” he said.

New Zealand’s borders are open only to returning Kiwis and their families, besides some exceptions for some foreigners on business and compassionate grounds, with everyone expected to undergo two weeks mandatory quarantine.

Officials say there are approximately 3,500 people in border quarantine, mostly staying in hotels where they are expected to remain isolated in their rooms and avoid social contact.

The programme that allowed recent arrivals to leave isolation early on compassionate grounds has been suspended and everyone in quarantine must test negative for the virus before they are allowed back into the community.

Ardern stressed that the women at the centre of the furore had done nothing wrong and complied with health protocols at all times.

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Researchers discover new member of novel drug family for ‘undruggable’ targets

In the last several years, excitement has surged for a promising class of drugs that work not by inhibiting the action of a molecular target, as most conventional drugs do, but instead by harnessing the cell’s recycling system to destroy the target. However, these unusual compounds, known as molecular glue degraders, have been difficult to find and engineer.

Now, a research team led by scientists at the Broad Institute of MIT and Harvard and the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland has discovered a new molecular glue degrader called CR8. By dissecting the details of CR8’s molecular mechanism of action, as described in a paper published in Nature, the researchers show how it may be possible to build more of these unique compounds as potential treatments for a variety of diseases.

“We have shown that it is possible to take a conventional kinase inhibitor and, by attaching a particular chemical group, transform it into a molecular glue degrader,” said co-senior author Benjamin Ebert, an institute member in the Broad Cancer Program and the chair of the Department of Medical Oncology at Dana-Farber Cancer Institute. “This offers the potential for creating molecular glue degraders for a much wider range of therapeutic targets than we had initially anticipated.”

Throw away the lock and key

Most drugs use a lock-and-key approach to target proteins, typically enzymes, by directly binding within distinct grooves in the target protein to block its activity. Yet many other kinds of proteins, like transcription factors, lack such binding sites, which has stymied efforts to design drugs against these traditionally “undruggable” targets.

About six years ago, Ebert and his colleagues revealed that a well-known multiple myeloma drug, called lenalidomide, works as a molecular glue degrader. Instead of directly binding to its targets, it operates more stealthily, by recruiting a molecular machine that tags target proteins for destruction in the cell. This machine, known as E3 ubiquitin ligase, attaches a small protein called ubiquitin to the ill-fated targets, which are then degraded by the cell’s recycling system.

To identify more molecular glue degraders, Ebert’s team, led by co-first author Mikolaj Slabicki, a postdoctoral researcher at Broad and the German Cancer Research Center in Heidelberg, studied data on more than 4,500 drugs and compounds from the Broad’s Drug Repurposing Hub, a collection of compounds that have been shown to be safe in humans, including many that are FDA-approved. The scientists combed through these publicly available data to pinpoint drugs that preferentially kill cancer cells with high E3 ubiquitin ligase levels.

“We were always brainstorming in the lab to figure out how we can find more molecular glue degraders,” said Slabicki. “We were incredibly fortunate to have access to such large, robust datasets. We wouldn’t have made this discovery without the dataset generated at the Broad Cancer Program.”

A path to creating more

CR8 is a compound that was originally designed to inhibit enzymes called cyclin-dependent kinases (CDKs), which play important roles in controlling cell growth. The researchers used their bioinformatic approach to discover that CR8’s cell-killing activity correlates with levels of a component of the E3 ubiquitin ligase complex called DDB1.

The team found that CR8 kills cancer cells by inducing degradation of a protein called cyclin K, which is a binding partner of some CDKs, in particular CDK12. CR8 does this by acting like a molecular glue, binding CDK12-cyclin K, and recruiting DDB1 and subsequently other parts of the E3 ubiquitin ligase complex, which results in the tagging of cyclin K for degradation.

Collaborators from the Friedrich Miescher Institute including co-senior author Nicolas Thomä and co-first authors Zuzanna Kozicka and Georg Petzold solved the crystal structure of key components of this CR8-induced protein complex, which revealed new molecular details about the interactions between all the glued-together parts.

The Boston and Basel teams looked at the activity of a drug that’s structurally similar to CR8 and found that it doesn’t lead to cyclin K degradation. The only structural difference between the two compounds is a lone chemical moiety known as a pyridyl substituent, that protrudes out. This moiety, the team concluded, is sufficient to enable CR8 to act like a molecular glue degrader. The finding suggests that chemical modifications of outward-facing parts of inhibitors could turn them into molecular glue degraders of a given protein target.

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Flu researchers say we should make a NEW antiviral to stop coronavirus

Flu researchers say we should make a NEW antiviral to prevent coronavirus from replicating throughout the body and stop focusing on repurposing old drugs

  • Researchers looked an older treatment for the flu, Tamiflu, and a newer treatment, Xofluza, the first new type of flu drug in 20 years
  • Xofluza limited the amount of time a person was sick by quickly stopping the virus from replicating and spreading throughout the body
  • The team says the same approach needs to work for coronavirus, creating a new drug that stops the virus from multiplying rather then repurposing old drugs
  • In the US, there are more than 1.8 million confirmed cases of the virus and more than 105,000 deaths
  • Here’s how to help people impacted by Covid-19

A new antiviral drug should be created to stop the novel coronavirus rather than repurposing old medication, a new study suggests.

Researchers compared an older antiviral treatment that most flu patients know compared to a newer one.

The newer treatment cut the amount of time people were sick with the flu, which limited the spread of the virus, because it stopped the disease from multiplying within an infected person. 

The team, from the University of Texas at Austin, says creating a drug that does the same for the coronavirus in early-stage patients would be more beneficial that trying to get existing drugs to treat late-stage patients.

A newer treatment fro flu Xofluza (blue) limited the amount of time a person was sick by quickly stopping the virus from replicating and spreading throughout the body rather than the older treatment of Tamiflu (green)

The team says the same approach needs to work for coronavirus, creating a new drug that stops the virus from multiplying rather then repurposing old drugs. Pictured: COVID-19 patients are taken into to the Wakefield Campus of the Montefiore Medical Center in the Bronx, New York, April 6

For the study, published in Nature Communications, the team looked at influenza and its implications for COVID, the disease caused by the virus.

Researchers first looked at the effects of Tamiflu, or its generic oseltamivir, one of three drugs the Centers for Disease Control and Prevention has endorsed to treat the flu.  

Then they looked at baloxavir, which is sold under the brand name Xofluza, the first new type of flu drug in 20 years.

The new treatment from the same company that developed Tamiflu, was shown in past studies to cut the amount of time people were sick and reduce the length of a fever. 

While Xofluza didn’t work faster than Tamiflu, it did reduce the level of the virus in patients’ nose and throat quicker. 

The new study showed that the newer treatment limited the amount of time a person was sick by quickly stopping the virus from replicating and spreading throughout the body. 

‘We found that treating even 10 percent of infected patients with baloxavir shortly after the onset of their symptoms can indirectly prevent millions of infections and save thousands of lives during a typical influenza season,’ said Dr Robert Krug, a professor emeritus of molecular biosciences, in a blog that accompanied the paper.  

Krug and his team say that a similar antiviral treatment would help to prevent thousands of infections and deaths from the coronavirus    

‘Imagine a drug that quashes viral load within a day and thus radically shortens the contagious period,’ said Dr Lauren Ancel Meyers, a professor of integrative biology.

‘Basically, we could isolate COVID-19 cases pharmaceutically rather than physically and disrupt chains of transmission.’

Most drugs being researched to treat COVID-19 have focused on existing antivirals that can be given to critically ill patient.

But the team says research should shift towards developing a new antiviral for the coronavirus that is used early on in infection and stops the virus from replicating,  , just as baloxavir does for the flu.

‘It may seem counterintuitive to focus on treatments, not for the critically ill patient in need of a life-saving intervention, but rather for the seemingly healthy patient shortly after a COVID-19 positive test,’ Krug said. 

‘Nonetheless, our analysis shows that the right early-stage antiviral treatment can block transmission to others and, in the long run, may well save more lives.’

In the US, there were more than 1.8 million confirmed cases of the virus and more than 105,000 deaths.

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Virus count revised, new clusters emerge as France reopens

France’s national health agency reported a sudden jump in new virus infections—just an hour after the prime minister announced a sweeping national reopening plan.

The agency clarified Friday that the surprising new figures were the result of a new accounting method, and not linked to a much-feared second wave of the virus.

But they highlighted concerns about the French government’s handling of the crisis, and served as a reminder that infections are continuing in one of the countries hit hardest by the pandemic.

“We are where we had hoped to be at the end of May, and maybe a little better,” Prime Minister Edouard Philippe said Thursday, as he announced that r estaurants, museums and parks could reopen next week for the first time since March. “It’s good news, but not good enough for everything to return to normal.”

Statistics released Friday showed 96 virus clusters have emerged around France since the government started easing confinement measures May 11. They are primarily in medical facilities, businesses and shelters.

And the virus remains a serious risk in two overseas French regions, where health care is weaker and poverty higher than on the mainland: the Indian Ocean island of Mayotte and French Guiana on South America’s Caribbean coast.

Overall COVID-19 is receding in France, with the number of virus patients in intensive care dropping every day since April 8 and now at 1,429.

But the public health agency DGS quietly released figures Thursday night showing a rise of more than 3,000 new infections from the day before—the biggest such jump in more than three weeks.

That puzzled epidemiologists like Dr. Laurent Toubiana, who has been closely following the curve of the virus in European countries, and thinks the epidemic is petering out in France. “It’s incomprehensible,” he said.

The DGS then said Friday the new cases included positive tests registered under a “better, more exhaustive” counting system put in place May 13, and did not correspond to a single-day rise. It insisted there are “no signs in favor of a return of the epidemic.”

France has confirmed 149,071 cases so far, though the government acknowledges the real number of infections is much higher because of limited testing.

The French government came under criticism for not testing widely enough earlier in the pandemic. It is now testing more than 200,000 people a week, according to the health agency.

Death figures are also difficult to pin down. France has reported 28,662 deaths overall in hospitals and nursing homes, and the state statistics agency Insee on Friday reported a 26% rise in overall deaths in March and April from all causes compared to the same period in 2019.

In May, it said the number of overall deaths in France is down 6% so far, though finalized death figures usually lag by a few weeks, so the number could still rise.

“During this whole epidemic, we have had intense problems of viability of data,” Toubiana said.

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