Establishing standards of care for forensic mental health: an international Delphi consensus-building study

ObjectivesThe present study aimed to establish a consensus on a definition of forensic mental health systems and services, and to identify principles and components of forensic mental health systems.MethodsA Delphi consensus-building process was employed among 23 experts in forensic mental health, defined by lived experience of forensic mental health services, professional, clinical or management practice in forensic settings, or academic research in the field. Items were rated on a 9-point Likert scale, with consensus defined as ≥75% of panelists rating an item between 7 and 9. Across three Delphi rounds, items were revised, merged, or added based on participant feedback. Data were collected anonymously using LimeSurvey, with reminders sent to maximize participation, followed by a structured consensus meeting to resolve remaining areas of disagreement.ResultsThe final consensus statement comprises three components: (1) a definition of forensic mental health services; (2) a general statement including 12 guiding principles; and (3) 43 core components organized across 10 thematic domains addressing models of care, pathways and processes, programs and activities, physical health, service user and peer involvement, evaluation and improvement, service integration, safe environments, restrictive practices, and other system-level considerations. While all items achieved consensus at the consensus meeting, areas of sustained discussion related to the integration of cultural expertise, the inclusion of a lived experience workforce, and the distinction between descriptive and aspirational elements of forensic mental health services.ConclusionsThis international consensus statement provides a structured framework for understanding forensic mental health systems. By articulating shared principles and core components while allowing flexibility across jurisdictions, the framework offers a foundation to support service development and evaluation across diverse jurisdictions.

Research progress on social participation of young and middle-aged stroke survivors: a narrative review

Stroke is characterized by high morbidity, disability, and mortality, and has become the third leading cause of death worldwide. In China, stroke accounts for 39.9% of all cerebrovascular diseases, with young and middle-aged survivors (aged 40–60 years) comprising 33% of global stroke survivors in this age group and over 51.51% of all stroke cases in China. Despite significant improvements in treatment, 70–80% of survivors still lose the ability to live independently, and social participation declines to varying degrees. Social participation plays an important role in rehabilitation outcome indicators, which can reflect the overall recovery of survivors and is closely related to quality of life. Guided by the International Classification of Functioning, Disability and Health (ICF) framework, this review aims to examine the current status, assessment tools, and influencing factors of social participation among young and middle-aged stroke survivors, with the goal of informing future research and guiding clinical practice.

STAT+: Roche to launch another Elevidys trial, with eyes on European approval

In an attempt to win European approval for the controversial medicine, Roche said Thursday it would run another trial of the Duchenne muscular dystrophy gene therapy Elevidys. 

The Swiss company’s move comes after European regulators last year gave a negative review to the therapy, saying it had failed to demonstrate long-term benefits for patients with the degenerative muscle condition. Roche has rights to the therapy outside the U.S., where it is marketed by its developer, Sarepta Therapeutics.

Roche said the Phase 3 trial will generate the type of evidence that could lead to a resubmission with European officials and to applications with regulatory agencies in other parts of the world. The study will evaluate the safety and efficacy of Elevidys versus placebo over 72 weeks in roughly 100 boys at the early stages of the disease. 

Continue to STAT+ to read the full story…

The noise we make is hurting animals. Can we learn to shut up?

When the covid-19 pandemic started, Jennifer Phillips thought about the songs of the sparrows.

They were easier to hear, because the world had suddenly become quieter. Car traffic plummeted as people sheltered at home and shifted to remote work. Air travel collapsed. Cities—normally filled with the honking, screeching, engine-gunning riot of transportation—became as silent as tombs.

For years, Phillips has studied how animals react to “anthropogenic noise,” or the racket created by human activity. Most animals really don’t like it, she and her colleagues have learned. Animals constantly listen to the world around them: They’re on the alert for the rustle of approaching predators, or a mating call from a member of their species. As human society has expanded—with sprawling cities, industrial mines, and roads crisscrossing the world—it has gotten noisier too, and animals have trouble hearing one another.

Noise is invisible; there’s no billowing smokestack, no soiled waterway. We just got used to it as it vibrated in the background.

Phillips and her colleagues had spent time in the 2010s in San Francisco recording the sound of white-crowned sparrows in the Presidio. It’s a park that is half peaceful nature and half automobile noise, since it’s filled with thick clumps of trees and grassy fields but also has two highways that slice through it, feeding onto the Golden Gate Bridge. In past recordings, starting in the 1950s, sparrows had sung with complex and lower-pitched melodies and three major “dialects.” But by the 2010s, traffic in the Presidio had exploded, and the hubbub was so loud that the birds began to sing with faster trills—and at a higher pitch—so their fellows could hear them. The two quietest dialects were either dead or on their way to extinction.

They’re “screaming at the top of their lungs,” says Phillips. “They really can’t hear the lower frequencies when the traffic noise is present.” Urban noise can even change birds’ bodies; they get thinner and more stressed out. Their mating calls aren’t as effective, because female birds, as researchers have found, generally don’t enjoy high-pitched, high-volume shouting. (It makes them wonder if the males are unhealthy.) The noise can increase bird-on-bird conflict, because when birds can’t hear warning cries they accidentally stumble into enemy territory. Perhaps worst of all, in situations like these biodiversity takes a hit: Entire species that can’t handle urban clamor simply head out of town and never come back.

But as the sudden, eerie silence of the pandemic descended, Phillips sat at home thinking, It’s really quiet. And then she wondered: Would the Presidio birds now be able to hear each other better?

She raced over to the park and started recording. Sure enough, the park was seven decibels quieter—a huge drop. (That’s like the difference between the noise of the average home and whispering.)

And remarkably, the researchers found that the songs of the white-crowned sparrows had transformed. They were singing more quietly, with a richer range of frequencies. A bird could be heard twice as far as before. And the mating calls had gotten more sultry.

“They could sing a higher performance, basically a sexier song, but not have to scream it so loud,” Phillips says. 

It was as if time had been reversed and all the damage abruptly repaired. And it proved what Phillips and her peers have been increasingly documenting: that anthropogenic noise is the newest form of pollution we need to tackle. The noise of our relentlessly on-the-move industrial society affects all life on Earth, wildlife and humans, in ways we’re just beginning to grasp. Yet strategies such as electrification and clever urban design could help. As the Presidio showed, noise can vanish overnight—once we figure out how to shut up.

Hidden impacts

Many forms of pollution are obvious to us humans. Dumping toxic goo into lakes? Sure, that’s bad. Coal smokestacks pumping soot and carbon dioxide, plastic bags and sea nets choking whales—we now understand that these, too, are problems. Even an idea as gauzy as light pollution has penetrated the public consciousness to some extent, since it’s why city dwellers can’t see many stars, and we’ve heard it confuses migratory birds.

But noise, mostly from transportation, took longer to hit our radar. This is partly because it’s invisible; there’s no billowing smokestack, no soiled waterway. We just got used to it as it vibrated in the background.

sparrow perched on a branch, singing
Sparrows in San Francisco’s Presidio began to sing with faster trills—and at a higher pitch—so their fellows could hear them over the noise of nearby traffic.
GETTY IMAGES
hummingbird in flight
The black-chinned hummingbird seems to prefer noisy areas, fledging more chicks than the same species does in quieter areas.
MDF/WIKIMEDIA COMMONS

There were a few studies in the ’70s and ’80s showing that animals were upset by our noise. But the field really began to take off in the ’00s, in part because digital technology made it easier to record long swathes of sound out in nature and analyze them. One early salvo came from the biologist Hans Slabbekoorn, who was studying doves in the city of Leiden and irritatedly noticed that he could rarely get a clean recording because of the background noise. Sometimes he’d see the doves’ throats moving as they cooed but couldn’t hear them. “If I’m having difficulty hearing them,” he thought, “what about them?”

So he and a colleague started recording ambient sound levels in different parts of Leiden. Some were quiet residential areas, which registered a soothing 42 decibels, and others were noisy intersections or areas near highways, which reached 63 decibels, about as loud as background music. Sure enough, he found that birds in the noisy areas were singing at a higher pitch.

Over the next two decades, research in the field bloomed. Noise, the scientists found, has a few common ill effects on animals. It disrupts communication, certainly. But it also generally stresses them, reducing everything from their body weight to their receptivity to mating calls. If an animal nests closer to a road, its reproduction rates can go down; eastern bluebirds, for example, produce fewer fledglings. Truly cacophonous noise—like planes taking off at a nearby airport—can cause hearing loss in birds. And animals can wind up becoming less aware of threats from predators. They’ll wander closer to danger, because they can’t hear it coming. (And sometimes they’ll do the opposite: They’ll develop a rageaholic hair-­trigger temper, because they’re constantly on high alert and regard everything as a threat.) 

Even in deep rural areas, where things are normally pretty quiet, highways can disrupt wildlife—the noise carries far into the fields nearby. Fraser Shilling, a biologist at the University of California, Davis, has stood up to half a mile from rural highways and recorded sound as loud as 60 decibels, which is at least 20 decibels higher than you’d typically find in the wilderness. “The motorcycles and the 18-wheelers are really the ones that project a lot of noise,” he told me. 

Above 55 decibels, many skittish animals get into a fight-or-flight panic. The prevalence of bobcats—an endangered species famously rattled by noise—“starts dropping off the cliff,” says Shilling. Above 65, “you’re really starting to exclude almost all wildlife.”

And that’s not even the upper limit of what wildlife is exposed to. There are roughly a half-million natural-gas wells around the US, and piercingly loud compressors are used to shoot water down into most of them. Up close, the compressors can kick out 95 decibels, a sound as loud as a subway train; at one Wyoming gas well the sound still registered around 48 decibels nearly a quarter-mile away.

Historically, it wasn’t always easy to prove that noise was causing whatever problems the animals were experiencing. Maybe it was other factors; maybe animal populations reduce near a road because some are hit by vehicles? 

But several clever experiments have proved that noise—and noise alone—can disrupt wildlife. One was the “phantom road” experiment by the conservation scientist Jesse Barber and his team, then at Boise State University. They went out to a quiet, uninhabited area of the Boise foothills in Idaho, far away from any roads. In this valley in the mountains, thousands of migratory birds stop on their way south each year; they’ll gorge themselves on cherry bushes, gaining weight for the next days of flying. The researchers strapped 15 pairs of speakers to Douglas fir trees, in a half-kilometer line. Then they blasted recordings of highway noise. They played the noise for four days and then turned it off for four days. Then they observed thousands of birds, capturing many to measure their body mass.

The noise truly rattled the birds. When the sound was turned on, nearly a third left the area. Those that stuck around ate less: While birds should be heavier after a day of foraging, these ones didn’t gain much. The noise seemed to have so interrupted their feeding that they weren’t packing on the weight needed for their migratory trip.

Other, similarly nifty A/B tests followed. One was led by David Luther, a biologist at George Mason University (who also worked with Phillips on the covid-19 study in San Francisco). In 2015, these researchers took 17 white-crowned sparrows at birth and raised them in a lab. To teach them their species’ songs, they played the nestlings recordings of adult sparrows singing, at low and high pitches. Six of the nestlings heard the songs without any interference; with the other half, the researchers played the sounds of city noise at the same time.

The results were stark. The lucky birds that were spared the traffic noise learned to perform the quieter, sweeter, more complex songs. But the birds that had traffic noise blasted learned only the higher, faster, more stressed-out songs. From the cradle, noise changed the way they communicated.

Humans hate noise too

You can’t pull the same experiment with humans, raising them in a lab to see how noise affects them. (Not ethically, anyway.) But if we could, we’d likely find the same thing. We, too, are animals—and it appears that we suffer in similar ways from anthropogenic noise, even though we’re the ones creating it.

The sound of traffic is correlated with lousy sleep, higher blood pressure, more heart disease, and higher stress.

Stacks of research in the last few decades have found that noise—most often, as with wildlife, the sound of traffic—is correlated with lousy sleep, higher blood pressure, more heart disease, and higher stress. A Danish study followed almost 25,000 nurses for years and found that an additional 10 decibels hit them hard; over a 23-year period they had an 8% higher rate of death, plus higher rates of nearly every bad thing that could happen to you: cancers, psychiatric problems, strokes. (They controlled for other malign health influences.) As you’d probably predict by now, children fare badly too. When Barcelona researchers followed almost 3,000 elementary school kids for a year, they found that those in noisier schools performed worse on assessments of working memory and ability to pay attention.

“We think of ourselves as being ‘used to it,’” says Gail Patricelli, a professor of evolution and ecology at the University of California, Davis. “We’re not as used to it as we think we are.”

It’s also true that there’s a trade-off. Many people understand that noise from cities and highways is aggravating, but we tolerate it because we get benefits along with the hassles. Cities are crammed with jobs and connections and dating opportunities; cars and trucks bring us the things we need and increase our personal mobility.

It turns out that animals make a similar calculus. Some species appear to benefit in certain ways from proximity to noise, so they move toward it. 

Clinton Francis, a biologist at California Polytechnic State University, and a team studied bird populations near noisy gas wells in rural New Mexico. Most species avoided the riot of the well pumps. But Francis was surprised to find that some hummingbirds and finches preferred it, and by one important measure they thrived: They were nesting more in the noisy areas than in the quieter areas. Additionally, several species had more success at fledging chicks in noisier locations.

What was going on? It’s likely that the noise makes it harder for predators to hear the birds and hunt down their nests. “It’s essentially a predator shield,” Francis says. Since his research found that predators can cause as much as 76% of failures of eggs to produce healthy offspring, that’s a significant survival advantage.

Cities can offer the same protections to certain species. Consider the case of Flaco, a Eurasian eagle-owl that escaped from the Central Park Zoo in February of 2023 and found he was in a terrific place to hunt. The incessant traffic ought to have caused him trouble. “An owl like this is among the most vulnerable species to intrusions from noise pollution. They’re listening for extremely faint signals or cues that their prey provide,” Francis notes. But New York has its compensations, because prey animals abound. They’re also naïve and unguarded, never expecting an owl with a six-foot wingspan to swoop down and devour them.

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Granted, these upsides don’t cancel out the negatives. Human noise may shield some birds from predators, but in other ways it leaves them faintly miserable, with high levels of stress hormones and lower weight. 

Worse, the species that manage to thrive in cities or near highways are often the same ones all over the country.  And they represent only a minority of species; most are driven further away, with less and less land to live on as civilization spreads ever outward. 

“Overall, it’s kind of a nightmare for diversity,” says Luther.

How to silence the world

In the early ’00s, the village of Alverna in the Netherlands began to get louder. A major intercity road cut straight through the town, and traffic had gone up by two-thirds in the previous decade. Facing complaints about the din, the town offered to put up some 13-foot walls on either side of the route. Residents hated the idea. Who wants to look out the window at massive walls?

So instead town planners redesigned the road in subtle ways. They lowered it by half a meter, slightly blocking the tire sounds. They built wedges that rise up three feet on either side, and surfaced them with attractive antique stone; that blocked even more sound. They planted sound-absorbing trees. And as a final coup de grâce, they reduced the speed limit from about 50 to 30 miles per hour. When a car is moving slowly, the engine is producing most of the roar—but once it’s going 45 mph or faster, the rumble of tires on the pavement takes over and is much louder. Each intervention had only a small effect, but cumulatively they made the road a blessed 10 decibels quieter.

This tale illustrates one curious upside of noise. Compared with other forms of pollution, it can be ended quickly. Toxic pollutants or CO2 can hang around for tens of thousands of years; the microplastics in your pancreas are probably never coming out. But with noise, the instant you reduce the source, the benefits are immediate. 

Plus, most of what works is “not rocket science,” Shilling says. A tall wall at the side of a highway will cut noise by 10 decibels; fill a double-sided wall with rubble and it’s even better. That could cut the traffic noise to below 55 decibels, he notes, which would help particularly skittish forms of wildlife. Walls can block animal movement, though, so in animal-heavy areas it’s better to build berms—small hills on either side of a highway. Areas of high ecological importance could be prioritized to keep costs down. 

“If there’s a great chunk of wetland habitat and it’s the only one around for 50 miles in any direction? Well, then we should build noise walls around it,” he says. We should also build overpasses and underpasses to help animals get around. And to quiet the din of gas wells out in the countryside, states could require companies to build walls around them. (They’ll likely only do that, though, when human neighbors complain or launch lawsuits; animals don’t have lawyers.)

Cities, too, can learn to shut up, as Alverna proved. At the most ambitious, some have buried noisy highways that once cut through the downtown core. Boston put a massive elevated highway underground in its “Big Dig”; in Slabbekoorn’s hometown of Amstelveen—a suburb of Amsterdam—they’re currently enclosing the A9 highway in a tunnel and turning the surface into a verdant park with new buildings. “That’s amazing, getting back a lot of the space as well,” he says. 

Granted, this sort of reengineering can be brutally expensive, which is why politicians blanch when they’re asked to reduce road noise. The Big Dig cost $15 billion, and with interest up to $24 billion. When I mentioned cost to Shilling, he sighed. “It’s not as expensive as a B-1 bomber or tax cuts for rich people,” he says. “Environmental stuff is considered expensive just because our expectations are low, not because we can’t afford to do it.”

There are cheaper and more politically palatable fixes, though. Reducing urban speed limits is one; Paris recently cut the top speed on its ring roads from 70 to 50 kilometers per hour (43 to 31 mph), and noise at night went down by an average 2.7 decibels—a noticeable drop. Planting more trees and vegetation all around roads and cities can cut a few decibels more, and residents love it. 

Growing adoption of electricity would also bring down the volume. “Electric vehicles of all kinds have the potential to make a big difference,” Patricelli says; when the light turns green and an EV next to you accelerates away, it’s up to 13 decibels quieter than a comparable gas-­powered vehicle. These benefits won’t be felt as much on highways, because EVs still make tire noise at high speeds. But in the slower stop-and-go traffic of urban life, they are far more pleasant to the ears, both animal and human. Indeed, the electrification of everything that currently uses a gas-powered motor will make urban life quieter. Cities like Alameda, California, and Alexandria, Virginia, are increasingly banning gas-powered leaf blowers and lawn mowers, which operate at hair-raising volume while electric ones whisper along. 

We’ve engineered a civilization that roars, but the next phase is making it purr. The animals will thank us. 

Clive Thompson is a science and technology journalist based in New York City.

[Comment] Youth mental health in central Asia: research needs

Little research has been published on mental health difficulties in young people (aged 10–24 years) living in central Asia,1 a region comprising Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan. As researchers and representatives from academic, non-governmental, governmental, and UN organisations working in Kyrgyzstan and Uzbekistan and beyond, we are noting an increasing number of young people reporting emotional and behavioural symptoms in central Asia in published articles2 and from our own observations.

Determinants of Digital Health Literacy Among Patients With Serious Mental Illness: Cross-Sectional Survey

Background: Individuals with serious mental illness increasingly use digital devices and the internet to access health information and services but often face challenges when navigating digital tools, which may limit the benefits they receive from online health resources and digital health care services. Objective: The objective of our study was to assess digital health literacy among individuals with serious mental illness and identify factors influencing this literacy. Methods: Participants were recruited, using convenience sampling, from 2 psychiatric clinics, 1 day-care center, and 4 halfway houses in Taipei, Taiwan, between May 2024 and February 2025. Self-reported data were collected using a survey that incorporated the eHealth Literacy Scale, the Attitudes Toward Computer/Internet Questionnaire, and the Mobile Device Proficiency Questionnaire. Generalized linear modeling was applied to identify factors associated with digital health literacy. Results: Among 255 participants included in the analysis, 83.5% (n=213) reported owning at least 1 digital device. Digital health literacy was significantly lower among individuals who reported greater perceived difficulty in using digital tools (=−1.533, 95% CI −2.350 to −0.717; <.001) and higher distrust in online information (=−0.986, 95% CI −1.916 to −0.056; =.04). By contrast, greater mobile device proficiency (=0.144, 95% CI 0.008‐0.281; =.04) and self-efficacy (=1.777, 95% CI 0.376‐3.177; =.01) were positively associated with digital health literacy. Conclusions: Despite widespread device ownership, digital health literacy was varied and generally suboptimal among patients with serious mental illness. Perceived difficulty and distrust emerged as major barriers; proficiency and self-efficacy facilitated higher literacy. These findings highlight the need for mental health professionals to integrate tailored digital skills training, confidence-building strategies, and ongoing support into digital health interventions for individuals with serious mental illnesses.

Pregnancy Sickness Study Identifies New Genetic Links

The University of Southern California (USC) research team that identified the hormone-encoding gene GDF15 as a key driver of pregnancy sickness has identified nine additional genes linked to its most severe form, hyperemesis gravidarum (HG). Six of the identified genes had not been previously linked to the condition.

The Keck School of Medicine of USC team and international collaborators conducted a genome-wide association study (GWAS), scanning the entire genome for differences between women who developed HG during pregnancy and those who did not. They analyzed data from more than 10,000 women with the condition and more than 450,000 controls across European, Asian, African, and Latino ancestries. Their findings offer new clues about the condition and new hope for those affected.

Marlena Fejzo, PhD, a clinical assistant professor of population and public health sciences in the Center for Genetic Epidemiology at the Keck School of Medicine, led the present study and earlier research linking GDF15 to HG. Fejzo told GEN, “The study is much larger than previous studies and on a more diverse population allowing for identification of new genes associated with HG … The new genes give us new directions to explore for prediction, diagnosis, treatment, and response to therapies.”

Fejzo is first author of the team’s published report in Nature Genetics (“Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting”), in which the team stated, “Potential roles for candidate genes in appetite, insulin signaling, and brain plasticity provide pathways to explore etiological mechanisms and therapeutic avenues.”

HG, which affects about 2% of women, causes nausea and vomiting so severe that eating can become extremely difficult. “Most pregnancies are affected by nausea and vomiting (NVP), but in 0.3–10.8% of pregnancies the symptoms can be severe enough to cause maternal weight loss and adverse maternal and fetal outcomes,” the authors wrote. HG in its most severe form can even be life threatening.

HG was long misunderstood and often dismissed as psychological, growing evidence shows that it has a strong biological and genetic basis and can lead to severe malnourishment, putting both mother and baby at risk. Current treatments for HG are frequently ineffective in improving patient symptoms, the authors further pointed out, and so increase the risk of pregnancy termination, postpartum depression, and suicidal ideation, along with other maternal and offspring comorbidities. “Therefore, understanding of HG etiology is critical to begin to address the negative impact severe NVP has on maternal and child health.”

While historical hypotheses have previously centered around human chorionic gonadotropin (hCG), recent large-scale genetic studies have implicated the GDF15 gene encoding growth differentiation factor-15—a hormone associated with nausea and vomiting, the authors further pointed out. Earlier research by Fejzo and an international team had shown that the link between HG and GDF15 lies in women’s sensitivity to the hormone. They found that women exposed to lower levels of the hormone before pregnancy because of a mutation in the gene experience more severe symptoms, while women exposed to higher levels of the hormone before pregnancy have less severe nausea and vomiting symptoms.

GDF15 was identified as the greatest genetic risk factor for HG in both a genome-wide and an exome-wide association study, and a rare mutation in GDF15 was associated with a greater than tenfold increased risk for HG,” the scientists noted in their newly reported study. Fejzo explained to GEN, “The mutation in GDF15 is rare. People who carry the mutation have abnormally low levels of GDF15 when they are not pregnant and that increases their risk of being hypersensitive to it during pregnancy when it is produced in massive amounts by the placenta.”

Commenting on their prior work implicating a role for GDF15 and HG, Fejzo further explained to GEN, “In our first GWAS study we found the association between the GDF15 gene and HG. Next, we published a whole-exome sequencing study that identified a mutation in GDF15 associated with HG. Then we published our study in Nature which provided strong evidence that hypersensitivity to the rise of GDF15 in pregnancy (due to low pre-pregnancy GDF15 in circulation) is the main driver of the condition.”

For their newly reported study the researchers carried out a multi-ancestry genome-wide association study of 10,974 HG/excessive vomiting in pregnancy cases and 461,461 controls across European, Asian, African, and Latino ancestries from nine contributing studies.

The results identified 10 genes that were linked to HG, including four that had previously been identified, and six new genes. “Because this is the largest study of HG ever conducted, we’ve been able to tease out important new details that were previously unknown,” said Fejzo. “The fact that we’ve studied women from multiple ancestry groups suggests that these results may be generalizable across a broad population.”

The four genes previously identified were growth differentiation factor 15 (GDF15), GFRAL, which produces the receptor for the GDF15 hormone of the same name, and IGFBP7 and PGR, both of which are involved in development of the placenta. The strongest link by far was to GDF15, which rises sharply during pregnancy. “We know that GDF15 and it’s receptor GFRAL are the main drivers and are in a signaling pathway that causes aversions, nausea, and vomiting,” Fejzo told GEN. “More work needs to be done to explore the other associations, but since studies suggest manipulating progesterone and/or IGFBP7 may not be safe in pregnancy, current studies are focusing on the GDF15 pathway.”

The six newly identified genes offer further clues that might help explain the basis of HG or point to new ways of treating it. They include FSHB, TCFL72 SLITRK1, SYN3, IGSF11, and CDH9. “Now that we’ve more than doubled the genes associated with HG, we can dig deeper into the biology behind this condition, as well as new possible pathways for treating it,” Fejzo said. Speaking to GEN, the researchers noted, “Because the new associations are novel, we need to understand the roles they may play in normal pregnancy and then compare that to pregnancies affected by HG.”

Of the newly identified genes, TCF7L2 stands out because it is one of the strongest genetic risk factors for type 2 diabetes and is also associated with gestational diabetes. “This is a brand-new target, and it’s not yet clear what it’s doing in pregnancy,” Fejzo said. In further commentary to GEN, Fejzo added, “The TCF7L2 gene is a type 2 diabetes-associated gene and a transcription factor that may control glucagon-like peptide-1 (GLP-1) expression and has been associated with liraglutide effects resulting in greater weight loss in obesity. So understanding its role in that rapidly evolving therapeutic arena has potential.”

Several of the other genes identified are involved in appetite and nausea, as well as brain plasticity, or how the brain learns and adapts to new information. Fejzo suggests the brain may learn to associate certain foods with feeling sick, leading to strong, lasting aversions during pregnancy. More research is needed to explore this possibility. “Other genes are associated with learning flexibility so we hypothesize that they may play a role in conditioned taste aversion and may provide new targets to alter or dampen learned aversions,” Fejzo told GEN. Historically, people believed the pregnancy hormone hCG was the cause, but we found no evidence to support that and instead, fascinatingly, we found a link to the follicle stimulating hormone receptor.”

Of the ten candidate genes six—GDF15, GFRAL, IGFBP7, PGR, TCF7L2 and SYN3—have been linked with cachexia—a wasting condition with similar symptoms to HG, including loss of appetite, weight loss and muscle wasting, the scientists noted. “Manipulation of GDF15, GFRAL, IGFBP7, PGR and TCF7L2 in animal models has shown effectiveness in reducing symptoms of cachexia. Thus, assuming analogous functions for these factors in HG, there is both genetic and biological support for causal and potentially reversible contributions for these genes in NVP.”

The researchers also found that some genes linked to HG were associated with other pregnancy outcomes. “This study also identified individual associations between risk genes and adverse outcomes including shorter pregnancy duration, pre-eclampsia, and birth weight,” they noted.

Several medications are available for treating HG, but even the most effective, Zofran, only partly relieves symptoms for about half of patients. The new findings reveal new potential treatment targets and could possibly also help match existing medications to patients based on their genetic profiles. “The ten genetic associations provide intriguing avenues to advance our understanding and pursue therapeutic pathways for a common pregnancy condition that in its most severe form is associated with substantial morbidity and even mortality for mothers and exposed offspring,” the scientists concluded.

Fejzo and her team just received approval to launch a clinical trial of metformin, a widely used diabetes medicine that increases GDF15 levels. The study will test whether taking metformin before pregnancy can desensitize women to the hormone, potentially reducing nausea and vomiting or preventing HG in women who have had it before. GEN was told, “We will be initiating a clinical trial to increase GDF15 prior to pregnancy in patients with a history of HG and planning to conceive to desensitize them to the hormone’s rapid rise in early pregnancy. We and others have shown preliminary evidence that this approach may work as in our retrospective study pre-pregnancy metformin use was associated with a significant reduction in HG risk.”

The post Pregnancy Sickness Study Identifies New Genetic Links appeared first on GEN – Genetic Engineering and Biotechnology News.

Cancer Cell Apoptosis Avoided by Membrane Oligomerization

Apoptosis in cancer cells may be easier to unleash than previously thought, according to new research led by scientists at Umeå University and collaborators. That finding could open up more cancers to treatment with anti-apoptotic drugs. The team used neutron reflectometry (NR) and ATR-FTIR to detail communication between proteins in and around the mitochondrial outer membrane (MOM). 

“We use neutrons as a kind of ‘x-ray’ magnifying glass to study how various proteins talk to each other inside the cell,” Gerhard Gröbner, PhD, told Inside Precision Medicine. He is a professor at Umeå University and senior author of a new study that looks at the role of the Bax protein in apoptosis. The findings appear in ACS Chemical Biology.

Apoptosis is a form of programmed cell death that removes old or damaged cells, enabling the immune system to function properly. When apoptosis does not work as it should, as in many cancers, cells can divide uncontrollably and form tumors.

Many cancer therapies (e.g. drugs and radiation) are designed to trigger apoptosis in tumors. But there are also many aggressive and often incurable cancers that current anti-apoptotic therapies do not work on due to these tumors’ intensive use of survival proteins, such as Bcl-2 and its relatives, which can stop apoptotic death.

“Finding new drugs to inhibit Bcl-2 and its relatives in a wider sense would thus help treat more cancers. Currently only one Bcl-2 drug is available, and it is used for very specific leukemia,” said Gröbner.

“Going forward we will test a range of potential drug candidates to block Bcl-2 to release cell-killing proteins like Bax again to improve therapies,” he added.

The cell‑killing protein Bax protein is one of the most important proteins controlling apoptosis. Once activated, Bax can initiate apoptosis by forming pores in the membranes of mitochondria. Another key protein from the same family, the cell‑protective protein Bcl‑2, instead prevents Bax from killing tumor cells. In nearly half of all human cancers, one of the underlying problems is an increased production of Bcl‑2, which promotes tumor growth and often leads to poor response to therapy.

“In our research, we have used advanced neutron experiments to show how Bcl‑2 protects cancer cells by blocking the death‑inducing proteins that are most often activated by therapy,” said Gröbner.

The team used NR and ATR-FTIR to elucidate the molecular communication between those proteins in and around the mitochondrial outer membrane (MOM). The spatial and temporal changes across model MOM surfaces were resolved during the interaction of Bax with Bcl-2. The NR-derived membrane surface Bax distributions suggested that Bcl-2 mediated Bax sequestration through both Bcl-2/Bax heterodimerization and Bax/Bax oligomerization. Kinetic analysis revealed a two-step process: rapid formation of Bcl-2/Bax heterodimers, followed by slower Bax oligomerization on these complexes

The experiments show that Bcl‑2 can capture and bind several Bax proteins at the same time. This makes the inhibition of cell death more efficient than previously thought. Cancer cells do not need to produce extremely large amounts of Bcl‑2 to protect themselves—even a moderate increase can be sufficient.

The researchers also investigated how the composition of the mitochondrial membrane affects the interaction between the proteins. They found one particular lipid, cardiolipin, can promote apoptosis and help Bax form pores in the membrane. However, even in membranes containing cardiolipin, a sufficiently high level of Bcl‑2 can still prevent cell death.

“In the longer term, this type of knowledge could open up new opportunities for cancer treatment, for example by targeting Bcl‑2 and its protective function,” says Gröbner.

The study was carried out in collaboration between researchers from Umeå University, Lund University, the European Spallation Source (ESS) in Lund, the ISIS Neutron and Muon Source and Diamond Light Source in the United Kingdom, and the Institut Laue‑Langevin (ILL) in France.

 

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Pivotal Phase III Pancreatic Cancer Trial Advances RAS-Targeting Daraxonrasib

This week, Revolution Medicines (RevMed) announced positive topline results from its global Phase III trial of RAS-targeting daraxonrasib in metastatic pancreatic ductal adenocarcinoma (PDAC) patients. In RASolute 302, patients on daraxonrasib showed improvements in progression-free survival (PFS) and overall survival (OS) compared with standard of care cytotoxic chemotherapy.

“With these unprecedented results, daraxonrasib has the potential to achieve our goal of bending the mortality curve in pancreatic cancer. Unlike chemotherapy, daraxonrasib is a RAS-targeted medicine that targets RAS in its active ‘ON’ state, shutting down a key signaling pathway that drives aggressive tumor growth. This is especially important in pancreatic cancer, which is among the most RAS-driven cancers, with more than 90% of tumors harboring a RAS mutation that is the driver of the cancer,”  Mark A. Goldsmith, MD, PhD, told Inside Precision Medicine. He is chief executive officer and chairman of Revolution Medicines.

Daraxonrasib patients achieved a median OS of 13.2 months versus 6.7 months for chemotherapy. The drug was generally well tolerated, with a manageable safety profile and with no new safety signals.

RAS is the key oncogenic driver of pancreatic cancer. Nearly all RAS mutations occur at KRAS position G12, but RAS mutations in other isoforms and at KRAS positions G13 and Q61 are also observed.  

RevMed now intends to submit the drug for approval by regulatory authorities, including the U.S. Food and Drug Administration as part of a future New Drug Application, and for presentation at the 2026 American Society of Clinical Oncology Annual Meeting. Information about current trials of the drug are available at  https://revmedclinicaltrials.com/.

“For patients with metastatic pancreatic cancer, new treatment options are urgently needed to increase survival time and improve quality of life,” said Brian M. Wolpin, MD, MPH, professor of medicine at Harvard Medical School, director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute, and principal investigator for the RASolute 302 trial. “The widely anticipated results of this study indicate that daraxonrasib provides a clear and highly meaningful step forward for patients with pancreatic cancer who have experienced progression on prior treatment, typically chemotherapy. I believe that this new approach is a very important advance for the field that I expect will be practice-changing for physicians and improve the care for patients with previously treated metastatic pancreatic cancer.”

Pancreatic cancer is the most RAS-addicted of all major cancers, with more than 90% of patients harboring tumors driven by mutations in RAS proteins. These mutations span a range of RAS variants that fuel aggressive tumor behavior. Daraxonrasib, a multi-selective inhibitor of RAS(ON) proteins, is the first investigational agent in a novel class of RAS inhibitors designed to address a diverse and broad spectrum of oncogenic RAS drivers.

The RASolute 302 trial enrolled patients with pancreatic tumors harboring a wide range of RAS variants, including those with RAS G12 mutations (such as G12D, G12V, and G12R), as well as those without an identified RAS mutation. The primary endpoints of the trial were PFS and OS in patients with tumors harboring RAS G12 mutations. Secondary endpoints assessed PFS and OS in all enrolled patients (the intent-to-treat population), including those with tumors with and without (wild type) an identified RAS mutation.

Daraxonrasib is an oral RAS(ON) multi-selective, non-covalent inhibitor. Cancers driven by a broad range of common RAS mutations include PDAC, non-small cell lung cancer (NSCLC), and colorectal cancer. The drug is currently being evaluated in four global Phase III registrational trials, including three in PDAC and one in NSCLC.

Daraxonrasib works by suppressing RAS signaling through inhibition of the interaction between both wild-type and mutant RAS(ON) proteins and their downstream effectors.

Pancreatic cancer is one of the deadliest malignancies, because of its typically late-stage diagnosis, resistance to standard chemotherapy, and high mortality rate. In the U.S., recent estimates indicate that each year approximately 60,000 people will be diagnosed with pancreatic cancer, and about 50,000 people will die from it.

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