Diabetes Drug Metformin’s Blood Glucose-Lowering Effects Tied to Action on Gut Cells

For decades, physicians and scientists have thought that metformin, a biguanide drug that is prescribed for millions of people worldwide for type 2 diabetes (T2D), mainly targets the liver to suppress glucose production. A Northwestern University-led study in mice has now found that this “wonder drug” instead acts primarily on the gut, and prevents glucose levels from rising in the blood by driving glucose utilization inside cells lining the intestine.

The research found that metformin slows mitochondrial energy production in gut cells by inhibiting mitochondrial complex I in the intestinal epithelium. This then “co-opts” the intestines to function as a glucose sink, forcing the intestine to metabolize extra sugar. The study also found that another biguanide drug, phenformin, and the structurally unrelated supplement berberine, which is known as “nature’s Ozempic,” appear to engage the same pathway in the gut as does metformin.

The preclinical findings could help to explain several gut-related clinical effects in people who take metformin and suggest that modulating mitochondrial metabolism in the gut may represent an effective strategy for controlling blood sugar. “Metformin essentially helps the intestine suck the glucose out of the bloodstream, which further highlights that the gut plays a major role in regulating blood sugar levels,” said corresponding author Navdeep Chandel, PhD, professor of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine.

Chandel is senior and co-corresponding author of the researchers’ published paper in Nature Metabolism, titled “Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.” Chandel is also the David W. Cugell, MD, Professor of Medicine (Pulmonology and Critical Care), Biochemistry and Molecular Genetics, and an investigator with the Chan Zuckerberg Initiative. The study’s first author is Zach Sebo, PhD, a postdoctoral fellow in the Chandel lab who will soon start his own research group at the University of Kansas School of Medicine.

Metformin is the most widely prescribed medication for type 2 diabetes and the biguanide class drug approved by the FDA, the authors wrote. However, they noted, “Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear.”

The body relies on glucose as a fast and versatile fuel, but too much glucose can lead to insulin resistance and ultimately damage blood vessels and organs. The newly reported study builds on findings from previous work in Chandel’s lab, which found that metformin lowers blood sugar by blocking a specific part of the cell’s energy-making machinery, mitochondrial complex I, a key enzyme in cellular respiration. The research reported in Nature Metabolism extends that work by pinpointing the specific tissue targeted by metformin.

The study used a mouse model genetically engineered to express a yeast enzyme (NDI1) that mimics mitochondrial complex I but is resistant to inhibition by metformin. By expressing NDI1 specifically in intestinal cells, those gut cells resisted metformin’s effects. In these mice, the drug’s ability to lower blood glucose was significantly reduced, demonstrating that inhibition of mitochondrial complex I in the gut is a key driver of its therapeutic action. “In this study, we show how metformin exerts multiple clinical effects through selective inhibition of mitochondrial complex I in the intestinal epithelium,” they wrote.

Corresponding author Navdeep Chandel in his lab in Chicago. [Kristin Samuelson, Northwestern University]
Corresponding author Navdeep Chandel, PhD, in his lab in Chicago. [Kristin Samuelson, Northwestern University]

Metformin is currently the only FDA-approved biguanide drug, but the team found that another biguanide, phenformin, which had previously been used to control blood glucose but was then withdrawn, also lowered blood glucose through the same mechanism. The findings suggest that directing drugs or supplements to the gut could be an effective strategy for controlling blood sugar, Chandel said. Sebo added, “Our study suggests that revisiting assumptions about metformin’s mechanism may offer a more detailed understanding of how it works.”

The study revealed unexpected parallels with berberine, a popular plant-derived OTC supplement that is often used to control blood sugar. Berberine has recently gained attention on social media as “nature’s Ozempic,” though experts caution that evidence is still limited, and it should not be used as a substitute for approved medications. The study by Chanel and colleagues has now found that berberine appears to engage the same pathway as metformin in the intestine. “Thus, we identify mitochondrial complex I in intestinal epithelium as a shared and essential therapeutic target for metformin, phenformin, and berberine,” the authors stated.

“Metformin has decades of clinical evidence behind it, whereas supplements like berberine are far less rigorously tested,” Chandel said. “If you’re going to use berberine, you may as well use the real deal.”

The study results may help to explain clinical observations among people who take metformin. According to Chandel, individuals who take metformin tend to have lower blood sugar after meals, and the study suggests that metformin turns the gut into a “sponge” that soaks up extra sugar. Individuals taking metformin also tend to have lower levels of circulating citrulline, which is made only by mitochondria in small intestine cells. If metformin inhibits mitochondria, citrulline production drops. Taking metformin also increases levels of GDF15, a hormone linked to reduced appetite and weight loss. The gut senses energy stress and sends out GDF15, which tells the brain to eat less and adjust metabolism.

“In addition to enhanced intestinal glucose utilization and blood glucose clearance, this mechanism accounts for metformin-induced citrulline depletion, improved postprandial glycaemia, and elevated lactoyl-phenylalanine (Lac-Phe) and growth differentiation factor 15 (GDF15) levels—all of which are definitive clinical outcomes caused by metformin treatment,” the authors wrote in summary.

“People have always wondered how one drug can do 10 things,” Chandel said. “Well, it can do that if the drug is hitting a big node in a cell, and hitting mitochondria in a cell is a big node. So, if you can get into those cells and inhibit mitochondria, it’s going to have huge effects.”

The post Diabetes Drug Metformin’s Blood Glucose-Lowering Effects Tied to Action on Gut Cells appeared first on GEN – Genetic Engineering and Biotechnology News.

Musk v. Altman week 2: OpenAI fires back, and Shivon Zilis reveals that Musk tried to poach Sam Altman

In the second week of the landmark trial between Elon Musk and OpenAI, Musk’s motivations for bringing the suit were under scrutiny.

Last week, Musk took the stand, alleging that OpenAI CEO Sam Altman and president Greg Brockman had deceived him into donating $38 million to the company. He claimed that they’d promised to maintain it as a nonprofit dedicated to developing AI for the benefit of humanity, only to later accept billions of dollars of investment from Microsoft and restructure the company to operate a for-profit subsidiary.  

This week, Brockman fired back with his side of the story, arguing that Musk had actually pushed for OpenAI to create a for-profit arm and fought a bitter battle to have “absolute control” over it. OpenAI has argued that Musk is suing because he didn’t get his way and is now trying to undermine a competitor to his own AI company, xAI.

Shivon Zilis, a former OpenAI board member and the mother of four of Musk’s children, also testified, revealing that Musk tried to recruit OpenAI CEO Sam Altman to lead a new AI lab at his electric-car company, Tesla. 

Musk cofounded OpenAI in 2015 with Altman, Brockman, and others but left in 2018. Now, he’s asking the court to remove Altman and Brockman from their roles and to unwind the restructuring OpenAI undertook last year, which converted its for-profit subsidiary into a public benefit corporation. He is also seeking as much as $134 billion in damages from OpenAI and Microsoft, OpenAI’s investor. 

The outcome of the trial could upend OpenAI’s race toward an IPO at a valuation approaching $1 trillion. Meanwhile, xAI, which Musk founded in 2023, is now a division of his rocket company, SpaceX; the combined companies are also expected to go public as early as June, at a target valuation of $1.75 trillion.

On Monday, Brockman walked into the courtroom in a blue suit and tie, holding hands with his wife, Anna Brockman. On the stand, he was serene, even chipper, as he recalled OpenAI’s early days. But he grew agitated under impassioned questioning from Elon Musk’s lawyer, Steven Molo. Altman listened in silence, while Anna Brockman sat behind him, fidgeting. Outside the courthouse, protesters rallying against the AI race sang hymns over the voices of lawyers giving press conferences.

Two days before trial began, according to Brockman, Musk messaged him to ask if he would be interested in settling. When Brockman suggested that both sides drop their claims, Musk texted back: “By the end of this week, you and Sam will be the most hated men in America. If you insist, so it will be.”

Musk stormed out with a Tesla painting

Last week, Musk testified that he’s suing to save OpenAI’s nonprofit mission to develop AI safely, but he said he was open to seeing OpenAI become a capped-profit company with moderate investments from Microsoft

This week, Brockman told the jury that Musk was never truly committed to keeping OpenAI a nonprofit. In the summer of 2017, when an AI model that OpenAI built beat the world’s best players in a video game called Dota 2, Musk hosted a gathering at his “Haunted Mansion” near San Francisco. The house was splattered with confetti and cups, Brockman recalled, and the actress Amber Heard, who was Musk’s girlfriend at the time, served whiskey.

“Time to make the next step for OpenAI. This is the triggering event,” Musk wrote in an email—having said weeks earlier that if OpenAI made a major public achievement, it would be “time to create a for-profit,” Brockman told the jury.

Over the next six weeks, Brockman said, Musk and the other cofounders had intense discussions about creating a for-profit entity to raise enough capital to build artificial general intelligence—powerful AI that can compete with humans on most cognitive tasks. Musk wanted to have majority equity in the entity and the right to choose a majority of the board members. He also wanted to be its CEO, said Brockman. 

Brockman testified that in August 2017, he and other cofounders gathered to hash out the terms of the for-profit structure. Ilya Sutskever, OpenAI’s chief scientist at the time, arrived bearing a painting of a Tesla as a “token of goodwill” in return for the actual Teslas Musk had given them days earlier. “It felt a little bit like [Musk] was buttering us up, right,that he wanted us to feel indebted to him,” Brockman told the jury.

When Brockman and Sutskever proposed that they all have equal shares of equity, said Brockman, Musk fell silent and finally said, “I decline.” Musk then stood up and “stormed around the table,” he said. “I actually thought he was going to hit me.” Musk grabbed the painting and walked out. 

Brockman said that afterwards he struggled to decide whether to continue building OpenAI with Musk or break away. “There was a fork in the road,” he said. “Do we accept Elon’s terms? Or do we reject the terms, he quits to create his own, and then we create our own?”

“The one thing we could not accept was to hand him unilateral, absolute control, potentially, over the AGI,” Brockman told the jury.

What was Brockman thinking?

In his theatrical baritone, Molo argued that Brockman was motivated by greed rather than a commitment to OpenAI’s nonprofit mission to develop AI that benefits humanity. He noted that while Brockman never invested money in the company, he now owns a stake worth close to $30 billion. 

“Solving for the mission has always been my primary motivation,” Brockman said, pushing back on Molo’s characterization of him. “It remains so today.” 

Molo pulled up Brockman’s electronic journal on a screen in the courtroom, trying to show the jury what Brockman was really thinking behind the scenes. In 2017, while negotiating with Musk about the future of OpenAI, Brockman wrote about wanting to become a billionaire: “Financially what will take me to $1B?” 

“Why didn’t you take the $29 billion and donate it to the nonprofit that you had a fiduciary duty to, for the good of humanity?” Molo asked Brockman, raising his voice to dramatize moral indignation. 

Molo then pulled up a journal entry Brockman had written in November 2017, while he was torn over whether to turn OpenAI into a for-profit without Musk: “it’d be wrong to steal the nonprofit from him. to convert to a b-corp without him. that’d be pretty morally bankrupt.” Brockman and Musk had previously considered creating a b-corp, which is a for-profit company that pursues a social mission.

Brockman explained, “I meant it would actually serve the mission, but it’d be hard to look at yourself in the mirror.”

Molo also tried to undermine Brockman’s credibility by revealing that he holds a stake in multiple companies with business ties to OpenAI, including the AI company Cerebras, the cloud provider CoreWeave, and the nuclear fusion startup Helion Energy. Altman has tried to steer OpenAI into deals with companies that he invests in, including Helion and the rocket maker Stoke Space, drawing scrutiny over potential conflicts of interest.

Former OpenAI chief technology officer Mira Murati and former OpenAI board member Helen Toner both appeared in video depositions. They addressed the brief firing of Altman in 2023, saying that they could not trust him because of his alleged history of lying. Murati’s text messages with Altman from that time, which were introduced as evidence, revealed his desperate attempts to understand what was happening and regain control. 

Musk plotted a rival AI lab at Tesla

After Brockman’s two days of testimony, Shivon Zilis, who left OpenAI’s board in 2023, took the stand in a black jacket and black jeans, appearing composed but with a flicker of nerves. OpenAI’s lawyer Sarah Eddy asked her in a deceptively soothing voice whether she acted as a conduit for Musk as he tried to poach OpenAI’s cofounders to work at a new AI lab within Tesla. Eddy argued that Musk is suing OpenAI only to undermine a competitor in the AI race. 

Zilis said she met Musk while working at OpenAI as an informal advisor in 2016, and that they had a “one-off” romantic encounter. In 2017, she joined Tesla and Musk’s brain-implant company, Neuralink. In 2020, she joined OpenAI’s board of directors. She became pregnant with Musk’s children through IVF but did not disclose her ties with Musk to OpenAI until Business Insider reported them in 2022. 

By late 2017, Musk had concluded that OpenAI was unlikely to build AGI and pivoted to building an AI lab at Tesla, according to an email sent to Zilis. 

Eddy pulled up a draft of an FAQ document that Zilis emailed a colleague at Tesla in 2017 about an event the company was organizing at the NeurIPS AI conference: “The purpose of this event is to share that Tesla is building a world leading AI lab(?) which will rival the likes of Google/DeepMind and Facebook AI Research.” 

Zilis told the jury that when Musk was still on OpenAI’s board, he tried to recruit Altman to lead that prospective AI lab. Musk had asked Andrej Karpathy, an OpenAI research scientist he’d recruited to work at Tesla, “to send a list of top OpenAI people to poach,” according to a text message by Zilis. 

“There is little chance of OpenAI being a serious force if I focus on TeslaAI,” Musk texted Zilis in 2018, just before he left OpenAI. Tesla’s AI lab never came to fruition.

Eddy pressed Zilis about whom she was loyal to when she was working for OpenAI and Musk at the same time. “I had an allegiance to the best outcome for AI for humanity,” Zilis told the jury.

What’s going on next week?

Next week, Ilya Sutskever will testify, as will Microsoft CEO Satya Nadella. The lawyers for both Musk and OpenAI will deliver their closing arguments. The jury will begin deliberating the week after and deliver an advisory verdict guiding the judge to decide the case.

This story is part of MIT Technology Review’s ongoing coverage of the Musk v. Altman trial. Follow @techreview or @michelletomkim on X for up-to-the-minute reporting.

Opinion: RFK Jr. allegedly ‘collected’ a dead raccoon’s penis. Was it bioethically justifiable?

During one of health secretary Robert F. Kennedy Jr.’s recent appearances on Capitol Hill, Rep. Adelita Grijalva (D-Ariz.) brought up an unusual allegation: that in 2001, he collected a dead raccoon’s penis. The incident was first described in the new book “RFK Jr.: The Fall and Rise” by Isabel Vincent, which quotes from a journal of Kennedy’s: “I was standing in front of my parked car on I-684 cutting the penis out of a road killed raccoon, thinking about how weird some of my family members have turned out to be.” According to Vincent, Kennedy cut off the penis “to study [it] later.”

While Kennedy did not respond to Grijalva about the raccoon incident, focusing instead on the National Institutes of Health budget and DEI, it has been widely treated as sensational news. But the jokes about it obscure an important question: whether his described actions meet fundamental standards of bioethical judgment.

Read the rest…

Multimodal Prehabilitation and Rehabilitation for Men Undergoing Robot-Assisted Radical Prostatectomy

Conditions: Erectile Dysfunction Following Radical Prostatectomy; Prostate Cancer; Urinary Incontinence Following Surgical Procedure

Interventions: Drug: Tadalafil 5 mg; Behavioral: Pelvic Floor Muscle Training (PFMT); Behavioral: Aerobic Exercise Program; Behavioral: Nutritional Recommendations; Behavioral: Psychological and Wellbeing Strategies; Behavioral: Standard Perioperative Care

Sponsors: Surgical Outcomes Research Centre (SOuRCe); Generic Health; National Health and Medical Research Council, Australia; Sydney Local Health District

Not yet recruiting

Phenotype, Genetics, and Interpretation: Further Considerations on Atypical Depression

We read with great interest the recent article by Shin et al. (1). The authors leveraged the substantial Australian Genetics of Depression Study (AGDS) cohort to provide compelling evidence for the clinical and biological validity of the atypical depression subtype. Their integrative analysis of clinical features, polygenic scores (PGSs) for mental, metabolic, and circadian traits, and self-reported treatment outcomes is a significant contribution to the field. The particularly robust finding of an association between a genetic predisposition for eveningness (lower-chronotype PGS) and atypical depression, which persisted after adjustment for body mass index (BMI), is noteworthy and points to a potentially core, BMI-independent pathway.

What Is Traumatic Separation?

You may have a memory of being separated from a parent when you were a child, even just for a few minutes. Maybe you lost them in a crowd or wandered a little too far at the store and felt panicked and afraid.

A moment like this might be among your earliest memories because the feeling was so intense, says Caitlyn Downie, LCSW, the Director of Trauma and Resilience at the Child Mind Institute. That offers some insight into the fear of a child of any age who is separated from a parent or caregiver in a more serious way. The effects of this stress are so powerful they can actually change the way a child develops.

A toddler whose mother goes to prison. A kindergartener whose father is detained and deported. A teen who is placed in foster care. These are a few examples of what experts call traumatic separation, a clinical concept based on the importance of the parent-child bond and the profound effects that can result from breaking it.

What is traumatic separation?

Traumatic separation isn’t a clinical diagnosis, but research shows that it can be profoundly harmful to kids. What makes it traumatic (as opposed to routine partings, like when an adult regularly leaves their child to go to work) is the character of the separation: ones that are sudden, unexpected, or confusing, or those that come about through larger distressing events, like a natural disaster or war. It’s not defined by the time spent apart — both short and long-term separations can be harmful.

Some common examples of separation that can become traumatic include:

  • Parental deportation
  • Immigration (e.g., forced separation at the border)
  • Parental military deployment
  • Parental incarceration
  • Termination of parental rights

Separating from a parent or primary caregiver can be distressing to a child even when it’s deemed necessary for their safety, as in cases where the parent they have been separated from has abused them, says Kimberly Alexander, PsyD, a psychologist at the Child Mind Institute. “There’s still a natural attachment that occurs. And the separation disrupts that relationship, even if it’s for the support and care of the child.”

Why is traumatic separation harmful?

More than eight decades of research has shown the profound developmental importance of the parent-child bond. This is the guiding principle of attachment theory, which was pioneered by a British psychologist who studied children who were evacuated during the Blitz, the aerial bombardment of London in World War II.

Here’s what the research tells us about the harms of traumatic separation:

It can disrupt secure attachment

Think of secure attachment as a “fundamental sense of security and safety” that a child feels with a parent or caregiver, says Dylan Gee, PhD, a psychologist at Yale University who studies how early-life stress affects children’s development.

“Attachment is the lens through which children come to know what they can expect from the world around them,” she explains. “Is this going to be a safe place or a dangerous place? This is foundational to a child’s sense of their ability to navigate the world. Traumatic separation can shatter that sense of safety.”

It can affect neurobiological development

Children’s brains are especially plastic, says Dr. Gee, constantly learning to understand their environment and how to deal with stress. “Trauma that occurs in childhood can be even more consequential than trauma that occurs later in life,” she says, and experiencing these disruptions in childhood can affect the way your brain and body are primed to react to stress later on.

But heightened plasticity is a paradox, she adds. “It confers more vulnerability, but it also confers more potential for resilience — children have heightened potential for supportive intervention and for healing and recovery.”

What do the effects of traumatic separation look like?

There are acute and short-term effects that are common across kids of all ages:

Sleep problems: “It’s often one of the first things that we see: nightmares, trouble falling asleep, or a lot of crying as kids are trying to fall asleep,” Dr. Gee says.

Separation anxiety: This might look like distraction, withdrawal, or clinginess because of fear of being separated from their new caregivers, Dr. Alexander says.

But signs may take weeks or months to show up. Dr. Alexander advises caregivers to consider the child’s baseline — their typical patterns of eating, sleeping, or engaging with others. “If they’re having more trouble with sleep, they’re eating more, eating less, they’re withdrawing or expressing a lot of worried thoughts three or four months later — that’s something worth getting looked at by a clinician,” she says.

Signs of traumatic separation at different ages

“Sometimes people ask, ‘Well, when is separation the most harmful?’ It can be extremely harmful at any age,” Dr. Gee emphasizes. But there are specific signs at different developmental stages:

Infants

Babies may not be as consciously aware of being separated from a parent as older children, “but they’re fundamentally aware that their primary source of regulation and safety is missing,” Dr. Gee says. Because infants are so reliant on caregivers for nurturing and sustenance, the separation “can be experienced as a threat to their survival.” That might look like “crying a lot or becoming withdrawn,” she says. “And at any age we can see intense fear.”

Toddlers and young children (3–6)

Toddlers and young children might become extra clingy with new caregivers or show regressive behaviors like bedwetting or baby talk. Regressive behaviors happen when kids are overwhelmed by stress and can’t express themselves another way, Downie says. “It’s like your nervous system goes kind of haywire,” she explains, “so it uses the body to signal that something is wrong.”

Similarly, kids at this age might act out more, throwing more tantrums, or withdraw. They might develop selective mutism, a condition where kids are too anxious or distressed to speak, even when they want to, in certain situations or with certain people.

School-age children

School-age children might act out or experience separation anxiety. They may also struggle to understand the meaning of the separation, why it happened, or who is at fault for it. Thus, kids at this age are more prone to magical or distorted thinking and feelings of guilt, thinking or saying things like, “I’m the one that caused this” or “This is my fault.”

The weight of these distorted thoughts or other worries, Dr. Alexander says, might make it appear as though a child is struggling to concentrate or that they’re disengaged or distracted. They might withdraw in a group or be averse to stepping outside of their comfort zone.

Children who are school age or older can also experience emotional desensitization — a kind of emptiness of feeling — Downie says, which can look like spikes in irritability, a lack of empathy, not smiling or expressing positive emotions, or an inability to relate to others.

Preteens and teenagers

“I’ve seen teenagers have a lot of mistrust with systems and be very oppositional,” says Downie. “Like, ‘I don’t trust you. I don’t trust my teacher. I don’t trust this child services worker.’” It might make sense that, say, a teen in foster care would be wary of the foster care system. But Downie says it’s often a larger instinct for anger and mistrust, one that extends beyond any specific entity or person.

The teenage years are also when kids are forming their identity, and traumatic separation can fundamentally alter that process. For example, a teen with younger siblings may step into a parent role, taking on new worries and responsibilities. Conversely, teens may become more reckless in a caregiver’s absence, putting them at risk for substance abuse or incarceration.

How to help kids separated from a parent

Adults caring for a child who has been separated from a parent — family members, foster parents, teachers — “can play a profound role in supporting their mental health and resilience,” says Dr. Gee.

Validate feelings

One of the most important things caregivers can do is be present as a child reacts to their experiences, especially if and when scary feelings come up. But be careful not to lead kids or assume they feel a certain way. “You don’t want to make something more distressing to a child if it’s not presenting itself,” says Downie.

If a child expresses guilt, or says something like, “This is my fault,” there are still ways to validate the feeling without endorsing the statement, says Dr. Alexander. You might say something like: “I can understand why that thought comes to mind and how difficult it is to feel that way. When you’re ready, let’s think about other possibilities to this situation.”

Create consistency and stability

One of the hardest things about traumatic separation is the uncertainty — Where did they go? When will they come back? What is happening? Giving kids some sense of consistency and stability can help them feel safe despite the unknowns. So as much as possible, help them stick to any routines: going to school, seeing friends, doing activities they enjoy.

Dr. Alexander advises focusing on things you can control — for example, shielding kids from potentially worrying discussions in a family where a parent has been deported.

“There would likely be a lot of conversations in the home about the situation, maybe a lot of watching the news, maybe making a lot of phone calls to attorneys,” she explains. “So where are you having those conversations, and can you have them in an area or at a time of day where your kid isn’t overhearing the discussions out of context?”

For young kids, it might be as simple as asking them to play in their room. For teens, it might be better to have certain conversations when they are out of the house and invite them to participate directly in others.

Be honest but reassuring

Caregivers might not have all the answers — like knowing when a child’s parent is coming back — but they can create a sense of consistency and stability in how they respond to kids’ questions, too.

Avoid undue reassurance (“Everything is going to be fine”) or over-promising (“They’ll be back in two weeks”) by focusing on what kids can expect, says Dr. Gee. For example: “What I can tell you is that I’m here for you, and I’m going to be with you until he’s back,” or “You’re safe with me, and I’m going to stay with you through this really hard time.”

Model handling stress

Children are sensitive to tone, Dr. Alexander says. “So, if you’re having really big emotions that are out of context for a child, the child is looking at these emotions and trying to understand what’s happening. ‘Am I in danger in this specific moment?’”

She says it helps to have conversations about these moments, especially with younger kids. “Like, ‘I know you noticed mommy crying. We’re feeling really big feelings, and this is how we’re going to deal with those big feelings. I’m going to take a break. I’m going to get a sip of water. Whenever you’re having big feelings, I want you to let me know so that I can help you try doing the same things,’” Dr. Alexander says, explaining the importance of naming the emotion and then teaching kids that there are ways of dealing with it.

Long-term risks of traumatic separation

The effects of traumatic separation can persist even after a child and their caregiver are reunited. Traumatic separation, like other adverse childhood experiences, puts kids at risk for a host of long-term medical and mental health conditions, including depression, anxiety, attention issues, and post-traumatic stress disorder (PTSD).

But Downie notes that not everyone who experiences traumatic separation develops PTSD. “Just because someone’s experiencing trauma now doesn’t mean that it’s going to become a PTSD diagnosis,” she says. “A lot of the behaviors that we’re talking about are normal and expected. There’s an adjustment period when a separation happens.” But if symptoms persist or escalate over several months, a child may need more serious support.

Treatment for a trauma diagnosis

While not every child who experiences a separation may receive a trauma diagnosis or require treatment, cognitive behavioral therapy (CBT) — and the more specific trauma-focused cognitive behavioral therapy (TF-CBT) — is the “gold standard,” says Downie. TF-CBT is specifically for children experiencing trauma-related symptoms. An important component of TF-CBT is creating a trauma narrative, where kids create a story about what happened to help them process it. “But if you have a child who is not ready to process and integrate that trauma, you can’t force the pacing of the treatment,” she says.

In short, a good clinician will follow a child’s lead — even if that means just sitting in the same room with them to build trust. “People really need to feel like they’re being heard and that they can trust someone,” Downie says. Which is why a supportive caregiver or trusted adult can make a big difference.

“If people can take anything away from this, it’s that you want to make kids understand that that they’re not responsible for what’s happened and that people do care about them,” Downie says. “Kids are really resilient, and they can adapt in a good-enough environment. They don’t have to have everything to be successful.”

The post What Is Traumatic Separation? appeared first on Child Mind Institute.

Medical Marijuana Initiation and Simulated Driving Performance Among Mid-to-Late-Life Adults With Chronic Pain: Prospective Observational Feasibility Cohort Study With Matched Controls

Background: Marijuana initiation among adults aged 50 years and older has increased substantially. Although acute tetrahydrocannabinol exposure can impair psychomotor function, less is known about how real-world medical marijuana initiation relates to functional tasks such as driving in mid-to-late life. Objective: The objective of our study was to evaluate the feasibility of recruiting and retaining adults aged 50 years and older, who are newly registered for medical marijuana, and matched non–marijuana-using controls, into a longitudinal high-fidelity driving simulator protocol, and to explore preliminary associations between medical marijuana initiation and simulated driving performance. Methods: This prospective, nonrandomized feasibility cohort study enrolled adults aged 50 years and older who are newly registered in the Florida Medical Marijuana Use Registry, along with age-, race-, and sex-matched controls. Assessments occurred at baseline (T1; preinitiation) and at 1 month (T2). Primary feasibility outcomes included recruitment, retention, simulator completion and tolerance, and exposure verification. Exploratory outcomes included reaction time and divided attention (DA) performance, which are measured using an immersive, high-fidelity driving simulator. Results: Recruitment and exposure verification procedures were feasible, but simulator sickness contributed to substantial missing data. Exploratory analyses suggested group differences in select DA outcomes at T2. At T2, reaction time to DA situation 3 (DA3) was significantly shorter in the medical marijuana group (n=14, mean 2.57, SD 1.63) than in the control group (n=7, mean 5.79, SD 4.32; =−2.50, =.02, =−1.11, 95% CI −2.04 to −0.16). These findings should be interpreted cautiously, given the small sample size, missing data, and multiple comparisons. Conclusions: A prospective protocol examining medical marijuana initiation and simulated driving among mid-to-late-life adults is feasible, but future studies should incorporate design and analytic refinements to address simulator sickness and missing data and to better characterize exposure timing and patterns. Trial Registration: ClinicalTrials.gov NCT04629716; https://clinicaltrials.gov/study/NCT04629716
<img src="https://jmir-production.s3.us-east-2.amazonaws.com/thumbs/c1cca72a6451a42e4950b3ade21e3848" />

Communication-Based Teaching on Childhood Obesity and the Planetary Health Diet in Medical Education: Proof-of-Concept Study Comparing 4 Information Sources

Background: Childhood obesity constitutes a complex medical and psychosocial challenge that requires both nutritional knowledge and sensitive, relationship-oriented doctor-patient communication. The Planetary Health Diet links individual health promotion with environmental sustainability and represents a relevant framework for contemporary medical education. Objective: This proof-of-concept study investigated how different information sources influence medical students’ acquisition, structuring, and application of knowledge on childhood obesity and the Planetary Health Diet within a communication-based teaching setting, including the exploratory use of artificial intelligence–based tools. Methods: A total of 359 second-year medical students participated in a mandatory communication seminar during the 2023‐2024 academic year. Following a precourse knowledge assessment and a brief theoretical introduction, students worked on a standardized counseling scenario addressing childhood obesity. In small groups, students used only 1 assigned information source (ChatGPT, Google Search, scientific papers, or instructional videos) to prepare a counseling approach. Group outcomes were assessed using a predefined scoring system based on a sample solution, complemented by thematic content analysis. Results: All information sources enabled students to acquire relevant knowledge on childhood obesity and the Planetary Health Diet. However, groups differed with regard to the depth, differentiation, and structuring of their responses. The ChatGPT group achieved the highest conformity scores with the sample solution and provided the most additional information, followed by the Google and video groups, while the paper group achieved the lowest scores. Prior to the course, students reported limited knowledge of the Planetary Health Diet and little practical experience in counseling children with obesity and their families. Conclusions: Communication-based teaching formats provide an effective framework for introducing medical students to complex topics such as childhood obesity and sustainability-related nutrition early in their training. Easily accessible digital tools, including artificial intelligence–based systems, may facilitate knowledge acquisition and elaboration; however, their use requires explicit didactic framing, critical source evaluation, and reflection on the complexity of chronic conditions to support responsible and realistic learning outcomes in future physicians.
<img src="https://jmir-production.s3.us-east-2.amazonaws.com/thumbs/d20d5cf254dd727152cf4ca863132a57" />

Feasibility of Integrating Wearable Devices and Ecological Momentary Assessment for Real-Time Environmental Exposure Estimation: Proof-of-Concept Study

Background: Environmental exposures such as heat and air pollution are critical determinants of health, yet traditional assessment methods rely on stationary monitors or residential address proxies that fail to capture the exposures that individuals experience throughout the day. Objective: This pilot study aimed to assess the feasibility of integrating ecological momentary assessment (EMA), wearable devices, and continuous GPS tracking to capture real-time environmental exposures and to explore associations with concurrent health outcomes. Methods: In total, 7 young adults (aged approximately 16 to 24 years; 5/7, 71% female) wore Fitbit Charge 6 watches from July 2025 to August 2025 (mean 28.1, SD 1.1 days), recording sleep quality and duration, resting heart rate, breathing rate, heart rate variability, and physical activity. GPS location measured at up to 5-minute intervals (mean 19.7, SD 25.8 measurements per day) was linked to ambient temperature, humidity, and air pollution data (particulate matter <2.5 um or <10 um in diameter, nitrogen dioxide, sulfur dioxide, ozone, and carbon monoxide) derived from monitoring stations, satellites, and climate models using data-integration algorithms accessed via an application programming interface. EMA surveys administered 3 times per day captured participants’ emotional states and location (inside or outside). Feasibility targets were ≥3 GPS measurements per day, ≥1 survey completed per day, and complete sleep data on ≥50% of days. We examined exploratory bivariate correlations between environmental exposures, physiological measures, and self-reported mood, adjusting for multiple comparisons using false discovery rate correction. Results: Of the 7 participants, 5 (71%) met predefined feasibility targets. Mean compliance included 565 (SD 457) GPS coordinates per participant, 1.4 (SD 0.2) EMA surveys per day, and complete Fitbit sleep data on 64% (SD 27%) of days. Surveys identified barriers to compliance, including perceived complexity of the system and forgetting to put the Fitbit watch back on after removing it. Exploratory correlations (6/7, 86% of participants with complete Fitbit data) revealed associations between nitrogen dioxide and heat exposure and reduced heart rate variability (a marker of parasympathetic tone), and between air pollutants (sulfur dioxide) and increased negative emotions. Heat exposure showed a paradoxical pattern of lower self-reported sadness but reduced heart rate variability with higher levels of heat exposure. Given the small sample size, these correlations should be considered preliminary and hypothesis generating rather than definitive findings. Conclusions: This study demonstrates that the multimodal integration of wearable devices, GPS tracking, and EMA is feasible for capturing real-time environmental exposures and concurrent health outcomes in young adults. This approach addresses critical exposure misclassification issues in environmental health research that relies on residential addresses as proxies. Preliminary patterns suggest complex relationships between environmental exposures and both physiological and emotional outcomes, warranting further investigation in larger, more diverse samples. This approach could inform future personalized environmental health interventions.

Leukemia Stem Cell Diversity Drives Treatment Resistance in AML

Scientists from the German Cancer Research Center and HI-STEM have uncovered a major reason why acute myeloid leukemia (AML) frequently returns after treatment. Their findings, published in Cell Stem Cell, reveal that leukemia stem cells, the rare but critical cells that sustain the disease, exist in multiple biologically distinct forms, each with different vulnerabilities and resistance mechanisms.

The discovery helps explain why venetoclax, one of the most important targeted therapies in AML, often loses effectiveness over time. More importantly, it provides a framework for designing personalized combination therapies that could prevent relapse by targeting resistant stem cell populations before they expand.

Why AML remains difficult to cure

Acute myeloid leukemia is an aggressive blood cancer characterized by the rapid accumulation of abnormal myeloid cells in the bone marrow. Although newer targeted therapies have improved outcomes, relapse remains the central clinical challenge.

One of the most transformative advances in AML treatment has been the introduction of venetoclax, a selective inhibitor of the anti-apoptotic protein BCL-2. Combined with hypomethylating agents or low-dose chemotherapy, venetoclax has substantially improved responses, particularly in older patients who are unable to tolerate intensive chemotherapy.

Yet despite these advances, most patients eventually relapse.

Researchers have long suspected that leukemia stem cells are responsible. These rare cells possess the ability to self-renew indefinitely and survive therapeutic pressure, allowing the disease to regenerate even after apparently successful treatment.

Not one leukemia stem cell—but four

In the new study, researchers analyzed samples from more than 150 AML patients to better understand how leukemia stem cells respond to therapy.

Their findings challenge the idea that AML stem cells represent a single uniform population. Instead, the team identified at least four distinct leukemia stem cell subtypes, each resembling different developmental stages of normal blood cell formation.

This developmental identity turned out to be critically important because it determined which survival pathways the cells depended on—and therefore how sensitive they were to venetoclax.

Some stem cell subtypes were highly dependent on BCL-2 and responded well to treatment. Others relied on alternative survival programs that rendered them intrinsically less sensitive to the drug.

Cancer stem cells adapt under therapeutic pressure

One of the study’s most significant findings was that leukemia stem cells are not fixed in a single state. Instead, they can dynamically reprogram themselves in response to therapy.

Venetoclax works by blocking BCL-2, a protein that protects leukemia cells from programmed cell death. When BCL-2 is inhibited, susceptible leukemia cells undergo apoptosis.

However, the researchers found that under treatment pressure, many leukemia stem cells transition into more resistant cellular states. Rather than relying on BCL-2, these resistant cells switch to using a related survival protein known as BCL-xL.

This adaptive shift effectively allows the cells to bypass venetoclax and survive treatment.

The findings strengthen a broader principle increasingly recognized across oncology: cancer is not only genetically heterogeneous but also highly plastic. Tumor cells can alter their identity to evade therapeutic pressure, making durable treatment responses difficult to achieve with single-agent therapies.

Combination therapies may overcome resistance

The study also points toward potential strategies for overcoming this resistance.

By identifying which survival pathways individual leukemia stem cell subtypes depend on, researchers showed that resistant populations could potentially be targeted with rational drug combinations. In particular, combining venetoclax with inhibitors targeting BCL-xL emerged as a promising approach.

In mouse models transplanted with patient-derived leukemia cells, these subtype-specific combination therapies were significantly more effective than current standard approaches.

This suggests that future AML therapy may require simultaneous targeting of multiple stem cell states to prevent resistant populations from emerging during treatment.

Biomarkers could guide precision medicine in AML

Another key advance from the study was the identification of biomarkers capable of distinguishing the different leukemia stem cell subtypes.

These biomarkers could eventually enable clinicians to determine, at the time of diagnosis, which resistance mechanisms are most likely to arise in a particular patient.

“This means that in the future, it may be possible to determine at the time of diagnosis which patient will benefit most from which therapy,” said Alexander Waclawiczek, PhD, first author of the study.

Such an approach would represent a major shift away from treating AML as a largely uniform disease and toward truly individualized therapy guided by stem cell biology.

A new framework for AML treatment

The findings also reinforce the growing importance of cancer stem cell biology in therapeutic design. Rather than focusing exclusively on eliminating bulk tumor cells, future strategies may increasingly aim to eradicate the specific stem cell populations capable of regenerating disease after therapy.

“The results should help to align AML therapy in the future more closely with the biological characteristics of individual AML cases and, in particular, their leukemia stem cells, rather than treating all patients according to a similar protocol,” said Andreas Trumpp, PhD, who led the study.

The next major step will be translating these findings into clinical trials testing personalized combination therapies tailored to leukemia stem cell subtype composition.

The post Leukemia Stem Cell Diversity Drives Treatment Resistance in AML appeared first on Inside Precision Medicine.