It’s well known that exercise is good for health and helps to prevent serious diseases, like cancer and heart disease, along with simply making people feel better overall. However, the molecular mechanisms responsible for preventing cancer or slowing its progression are not well understood. But, a new study, published in the Proceedings of the National Academy of Sciences, reveals how exercise can increase glucose and oxygen uptake in the skeletal and cardiac muscles, instead of allowing it to “feed” tumors.

Reduced tumor growth in exercised mice

To study how exercise-induced metabolic changes affect tumor growth, the research team injected mice with breast cancer cells and fed some of the mice a high-fat diet (HFD), consisting of 60% calories from fat, while others were fed a normal diet as a control. The HFD mice were given running wheels for exercise, although exercise was voluntary. The team used stable isotope tracer studies [U-13C6] glucose and [U-13C5] glutamine to track metabolic changes.

After 4 weeks of wheel running, the team found a significant difference in tumor sizes between mice that chose to exercise, compared to those that did not—even when they were fed the same diet.

The study authors write, “Obese mice which underwent 4 weeks of voluntary wheel running after tumor injection exhibited nearly a 60% reduction in tumor size. The exercised mice had greater lean mass and lower fat mass than their nonexercised, obese counterparts, with plasma glucose and insulin concentrations comparable to the sedentary chow fed controls.

“After a 30-min bout of acute moderate intensity (15 m/min) treadmill exercise, the exercised obese mice had higher cardiac and skeletal muscle 2-deoxyglucose uptake and reduced tumor glucose uptake.”

The researchers also analyzed exercise-induced changes in mice with a type of melanoma that is typically not exacerbated by obesity (in contrast to breast cancer). Still, after four weeks of exercise, obese mice with melanoma had significantly smaller tumor sizes, along with reductions in tumor glucose uptake and oxidation compared to the sedentary controls. These results suggest that the shift in glucose (and thus the slowing of tumor growth) is not tumor-type specific.

Some mice also underwent “prehabilitation”—exercise undertaken before tumors were introduced. Similar beneficial results were found in these mice. The study authors explain, “These observations may be due to an earlier achievement and maintenance of body composition or overall fitness (VO₂ peak) with early exercise exposure.”

Exercise-induced metabolic changes

The repartitioning of glucose to cardiac and skeletal muscles instead of tumors appears to play a major role in slowing tumor growth, but there are other changes taking place, as well. The team also found 417 genes related to energy metabolism and other metabolic pathways that were expressed differently between exercised and sedentary lean mice.

The team says that a downregulation in a protein referred to as mTOR, is seen in the exercised mice and this may be helping to slow tumor growth, along with processes like shifts in the use of amino acids, which tumors have been documented to utilize.

Does exercise slow tumor growth in humans?

The team also gathered gene expression data from another study, which analyzed exercise training in women with breast cancer and a metaanalysis of skeletal muscle responses to multiple types of acute and chronic exercise. The data revealed an upregulation in the glutamine and leucine channeling genes in the muscle tissue of humans who exercise. They say that no distinct differences were observed in the expression pattern of these genes when comparing exercise intensity, which may be due to the small sample size or the limited number of analyzed genes.

So, more research is certainly required, but since metabolic pathways are similar in humans, mice, and other mammals, there is likely a similar relationship between exercise and tumor growth in humans. This would be in line with other studies indicating tumor suppression with the help of exercise in humans.

Overall, researchers remain optimistic about exercise in the role of cancer treatment in humans. A better understanding of how glucose is utilized after exercise in humans with tumors can inform prehabilitation strategies for cancer patients, help doctors integrate fitness into cancer therapies, and potentially assist researchers in identifying new therapeutic targets.

“We anticipate that this work may lay the groundwork to reveal key insights into the role of systemic adaptations to exercise in broader antitumor therapies. Further, examination of the role of fitness on the molecular pathways altered by exercise may uncover new therapeutic targets in precision oncology, particularly in patients who cannot tolerate exercise,” the study authors explain.

California State University, Sacramento, researchers traced how disordered childhood social worlds in women connected to faster life history traits and greater mating effort, with those traits explaining 22.2% of the association between childhood microsystems and adult sexual behavior.

Childhood environments and strategies

Life History theory treats childhood ecology as a starting point for strategies that govern survival, mating effort, and parental effort. Mating effort involves behavior that increases access to sexual opportunities, while parental effort involves investing time and resources so children survive to reproduce.

Faster strategies align with earlier sexual debut, more short-term mating, more lifetime partners, and more offspring at younger ages. Slower strategies align with later sexual debut, safer reproductive behavior such as monogamy and contraceptive use, fewer lifetime partners, and greater parental investment.

Childhood harshness and unpredictability show up in prior work through divorce, parental job loss, frequent moves, unsafe neighborhoods, and parental substance misuse or violence. Supportive and predictable childhood environments appear with nurturing parents, stable housing, and safer neighborhoods.

Bioecological theory describes environmental layers that interact with the child over time. Microsystems contain parents, extended family, teachers, and neighbors who interact frequently and reciprocally with the child. Exosystems include factors that affect the child indirectly, such as parental employment or frequent moves.

Prior studies linked parental disengagement, father absence, and neighborhood violence to short-term mating, early sexual debut, and sexually risky behavior in adolescence and adulthood. Harsh and unpredictable environments relate to present-oriented thinking and impulsivity, which then link to risky sexual behavior. Dark Triad traits, including psychopathy and Machiavellianism, support resource control, low self-control, and mating effort, along with sexually risky behavior.

Slower profiles are associated with traits such as long-term planning, agreeableness, conscientiousness, mental and physical health, well-being, self-esteem, positive affect, and emotional intelligence.

In the study, “Using SEM to test the associations among women’s childhood ecology, adult psychosocial life history traits, and mating effort,” published in Evolution and Human Behavior, researchers used structural equation modeling to investigate how childhood microsystem and exosystem experiences, adult psychosocial traits, and mating effort fit together in women.

Participants were 875 ethnically mixed, self-identified female undergraduate college students at a university in Northern California. Ages ranged from 18 to 46 years, with a mean age of 20.55. Questionnaires included childhood ecology, adult psychosocial traits, and mating effort along with Adverse Childhood Experiences (ACE) Inventory, a 20-item checklist of hardships in childhood.

Childhood trauma, control, and partners

Correlations between microsystem indicators, faster traits, and mating effort unpacked those paths. Higher microsystem scores related to higher ACE scores, paternal and maternal disengagement, more parental cohabitation, and higher neighborhood crime. Higher microsystem scores also related to higher, faster scores and Dark Triad psychopathy, higher coercive and power-seeking resource control, higher Machiavellianism, and lower self-control.

Psychopathy showed strong links to mating effort. Higher psychopathy correlated with more lifetime sexual partners, stronger short-term mating orientation, and greater future sexual risk intentions. Machiavellianism correlated with stronger short-term mating orientation and greater future sexual risk intentions.

Self-control scores related inversely to harsh childhood conditions. Higher ACE scores and more neighborhood crime correlated with lower self-control. Lower self-control correlated with more lifetime sexual partners, more openness to casual sex, and higher future sexual risk intentions.

Resource control strategies formed another bridge. Neighborhood crime correlated with higher coercive and power-seeking resource control. Higher coercive and power-seeking scores correlated with more partners, stronger short-term mating orientation, and higher future risk intentions.

Higher neuroticism correlated with higher ACE scores, more neighborhood crime, higher father disengagement, stronger short-term mating orientation, and greater future sexual risk intentions.

Sexual start patterns

Age at first sexual encounter could not be included in the structural equation model because a substantial number of participants reported no sexual experience. 284 women reported never having sex, leaving 591 with a reported age at sexual debut. A hierarchical multiple regression used microsystem, exosystem, slower traits, and faster traits as predictors of age at sexual debut in that subgroup.

Women who grew up in more chaotic or troubled family and neighborhood environments tended to start having sex at younger ages. Broader issues such as money instability and slower life history traits did not change that pattern much.

Women with higher adversity scores, more disengaged fathers, more non-relatives living in the home, higher psychopathy, a stronger drive to control others and resources, and higher neuroticism reported younger ages at first sex.

Mothers

A total of 33 participants reported having children. For this analysis, 37 participants without children were randomly sampled to form a comparison group of 70 women.

Microsystem and exosystem scores did not significantly predict having children. Slower and faster traits did. Women in this small subgroup who showed more of the slower life history traits (things like resilience, well-being, conscientiousness, secure attachment, and grit) were more likely to have children than women with lower scores on those traits.

Women in this small subgroup who had children differed from those without children mainly in their adult traits, not in their reported childhood environments. Mothers tended to score lower on fast life history traits such as psychopathy, low self-control, and power-seeking, and higher on slow traits, while the childhood microsystem and exosystem scores did not clearly separate mothers from non-mothers.

Life history patterns and implications

Psychosocial life history traits clustered into two partly independent sets, one faster and one slower. Faster traits were linked both to harsher childhood microsystems and to higher mating efforts, many of which are explicitly risky or short term. Slower traits were linked to kinder childhood microsystems, and showed statistically non-significant associations with mating effort.

Microsystem conditions before age 10 are linked more strongly to psychosocial traits and mating effort than exosystem conditions. Childhood trauma, parental disengagement, parental cohabitation with non-kin adults, and neighborhood crime all clustered within higher microsystem scores and connected to faster traits, more partners, shorter-term mating orientation, and higher future sexual risk intentions.

Perceived resource inconsistency in the exosystem added further associations with partner counts, short-term orientation, and risk intentions.

Conclusions, limitations and open questions

Results showed that the childhood microsystem had a far greater impact than the external environment on personality development and mating strategies. Good parenting and a protective early environment that allowed security and predictability showed a trajectory of positive associations.

The cohort included only college students, a major limitation for generalizing the findings, as college attendance is conceivably a measurable outcome of Life History theory. How the findings might compare to women who did not attend college, and how this socioeconomic cutoff might alter the strength of the associations is unclear.

The health benefits of nature are well-known, but its role in encouraging day-to-day physical activity across different regions and demographics has been less clear. This question carries new urgency as the world faces a “physical inactivity pandemic,” with trends especially stark in the United States, where many people fall short of recommended activity levels.

To investigate how urban green spaces influence movement, researchers with the Stanford-based Natural Capital Project (NatCap), a global alliance focused on valuing nature’s benefits to people, analyzed wearable step-counter data in their new study published in Nature Health. They found that higher park accessibility, not simply more greenery, is associated with higher daily activity.

“Greenness alone doesn’t seem to encourage movement,” said Youngeng Lu, lead author of the paper, who did the work while he was a postdoctoral scholar at NatCap. “Even if you have lots of trees or vegetation, if you can’t easily reach them, it doesn’t translate to more physical activity. Accessibility to parks was the factor that mattered most.”

Measuring movement at scale

Past research links nature to physical activity, but many studies rely on self-reported data, focus on only a few cities, or track people for short periods. Those constraints limit how broadly the findings can be applied.

To take the next step in understanding these patterns, the team used multi-year wearable-device data from the All of Us Research Program, a national health initiative. Participants volunteered their Fitbit records, giving researchers three years of daily step counts and activity intensity from 7,013 anonymous users in 53 U.S. metropolitan areas. The team then used modeling that accounted for variations between individual people and cities to test how activity levels shifted with different types of urban nature.

The researchers distinguished between two aspects of urban nature: total greenness (measured from satellite imagery and including forests, gardens, and other vegetation) and park accessibility, which encompasses park existence, distance from population centers, and connectivity to one another. Using participants’ home locations, the team calculated how easy it is for residents to travel to nearby parks on foot.

Although overall greenness didn’t appear to be linked with higher physical activity, park accessibility was a strong predictor of movement. A 10% increase in park accessibility corresponded to roughly 107 additional steps per day.

Who benefits most?

The multi-year dataset allowed researchers to examine how the benefits of park access vary by region and demographic group over time. They also considered variables such as temperature, precipitation, population density, city walkability, and air quality, revealing some telling patterns in the game of step tracking.

Western and southern cities showed stronger links between park accessibility and movement, a trend the team suspects may be influenced by climate, culture, or outdoor habits. Lu emphasized the significant role temperature played in daily step counts. In mild climates, park accessibility had a much stronger effect on physical activity than in cities that are extremely hot or cold, where conditions are less favorable for outdoor exercise.

Demographic trends were also clear. Non-white residents, older adults, and people who were less active at baseline experienced the greatest increase in activity when parks were easier to reach. These results support the “equigenic effect,” in which improved access to green space disproportionately benefits more vulnerable communities.

“For non-white and lower-income neighborhoods, even small increases in park accessibility can encourage significantly more activity,” Lu said. “Parks need to be accessible to everyone, not just higher-income, white populations.”

Designing healthier cities

The study suggests that building new parks isn’t the only way for cities to increase the physical activity of their residents. Enhancing access to existing parks by improving walkability, removing barriers, and connecting parks to nearby neighborhoods (such as creating pedestrian overpasses) can also deliver public health benefits.

“It’s promising from a health perspective,” said Lisa Mandle, senior author on the paper, and director of science-software integration and lead scientist with NatCap. “Investing in access helps residents be more active and promotes equity in urban health.”

Lu added that the priority now is ensuring that the benefits of park access are shared equitably across cities. Future research could track changes in accessibility over time, incorporate GPS data to measure actual park use, and recruit more diverse participants to strengthen the evidence.

By continuing to explore nature’s role in public health, the team hopes to “inform urban planning decisions and inspire interventions that make cities healthier, greener, and more equitable for everyone,” Lu said.

“This study arose out of our efforts to understand how parks and nature in cities can benefit the people living there,” said Mandle. “We know green spaces provide mental health benefits, but we wanted to look more closely at physical activity, and specifically, who benefits most and in what contexts.”

This aligns with the broader goals of NatCap: “to advance understanding of the diversity of ways that nature benefits people in order to incorporate these values into decision-making,” Mandle said.

Electrotherapy using injectable nanoparticles delivered directly into the tumor could pave the way for new treatment options for glioblastoma, according to a new study from Lund University in Sweden.

Glioblastoma is the most common and most aggressive form of brain tumor among adults. Even with intensive treatment, the average survival period is 15 months. The tumor has a high genetic variation with multiple mutations, which often makes it resistant to radiation therapy, chemotherapy and many targeted drugs. The prognosis for glioblastoma has not improved over the past few decades despite extensive research.

How electrotherapy targets tumors

Electrotherapy offers another strategy to combat solid tumors. Using short, strong electric pulses (irreversible electroporation), non-reversible pores are created in the cancer cells leading to their death. The body’s immune system is simultaneously stimulated.

The problem is that surgery is required to place the stiff metal electrodes that are necessary for the treatment. In sensitive tissue, in the brain for example, this often entails a very difficult procedure, which has led to strict criteria regarding which patients can be treated.

Johan Bengzon is a researcher in glioblastoma and adjunct professor at Lund University, and consultant in neurosurgery at the Skåne University Hospital. He regularly treats patients with glioblastoma and is frustrated by the limited treatment options.

“The short distance between the hospital and the University in Lund facilitates cooperation and that’s why I contacted research colleagues to find out if injectable electrodes could be an alternative solution in electrotherapy,” says Johan Bengzon.

Injectable nanoparticles as a new approach

The research team, with Amit Singh Yadav, Martin Hjort, and Roger Olsson at the helm, had previously used nanoparticles to form injectable and electrically conductive hydrogels to control brain signaling and heart contractions. It is a minimally invasive method in which the particles are injected using a thin syringe directly into the body.

The particles break down after the treatment and thus do not need to be surgically removed. Perhaps the same technology could be used to destroy tumor cells in glioblastoma.

“After surgical treatment, unfortunately the glioblastoma tumor often returns on the outer edge of the area operated on. By drop casting the nanoparticles into the tumor cavity after an operation, we could electrify the edges while the immune system is also activated. In animal models, the procedure, due to this irreversible electroporation, led to tumors being wiped out within three days,” says Olsson, professor of chemical biology and drug development at Lund University, who led the study.

Early results and future prospects

The prospects are good and the researchers are very hopeful for the future, even though there is a long way to go before it becomes a clinical reality. The challenge is now to test the method on larger tumors.

“We have seen that the electrode is well received in the brain. We have not noted any problems relating to side effects and after 12 weeks the electrode disappeared by itself as it’s biodegradable. The technology combines direct tumor destruction with activation of the immune system and can be an important step towards more effective treatment of glioblastoma,” concludes Singh Yadav, researcher at Lund University and first author of the study.

A regional New South Wales public hospital will soon close its mental health inpatient facility, in favor of a home-based service.

The ABC reports voluntary patients at Kempsey District Hospital will either be transferred to a new “hospital in the home” program or a neighboring hospital, while involuntary patients will be transferred to Port Macquarie Base Hospital, 55 kilometers away.

The NSW government says if the hospital in the home program is successful, it could be rolled out across the state.

While some locals have raised concerns about the risks of care at home, the move is the next step in a long process of establishing good mental health care in the community.

Governments committed to de-institutionalization about 40 years ago, promising a range of services to support people with mental illness to live well and get the treatment they need in the community.

However, this shift has been slow going.

Mental health system under financial pressure

Our mental health system is under enormous pressure. The amount of funding mental health receives as a share of total health spending, about 7%, hasn’t changed since 1992.

But the burden of disease attributable to mental health and addictions has. It now accounts for around 15% of the total disease burden.

Australia’s response to mental illness has become hospital-centric. Hospital-based expenditure accounts for the largest component of state and territory spending on mental health, close to 80%. This type of care is also the most expensive, leaving only a fraction to spend on mental health care in other settings.

Australia was a pioneer in hospital alternatives

Australia has pioneered alternatives to hospitalization for mental illness. As early as 1907, community organizations such as the Aftercare Association were working to find patients housing, care and work in the community, outside the asylums.

By the 1970s and ’80s, spurred by key inquiries such as the Richmond Report, Australia’s response to mental illness shifted to providing care through a network of services focused on treating and supporting people in the community.

As part of this mix, the hospital in the home model emerged, offering patients more options and helping to manage hospital bed demand. It’s now an established model of mental health care across Australia.

So what is hospital in the home for mental health?

Hospital in the home provides acute, hospital-level mental health care for patients in their own home, rather than having to be admitted to hospital.

It offers a comparable level of care in a familiar environment. The hospital in the home team, which can include psychiatrists, psychologists, nurses, allied health and peer workers, develops a treatment plan and provides care at home. This may involve daily home visits or, in some cases, appointments at a clinic or online.

The team works with the patient to create a treatment and recovery plan, often involving family and carers with the patient’s permission.

Discharge planning begins at the start of admission, with the goal of getting the patient back to their usual level of functioning in the community as soon as possible.

What does the evidence say?

Hospital in the home is backed by good evidence which shows it’s an effective alternative to hospital-based care and can shorten length of stay and reduce the need for subsequent admissions.

Compared with hospital-based care, hospital in the home also has a reduced risk of adverse events such as seclusion and restraint.

Many people find it more comfortable and would prefer hospital in the home to hospital admission. As one person pointed out, hospital in the home care: “Felt like I was being checked in with, rather than checked on, which is quite a different distinction. It was like I was part of the team, rather than a number being treated.”

There are also clients for whom this kind of service may not be appropriate, including those at very high risk of suicide.

Expanding options for care in the community

New Zealand spends more than 20% of its mental health funding on community-based services, compared with Australia’s 7%. NZ offers consumers many more alternatives to hospital care.

One such service is Tupu Ake, a consumer-run acute public psychiatric “ward,” supported by clinical and professional staff, but in a lovely house in south Auckland. Tupu Ake has reduced the need for acute hospital admission.

Successive mental health reports and inquiries in Australia have long recommended the establishment of a vibrant community mental health sector, including hospital in the home.

But this choice remains rare. Access to programs—including Orygen @ Home, which provides acute mental health care for young people in their home—is sought-after but very limited.

Home-based programs need adequate funding

The unsustainable acute pressure facing hospitals is now driving health services to urgently consider alternative models of care.

St Vincent’s Health Australia, for example, this week announced it would shift half of its services to home-based or online care over the next five years. Hospitals would be dedicated to emergency wards and intensive care.

This comes as federal and state/territory governments negotiate the next five-year next national health and hospital funding agreement.

Alternatives such as hospital in the home should feature prominently in the new funding agreement, as part of an overall strategy to reduce the hospital-centric nature of our mental health system.

But in doing so, it will be important to stay faithful to both the philosophy and the model of care that underpins hospital in the home for mental health. Replacing suboptimal hospital-based care with suboptimal home-based care is unacceptable.

Patients with major depressive disorder, including those who have not responded to first-line antidepressants, may benefit from short-term nitrous oxide treatment, a major meta-analysis led by the University of Birmingham has found.

The paper published in eBioMedicine has assessed the best available clinical information to show how clinically administered nitrous oxide (N2O) can offer fast-acting depressive symptom relief for adults with major depressive disorder (MDD) and treatment-resistant depression (TRD).

TRD is characterized as depression that isn’t effectively managed after a patient tries two different antidepressants. It affects approximately 48% of UK patients who experience limited benefit from standard treatments, according to a previous study led by the research team.

Researchers from the University of Birmingham, University of Oxford, and Birmingham and Solihull Mental Health NHS Foundation Trust assessed seven clinical trials and four protocol papers published by investigators from around the world.

Each research study looked at the use of nitrous oxide, also used as pain relief in a range of medical situations, for treating depressive disorders, including MDD, TRD and bipolar depression.

The team found that a single treatment of inhaled clinical nitrous oxide at 50% concentration (in three trials), produced rapid and significant reductions in depressive symptoms within 24 hours, although these effects were not sustained at one week. In contrast, repeated dosing over several weeks led to more durable improvements, suggesting that multiple treatment sessions (compared to a single dose) may be required to maintain clinical benefit.

It is thought to target glutamate receptors in a similar way to ketamine, another rapid-acting antidepressant, and this may help explain why improvements in mood can be observed soon after inhalation.

Kiranpreet Gill, a Ph.D. researcher at the University of Birmingham and first author of the study, said, “Depression is a debilitating illness, made even more so by the fact that antidepressants make no meaningful difference for almost half of all patients diagnosed with it. There is a growing body of research on repurposing treatments from other clinical domains to alleviate low mood.

“This study brings together the best possible evidence indicating that nitrous oxide has the potential to provide swift and clinically significant short-term improvements in patients with severe depression.

“Our analyses show that nitrous oxide could form part of a new generation of rapid-acting treatments for depression. Importantly, it provides a foundation for future trials to investigate repeated and carefully managed dosing strategies that can further determine how best to use this treatment in clinical practice for patients who don’t respond to conventional interventions.”

Strong evidence, but limited numbers of trials currently

The meta-analysis of studies found strong evidence for short-term improvements in mood following nitrous oxide administration. Due to the limited number of existing trials, there was notable variability in how depressive symptoms were measured and reported, as well as in the timing of these assessments.

Further studies are needed to determine the optimal dose, nitrous oxide’s long-term safety, and the best way to integrate it into existing treatment pathways.

The team also examined the safety and potential side effects of nitrous oxide. Some patients experienced side effects such as nausea, dizziness and headaches, all of which passed quickly and resolved without medical intervention.

While higher dosing (at 50% concentration) increased the likelihood of these side effects, none of the studies reported any short-term safety concerns. The researchers emphasized that longer-term safety must be assessed through future studies with extended follow-up periods.

Professor Steven Marwaha from the University of Birmingham, Honorary Consultant Psychiatrist at Birmingham and Solihull Mental Health Foundation Trust, and senior author of the study said, “This is a significant milestone in understanding the potential of nitrous oxide as an added treatment option for patients with depression who have been failed by current treatments. This population has often lost hope of recovery, making the results of this study particularly exciting.

“These findings highlight the urgent need for new treatments that can complement existing care pathways, and further evidence is needed to understand how this approach can best support people living with severe depression.”

The study was conducted by researchers at the Mental Health Mission Midlands Translational Center, led by the University of Birmingham. The team are working on improving treatment options for treatment-resistant depression in superdiverse and deprived populations.

The Center aims to accelerate the development and delivery of innovative, evidence-based interventions to improve outcomes and reduce disparities in mental health care.

This work also aligns with ongoing efforts within the Birmingham Clinic for Advanced Mood Disorder Management (CALM), where innovative, evidence-based treatments such as ketamine and neuromodulation are being delivered to people with severe or treatment-resistant depression.

Building on this translational pathway from discovery to clinical practice, the team is now preparing the first NHS trial in the UK to assess whether nitrous oxide can be delivered safely and acceptably as a treatment for major depression.

The findings will help determine how nitrous oxide could be integrated into NHS care and may expand the range of innovative options available for patients who have not benefited from standard approaches.

Eli Lilly and Company, along with partner institutions in the US and United Kingdom, describe how short-term pharmacologic intervention does not appear to have lasting effects for most tirzepatide patients. People with obesity who lost weight on tirzepatide often regained at least 25% of that loss within a year of stopping treatment, along with reversals in improvements in waist circumference, blood pressure, lipids, and glycemic measures.

Chronic obesity is a disease associated with an elevated risk for cardiometabolic complications. Treatment goals extend beyond weight reduction toward lowering that risk across blood pressure, lipid levels, glucose regulation, and insulin resistance.

Tirzepatide is a dual-action synthetic hormone that regulates blood sugar, appetite, and digestion. Drugs with tirzepatide are currently the top selling drugs in the world (Eli Lilly brands Mounjaro and Zepbound).

Current guidelines recommend obesity management medications in combination with a healthy diet and exercise to achieve and maintain weight reduction and to improve cardiometabolic parameters. Calibrating how healthy a diet is, and how effective exercise routines are, can be difficult under pharmacologically assisted weight loss.

Results can be positive without a change or even a less healthy lifestyle. Consequently, those that see weight loss while on weight loss medications frequently regain the weight when they stop using.

In the study, “Cardiometabolic Parameter Change by Weight Regain on Tirzepatide Withdrawal in Adults With Obesity,” published in JAMA Internal Medicine, researchers performed a post hoc analysis on a select group of patients within a larger trial to assess changes in cardiometabolic parameters by degree of weight regain after withdrawal of tirzepatide.

SURMOUNT-4 enrolled 783 participants, with 670 who completed the initial 36-week open-label period being randomized to either continue tirzepatide (n=335) or switch to a placebo (n=335) for the 52-week double-blind phase. The current study followed 308 of the “switch to a placebo” group, eliminating those that did not lose at least 10% of their weight while on treatment.

During tirzepatide treatment

Weight loss during the 36 week tirzepatide exposure was large across later weight regain groups. Mean percentage change in weight from week 0 to week 36 was −21.9%.

Body mass index and waist circumference followed similar trajectories. Mean body mass index at week 36 had a mean reduction of 8.3 units and a mean waist circumference reduction of 18.3 cm

Cardiometabolic parameters improved for all categories during the lead-in. Systolic and diastolic blood pressure, triglycerides, non–high density lipoprotein cholesterol, HDL cholesterol, hemoglobin A1c, fasting serum glucose, fasting insulin, HOMA2 insulin resistance, and HOMA2 β cell function all decreased between week 0 and week 36.

After stopping

Weight trajectories diverged once tirzepatide stopped at week 36 and placebo replaced it while lifestyle measures continued. Weight regain between week 36 and week 88 was defined as a percentage of the earlier weight reduction achieved from week 0 to week 36. That percentage was determined by four groups at week 88.

One group of 54 participants showed less than 25% weight regain relative to the initial loss. A second group of 77 participants showed a 25% to less than 50% regain. A third group of 103 participants showed a 50% to less than 75% regain. A fourth group of 74 participants showed 75% or more regain.

Around half of participants regained 50% or more of the earlier weight reduction and approximately one in four regained at least 75% of it. Almost 9% surpassed their starting weight with more than 100% weight regain.

Approximately 4% continued to lose weight under lifestyle intervention alone after tirzepatide withdrawal. Greater weight regain at week 88 was associated with smaller initial reductions in weight, body mass index, and waist circumference during the tirzepatide phase.

Cardiometabolic parameters tracked closely with these weight patterns during withdrawal. At week 36, systolic blood pressure averaged 114.3 mm Hg with a standard deviation of 12.0 mm Hg and diastolic blood pressure averaged 76.2 mm Hg with a standard deviation of 8.6 mm Hg.

From week 36 to week 88, systolic blood pressure increased in all weight regain groups. Least squares mean increases reached 6.8 mm Hg in the less than 25% group, 7.3 mm Hg in the 25% to less than 50% group, 9.6 mm Hg in the 50% to less than 75% group, and 10.4 mm Hg in the 75% or more group. Diastolic blood pressure increased by 2.8 mm Hg, 1.6 mm Hg, 3.9 mm Hg, and 4.3 mm Hg respectively.

Waist circumference rose in step with weight regain. From week 36 to week 88, mean change was 0.8 cm in the less than 25% group, 5.4 cm in the 25% to less than 50% group, 10.1 cm in the 50% to less than 75% group, and 14.7 cm in the 75% or more group.

Triglycerides and non–high density lipoprotein cholesterol also moved upward after withdrawal. From week 36 to week 88, estimated percentage changes in triglycerides were 5.5%, 5.3%, 29.6%, and 18.9% across categories from lowest to highest regain. Estimated percentage changes in non–high density lipoprotein cholesterol were −0.4%, 1.6%, 8.4%, and 10.8% across the same four groups.

Glycemic measures followed a similar pattern. Hemoglobin A1c increased from week 36 to week 88 by least squares mean values of 0.14%, 0.15%, 0.27%, and 0.35% in the ascending weight regain categories. Fasting serum glucose increased by 3.8 mg/dL, 6.9 mg/dL, 9.2 mg/dL, and 9.0 mg/dL across categories.

Markers of insulin resistance changed along with glycemia and lipids. Fasting insulin decreased by 4.0% in the less than 25% group and 15.4%, 46.2%, and 26.3% in the 25% to less than 50%, 50% to less than 75%, and 75% or more groups, respectively. HOMA2 insulin resistance increased by 0.6%, 12.6%, 39.5%, and 27.0%.

Participants who limited weight regain to less than 25% showed no statistically significant changes between week 36 and week 88 in waist circumference, triglycerides, non–high density lipoprotein cholesterol, fasting insulin, and HOMA2 insulin resistance. Several lipid and insulin markers remained similar to values at the end of tirzepatide treatment and continued to differ from baseline.

HDL cholesterol followed a distinct sequence. Levels decreased during tirzepatide treatment, then rose in all weight regain categories after withdrawal. From week 36 to week 88, estimated percentage increases were 19.7%, 16.7%, 13.6%, and 13.4% across the four categories.

HOMA2 β cell function decreased during tirzepatide treatment and decreased further after withdrawal in some categories. That pattern differs from earlier post hoc analyses in adults with type 2 diabetes and obesity that reported increases in HOMA2 β cell function during tirzepatide therapy, and the current work calls for further investigation of insulin resistance and β cell function in adults with obesity under tirzepatide treatment and after discontinuation.

Across the full week 0 to week 88, participants with 75% or more weight regain showed cardiometabolic parameters at week 88 similar to baseline values.

Short-term pharmacologic intervention did not appear to have long-term benefits for most tirzepatide patients who ceased taking the treatment. Continued treatment for those living with chronic obesity may be needed to sustain weight reduction and cardiometabolic benefits, according to the study authors.

Limitations include the post hoc selection structure, absence of body composition and objective diet and physical activity measurements, and potential for conflict of interest and conclusion biasing.

Neurodegenerative diseases, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are medical conditions characterized by the progressive degradation of cells in the brain, spinal cord and nerves. Over time, these diseases cause a decline in varying mental and physical functions, such as memory and cognitive deficits or a loss of voluntary muscle control and an inability to move parts of the body.

Past studies showed that both ALS and FTD are associated with the dysfunction of the TAR DNA-binding protein 43 (TDP-43). In patients diagnosed with these diseases, this protein was found to abnormally accumulate in the cytoplasm (i.e., the gelatinous liquid that fills the inside of cells), while being depleted from the nucleus (i.e., the “control center” of cells that contains their genetic material).

The link between this pattern of TDP-43 accumulation and some neurodegenerative diseases is now well-documented. However, the molecular processes via which this protein regulates the RNA of the patient and contributes to progression of these diseases have not yet been fully elucidated.

Two research teams at Stanford University and University College London (UCL)Nature Neuroscience, suggest that this loss of TDP-43 could influence a mechanism known as alternative polyadenylation (APA), which plays a key role in the expression of genes and the function of proteins.

“Our project emerged from a critical gap in understanding how TDP-43 dysfunction affects RNA processing in ALS and FTD. TDP-43 is a master editor of RNA in cells,” Yi Zeng, researcher at Stanford and co-author of the first paper, told Medical Xpress.

“In ALS and FTD, it leaves the nucleus and forms toxic clumps in the cytoplasm of degenerating neurons. Recent breakthroughs showed this causes splicing defects, where the missing editor fails to remove unwanted sections from RNA messages. This affects important genes like STMN2 and UNC13A; our lab co-discovered the splicing defects in UNC13A.”

In addition to this widely investigated function, the protein TDP-43 is known to have other functions that remain less investigated in the context of neurodegeneration. Some earlier studies had found that this protein helps to determine where RNA “messages” will end, via polyadenylation.

“Think of it like deciding where to put the period at the end of a sentence—put it in the wrong place and you completely change the meaning,” said Zeng. “Where an RNA ends determines its stability, localization, how much protein gets made, and even what kind of protein gets made, so different ending points can completely change a gene’s output.”

The approach employed by the Stanford team

Both the team at Stanford and the one at UCL drew inspiration from earlier works suggesting that polyadenylation processes are somewhat disrupted in neurodegenerative diseases and that this could be linked to the abnormal accumulation of TDP-43.

“For instance, when TDP-43 is lost, STMN2 RNA not only includes unwanted sections but also ends prematurely,” said Zeng. “Our primary objectives were to systematically map how many genes show altered polyadenylation when TDP-43 is lost and understand the molecular rules governing how TDP-43 binding controls where RNAs end. In addition, we set out to validate these changes in patient tissue and determine whether these changes affect protein behavior in disease-relevant ways.”

To perform their experiments, Zeng and his colleagues used a combination of techniques to map how the loss of TDP-43 in nuclei affects cell APA processes. First, they analyzed publicly available datasets collected from patients with ALS or FTD, specifically looking for hints of altered polyadenylation.

“We then used human stem cell-derived neurons where we could reduce TDP-43 levels to mimic disease, directly comparing normal and TDP-43-deficient neurons,” explained Zeng. “Because standard RNA sequencing isn’t designed to map polyadenylation sites precisely, we employed specialized 3′ end sequencing that maps exactly where each RNA molecule ends at single-nucleotide resolution.”

As part of their experiments, the researchers also knocked down the TDP-43 protein in neurons and used a technique known as 3′ end sequencing to map all polyadenylation sites across the genome. Using computational tools, they identified sites that were altered by the loss of TDP-43 and combined their observations with data collected by earlier studies.

“Importantly, we validated our findings in patient samples, confirming these polyadenylation changes occur in actual patients, not just models,” added Zeng. “For select genes like TMEM106B, a known FTLD-TDP risk gene, we performed functional studies showing that altered 3′ UTR lengths from polyadenylation changes affect protein production levels, demonstrating real biological consequences.”

The approach employed by the UCL team

For their paper, researchers at UCL studied the link between TDP-43 loss and APA processes using similar methods to those employed by the team at Stanford. First, they developed a new bioinformatic framework that allowed them to identify various APA sites.

They then examined pluripotent stem cell-derived neurons in which TDP-43 was depleted, looking for APA alterations in these cells. This allowed them to pin-point APA sites around which TDP-43 binding occurred and shed light on how the protein regulates the selection of these sites.

Similarly to the team at Stanford, these researchers also set out to investigate whether the APA changes were also evident in tissue extracted from individuals with ALS or FTD post-mortem. They also used techniques known as RNA-sequencing, SLAM-sequencing and ribosome profiling to shed further light on the effects of TDP-43 on specific aspects of APA.

Impact of TDP-43 loss on alternative polyadenylation

The two studies concurrently carried out by the research team at UCL and by Zeng and his colleagues at Stanford offer important new insight into the molecular underpinnings of both ALS and FTD. Specifically, the researchers showed that the loss of TDP-43 in nuclei causes polyadenylation defects in hundreds of genes.

“We uncovered an entirely new dimension of RNA misprocessing in ALS and FTD,” said Zeng. “These changes were found to occur in patients, establishing polyadenylation dysregulation as a bona fide disease feature. TDP-43 binding strength and position determine its effect, with TDP-43 acting like a guard blocking inappropriate ending sites that get used when it’s gone.”

The researchers also showed that the altered polyadenylation of the gene TMEM106B following TDP-43 loss impaired the production of proteins. Notably, variations in this gene were previously linked to a greater risk of developing FTD.

“Importantly, three independent labs published similar findings simultaneously using different approaches, including the team at UCL and another research group at UC Irvine,” said Zeng. “We now have a more complete picture of TDP-43 dysfunction: both splicing and polyadenylation defects affecting hundreds of genes critical for neuron survival. These polyadenylation changes could help detect TDP-43 pathology, track disease progression, and measure therapeutic response, addressing a key field need.”

Therapeutic implications and future research directions

The recent work by these independent research teams could potentially inform the development of future treatments for ALS, FTD and potentially other neurodegenerative diseases. While translating their findings into therapeutic strategies could take time, their papers offer a comprehensive map that could guide further studies focusing on how TDP-43 loss contributes to neurodegeneration.

“As TDP-43 pathology occurs across ALS, FTD, certain Alzheimer’s forms, and other conditions, understanding polyadenylation dysregulation may have broad implications across this spectrum of diseases,” said Zeng. “We are pursuing several research directions that will allow us to move from discovery to patient impact.

“First, we must distinguish drivers from passengers. Not all hundreds of polyadenylation changes necessarily contribute to disease, so we need to determine which drives neurodegeneration by testing whether correcting specific events improves neuron survival and identifying which appear earliest in disease progression.”

In their next studies, the researchers are planning to also explore the impact of TDP-43 loss on different types of cells and across varying neurodegenerative diseases. For instance, they could investigate whether motor neurons exhibit different alterations than cortical neurons, which could ultimately be linked to the distinct symptoms of ALS, FTD and some types of Alzheimer’s disease.

“As part of our next studies, we will also try to determine if these changes track disease progression or measure therapeutic response. This work is already underway,” said Zeng.

The development of pharmaceutical drugs aimed at preventing or reversing the effects of the APA alterations uncovered by the researchers will take some time. Nonetheless, upcoming studies could pin-point genes and pathways that are most affected by TDP-43 loss, which could be promising therapeutic targets.

“Our mechanistic insights into how TDP-43 controls polyadenylation may also inform strategies to compensate for its loss,” added Zeng. “The overarching goal is to use this more complete understanding of TDP-43 dysfunction to develop tools that help patients.”

Grant funding disruptions affected about one in 30 trials, according to a research letter published online Nov. 17 in JAMA Internal Medicine.

Vishal R. Patel, M.D., M.P.H., from Harvard Medical School in Boston, and colleagues identified all National Institutes of Health (NIH)-funded interventional clinical trials supported by active grants as of Feb. 28, 2025, and examined grants terminated since this date.

There were 11,008 clinical trials funded by NIH grants between Feb. 28, 2025, and Aug. 15, 2025, of which 383 (3.5%) subsequently lost grant funding. The researchers found that of the trials affected by terminated funding, the status at the time of termination included completed, recruiting, not yet recruiting, active and not recruiting, and enrolling by invitation (36.1%, 34.5%, 13.7%, 11.1%, and 3.4%, respectively). Compared with trials with retained funding, trials affected by terminated funding had higher median anticipated enrollment (105 versus 72, respectively).

A total of 74,311 individuals had been enrolled in trials classified as active and not recruiting at the time of funding termination, in which participants may have been receiving interventions. Terminated funding disproportionately affected trials conducted outside the United States compared with U.S.-based trials (5.8% versus 3.4%). Trials affected by terminated grants differed by primary condition, from 14.4% to 2.2% for infectious disease trials and neurologic and reproductive health trials, respectively.

“Because trials require sustained financial support to ensure operations and participant safety, unanticipated funding disruptions raise concerns about avoidable waste, data quality, and compromised ethical obligations to participants,” the authors write.

One author disclosed ties to the publishing industry.

A monthly injection has helped 90% of severe asthma patients reduce daily steroid tablets, which are associated with long-term side effects. More than half of the participants who had received the injection were able to stop their daily steroid tablets entirely, without any impact on their symptoms.

The clinical trial led by a King’s College London academic followed patients who had been injected with tezepelumab every four weeks for a year. Tezepelumab is a type of antibody which targets parts of the immune system, reducing lung inflammation.

Treatment with tezepelumab was also shown to significantly improve asthma symptoms, lung function, and overall quality of life. During the study, two-thirds of patients stopped having any asthma attacks. These improvements were seen as early as two weeks into treatment and lasted for the duration of the study.

Scientists are trying to identify alternative treatments for managing severe asthma, as long-term daily steroid use can lead to serious health problems, including osteoporosis, diabetes, and increased vulnerability to infections.

The WAYFINDER study, published in The Lancet Respiratory Medicine today, is among long-standing research into severe asthma at King’s College London. Last year, another team at King’s discovered that another antibody, benralizamab, could be injected during some asthma and COPD attacks to reduce the need for further treatment. The latest discovery could help people manage their asthma long term.

Participants in the trial had a diagnosis of severe asthma and were recruited from 68 clinical centers across 11 countries. They received tezepelumab every four weeks and completed questionnaires on their asthma symptoms and medication at 28 and 52 weeks.

Professor David Jackson, Respiratory Medicine expert at King’s College London, and Clinical Lead of the asthma services across Guy’s and Royal Brompton Hospitals, Guy’s and St Thomas’ NHS Foundation Trust, said, “The WAYFINDER study is an important step forward for patients with the most severe form of asthma who require daily oral steroids in order to achieve reasonable disease control.

“In this International, multicenter clinical trial of more than 300 patients, the NICE-approved asthma treatment tezepelumab, a biologic therapy that targets asthma-related inflammation but without all the side effects of steroids, was capable of allowing the vast majority of patients to wean their steroids down to a low dose with over half able to stop their steroids altogether.

“As tezepelumab also suppresses allergy-related symptoms and improves chronic rhinosinusitis as well, the results are particularly exciting for patients with severe asthma who suffer with both upper and lower airway symptoms.”

Dr. Samantha Walker, Director of Research & Innovation at Asthma + Lung UK, said, “This study is a promising sign that tezepelumab injections support certain people with severe asthma to reduce or stop taking steroid tablets, which can have serious unwanted health consequences. Tezepelumab, an injectable biologic, significantly improves asthma symptoms, lung function and overall quality of life for participants.

“This is an incredibly encouraging development for the future of asthma care that could transform the lives of people with severe asthma. It’s vital that research into new types of treatment continues, but we know current funding for lung health research is on life-support, despite lung conditions remaining the third biggest cause of death in the U.K. Studies like this show the positive impact that research can make on providing potentially life-changing treatment for people with asthma and other lung conditions.”

The findings of the WAYFINDER study will be presented at the British Thoracic Society Winter Meeting (BTS 2025) on Thursday 27 November 2025.