The STEP UP and STEP UP T2D clinical trials are the first to investigate whether increasing the dose of semaglutide from the currently approved dose of 2·4 mg to 7·2 mg is safe and leads to additional weight reduction. Trial participants were randomized to receive either the higher 7·2 mg dose of semaglutide, the currently approved 2.4 mg dose, or placebo over 72 weeks. All participants — regardless of treatment group — received lifestyle interventions such as dietary counseling and increased physical activity recommendations.

In adults without diabetes, a 7·2 mg dose of semaglutide led to an average weight loss of nearly 19%, surpassing the 16% loss seen with 2·4 mg and 4% with placebo. Nearly half of the participants on the higher dose lost 20% or more of their body weight, with about one-third losing at least 25%. Participants also experienced improvements in waist circumference, blood pressure, blood sugar, and cholesterol levels, all key factors in reducing obesity-related health risks. Similarly, in adults with obesity and T2D, the 7·2 mg dose resulted in an average 13% weight loss compared to 10% with 2.4 mg and 3.9% with placebo, along with significant reductions in blood sugar levels and waist size.

Both trials reported that the higher dose of semaglutide was safe and generally well tolerated. Gastrointestinal side effects like nausea and diarrhea, and some sensory symptoms like tingling, were the most common. However, most side effects were manageable, resolved over time, and did not lead to participants dropping out of the trial. No increase in serious adverse events or severe hypoglycemia was observed with the higher dose.

By delivering greater weight reduction and metabolic benefits while maintaining a favorable safety profile, the authors say this higher dose could help more people reach their health goals and reduce the burden of obesity-related complications worldwide. However, they highlight that further research is needed to fully understand the long-term benefits and risks.

There are two forms of vitamin D supplements available: vitamin D2 and vitamin D3. Researchers have found that taking vitamin D2 supplements can lead to a drop in the body’s concentration of vitamin D3, which is the form our bodies naturally produce from sunlight and use most effectively to raise overall vitamin D levels.

The study, published in Nutrition Reviews, analysed data from randomised controlled trials and found that vitamin D2 supplementation resulted in a reduction in vitamin D3 levels compared to those not taking a vitamin D2 supplement. In many of the studies, the vitamin D3 levels went lower than in the control group.

Emily Brown, PhD Research Fellow and Lead Researcher of the study from the University of Surrey’s Nutrition, Exercise, Chronobiology & Sleep Discipline, said:

“Vitamin D supplements are important, especially between October and March, when our bodies cannot make vitamin D from sunlight in the UK. However, we discovered that vitamin D2 supplements can actually decrease levels of vitamin D3 in the body, which is a previously unknown effect of taking these supplements. This study suggests that subject to personal considerations, vitamin D3 supplements may be more beneficial for most individuals over vitamin D2.”

Professor Cathie Martin, Group Leader at the John Innes Centre, said:

“This meta-analysis highlights the importance of ensuring plant-based vitamin D3 is accessible in the UK.”

This research supports a previous study published in Frontiers in Immunology, led by Professor Colin Smith from the University of Surrey, which suggests that vitamin D2 and D3 do not have identical roles in supporting immune function. Vitamin D3 has a modifying effect on the immune system that could fortify the body against viral and bacterial diseases.

Professor Colin Smith said:

“We have shown that vitamin D3, but not vitamin D2, appears to stimulate the type I interferon signalling system in the body — a key part of the immune system that provides a first line of defence against bacteria and viruses. Thus, a healthy vitamin D3 status may help prevent viruses and bacteria from gaining a foothold in the body.”

Further research into the different functionalities of vitamin D2 and D3 should be a priority in deciding whether vitamin D3 should be the first-line choice of vitamin D supplement, subject to individual requirements.

Professor Martin Warren, Chief Scientific Officer at the Quadram Institute, said:

“Vitamin D deficiency represents a significant public health concern, especially during the winter months with significant deficiency across the UK population. This collaborative research effort aligns well with the Quadram Institute’s mission to deliver healthier lives through food innovation to enhance the nutrient density of the food we eat. Tackling this with the most effective form of vitamin D supplementation or fortification is of the utmost importance to the health of the nation.”

MASLD occurs when fat builds up in the liver and is associated with one or more of five conditions: obesity, Type 2 diabetes, high blood pressure, high blood sugar and low HDL cholesterol, known as “good” cholesterol. These conditions are characterized as cardiometabolic risk factors because they affect the heart or metabolism.

MASLD can lead to serious illness, such as advanced liver, heart and kidney disease, but little research has been done to examine if certain cardiometabolic risk factors for those with MASLD are more associated with death than others.

The deadliest cardiometabolic risk factors

Now, a new study from Keck Medicine of USC published in Clinical Gastroenterology and Hepatology reveals that three of the cardiometabolic risk factors carry the greatest risk of death for those with MASLD: high blood pressure, pre-diabetes or Type 2 diabetes, and low HDL, which raise the risk of death by 40%, 25% and 15%, respectively.

These results were independent of how many or which combination of cardiometabolic risk factors patients had, and held steady despite individuals’ gender, sex, race or ethnicity.

“MASLD is a complicated disease, and this study sheds new light on where doctors may want to focus their efforts when treating patients,” said Norah A. Terrault, MD, a hepatologist with Keck Medicine and a senior author of the study. “Knowing which aspects of MASLD might lead to poorer outcomes can help us offer patients the best possible care.”

Researchers were especially surprised to discover that high blood pressure was associated with a higher chance of death than diabetes, said Matthew Dukewich, MD, PharmD, MS, a USC transplant hepatology fellow and lead author of the study. “Until now, it was commonly thought that diabetes was the most pressing health problem for MASLD patients, which is a key insight.”

The study also found that obesity, the most common cardiometabolic risk factor of MASLD, can substantially raise the risk of mortality depending on a patient’s body mass index (BMI), which is a formula used to estimate body fat percentage based on an individual’s height and weight. The higher a patient’s BMI, the higher the association with death.

Additionally, the research adds to the growing body of research that patients with more cardiometabolic risk factors have poorer outcomes. The study found that the risk of death in MASLD patients increased by 15% for each additional cardiometabolic risk factor present.

How the study was conducted

Researchers used data from the National Health and Nutrition Examination Survey (NHANES), which collected health information about children and adults in the United States from 1988-2018, the most current year for which data was available for their study. Out of 134,515 participants 20 years or older, some 21,000 patients qualified as having MASLD.

The study authors tracked all-cause mortality rates by individual cardiometabolic risk factors to reach their conclusions.

Looking ahead, the study authors hope to conduct further studies examining patients’ genetic background, dietary habits and alcohol use in relation to MASLD outcomes to provide more comprehensive risk profiles. “The more we can understand about the drivers of the disease, the more we can identify those most in need of interventions and prioritize our resources for enhanced outcomes,” said Terrault.

Liyun Yuan, MD, a transplant hepatologist with Keck Medicine, is also a study author.

Every year, nearly two million people worldwide are diagnosed with colorectal cancer. Between 20 and 40 percent develop metastases, which makes the disease both more difficult to treat and more deadly.

Previous observational studies have suggested that aspirin may reduce the risk of certain cancers and possibly also the risk of recurrence after surgery in patients with colorectal cancer harboring mutations in genes within the PIK3 signaling pathway.

These genes regulate key cellular processes such as growth and division. When mutated, these processes can become dysregulated, leading to uncontrolled cell proliferation and cancer development. However, prior findings have been inconsistent and no randomized clinical trials had previously confirmed the association. To address this gap, the ALASCCA trial was initiated and has now been published in The New England Journal of Medicine.

The current study included more than 3,500 patients with colon and rectal cancer from 33 hospitals in Sweden, Norway, Denmark, and Finland. Patients whose tumors showed a specific genetic mutation in the PIK3 signaling pathway — a mutation found in approximately 40 percent of patients — were randomized to receive either 160 mg of aspirin daily or a placebo for three years after surgery.

For patients with the genetic mutation in PIK3, the risk of recurrence was reduced by 55 percent in those who received aspirin compared with the placebo group.

“Aspirin is being tested here in a completely new context as a precision medicine treatment. This is a clear example of how we can use genetic information to personalize treatment and at the same time save both resources and suffering,” says first author Anna Martling, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet, and senior consultant surgeon at Karolinska University Hospital.

So how does aspirin reduce the risk of recurrence of colon and rectal cancer? The researchers believe that the effect is likely due to aspirin acting through several parallel mechanisms – it reduces inflammation, inhibits platelet function and tumor growth. This combination makes the environment less favorable for cancer.

“Although we do not yet fully understand all the molecular links, the findings strongly support the biological rationale and suggest that the treatment may be particularly effective in genetically defined subgroups of patients,” says Anna Martling.

The researchers believe that the results could have global significance and influence treatment guidelines for colon and rectal cancer worldwide. Anna Martling sees the fact that the drug is well established as a major advantage.

“Aspirin is a drug that is readily available globally and extremely inexpensive compared to many modern cancer drugs, which is very positive,” says Anna Martling.

The study was funded in part by the Swedish Research Council and the Swedish Cancer Society. The researchers state that there are no conflicts of interest.

Facts: What is aspirin?

Aspirin is a medicine that contains acetylsalicylic acid, a substance that relieves pain, fever, and inflammation. It belongs to the group of NSAIDs (non-steroidal anti-inflammatory drugs). The effect usually occurs within 30 minutes. In low doses, it is also used to prevent blood clots.

Common side effects include stomach problems and increased bleeding tendency. People with stomach ulcers, bleeding disorders, or asthma should avoid aspirin. Aspirin is available over the counter in higher doses, but should be used with caution, especially in combination with other blood-thinning agents or alcohol.

Gravitational waves—ripples in spacetime predicted by Einstein—have been observed at high frequencies by ground-based interferometers such as LIGO and Virgo, and at ultra-low frequencies by pulsar timing arrays. However, the mid-band range has remained a scientific blind spot.  

Developed by researchers at the Universities of Birmingham and Sussex, the new detector concept uses cutting-edge optical cavity and atomic clock technologies to sense gravitational waves in the elusive milli-Hertz frequency band (10⁻⁵ – 1 Hz).  

Publishing their proposal today (Oct. 3) in Classical and Quantum Gravity, the scientist reveal a detector that uses advances in optical resonator technology, originally developed for optical atomic clocks, to measure tiny phase shifts in laser light caused by passing gravitational waves. Unlike large-scale interferometers, these detectors are compact, relatively immune to seismic and Newtonian noise.  

Co-author Dr Vera Guarrera, from the University of Birmingham, commented: “By using technology matured in the context of optical atomic clocks, we can extend the reach of gravitational wave detection into a completely new frequency range with instruments that fit on a laboratory table. This opens the exciting possibility of building a global network of such detectors and searching for signals that would otherwise remain hidden for at least another decade.” 

The milli-Hertz frequency band – sometimes called the ‘mid-band’ – is expected to host signals from a variety of astrophysical and cosmological sources, including compact binaries of white dwarfs and black hole mergers. Ambitious space missions such as LISA also target this frequency band, but they are scheduled for launch in the 2030s. The proposed optical resonator detectors could begin exploring this territory now. 

Co-author Professor Xavier Calmet, from the University of Sussex, commented: “This detector allows us to test astrophysical models of binary systems in our galaxy, explore the mergers of massive black holes, and even search for stochastic backgrounds from the early universe. With this method, we have the tools to start probing these signals from the ground, opening the path for future space missions.” 

While future space-based missions like LISA will offer superior sensitivity, their operation is over a decade away. The proposed optical cavity detectors provide an immediate, cost-effective means to explore the milli-Hz band.  

The study also suggests that integrating these detectors with existing clock networks could extend gravitational wave detection to even lower frequencies, complementing high-frequency observatories like LIGO. 

Each unit consists of two orthogonal ultrastable optical cavities and an atomic frequency reference, enabling multi-channel detection of gravitational wave signals. This configuration not only enhances sensitivity but also allows for the identification of wave polarisation and source direction.