Investigators have developed an artificial intelligence-assisted diagnostic system that can estimate bone mineral density in both the lumbar spine and the femur of the upper leg, based on X-ray images. The advance is described in a study published in the Journal of Orthopaedic Research.
A total of 1454 X-ray images were analysed using the scientists’ system. Performance rates for the lumbar and femur of patients with bone density loss, or osteopenia, were 86.4% and 84.1%, respectively, in terms of sensitivity. The respective specificities were 80.4% and 76.3%. (Sensitivity reflected the ability of the test to correctly identify people with osteopenia, whereas specificity reflected its ability to correctly identify those without osteopenia). The test also had high sensitivity and specificity for categorising patients with and without osteoporosis.
“Bone mineral density measurement is essential for screening and diagnosing osteoporosis, but limited access to diagnostic equipment means that millions of people worldwide may remain undiagnosed,” said corresponding author Toru Moro, MD, PhD, of the University of Tokyo. “This AI system has the potential to transform routine clinical X-rays into a powerful tool for opportunistic screening, enabling earlier, broader, and more efficient detection of osteoporosis.”
Dementia poses a major health challenge with no safe, affordable treatments to slow its progression. Researchers at Lawson Research Institute (Lawson), the research arm of St. Joseph’s Health Care London, are investigating whether Ambroxol – a cough medicine used safely for decades in Europe – can slow dementia in people with Parkinson’s disease.
Published in JAMA Neurology, this 12-month clinical trial involving 55 participants with Parkinson’s disease dementia (PDD) monitored memory, psychiatric symptoms and GFAP, a blood marker linked to brain damage.
Parkinson’s disease dementia causes memory loss, confusion, hallucinations and mood changes. About half of those diagnosed with Parkinson’s develop dementia within 10 years, profoundly affecting patients, families and the health care system.
Led by Cognitive Neurologist Dr Stephen Pasternak, the study gave one group daily Ambroxol while the other group received a placebo.
“Our goal was to change the course of Parkinson’s dementia,” says Pasternak. “This early trial offers hope and provides a strong foundation for larger studies.”
Key findings from the clinical trial include:
Ambroxol was safe, well-tolerated and reached therapeutic levels in the brain.
Psychiatric symptoms worsened in the placebo group but remained stable in those taking Ambroxol.
Participants with high-risk GBA1 gene variants showed improved cognitive performance on Ambroxol.
A marker of brain cell damage (GFAP) increased in the placebo group but stayed stable with Ambroxol, suggesting potential brain protection.
Although Ambroxol is approved in Europe for treating respiratory conditions and has a long-standing safety record – including use at high doses and during pregnancy – it is not approved for any use in Canada or the U.S.
“Current therapies for Parkinson’s disease and dementia address symptoms but do not stop the underlying disease,” explains Pasternak. “These findings suggest Ambroxol may protect brain function, especially in those genetically at risk. It offers a promising new treatment avenue where few currently exist.”
An old drug with new possibilities
Ambroxol supports a key enzyme called glucocerebrosidase (GCase), which is produced by the GBA1 gene. In people with Parkinson’s disease, GCase levels are often low. When this enzyme doesn’t work properly, waste builds up in brain cells, leading to damage.
Pasternak learned about Ambroxol during a fellowship at The Hospital for Sick Children (SickKids) in Toronto, where it was identified as a treatment for Gaucher disease – a rare genetic disorder in children caused by a deficiency of GCase. He is now applying that research to explore whether boosting GCase with Ambroxol could help protect the brain in Parkinson’s related diseases.
“This research is vital because Parkinson’s dementia profoundly affects patients and families,” says Pasternak. “If a drug like Ambroxol can help, it could offer real hope and improve lives.”
Funded by the Weston Family Foundation, this study is an important step toward developing new treatments for Parkinson’s disease and other cognitive disorders, including dementia with Lewy bodies. Pasternak and his team plan to start a follow-up clinical trial focused specifically on cognition later this year.
During South Africa’s COVID-19 hard lockdown, Dr Sandile Cele became the first to successfully grow the beta variant of SARS-CoV-2 in the lab. PHOTO: Rosetta Msimango/Spotlight
In a Durban laboratory in 2020, there was dancing and scientists jumping with joy when Dr Sandile Cele realised they had finally successfully “grown” the SARS-CoV-2 Beta variant. It was the holiday season and Cele and a few colleagues had sacrificed their Christmas to continue research at an otherwise deserted laboratory.
The Beta variant (501Y.V2) was first detected in the Eastern Cape in October 2020 and was announced to the public on 18 December that year.
“It was December 2020 and Tulio [Professor Tulio de Oliveira] had just flagged the beta variant and we had been struggling trying to grow it, really struggling for about two weeks,” says Cele. “But then as a scientist, you have to think outside the box and eventually it [the virus] did catch on. I was with Professor Alex Sigal that day in the laboratory. We were so excited. There was a lot of dancing in the lab, jumping up and down…”
The 35-year-old’s work on the Beta and Omicron variants helped propel South Africa to the forefront of COVID-19 research. Cele is the scientist credited with growing both Beta and Omicron in record time as the world reeled under lockdown pressure. Last year, he was awarded a special ministerial Batho Pele excellence award for his contribution to COVID-19 research in South Africa.
The moment of greatest fulfilment
Speaking to Spotlight, Cele says growing the beta variant was the moment of greatest fulfilment in his career so far.
“It was just a crazy, crazy moment. Like, you know when you are with your superior, usually you meet on a basis of respect. I mean, you talk seriously. They ask a question, you answer, and so on. But [at] that moment, all that got thrown out the window. We were celebrating. So yes, it was really special.”
At the time, they were leaping with joy inside PPE (personal protective equipment), including specialised masks, double gloves, plastic sleeves, and boots. Cele points out that due to all the safety measures in place, infection risk was smaller in their lab than at an average mall.
He was working inside a state-of-the-art biosafety level 3 (BSL-3) laboratory at the Africa Health Research Institute (AHRI). The laboratory is on the third floor of the University of KwaZulu-Natal’s medicine building. In the same eight-storey glass and face brick building, on the first floor, de Oliveira had been studying virus samples for genetic clues at KRISP, the KwaZulu-Natal Research and Innovation Sequencing Platform, from where the discovery of Beta and Omicron was first announced.
How he did it – growing the beta variant
Cele explains that viruses are isolated or “outgrown” by infecting cells in the laboratory, using swab samples from infected individuals.
“Growing a virus simply means isolating it from an infected host (humans) and making more of it in the lab for research purposes,” Cele explains. “You cannot study a virus within an infected person, especially a new virus. You need to have it in the lab for identification and clarification. Usually, you get small quantities from an infected person, thus you have to expand or grow – or make more of it – for research.”
Photo by Shvets Production on Pexels
However, the beta variant had not responded like previous SARS-CoV-2 variants. At the time, Cele found a creative solution using both human and monkey cell lines. First, he infected human cell lines with the beta variant, incubating the assay for four days. Then he used the infected human cell lines to infect monkey cell lines, which successfully lead to production of the virus.
Their moment of triumph arrived when they noticed the monkey cell lines starting to die, meaning that the virus was growing. The isolated virus could then be used in the laboratory to run experiments, like testing vaccine efficacy.
“Looking at the cells under the microscope, you can see them starting to die,” he says. “That they’re not happy. That they have been infected, which then obviously needed to be confirmed.”
While Cele’s Durban mentors – de Oliveira and Sigal – kept the public abreast of research developments, the young scientist kept his head down, pouring over his microscopes. “The world was going crazy, everything was crazy, but I had work to do,” he says.
‘a rising star’
During the interview, Cele readily shares anecdotes and laughs often.
From Ndwedwe, a rural area forty kilometres north of Durban, Cele joined Sigal’s laboratory team at the AHRI in 2014, where he studied HIV drug resistance and later COVID-19. His PhD obtained from UKZN in 2021, focused specifically on understanding the beta variant and its escape from antibodies.
“Actually, Professor Alex Sigal really took a chance on me,” he says. “Because on that post for a laboratory technologist, they stipulated that they wanted someone with three years experience. And I had only been doing my internship [at the Technology Innovation Agency] for eight months.”
But Sigal’s faith paid off, and he subsequently praised Cele in national press interviews on COVID-19. “Sandile is a rising star who spent all his holidays in a laboratory,” Sigal told journalists in January 2021.
Last year, the Bill and Melinda Gates Foundation invited Cele to present his findings at the Grand Challenges Annual Meeting in Brussels. This was his first time abroad. “It was my first time traveling outside South Africa and my first time talking in front of so many people. I presented my go-to talk – based on a paper I did on COVID-infection and HIV – and it went well,” he says.
Earlier this year, Cele was named one of Mail & Guardian’s 200 trailblazing young South Africans in the technology and innovation category. At the time, he could not attend the gala event as he was at the University of Nairobi in Kenya for training relating to a project involving HIV research for the Aurum Institute. Cele started a new job at the Aurum Institute in Johannesburg in March.
Over Zoom, Cele is speaking from his new home in Johannesburg. He is wearing a fluffy blue robe over his clothes, laughing as he says how cold Johannesburg is coming from Durban.
A sudden death
In Ndwedwe, Cele was one of ten boys born to his father, who was away from home often for work. Describing his mother as “a busy lady”, Cele says she was the one who shaped his young everyday life. Growing up in a mud hut without electricity and running water, he recalls how his mother would get up early every morning to prepare vetkoek, which she sold at a local school, and to boil water so her children could have a bath before leaving for school.
In the afternoons, he would look after his father’s goats and play soccer. He says that as a child he preferred herding goats to cows, as goats grazed for only about five hours, whereas cows took all day to eat their fill. From Grade 9 on, he attended school in Durban, at Overport Secondary School.
A childhood memory that inspired him? “Before my mother died, she sat us down and said one day I will be gone and I want you to know there are no shortcuts in life. Work hard and look after one another and you will be okay.”
His mother’s death was sudden, following complications from minor surgery.
“Like, I came back from school on a Friday only to find my father wasn’t around and had left a note… On the Saturday morning, I found out my mother had passed. And I think she went for, I don’t know, an operation or something. But as a kid, I guess they didn’t tell us because they thought it was something minor; that she would get operated [on], then go back home. I’m not really sure what happened. So, yes, it was a sudden death.”
The year after his mother died, Cele’s matric marks suffered. He says his final grade 12 marks had been 48% for maths, 53% for physics, and 66% for biology.
“I wasn’t really studying, I couldn’t really concentrate,” he says. “There was a lot going on when I was doing my matric. My mother passing away… and also the move from a rural school to the city where we were taught in English, everything in English.”
Cele came to study biology quite at random. He applied to study at UKZN only in October of his matric year – with admissions to most of the university’s courses having closed the previous month. He picked one of the last remaining options, which had been biology.
Soon, the young student started excelling. Cele obtained his BSc Biomedical Sciences degree with a Dean’s commendation and his Honours in Medical Microbiology, summa cum laude. He completed his Masters in Biochemistry with an upper-class pass.
To the Mail and Guardian, he shared advice he would give to his younger self: “Do not be afraid, you are a force to be reckoned with.”
Cele’s driving passion is to advance public healthcare, which he will continue to do at the Aurum Institute – an organisation that amongst others does research into Africa’s tuberculosis and HIV response. Cele has a ten-year-old son who lives in Durban.
Note:The Bill and Melinda Gates Foundation is mentioned in this article. Spotlight receives funding from the foundation, but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
Detail from Small’s reprocessed cryo-EM data zooming in on an unoccupied area of the SARS-CoV-2 NiRAN domain. (Courtesy of Campbell lab)
The COVID pandemic illustrated how urgently we need antiviral medications capable of treating coronavirus infections. To aid this effort, researchers quickly homed in on part of SARS-Cov-2’s molecular structure known as the NiRAN domain – an enzyme region essential to viral replication that’s common to many coronaviruses. A drug targeting the NiRAN domain would likely work broadly to shut down a range of these pathogens, potentially treating known diseases like COVID as well as helping to head off future pandemics caused by related viruses.
In 2022, scientists (Yan et. al.) published a structural model describing exactly how this domain works. It should have been a tremendous boon for drug developers.
But the model was wrong.
“Their work contains critical errors,” says Gabriel Small, a graduate fellow in the laboratories of Seth A. Darst and Elizabeth Campbell at Rockefeller. “The data does not support their conclusions.”
Now, in a new study published in Cell, Small and colleagues demonstrate exactly why scientists still don’t know how the NiRAN domain works. The findings could have sweeping implications for drug developers already working to design antivirals based on flawed assumptions, and underscore the importance of rigorous validation.
“It is absolutely important that structures be accurate for medicinal chemistry, especially when we’re talking about a critical target for antivirals that is the subject of such intense interest in industry,” says Campbell, head of the Laboratory of Molecular Pathogenesis. “We hope that our work will prevent developers from futilely trying to optimise a drug around an incorrect structure.”
A promising lead
By the time the original paper was published in Cell, the Campbell and Darst labs were already quite familiar with the NiRAN domain and its importance as a therapeutic target. Both laboratories study gene expression in pathogens, and their work on SARS-CoV-2 focuses in part on characterizing the molecular interactions that coordinate viral replication.
The NiRAN domain is essential for helping SARS-CoV-2 and other coronaviruses cap their RNA, a step that allows these viruses to replicate and survive. In one version of this process, the NiRAN domain uses a molecule called GDP to attach a protective cap to the beginning of the virus’s RNA. Small previously described that process in detail, and its structure is considered solved. But the NiRAN domain can also use a related molecule, GTP, to form a protective cap. Determined to develop antivirals that comprehensively shut down the NiRAN domain, scientists were keen to discover the particulars of the latter GTP-related mechanism.
In the 2022 paper, researchers described a chain of chemical steps, beginning with a water molecule breaking a bond to release the RNA’s 5′ phosphate end. That end then attaches to the beta-phosphate end of the GTP molecule, which removes another phosphate and, with the help of a magnesium ion, transfers the remaining portion of the GTP molecule to the RNA, forming a protective cap that allows the virus to replicate and thrive.
The team’s evidence? A cryo-electron microscopy image that showed the process caught in action. To freeze this catalytic intermediate, the team used a GTP mimic called GMPPNP.
Small read the paper with interest. “As soon as they published, I went to download their data,” he says. It wasn’t there. This raised a red flag—data is generally available upon release of a structural biology paper. Months later, however, when Small was finally able to access the data, he began to uncover significant flaws. “I tried to make a figure using their data, and realized that there were serious issues,” he says. Small brought his concerns to Campbell and Darst.
They agreed. “Something was clearly wrong,” Campbell says. “But we decided to give the other team the benefit of the doubt, and reprocess all of their data ourselves.”
An uphill battle
It was painstaking work, with Small leading the charge. Working frame by frame, he compared the published atomic model to the actual cryo-EM map and found something striking: the key molecules that Yan and colleagues claimed to have seen, specifically, the GTP mimic GMPPNP and a magnesium ion in the NiRAN domain’s active site, simply were not there.
Not only was there no supporting image data, but the placement of these molecules in the original model also violated basic rules of chemistry, causing severe atomic clashes and unrealistic charge interactions. Small ran additional tests, but even advanced methods designed to pick out rare particles turned up empty. He could find no evidence to support the model previously produced by Yan and colleagues.
Once the Rockefeller researchers validated their results, they submitted their findings to Cell. “It was very important that we publish our corrective manuscript in the same journal that published the original model,” Campbell says, noting that corrections to high-profile papers are often overlooked when published in lower tier journals.
Otherwise, this confusion in the field could cause problems that reach far beyond the lab bench, Campbell adds – a costly reminder that rigorous basic biomedical research is not just academic, but essential to real-world progress. “Companies keep their cards close to their chests, but we know that several industry groups are studying this,” she says. “Efforts based on a flawed structural model could result in years of wasted time and resources.”
A blood-test analysis developed at Stanford Medicine can determine the “biological ages” of 11 separate organ systems in individuals’ bodies and predict the health consequences.
Beside our chronological age, research has shown that we also have what’s called a “biological age,” a cryptic but more accurate measure of our physiological condition and likelihood of developing aging-associated disorders from heart trouble to Alzheimer’s disease.
How old someone’s internal organs are is a challenge to determine compared to looking at wrinkles and greying hair. Internal organs are ageing at different speeds, too, according to a new study by Stanford Medicine investigators.
“We’ve developed a blood-based indicator of the age of your organs,” said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences and director of the Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute. “With this indicator, we can assess the age of an organ today and predict the odds of your getting a disease associated with that organ 10 years later.”
They can even predict who is most likely to die from medical conditions associated with one or more of the 11 separate organ systems the researchers looked at: brain, muscle, heart, lung, arteries, liver, kidneys, pancreas, immune system, intestine and fat.
The brain is the gatekeeper of longevity. If you’ve got an old brain, you have an increased likelihood of mortality. If you’ve got a young brain, you’re probably going to live longer.”
The biological age of one organ, the brain, plays an outsized role in determining how long you have left to live, Wyss-Coray said.
“The brain is the gatekeeper of longevity,” he said. “If you’ve got an old brain, you have an increased likelihood of mortality. If you’ve got a young brain, you’re probably going to live longer.”
Wyss-Coray is the senior author of the study, published online July 9 in Nature Medicine. The lead author is Hamilton Oh, PhD, a former graduate student in Wyss-Coray’s group.
Eleven organ systems, 3000 proteins, 45 000 people
The scientists used 44 498 randomly selected participants, ages 40 to 70, who were drawn from the UK Biobank. This ongoing effort has collected multiple blood samples and updated medical reports from some 600 000 individuals over several years. These participants were monitored for up to 17 years for changes in their health status.
Wyss-Coray’s team made use of an advanced commercially available laboratory technology that counted the amounts of nearly 3000 proteins in each participant’s blood. Some 15% of these proteins can be traced to single-organ origins, and many of the others to multiple-organ generation.
The researchers fed everybody’s blood-borne protein levels into a computer and determined the average levels of each of those organ-specific proteins in the blood of those people’s bodies, adjusted for age. From this, the scientists generated an algorithm that found how much the composite protein “signature” for each organ being assessed differed from the overall average for people of that age.
Based on the differences between individuals’ and age-adjusted average organ-assigned protein levels, the algorithm assigned a biological age to each of the 11 distinct organs or organ systems assessed for each subject. And it measured how far each organ’s multiprotein signature in any given individual deviated in either direction from the average for people of the same chronological age. These protein signatures served as proxies for individual organs’ relative biological condition. A greater than 1.5 standard deviation from the average put a person’s organ in the “extremely aged” or “extremely youthful” category.
One-third of the individuals in the study had at least one organ with a 1.5-or-greater standard deviation from the average, with the investigators designating any such organ as “extremely aged” or “extremely youthful.” One in four participants had multiple extremely aged or youthful organs.
For the brain, “extremely aged” translated to being among the 6% to 7% of study participants’ brains whose protein signatures fell at one end of the biological-age distribution. “Extremely youthful” brains fell into the 6% to 7% at the opposite end.
Health outcomes foretold
The algorithm also predicted people’s future health, organ by organ, based on their current organs’ biological age. Wyss-Coray and his colleagues checked for associations between extremely aged organs and any of 15 different disorders including Alzheimer’s and Parkinson’s diseases, chronic liver or kidney disease, Type 2 diabetes, two different heart conditions and two different lung diseases, rheumatoid arthritis and osteoarthritis, and more.
Risks for several of those diseases were affected by numerous different organs’ biological age. But the strongest associations were between an individual’s biologically aged organ and the chance that this individual would develop a disease associated with that organ. For example, having an extremely aged heart predicted higher risk of atrial fibrillation or heart failure, having aged lungs predicted heightened chronic obstructive pulmonary disease (COPD) risk, and having an old brain predicted higher risk for Alzheimer’s disease.
The association between having an extremely aged brain and developing Alzheimer’s disease was particularly powerful: 3.1 times that of a person with a normally aging brain. Meanwhile, having an extremely youthful brain was especially protective against Alzheimer’s – barely one-fourth that of a person with a normally aged brain.
In addition, Wyss-Coray said, brain age was the best single predictor of overall mortality. Having an extremely aged brain increased subjects’ risk of dying by 182% over a roughly 15-year period, while individuals with extremely youthful brains had an overall 40% reduction in their risk of dying over the same duration.
Predicting the disease, then preventing it
“This approach could lead to human experiments testing new longevity interventions for their effects on the biological ages of individual organs in individual people,” Wyss-Coray said.
Medical researchers may, for example, be able to use extreme brain age as a proxy for impending Alzheimer’s disease and intervene before the onset of outward symptoms, when there’s still time to arrest it, he said.
Careful collection of lifestyle, diet and prescribed- or supplemental-substance intake in clinical trials, combined with organ-age assessments, could throw light on the medical value of those factors’ contributions to the aging of various organs, as well as on whether existing, approved drugs can restore organ youth before people develop a disease for which an organ’s advanced biological age puts them at high risk, Wyss-Coray added.
If commercialised, the test could be available in the next two to three years, Wyss-Coray said. “The cost will come down as we focus on fewer key organs, such as the brain, heart and immune system, to get more resolution and stronger links to specific diseases.”
Scientists have produced the first detailed characterisation of the changes that weight loss causes in human fat tissue by analysing hundreds of thousands of cells. They found a range of positive effects, including clearing out of damaged, ageing cells and increased metabolism of harmful fats.
The researchers say the findings help to better understand how weight loss leads to health improvements at a molecular level. In the future this could help to inform the development of therapies for diseases such as type 2 diabetes.
The study
The study, published in Nature, compared samples of fat tissue from healthy weight individuals with samples from people with severe obesity, meaning a BMI over 35, undergoing bariatric weight loss surgery.
The weight loss group had fat samples taken during surgery and more than five months after surgery, at which point they had lost an average of 25kg.
Lipid recycling
The researchers, who were from the Medical Research Council (MRC) Laboratory of Medical Sciences and Imperial College London, analysed gene expression in more than 170,000 cells that made up the fat tissue samples, from 70 people.
They unexpectedly found that weight loss triggers the breakdown and recycling of fats called lipids.
This recycling process could be responsible for burning energy and reversing the harmful build-up of lipids in other organs like the liver and pancreas.
The researchers say that further study will be needed to establish if lipid recycling is linked to the positive effects of weight loss on health, such as remission of type 2 diabetes.
Senescent cells
They also found that the weight loss cleared out senescent cells, which are ageing and damaged cells that accumulate in all tissues.
The senescent cells cause harm because they no longer function properly and release signals that lead to tissue inflammation and scarring.
Immune system
In contrast, the researchers found that weight loss did not improve the effects of obesity on certain aspects of the immune system.
They found that inflammatory immune cells, which infiltrated the fat of people with obesity, did not fully recover even after weight loss.
This type of inflammatory cell memory could be harmful in the long term if people regain weight.
Detailed map of what drives health benefits
Dr William Scott, from the MRC Laboratory of Medical Sciences and from Imperial College London, who led the study, said:
We’ve known for a long time that weight loss is one of the best ways to treat the complications of obesity, such as diabetes, but we haven’t fully understood why. This study provides a detailed map of what may actually be driving some of these health benefits at a tissue and cellular level.
Fat tissues have many underappreciated health impacts, including on blood sugar levels, body temperature, hormones that control appetite, and even reproductive health.
We hope that new information from studies like ours will start to pave the way for developing better treatments for diabetes and other health problems caused by excess body fat.
The largest review of ‘gold standard’ antidepressant withdrawal studies to date has identified the type and incidence of symptoms experienced by people discontinuing antidepressants, finding most people do not experience severe withdrawal.
In a systematic review and meta-analysis of previous randomised controlled trials relating to antidepressant withdrawal, a team of researchers led by Imperial College London and King’s College London concluded that, while participants who stopped antidepressants did experience an average of one more symptom than those who continued or were taking placebos, this was not enough to be judged as significant. The results are out now in JAMA Psychiatry.
The most common symptoms were dizziness, nausea, vertigo and nervousness. Importantly, depression was not a symptom of withdrawal from antidepressants, and was more likely to reflect illness recurrence.
Researchers at Imperial College London, King’s College London, UCL and UK collaborators say their study provides much needed, clearer guidance for clinicians, patients and policymakers.
Dr Sameer Jauhar, lead author, at Imperial College London, said: “Our work should reassure the public because we replicated other findings, from high-quality studies, and have highlighted the clinical symptoms to look out for. Despite previous concern about stopping antidepressants, our work finds that most people do not experience severe withdrawal, in terms of additional symptoms. Importantly, depression relapse was not linked to antidepressant withdrawal in these studies, suggesting that if this does occur, people will need to see their health professional to rule out a recurrence of their depressive illness.”
Clinical academics from around the UK worked collaboratively to conduct the largest and most rigorous analysis of randomised controlled trials in antidepressant withdrawal, examining data from 50 trials across multiple conditions. The data involved a total of 17,828 participants, with an average age of 44 years, of whom 70% were female. Two meta-analyses were conducted, one of the trials that used a standardised measure known as the Discontinuation Emergent Signs and Symptoms scale (DESS), and the other of the trials that used various other scales.
Across antidepressants, irrespective of type taken, the number of extra symptoms generally equated to one more symptom on the 43-symptom item scale. In placebo-controlled randomised controlled trials, the most common symptoms across antidepressants were dizziness (7.5% vs 1.8%), nausea (4.1% vs 1.5%), vertigo (2.7% vs 0.4%) and nervousness (3% vs 0.8%).
Experiencing just one symptom is below the 4 or more cutoff for clinically important discontinuation syndrome.
The nature and rates of different symptoms varied between antidepressants, and some symptoms were also seen with placebo. This helped to clarify which symptoms were likely to be illness recurring, such as the participant relapsing into depression.
The data involved different types of antidepressants, including the serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine and duloxetine; the selective serotonin reuptake inhibitors escitalopram, sertraline and paroxetine; agomelatine, which is a melatonin receptor agonist and selective serotonin receptor antagonist; and vortioxetine, which inhibits the reuptake of serotonin as well as partial agonist and antagonist effects on various serotonin receptors.
The most symptoms were seen with discontinuance of venlafaxine, where approximately 20% of people suffered from dizziness, compared to 1.8% taking placebo. With vortioxetine, fewer than one extra symptom was seen on the standardised discontinuation scale. No extra symptoms were seen with agomelatine.
Relapse of depression was not seen in those withdrawing from antidepressants, even in people with existing depression.
The review included studies with different discontinuation regimes, but in the majority of studies (44), people either discontinued abruptly or tapered over 1 week.
Michail Kalfas, of the Institute of Psychiatry, Psychology & Neuroscience at King’s College London, said: “While uncommon, our study highlights that there could be a sub-group of people who develop more severe withdrawal symptoms than the wider population of antidepressant users. Our focus must now turn to look at the pharmacological basis for this reaction, and ask whether it relates to the way they metabolise these drugs.”
In terms of study limitations, 38 of the trials followed people up for up to two weeks post-discontinuation (the time period one would expect most discontinuation symptoms to occur), so researchers say this limits long-term conclusions. However, they note that findings from the 2021 UCL-led ANTLER trial involving long-term antidepressant users – which was included in this review – suggested severe withdrawal is infrequent, even after prolonged use.
The study follows recent concerns about the effects of stopping antidepressants, as well as various guidance changes on their prescribing. This current meta-analysis helps resolve the debate by showing that withdrawal is a real and drug-specific phenomenon, though not an inevitable outcome.
Although postoperative complications, such as infections, can pose significant health risks to children after undergoing surgical procedures, timely detection following hospital discharge can prove challenging.
A new study from Northwestern University, along with other institutions, is the first to use consumer wearables to quickly and precisely predict postoperative complications in children and shows potential for facilitating faster treatment and care. The study appears in Science Advances.
“Today, consumer wearables are ubiquitous, with many of us relying on them to count our steps, measure our sleep and more,” said senior author Arun Jayaraman, professor at Northwestern University Feinberg School of Medicine and a scientist at Shirley Ryan AbilityLab. “Our study is the first to take this widely available technology and train the algorithm using new metrics that are more sensitive in detecting complications. Our results suggest great promise for better patient outcomes and have broad implications for paediatric health monitoring across various care settings.”
How the study worked
As part of the study, commercially available Fitbit devices were given to 103 children for 21 days immediately after appendectomy, the most common surgery in children, which results in complications up to 38% of the time. Rather than just using the metrics automatically captured by the Fitbit to identify signs of complications (eg, low activity, high heart rate, etc.), Shirley Ryan AbilityLab scientists trained the algorithm using new metrics related to the circadian rhythms of a child’s activity and heart rate patterns.
In the process, they found such metrics were more sensitive to picking up complications than the traditional metrics. In fact, in analysing the data, scientists were able to retrospectively predict postoperative complications up to three days before formal diagnosis with 91% sensitivity and 74% specificity.
“Historically, we have been reliant upon subjective reporting from children – who often have greater difficulty articulating their symptoms – and their caregivers following hospital discharge. As a result, complications are not always caught right away,” said study author Dr Fizan Abdullah, who at the time of the study was an attending physician of paediatric surgery at Ann & Robert H. Lurie Children’s Hospital of Chicago and a professor at Feinberg. “By using widely available wearables, coupled with this novel algorithm, we have an opportunity to change the paradigm of postoperative monitoring and care – and improve outcomes for kids in the process.”
What’s next?
This research is part of a four-year National Institutes of Health-funded project. As a next step, scientists plan to transition this approach into a real-time (vs retrospective) system that analyses data automatically and sends alerts to children’s clinical teams.
“This study reinforces wearables’ potential to complement clinical care for better patient recoveries,” said Hassan M.K. Ghomrawi, vice chair of research and innovation in the department of orthopaedic surgery at University of Alabama at Birmingham. “Our team is eager to enter the next phase of research exploration.”
Salk scientists uncover a key neural circuit in mice that gives pain its emotional punch, opening new doors for treating fibromyalgia, migraine, and PTSD
CGRP-expressing neurons (green) in the parvocellular subparafascicular nucleus (SPFp) of the thalamus. Credit: Salk Institute
More than just a physical sensation, pain also carries emotional weight. That distress, anguish, and anxiety can turn a fleeting injury into long-term suffering.
Salk Institute researchers have now identified a brain circuit that gives physical pain its emotional tone, revealing a new potential target for treating chronic and affective pain conditions such as fibromyalgia, migraine, and post-traumatic stress disorder (PTSD).
Published in PNAS, the study identifies a group of neurons in a central brain area called the thalamus that appears to mediate the emotional or affective side of pain in mice. This new pathway challenges the textbook understanding of how pain is processed in the brain and body.
“For decades, the prevailing view was that the brain processes sensory and emotional aspects of pain through separate pathways,” says senior author Sung Han, associate professor and holder of the Pioneer Fund Developmental Chair at Salk. “But there’s been debate about whether the sensory pain pathway might also contribute to the emotional side of pain. Our study provides strong evidence that a branch of the sensory pain pathway directly mediates the affective experience of pain.”
The physical sensation of pain allows immediate detection, assessment of its intensity, and identification of its source. The affective part of pain is what makes it so unpleasant – the emotional discomfort motivates avoidance.
This is a critical distinction. Most people start to perceive pain at the same stimulus intensities, meaning the sensory side of pain is processed similarly. But the ability to tolerate pain varies greatly. The degree of suffering or feeling threatened by pain is determined by affective processing, and if that becomes too sensitive or lasts too long, it can result in a pain disorder. This makes it important to understand which parts of the brain control these different dimensions of pain.
Sensory pain was thought to be mediated by the spinothalamic tract, a pathway that sends pain signals from the spinal cord to the thalamus, which then relays them to sensory processing areas across the brain.
Affective pain was generally thought to be mediated by a second pathway called the spinoparabrachial tract, which sends pain information from the spinal cord into the brainstem.
However, previous studies using older research methods have suggested the circuitry of pain may be more complex. This long-standing debate inspired Han and his team to revisit the question with modern research tools.
Using advanced techniques to manipulate the activity of specific brain cells, the researchers discovered a new spinothalamic pathway in mice. In this circuit, pain signals are sent from the spinal cord into a different part of the thalamus, which has connections to the amygdala, the brain’s emotional processing center. This particular group of neurons in the thalamus can be identified by their expression of CGRP (calcitonin gene-related peptide), a neuropeptide originally discovered in Professor Ronald Evans’ lab at Salk.
When the researchers “turned off” (genetically silenced) these CGRP neurons, the mice still reacted to mild pain stimuli, such as heat or pressure, indicating their sensory processing was intact. However, they didn’t seem to associate lasting negative feelings with these situations, failing to show any learned fear or avoidance behaviors in future trials. On the other hand, when these same neurons were “turned on” (optogenetically activated), the mice showed clear signs of distress and learned to avoid that area, even when no pain stimuli had been used.
“Pain processing is not just about nerves detecting pain; it’s about the brain deciding how much that pain matters,” says first author Sukjae Kang, a senior research associate in Han’s lab. “Understanding the biology behind these two distinct processes will help us find treatments for the kinds of pain that don’t respond to traditional drugs.”
Many chronic pain conditions—such as fibromyalgia and migraine—involve long, intense, unpleasant experiences of pain, often without a clear physical source or injury. Some patients also report extreme sensitivity to ordinary stimuli like light, sound, or touch, which others would not perceive as painful.
Han says overactivation of the CGRP spinothalamic pathway may contribute to these conditions by making the brain misinterpret or overreact to sensory inputs. In fact, transcriptomic analysis of the CGRP neurons showed that they express many of the genes associated with migraine and other pain disorders.
Notably, several CGRP blockers are already being used to treat migraines. This study may help explain why these medications work and could inspire new nonaddictive treatments for affective pain disorders.
Han also sees potential relevance for psychiatric conditions that involve heightened threat perception, such as PTSD. Growing evidence from his lab suggests that the CGRP affective pain pathway acts as part of the brain’s broader alarm system, detecting and responding to not only pain but a wide range of unpleasant sensations. Quieting this pathway with CGRP blockers could offer a new approach to easing fear, avoidance, and hypervigilance in trauma-related disorders.
Importantly, the relationship between the CGRP pathway and the psychological pain associated with social experiences like grief, loneliness, and heartbreak remains unclear and requires further study.
“Our discovery of the CGRP affective pain pathway gives us a molecular and circuit-level explanation for the difference between detecting physical pain and suffering from it,” says Han. “We’re excited to continue exploring this pathway and enabling future therapies that can reduce this suffering.”
Researchers at Princeton University and the Simons Foundation have identified four clinically and biologically distinct subtypes of autism, marking a transformative step in understanding the condition’s genetic underpinnings and potential for personalised care.
Analysing data from over 5000 children in SPARK, an autism cohort study funded by the Simons Foundation, the researchers used a computational model to group individuals based on their combinations of traits. The team used a “person-centred” approach that considered a broad range of over 230 traits in each individual, from social interactions to repetitive behaviours to developmental milestones, rather than searching for genetic links to single traits.
This approach enabled the discovery of clinically relevant autism subtypes, which the researchers linked to distinct genetic profiles and developmental trajectories, offering new insights into the biology underlying autism. Their results were published July 9 in Nature Genetics.
The study defines four subtypes of autism: Social and Behavioural Challenges, Mixed ASD with Developmental Delay, Moderate Challenges, and Broadly Affected. Each subtype exhibits distinct developmental, medical, behavioural and psychiatric traits, and importantly, different patterns of genetic variation.
Individuals in the Social and Behavioural Challenges group show core autism traits, including social challenges and repetitive behaviours, but generally reach developmental milestones at a pace similar to children without autism. They also often experience co-occurring conditions like ADHD, anxiety, depression or obsessive-compulsive disorder alongside autism. One of the larger groups, this constitutes around 37% of the participants in the study.
The Mixed ASD with Developmental Delay group tends to reach developmental milestones, such as walking and talking, later than children without autism, but usually does not show signs of anxiety, depression or disruptive behaviours. “Mixed” refers to differences within this group with respect to repetitive behaviours and social challenges. This group represents approximately 19% of the participants.
Individuals with Moderate Challenges show core autism-related behaviours, but less strongly than those in the other groups, and usually reach developmental milestones on a similar track to those without autism. They generally do not experience co-occurring psychiatric conditions. Roughly 34% of participants fall into this category.
The Broadly Affected group faces more extreme and wide-ranging challenges, including developmental delays, social and communication difficulties, repetitive behaviours and co-occurring psychiatric conditions like anxiety, depression and mood dysregulation. This is the smallest group, accounting for around 10% of the participants.
“These findings are powerful because the classes represent different clinical presentations and outcomes, and critically we were able to connect them to distinct underlying biology,” said Aviya Litman, a PhD student at Princeton.
Distinct genetics behind the subtypes
For decades, autism researchers and clinicians have been seeking robust definitions of autism subtypes to aid in diagnosis and care. Autism is known to be highly heritable, with many implicated genes.
“While genetic testing is already part of the standard of care for people diagnosed with autism, thus far, this testing reveals variants that explain the autism of only about 20% of patients,” said co-author Jennifer Foss-Feig, a clinical psychologist at the Icahn School of Medicine at Mount Sinai and vice president and senior scientific officer at the Simons Foundation Autism Research Initiative (SFARI). This study takes an approach that differs from classic gene discovery efforts by identifying robust autism subtypes that are linked to distinct types of genetic mutations and affected biological pathways.
For example, children in the Broadly Affected group showed the highest proportion of damaging de novo mutations, while only the Mixed ASD with Developmental Delay group was more likely to carry rare inherited genetic variants. While children in both of these subtypes share some important traits like developmental delays and intellectual disability, these genetic differences suggest distinct mechanisms behind superficially similar clinical presentations.
“These findings point to specific hypotheses linking various pathways to different presentations of autism,” said Litman, referring to differences in biology between children with different autism subtypes.
Moreover, the researchers identified divergent biological processes affected in each subtype. “What we’re seeing is not just one biological story of autism, but multiple distinct narratives,” said Natalie Sauerwald, associate research scientist at the Flatiron Institute and co-lead author. “This helps explain why past genetic studies often fell short – it was like trying to solve a jigsaw puzzle without realising we were actually looking at multiple different puzzles mixed together. We couldn’t see the full picture, the genetic patterns, until we first separated individuals into subtypes.”
Autism biology unfolds on different timelines
The team also found that autism subtypes differ in the timing of genetic disruptions’ effects on brain development. Genes switch on and off at specific times, guiding different stages of development. While much of the genetic impact of autism was thought to occur before birth, in the Social and Behavioural Challenges subtype – which typically has substantial social and psychiatric challenges, no developmental delays, and a later diagnosis – mutations were found in genes that become active later in childhood. This suggests that, for these children, the biological mechanisms of autism may emerge after birth, aligning with their later clinical presentation.
“By integrating genetic and clinical data at scale, we can now begin to map the trajectory of autism from biological mechanisms to clinical presentation,” said co-author Chandra Theesfeld, senior academic research manager at the Lewis-Sigler Institute and Princeton Precision Health.
A paradigm shift for autism research
This study builds on more than a decade of autism genomics research led by Troyanskaya and collaborators. It is enabled by the close integration of interdisciplinary expertise in genomics, clinical psychology, molecular biology, computer science and modelling, and computational biology.
“The Princeton Precision Health initiative uses artificial intelligence and computational modelling to integrate across biological and clinical data,” said Jennifer Rexford, Princeton University provost and Gordon Y.S. Wu Professor in Engineering. “This initiative could not exist without the University’s charitable endowment. Our investments allow experts to collaborate across a range of disciplines to conduct transformative research that improves human health, including the potential for major advances in the diagnosis and treatment of autism made possible in this exciting project.”
“It’s a whole new paradigm, to provide these groups as a starting point for investigating the genetics of autism,” said Theesfeld. Instead of searching for a biological explanation that encompasses all individuals with autism, researchers can now investigate the distinct genetic and biological processes driving each subtype.
This shift could reshape both autism research and clinical care – helping clinicians anticipate different trajectories in diagnosis, development and treatment. “The ability to define biologically meaningful autism subtypes is foundational to realising the vision of precision medicine for neurodevelopmental conditions,” said Sauerwald.
While the current work defines four subtypes, “this doesn’t mean there are only four classes,” said Litman. “It means we now have a data-driven framework that shows there are at least four – and that they are meaningful in both the clinic and the genome.”
Looking ahead
Beyond its contributions to understanding autism subtypes and their underlying biology, the study offers a powerful framework for characterising other complex, heterogeneous conditions and finding clinically relevant disease subtypes. As Theesfeld put it: “This opens the door to countless new scientific and clinical discoveries.”
