Background

Clozapine is currently the only antipsychotic drug approved by the Food and Drug Administration (FDA) of the United States for treatment-resistant schizophrenia. It is widely known for its high efficacy in reducing symptoms, relapse rate, and all-cause mortality in schizophrenia and is widely regarded as a drug of last resort. Recent Finnish and American studies suggested that clozapine may be associated with a significantly increased risk of blood cancer. However, owing to data restrictions and study design, the additional number of blood cancer cases associated with prior clozapine exposure could not be estimated and remained unclear. The clinical significance of this risk, therefore, had yet to be determined.

Research methods and findings

The research team utilised territory-wide electronic health records from the Hospital Authority of Hong Kong to comb through 400,000 patient records to construct a retrospective cohort of approximately 10,000 patients diagnosed with schizophrenia between 2001 and 2022 and followed up for a median of seven years since their drug initiation. The team’s observations of the patients showed the following:

• The absolute risk of blood cancer is very rare: In the cohort of 10,000 patients followed over a period of about seven years, only 39 developed blood cancer. After statistical adjustment, the study estimated that there were fewer than six cases of blood cancer per 10,000 patients using clozapine for one year.
• Consistent with Western studies: The weighted incidence rate ratio of blood cancer in clozapine users versus controls was estimated at 2.22, suggesting that there is a slight association. This observation is consistent with the findings of previous Finnish and American case-control studies.
• No risk for other cancers: No association was observed for other cancer types.

Significance of the study

‘In response to Western studies suggesting a potential risk of blood cancer after clozapine use, this study provides reliable evidence for patients and healthcare professionals supporting the safety of the drug. The current blood monitoring measures are very comprehensive. Patients do not need to be overly concerned about the risk of blood cancer caused by clozapine given the rarity of its occurrence demonstrated in this study. Clinicians should weigh the risks and benefits of the drug, taking into account the rarity of the association between clozapine and blood cancer, and make appropriate arrangements according to patients’ needs,’ said Professor Francisco Lai Tsz-tsun, the project leader and Assistant Professor in both the Department of Pharmacology and Pharmacy and the Department of Family Medicine and Primary Care under the School of Clinical Medicine of HKUMed.

‘Because of the readily linked and longitudinally available data across all public healthcare facilities in Hong Kong, we were able to come up with a better study design than those in other countries,’ said Professor Lai. ‘This enabled us to make immediate use of big data to better address clinically meaningful healthcare issues than researchers in many other countries, highlighting the key strengths of Hong Kong’s healthcare big data and its potential application in drug safety monitoring.’

The research team is currently re-examining a wide range of potential adverse effects of other psychotropic drugs, especially cancer risks, and their overall long-term safety and effectiveness. ‘Ultimately, through our joint interdisciplinary efforts, we hope to better inform day-to-day clinical decisions and make medication use in patients with mental illness much safer and more effective,’ Professor Lai added.

“Ovarian tumours are common and are often detected by chance,” says Professor Elisabeth Epstein at the Department of Clinical Science and Education, Södersjukhuset (Stockholm South General Hospital), at Karolinska Institutet and senior consultant at the hospital’s Department of Obstetrics and Gynecology. “There is a serious shortage of ultrasound experts in many parts of the world, which has raised concerns of unnecessary interventions and delayed cancer diagnoses. We therefor wanted to find out if AI can complement human experts.”

AI outperforms experts

The researchers have developed and validated neural network models able to differentiate between benign and malignant ovarian lesions, having trained and tested the AI on over 17,000 ultrasound images from 3,652 patients across 20 hospitals in eight countries. They then compared the models’ diagnostic capacity with a large group of experts and less experienced ultrasound examiners.

The results showed that the AI models outperformed both expert and non-expert examiners at identifying ovarian cancer, achieving an accuracy rate of 86.3 per cent, compared to 82.6 per cent and 77.7 per cent for the expert and non-expert examiners respectively.

“This suggests that neural network models can offer valuable support in the diagnosis of ovarian cancer, especially in difficult-to-diagnose cases and in settings where there’s a shortage of ultrasound experts,” says Professor Epstein.

Reducing the need for expert referrals

The AI models can also reduce the need for expert referrals. In a simulated triage situation, the AI support cut the number of referrals by 63 per cent and the misdiagnosis rate by 18 per cent. This can lead to faster and more cost-effective care for patients with ovarian lesions.

Despite the promising results, the researchers stress that further studies are needed before the full potential of the neural network models and their clinical limitations are fully understood.

“With continued research and development, AI-based tools can be an integral part of tomorrow’s healthcare, relieving experts and optimising hospital resources, but we need to make sure that they can be adapted to different clinical environments and patient groups,” says Filip Christiansen, doctoral student in Professor Epstein’s research group at Karolinska Institutet and joint first author with Emir Konuk at the KTH Royal Institute of Technology.

Evaluating the safety of the AI support

The researchers are now conducting prospective clinical studies at Södersjukhuset to evaluate the everyday clinical safety and usefulness of the AI tool. Future research will also include a randomised multicentre study to examine its effect on patient management and healthcare costs.

The study was conducted in close collaboration with researchers at the KTH Royal Institute of Technology and was financed by grants from the Swedish Research Council, the Swedish Cancer Society, the Stockholm Regional Council, the Cancer Research Funds of Radiumhemmet and the Wallenberg AI, Autonomous Systems and Software Program (WASP).

Elisabeth Epstein, Filip Christiansen and three co-authors have applied for a patent through the company Intelligyn for methods of computer-supported diagnostics. Elisabeth Epstein, Filip Christiansen and Kevin Smith, researcher at the KTH Royal Institute of Technology, also own shares in Intelligyn, for which Professor Epstein is an unsalaried manager.

After a heart attack, the human heart loses millions of muscle cells that cannot regrow. This often leads to heart failure, where the heart struggles to pump blood effectively. Unlike humans, zebrafish grow new heart muscle cells: they have a regenerative capacity. When a zebrafish heart is damaged, it can fully restore its function within 60 days. “We don’t understand why some species can regenerate their hearts after injury while others cannot,” explains Jeroen Bakkers, the study’s leader. “By studying zebrafish and comparing them to other species, we can uncover the mechanisms of heart regeneration. This could eventually lead to therapies to prevent heart failure in humans.”

A protein that repairs damage

The research team identified a protein that enables heart repair in zebrafish. “We compared the zebrafish heart to the mouse heart, which, like the human heart, cannot regenerate,” says Dennis de Bakker, the study’s first author. “We looked at the activity of genes in damaged and healthy parts of the heart,” he explains. “Our findings revealed that the gene for the Hmga1 protein is active during heart regeneration in zebrafish but not in mice. This showed us that Hmga1 plays a key role in heart repair.” Typically, the Hmga1 protein is important during embryonic development when cells need to grow a lot. However, in adult cells, the gene for this protein is turned off.

Clearing ‘roadblocks’

The researchers investigated how the Hmga1 protein works. “We discovered that Hmga1 removes molecular ‘roadblocks’ on chromatin,” explains Mara Bouwman, co-first author. Chromatin is the structure that packages DNA. When it is tightly packed, genes are inactive. When it unpacks, genes can become active again. “Hmga1 clears the way, so to say, allowing dormant genes to get back to work,” she adds.

From fish to mammals

To test if the protein works similarly in mammals, the researchers applied it locally to damaged mouse hearts. “The results were remarkable: the Hmga1 protein stimulated heart muscle cells to divide and grow, significantly improving heart function,” says Bakkers. Surprisingly, cell division occurred only in the damaged area — precisely where repair was needed. “There were no adverse effects, such as excessive growth or an enlarged heart. We also didn’t see any cell division in healthy heart tissue,” Bouwman emphasizes. “This suggests that the damage itself sends a signal to activate the process.”

The team then compared the activity of the Hmga1 gene in zebrafish, mice, and humans. In human hearts, as in adult mice, the Hmga1 protein is not produced after a heart attack. However, the gene for Hmga1 is present in humans and active during embryonic development. “This provides a foundation for gene therapies that could unlock the heart’s regenerative potential in humans,” Bakkers explains.

What’s next?

These findings open doors for safe, targeted regenerative therapies, but there is still much work to do. “We need to refine and test the therapy further before it can be brought to the clinic,” says Bakkers. “The next step is to test whether the protein also works on human heart muscle cells in culture. We are collaborating with UMC Utrecht for this, and in 2025, the Summit program (DRIVE-RM) will begin to explore heart regeneration further.”

Heart for collaboration

This research brought together scientists from the Hubrecht Institute and beyond. It was conducted as part of the OUTREACH consortium and funded by the Dutch Heart Foundation and Hartekind Foundation. The OUTREACH consortium is a collaboration between research institutes and all academic hospitals involved in treating patients with congenital heart defects in the Netherlands. “Normally, our group only focusses on zebrafish,” says Bouwman. “But to understand how our findings could be applied to mammals, we collaborated with the Van Rooij group and Christoffels group (Amsterdam UMC), experts in mouse research. Thanks to the Single Cell Core at the Hubrecht Institute, we were able to study heart regeneration at a detailed level.”

“We’re very lucky that we were able to set up these collaborations,” Bouwman continues. “It allows us to translate discoveries from zebrafish to mice and, hopefully, eventually to humans. We are learning so much from the zebrafish and its remarkable ability to regenerate its heart.”

Thermal switches, which electrically control heat transfer, are essential for the advancement of sophisticated thermal management systems. Historically, electrochemical thermal switches have been constrained by suboptimal performance, which impedes their extensive utilization in the electronics, energy, and waste heat recovery sectors.

A research team led by Professor Hiromichi Ohta of the Research Institute for Electronic Science, Hokkaido University employed a novel approach of using cerium oxide (CeO₂) thin films as the active material in thermal switches, providing a highly efficient and sustainable alternative. Their findings have been published in Science Advances.

The research team showed that CeO₂-based thermal switch performance can exceed prior benchmarks. “The novel device features an on/off thermal conductivity ratio of 5.8 and a thermal conductivity (κ)-switching width of 10.3 W/m·K, establishing a new benchmark for electrochemical thermal switches,” Ohta explains. “The thermal conductivity in its minimal state (off-state) is 2.2 W/m·K, but in the oxidized state (on-state), it significantly rises to 12.5 W/m·K. These performance metrics remain consistent after 100 cycles of reduction and oxidation, demonstrating remarkable durability and reliability for extended usage in practical applications.”

A notable benefit of this technology is the utilization of cerium oxide, a substance abundant in the earth, recognized for its economic viability and ecological sustainability. In contrast to conventional thermal switches that depend on scarce and costly materials, CeO₂ offers a sustainable and readily available alternative, reducing expenses and the ecological footprint of thermal management solutions. This enhances the technology’s efficiency, scalability, and applicability across diverse industrial sectors.

The development of CeO₂-based thermal switches represents a significant breakthrough in thermal management technology, offering broad applications across industries such as electronics cooling and renewable energy systems. These switches, utilized in thermal shutters and advanced displays, efficiently regulate infrared heat transfer, enhance waste heat recovery, and contribute to energy-efficient systems.

The new approach uses samples from infected humans to allow real-time monitoring of pathogens circulating in human populations, and enable vaccine-evading bugs to be quickly and automatically identified. This could inform the development of vaccines that are more effective in preventing disease.

The approach can also quickly detect emerging variants with resistance to antibiotics. This could inform the choice of treatment for people who become infected — and try to limit the spread of the disease.

It uses genetic sequencing data to provide information on the genetic changes underlying the emergence of new variants. This is important to help understand why different variants spread differently in human populations.

There are very few systems in place to keep watch for emerging variants of infectious diseases, apart from the established COVID and influenza surveillance programmes. The technique is a major advance on the existing approach to these diseases, which has relied on groups of experts to decide when a circulating bacteria or virus has changed enough to be designated a new variant.

By creating ‘family trees’, the new approach identifies new variants automatically based on how much a pathogen has changed genetically, and how easily it spreads in the human population — removing the need to convene experts to do this.

It can be used for a broad range of viruses and bacteria and only a small number of samples, taken from infected people, are needed to reveal the variants circulating in a population. This makes it particularly valuable for resource-poor settings.

The report is published today in the journal Nature.

“Our new method provides a way to show, surprisingly quickly, whether there are new transmissible variants of pathogens circulating in populations — and it can be used for a huge range of bacteria and viruses,” said Dr Noémie Lefrancq, first author of the report, who carried out the work at the University of Cambridge’s Department of Genetics.

Lefrancq, who is now based at ETH Zurich, added: “We can even use it to start predicting how new variants are going to take over, which means decisions can quickly be made about how to respond.”

“Our method provides a completely objective way of spotting new strains of disease-causing bugs, by analysing their genetics and how they’re spreading in the population. This means we can rapidly and effectively spot the emergence of new highly transmissible strains,” said Professor Julian Parkhill, a researcher in the University of Cambridge’s Department of Veterinary Medicine who was involved in the study.

Testing the technique

The researchers used their new technique to analyse samples of Bordetella pertussis, the bacteria that causes whooping cough. Many countries are currently experiencing their worst whooping cough outbreaks of the last 25 years. It immediately identified three new variants circulating in the population that had been previously undetected.

“The novel method proves very timely for the agent of whooping cough, which warrants reinforced surveillance, given its current comeback in many countries and the worrying emergence of antimicrobial resistant lineages,” said Professor Sylvain Brisse, Head of the National Reference Center for whooping cough at Institut Pasteur, who provided bioresources and expertise on Bordetella pertussis genomic analyses and epidemiology.

In a second test, they analysed samples of Mycobacterium tuberculosis, the bacteria that causes Tuberculosis. It showed that two variants with resistance to antibiotics are spreading.

“The approach will quickly show which variants of a pathogen are most worrying in terms of the potential to make people ill. This means a vaccine can be specifically targeted against these variants, to make it as effective as possible,” said Professor Henrik Salje in the University of Cambridge’s Department of Genetics, senior author of the report.

He added: “If we see a rapid expansion of an antibiotic-resistant variant, then we could change the antibiotic that’s being prescribed to people infected by it, to try and limit the spread of that variant.”

The researchers say this work is an important piece in the larger jigsaw of any public health response to infectious disease.

A constant threat

Bacteria and viruses that cause disease are constantly evolving to be better and faster at spreading between us. During the COVID pandemic, this led to the emergence of new strains: the original Wuhan strain spread rapidly but was later overtaken by other variants, including Omicron, which evolved from the original and were better at spreading. Underlying this evolution are changes in the genetic make-up of the pathogens.

Pathogens evolve through genetic changes that make them better at spreading. Scientists are particularly worried about genetic changes that allow pathogens to evade our immune system and cause disease despite us being vaccinated against them.

“This work has the potential to become an integral part of infectious disease surveillance systems around the world, and the insights it provides could completely change the way governments respond,” said Salje.

Key findings

• Sensitive cells: Scientists discovered dozens of specific cell types, mostly glial cells, known as brain support cells, that underwent significant gene expression changes with age. Those strongly affected included microglia and border-associated macrophages, oligodendrocytes, tanycytes, and ependymal cells.
• Inflammation and neuron protection: In aging brains, genes associated with inflammation increased in activity while those related to neuronal structure and function decreased.
• Aging hot spot: Scientists discovered a specific hot spot combining both the decrease in neuronal function and the increase in inflammation in the hypothalamus. The most significant gene expression changes were found in cell types near the third ventricle of the hypothalamus, including tanycytes, ependymal cells, and neurons known for their role in food intake, energy homeostasis, metabolism, and how our bodies use nutrients. This points to a possible connection between diet, lifestyle factors, brain aging, and changes that can influence our susceptibility to age-related brain disorders.

“Our hypothesis is that those cell types are getting less efficient at integrating signals from our environment or from things that we’re consuming,” said Kelly Jin, Ph.D., a scientist at the Allen Institute for Brain Science and lead author of the study. “And that loss of efficiency somehow contributes to what we know as aging in the rest of our body. I think that’s pretty amazing, and I think it’s remarkable that we’re able to find those very specific changes with the methods that we’re using.”

To conduct the study, funded by the National Institutes of Health (NIH), researchers used cutting-edge single-cell RNA sequencing and advanced brain-mapping tools developed through NIH’s The BRAIN Initiative® to map over 1.2 million brain cells from young (two months old) and aged (18 months old) mice across 16 broad brain regions. The aged mice are what scientists consider to be the equivalent of a late middle-aged human. Mouse brains share many similarities with human brains in terms of structure, function, genes, and cell types.

“Aging is the most important risk factor for Alzheimer’s disease and many other devastating brain disorders. These results provide a highly detailed map for which brain cells may be most affected by aging,” said Richard J. Hodes, M.D., director of NIH’s National Institute on Aging. “This new map may fundamentally alter the way scientists think about how aging affects the brain and also provides a guide for developing new treatments for aging-related brain diseases.”

A path toward new therapies

Understanding this hot spot in the hypothalamus makes it a focal point for future study. Along with knowing which cells to specifically target, this could lead to the development of age-related therapeutics, helping to preserve function and prevent neurodegenerative disease.

“We want to develop tools that can target those cell types,” said Hongkui Zeng, Ph.D., executive vice president and director of the Allen Institute for Brain Science. “If we improve the function of those cells, will we be able to delay the aging process?”

The latest findings also align with past studies that link aging to metabolic changes as well as research suggesting that intermittent fasting, balanced diet, or calorie restriction can influence or perhaps increase life span.

“It’s not something we directly tested in this study,” said Jin. “But to me, it points to the potential players involved in the process, which I think is a huge deal because this is a very specific, rare population of neurons that express very specific genes that people can develop tools for to target and further study.”

Future brain aging research

This study lays the groundwork for new strategies in diet and therapeutic approaches aimed at maintaining brain health into old age, along with more research on the complexities of advanced aging in the brain. As scientists further explore these connections, research may unlock more specific dietary or drug interventions to combat or slow aging on a cellular level.

“The important thing about our study is that we found the key players — the real key players — and the biological substrates for this process,” said Zeng. “Putting the pieces of this puzzle together, you have to find the right players. It’s a beautiful example of why you need to study the brain and the body at this kind of cell type-specific level. Otherwise, changes happening in specific cell types could be averaged out and undetected if you mix different types of cells together.”

This study was funded by NIH grants R01AG066027 and U19MH114830. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.