A pair of postgraduate students have developed a ground-breaking method for predicting which intensive care unit (ICU) patients will survive a severe brain injury. The two researchers combined functional magnetic resonance imaging (fMRI) with state-of-the art machine learning techniques to tackle one of the most complex issues in critical care. They describe the new technology in the Journal of Neurology.
Whether it is the result of a stroke, cardiac arrest or traumatic brain injury, lives can forever be changed by a serious brain injury. But the potential of a good recovery is highly uncertain.
The University of Western Ontario researchers, Matthew Kolisnyk and Karnig Kazazian, are PhD candidates at Schulich School of Medicine & Dentistry in the lab of neuroscientist Adrian Owen.
“For years we’ve lacked the tools and techniques to know who is going to survive a serious brain injury,” said Owen.
An interdisciplinary team of researchers from Western, in collaboration with neurologists at London Health Sciences Centre and Lawson Health Research Institute sought to find a solution to this problem. They were led by Loretta Norton, a psychology professor at King’s University College at Western, who was one of the first researchers in the world to measure brain activity in the ICU.
The team measured brain activity in 25 patients at one of London’s two ICUs in the first few days after a serious brain injury and tested whether it could predict who would survive and who would not.
“We previously found that information about the potential for recovery in these patients was captured in the way different brain regions communicate with each other,” said Norton. “Intact communication between brain regions is an important factor for regaining consciousness.”
The breakthrough occurred when the team realized they could combine this imaging technique with an application of AI known as machine learning. They found they could predict patients who would recover with an accuracy of 80 per cent, which is higher than the current standard of care.
“Modern artificial intelligence has shown incredible predictive capabilities. Combining this with our existing imaging techniques was enough to better predict who will recover from their injuries,” said Kolisnyk.
While encouraging, the researchers say the prediction was not perfect and needs further research and testing.
“Given that these models learn best when they have lots of data, we hope our findings will lead to further collaborations with ICUs across Canada,” said Kazazian.
Researchers have developed a non-invasive method for mapping the human auditory pathway, which could potentially be used as a tool to help clinicians decide the best surgical strategy for patients with profound hearing loss. The findings, published online in the journal eLife, highlight the importance of early interventions to give patients the ability to hear and understand speech, so that their auditory-language network can develop properly and their long-term outcomes are improved.
Sensorineural hearing loss (SNHL) occurs when the sensitive hair cells inside the cochlea are damaged, or when there is damage to the auditory nerve which transmits sound to the brain. A person with profound hearing loss is typically unable to hear any sounds, or at best, only very loud sounds. Congenital SNHL has increased in prevalence over the past two decades, from 1.09 to 1.7 cases per 1000 live births.
The sound of speech is carried through the brain by nerve fibres in regions known as the auditory pathway, and are processed in a region called the language network. In cases of congenital SNHL, the lack of speech inputs reaching the language network may hinder its proper development, leading to poorer spoken language skills.
Currently, the primary treatments for profound SNHL are cochlear and auditory brainstem implantation, where a device is used to stimulate the peripheral cochlea or the central cochlear nucleus, respectively. Both techniques can partially restore hearing in patients, but their language development outcomes can vary. This is especially true for patients with inner ear malformations (IEM) or cochlear nerve deficiencies (CND), which contribute to 15-39% of congenital SNHL cases.
“Where SNHL is caused by CNDs and/or IEMs, there is a great deal of uncertainty around the best method of treatment. This is due to the difficulty of assessing the condition of the cochlear nerve and distinguishing between certain types of IEM, both of which impact surgical decision making,” says senior authors Hao Wu, a professor and Chief Physician specialising in Otolaryngology at Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, China. Wu also serves as the Hospital Administrator and the Clinical and Academic Lead for the department. “We therefore need a more effective method for mapping the auditory pathway and diving deeper into how IEMs and CNDs affect the development of the auditory-language network.”
In their study, professor Wu’s team investigated the auditory and language pathways in 23 children under the age of six. They included 10 children with normal hearing, and 13 with profound SNHL. In the latter group, seven children had received cochlear implantations, two had received auditory brainstem implantations, and four were candidates for auditory brainstem implantations.
The human auditory pathway is difficult to investigate non-invasively due to its delicate and intricate subcortical structures located deep within the brain. To navigate this, the team developed a new methodology to reconstruct the pathway. First, they segmented the subcortical auditory structures using track density imaging, which are reconstructed from a specific type of MRI scan and provide much greater detail and information on the structural connectivity of the brain. This allowed them to delineate the cochlear nucleus and the superior olivary complex of the auditory pathway. They then tracked the auditory and language pathways using a neuroimaging technique called probabilistic tractography, which uses the information from an MRI scan to provide the most likely view of structural brain connectivity. Next, the team assessed the density and cross-section of the nerve fibres in the auditory and language pathways.
This combined methodology allowed them to investigate three key areas to inform surgical decision making: the condition of the nerve fibres in the auditory-language network of children with profound SNHL; the potential impact of IEMs and CNDs on the development of the network before surgical intervention; and the relationship between the pre-implant structural development of the network and the auditory-language outcomes following implantation.
The team’s observations revealed a lower nerve fibre density in children with profound SNHL, in comparison to those with normal hearing. This reduction was most pronounced in two regions of the inferior central auditory pathway, as well as the left language pathway.
In addition, the findings revealed that the language pathway is more sensitive than the central auditory system to IEMs and/or CNDs, implying that the structural development of the language pathway is more negatively impacted by the condition of the peripheral auditory structure. However, the authors caution that further study is required to validate this finding. As it is more difficult to image the central auditory pathway than the language pathway, this difference could have arisen due to the limitations of current neuroimaging technologies.
The authors say the study is also limited by a relatively small cohort of patients and an incomplete genetic dataset, so more studies with a more diverse patient population will also be needed. But with further validation, they add that the methodology could be used more widely for informing decisions in treating profound SNHL.
New research led by King’s College London researchers has found that depression and the risk of depression are linked to different inflammatory cytokines in boys and girls. Previous research has shown that higher levels of inflammatory cytokines are associated with depression in adults, but little is known about this relationship in adolescence.
This study, published in the Journal of Affective Disorders, found that different cytokines were implicated in depression risk and severity in boys compared to girls. The research was part of the IDEA (Identifying Depression Early in Adolescence) project funded by MQ Mental Health Research.
To assess inflammation, researchers measured the blood cytokine levels in 75 adolescent boys and 75 adolescent girls (aged 14–16 years) from Brazil. The 150 participants had been recruited into three groups with equal numbers (50 participants in each group: 25 girls and 25 boys). The groups were those at low-risk for depression and not depressed, those at high risk of depression and not depressed, and those currently experiencing major depressive disorder (MDD).
The findings indicated that there are sex differences between the individual cytokines that are associated with depression in adolescents. Higher levels of the cytokine interleukin-2 (IL-2) were associated with both increased risk for depression and the severity of depressive symptoms in boys, but not in girls. However, higher levels of IL-6 were associated with severity of depression in girls, but not boys. In boys the levels of IL-2 were higher in the high-risk than the low-risk group and even higher in the group diagnosed with depression, indicating that in boys IL-2 levels in the blood could help indicate the onset of future depression.
Dr Zuzanna Zajkowska, Postdoctoral Researcher at King’s IoPPN and first author of the study, said: “This is the first study to show differences between boys and girls in the patterns of inflammation that are linked to the risk and development of adolescent depression.
“We found that the severity of depressive symptoms was associated with increased levels of the cytokine interleukin-2 in boys, but interleukin-6 in girls. We know more adolescent girls develop depression than boys and that the disorder takes a different course depending on sex so we hope that our findings will enable us to better understand why there are these differences and ultimately help develop more targeted treatments for different biological sexes.”
Researchers recruited adolescents from public schools in Brazil. Risk of depression was assessed by a composite risk score for depression based on 11 sociodemographic variables that had been developed as part of the IDEA project. Adolescents completed several questionnaires, self-reporting their emotional difficulties, relationships, experiences, and mood. They also completed a clinical assessment with a child and adolescent psychiatrist.
Senior author on the study Professor Valeria Mondelli, Clinical Professor of Psychoneuroimmunology at King’s IoPPN and theme-lead for Psychosis and Mood Disorders at the NIHR Maudsley BRC, said:
“Our findings suggest that inflammation and biological sex may have combined contribution to the risk for depression. We know that adolescence is a key time when many mental disorders first develop and by identifying which inflammatory proteins are linked to depression and how this is different between boys and girls we hope that our findings can pave the way to understanding what happens at this critical time in life. Our research highlights the importance of considering the combined impact of biology, psychology, and social factors to understand the mechanisms underlying depression.”
A new study published in the journal ACS Infectious Diseases has found that a natural compound found in many plants inhibits the growth of drug-resistant Candida fungi – including its most virulent species, Candida auris, an emerging global health threat.
Led by Emory University researchers, the study used in vitro experiments that showed that the natural compound, a water-soluble tannin known as PGG, blocks 90% of the growth in four different species of Candida fungi. The researchers also discovered the mechanism by which PGG inhibits the growth: It grabs up iron molecules, essentially starving the fungi of an essential nutrient.
By starving the fungi rather than attacking it, the PGG mechanism does not promote the development of further drug resistance, unlike existing antifungal medications. In vitro testing also showed minimal toxicity of PGG to human cells.
“Drug-resistant fungal infections are a growing healthcare problem but there are few new antifungals in the drug-development pipeline,” says Cassandra Quave, senior author of the study and assistant professor at Emory University. “Our findings open a new potential approach to deal with these infections, including those caused by deadly Candida auris.”
C. auris is often multidrug-resistant and has a high mortality rate, leading the Centers for Disease Control and Prevention (CDC) to label it a serious global health threat.
“It’s a really bad bug,” says Lewis Marquez, first author of the study and a graduate student in Emory’s molecular systems and pharmacology programme. “Between 30 to 60% of the people who get infected with C. auris end up dying.”
An emerging threat
Some species of Candida, a yeast commonly found on the skin or in the digestive tract, can cause infection, which can be invasive and life-threatening. Immunocompromised people, including many hospital patients, are most at risk for invasive Candida infections, which are rapidly evolving drug resistance.
In 2007, the new Candida species, C. auris, emerged in a hospital patient in Japan. Since then, C. auris has caused health care-associated outbreaks in more than a dozen countries around the world with more than 3000 clinical cases reported in the United States alone.
A ‘natural’ approach to drug discovery
Quave is an ethnobotanist, studying how traditional people have used plants for medicine to search for promising new candidates for modern-day drugs. Her lab curates the Quave Natural Product Library, which contains 2500 botanical and fungal natural products extracted from 750 species collected at sites around the world.
“We’re not taking a random approach to identify potential new antimicrobials,” Quave says. “Focusing on plants used in traditional medicines allows us to hone in quickly on bioactive molecules.”
Previously, the Quave lab had found that the berries of the Brazilian peppertree, a plant used by traditional healers in the Amazon for centuries to treat skin infections and some other ailments, contains a flavone-rich compound that disarms drug-resistant staph bacteria. They had also found that the leaves of the Brazilian peppertree contain PGG, a compound that has shown antibacterial, anticancer and antiviral activities in previous research.
A 2020 study by the Quave lab, for instance, found that PGG inhibited growth of Carbapenem-resistant Acinetobacter baumannii, a bacterium that infects humans and is categorised as one of five urgent threats by the CDC.
The Brazilian peppertree is a member of the poison ivy family. “PGG has popped up repeatedly in our laboratory screens of plant compounds from members of this plant family,” Quave says. “It makes sense that these plants, which thrive in really wet environments, would contain molecules to fight a range of pathogens.”
Experimental results
The Quave lab decided to test whether PGG would show antifungal activity against Candida.
In vitro experiments demonstrated that PGG blocked around 90% of the growth in 12 strains from four species of Candida: C. albicans, multidrug-resistant C. auris and two other multidrug-resistant non-albicans Candida species.
PGG is a large molecule known for its iron-binding properties. The researchers tested the role of this characteristic in the antifungal activity.
“Each PGG molecule can bind up to five iron molecules,” Marquez explains. “When we added more iron to a dish, beyond the sequestering capacity of the PGG molecules, the fungi once again grew normally.”
Dish experiments also showed that PGG was well-tolerated by human kidney, liver and epithelial cells.
“Iron in human cells is generally not free iron,” Marquez says. “It is usually bound to a protein or is sequestered inside enzymes.”
A potential topical treatment
Previous animal studies on PGG have found that the molecule is metabolised quickly and removed from the body. Instead of an internal therapy, the researchers are investigating its potential efficacy as a topical antifungal.
“If a Candida infection breaks out on the skin of a patient where a catheter or other medical instrument is implanted, a topical antifungal might prevent the infection from spreading and entering into the body,” Marquez says.
The researchers will bext test PGG as a topical treatment for fungal skin infections in mice.
Meanwhile, Quave and Marquez have applied for a provisional patent for the use of PGG for the mitigation of fungal infections.
“These are still early days in the research, but another idea that we’re interested in pursuing is the potential use of PGG as a broad-spectrum microbial,” Quave says. “Many infections from acute injuries, such as battlefield wounds, tend to be polymicrobial so PGG could perhaps make a useful topical treatment in these cases.”
The vertebral bones that constitute the spine are derived from a distinct type of stem cell that secretes a protein favouring tumour metastases, according to a study led by researchers at Weill Cornell Medicine. The discovery, published in Nature, opens up a new line of research on spinal disorders and helps explain why solid tumours so often spread to the spine, and could lead to new orthopaedic and cancer treatments.
Vertebral bone was found to be derived from a stem cell that is different from other bone-making stem cells. Using bone-like “organoids” made from vertebral stem cells, they showed that the known tendency of tumours to spread to the spine rather than long bones is due largely to a protein called MFGE8, secreted by these stem cells.
“We suspect that many bone diseases preferentially involving the spine are attributable to the distinct properties of vertebral bone stem cells,” said study senior author Dr Matthew Greenblatt.
In recent years, Dr Greenblatt and other scientists have found that different types of bone are derived from different types of bone stem cells. Since vertebrae develop along a different pathway early in life, and also appear to have had a distinct evolutionary trajectory, Dr Greenblatt and his team hypothesised that a distinct vertebral stem cell probably exists.
The researchers started out by isolating what are broadly known as skeletal stem cells, which give rise to all bone and cartilage, from different bones in lab mice based on known surface protein markers of such cells. They then analysed gene activity in these cells to see if they could find a distinct pattern for the ones associated with vertebral bone.
This effort yielded two key findings. The first was a new and more accurate surface-marker-based definition of skeletal stem cells as a whole. This new definition excluded a set of cells that are not stem cells that had been included in the old stem cell definition, thus clouding some prior research in this area.
The second finding was that skeletal stem cells from different bones do indeed vary systematically in their gene activity. From this analysis, the team identified a distinct set of markers for vertebral stem cells, and confirmed these cells’ functional roles to form spinal bone in further experiments in mice and in lab-dish cell culture systems.
The researchers next investigated the phenomenon of the spine’s relative attraction for tumour metastases, including breast, prostate and lung tumours, compared to other types of bone. The traditional theory, dating to the 1940s, is that this “spinal tropism” relates to patterns of blood flow that preferentially convey metastases to the spine versus long bones. But when the researchers reproduced the spinal tropism phenomenon in animal models, they found evidence that blood flow isn’t the explanation, finding instead a clue pointing to vertebral stem cells as the possible culprits.
“We observed that the site of initial seeding of metastatic tumour cells was predominantly in an area of marrow where vertebral stem cells and their progeny cells would be located,” said study first author Dr Jun Sun, a postdoctoral researcher in the Greenblatt laboratory.
Subsequently, the team found that removing vertebral stem cells eliminated the difference in metastasis rates between spine bones and long bones. Ultimately, they determined that MFGE8, a protein secreted in higher amounts by vertebral compared to long bone stem cells, is a major contributor to spinal tropism. To confirm the relevance of the findings in humans, the team collaborated with investigators at Hospital for Special Surgery to identify the human counterparts of the mouse vertebral stem cells and characterise their properties.
The researchers are now exploring methods for blocking MFGE8 to reduce the risk of spinal metastasis in cancer patients. More generally, said Dr Greenblatt, they are studying how the distinctive properties of vertebral stem cells contribute to spinal disorders.
“There’s a subdiscipline in orthopaedics called spinal orthopaedics, and we think that most of the conditions in that clinical category have to do with this stem cell we’ve just identified,” Dr Greenblatt said.
