Publisher Health

A nurse has been filmed warning of delays of more than seven-and-a-half hours to see a doctor at an accident and emergency department.Footage was posted on Twitter showing the nurse addressing patients at Princess Alexandra Hospital, in Harlow, Essex, on Monday night.Gary Sitton, whose son-in-law visited A&E after being involved in a road crash, said the video showed “our NHS on its knees”.Stephanie Lawton, chief operating officer at The Princess Alexandra Hospital NHS Trust, said: “We are currently experiencing extremely high demand for our emergency care services and have seen a significant increase in attendances in our emergency department.“Our teams are working hard to assess and treat patients as quickly and effectively as possible to reduce delays, prioritising those in most clinical need.”

Researchers from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) have found that oral administration of rapamycin to an Alzheimer’s disease mouse model causes an increase in beta (β)-amyloid protein plaques. β-amyloid buildup is a hallmark of Alzheimer’s disease.
Rapamycin is approved to treat transplant and cancer patients. Publicly available data suggest that the drug might also improve learning and memory in aged mice. However, the UT Health San Antonio researchers observed that after rapamycin treatment, a protein called Trem2 (triggering receptor expressed on myeloid cells 2) is dramatically diminished. Trem2 is present in microglia, which are immune cells in the brain and spinal cord.
“Trem2 is a receptor located on the surface of the microglia, and it enables these cells to engulf and degrade β-amyloid,” said study senior author Manzoor Bhat, PhD. “Loss of Trem2 in microglia impairs the vital function of amyloid degradation, which in turn causes a buildup of β-amyloid plaques.” Dr. Bhat is professor and chairman of the Department of Cellular and Integrative Physiology at UT Health San Antonio and vice dean for research in the university’s Joe R. and Teresa Lozano Long School of Medicine.
Drug target
Importantly, the study, published June 7 in the Journal of Neuroscience, also featured a novel way to increase Trem2 in microglia. When the study lead author, Qian Shi, PhD, assistant professor in the Department of Cellular and Integrative Physiology, deleted a gene called Tsc1 from the microglia, there was a marked increase in Trem2 levels and a decrease in β-amyloid plaques.
Previous research has shown that loss of Tsc1 leads to activation of the mTOR (mammalian target of rapamycin) signaling pathway. Rapamycin, in contrast, blocks this pathway. “We expected that selective loss of Tsc1, only in microglia and not in neurons or other cells, would have negative consequences because inhibiting mTOR with rapamycin has known therapeutic uses in some disease models,” Dr. Shi said. “But the opposite was occurring.” Thus, repressing Tsc1 solely in microglia to enhance β-amyloid uptake could be a potential drug target, Dr. Shi said.
The experiments were conducted in a specific mouse strain called the 5XFAD, which is used as a model for human Alzheimer’s disease. The study is relevant to β-amyloid-associated Alzheimer’s and is not generalizable to other Alzheimer’s pathologies, Dr. Bhat said.
More investigation warranted
Findings from this study may give the medical world a reason to pause testing rapamycin on anyone at risk of Alzheimer’s disease. “Rapamycin may have benefits in terms of suppressing the immune system and as a tumor suppressor,” Dr. Bhat said. “But in a situation where it negatively impacts the expression of Trem2 or other critical proteins, it may have a detrimental effect. We caution that rapamycin’s benefits in β-amyloid-associated Alzheimer’s must be studied more carefully.”
The Bhat laboratory specializes in creating and analyzing genetic models of human diseases. The lab’s investigators have uncovered a number of novel pathways that involve axonal myelination and demyelination and how mTOR signaling in glial cells, such as microglia, could be exploited for therapeutic benefits in human diseases including Alzheimer’s disease.

In today’s post-pandemic world, strained global supply chains have emerged as a new norm. But in the case of prescription opioids, namely oxycodone and hydrocodone in the early 2000s, that supply chain flowed freely without any kinks.
This is in part due to the influence of supplier pool pressure on pharmacy participation in oversupply, according to research conducted by Ednilson Bernardes, professor and program coordinator of global supply chain management at the West Virginia University John Chambers College of Business and Economics.
In other words, pressure from manufacturers and suppliers of opioids, particularly national corporations, influenced how pharmacies bought and distributed those prescriptions.
“We argued that when the pool of suppliers has cohesive expectations for how buyers should behave and sufficient power to dominate the supply relationship, then buyers are under pressure to act in line with those expectations,” Bernardes said.
Bernardes and co-author, Paul Skilton of Washington State University, analyzed transactions involving oxycodone and hydrocodone between 2006 and 2012. They chose those two drugs, Bernardes said, because they’re the most commonly abused, legally prescribed products and central to the American opioid epidemic. According to the Centers for Disease Control and Prevention, as of 2019, an average of 38 people die each day from prescription opioid overdoses.
The researchers tested a model using a dataset combining geographic, market and public health data. The study revealed that more than 90% of supply originated with three generics manufacturers that aggressively competed for shelf space in distributors and pharmacies. Their findings are published in the Journal of Supply Chain Management.

As people across the globe look forward to longer life expectancies, malignant cancers continue to pose threats to human health. The exploration and development of immunotherapy aims to seek new breakthroughs for the treatment of solid tumours.
The successful establishment of anti-tumour immunity requires the activation, expansion and differentiation of antigen-specific lymphocytes. This process largely depends on specific interactions between various T cells and antigen-presenting cells (APCs) in the body. However, existing tumour vaccines, such as neoantigen vaccines and various vector vaccines, all rely on random interactions with APCs in the body. Furthermore, inappropriate interactions may lead to the silencing of other immune responses.
Although immune checkpoint-based immunotherapy has been shown to have great potential, only a small proportion of patients fully respond to this therapy, and the relevant molecular mechanisms need to be further explored. This delivery method is however complex and inefficient.
In a breakthrough development, a team of scientists led by Narat Muzayyin Chair Professor Chen Xiaoyuan from the NUS Yong Loo Lin School of Medicine and Professor Liu Gang from Xiamen University has formulated a novel vaccine which showed high efficacy in the treatment of solid tumors, achieving complete clearance of solid tumors and inducing long-lasting immune memory. This prevents the relapse of tumour growth that the patient originally presented with and provides immunity against similar tumour types. This was shown through the application of this vaccine on melanoma tumour models.
The team was able to engineer a dendritic cell (a type of APC) membrane that was used to naturally stimulate the immune system and activate multi-dimensional anti-tumor immunity. This was done through an antigen self-presentation and immunosuppression reversal nanovesicle vaccine platform, which prompted the team to coin its moniker, ASPIRE.
The ASPIRE vaccine system can quickly elicit appropriate, antigen-specific immune responses in a way that traditional vaccine methods could not. This mode of antigen presentation greatly improves the efficiency of immune activation, which facilitates this novel vaccine’s high efficacy relative to other vaccines currently available. In addition, the vaccine can also activate both previously unexposed T cells and exhausted T cells which facilitates ASPIRE’s superior anti-tumour immune capabilities.
“We are excited at this platform technology’s potential for further application in other diseases as well, such as chronic viral infection, in which T-cell exhaustion often occurs during infection and prevents the optimal viral control,” said Prof Chen. “Next, the team hopes to establish a standard operating procedure for scaled synthesis of the vaccine, with proper quality control of the membrane vesicles, for clinical translation, he added.
Speaking independently on the study, Professor Chng Wee Joo, Senior Consultant of the Division of Haematology at the Department of Haematology-Oncology in the National University Cancer Institute, Singapore and myeloma specialist said: “The field of cancer immunotherapy is offering tremendous hope to cancer patients. However, there are some shortcomings with the current technologies. The present innovation from Prof Chen and his colleagues overcome some of these deficiencies and improved the effectiveness and sustainability of the immune response to these treatments. This will provide a significant advance that will have important impact on patients.”

The world is rife with rankings and orderings. They show up in tennis — as in the French Open, which ends with a final ranking of champion players. They show up in pandemics — as when public health officials can record new infections and use contact tracing to sketch networks of COVID-19 spread. Systems of competition, conflict, and contagion can all give rise to hierarchies.
However, these hierarchies are observed after the fact. That makes it difficult to know the true rankings of the system: Who was actually the best player? Who infected whom? “You can’t go back in time and learn exactly how this thing happened,” says Santa Fe Institute Postdoctoral Fellow George Cantwell. One could build a model of the network and compare all possible outcomes, but such a brute-force approach quickly becomes untenable. If you were trying to rank some group with just 60 participants, for example, the number of possible permutations reaches the number of particles in the known universe.
For a recent paper published in Physical Review E, Cantwell collaborated with SFI Professor Cris Moore, a computer scientist and mathematician, to describe a new way to evaluate rankings. Their goal wasn’t to find one true hierarchy, but to calculate the spread of all possible hierarchies, with each one weighted by its probability.
“We were willing to not be exactly right, but we wanted to get good answers with some sense about how good they are,” Cantwell says. The new algorithm is inspired by physics: Ranks are modeled as interacting entities that can move up or down. Through that lens, the system then behaves like a physical system that can be analyzed using methods from spin glass theory.
Soon after the start of the COVID-19 pandemic, Cantwell and Moore began thinking about models of how disease spreads through a network. They quickly recognized the situation as an ordering problem that emerges over time, not unlike the spread of a meme on social media or the emergence of championship rankings in professional sports. “How do you order things when you have incomplete information?” asks Cantwell.
They started by imagining a function that could score a ranking on accuracy. For example: A good ranking would be one that agrees with the outcomes of matchups 98% of the time. A ranking that agrees with outcomes only 10% of the time would be lousy — worse than a coin flip without any prior knowledge.
One problem with rankings is that they’re typically discrete, which means they follow the whole numbers: 1, 2, 3, and so on. That ordering suggests that the “distance” between the first- and second-ranked members is the same as that between the second and third. But that’s not the case, says Cantwell. The top players in a game, worldwide, are going to be close together in terms of skill, so the difference between top-ranked players may be closer than it seems.
“You quite often see that lower-ranked players can beat higher-ranked players, and the only way the model can make sense and fit the data is by squishing all the ranks together,” says Cantwell.
Cantwell and Moore described a system that evaluates rankings based on a continuous numbering system. A ranking could assign any real number — whole number, fraction, infinitely repeating decimal — to a player in the network. “Continuous numbers are easier to work with,” Cantwell says, and those continuous numbers can still be translated back to discrete rankings.
In addition, this new approach can be used for predicting something about the future, like the outcome of a tennis tournament, and also inferring something about the past, such as how a disease has spread. “These rankings could tell us the order of sports teams from best to worst. But they could also tell us the order in which people in a community became infected with a disease,” says Moore. “Even before his postdoc, George was working on this problem as a way to improve contact tracing in an epidemic. Just as we can predict which team will win a game, we can infer which of two people infected the other when they came in contact with each other.”
In future work, the researchers say they plan to investigate some of the deeper questions that have emerged. More than one ranking might agree with data but disagree radically with other rankings, for example. Or a ranking that seems incorrect may have high uncertainty but not be inaccurate. Cantwell says he also wants to compare the model’s predictions to outcomes from real-world competitions. Ultimately, he says, the model might be used to improve predictions in a wide range of systems that lead to rankings, from infectious disease models to sports betting.
Cantwell says he’ll hold on to his money — for now. “I’m not quite ready to start betting on it,” he says.

Micronutrient deficiencies can promote inflammation and render the immune system particularly sensitive to allergenic substances. In particular, iron deficiency signals danger to immune cells and leads to a more pronounced, exaggerated immune response. For the first time, scientists at the Messerli Research Institute of MedUni Vienna, Vetmeduni Vienna and the University of Vienna conducted a placebo-controlled trial and showed that targeted dietary measures can reduce the symptom burden in allergic reactions. The researchers are therefore treading a completely new path in the care of allergy sufferers. The study was recently published in The Journal of Allergy and Clinical Immunology: In Practice.
The background to the studies conducted by researchers at the inter-university Messerli Research Institute in collaboration with the University Department of Ear, Nose and Throat Diseases at MedUni Vienna is the vicious circle of allergy: a hyperactive immune system sets the body on alert and inhibits adequate absorption of iron — even though this is precisely the micronutrient needed to moderate the overreaction. To compensate micronutrional deficiencies in immune cells, the scientific team developed a lozenge that was tested for the first time in a double-blind, placebo-controlled manner as part of the study.
Circumventing inhibition of iron absorption
The lozenge is based on the whey protein beta-lactoglobulin from cows, which acts as a carrier for numerous micronutrients. “Thanks to this carrier, absorption takes place via the lymph instead of blood vessels — in other words, exactly where immune cells are present in abundance ensuring micronutrient uptake in a targeted manner,” explains study leader Franziska Roth-Walter from the Messerli Research Institute. Since a tablet only contains a very small amount of iron, less than one milligram, it is not considered an iron supplement. Instead, the micronutrients are in a suitable form to be carried by the whey protein beta-lactoglobulin and thus to the immune cells. According to the study results, supplementation with this lozenge significantly reduced the symptom burden in birch and grass pollen-allergic individuals. In addition, after six months of intake, there was an improvement identifiable in the iron status of circulating monocytes and red blood cell parameters. Supplementation with the lozenge resulted in a 45% reduction of the Combined Symptom Medication Score, a measure for the symptoms and medication use, during the peak birch pollen season.
Reducing immune cell hypersensitivity
To date, specific allergen immunotherapy is considered the only causal treatment option for alleviating allergic diseases. This involves using an allergen specifically against the allergy in question, e.g. birch pollen against birch pollen allergy. “Supplying the immune cells with micronutrients via the lozenge showed a strikingly similar efficacy, but in a completely allergen-independent and therefore universal way,” clarifies Franziska Roth-Walter. The study therefore presents a new approach in the care of allergy sufferers. In this approach, a dietary measure is used to reduce the underlying hypersensitivity of the immune cells to allergenic substances rather than targeting the allergy itself.
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Ketamine, a well-known anesthetic used in smaller doses as a party drug, was hailed as a “new hope for depression” in a Time magazine cover story in 2017. Two years later, the arrival of the first ketamine-based antidepressant — the nasal spray esketamine, made by Johnson & Johnson — was applauded as the most exciting development in the treatment of mood disorders in decades. Yet the U.S. Food and Drug Administration still limits the spray’s use. It is mainly given to depressed patients who have not been helped by other therapies — in part, because the new drug’s mechanism of action is insufficiently understood, leading to concerns over its safety.
Today, a study published in Neuron reveals new details about how ketamine works, paving the way toward the development of safe, effective treatments for depression. The research was conducted at the Weizmann Institute of Science in Rehovot, Israel, and at the Max Planck Institute of Psychiatry in Munich, Germany, in collaboration with the Helmholtz Zentrum, Munich.
Even though depression is on the rise in developed countries, taking a heavy toll in terms of human suffering and economic loss, there have been no major breakthroughs in the treatment of depression since the 1987 approval of the most famous antidepressant of all time, Prozac. Meanwhile, existing drugs bring no relief to about a third of depressed patients. Even when the drugs do work, they take four to eight weeks to take effect, a delay that can prove fatal in suicidal cases. That’s precisely the reason for much of the excitement over ketamine-based therapies: They make people feel better within hours. Their antidepressant action then lasts for days after the drug itself has cleared from the body. Evidently, it’s the body’s response to ketamine, rather than ketamine itself, that produces the desired effect, but the nature of this response has until now been unclear.
When scientists tried to clarify ketamine’s mechanism of action in previous studies, they examined its impact on gene expression in brain tissues, but not in individual brain cells. This approach can miss crucial differences between different cell types. Recent technological advances, however, have made it possible to assess gene expression at an unprecedented level of resolution: that of the single cell. These technologies were employed in the new study, conducted under the guidance of Prof. Alon Chen, former managing director of the Max Planck Institute of Psychiatry and current president of the Weizmann Institute of Science.
In this study, researchers led by Dr. Juan Pablo Lopez mapped out gene expression in thousands of individual neurons in the brains of mice that had been given a dose of ketamine. These neurons belong to networks that convey their signals by means of the neurotransmitter glutamate. Ketamine had been known since the 1990s to produce its effects by acting on such neurons — this in contrast to older antidepressants, which mainly affect neurons influenced by serotonin. But since ketamine’s effect persists long after it leaves the body, its action could not be explained by mere blockage of glutamate receptors on the surfaces of neurons. “We wanted to clarify the molecular cascade that is triggered by ketamine, leading to its sustained antidepressant effects,” Lopez says.
To this end, the scientists focused on the ventral hippocampus, a brain region that in previous studies had been associated with the antidepressant effects of ketamine. After mapping out gene expression in cells from this area of the mouse brain, the researchers identified a subpopulation of neurons with a characteristic genetic signature. Ketamine had increased these neurons’ expression of a gene called Kcnq2, which encodes a potassium channel — that is, a tunnel that opens up in the cell membrane, enabling the passage of potassium ions. Potassium channels play a central role in the life of neurons, maintaining their stability and preventing their excessive firing. In a series of elaborate experiments on the molecular and cellular levels, which included electrophysiological, pharmacological, behavioral and functional studies, the scientists confirmed their major finding: Ketamine exerts its lasting antidepressant effect by enhancing the Kcnq2 potassium channels in a certain subtype of glutamate-sensitive neurons.
“In the past, other researchers used whole tissue samples, which are composed of different cell types, so ketamine’s effects on specific cell types were averaged out,” Lopez explains.
The researchers then tested ketamine’s effects in combination with an epilepsy drug, retigabine, known to activate potassium channels in the brain. When the drugs were given together, ketamine’s antidepressant effects were significantly enhanced. “A single dose of retigabine was enough to amplify and prolong ketamine’s antidepressant action in mice,” Lopez says. “Not only that, ketamine produced the same benefits when given in smaller doses than usual, which may help reduce its unwanted side effects.” Since both drugs already have FDA approval, the way is open toward testing their combined action in humans.
According to the World Health Organization, depression afflicts nearly 300 million people worldwide; more than 700,000 people commit suicide every year. Yet despite decades of research, much remains to be learned about the neuronal mechanisms underlying depression and the ways of manipulating those mechanisms with drugs.
By revealing a new mechanism of ketamine’s action, the study may make it possible to expand the use ketamine-based drugs. This, in turn, might help these drugs fully deliver on their promise of providing new hope for depression.
“In-depth knowledge of how antidepressants work might lead to a better understanding of depression and help improve existing treatments,” Chen sums up.
Prof. Chen’s research is supported by the Ruhman Family Laboratory for Research in the Neurobiology of Stress and the Licht Family. He is the incumbent of the Vera and John Schwartz Professorial Chair in Neurobiology.

Researchers at Nagoya University in Japan have developed a new chemical-only process that may represent an important breakthrough in creating customized mRNA vaccines for a variety of diseases and allow for the inexpensive preparation of mRNA in large quantities.
During the COVID-19 pandemic, mRNA vaccines were successfully used to boost immunity. These vaccines teach cells how to make a protein that triggers the body’s immune response, allowing its natural defenses to recognize the invading virus. However, current vaccines that use biological processes do not allow for the precise molecular design of mRNA, which limits their use in creating new vaccines as variants emerge.
As published in ACS Chemical Biology, a research group led by Professor Hiroshi Abe and Associate Professor Naoko Abe of the Graduate School of Science at Nagoya University has developed the first completely chemical synthesis method for mRNA.
In their study, the group synthesized a part of the mRNA called the cap. The cap is important because it promotes the translation of mRNA into proteins and protects mRNA from degradation. To prepare synthetic mRNA, such as that used in vaccines, the two currently used biological methods rely on enzymes to incorporate the cap structure into the mRNA. However, the researchers found that their technique could synthesize a variety of chemically modified mRNA strands with a cap structure.
According to Professor Hiroshi Abe: “our research suggests that it is possible to make mRNAs with precisely introduced chemical modifications with complete control over the process. The molecular design reported in our study exhibits five times higher translational activity than that of enzyme-produced natural-type mRNA. This means that mRNA can be synthesized in large quantities at low cost using chemical synthesis.”
Chemically modified mRNA could be used to create customized vaccines against a variety of infectious diseases including viruses and cancers. Professor Abe explains, “By introducing these chemical modifications, the mRNA becomes stable. This could allow for the creation of long-lasting and effective mRNA vaccines. In addition, it could allow mRNA to be administered directly instead of using lipid nanoparticles, which are used for delivery in current vaccines.”
“One of the exciting implications of this research is that this could be used in the next generation of vaccines,” the researchers said. “We hope that the capping method reported here will be of great use in the development of RNA therapeutics.”
Funding: The study was supported by the AMED LEAP project ‘Innovation of Chemistry-Based Molecular Design and Production Methods for mRNA and its Application to Vaccines’, which started in FY2021.
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Researchers from the Buck Institute have demonstrated for the first time a link between diet, circadian rhythms, eye health and lifespan in Drosophila. Publishing in the June 7, 2022 issue of Nature Communications, they additionally and unexpectedly found that processes in the fly eye are actually driving the aging process.
Previous studies have shown in humans that there is an association between eye disorders and poor health. “Our study argues that it is more than correlation: dysfunction of the eye can actually drive problems in other tissues,” said senior author and Buck Institute Professor Pankaj Kapahi, PhD, whose lab has demonstrated for years that fasting and caloric restriction can improve many functions of the body. “We are now showing that not only does fasting improve eyesight, but the eye actually plays a role in influencing lifespan.”
“The finding that the eye itself, at least in the fruit fly, can directly regulate lifespan was a surprise to us,” said lead author, Brian Hodge, PhD, who did his postdoctoral studies in Kapahi’s lab.
The explanation for this connection, Hodge said, lies in circadian “clocks,” the molecular machinery within every cell of every organism, which have evolved to adapt to daily stresses, such as changes in light and temperature caused by the rising and setting of the sun. These 24-hour oscillations — circadian rhythms — affect complex animal behaviors, such as predator-prey interactions and sleep/wake cycles, down to fine-tuning the temporal regulation of molecular functions of gene transcription and protein translation.
In 2016 Kapahi’s lab published a study in Cell Metabolism showing that fruit flies on a restricted diet had significant changes in their circadian rhythms in addition to extending lifespan. When Hodge joined the lab later that year, he wanted to dig deeper to figure out which processes that enhance circadian functions were altered by the diet change, and whether circadian processes were required for the longer lifespan seen with dietary restriction.
“The fruit fly has such a short lifespan, making it a really beautiful model that allows us to screen a lot of things at once,” said Hodge, who is currently a scientist at Fountain Therapeutics in South San Francisco. The study began with a broad survey to see what genes oscillate in a circadian fashion when flies on an unrestricted diet were compared with those fed just 10 percent of the protein of the unrestricted diet.

A major study, coordinated by neuroscientists at the University of Bath (UK) with international partners, has revealed key differences in brain structure between people with and without anorexia nervosa.
Anorexia — which is a severe eating disorder and mental health condition — affects over a quarter of a million people aged 16 and over in the UK. Symptoms are characterised by people trying to keep their weight as low as possible by not eating enough.
Understanding why some people develop anorexia whilst others do not is still largely unknown, although biological factors are widely recognised. These new findings, which draw on extensive analyses of brain scans taken from patients around the world and are published in the journal Biological Psychiatry, go some way to answering the question.
They reveal that people with anorexia demonstrate ‘sizeable reductions’ in three critical measures of the brain: cortical thickness, subcortical volumes and cortical surface area. Reductions in brain size are significant because they are thought to imply the loss of brain cells or the connections between them.
The results are some of the clearest yet to show links between structural changes in the brain and eating disorders. The team says that the effect sizes in their study for anorexia are in fact the largest of any psychiatric disorder investigated to date.
This means that people with anorexia showed reductions in brain size and shape between two and four times larger than people with conditions such as depression, ADHD, or OCD. The changes observed in brain size for anorexia might be attributed to reductions in people’s body mass index (BMI).