Monash University researchers have made a breakthrough discovery that might lead to new non-opioid analgesics to treat neuropathic pain safely and effectively, without the risk of opioid addictions.
Neuropathic pain occurs when nerves are damaged or dysfunctional, and can be caused by injury, virus infection or cancer treatment, or it can be a symptom or complication of conditions such as multiple sclerosis and diabetes.
The new study, published in Nature, has shown a new mode of targeting the adenosine A1 receptor protein, which had long been a promising therapeutic target for non-opioid painkillers to treat neuropathic pain. However, development of analgesics using it had failed due to a lack of sufficient on-target selectivity, as well as undesirable adverse effects.
In the study, Monash researchers used electrophysiology and preclinical pain models to show that a particular class of molecule, called a ‘positive allosteric modulator’ (PAM), can enhance the targeting of the A1 receptor by binding to a different region of the protein.
Another breakthrough in the study was observing the high-resolution structure of the A1 receptor bound to both its natural activator, adenosine, and an analgesic PAM, which was facilitated by the application of cryo electron microscopy (cryoEM), providing the first atomic level snapshot of the drug binding location.
Chronic pain remains a widespread global health burden. A lack of treatment options has led to over-reliance on opioid painkillers, which provide only limited relief in patients with chronic (particularly neuropathic) pain, while having severe adverse effects, such as respiratory depression and addiction. In 2016, 42 000 deaths related to opioid misuse were recorded in the US, while 25 million Americans suffer from chronic pain.
This new discovery opens the door to the development of non-opioid drugs that lack such side effects.
Co-corresponding author of the study and Dean of the Faculty of Pharmacy and Pharmaceutical Sciences, Professor Arthur Christopoulos said: “The world is in the grip of a global opioid crisis and there is an urgent need for non-opioid drugs that are both safe and effective.”
New research finds that one cause of organ damage in COVID patients is abnormal crosstalk between blood platelets and cells lining blood vessels.
The study published in Science Advances, revealed the protein signals released by platelets cause inflammation, abnormal clotting, and damage to vessels when exposed to SARS-CoV-2.
The work identified two related genes, S1000A8 and S1000A9, which are turned up in the platelets of COVID patients, causing them to make more of myeloid-related proteins (MRP) 8 and 14. Higher levels of the dual proteins were linked in the study to higher levels of clotting and inflammation in vessels and worse outcomes.
In support of the theory that platelets are at the core of blood vessel damage in COVID, the research team also presented evidence that approved medications known to block platelet activation via the platelet surface protein P2Y12 (clopidogrel or ticagrelor) reduced COVID-related inflammation in vessels. The study also found that COVID-exposed platelets change cells lining blood vessels (endothelial cells) largely through a protein called p-selectin, which makes platelets stickier and more likely to form clots.
“Our findings reveal a new role for platelets in COVID blood vessel damage, and may explain in large part what makes the COVID virus so much more deadly than its relatives that cause the common cold,” said corresponding author Tessa Barrett, PhD,.
Abnormal, body-wide inflammation and blood clotting were identified early in the pandemic as central features of severe COVID-19, with the two thought to be interrelated, say the study authors. As blood components that react to injuries in vessels by triggering inflammation, and by becoming sticky to clump together in clots, platelets are a possible culprit. Increasing evidence shows that interplay between platelets and endothelial cells may be important to these disease mechanisms.
For the current study, endothelial cells from small blood vessels were exposed to fluid released from the platelets of either COVID patients or healthy controls. RNA was then sequenced, In the presence of COVID-activated platelets, changes were observed in the activity of the exposed endothelial cells. Genes expressed differently in COVID-19 were linked to clotting, inflammation, and the weakening of junctions between endothelial cells, which lets blood serum seep into tissue to cause the pulmonary oedema seen in severe cases, where patients’ lungs fill with fluid.
The large list was narrowed down to S100A8 and S100A9, which coded for the building of MRP 8 and 14. COVID in patients was found to increase the amount of MRP8/14 produced by platelets and other cells by 166 percent compared to controls. Higher levels of these proteins were linked to abnormal thrombosis, inflammation, and critical illness among hospitalised COVID patients. Curiously S100A8/A9 were not upregulated after exposure of platelets to a coronavirus relative, CoV-OC43, which causes the common cold.
Additionally, damage and abnormal clotting could arise from p-selectin, which promotes platelet clumping and immune-boosting signals. The researchers also found that the anti-clotting P2Y12 inhibitors reduced the expression of S100A8 and S100A9 in platelets by 18 percent over four weeks, and in lab tests prevented COVID platelets from inducing blood vessel damage.
“The current study supports the theory that platelets are activating endothelial cells through P-selectin, and that both p-selectin and MRP8/14 contribute to vessel damage and an increased risk of dying,” said senior study author Jeffrey S. Berger, MD. “As our team also leads ACTIV4a, a large, ongoing NIH-funded, anti-clotting trial in COVID, we are currently testing in patients whether P2Y12 inhibitors can better prevent severe disease, with the results to be presented at the American Heart Association annual meeting in November.”
People with shortened telomeres caused by rare disorders may be more likely to have blood cancers such as leukaemia or myelodyplastic syndrome (MS). Now researchers have discovered several “self-correcting” genetic mutations in bone marrow that may protect such patients from these cancers.
In a study published in the Journal of Clinical Investigation, these mutations can serve as biomarkers to indicate if patients with short telomere syndromes (STS) are likely to develop blood cancers.
“These are the most common cancers we see in patients with short telomere syndromes,” said Mary Armanios, MD, director of the Telomere Center and professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. “We know that at a certain point, the cells of patients with shortened telomeres either become cancerous or stay healthy.”
Dr Armanios and her team suspected that a self-correcting mechanism in areas of the body with high cell turnover, such as bone marrow, was allowing normal cells to turn malignant. Instead, it appears this mechanism protects against cells from becoming cancerous.
As over 300 billion blood cells are produced in the bone marrow daily, the researchers suspected they could find evidence of cellular self-correction in this area of the body, especially amid the spongey interior of bones, where quick adaptation is crucial for high-volume cell production. The researchers tested the bone marrow and blood cells of 84 study participants divided into three groups: Those with STS and MS or leukaemia; those with short telomere syndromes and no MS or leukemia; and those in the control group without short telomere syndromes or any cancers.
Using ultra-deep genetic sequencing which picks up hard-to-detect mutations, Armanios and her team observed genetic mutations and self-correction in several telomere-associated genes. Nearly a quarter of patients with STS had these mutations, some even showing multiple mutations.
One such mutation in a gene called TERT enables the production of crucial parts of telomerase, which stabilises telomeres. By boosting telomerase production and overwriting faulty copies of the TERT gene, the researchers found that bone marrow cells seemed to self-correct to avoid becoming cancerous.
“Our findings speak to the versatility of the bone marrow and other areas with high cell turnover in the body,” says Armanios. “Such advantageous mutations provide the body with a better chance to protect itself. These findings may be important in the screening process of shortened telomere patients so that we can predict who may be protected from cancer.”
A study based on self-reported app data showed that people who eat a high quality, gut friendly diet are less likely to develop COVID-19 or become severely ill. Those eating poorer quality diets are more at risk, especially if they live in a more socioeconomically deprived area.
The study, presented in GUT, analysed data from almost 600 000 ZOE COVID Study app contributors. Participants completed a survey about the food they ate before the pandemic, in February 2020, making it the largest study in this space. 19% of these contributors contracted COVID-19.
People with the highest quality diet were around 10% less likely to develop COVID than those with the lowest quality diet, and 40% less likely to fall severely ill.
This is the first longitudinal study of diet and COVID and the first to show that a healthy diet cuts the chances of developing the disease in the first place.
Instead of looking at specific foods, the survey aimed to broadly capture people’s diets. A ‘diet quality score’ reflected the overall merit of each person’s diet. Diets with high quality scores were found to contain plant-based foods such as fruits, vegetables and whole grains, as well as oily fish, less processed foods and refined carbohydrates. A low diet quality score is associated with diets high in ultra processed foods and low amounts of plant based foods.
The researchers found that people who ate the highest quality diet were around 10% less likely to develop COVID-19 than those with the least nutritious diet and 40% less likely to become severely ill if they developed COVID.
The link between diet quality and COVID risk persisted after accounting for all potential confounding factors such as age and BMI. Mask-wearing habits and population density were also considered.
The effect of diet was amplified by individual life situations, with people living in low-income neighbourhoods with the lowest quality diet being around 25% more at risk from COVID than people in more affluent communities eating the same kind of diet.
Based on these results, the researchers estimate that nearly a quarter of COVID cases could have been prevented if these differences in diet quality and socioeconomic status had not existed. The study also showed that improved access to better food is an important public health consideration.
Dr Sarah Berry, study co-lead and Reader in nutritional sciences at the School of Life Course Sciences said: “For the first time we’ve been able to show that a healthier diet can cut the chances of developing COVID, especially for people living in the more deprived areas. Access to healthier food is important to everyone in society, but our findings tell us that helping those living in more deprived areas to eat more healthily could have the biggest public health benefits.”
Professor Tim Spector, professor of genetic epidemiology at the School of Life Course Sciences, said: “These findings chime with recent results from our landmark PREDICT study, showing that people who eat higher quality diets (with low levels of ultra-processed foods) have a healthier collection of microbes in their guts, which is linked to better health. You don’t have to go vegan, but getting more diverse plants on your plate is a great way to boost the health of your gut microbiome, improve your immunity and overall health, and potentially reduce your risk from COVID.”
A review published in Developmental Medicine & Child Neurology investigates the knowledge base of cannabis-based medicinal products in paediatric epilepsies, highlighting areas in need of additional research.
Following reports in the media of children with epilepsies apparently deriving benefits from medical marijuana (or cannabis-based medicinal products) accessed abroad, the UK government allowed clinicians to prescribe these products. A previous review found that there was some benefit in certain drug-resistant epilepsies in children.
In the review, the authors also looked at the prescribing environment surrounding these products. They found that the major obstacle to prescribing is a lack of quality evidence for efficacy and safety. The authors stress that unlicensed cannabis-based medicinal products should not circumvent the usual regulatory requirements before being prescribed. They are also concerned that children with epilepsy are at risk of being exploited as a “Trojan horse” for the cannabis industry, with widespread acceptance of medicinal cannabis accelerating the wider legalisation of marijuana and opening up a highly lucrative commercial market.
On Wednesday, the trial of Elizabeth Holmes, founder of medical technology company Theranos, began. Prosecutors alleged she “lied and cheated” for money and fame.
Ms Holmes faces 12 fraud charges over her role at the failed company which was once worth $9bn, facing up to 20 years in prison if found guilty.
She is accused of deceiving patients and investors about the company’s testing technology, which was claimed to diagnose basic illnesses from a few drops of blood. Her defence team argues that she was naive and her company simply failed.
“Failure is not a crime. Trying your hardest and coming up short is not a crime,” said defence lawyer Lance Wade in his opening statement on Wednesday.
Former Theranos executive Ramesh “Sunny” Balwani faces the same charges next year. He was romantically involved with Ms Holmes.
Ms Holmes, who founded Theranos in 2003 aged 19, was dubbed the world’s youngest self-made female billionaire and hailed as the “next Steve Jobs”.
In 2015 and 2016, investigations by the Wall Street Journal revealed Theranos’ blood-testing devices did not work and the company was doing most of its testing on commercially available machines made by other manufacturers. She initially denied these reports.
Prosecutor Robert Leach alleges that, after running out of funds, Ms Holmes and Mr Balwani turned to fraud in 2009, lying about the tests and exaggerating the firm’s performance. Mr Leach said this included falsely claiming the tests were vetted by Pfizer and being used by the US military.
The case will probably take months and Ms Holmes will likely take the stand — a necessary gamble in the face of overwhelming evidence that the technology did not work.
Ms Holmes “dazzled” Walgreens into using the company’s services, and the company brought her fame.
“She had become, as she sought, one of the most celebrated CEOs in Silicon Valley and the world. But under the facade of Theranos’ success there were significant problems brewing.”
The defence’s Mr Wade said Ms Holmes “naively underestimated” the business challenges but did not attempt to defraud investors. Ms Holmes has also alleged years of emotional and psychological abuse by Mr Balwani, who has denied the allegations. She is likely to testify as to how this affected her.
Stepping patterns become slower and more variable when a person is not comfortable with their environment, researchers have found.
The findings, published in PLoS One, shows that the perceived comfort of an environment, rather than it being natural or not, affects how people walk, with potential lessons for urban design.
Lead author Daria Burtan of Bristol’s School of Psychological Science said: “Measuring the changes of a person’s walking patterns through an environment allows us to understand their experienced comfort on a moment-to-moment basis.
“This is an important step toward being able to objectively quantify the impact of particular architectural designs on people’s wellbeing.”
Research has shown that spending time in green spaces such as parks helps improve attention spans, concentration and wellbeing, which can be shown by improvements in measured stepping patterns when walking in different environments.
Daria added: “As our cognitive faculties begin to decline in older age, the stepping patterns we make with our feet become slower and more variable, relative to when we are younger in the prime of our health. We found that the same thing happened when people walked toward images of urban and nature scenes they didn’t feel comfortable with – their stepping patterns became slower and more varied, relative to when they were looking at scenes they found comfortable and which they liked.
“Not only does this suggest that environments in which we feel comfortable and safe, place fewer processing demands on our brains; it demonstrates how measuring the real-time dynamics of our gait provides us with a powerful new tool for informing on the cognitive impacts of architecture and urban design.”
The researchers are now seeking to understand which psychological factors contribute to sensory discomfort.
A series of studies in recent months has found that, thanks to the mRNA vaccine and previous infection, some people mount an extraordinarily powerful immune response against SARS-CoV-2 which some scientists have referred to as ‘superhuman’.
Called ‘hybrid immunity’, their bodies produce very high levels of antibodies, with great flexibility: likely capable of fighting off the SARS-CoV-2 variants currently circulating but also likely effective against future variants.
“Overall, hybrid immunity to SARS-CoV-2 appears to be impressively potent,” Crotty wrote in commentary in Science published in June.
“One could reasonably predict that these people will be quite well protected against most and perhaps all of — the SARS-CoV-2 variants that we are likely to see in the foreseeable future,” says Paul Bieniasz, a virologist at Rockefeller University who helped lead several of the studies.
Bieniasz and his colleagues found antibodies in these individuals capable of strongly neutralising the six variants of concern tested, including Delta and Beta, as well as several other viruses related to SARS-CoV-2, including SARS-CoV-1.
“This is being a bit more speculative, but I would also suspect that they would have some degree of protection against the SARS-like viruses that have yet to infect humans,” Bieniasz said.
People who have had a ‘hybrid’ exposure to the virus, were infected with it in 2020 and then immunised with mRNA vaccines this year. “Those people have amazing responses to the vaccine,” said virologist Theodora Hatziioannou at Rockefeller University, who also helped lead several of the studies. “I think they are in the best position to fight the virus. The antibodies in these people’s blood can even neutralize SARS-CoV-1, the first coronavirus, which emerged 20 years ago. That virus is very, very different from SARS-CoV-2.”
These antibodies were so effective they were even able to deactivate a virus purposefully engineered to be highly resistant to neutralisation, containing 20 mutations that are known to prevent SARS-CoV-2 antibodies from binding to it. Antibodies from those who were only vaccinated or who only had prior coronavirus infections were ineffecgtive against this engineered virus..
This shows how powerful the mRNA vaccine can be in those infected with SARS-CoV-2, she said. “There’s a lot of research now focused on finding a pan-coronavirus vaccine that would protect against all future variants. Our findings tell you that we already have it.
The catch is getting COVID. “After natural infections, the antibodies seem to evolve and become not only more potent but also broader. They become more resistant to mutations within the [virus].”
Hatziioannou and colleagues don’t know if this applies to all those mRNA-vaccinated and previously COVID-infected. “We’ve only studied the phenomena with a few patients because it’s extremely laborious and difficult research to do,” she said. “With every single one of the patients we studied, we saw the same thing.” The study reports data on 14 patients.
Several other studies lend credence to her hypothesis and reinforce the idea that exposure to both a coronavirus and an mRNA vaccine triggers an exceptionally powerful immune response. In one study in NEJM, scientists analysed antibodies generated by people who had been infected with SARS-CoV-1 back in 2002 or 2003 and who then received an mRNA vaccine this year.
Remarkably, these people also produced high levels of antibodies that could neutralise a whole range of variants and SARS-like viruses. Many questions remain, such as the effect of a third booster shot, or being infected again.
“I’m pretty certain that a third shot will help a person’s antibodies evolve even further, and perhaps they will acquire some breadth [or flexibility], but whether they will ever manage to get the breadth that you see following natural infection, that’s unclear.”
Immunologist John Wherry, at the University of Pennsylvania, is a bit more hopeful. “In our research, we already see some of this antibody evolution happening in people who are just vaccinated,” he said, “although it probably happens faster in people who have been infected.”
In a recent study, Wherry and colleagues showed that, over time, uninfected people with only two doses of the vaccine begin to produce more flexible antibodies, so a third dose would give even more of an evolutionary boost to the antibodies, Wherry said. So a person will be better equipped to fight off whatever variant the virus puts out there next.
“Based on all these findings, it looks like the immune system is eventually going to have the edge over this virus,” said Bieniasz, of Rockefeller University. “And if we’re lucky, SARS-CoV-2 will eventually fall into that category of viruses that gives us only a mild cold.”
Emoji, those colourful symbols we use in WhatsApp and other communication applications, could be a valuable medical tool which lets patients better communicate symptoms, concerns, and other clinically relevant information, researchers argue.
In a commentary in the Journal of the American Medical Association, senior author Shuhan He, MD, an emergency department attending, advises that each medical discipline start to come up with its own unique set of iconography for official adoption and incorporation into everyday practice.
“The need to listen to patients is at the core of our mission as physicians, and the use of emoji is a great opportunity to take communication to another level,” said Dr He. “Emoji could be particularly important in treating children with still-developing language skills, people with disabilities that impair their ability to communicate, and the many patients who speak a different language.”
While around 3500 emoji are currently within the domain of the Unicode Consortium – the nonprofit organisation that maintains text standards across computers – only about 45 emoji can be considered relevant to medicine. The first, introduced in 2015, were the syringe and the pill. Apple added emoji in 2017 to represent people with disabilities, followed by symbols of the stethoscope, bone, tooth and microbe in 2019. He was co-creator of the anatomical heart and the lung emoji introduced globally in 2020 and is now working with colleagues, as well as with a wide range of medical societies and organisations to advocate for an additional 15 medically related emoji.
“It’s tempting to dismiss emoji as a millennial fad, but they possess the power of standardisation, universality and familiarity, and in the hands of physicians and other health care providers could represent a new and highly effective way to communicate pictorially with patients,” said Dr He. In emergency medical settings where time is critical, emoji could lead to a point-and-tap form of communication that could facilitate important clinical decisions, he adds. The tiny graphic symbols which now span all digital platforms – from mobile to tablet to desktop – could also have utility as annotations to hospital discharge instructions, which are often confusing if not incomprehensible to some patients.
The recent surge of telemedicine presents a great opportunity for medical emojis. It is well suited for patients visually conveying to healthcare providers the intensity of pain they have experienced over time, and for those providers to incorporate it into digital health records.
His research is on emoji to help patients and doctors communicate common symptoms – such as mobility, mood, and duration and quality of pain – that are associated with various diseases and conditions. “It’s clear that emoji have become part of the global, mainstream conversation, and that medical societies and physician committees and organisations need to take them seriously,” said Dr He. “Which means they should be determining now which emoji would best serve the interests of their patients, building consensus around the medical accuracy of these emoji, then working to get them approved through the global standard-setting body and working through the long adaptation and implementation process.”
A study into food purchasing behaviours shows that placing fruit and vegetables near store entrances and removing confectionery and other unhealthy products from checkouts and the end of nearby aisles prompts customers to make healthier food purchases.
The study, led by Dr Christina Vogel, Principal Research Fellow in Public Health Nutrition and Janis Baird, Professor of Public Health and Epidemiology at the University’s MRC Lifecourse Epidemiology Centre, was conducted in partnership with the national supermarket chain Iceland Foods Ltd. The trial took place in a number of Iceland stores in England, monitoring store sales as well as dietary patterns of sample customers.
The results showed confectionery sales decreased throughout the store while fruit and vegetable sales increased when non-food items and water were placed at checkouts and at the end of the opposite aisles, and an expanded fruit and vegetable section was repositioned near the store entrance. Beneficial effects were also observed for household fruit and vegetable purchasing and individual dietary quality. The findings are presented in the open-access journal PLOS Medicine.
Discussing the results of the study Dr Vogel said “Altering the layouts of supermarkets could help people make healthier food choices and shift population diet towards the government’s dietary recommendations. The findings of our study suggest that a healthier store layout could lead to nearly 10 000 extra portions of fruit and vegetables and approximately 1500 fewer portions of confectionery being sold on a weekly basis in each store.”
This research is more comprehensive than previous studies testing whether placement strategies can promote healthier food purchasing which have been limited in scope, for example including only a single location (ie at checkouts) or placing healthy and unhealthy products together. This study further aimed to reduce exposure of customers to calorie opportunities by placing non-food items at checkout and aisle-ends opposite and measuring effects on store sales, purchasing patterns on customer loyalty cards and the diets of more than one household member.
Matt Downes, Head of Format Development at Iceland, said: “We have been pleased to support this long-term study and the evaluation of how product placement in supermarkets can affect the diets of our customers. We know that childhood obesity is a growing issue and the retail industry has its part to play in tackling this. We hope that the outcomes of the study provide insights for the wider retail industry and policy makers about the impact of store merchandising on purchasing decisions.”
Prof Baird added “These results provide novel evidence to suggest that the intended UK government ban on prominent placement of unhealthy foods across retail outlets could be beneficial for population diet, and that effects may be further enhanced if requirements for a produce section near supermarket entrances were incorporated into the regulation.”
