Culture

Researchers at the Francis Crick Institute and the Latvian Institute of Organic Synthesis have designed a drug-like compound which effectively blocks a critical step in the malaria parasite life cycle and are working to develop this compound into a potential first of its kind malaria treatment.

While drugs and mosquito control have reduced levels of malaria over recent decades, the parasite still kills over 400,000 people every year, infecting many more. Worryingly, it has now developed resistance to many existing antimalarial drugs, meaning new treatments that work in different ways are urgently needed.

In their research, published in PNAS, the scientists developed a set of compounds designed to stop the parasite being able to burst out of red blood cells, a process vital to its replication and life cycle. They found one compound in particular was highly effective in human cell tests.

"Malaria parasites invade red blood cells where they replicate many times, before bursting out into the bloodstream to repeat the process. It's this cycle and build-up of infected red blood cells which causes the symptoms and sometimes fatal effects of the disease," says Mike Blackman, lead author and group leader of the Malaria Biochemistry Laboratory at the Crick.

"If we can effectively trap malaria in the cell by blocking the parasite's exit route, we could stop the disease in its tracks and halt its devastating cycle of invading cells."

The compound works by blocking an enzyme called SUB1, which is critical for malaria to burst out of red blood cells. Existing antimalarials work by killing the parasite within the cell, so the researchers hope this alternative drug action will overcome the resistance the parasite has acquired.

Importantly the compound is also able to pass through the membranes of the red blood cell and of the compartment within the cell where the parasites reside.

The team is continuing to optimise the compound, making it smaller and more potent. If successful, it will need to be tested in further experiments and in animal and human trials to show it is safe and effective, before being made available to people.

Chrislaine Withers-Martinez, author and researcher in the Malaria Biochemistry Laboratory, says: "Many existing antimalarial drugs are plant derived and while they're incredibly effective, we don't know the precise mechanisms behind how they work. Our decades of research have helped us identify and understand pathways crucial to the malaria life cycle allowing us to rationally design new drug compounds based on the structure and mechanism of critical enzymes like SUB1.

"This approach, which has already been highly successful at finding new treatments for diseases including HIV and Hepatitis C, could be key to sustained and effective malaria control for many years to come."

Multiple sclerosis, or MS for short, manifests itself slightly differently in each person - which is why some call it "the disease of a thousand faces." Arguably the worst manifestation of MS is its chronic progressive form. Unlike the more common relapsing-remitting variant (RRMS), in which sufferers are often symptom-free for months or even years, patients with the primary progressive form of the disease (PPMS) see their condition steadily deteriorate with no remissions.

Poorly insulated neurons die off

Today's therapeutic approaches are based on the assumption that the immune system is making a mistake and waging an inappropriate attack on the layer of myelin that surrounds and insulates the nerve cells' long, cable-like branches called axons. "In progressive MS, neurodegenerative processes steadily multiply and cause more and more neurons in the brain and spinal cord to die," explains Dr. Alexander Brandt, lead author of the study that has now been published in the journal JAMA Neurology. "However, we still do not know what exactly causes this disease variant."

Together with Professor Friedemann Paul from the Experimental and Clinical Research Center (ECRC), a joint institution of Charité - Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), as well as eleven colleagues from Berlin, Irvine and Toronto, Brandt now hopes he has shed some more light on the subject. As the team reports in their study, it appears that the simple sugar N-acetylglucosamine, or GlcNAc for short, could play an important role in the development of progressive MS. Inside an organism, GlcNAc and other sugar molecules attach to proteins on the cell surface in the form of chains. This mechanism, which is known as glycosylation, controls various cell functions by forming branched structures from these sugar chains.

The sugar molecule could serve as a biomarker

"We studied 120 subjects from Irvine and were able to show that, in this particularly severe form of the disease, there are significantly lower concentrations of N-acetylglucosamine in the blood serum than there are in healthy people or patients with relapsing-remitting MS," reports Brandt. At the time of this study, the physician was head of the Translational Neuroimaging laboratory in Paul's Clinical Neuroimmunology group at Charité. Brandt has since moved to the School of Medicine at the University of California, Irvine (UCI) as an associate professor of neurology, but remains a guest researcher at Charité.

"In another study of 180 patients from Berlin with relapsing-remitting or progressive MS, we also found that low serum levels of GlcNAc are associated with the development of the progressive form of the disease, clinical disability and neurodegeneration," adds the study's corresponding author, Professor Michael Demetriou of UC Irvine. "This opens up potential new avenues for identifying, at an early stage, which patients are at higher risk of progressive MS and adjusting their treatment accordingly."

Human treatment studies now in the pipeline

Back in autumn 2020, Brandt, Demetriou and other researchers working with the then lead author Dr. Michael Sy from UC Irvine published a study in the Journal of Biological Chemistry. They had administered GlcNAc to lactating mice and found that the animals passed on this simple sugar, which incidentally is also contained in human breast milk, to their offspring. This stimulated primary myelination of the neuronal axons in the young animals. "We also observed in the mouse experiments that N-acetylglucosamine activates myelin progenitor cells, thus promoting both primary myelination and the repair of damaged myelin," says Brandt.

The researchers therefore hope that GlcNAc not only has potential as a suitable biomarker for progressive MS, but could also pave the way for new therapeutic strategies. "Our hope is that we can use GlcNAc and the associated glycosylation mechanism to promote myelin repair and thus reduce neurodegeneration," summarizes Brandt. An initial, as-yet-unpublished phase I trial has just been completed with around 30 subjects, where the scientists investigated the safety of taking GlcNAc in certain doses. If it is shown to be safe, the scientists hope to be able to conduct further studies into this simple sugar's possible efficacy as an MS therapy.

A giant mosasaur from the end of the Cretaceous period in Morocco that could have reached up to eight metres long is the third new species to be described from the region in less than a year, bringing the total number of species up to at least 13.

The high diversity of the fauna shows how mosasaurs, giant marine lizards related to snakes and Komodo dragons, thrived in the final million years of the Cretaceous period before they, and most of all species on Earth, were wiped out by the impact of a giant asteroid 66 million years ago.

The new species, named Pluridens serpentis, had long, slender jaws with over a hundred sharp, fanglike teeth to grab small prey like fish and squid. Compared to related species, it had small eyes, suggesting poor vision. But the snout had dozens of openings for nerves, hinting at the ability to hunt by sensing water movements and changes in pressure. These nerves may have been sensitive to tiny variations in water pressure, an adaptation seen in sea snakes.

"Typically, when animals evolve small eyes, it's because they're relying more heavily on other senses," said Dr Nick Longrich, senior lecturer at the Milner Centre for Evolution at the University of Bath, who led the study.

The fact that Pluridens had so many nerves in the face may mean that it was using changes in water pressure to detect animals in low-light conditions, either at night or in deep, dark water. Mosasaurs may also have had other senses at their disposal.

"If it wasn't using the eyes, then it's very likely that it was using the tongue to hunt, like a snake," he said. "Many aquatic snakes and lizards - sea snakes, filesnakes, water monitors- flick their forked tongues underwater, using chemical cues to track their prey. Mosasaurs would have resembled whales and dolphins, so it's tempting to assume they lived like them.

"But they're very different beasts - they're huge lizards - so they probably acted like them."

While most of its relatives were small, just a few meters long, Pluridens got big, perhaps eight meters long. The largest individuals had thick, heavily built jawbones.

"It's possible that big males were fighting with these jaws," said Dr Longrich. "In some beaked whales, the males have massive jaws they use to fight with, and male sperm whales can be highly aggressive. Some Pluridens jaws show healing injuries, which suggests some violent fights."

The Moroccan mosasaurs were wildly diverse. Some had small teeth for seizing fish and squid, others evolved blunt teeth to crush crustaceans, clams, and ammonites, while others had teeth designed to cut or tear apart other marine animals - including other mosasaurs.

Pluridens brings the number of mosasaurs known from latest Cretaceous of Morocco up to 13, but the researchers suggest it's unlikely to be the last new species.

Dr Longrich said: "The diversity in these fossils is just astonishing. Far from declining in diversity, the mosasaurs seem to be peaking just before they went extinct.

"We're not seeing any evidence that this group was struggling before they went extinct - From an evolutionary standpoint, they were succeeding, they did everything right- but nothing can prepare you for an asteroid."

Co-author on the study, Dr Nour-Eddine Jalil from the Natural History Museum of Sorbonne University (France) said: "It's a new species of a large predator which, with its eight metre length, comes to confirm the diversity of the faunas of the seas just before the Cretaceous crisis.

"Pluridens serpentis highlights the importance of the paleontological heritage of Morocco to help illustrate the history of life."

Dr Nathalie Bardet, a specialist in mosasaurs, particularly those from the Phosphates of Morocco, at the Muséum National d'Histoire Naturelle of Paris, was also co-author on the paper.

She said: "Working on this group of marine reptiles since more than 20 years, I never stop being surprised by the incredible diversity of these predators, who all lived there and shared the available space and food resources.

"These latest discoveries show perfectly that the list of species present here is far from being closed and that the future still holds great surprises and discoveries!"

A study published in the journal Scientific Reports reveals the genetic structure of the land snail Xerocrassa montserratensis and it provides new scientific tools for the improvement of the conservation of this endemic and threatened species in Catalonia. This land mollusc, identified in the late 19th century in the Montserrat mountain, has a reduced geographical distribution limited to the province of Barcelona, and it is a protected species in the area of the natural parks of Montserrat and Sant Llorenç del Munt i l'Obac.

The study is led by the lecturer Marta Pascual, from the Faculty of Biology and the Biodiversity Research Institute of the University of Barcelona (IRBio), and signed by Cristina Català (UB-IRBio), Vicenç Bros (Barcelona Provincial Council), Xavier Castelltort (University of Lleida), and Xavier Santos (Research Center in Biodiversity and Genetic Resources - CIBIO, Portugal). Both the paper and its publication received the collaboration of the team of the Office of the Natural Park of Sant Llorenç del Munt i l'Obac, and the economic support of the Technical Office of the Natural Parks from the Barcelona Provincial Council park network.

An endemic species described more than a hundred years ago in Montserrat

The species Xerocrassa montserratensis --previously named Helix montserratensis--, is a uniqueness of the terrestrial malacological fauna in Catalonia described by Joaquín González Hidalgo in 1870 in the Montserrat mountain. Also, in the late 19th century, Artur Bofill had described two sub-species according to the morphological character of the shell: X. m. betulonensis and X. m. delicatula.

This Catalan endemism, considered to be an excellent model in phylogeographical studies, is found in open spaces of typical bare stony slopes of conglomerate lithology, but not in forestal areas. Surprisingly, the species was detected in areas that had been previously burnt, "which would indicate a high ability to survive or colonize which is not described yet in the scientific literature", notes the expert Xavier Santos, from CIBIO.

As part of the research study, the team applied the methodology based on the so-called DNA barcoding, which uses a short and standardized fragment of DNA --in this case, the mitochondrial gen Cytochrome Oxidase I (COI)-- to facilitate the identification of species and detection of differenced evolutionary groups. This methodology allows researchers to classify most of the species with a high resolution, and in many cases, it provides a great intraspecific variability to detect barriers in the genic flow between populations.

"Since these molluscs have a low mobility, from the from a scientific perspective it was quite interesting to determine whether this endangered species had a populational structure", reveals Marta Pascual, lecturer at the Department of Genetics, Microbiology and Statistics.

The study enabled the researchers to test the hypothesis from a hundred years ago, which related the population of the mountain chain of Marina --in the Catalan littoral mountain chain-- with populations in the upstream waters in the Besòs River.

The team identified genetic groups in areas where different sub-species had been described, a hypothesis that had been under doubts recently by several morphological studies. The results show that the genetically differenced groups are in those populations where the different sub-species had been described more than a century ago. Moreover, researchers also identified a new area where the groups are strongly differenced --Munts, in the Catalan transversal mountain chain--, which should be studied in detail in future studies.

"Our study provides information favouring the validity of these sub-species but we need to advance with the research studies and to conduct morphometric and genomic studies to determine whether there is a reproductive isolation among the different mitochondrial groups", notes Marta Pascual.

A genetic diversification situation during the Pleistocene

According to the authors, the process of diversification of the genetic groups --combined with the specificity of their natural habitat-- could be related to the geological and paleoclimate processes during the Pleistocene, which finally contributed to shaping the current genetic structure of the species. These processes could explain the origins of the vast radiation of species of the gender Xerocrassa in some Mediterranean islands, such as Crete or the Balearic Islands, as stated by the authors.

"It is shocking to find that close populations are that genetically differenced, and at the same time, that a species with such a reduced distribution area can present genetically differenced groups at a mitochondrial level", notes Xavier Santos.

Skeletal muscles make a tremendous variety of actions stabilizing the body in different positions. Despite their endurance during daily activities, they can undergo several mild injuries caused by sport, accidental overstretching, or sudden overtwisting. Luckily mild injuries can be quickly healed; however, when a large part of muscles is damaged or resected surgically, the full recovery can be impossible. Muscle regeneration is challenging, but the development of innovative biocompatible materials tackles that problem. Recently, a multinational team of scientists led by dr. Marco Costantini from the Institute of Physical Chemistry, Polish Academy of Sciences (IPC PAS), and dr. Cesare Gargioli from the University of Rome Tor Vergata (Italy) presented a biofabricated myo-substitutes to restore significantly injured skeletal muscles with unprecedented efficiency.

3xM - muscles, myofibers, and myogenesis

Muscles are the largest tissue in the body. They are essential for motion, and without them, we would be unable even to stand up, walk or pick a food from the table. Every day, our muscular system performs an endless variety of movements that engage millions of fiber-like tissues into the contracting, shortening, returning to their original shape, relaxing, and even lengthening passively when the other muscles contract. There are two types of muscles: involuntary and voluntary muscles. Involuntary muscles are automatically controlled by the brain, like the muscles shrinking during heartbeats or breathing, while voluntary muscles are actioned when deciding to make a move. Some of them are short like muscles in the ear, while others are long, like the calf muscle controlling the ankle, foot, and toes movement. Each one is highly resistant to stretching and pressure, while there are some limits to their performance. Likewise all tissues in the body, muscles can be injured. Sudden pulling or twisting occurring by accident or in sports can lead to muscle strains, tears, or even ruptures. In some diseases like cancers, dystrophy, or mechanical damage, they can be affected entirely or mechanically cut.

Despite our body's impressive ability to regenerate itself daily, skeletal muscles in some cases cannot be fully revived. When they are damaged, just after the inflammation and swelling, the body tries to bundle, contracting individual muscle fibers step by step, activating them to grow. These tiny fibrils called myofibers are generated to create the new muscle tissue within the myogenesis process. When the muscles' damage is slight, they can recover completely, although repairing significant mass defects complicates the total healing. That makes muscle restoration and their functionalities improvement one of the biggest biomedical challenges of our times.

Let's get starting - regeneration in progress.

Recently, Marco Costantini from IPC PAS with a multinational team presented a biofabrication solution to tackle volumetric muscle loss. They have created a biocompatible spaghetti-like gel resembling a native muscle structure that can be easily made using a 3D bioprinting process. Researchers have synthesized such a gel from an aqueous solution containing natural polymers and encapsulated muscle progenitors, forming a matrix for natural fibers growth. Such highly biomimetic gel was created using a new bioprinting platform that combines a microfluidic printing head with a wet-spinning technology.

Dr. Marco Costantini remarks, "Our bioprinting system has been envisioned to precisely mimic the highly anisotropic architecture of skeletal muscles, resulting in an improved guidance and differentiation of muscle progenitors into functional structures".

Then, the gel was pre-cultured for a week in vitro to stimulate cell growth and then was implanted into the damaged tissues of a mouse patient having resected muscle. The injury presented in this work was significant as it would need up to several months for healing without restoring the full spectrum of initial functions. The bioprinted skeletal muscle substitute enabled restoring up to 90% of the actual functionalities. Moreover, the muscles were recovered within just 20 days making the synthesized gel a promising material for biomedical application supporting tissue regeneration.

"Restoring the mass and functionalities of a 90% ablated muscle in just 20 days is an absolute record that motivates us in further exploring this approach in the near future. Now, we need to upscale our platform to biofabricate constructs that could support the regeneration of muscles in large-size animals, proving that this technology could be ready in a reasonable time for clinical use in humans." - claims dr. Marco Costantini

The technology presented by scientists from IPC PAS makes it possible to bioprint living materials on-demand, offering a new alternative of a faster and better recovery to those who suffer from severe skeletal muscle mass loss.

The research was published on 15th February in EMBO Molecular Medicine, opening new horizons for the regeneration of tissues that would not be recovered at all in natural conditions.

This study was supported by the National Science Centre Poland (NCN) within SONATA 14 Project No. 2018/31/D/ST8/03647 to dr. Marco Costantini.

Tuberous Sclerosis Complex (TSC) affects between one and two of every 10,000 new-born babies. This genetic disease leads to the formation of benign tumours which can massively impair the proper functioning of vital organs such as the kidneys, the liver and the brain. The disease affects different patients to varying degrees and is triggered by mutations in one of two genes, the TSC1 or TSC2 gene. An interdisciplinary team of researchers led by biochemists Prof. Daniel Kümmel and Dr. Andrea Oeckinghaus from the University of Münster (Germany) examined the "tumour suppressor protein TSC1" and, for the first time, gained insights into its hitherto unclear functions. The team identified a new mechanism, in a central cellular process, which regulates cell growth. The results can also help in understanding how Tuberous Sclerosis Complex arises. The results of the study have now been published in the journal Molecular Cell (advance publication online).

Mutations concern a "burr effect"

The TSC1 protein and the TSC2 protein together form the TSC protein complex. This has the task of controlling cell growth and, as a result, of suppressing the emergence of tumours - hence the term "tumour suppressor". Previously, it had largely been unclear what the functions of TSC1 were. Similarly, little was known about the mechanism which is affected by certain mutations in the TSC1 gene in the occurrence of the disease. The researchers have now found out that one part of the TSC1 protein, a so-called domain, can bind to the surfaces of lysosomal membranes. Lysosomes are small compartments in the interior of the cell, surrounded by a membrane, which contain digestive enzymes. On their surface there are certain control centres which are important for the regulation of cell growth. The TSC1 protein ensures that the entire TSC complex arrives at these control centres and prevents any uncontrolled cell growth by inhibiting the activity of an important signal protein called "mTOR" - "Mechanistic Target of Rapamycin".

"In this process," Daniel Kümmel explains, "TSC1 uses a strategy reminiscent of the principle of the burr. The burr's individual hooks stick to material only very weakly, but lots of hooks together provide a firm attachment." The study shows that TSC1's individual membrane binding domain only forms a weak attachment. However, a strong attachment becomes possible with a controlled aggregation of a large number of TSC1 molecules. "Mutations occur particularly frequently in the membrane binding domain," says Andrea Oeckinghaus. "We assume that some of the pathogenic effects can now be explained by a loss of the correct localization of the TSC complex."

Membrane component regulates cell growth

Another discovery the team made is that the properties of the membrane surface can influence the way the TSC complex functions and, as a result, the growth processes in the cell. More precisely, the team identified a special component in the membrane: a lipid called phosphatidylinositol 3,5-bisphosphate (PI3,5P2), which is necessary for the activity of the TSC complex. Depending on how often it occurs on the membrane's surface, it has different effects on the activity. "As the production and breakdown of this lipid are regulated," says Daniel Kümmel, "this opens up entirely new perspectives on how cell growth can be controlled. This means that our results are an exciting starting point for further studies."

The team of researchers used a broad range of methods in its investigations, starting from approaches using structural biology and biochemistry, and also involving cell-biological experiments. "The resulting insights into mechanistic and physiological aspects were only possible through our interfaculty collaboration," says Kümmel.

The work was carried out jointly by the team headed by Dr. Andrea Oeckinghaus (Münster University Faculty of Medicine and Münster University Hospital, Institute of Molecular Tumour Biology) and the team led by Prof. Daniel Kümmel (Münster University Faculty of Chemistry and Pharmacy, Institute of Biochemistry). Important contributions were made by partners at the Max Planck Institute for the Biology of Ageing, Cologne (team headed by Dr. Constantinos Demetriades) and at the Max Planck Institute for Molecular Physiology, Dortmund (team led by Prof. Stephan Raunser).

Meat that is certified organic by the U.S. Department of Agriculture is less likely to be contaminated with bacteria that can sicken people, including dangerous, multidrug-resistant organisms, compared to conventionally produced meat, according to a study from researchers at the Johns Hopkins Bloomberg School of Public Health.

The findings highlight the risk for consumers to contract foodborne illness--contaminated animal products and produce sicken tens of millions of people in the U.S. each year--and the prevalence of multidrug-resistant organisms that, when they lead to illness, can complicate treatment.

The researchers found that, compared to conventionally processed meats, organic-certified meats were 56 percent less likely to be contaminated with multidrug-resistant bacteria. The study was based on nationwide testing of meats from 2012 to 2017 as part of the U.S. National Antimicrobial Resistance Monitoring System (NARMS).

In order for meat to be certified organic by the USDA, animals can never have been administered antibiotics or hormones, and animal feed and forage such as grass and hay must be 100 percent organic. A longstanding concern about antibiotic use in livestock and livestock feed is the increased prevalence of antibiotic-resistant pathogens. To monitor this trend, in 1996 the federal government developed NARMS to track antibiotic resistance in bacteria isolated from retail meats, farmed animals, and patients with foodborne illness in the U.S.

For their study, the Bloomberg School research team analyzed U.S. Food and Drug Administration-NARMS data from randomly sampled chicken breast, ground beef, ground turkey, and pork for any contamination and for contamination by multidrug-resistant organisms. The analysis covers four types of bacteria: Salmonella, Campylobacter, Enterococcus, and Escherichia coli.

The study covered a total of 39,348 meat samples, of which 1,422 were found to be contaminated with at least one multidrug-resistant organism. The rate of contamination was 4 percent in the conventionally produced meat samples and just under 1 percent in those that were produced organically.

The study was published May 12 in Environmental Health Perspectives.

"The presence of pathogenic bacteria is worrisome in and of itself, considering the possible increased risk of contracting foodborne illness," says senior author Meghan Davis, DVM, PhD, associate professor in the Department of Environmental Health and Engineering at the Bloomberg School. "If infections turn out to be multidrug resistant, they can be more deadly and more costly to treat."

The analysis also suggested that the type of processing facility may influence the likelihood of meat contamination. Meat processors fall into three categories: exclusively organic, exclusively conventional, or those that handle both organic and conventional meats--so-called "split" processors. The study found that among conventional meats, those processed at facilities that exclusively handled conventional meats were contaminated with bacteria one-third of the time, while those handled at facilities that processed both conventional and organic meats were contaminated one-quarter of the time. The prevalence of multidrug-resistant bacteria was roughly the same in these two meat processor categories.

"The required disinfection of equipment between processing batches of organic and conventional meats may explain our findings of reduced bacterial contamination on products from facilities that process both types of meats," says Davis.

The authors believe their findings have relevance for regulatory agencies and consumers. "How we raise animals matters," says Davis. "As a veterinarian, I recognize that we sometimes need to use antibiotics to treat sick animals, but taking advantage of opportunities to reduce antibiotics use could benefit everyone. Consumer choice and regulatory oversight are two strategies to do this."

JOHNS HOPKINS MEDICINE TEAM TESTS MEDICAL MARIJUANA AS POSSIBLE THERAPY FOR CHRONIC ITCH

https://www.hopkinsmedicine.org/news/newsroom/news-releases/research-story-tip-johns-hopkins-medicine-team-tests-medical-marijuana-as-possible-therapy-for-chronic-itch

Media Contact: Sheree-Monet Wisdom, swisdom1@jhmi.edu

Chronic itch -- known clinically as chronic pruritus -- is characterized as an unrelenting and sometimes even debilitating sensation to itch, and often lowers the quality of life for those who suffer with it. Treating the condition has been difficult because there are few Food and Drug Administration-approved therapies. Now, a recent case study by Johns Hopkins Medicine researchers provides evidence that a promising option for patients with chronic itch may already be available: medical marijuana (cannabis).

A report on the team's findings was published April 9, 2021, in JAMA Dermatology.

"Chronic itch can be an especially difficult condition to treat, with off-label therapeutics often utilized," says Shawn Kwatra, M.D., assistant professor of dermatology at the Johns Hopkins University School of Medicine. "With the increased utilization of medical marijuana and our knowledge of the role of the endocannabinoid system [a complex cell-signaling system that regulates a variety of functions in the body] in chronic itch, we decided to try medical marijuana with a patient who failed several therapies and had few options left."

Kwatra and his colleagues examined an African American woman in her 60s with a 10-year history of chronic itch. The patient initially arrived at the Johns Hopkins Itch Center with complaints of extreme pruritus on her arms, legs and stomach. Upon a skin examination, numerous hyperpigmented, raised skin lesions were revealed. Several treatments were offered to the patient -- including several systemic therapies, centrally acting nasal sprays, steroid creams and phototherapy -- but they all failed.

Kwatra says that using medical marijuana -- either by smoking or in liquid form --provided the woman with nearly instantaneous improvement.

"We had the patient rate her symptoms using a numerical rating scale, where 10 is the worst itch and zero is no itch at all," Kwatra says. "She started at 10 but dropped to 4 within 10 minutes after initial administration of the medical marijuana. With continued use of the cannabis, the patient's itch disappeared altogether."

The researchers believe that one of the active ingredients in medical marijuana, tetrahydrocannabinol -- commonly known by its abbreviation THC -- attaches itself to brain receptors that influence the nervous system. When this occurs, inflammation and nervous system activity decrease, which also could lead to a reduction in skin sensations such as itchiness.

Kwatra says that although conclusive studies have yet to be done to validate medical marijuana as an effective measure for the relief of previously unmanageable itch, he believes it warrants further clinical trials.

"Controlled studies are needed to determine dosing, efficacy and safety for medical marijuana in the treatment of various human itch subtypes, and once those are performed, we will better understand which patients are most likely to benefit from this therapy," he says.

Kwatra is available for interviews.

JOHNS HOPKINS MEDICINE PUTS FAT TO GOOD USE AS STEM CELL SOURCE FOR SPINAL FUSION SURGERY

https://www.hopkinsmedicine.org/news/newsroom/news-releases/research-story-tip-johns-hopkins-medicine-puts-fat-to-good-use-as-stem-cell-source-for-spinal-fusion-surgery

Media Contact: Michel Morris, melben1@jhmi.edu

Adipose cells, better known as fat, may be the least popular component of the human body. However, most people don't realize that fat actually has many important functions in establishing and maintaining good health -- providing energy, insulating the body against heat loss and protecting nerves, just to name a few. Now, researchers at Johns Hopkins Medicine suggest there's another role for the poor maligned adipose cell: a practical and plentiful source of stem cells for use in spinal fusion surgeries.

Spinal fusion, used to correct problems in the spine, is the "welding" together of two or more vertebrae so that they heal into a single, solid bone. Unfortunately, the surgery -- using bone taken from other parts of the patient's body -- fails in up to one out of every five procedures. Researchers have found that stem cells, harvested from a patient's marrow and allowed to mature into bone cells, can yield successful outcomes when used in spinal fusions. However, the aspiration method for extracting stem cells from the marrow carries a risk of infection and often is painful.

In a study published in the May 2021 issue of the journal Spine, Timothy Witham, M.D., director of the Johns Hopkins Neurosurgery Spinal Fusion Laboratory, Alexander Perdomo-Pantoja, M.D., a postdoctoral fellow at the Johns Hopkins University School of Medicine, and Christina Holmes, Ph.D., a former Johns Hopkins Medicine postdoctoral fellow now at Florida State University, worked together with colleagues to try out adipose cells rather than bone marrow as a source for the stem cells.

Performing spinal fusion procedures in rats, the researchers found that freshly isolated stem cells from fat worked just as well as the more commonly used bone marrow stem cells. The researchers say this suggests the technique could be a candidate for human clinical trials.

"Bone marrow stem cells are isolated in human patients from the hip," says Holmes. "But using a huge needle to take out bone marrow is a painful procedure, and we can only get a limited number of cells, so we've found an alternative source by using stem cells from fat."

Perdomo-Pantoja says spinal fusion procedures are used to treat many different conditions.

"Spinal fusions are used for anything that causes spinal instability, which usually produces significant mechanical pain," he says. "You see it frequently when we get older as the intervertebral discs, ligaments and muscles in the spine deteriorate. But these procedures can also be used to treat instability when it is caused by tumors, fractures, deformities or trauma."

In this study, Witham, Perdomo-Pantoja, Holmes and their team isolated stem cells from fat and bone marrow, and then implanted them into rat spines. For the adipose-derived stem cells, the researchers chose to use freshly isolated cells to see if they could make the procedure simpler and faster.

Currently, stem cells from either bone marrow or fat are frequently grown in a laboratory culture to get them mature enough for a spinal fusion. During culturing, there is some risk of contamination or transformation into unusable bone. Holmes says that freshly isolating cells avoids these problems, along with being less labor intensive and cheaper because expensive processing materials are not needed.

While stem cells from fat are commonly used in cosmetic procedures, they are not often used in spinal fusions, she adds.

"We feel that fat cells are a logical alternative to bone marrow cells because most patients have an adequate supply of fat cells," Witham says. "Fat also is much more accessible during surgery and can be harvested with less stem cell death than bone marrow. Spinal fusion is a very common procedure, and we feel this approach could be applied across a wide cohort of spinal fusion patients."

The researchers also were pleased to see the quality of the bone created by both forms of stem cells. They found significantly more bone formation and blood supply in the fresh adipose-derived stem cells compared with what they observed in previous studies with cultured cells from both fat and bone marrow.

Witham and his team hope to further their research by next identifying which cells are the most advantageous for spinal fusions and then characterizing them.

Witham is available for interviews.

NEW AUTOMATED INSULIN INFUSION SYSTEM MAY POTENTIALLY REDUCE MEDICAL ERRORS, IMPROVE CARE

https://www.hopkinsmedicine.org/news/newsroom/news-releases/research-story-tip-new-automated-insulin-infusion-system-may-potentially-reduce-medical-errors-improve-care

Media Contact: Marisol Martinez, mmart150@jhmi.edu

Nurses traditionally manage insulin intake for critically ill patients by following precise steps to manually calculate the correct dose for each person. Looking for ways to improve this process, researchers at the Johns Hopkins Armstrong Institute for Patient Safety and Quality recently tested a "smart agent" system that integrates electronic health records and infusion pumps to automate insulin dose selection.

The study showed that Smart Agent -- developed as a joint effort between the Johns Hopkins University Applied Physics Laboratory and the Johns Hopkins University School of Medicine -- may reduce errors and provide faster insulin delivery when compared with manual dosing calculation. In turn, the researchers say, this could free up nurses and clinicians to focus their attention on other patient care priorities.

The findings, published online March 10, 2021, in the journal BMJ Quality & Safety, suggest that a smart agent system could potentially optimize safety and efficiency of insulin infusion practices in intensive care unit settings.

"Glucose management improves outcomes for critically ill patients; however, current insulin infusion protocols are work-intensive for nurses and may be error prone," says study lead author Michael Rosen, Ph.D., M.A., associate professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine.

The current infusion process requires a nurse to manage insulin doses hourly, based on the patient's condition. Because neither the patient's medical record nor the infusion pump's operating data communicate electronically, a nurse is required to first retrieve the patient's blood glucose level from the health record. Then, he or she must manually calculate the medication rate change using an algorithm to determine the new insulin dosage. A second nurse double checks this process before it's documented in the medical record, and finally, the new dose is manually programed into the infusion pump to administer insulin to the patient.

For the study, 20 critical care nurses at The Johns Hopkins Hospital in Baltimore, Maryland, tried a specific smart agent system in a simulation-based setting between May and July 2018. Participants completed 12 mock situations, in four blocks of three scenarios each. Each block was performed with either the manual protocol or Smart Agent.

Nurses were surveyed after each session to get their impressions of safety levels (rates of errors), efficiency (time to complete each task), perceived workload, trust in the system and usability.

The researchers say their findings show that the automated system was significantly better in dosing accuracy calculation compared with manual calculation. In 120 scenarios, nurses never made a calculation error when using the smart agent system compared with 20 errors (16.6%) made using the manual system.

Smart Agent enabled the nurses to complete the process an average of 29 seconds faster than the manual system, along with reducing their overall workload. The tasks that consumed the most time using the manual system were retrieving information from the electronic health record and performing manual calculations -- neither of which is required in a smart agent system. The nurses also found that after using Smart Agent at least twice, they trusted it more than doing the manual calculations.

In general, Smart Agent received positive remarks from all 20 nurses. Most found it to be helpful and more efficient than the manual system, and 18 (90%) found it easier to use. Fifteen (75%) nurses believed that the automated system was safer than the manual process, while five (25%) were unsure or believed both systems were about as safe.

"This approach can be applied to improve a fragmented and inefficient health care IT infrastructure through design, testing and system integration," says senior study author Adam Sapirstein, M.D., associate professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine.

The researchers believe that Smart Agent can serve as a template for similar systems that use algorithms built directly into electronic medical records so that they can be integrated with devices for automatically delivering medication to patients.

This study was done in collaboration with University Hospitals of Cleveland.

Rosen and Sapirstein are available for interviews.

Many people live with chronic pain, and in some cases, cannabis can provide relief. But the drug also can significantly impact memory and other cognitive functions. Now, researchers reporting in ACS' Journal of Medicinal Chemistry have developed a peptide that, in mice, allowed Δ9-tetrahydrocannabinol (THC), the main component of Cannabis sativa, to fight pain without the side effects.

According to the U.S. Centers for Disease Control and Prevention, about 20% of adults in the U.S. experienced chronic pain in 2019. Opioids, the mainstay for severe pain management, are effective, but patients can easily become addicted to them. In some studies, medical marijuana has been helpful in relieving pain from migraines, neuropathy, cancer and other conditions, but the side effects present hurdles for widespread therapeutic use. Previously, researchers identified two peptides that disrupt an interaction between a receptor that's the target of THC and another receptor that binds serotonin, a neurotransmitter that regulates learning, memory and other cognitive functions. When the researchers injected the peptides into the brains of mice, the mice had fewer memory problems caused by THC. Now, this team, led by Rafael Maldonado, David Andreu and colleagues, wanted to improve these peptides to make them smaller, more stable, orally active and able to cross the blood-brain barrier.

Based on data from molecular dynamic simulations, the researchers designed two peptides that were less than half the length of the original ones but preserved their receptor binding and other functions. They also optimized the peptide sequences for improved cell entry, stability and ability to cross the blood-brain barrier. Then, the researchers gave the most promising peptide to mice orally, along with a THC injection, and tested the mice's pain threshold and memory. Mice treated with both THC and the optimized peptide reaped the pain-relieving benefits of THC and also showed improved memory compared with mice treated with THC alone. Importantly, multiple treatments with the peptide did not evoke an immune response. These findings suggest that the optimized peptide is an ideal drug candidate for reducing cognitive side effects from cannabis-based pain management, the researchers say.

The abstract that accompanies this paper can be viewed here.

The authors acknowledge funding from Rhodes Pharmaceuticals, Marie Skłodowska-Curie Research and Innovation Staff Exchange, the Spanish Ministry of Science and Innovation and La Caixa Foundation.

The American Chemical Society (ACS) is a nonprofit organization chartered by the U.S. Congress. ACS' mission is to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and all its people. The Society is a global leader in promoting excellence in science education and providing access to chemistry-related information and research through its multiple research solutions, peer-reviewed journals, scientific conferences, eBooks and weekly news periodical Chemical & Engineering News. ACS journals are among the most cited, most trusted and most read within the scientific literature; however, ACS itself does not conduct chemical research. As a leader in scientific information solutions, its CAS division partners with global innovators to accelerate breakthroughs by curating, connecting and analyzing the world's scientific knowledge. ACS' main offices are in Washington, D.C., and Columbus, Ohio.

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Alexandria, Va., USA -- COVID-19 was declared a global pandemic in March 2020 and given an incomplete understanding of the transmission of SARS-CoV-2 at that time, the American Dental Association recommended that dental offices refrain from providing non-emergency services. As a result, 198,000 dentists in the United States closed their doors to patients. The study "Sources of SARS-CoV-2 and Other Microorganisms in Dental Aerosols," published in the Journal of Dental Research (JDR), sought to inform infection-control science by identifying the source of bacteria and viruses in aerosol generating dental procedures.

Researchers at The Ohio State University College of Dentistry, Division of Periodontology, Columbus, USA, tracked the origins of microbiota in aerosols generated during treatment of 28 patients undergoing ultrasonic scaling, implant osteotomy or restorative procedures by combining reverse transcriptase qPCR, to identify and quantify SARS-CoV-2, and 16S sequencing, to characterize the entire microbiome, with fine-scale enumeration and source-tracking. Thirty minutes following the procedure, condensate was collected from the operator and assistant's face shield, the patient's chest and an area 6-feet distant from the site of operation.

The results show that it is possible to trace the source of contamination through DNA microbiome analysis and that the major source of microbes in aerosols came from the dental irrigant. Saliva did not significantly contribute as infection control measures such as pre-operative mouthrinses and intra-oral high-volume evacuation were used. The authors conclude that the risk for transmission of SARS-CoV-2 and other respiratory pathogens from aerosolized saliva in dental operatories is moderately low and that current infection control practices are adequately robust to protect personnel and patients alike.

"Understanding the sources of microbial load in aerosols is important, not only for infection control in dental operatories during the COVID pandemic, but also to inform best practices in aerosol reduction, mitigation and abatement in the long term." said JDR Editor-in-Chief Nicholas Jakubovics, Newcastle University, England. "While further studies are needed with larger sample sizes, this study sets the stage for future work on risk of microbial transmission in oral health care settings."

Are you empathic, generous and altruistic? In short, do you possess that specific personality trait defined as agreeableness in the language of psychologists? New research from SISSA recently published in the journal NeuroImage sheds light on brain mechanisms underlying this trait.

The study showed that detached and individualistic subjects seem to process information associated with social and non-social contexts in similar ways, as demonstrated by similar activation patterns in the prefrontal cortex, whereas in more agreeable subjects the activation patterns arising from social and non-social situations show more differences. This suggests that individuals with high levels of agreeableness are able to discern social contents that are important, and particularly informative, for achieving successful interactions with others. This should not be surprising, since individual agreeableness is associated with characteristics, such as empathy, cooperation and generosity, which require the ability to recognise the cognitive, emotional and motivational aspects of others in social situations. These findings could contribute to future development of more objective and sensitive personality tests, including individuals' brain responses to stimuli varying in social content as a measure of agreeableness. The research was carried out by Dr. Sandra Arbula and Elisabetta Pisanu, and coordinated by Professor Raffaella I. Rumiati.

Visual tests and functional magnetic resonance imaging

"Personality traits reflect key aspects of variability among individuals. Understanding the mechanisms that give rise to these differences requires an in depth investigation of the behaviors associated with such traits, and their underlying neural sources" explain the scientists. The SISSA team recruited dozens of volunteers for their research according to their degree of agreeableness, one of the five major dimensions of personality, assessed with a questionnaire. "Participants were presented with short animations of different shapes that moved randomly or interacted in a socially meaningful way. Their brain activity was then recorded using functional magnetic resonance imaging, which enables detection of brain areas activated while they perform a given task, and has application in both research and clinical fields".

An important link between neural mechanisms and social behaviour

"Our results suggest something particularly interesting about agreeableness" explain Arbula and Rumiati. "We observed that representations of social information extracted form visual scenes are formed in the dorsomedial prefrontal cortex: based on their distinctiveness we are able to predict individual variations in agreeableness. The present finding reveals the link between neural and behavioral mechanisms underlying this specific personality trait" conclude Arbula and Rumiati. "Additionally, these sorts of connections provide new opportunities for the development of more objective personality measures".

When Museums closed their doors in March 2020 for the first COVID-19 lockdown in the UK a majority moved their activities online to keep their audiences interested. Researchers from WMG, University of Warwick have worked with OUMNH, to analyse the success of the exhibitions, and say the way Museums operate will change forever.Caption: Compton Verney's homepage for the Cranach exhibition which opened in March 2020 Credit: Compton Verney

The cultural impact of the COVID-19 pandemic has been analysed by researchers from WMG, University of Warwick in collaboration with OUMNH (Oxford University Museum of Natural History) who in the paper, 'Digital Responses of UK Museum Exhibition to the COVID-19 Crisis March-June 2020' published in the journal Curator: The Museum Journal, have analysed the success of online museum exhibitions, and investigated what the future of Museums holds.

Researchers analysed 21 museums who had temporary exhibitions due to open between March and June 2020, and decided to go ahead with the exhibition virtually. The analysis included noting how COVID was considered, how content was presented, and discussing themes of access, embodiment, and human connection.

The research team found that in May-June Museums had more online content for their exhibitions, suggesting there was time to prepare the transfer of exhibition online. All exhibitions were different, with some hosting podcasts, some doing filmed walk-arounds and some hosting a virtual room where you click on exhibits.

Although digital exhibitions were a success, researchers concluded online exhibitions do not provide the same social and embodied experience as the physical museum, as you miss the travelling there, welcome from staff, chatting with other visitors and the gift shop or coffee shop after.

They did however highlight that extra material was provided for online content which isn't traditionally presented in the Museum, this included behind the scenes videos for example. Researchers say this suggests Museums were trying to give their audiences some exclusives that they would not receive from a normal visit.

Lead author, PhD Student Ellie King from WMG, University of Warwick comments:

"The COVID-19 lockdowns have created a crucial turning point in the Museum sector, as they now see themselves working in a physical-digital overlap. It is interesting to note how in being forced to shut, museums focused their online provisions around existing physical exhibitions.

"Museums and galleries will continue to adapt in light of a post?COVID world where practices, both digital and physical, will undoubtedly shift. It is important to see the digital exhibition world as an opportunity to provide unseen materials and attract audiences who may not be able to visit in person."

Although it's likely there will be more online material generated by Museums and galleries from now on due to the pandemic, there is the issue of staff having the digital skills to manage a new arena of engagement.

Professor Mark Williams, from WMG, University of Warwick explains:

"One of the major tasks of converting to online is the financial implications, 30% of museums have changed staff tasks to provide services online. Despite this, there are concerns that staff teams are not fully equipped to handle such monumental changes.

"This highlights the practical challenge of enabling the rise of digital content for museums, which will be dif?cult for the sector in such a stretched resource environment."

Professor Paul Smith, Director at the Oxford Museum of Natural History adds:

"The first COVID-19 lockdown imposed a real-time stress test on museums, and their ability to respond in an agile way to events. The paper highlights the creative ways in which some museums were able to adapt to the unique and unprecedented circumstances they faced."

This research is part of a wider interest of the CiMAT team in WMG to engage with subject areas beyond engineering. Based on previous research into User Experience, the research group is seeking to apply concepts into areas of the arts and humanities. The research has blossomed with the collaboration between WMG and Oxford University Museum of Natural History. This research, which analyses how visitors experience museums online, is a welcome starting point. The researchers stress to Museums that with this rising atmosphere of change on the horizon, it is important they consider such conceptual issues and evaluate audience needs rigorously when developing online offerings to maintain such cultural importance.

Surface plasmon polaritons (SPPs) are highly localized surface waves on the interface between metal and dielectric in the optical frequency band. SSPs do not naturally exist in the microwave and terahertz frequencies, so "spoof" surface plasmon polaritons (SSPPs) are necessary for operations in those lower frequency bands.

Like optical SPPs, microwave SSPPs exhibit highly localized electromagnetic fields, subwavelength resolution, and extraordinary field confinement. Therefore, SSPP transmission lines (TLs) have been proposed as novel types of microwaveguides that offer new solutions for miniaturization, signal integrity, and low crosstalk in compact circuits for use in wireless communications and wearable electronics.

Recently, a research team from Southeast University in China applied a typical form of higher symmetry called "glide symmetry" in dual-strip SSPP TLs to achieve flexible control of modal fields, dispersion characteristics, and mutual coupling between TLs. As reported in Advanced Photonics, they constructed a hybrid TL array with a nonglide symmetric TL and a glide symmetric TL, in which a misalignment of half period is observed between the upper and lower strips. A broadened working bandwidth resulted from the glide symmetric TL, and the team demonstrated that the glide symmetry helps suppress channel crosstalk significantly without requiring extra space or feeding networks.

In their experimental demonstration, the cutoff frequency of the fundamental mode increases from 5 GHz (for a nonglide symmetric TL) to 9.5 GHz (for a glide symmetric TL). Because the fundamental mode of the glide symmetric TL is totally different from that of the nonglide one, the coupling coefficient between them is significantly lower than that between two uniform SSPP TLs. The team noted that, due to the mode mismatch in the hybrid array, a very limited portion of energy could be coupled to the neighboring TL.

Four-port model composed of two channels: one is the nonglide symmetric transmission line channel, and the other is the glide symmetric one. Credit: Xiao Tian Yan et al., doi 10.1117/1.AP.3.2.025001

Tie Jun Cui, professor at Southeast University's Institute of Electromagnetic Space, remarks, "Glide symmetry offers powerful and flexible control of SSPPs and may bring about new solutions in future integrated circuits." Cui envisions that when serious line-to-line interference damages the performance of circuits, an alternating arrangement of glide and nonglide symmetric TLs can restore and guarantee signal accuracy. Cui notes, "No extra space or design of circuits is needed when the nonglide symmetric TL is replaced with a glide one." This space-saving solution may supply significant improvements to future integrated circuits and systems.

Read the open access article: Xiao Tian Yan et al., "Glide symmetry for mode control and significant suppression of coupling in dual-strip SSPP transmission lines," Adv. Photon. 3(2), 026001 (2021), doi 10.1117/1.AP.3.2.025001.

Journal

Advanced Photonics

DOI

10.1117/1.AP.3.2.026001

BOSTON - During the development and progression of Alzheimer's disease, a protein called tau accumulates and spreads in the brain. Understanding the mechanisms behind tau spread--and its consequences--may point to new prevention and treatment strategies for Alzheimer's disease and other forms of dementia. New insights now come from research that was led by investigators at Massachusetts General Hospital (MGH) and involves an anesthetic known to affect cognitive function. The findings are published in Communications Biology.

The scientists note that inflammation plays an important role in Alzheimer's disease, and microglia--immune cells that reside in the brain--are thought to be involved in this process by producing an inflammatory molecule called interleukin-6. To see if tau stimulates microglia to drive the development of Alzheimer's disease pathology, the MGH investigators and their colleagues conducted experiments with an inhaled anesthetic called sevoflurane. Their previous work showed that sevoflurane can cause a change (specifically, phosphorylation, or the addition of phosphate) to tau that leads to cognitive impairment in mice. Other researchers have also found that sevoflurane and certain other anesthetics may affect cognitive function.

In this current study, the team developed a novel method to measure tau levels, called nanobeam-sensor technology. "The nanobeam sensor is ultrasensitive, requires a small volume, and can measure low concentrations of molecules, including tau and phosphorylated tau," says co-lead author Feng Liang, MD, PhD, an instructor in the Department of Anesthesia, Critical Care and Pain Medicine (DACCPM) at MGH.

The group conducted experiments in mice and cells and discovered that sevoflurane causes tau to leave neurons and enter microglia, where it stimulates the cells' production of interleukin-6, which in turn leads to inflammation and cognitive impairment. The trafficking of tau from neurons to microglia involves tau phosphorylation and membrane-bound carriers called extracellular vesicles that are released from cells.

"These data demonstrate anesthesia-associated tau spreading and its consequences," says senior author Zhongcong Xie, MD, PhD, director of the Geriatric Anesthesia Research Unit in the DACCPM. "This tau spreading could be prevented by inhibitors of tau phosphorylation or extracellular vesicle generation."

Sevoflurane did not increase the release of lactate dehydrogenase, a molecule with a similar size and weight as tau, from neurons. "This finding indicates that neuronal cell membranes and cell viability were not compromised by sevoflurane treatment and that the sevoflurane-induced leaking of tau was not a passive process," says co-lead author Yuanlin Dong, MD, a research fellow in the department.

Another inhaled anesthetic called desflurane did not have the same effects as sevoflurane. "Our results suggest that the anesthetics sevoflurane and desflurane may have different impacts on tau phosphorylation and tau spreading. More important, sevoflurane may be used as a clinically relevant tool to study tau spreading and its underlying mechanisms," says Xie. "We hope this work will lead to more research on anesthesia, tau proteins, and Alzheimer's disease pathology that will ultimately improve care for patients."

NEW YORK, NY--While there was extensive use of drug repurposing throughout the first 10 months of the COVID-19 pandemic, there was substantial heterogeneity over the types of drugs used for treatment purposes globally. Some drugs, including hydroxychloroquine, saw sharp declines in use, while adjunctive therapies grew into a more relied upon method for patient management.

In a number of cases, scientific discovery overturned misconceptions proclaimed via press conferences and social media.

The OHDSI network study "Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study," published May 11 by The BMJ, provides a global view of drug utilization in routine practice of more than 303,000 hospitalized patients from China, South Korea, Spain and the United States. The study highlights the need for future research on the safety and efficacy of the more commonly used treatments.

"At the start of the pandemic, when we knew little about COVID-19 and how to treat it, there were many differences between hospitals around the world on how health professionals were treating it," said study co-lead Albert Prats-Uribe, a DPhil candidate and Research Assistant in Clinical Epidemiology at the University of Oxford.

"This was also influenced by political and social media pressures that spread misinformation," said senior author Dani Prieto-Alhambra, Professor of Pharmaco- and Device Epidemiology at the University of Oxford. "Once reliable evidence from well-designed and performed studies came in, the situation quickly improved, and hospitals stopped using the ineffective treatments and turned to more effective ones."

Deidentified patient data from 11 databases across three continents (Asia, Europe and North America) showed that more than 3,400 different medicines were used in the treatment of COVID-19 patients. Among the most popular in the earliest stages of the pandemic was hydroxychloroquine, which was heavily promoted without the backing of reliable evidence and later revoked from emergency approval status following both randomized controlled trials (RCTs) and related studies, including an OHDSI study showing dangerous risk of combining hydroxychloroquine with another early popular prescribed COVID-19 therapeutic, azithromycin.

Heterogeneity in drug therapy choice was dramatic across databases around the world. For example, lopinavir-ritonavir was used 50% of the time in one Spanish setting (HM Hospitals), 35% of the time in a South Korean setting (HIRA), and 0% of the time in a U.S. setting (Department of Veterans Affairs).

Adjunctive therapies developed into popular forms of management for supportive care, with the most recognized being corticosteroids and anti-cytokines, both of which have been shown to reduce mortality in more serious cases. While these were lightly used early in the pandemic, results from the RECOVERY RCT showed efficacy in reducing death on hospitalized patients with severe respiratory disease.

Scientific discovery through observational data often reversed false information being distributed through political channels and/or social media. This study highlights the role observational studies can fit into informing clinical decision-making moving forward.

"The use of ineffective medicines and potentially harmful combinations started with information from promising in vitro analyses, and were fueled by poorly performed observational studies, as well as misinformation campaigns in social and traditional media with clearly political intentions," Prats-Uribe said. "This would have taken a long time to counter in the traditional scientific timings. With the work of a community of people around the world producing reliable evidence using observational data, we were able to shift these tendencies and influence decision-making to improve COVID-19 patients."

The study was developed and executed by the OHDSI (Observational Health Data Sciences and Informatics) community, a multi-stakeholder, interdisciplinary network that collaborates globally to bring out the value of health data through open science and large-scale analytics.