Category: Medical Research & Technology

Categories : Medical Research & TechnologyTags :

Could Carbon Monoxide Treat Inflammation?

On By ModernMedia
Photo by Samuel Ramos on Unsplash

While carbon monoxide is associated with asphyxiation cases, in small doses it also has beneficial qualities, helping reduce inflammation and stimulate tissue regeneration.

But now, a team of researchers have devised a novel way to deliver carbon monoxide to the body without its hazardous effects. Inspired by techniques used in molecular gastronomy, they were able to incorporate carbon monoxide into stable foams that can be delivered to the digestive tract.

In a mouse study, the researchers showed that these foams reduced inflammation of the colon and helped to reverse acute liver failure caused by acetaminophen overdose. The researchers said that their new technique, described today in a Science Translational Medicine paper, could also be used to deliver other therapeutic gases.

“The ability to deliver a gas opens up whole new opportunities of how we think of therapeutics. We generally don’t think of a gas as a therapeutic that you would take orally (or that could be administered rectally), so this offers an exciting new way to think about how we can help patients,” said Giovanni Traverso, a professor at MIT and a gastroenterologist at Brigham and Women’s Hospital.

Inspired by fine cuisine

Since the late 1990s, Leo Otterbein, a professor of surgery at Harvard Medical School and Beth Israel Deaconess Medical Center, has been studying the therapeutic effects of low CO doses. The gas has been shown to impart beneficial effects in preventing rejection of transplanted organs, reducing tumour growth, and modulating inflammation and acute tissue injury. 

When inhaled at high concentrations, CO binds to haemoglobin in the blood and prevents the body from obtaining enough oxygen, which can be fatal in same cases. However, at lower doses, it has beneficial effects such as reducing inflammation and promoting tissue regeneration, Prof Otterbein said.

“We’ve known for years that carbon monoxide can impart beneficial effects in all sorts of disease pathologies, when given as an inhaled gas,” he saud. “However, it’s been a challenge to use it in the clinic, for a number of reasons related to safe and reproducible administration, and health care workers’ concerns, which has led to people wanting to find other ways to administer it.”

Prof Traverso’s lab specialises in developing novel methods for delivering drugs to the gastrointestinal tract. They came up with the idea of incorporating the gas into a foam, much the way that chefs use carbon dioxide to create foams infused with fruits, vegetables, or other flavours.

Culinary foams are usually created by adding a thickening or gelling agent to a liquid or a solid that has been pureed, and then either whipping it to incorporate air or using a specialised siphon that injects gases such as carbon dioxide or compressed air.

The MIT team created a modified siphon that could be attached to any kind of gas canister, allowing them to incorporate CO into their foam. To create the foams, they used food additives such as alginate, methyl cellulose, and maltodextrin. Xantham gum was also added to stabilise the foams. By varying the amount of xantham gum, the researchers could control the release rate of CO gas from the foam.

After showing that they could control the timing of the gas release in the body, the researchers decided to test the foams for a few different applications. First, they studied two types of topical applications, analogous to applying a cream to soothe itchy or inflamed areas. In a study of mice, they found that delivering the foam rectally reduced inflammation caused by colitis or radiation-induced proctitis (inflammation of the rectum that can be caused by radiation treatment for cervical or prostate cancer).

Current treatments for colitis and other inflammatory conditions such as Crohn’s disease usually involve drugs that suppress the immune system, which can make patients more susceptible to infections. Treating those conditions with a foam that can be applied directly to inflamed tissue offers a potential alternative, or complementary approach, to those immunosuppressive treatments, the researchers said. While the foams were given rectally in this study, it could also be possible to deliver them orally, the researchers say.

Controlling the dose

The researchers then investigated possible systemic applications to deliver CO to remote organs, such as the liver, because of its ability to diffuse from the GI tract elsewhere in the body. For this study, they used a mouse model of acetaminophen overdose, which causes severe liver damage. They found that gas delivered to the lower GI tract was able to reach the liver and greatly reduce the amount of inflammation and tissue damage seen there.

In these experiments, the researchers did not find any adverse effects after the carbon monoxide administration. A healthy individual has CO levels of ~1% in the bloodstream, and studies of human volunteers have shown that levels as high as 14% can be tolerated without adverse effects.

“We think that with the foam used in this study, we’re not even coming close to the levels that we would be concerned about,” Otterbein says. “What we have learned from the inhaled gas trials has paved a path to say it’s safe, as long as you know and can control how much you’re giving, much like any medication. That’s another nice aspect of this approach — we can control the exact dose.”

In this study, the researchers also created carbon-monoxide containing gels, as well as gas-filled solids, using techniques similar to those used to make Pop Rocks, the hard candies that contain pressurised carbon dioxide bubbles. They plan to test those in further studies, in addition to developing the foams for possible tests in human patients.

Source: MIT

Categories : Ethics and Law Medical Research & TechnologyTags :

Scientists Sound Alarm on Badly Run Medical Studies

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Woman using lab equipment
Source: NCI on Unsplash

A new research paper has signalled a crisis in medical research: “over 60% of trials are so methodologically flawed we cannot believe their results”. Researchers estimate that 88% of trial spending is wasted.

Dodgy research design and bad statistical methodology mean that most randomised trials are a waste of time, money and effort, and of no or dubious scientific value, say Stefania Pirosca, Frances Shiely, Mike Clarke and Shaun Treweek, in a new paper published in the journal Trials in early June.

Their paper examined 1659 randomised trials, involving 400,000 participants, that took place between May 2020 and April 2021 in 84 countries as well as 193 multinational trials. 

The majority of trials (62%) showed a high risk of bias. More than half of trial participants were in these high risk of bias trials. Trials where the risk of bias was unclear accounted for 30% of those reviewed, while trials with a low risk of bias – those that can be trusted – accounted for just 8% of the total.

Bad trials – ones where we have little confidence in the results – are not just common, they represent the majority of trials in all countries and across most clinical areas. For instance, all trials looking at drugs and alcohol exhibited a high risk of bias. The most reliable field was anaesthesia, with 60% of trials exhibiting a low risk of bias.

The research team drew trial data from 96 reviews from 49 of the 53 clinical Cochrane Review Groups. Cochrane is an international organisation that helps to gather and propagate the results of medical research to better guide medical decision-making. This is done by experts compiling and evaluating research trials and results in “standardised, high-quality systematic reviews”.

Bad science was common everywhere. “No patient or member of the public should be in a bad trial and ethical committees, like funders, have a duty to stop this happening,” the paper’s authors write.

South Africa was bad, but Spain and Germany may be worse

In the seven trials reviewed that took place in South Africa, four had a high risk of bias, two had an unclear bias risk, and one trial was “good science”. This share of bad science is roughly similar to those found in the clinical trials done in the UK and USA. The most reliable health research science was done in multinational trials – with these, 23% of trials were a low risk of bias. (The authors didn’t identify the trials.)

The least reliable science, in countries that conducted 20 or more RCTs, was done in Spain and Germany, with 86% and 83% of the trials exhibiting a high risk of bias.

While results from just one year were interrogated, the paper’s authors found that their results map to similar studies, and that bad science can be expected to be the norm, over time.

This amounts to a massive waste of money and effort.

Statisticians and research method experts have been sounding the alarm on biased research for years, since Doug Altman’s 1994 paper in the British Medical Journal, “The scandal of poor medical research”.

Doctors want to know if they can rely on a particular treatment to produce a desired outcome, and need research that confers a degree of confidence. One way to do that – the most popular – is randomised control trials.

Randomised trials are great – but you need statisticians

Randomised control trials, also known as randomised trials, or RCTs, are for many (though not all), the gold standard for achieving scientific knowledge about a medical intervention – whether a drug or another type of therapy. The way that RCTs are conducted is crucial, as it is adherence to the method that gives people relying on the research confidence that the results produce scientific knowledge. See this explainer video for more: How do we know vaccines work?

But, if there is a high risk that the results were biased by errors in how they were conducted and how results were achieved, they should not be relied on. Pirosca and colleagues did not examine the type (or domain) of bias in the studies, arguing that having a high risk in one type of bias is sufficient to undermine the trial’s results.

In short, for Pirosca and colleagues, health research in randomised trials is bad when there is an identifiable risk of bias in the way that the results were obtained.

The large number of high risk of bias trials appears to be due to “a lack of input from methodologists and statisticians at the trial planning stage combined with insufficient knowledge of research methods among the trial teams”. You would not, they say by analogy, think it appropriate that a statistician conduct surgery, just because they are doing work in a surgical domain.

Bad science during COVID

Recent medical scandals in the headlines have highlighted the risks of bad science in medicine. The Covid pandemic has brought a boom in medical research, and popular attention to the results of medical research. This environment has produced some remarkable science, but it has also created scientific fiascos, like the one that surrounded ivermectin.

As GroundUp has previously reported, a review of studies investigating ivermectin as a possible therapy for Covid initially suggested that the deworming drug led to better outcomes in those that used it. On the face of it, the small studies that supported this conclusion seemed to provide promise for a low-cost, life-saving Covid intervention. But once the methodology and statistics were looked at closely, many of these papers were deemed unscientific – for instance, patients were excluded from analysis for no good reason. And once these trials were excluded from the review, the drug’s promise as a Covid treatment vanished.

Medical research watchdog Retraction Watch currently lists 12 papers purporting to investigate ivermectin that were subsequently withdrawn or for which concerns have been expressed. According to their records, 235 Covid papers have been withdrawn to date.

But the crisis is not insurmountable. Pirosca and colleagues say that relatively simple fixes would dramatically reduce the amount of untrustworthy health research – by ensuring that methodological principles that underlie RCTs are not compromised.

More expenditure on statistical expertise will save money

A 2015 review examined 142 trials that exhibited a high risk of bias. The authors found that in half of the high risk trials, the methodological adjustments required to reduce the risk of bias would have been low or zero cost. Easy adjustments at the design stage would have made important improvements to 42% of trials that exhibited high risk of bias.

Pirosca and colleagues propose that no medical RCT should be funded or given ethical approval if it cannot prove that the team conducting the trial has a member that has methodological and statistical expertise. Every RCT should, in its design, use risk of bias tools to make sure that results are not compromised.

The expertise that could restore the worth to medical research is in short supply.

More methodologists and statisticians are needed, and money should be invested in training people with this expertise, and investing in applied methodology research and supporting infrastructure. The authors call for 10% of a funder’s budget.

This might seem like a lot of money, but, argue Pirosca and co, it would be a fraction of the cost of the wasted research in the year under review – estimated to be billions of rands.

The task is urgent: “Randomised trials have the potential to improve health and wellbeing, change lives for the better and support economies through healthier populations … Society will only see the potential benefits of randomised trials if these studies are good, and, at the moment, most are not.”

Written by James Stent

Republished from GroundUp under a Creative Commons Attribution-NoDerivatives 4.0 International License.

Source: GroundUp

Categories : Medical Research & Technology UncategorizedTags :

Bacteriophage Therapy over 50% Successful against Mycobacterium Infections

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A bacteriophage. Credit: Wikimedia CC0

Using bacteriophages, viruses which prey on bacteria, is an emerging alternative to antibiotic use but with limited evidence. Now, with a new paper published in Clinical Infectious Diseases, collaborators report 20 new case studies on the use of the experimental treatment in Mycobacterium infections, with successes in more than half of the patients.

This is the largest ever set of published case studies for bacteriophage (or ‘phage’) therapy, giving unprecedented detail on their use to treat dire infections while laying the groundwork for a future clinical trial.

“Some of those are spectacular outcomes, and others are complicated,” said Professor Graham Hatfull at the University of Pittsburgh. “But when we do 20 cases, it becomes much more compelling that the phages are contributing to favourable outcomes – and in patients who have no other alternatives.”

The patients in the study had an infection from one or more strains of Mycobacterium, a group of bacteria that can cause deadly, treatment-resistant infections in those with compromised immune systems or cystic fibrosis. In 2019, Prof Hatfull led a team showing the first successful use of phages to treat one of these infections.

“For clinicians, these are really a nightmare: They’re not as common as some other types of infections, but they’re amongst some of the most difficult to treat with antibiotics,” said Prof Hatfull. “And especially when you take these antibiotics over extended periods of time, they’re toxic or not very well-tolerated.”

Since 2019, Prof Hatfull and his lab have fielded requests from more than 200 clinicians looking for treatments for their patients, working with them to find phages that could be effective against the particular strain of bacteria infecting each patient.

This newest paper, with collaborators from 20 institutions, dramatically expands the body of published evidence on the effectiveness of the therapy.

“These are incredibly brave physicians, jumping off the ledge to do an experimental therapy to try to help patients who have no other options,” said Prof Hatfull. “And each of these collaborations represents a marker that can move the field forward.”

Going on patient health and presence of Mycobacterium in samples, the team found that the therapy was successful in 11 out of 20 cases. No patients showed any adverse reactions to the treatment.

In another five patients the results of the therapy were inconclusive, and four patients showed no improvement. According to Prof Hatfull, even these apparent failures are key to making the therapy available to more patients. “In some ways, those are the most interesting cases,” he said. “Understanding why they didn’t work is going to be important.”

Several unexpected patterns emerged from the case studies. In 11 cases, researchers were unable to find more than one kind of phage that could kill the patient’s infection, even though standard practice would be to inject a cocktail of different viruses so the bacteria would be less likely to evolve resistance.

“If you’d asked me whether that was a good idea three years ago, I would have had a fit,” Prof Hatfull said. “But we just didn’t observe resistance, and we didn’t see a failure of treatment from resistance even when using only a single phage.”

Additionally, the team saw that some patients’ immune systems attacked the viruses, but only in a few cases did that render the virus ineffective. And in some instances, the treatment was still successful despite such an immune reaction. The study paints an encouraging picture for the therapy, said Prof Hatfull, opening up the possibility for new phage regimens that clinicians could use to maximise the treatment’s chance of success.

Along with the study’s significance to patients facing Mycobacterium infections, it also represents a substantial advance for the wider field of phage therapy. One concern is that researchers may be only publishing case studies of successful phage therapy.

“A series of consecutive case studies, where we’re not cherry-picking, is a much more transparent way of looking to see what works and what doesn’t,” said Prof Hatfull. “This adds considerable weight to the sense that the therapy is safe.”

This is still a very early stage in the development of phage therapy, and phages have not even begun to be tailored for treatment, Prof Hatfull said.

Source: University of Pittsburgh

Categories : Ebola Medical Research & TechnologyTags :

The Ebola Relative, Lloviu Virus, Has Pandemic Potential

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Photo by Todd Cravens on Unsplash

Researchers have helped isolate the Lloviu virus (LLOV), a close relative of Ebola virus, for the first time, showing that it could cross over into humans, highlighting the need for future research to ensure pandemic preparedness. The study is reported in Nature Communications.

LLOV is part of the filovirus family, which also includes the Ebola virus. While Ebola (and other filoviruses including the lethal Marburg virus) have only occurred naturally in Africa, Lloviu has been discovered in Europe. The filovirus LLOV, was genetically identified in 2002 in Schreiber’s bats in Spain and was subsequently detected in bats in Hungary.

As a zoonotic virus, LLOV is of public health interest to public health around the world due to our close relationship with animals in agriculture, as companions and in the natural environment. Increasing encroachment on the natural environment is creating more opportunities for zoonotic viruses to cross over into humans.

Dr Simon Scott, from the Viral Pseudotye Unit (VPU) at Medway School of Pharmacy were part of a team led by Dr Gábor Kemenesi from Pécs University/National Laboratory of Virology in Hungary. The VPU were involved in conducting all the antibody detection experiments using bat sera as part of the study, even before the virus itself was isolated. This isolation occurred in the Hungarian lab from the very last bat which tested LLOV positive.

The team discovered that Lloviu has the potential to both infect human cells and replicate, raising concerns about potential widespread transmission in Europe and urges immediate pathogenicity and antiviral studies. The VPU work also revealed no antibody cross-reactivity between LLOV and Ebola, suggesting that existing Ebola vaccines might not protect against Lloviu.

Dr Scott said that their research “is a smoking gun. It’s vital that we know both more about the distribution of this virus and that research is done in this area to assess the risks and to ensure we are prepared for potential epidemics and pandemics.”

The research revealed a considerable knowledge gap regarding the pathogenicity, animal hosts, and transmissibility of these newly discovered viruses. Dr Scott created a consortium of European bat virologists, harnessing expertise in the field, from ecology to virology, which is aiming to carry out essential further research across Europe into the risks of the Lloviu virus to humans.

Source: University of Kent

Categories : COVID Medical Research & TechnologyTags :

Natural Facial Asymmetry Affects Mask Fit

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Image by Quicknews

In research published in Physics of Fluids, researchers used computer modelling investigate mask fit and found that face shape, especially natural facial asymmetry, influences the most ideal fit. The findings suggested that double masking with improperly fitted masks may not greatly improve mask efficiency and produces a false sense of security.

Using more layers results in a less porous face covering, leading to more flow forced out the sides, top, and bottom of masks with a less secure fit. Double layers increase filtering efficiency only with good mask fit, however they could also lead to difficulties in breathing.

The researchers modelled a moderate cough jet from a mouth of an adult male wearing a cloth mask over the nose and mouth with elastic bands wrapped around the ears. They calculated the maximum volume flow rates through the front of mask and peripheral gaps at different material porosity levels.

To create a more realistic 3D face shape and size, the researchers used head scan data for 100 adult male and 100 adult female heads.

Their model showed how the slight asymmetry typical in all facial structures can affect proper mask fitting. For example, a mask can have a tighter fit on the left side of the face than on the right side.

“Facial asymmetry is almost imperceivable to the eye but is made obvious by the cough flow through the mask,” explained co-author Tomas Solano, from Florida State University. “For this particular case, the only unfiltered leakage observed is through the top. However, for different face shapes, leakage through the bottom and sides of the mask is also possible.”

Producing individually customised ‘designer masks’ is not practical at large scales. Still, better masks can be designed for different populations by revealing general differences between male and female or child versus elderly facial structures and the associated air flow through masks.

Source: American Institute of Physics

Categories : Medical Research & TechnologyTags :

A Promising Antidote for Carbon Monoxide Poisoning

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Carbon monoxide (CO) is an odourless and colourless gas is produced from incomplete burning, and is a silent killer, binding to haemoglobin with few treatments available other than administering oxygen. Now, research published in Chemical Communications suggests a path to a possible antidote.

In the US, more than 400 deaths and 20 000 emergency room visits are attributable to carbon monoxide (CO) poisoning every year. While CO detectors and making sure fireplace and heaters work correctly can help prevent exposure, there are limited treatment options for those suffering from CO poisoning.

To address this, Tim Johnstone, an assistant professor of chemistry and biochemistry at UC Santa Cruz, has been working to develop an easy-to-administer antidote.

“If you are exposed to carbon monoxide, the primary treatment right now is fresh air,” said A/Prof Johnstone. “It is a question of time. In fresh air, you need four to six hours for the level of CO in your blood to be cut in half. With 100 percent oxygen or hyperbaric oxygen, the half-life shortens further. Even then, the high blood levels of CO can persist long enough to lead to long-term deficits and neurological problems.”

A/Prof Johnstone has been studying the chemistry of carbon monoxide. In a biological context, CO binds to metal centres such as the iron in haemoglobin, preventing this protein from carrying out its oxygen carrying function.

To mitigate this, A/Prof Johnstone has designed small molecules that possess many of the features of the active site of haemoglobin but can bind CO much more tightly than the protein. In his most recent study, his group described the ability of one such molecule to bind CO, sequester CO that is already bonded to haemoglobin, and rescue red blood cells exposed to CO: all promising signs for a future antidote.

These are early results, said A/Prof Johnstone, but the hope is to create a point-of-care treatment that can be administered quickly. The most common carbon monoxide poisoning symptoms are headache, dizziness, weakness, upset stomach, vomiting, chest pain, and confusion. Because it mimics the flu, people may experience symptoms without realizing the danger and delay seeking treatment.

Source: University of California Santa Cruz

Categories : Hospitals Medical Research & TechnologyTags :

The Pros and Cons of Robotics in Healthcare

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Photo by Alex Knight on Unsplash

Having to cope with the strain of COVID on an already fragile healthcare system, a few hospitals in the Western Cape have been introducing robotics for specialised tasks – but are they worth the hype?

Robotics was able to fill an unprecedented need during the COVID pandemic – the ability to remotely conduct ward rounds from remote locations. Tygerberg Hospital made use of ‘Quintin’, a robot that is essentially a tablet on a mobile stand that allows users to remotely communicate and inspect the area, but it can’t physically interact with its environment.

Robotics offers greater surgical precision, which may translate into reduced healthcare load. IOL reported that the provincial Department of Health plans to use a pair of new robotic surgery machines installed at the Groote Schuur and Tygerberg hospitals to fast-track surgeries and address the province’s surgical backlogs caused by COVID. These robotic surgery units will be used for procedures on colorectal, liver, prostate, kidney and bladder cancers, and women with severe endometriosis. In the province’s private sector, Netcare Christiaan Barnard Memorial Hospital also makes use of robotic-assisted surgery.

Robotic surgery has a number of advantages. The small robotic arms allow for smaller incisions and faster recovery times, reducing the strain on hospitals. A liver resection that would have a patient in hospital for a week can be reduced to one or two days with robotic surgery. More complex surgery becomes possible, eg in difficult to access areas or in patients with obesity. Robotic surgery allows surgeons to be off their feet, easing an extremely fatiguing job, and the software automatically compensates for any tremor in the surgeon’s hands.

However, robotic surgery still has drawbacks – chief among them is cost and the need to have trained personnel to operate them. There is also some latency between the surgeon’s hands movements and the corresponding movement of the robot, leading to possible errors. Shorting of the electrical current running through the robotic arms can also cause burns to the patient’s tissue, and there is also the possibility of nerve compression injuries due to the positioning of the patient. Furthermore, operator errors, especially when operators are inexperienced or robotic surgery is performed in lower volumes, is always a possibility.

Robotics have promising applications in sanitation – they can easily disinfect areas using UV light, for example – and can also assist nurses with certain tasks, such as making a 3D vein map prior to a venipuncture. Some robots can even assist the elderly, conversing with them and can perform simple tasks like calling a nurse. Other applications include the much simpler technology of exoskeletons, a wearable frame which amplify users’ strength (though nowhere near that of the fictional Iron Man) and are useful in rehabilitation and for enhancing mobility in the elderly. Other applications include increasing strength of care staff for assisting patients, freeing up other staff.

Some exoskeletons are even purely mechanical, merely readjusting loads without any sophisticated electronics or motors. Yet even these are prohibitively expensive: the Phoenix Medical Exoskeleton goes for about US$30 000 each.

While promising, robotic systems are at present still hugely expensive, limited in function and can only assist with a small fraction of the tasks that healthcare workers perform. Even if the cost could be reduced enough to help ease healthcare worker burden in South Africa to help, that still leaves the problem of enough experienced and motivated healthcare workers, beds and neglected rural areas.

Categories : Antibiotics Medical Research & TechnologyTags :

Gut Bacteria Alter Gene Expression to Evade Phage Therapy

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A bacteriophage, Credit: CC0

Phage therapy is a long-standing technique which makes use of bacteriophage viruses to kill bacteria, but poses the challenge of some strains working in vitro but failing in vivo. Scientists have now found that gut bacteria alter their gene expression to avoid attack by bacteriophages. This research, published in Cell Host & Microbe, helps explains the difference in bacteriophage efficacy.

Phage therapy is a medical approach that involves treating bacterial infectious diseases using the natural ability of certain viruses, known as bacteriophages, to kill bacteria that they specifically recognise. Following the development of antibiotics, the West saw a significant decline in the use of this century-old therapeutic strategy. In the face of the growing threat of antibiotic resistance, scientists are returning to bacteriophages and to understand their mechanism of action.

Bacteria and bacteriophages are the most abundant entities in the human gut microbiota. Although bacteriophages kill bacteria, the two antagonist populations coexist in a balance in the gut.

To date, there has been little data on how phage therapy works in vivo. Interactions between bacteria and bacteriophages have, in contrast, been extensively studied in vitro. In these conditions, bacteriophages quickly infect bacteria, replicate, and destroy bacteria, while releasing new viruses capable of infecting other bacteria. However, the dynamics observed between these two microorganisms are very different in mammalian guts. Some bacteriophages that are effective in culture medium are totally ineffective in the gut environment.

In order to understand this difference, scientists decided to compare the gene expression profile, or transcriptome, of the bacterium Escherichia coli in both contexts: culture media and the gut. Using this method, they revealed genetic regulations that characterise the bacterium’s adaptation to the gut environment.

By closely examining the genes involved in this adaptation, they revealed four genes that modulate the bacterium’s susceptibility to bacteriophages. “We observed that certain genes required for infection by bacteriophages are expressed less in the gut than in vitro, thus protecting bacteria from bacteriophages,” commented Laurent Debarbieux, last author of the study.

The scientists verified their theory by eliminating the expression of one particular gene. They observed that bacterial susceptibility to a bacteriophage was significantly reduced. As a result, bacteria in the gut are able to resist predation by bacteriophages by modulating the expression of certain genes rather than mutating their genome.

This study therefore demonstrates that environment plays a predominant role in interactions between bacteria and bacteriophages. These findings pave the way for improved use of bacteriophages for therapeutic purposes.

Source: Pasteur Institute

Categories : Medical Research & TechnologyTags :

Experiment Turns Back the Age of Human Skin Cells by 30 Years

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This normal human skin cell was treated with a growth factor that triggered the formation of specialised protein structures that enable the cell to move.
Credit: Torsten Wittmann, University of California, San Francisco

In a finding which could revolutionise regenerative medicine, researchers have found a way to reverse the age of human skin cells by 30 years, reversing genetic ageing measures for cells without losing their specialised function. The function of older cells was partly restored, as well as rejuvenating the molecular measures of biological age. The research was published in the journal eLife.

One of the ways regenerative medicine aims to replace damaged or old cells is by creating ‘induced’ stem cells, which differentiate into specialised cells. Currently the process is not reversible.

The new method, based on stem cell production, overcomes the problem of entirely erasing cell identity by halting reprogramming part of the way through the process. This let researchers find the precise balance between reprogramming cells, making them biologically younger, while still being able to regain their specialised cell function.

Currently, cell reprogramming takes around 50 days using four key molecules called the Yamanaka factors. The new method, called ‘maturation phase transient reprogramming’, exposes cells to Yamanaka factors for just 13 days. At this point, age-related changes are removed and the cells have temporarily lost their identity. The partly reprogrammed cells were given time to grow under normal conditions, to observe whether their specific skin cell function returned. Genome analysis showed that cells had regained markers characteristic of skin cells (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells.

To show that the cells had been rejuvenated, the researchers looked for changes in ageing indicators. Dr Diljeet Gill, who conducted the work as a PhD student explained: “Our understanding of ageing on a molecular level has progressed over the last decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the extent of reprogramming our new method achieved.”

Cellular ages examined included the epigenetic clock, where chemical tags present throughout the genome indicate age. Another is the transcriptome, all the gene readouts produced by the cell. According to these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger compared to reference data sets.

However, ‘rejuvenated’ cells need to function as if they were younger as well as looking younger. The rejuvenated fibroblasts were able to produce more collagen proteins compared to control cells that did not undergo the reprogramming process. Fibroblasts also move into areas that need repairing. Researchers tested the partially rejuvenated cells in vitro, and the treated fibroblasts moved into the gap faster than older cells – a sign that these could be used to improve wound healing,

The method also had an effect on other genes linked to age-related diseases and symptoms, the researchers saw, indicating possible future therapies. The APBA2 gene, associated with Alzheimer’s disease, and the MAF gene with a role in the development of cataracts, both showed changes towards youthful levels of transcription.

The researchers plan to explore the mechanism behind the successful transient programming, which is not yet completely understood. It is speculated that key areas of the genome involved in shaping cell identity might escape the reprogramming process.

Dr Diljeet concluded: “Our results represent a big step forward in our understanding of cell reprogramming. We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of ageing indicators in genes associated with diseases is particularly promising for the future of this work.”

Professor Wolf Reik, a group leader in the Epigenetics research programme who has recently moved to lead the Altos Labs Cambridge Institute, said: “This work has very exciting implications. Eventually, we may be able to identify genes that rejuvenate without reprogramming, and specifically target those to reduce the effects of ageing. This approach holds promise for valuable discoveries that could open up an amazing therapeutic horizon.”

Source: Babraham Institute

Categories : Ethics and Law Medical Research & TechnologyTags :

Controversial Vitamin C Sepsis Trial Faked?

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Patient's hand with IV drip
Photo by Anna Shvets on Pexels

The data underpinning a controversial study of the use as vitamin C as a sepsis treatment may in fact be fraudulent, according to an analysis by an Australian physician and statistician, reports MedPage Today.

PhD student Kyle Sheldrick, MBBS, alleges that the pre- and post- comparison groups involved in the 94-patient study were too similar to be realistic.

In an interview with MedPage Today, Sheldrick said the case is “extreme”, stating that “This is probably the most obviously fake data I have seen. … These groups are more similar than would be probable.”

The paper, led by Paul Marik, MD – who led another COVID protocol study that has since been retracted – has been the subject of much debate in the intensive care community since it was published in 2017. The so-called HAT protocol was a simple regimen of hydrocortisone, ascorbic acid (vitamin C), and thiamine which could have saved many lives easily if it indeed worked. Obviously, there was much excitement worldwide about the significance of the findings – but not all were convinced.

“The effect size seemed just impossible,” said Nick Mark, MD, an ICU physician at Swedish Medical Center. “It seemed too good to be true.”

The trial was followed by larger studies, and so far none have shown shown a similar reduction in mortality, raising suspicions even further, Dr Mark said. With Sheldrick’s analysis, the penny dropped: “This was under our noses for 5 years,” Mark said. “This isn’t just a mistake. We know things can be done unethically, but to actually fake it? That it’s not just flawed, but perhaps actually fraudulent?”

Sheldrick told MedPage Today the key problem with the Marik paper is “probably the most common sign of fraud that we see, which is overly similar groups at baseline.” That is, people tend to fake data which do not vary enough from the average.

Sheldrick said he first looked at the study methods, which noted a pre- and post- comparison design, rather than a randomised or matched case-control design. With such a design, one would expect a more random distribution of baseline characteristics, but that wasn’t the case for the Marik paper, he said.

A further analysis with Fisher’s test showed that most P-values were 1, meaning they were distributed perfectly evenly across two time periods – and only one fell below 0.5. Instead, an even spread should be expected with an overall value of 0.5.

Sheldrick sent his findings to the journal CHEST and to Marik’s former employer Sentara Norfolk General Hospital, but had not heard back from either.

While Sentara Norfolk General Hospital did not respond to comment, and the journal CHEST could not confirm whether an investigation was underway but that it did take ethical concerns very seriously.

A spokesperson for Dr Marik emailed a statement to MedPage Today, claiming that the conclusions had been validated in several meta-analyses, and recommended the source examine “this and other research on the data before making false allegations on social media. Such claims are harmful and do not add to the public discourse.”

This wouldn’t be the first time concerns have been raised about data in a paper that Dr Marik co-authored. In November 2021, the Journal of Intensive Care Medicine (JICM) retracted an article by Marik and others on their MATH+ protocol for COVID. The retraction followed a communication that raised concerns about the accuracy of COVID mortality data from the hospital used in the article.

“It seems a bit improbable for someone to discover two miracle cures in three years,” Dr Mark commented to MedPage Today.

Dr Mark noted that the 2017 paper is widely cited, and even if the intervention was not directly harmful, the resources invested in subsequent large, high-quality trials of vitamin C and sepsis could have been better spent.

“While I’m really glad we did high-quality studies and had brilliant people working on this, it’s kind of a shame,” he said. “Instead of studying vitamin C based on a faulty premise, we could have spent our efforts elsewhere.”

Source: MedPage Today