E-News

Researchers create bioengineered organism that could diagnose Crohn’s disease flareups

Research, 19 May 2021/in E-News /by panglobal

Jeff Tabor, associate professor of bioengineering in Rice’s Brown School of Engineering (Credit: Jeff Fitlow/Rice University)

In an important step toward the clinical application of synthetic biology, Rice University researchers have engineered a bacterium with the necessary capabilities for diagnosing a human disease.

The engineered strain of the gut bacteria E. coli senses pH and glows when it encounters acidosis, an acidic condition that often occurs during flareups of inflammatory bowel diseases like colitis, ileitis and Crohn’s disease.

Rice University researchers engineered a strain of the gut bacteria E. coli to detect gastrointestinal acidosis. The organism produces fluorescent molecules that allow researchers to see it with standard optical equipment. Under normal conditions (left) it produces molecules that glow red. When it encounters acidic conditions (right), it glows green, and the brightness of the glow reflects the level of acidity. (Image courtesy of Jeff Tabor/Rice University)

Researchers at the University of Colorado (CU) School of Medicine used the Rice-created organism in a mouse model of Crohn’s disease to show acidosis activates a signature set of genes. The corresponding genetic signature in humans has previously been observed during active inflammation in Crohn’s disease patients. The results are available online in the Proceedings of the National Academy of Sciences.

Colours that show up in the toilet

Study co-author Jeffrey Tabor, whose lab engineered the pH-sensing bacterium, said it could be reprogrammed to make colours that show up in the toilet instead of the fluorescent tags used in the CU School of Medicine experiments.

“We think it could be added to food and programmed to turn toilet water blue to warn patients when a flareup is just beginning,” said Tabor, an associate professor of bioengineering in Rice’s Brown School of Engineering.

Over their 3.5 billion-year history, bacteria have evolved countless specific and sensitive genetic circuits to sense their surroundings. Tabor and colleagues developed a biohacking toolkit that allows them to mix and match the inputs and outputs of these bacterial sensors. The pH-sensing circuit was discovered by Rice Ph.D. student Kathryn Brink in a 2019 demonstration of the plug-and-play toolkit.

pH sensor

PNAS study co-authors Sean Colgan, the director of the CU School of Medicine’s mucosal inflammation program, and Ian Cartwright, a postdoctoral fellow in Colgan’s lab, read about the pH sensor and contacted Tabor to see if it could be adapted for use in a mouse model of Crohn’s disease.

“It turns out that measuring pH within the intestine through noninvasive ways is quite difficult,” said Colgan, the Levine-Kern Professor of Medicine and Immunology in the CU School of Medicine.

So Brink spent a few weeks splicing the necessary sensor circuits into an organism and sent it to Colgan’s lab.

“Normally, the pH in your intestines is around seven, which is neutral, but you get a lot of inflammation in Crohn’s disease, and pH goes to something like three, which is very acidic,” Tabor said.

Colgan and colleagues have studied the genes that are turned on and off under such conditions and “needed a tool to measure pH in the intestine to show that the things they were observing in in vitro experiments were also really happening in a live animal,” Tabor said.

Biological tool

“Colonizing this bacterial strain was the perfect biological tool to monitor acidosis during active inflammation,” Colgan said. “Correlating intestinal gene expression with the bacterial pH sensing bacteria proved to be a useful and valuable set of biomarkers for active inflammation in the intestine.”

Tabor said he believes the pH-sensing bacterium could potentially be advanced for human clinical trials in several years.

more nurses leads to shorter patient stays

More nurses lead to shorter hospital stays, less readmissions and fewer patient deaths

Research, 19 May 2021/in E-News /by panglobal

Australian study shows that savings made from shorter stays are double the cost of hiring more staff

A study across 55 hospitals in Queensland, Australia suggests that a recent state policy to introduce a minimum ratio of one nurse to four patients for day shifts has successfully improved patient care, with a 7% drop in the chance of death and readmission, and 3% reduction in length of stay for every one less patient a nurse has on their workload.

The study of more than 400,000 patients and 17,000 nurses in 27 hospitals that implemented the policy and 28 comparison hospitals is published in The Lancet. It is the first prospective evaluation of the health policy aimed at boosting nurse numbers in hospitals to ensure a minimum safe standard and suggests that savings made from shorter hospital stays and fewer readmissions were double the cost of hiring more staff.

Despite some evidence that more nurses in hospitals could benefit patient safety, similar policies have not been widely implemented across the globe, partly due to an absence of data on the long-term effects and costs, as well as limited resources. In recent years, Scotland, Wales, and Ireland have mandated numbers of patients per nurse, but strategies to improve nursing levels remains debated worldwide.

Study fills data gap

“Our findings plug a crucial data gap that has delayed a widespread roll-out of nurse staffing mandates. Opponents of these policies often raise concerns that there is no clear evaluation of policy, so we hope that our data convinces people of the need for minimum nurse-to-patient ratios by clearly demonstrating that quality nursing is vital to patient safety and care,” says lead author, Professor Matthew McHugh of the University of Pennsylvania School of Nursing, USA.

In 2016, 27 public hospitals in Queensland were required to instate a minimum of one dedicated nurse for every four patients during day shifts and one for every seven patients for night shifts on medical-surgical wards.

The research team collected data from those 27 Queensland hospitals that instated ratios and from 28 other hospitals in the state that did not, at baseline in 2016 and at follow-up in 2018 (two years after the policy was implemented). Only nurses in direct contact with adult patients in medical-surgical wards were included – data from patients in birthing suites and psychiatric units were not assessed in the study.

Researchers used patient data to assess demographics, diagnoses, and discharge details for patients, as well as length of hospital stay. These data were then linked to death records for 30 days following discharge, and to readmissions within seven days of discharge.

The researchers sent an email survey to nurses in each hospital to ask about the numbers of bedside nurses and patients on their most recent shift. The responses were used to establish the numbers of nurses per patient and then averaged across wards and hospitals. Responses were received from 8,732 nurses (of a possible 26,871) at baseline in 2016, and 8,278 (of a possible 30,658) in 2018.

The study includes baseline data for 231,902 patients (142,986 in hospitals that implemented the policy and 88,916 in comparison hospitals), and for 257,253 patients (160,167 in hospitals that implemented the policy and 97,086 in comparison hospitals) after the policy was brought in.

Comparison hospitals had no change in staffing, with six patients per nurse in 2016 and the same ratio (1:6) in the follow-up period in 2018. Intervention hospitals averaged five patients per nurse at baseline in 2016, with a reduction to four per nurse after the policy implementation.

Patient deaths

To compare the changes in outcomes in the intervention and comparison hospitals over time, the researchers estimated the odds of dying within 30 days of admission and of being readmitted within seven days of discharge, and the additional length of stay, after adjusting for factors such as patient age, sex, existing health conditions and hospital size. They found that the chance of death rose between 2016 and 2018 by 7% in hospitals that did not implement the policy, and fell by 11% in hospitals that did implement the policy.

Readmissions

The chances of being readmitted increased by 6% in the comparison hospitals over time, but stayed the same in hospitals that implemented the policy. Between 2016 and 2018, the length of stay fell by 5% in the hospitals that did not implement the policy, and by 9% in hospitals that did.

Nurse workloads

Further analyses found that when nurse workloads improved by one less patient per nurse, the chance of death and readmissions fell by 7%, and the length of hospital stay dropped by 3%.

Using their modelling to predict figures that would have been expected without the policy in place, the researchers estimated that there could have been 145 more deaths, 255 more readmissions and 29,222 additional days in hospital in the 27 hospitals that implemented the policy between 2016 and 2018.

Financial impact of employing more nurses

To calculate the financial impact of the staffing policy, the researchers used state data to estimate the cost of funding the 167 extra staff needed to reduce workload by one patient per nurse at approximately $33,000,000 (AUD) in the first two years. Based on Australian health economic data, they further estimated that preventing readmissions and reducing lengths of stay resulted in an approximate saving of $69,150,858 in the 27 hospitals across the two years following the mandate.

“Part of the reluctance to bring in a minimum nurse-patient ratio mandate from some policy-makers is the expected rise in costs from increased staffing. Our findings suggest that this is short-sighted and that the savings created by preventing readmissions and reducing length of stay were more than twice the cost of employing the additional nurses needed to meet the required staffing levels – a clear return on investment. Often, policy-makers are concerned about whether they can afford to implement such a policy. We would encourage governments to look at these figures and consider if they can afford not to,” says Professor Patsy Yates of the Queensland University of Technology School of Nursing, Australia.

Study limitations

The authors note that there are a number of limitations associated with the study. Hospitals in the research were not randomly assigned to comparison or intervention groups, as only 27 hospitals in the state were mandated to follow the policy. Furthermore, the hospitals included in both groups were not matched for size or patient demographics and health conditions, although this is accounted for in adjusted analyses.

Access the study: Effects of nurse-to-patient ratio legislation on nurse staffing and patient mortality, readmissions, and length of stay: a prospective study in a panel of hospitals. The Lancet. May 11, 2021. https://doi.org/10.1016/S0140-6736(21)00768-6

COVID vaccines: some fully vaccinated people will still get infected – here’s why

, 18 May 2021/in Corona News, E-News /by panglobal

By Tara Hurst
Lecturer, Biomedical Science, Birmingham City University

The development of several COVID vaccines in less than a year has given us all hope of a release from the pandemic. Now the goal has shifted to ensuring widespread vaccine coverage is achieved as quickly as possible around the globe.

However, it is unlikely that any of the vaccines will be 100% effective at stopping transmission or infection. There is a small risk that some fully vaccinated people will get infected. This is known as a “breakthrough infection” – and it’s entirely expected.

It is important to realise the limitations of vaccines. No vaccine offers full protection to everyone who receives it. The measles vaccine has been highly effective at preventing infection, leading to the virus being nearly eradicated in some countries.

Yet there are infections reported even in populations with widespread vaccination. These infections occur not only in the unvaccinated; there are cases of breakthrough infections in fully vaccinated people.

The seasonal flu vaccine offers protection from the circulating viruses. But the circulating flu viruses vary, and vaccinated people may still get ill but have less severe illness.

This is possibly because different arms of the immune response produce different defences, namely antibodies, which are Y-shaped proteins that lock onto germs and neutralise them, and T cells, which find and destroy infected cells. Antibodies are typically raised against the more variable proteins on the surface of the virus, while the more consistent proteins inside the virus are targeted by the T cells. T cells are important for limiting the severity of illness.

For SARS-CoV-2 (the virus that causes COVID-19) there is anecdotal evidence, including from Seychelles, of breakthrough infections, but little has yet been published in scientific journals. A recent report in the New England Journal of Medicine described two COVID-19 cases following vaccination, with both showing mild symptoms that resolved within one week.

And a study from Stanford University, which is yet to be reviewed by other scientists, describes 189 post-vaccination COVID cases out of 22,729 healthcare workers, but attributes at least some of these to partial vaccination. Vaccination will probably make the disease less severe should such breakthroughs occur.

Several explanations

There are several possible explanations for breakthrough infections. The human immune response is encoded in our DNA and varies from person to person. This variability helps us to respond to an array of germs. But the effectiveness of these responses is also variable. This could also be due to several things, including poor health, medication or age.

The ageing immune system does not respond to new antigens (foreign substance that causes your immune system to produce antibodies against it) and vaccines as well as younger immune systems. For one COVID vaccine, there was a measurable difference in the concentration of neutralising antibodies in the elderly compared with younger adults. Some of the elderly participants had no neutralising antibodies at all after both doses of the vaccines.

Another reason for breakthrough infections is due to viral variants that escape immune detection and flourish even in vaccinated people. A virus, especially an “RNA virus” such as SARS-CoV-2, is expected to mutate and give rise to variants, some of which may be more easily transmitted. These variants may also be more or less effectively neutralised by the immune system since the mutations could alter the parts of the virus that are recognised by antibodies and T cells.

A new SARS-CoV-2 variant identified in India (B16172) is thought to make the virus more transmissible and this is a cause for concern in light of the COVID crisis unfolding there. Despite the absence of scientific studies, there are many reports in the media of frequent breakthrough infections and the B16172 variant is blamed, but this has yet to be proved.

In the one study, done on post-vaccine infections with SARS-CoV-2 in California, there was no significantly higher risk of infection due to the variants circulating in that region. Despite the evidence that the vaccines work well against the variants, the rapid increase in the proportion of cases in the UK that are due to B16172 as compared to the dominant Kent strain (B117) has meant that it has been raised to a variant of concern by Public Health England.

While widespread vaccination remains the pandemic end game, it bears mentioning that this is unlikely to prevent all infections. Those who develop COVID after vaccination will probably have a milder illness, and so the risk of breakthrough infections should not deter us from using the current vaccines. Further study into the causes of breakthrough SARS-CoV-2 infections could help scientists to refine COVID vaccines or the schedule of booster doses.

This article is republished from The Conversation under a Creative Commons license.

Brain-to-text: Researchers develop brain-computer interface that turns neural signals into typed text in real time

Research, 13 May 2021/in E-News /by panglobal

Thoughts turned into text: Two implanted electrode arrays record the brain activity produced by thinking about writing letters. This information is then collected and processed in real-time by a computer, which converts that data into words on a screen. Courtesy Shenoy lab & Erika Woodrum (artist)

Scientists have developed a brain-computer interface (BCI) which for the first time enables neural signals associated with handwriting to be decoded and turned into text in real time.

This breakthrough in BCI technology has the potential to enable paralysed or paraplegic individuals – unable to write or speak – to communicate in writing, at speed, in real time.

The study was published in Nature, May 12.

The researchers developed an intracortical BCI that decodes attempted handwriting movements from neural activity in the motor cortex and translates it to text in real time, using a recurrent neural network decoding system.

They tested the device in a participant with paralysis which in essence enabled him to type without using his hands. By thinking about handwriting letters, the researchers were able to decode the neural signals with an algorithm which turned the letters into typed text on a screen in real time.

The study participant typed 90 characters per minute – more than double the previous record for typing with such a BCI. However, previous studies had not used decoded neural handwriting signals. They had instead used thought-controlled cursor movements on a virtual keyboard.

Neural signals associated with handwriting

Study coauthor Krishna Shenoy, a Howard Hughes Medical Institute (HHMI) investigator at Stanford University and his team have in recent years been studying neural activity associated with speech in an effort to reproduce it. However, they had not considered trying to decode neural signals associated with handwriting, says Frank Willett, an HHMI research specialist and neuroscientist in Shenoy’s group.

First, the participant was asked to copy letters that were displayed on the screen, which included the 26 lower-case letters along with some punctuation: “>” which was used as a space and “~” which was used as a “full stop.” At the same time, implanted electrodes recorded the brain activity from approximately 200 individual neurons associated with handwriting that responded differently while he mentally “wrote” each individual character. After a series of training sessions, the BCI’s computer algorithms learned how to recognize neural patterns corresponding to individual letters, allowing the participant to “write” new sentences that hadn’t been printed out before, with the computer displaying the letters in real time.

“This method is a marked improvement over existing communication BCIs that rely on using the brain to move a cursor to ‘type’ words on a screen,” said Willett, the study’s lead author. “Attempting to write each letter produces a unique pattern of activity in the brain, making it easier for the computer to identify what is being written with much greater accuracy and speed.”

Level of flexibility

This system also provides a level of flexibility that is crucial to restoring communication. Some studies have gone as far as attempting direct thought-to-speech BCIs that, while promising, are currently limited by what is possible through recordings from the surface of the brain which averages responses across thousands of neurons.

“Right now, other investigators can achieve about a 50-word dictionary using machine learning methods when decoding speech,” said Dr. Shenoy. “By using handwriting to record from hundreds of individual neurons, we can write any letter and thus any word which provides a truly ‘open vocabulary’ that can be used in almost any life situation.”

Although it is still relatively early days for this technology, it offers the potential to help those who have completely lost the ability to write and speak.

In the future, Dr. Shenoy’s team intends to test the system on a patient who has lost the ability to speak, such as someone with advanced ALS. In addition, they are looking to increase the number of characters available to the participants (such as capital letters and numbers).

The participant is part of a clinical trial, called BrainGate2, which is being conducted by a collaboration of internationally recognized laboratories, universities, and hospitals working to advance brain-computer interface technologies.

Reference

Willett, F.R., Avansino, D.T., Hochberg, L.R. et al. High-performance brain-to-text communication via handwriting. Nature 593, 249–254 (2021). https://doi.org/10.1038/s41586-021-03506-2

14-year-old becomes youngest patient to receive living donor liver transplant at Cleveland Clinic Abu Dhabi

Surgery, 13 May 2021/in E-News /by panglobal

A 14-year-old boy has received a living liver donation from his elder brother at Cleveland Clinic Abu Dhabi, an integral part of Mubadala Health, becoming the youngest patient to undergo the operation in the hospital’s history.

Montasir Elfatih Mohyeldin Taha was diagnosed with biliary atresia in infancy, a condition where the bile ducts outside the liver fail to form during fetal development, not allowing the bile to reach the small intestine where it helps in the digestion of fat. At 10 months, he had to undergo the Kasai procedure, which is done to connect a loop of small bowel directly to the liver so that the bile can drain into it. Montasir’s doctors back home in Sudan knew that it was only a matter of time before he would have to undergo a liver transplant, an inevitable consequence for most children who have this procedure.

Portal hypertension

Earlier this year, Montasir’s symptoms and blood tests revealed that he had started developing liver failure and was suffering from portal hypertension, an increase in the pressure within the vein that carries blood from the digestive organs to the liver, resulting in varicose veins in his esophagus. Seeing the high risk of potential complications, his doctors in Sudan recommended that he undergo a liver transplant at Cleveland Clinic Abu Dhabi.

Dr. Luis Campos, the Director of Liver Transplant and Hepatobiliary at Cleveland Clinic Abu Dhabi, who was part of the interdisciplinary team that cared for Montasir, says this was one of the most complex living donor liver transplant surgeries that they have performed at the hospital.

“There were additional nuances that had to be taken into consideration because of his age, which made it even more challenging. Factors such as height and weight impact the surgery and after-care, and determine the dose of immunosuppressive medication during and after the transplant. There is also a risk of other infectious complications in pediatric liver transplant that do not apply to adult surgeries,” says Dr. Campos.

Multidisciplinary medical team

The multidisciplinary medical team at Cleveland Clinic Abu Dhabi studied the case and evaluated Montasir’s mother and brother for a match in February. After careful discussion with colleagues in the US-based Cleveland Clinic, doctors here decided that his sibling would be a more suitable match.

“My little brother needed me. I was very relieved when I was told that I can help be the cure to his illness. This was one of the easiest decisions that I have had to make,” says Khalifa Elfatih Mohyeldin Taha. “My father passed away six months back and as the eldest son in the family, it was my responsibility to save him.”

Kasai procedure

Dr. Shiva Kumar, the Chair of Gastroenterology and Hepatology in the Digestive Disease Institute at Cleveland Clinic Abu Dhabi, who was also part of the patient’s care team, says one of the biggest challenges during Montasir’s transplant was posed by the young patient’s Kasai procedure.

“While the Kasai procedure is commonly performed to prolong the need for a liver transplant in children, this is a major operation and makes the transplant more challenging to perform,” says Dr. Kumar.

“However, the surgeries of both brothers were successful and without complications. Montasir received a left lobe graft from his brother. This is a smaller portion of the liver than if we were transplanting a right lobe graft. This makes it a safer operation for the donor and helps them recover faster.”

Immunosuppressive regimen

The brothers are on their way to a full recovery. Khalifa is back to his normal life now while the Cleveland Clinic Abu Dhabi care team is monitoring Montasir’s immunosuppressive regimen, which he will be on for the rest of his life.

Khalifa says he could not contain his joy when he was told that the surgery was a success. “The best part of my transplant journey was to see that Montasir’s body had accepted the new organ. My family and I are very grateful to the care team at Cleveland Clinic Abu Dhabi for saving my brother’s life.”

He also hopes that more people consider organ donation. “The feeling of giving a chance to someone to live a normal life is incomparable. Seeing the result of your donation will fill you with contentment.”

Lung cells in patients with severe COVID become trapped in a state (indicated by the green color) that prevents the cells from repairing damage caused by the infection. The left image shows cells from a healthy lung; the right image shows lung cells from a patient who died from COVID-19

New Cell Atlas of COVID lungs reveals why SARS-CoV-2 is different and deadly

, 3 May 2021/in Corona News, E-News /by panglobal

Lung cells in patients with severe COVID become trapped in a state (indicated by the green color) that prevents the cells from repairing damage caused by the infection. The left image shows cells from a healthy lung; the right image shows lung cells from a patient who died from COVID-19. Images: Benjamin Izar / Columbia University Vagelos College of Physicians and Surgeons.

A new study published in Nature [1] draws the most detailed picture yet of SARS-CoV-2 infection in the lung, revealing mechanisms that result in lethal COVID-19, and may explain long-term complications and show how COVID-19 differs from other infectious diseases.

Led by researchers at Columbia University Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center, the study found that in patients who died of the infection, COVID-19 unleashed a detrimental trifecta of runaway inflammation, direct destruction and impaired regeneration of lung cells involved in gas exchange, and accelerated lung scarring.

Though the study looked at lungs from patients who had died of the disease, it provides solid leads as to why survivors of severe COVID may experience long-term respiratory complications due to lung scarring.

“It’s a devastating disease, but the picture we’re getting of the COVID-19 lung is the first step towards identifying potential targets and therapies that disrupt some of the disease’s vicious circuits. In particular, targeting cells responsible for pulmonary fibrosis early on could possibly prevent or ameliorate long-term complications in survivors of severe COVID-19,” says Benjamin Izar, MD, PhD, assistant professor of medicine, who led a group of more than 40 investigators to complete in several months a series of analyses that usually takes years.

This study and a companion paper [2] led by researchers at Harvard/MIT, to which the Columbia investigators also contributed, were published in the journal Nature on April 29.

Study creates atlas of cells in COVID lung

The new study is unique from other investigations in that it directly examines lung tissue (rather than sputum or bronchial washes) using single-cell molecular profiling that can identify each cell in a tissue sample and record each cell’s activity, resulting in an atlas of cells in COVID lung.

“A normal lung will have many of the same cells we find in COVID, but in different proportions and different activation states,” Izar says. “In order to understand how COVID-19 is different compared to both control lungs and other forms of infectious pneumonias, we needed to look at thousands of cells, one by one.”

Izar’s team examined the lungs of 19 individuals who died of COVID-19 and underwent rapid autopsy (within hours of death) – during which lung and other tissues were collected and immediately frozen – and the lungs of non-COVID-19 patients. In collaboration with investigators at Cornell University, the researchers also compared their findings to lungs of patients with other respiratory illnesses.

Drugs targeting IL-1ß may reduce inflammation

Compared to normal lungs, lungs from the COVID patients were filled with immune cells called macrophages, the study found.

Typically during an infection, these cells chew up pathogens but also regulate the intensity of inflammation, which also helps in the fight.

“In COVID-19, we see expansion and uncontrolled activation of macrophages, including alveolar macrophages and monocyte-derived macrophages,” Izar says. “They are completely out of balance and allow inflammation to ramp up unchecked. This results in a vicious cycle where more immune cells come in causing even more inflammation, which ultimately damages the lung tissue.”
One inflammatory cytokine in particular, IL-1ß, is produced at a high rate by these macrophages.
“Unlike other cytokines such as IL-6, which appears to be universally prevalent in various pneumonias, IL-1ß production in macrophages is more pronounced in COVID-19 compared to other viral or bacterial lung infections,” Izar says. “That’s important because drugs exist that tamp down the effects of IL-1ß.”
Some of these drugs are already being tested in clinical trials of COVID patients.

Severe COVID also prevents lung repair

In a typical infection, a virus damages lung cells, the immune system clears the pathogen and the debris, and the lung regenerates.

But in COVID, the new study found that not only does SARS-CoV-2 virus destroy alveolar epithelial cells important for gas exchange, the ensuing inflammation also impairs the ability of the remaining cells to regenerate the damaged lung.

Though the lung still contains cells that can do the repairs, inflammation permanently traps these cells in an intermediate cell state and leaves them unable to complete the last steps of differentiation needed for replacement of mature lung epithelium.

“Among others, IL-1ß appears to be a culprit in inducing and maintaining this intermediate cell state,” says Izar, “thereby linking inflammation and impaired lung regeneration in COVID-19. This suggests that in addition to reducing inflammation, targeting IL-1ß may help take the brakes off cells required for lung repair.”

Preventing accelerated fibrosis

The researchers also found a large number of specific fibroblast cells, called pathological fibroblasts, that create rapid scarring in COVID-19 lungs. When the fibroblast cells fill the lung with scar tissue, a process called fibrosis, the lung has less space for cells involved in gas exchange and is permanently damaged.

Given the importance of pathological fibroblasts in the disease, Izar’s team closely analysed the cells to uncover potential drug targets. An algorithm called VIPER, developed previously by Andrea Califano, Dr, chair of systems biology at Columbia University Vagelos College of Physicians and Surgeons, identified several molecules in the cells that play an important role and could be targeted by existing drugs.

“This analysis predicted that inhibition of STAT signalling could alleviate some of the deleterious effects caused by pathological fibroblasts,” Izar says.

“Our hope is that by sharing this analysis and massive data resource, other researchers and drug companies can begin to test and expand on these ideas and find treatments to not only treat critically ill patients, but also reduce complications in people who survive severe COVID-19.”

References

[1] A molecular single-cell lung atlas of lethal COVID-19. Nature (2021).
https://doi.org/10.1038/s41586-021-03569-1

[2] COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature (2021).
https://doi.org/10.1038/s41586-021-03570-8

RESPIRE trial of therapeutic for all strains of COVID-19 gets underway in Germany

, 13 April 2021/in Corona News, E-News /by panglobal

Investigators hope ATR-002 drug will also be effective against ‘Long-Covid’

Tübingen, Germany-based Atriva Therapeutics, a biopharmaceutical company that is pioneering the development of host-targeting antiviral therapies, has enrolled its first patient in its Phase II RESPIRE [1] trial in COVID-19. Prof. Martin Witzenrath, M.D., Vice Director Department of Infectious Diseases and Respiratory Medicine, supervised the first administration of study medication (MEK inhibitor ATR-002 or placebo) at the Charité – Universitätsmedizin Berlin, Germany.

Dr Rainer Lichtenberger, CEO of Atriva Therapeutics, commented: “We are excited to assess the efficacy of ATR-002 in treating COVID-19 and are looking forward to the results of the clinical trial. We can now test our lead candidate against SARS-CoV-2 because our pharmacological target is a common cellular mechanism that RNA viruses use. ATR-002 leaves the virus itself untouched but blocks a cellular factor that the virus needs for its replication and has the potential to reduce the viral load in the infected host.

“Host-directed approaches maintain efficacy also against mutated viruses – a problem that we are commonly seeing in the influenza virus and, unfortunately, in SARS-CoV-2 as well. If we were to see the positive outcomes of the trial we hope for, ATR-002 could provide efficient help against COVID-19 regardless of the given genetic subtype of the underlying viral strain.”

Prof. Gernot Rohde, M.D., Head of Pneumology and Professor for Respiratory Medicine and Allergology at the Goethe University Hospital, Frankfurt am Main, Germany and Global Coordinating Investigator of the RESPIRE trial, said: “While we have been lucky that SARS-CoV-2 vaccines were developed at unprecedented speed, we still are in desperate need for effective therapies against COVID-19. The pandemic situation remains very critical and is far from being under control.

“Being able to contribute to the development of a COVID-19 therapy, I am very much looking forward to the effects that we may see with ATR-002. I am convinced that a medication that can prevent hospitalized patients with a moderate to severe stage of COVID-19 from deteriorating and requiring ICU admission and ventilator support would mean huge progress and could also play a role in impeding the severe long-term effects that are being described as “Long COVID” Syndrome (PASC).”

RESPIRE trial

RESPIRE is a randomized, double-blind, placebo-controlled, international, multi-center Phase II clinical trial in 220 adult patients with moderate to severe COVID-19, requiring hospitalization, but not requiring ICU admission or ventilator support at the time of screening or randomization. On top of standard of care, half of the patients will receive ATR-002 900 mg, administered as tablets once daily on day 1, followed by ATR-002 600 mg once daily on days 2 to 6. Patients in the control group will receive placebo in a matching scheme, on top of standard of care.

The primary objective of the study is to demonstrate the efficacy of ATR-002 versus placebo in addition to standard of care; secondary endpoints include the measurement of changes in clinical signs and symptoms as well as other relevant clinical parameters. Outcomes will be assessed based on the clinical severity status on day 15, using a 7-point ordinal scale as suggested by the WHO COVID-19 Therapeutic Trial Synopsis [2]. All patients will be followed-up for 90 days. The study will also evaluate the pharmacokinetics of ATR-002.

ATR-002’s mode of action

Atriva’s lead product ATR-002 is developed specifically to treat diseases such as influenza and COVID-19, caused by RNA viruses. ATR-002 is a clinical stage MEK inhibitor drug candidate targeting the intracellular Raf/MEK/ERK signaling pathway. This pathway is central for replication of many RNA viruses, such as the influenza virus, hantavirus or respiratory syncytial virus (RSV) and also SARS-CoV-2, the virus that causes COVID-19.

In influenza virus infected cells, the interaction of ATR-002 with MEK (MAPK/ERK kinase) prevents export of the viral genome protein complexes (ribonucleoprotein, RNP) from the nucleus to the cytoplasm, thus blocking the formation of functional new viral particles. This ultimately reduces the viral load in the body. In addition, ATR-002 has the potential to modulate the pro-inflammatory cytokine response of the body, avoiding overshooting cytokine response that can be caused by such viral infections. MEK inhibition can reduce the gene expression of some of the cytokines involved, like TNF-α, IL-1ß, IP-10, IL-8, MCP-1 and MIP-1a, and thus mitigate the overactive inflammatory response in the lungs of patients who are severely ill with influenza or COVID-19.

References

[1] RESPIRE – A Randomized, Double-Blind, Placebo-Controlled, Multi-Centre Clinical Trial to Evaluate the Safety and Efficacy of ATR-002 in Adult Hospitalized Patients with COVID-19.

[2] https://www.who.int/publications/i/item/covid-19-therapeutic-trial-synopsis.

MedUni Vienna and Vienna General Hospital develop criteria for selecting COVID-19 patients for lung transplantation

COVID-19, Lung transplant, Surgery, 6 April 2021/in Corona News, E-News /by panglobal

In May 2020, a team led by thoracic surgeon Konrad Hoetzenecker of the Department of Surgery of MedUni Vienna and Vienna General Hospital performed a lung transplant on a 44-year-old patient who had been seriously ill with Covid-19, making her the first patient in Europe to receive a lung transplant for this indication. The Vienna lung transplantation programme now plays a leading role in an international consortium comprising experts from the USA, Europe and Asia. Based on the expertise from Vienna, approximately 40 transplants have now been carried out on Covid-19 patients throughout the world.

In a study published in The Lancet Respiratory Medicine, the consortium has now proposed the first general selection criteria for lung transplantation in Covid-19 patients.

“We have collated the first experiences in the world of performing lung transplants on Covid-19 patients. It is clear that such a complex intervention should only be considered for patients who, by virtue of their age and good general health, have a good chance of recovery with new lungs,” explaindc Konrad Hoetzenecker, Head of the lung transplantation programme at MedUni Vienna and Vienna General Hospital. The Vienna team performs around 100 lung transplants a year, making it one of the largest programmes in the world, alongside Toronto, Cleveland and Hanover.

Candidates for a lung transplant

The following factors were established as criteria for potential transplantation: exhaustion of all conservative treatment options, no recovery of the Covid-19-damaged lungs despite at least four weeks of ventilation/ECMO, evidence of advanced and irreversible lung damage in several consecutive CT scans, age below 65 and no relevant comorbidities. In addition to this, candidates for a lung transplant must be in good physical condition and have a good chance of complete physical rehabilitation following the transplant.

“These guidelines can be applied worldwide for making a sound selection of patients who are suitable for a lung transplant following a Covid-19 infection,” according to a statement released by MedUni Vienna.

The surgical team at MedUni Vienna and Vienna General Hospital has meanwhile carried out 12 lung transplantations on Covid-19 patients, demonstrating that even the most seriously ill patients, who would otherwise die, can survive with a lung transplant.

Patient No. 1

In March 2020, patient number one suffered total pulmonary failure as a result of Covid-19, so that artificial ventilation was no longer possible. She could only be kept alive by the circulation pump. At the time of the transplant, the PCR test showed that virus particles were still present but were no longer infectious. The MedUni Vienna/Vienna General Hospital thoracic surgeons and surgical team managed to replace the patient’s completely destroyed lungs with new donor lungs.

Reference:

Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries.
The Lancet Respiratory Medicine, 2021
https://doi.org/10.1016/S2213-2600(21)00077-1
https://www.sciencedirect.com/science/article/pii/S2213260021000771

Gold nanoparticles embedded in a porous hydrogel can be implanted under the skin and used as medical sensors

Implantable sensor made of gold nanoparticles could revolutionize medical diagnostics

, 6 April 2021/in E-News /by panglobal

Gold nanoparticles embedded in a porous hydrogel can be implanted under the skin and used as medical sensors. The sensor is like an invisible tattoo revealing concentration changes of substances in the blood by colour change.
— © Nanobiotechnology Group, JGU Department of Chemistry

Scientists at Johannes Gutenberg University Mainz (JGU) have developed a novel type of implantable sensor which can be operated in the body for several months to detect concentrations of substances or drugs in the body. Until now implantable sensors have not been suitable to remain in the body permanently but had to be replaced after a few days or weeks.

On the one hand, there is the problem of implant rejection. On the other hand, the sensor’s colour which indicates concentration changes has been unstable and faded over time.

The newly developed sensor is based on colour-stable gold nanoparticles that are modified with receptors for specific molecules. Embedded into an artificial polymeric tissue, the nanogold is implanted under the skin where it reports changes in drug concentrations by changing its colour.

Invisible tattoo

Professor Carsten Sönnichsen’s research group at JGU has been using gold nanoparticles as sensors to detect tiny amounts of proteins in microscopic flow cells for many years. Gold nanoparticles act as small antennas for light: They strongly absorb and scatter it and, therefore, appear colourful. They react to alterations in their surrounding by changing colour. Prof. Sönnichsen’s team has exploited this concept for implanted medical sensing.

To prevent the tiny particles from swimming away or being degraded by immune cells, they are embedded in a porous hydrogel with a tissue-like consistency. Once implanted under the skin, small blood vessels and cells grow into the pores. The sensor is integrated in the tissue and is not rejected as a foreign body.

“Our sensor is like an invisible tattoo, not much bigger than a penny and thinner than one millimetre,” said Prof Sönnichsen, head of the Nanobiotechnology Group at JGU. Since the gold nanoparticles are infrared, they are not visible to the eye. However, a special measurement device can detect their colour noninvasively through the skin.

In their study published in Nano Letters, the JGU researchers implanted their gold nanoparticle sensors under the skin of hairless rats. Colour changes in these sensors were monitored following the administration of various doses of an antibiotic. The drug molecules are transported to the sensor via the bloodstream. By binding to specific receptors on the surface of the gold nanoparticles, they induce colour change that is dependent on drug concentration. Thanks to the colour-stable gold nanoparticles and the tissue-integrating hydrogel, the sensor was found to remain mechanically and optically stable over several months.

Ideal platform for implantable sensors

“We are used to coloured objects bleaching over time. Gold nanoparticles, however, do not bleach but keep their colour permanently. As they can be easily coated with various different receptors, they are an ideal platform for implantable sensors,” explained Dr Katharina Kaefer, first author of the study.

The novel concept is generalizable and has the potential to extend the lifetime of implantable sensors. In future, gold nanoparticle-based implantable sensors could be used to observe concentrations of different biomarkers or drugs in the body simultaneously. Such sensors could find application in drug development, medical research, or personalized medicine, such as the management of chronic diseases.

Reference:
Implantable Sensors Based on Gold Nanoparticles for Continuous Long-Term Concentration Monitoring in the Body, Nano Letters, 30 March 2021. DOI: 10.1021/acs.nanolett.1c00887
https://pubs.acs.org/doi/10.1021/acs.nanolett.1c00887

Graphene nanotech neural implant company – INBRAIN Neuroelectronics – receives €14.35 million investment

, 30 March 2021/in E-News /by panglobal

INBRAIN Neuroelectronics, a spin-off Graphene Flagship partners the Catalan Institute of Nanoscience and Nanotechnology (ICN2) and ICREA, Spain, has received a €14.35 million Series A investment, one of the biggest rounds in the Spanish MedTech industry. The investment will allow INBRAIN to bring their novel neurotechnology to humans for the first time.

INBRAIN Neuroelectronics was established in 2019, at the intersection between MedTech, DeepTech and Digital Health, with a mission to decode brain signals to develop medical solutions for patients with epilepsy, Parkinson’s disease and other neurological disorders. The company designs small implantable brain intelligent systems – built around an innovative nanoscale graphene electrode – with the ability to interpret brain signals with unprecedented high fidelity, producing a therapeutic response adapted to the clinical condition of each patient.

Disruptive technology based on graphene

Existing brain interfaces are based on metals such as platinum and iridium, which impose significant restrictions in terms of miniaturisation and signal resolution, and therefore cause considerable side effects. For this reason, there is a 50% rejection rate in candidate patients. INBRAIN Neuroelectronics uses a disruptive technology based on graphene which will overcome the current limitations of metal-based neural interfaces.

INBRAIN is now a Graphene Flagship partner and is directed by Carolina Aguilar, who was the former Medtronic Deep Brain Stimulation European and Global Commercialization Director. The spin-off was founded, among others, by Graphene Flagship researchers in Spain and the UK, including Jose Garrido, researcher at Graphene Flagship partners ICN2 and ICREA; Kostas Kostarelos, researcher at Graphene Flagship partners ICN2 and the University of Manchester and Graphene Flagship Work Package Leader for Biomedical Technologies; and Anton Guimerà, researcher at Graphene Flagship partner IMB-CNM-CSIC. The technology development team consists of neurotechnology experts such as Bert Bakker (CTO) and Michel Decre (Technology Advisor & Board Member) from Philips, and other European successful neurotechnology start-ups.

According to a 2010 study commissioned by the European Brain Council, the cost of brain disorders in Europe alone is approximately €800 billion per year, with more than one-third of the population affected. Around 30% of patients with a neuronal disease are resistant to pharmacological treatment and do not have an effective therapy. The high incidence of brain-related diseases worldwide, and their huge social cost, call for greater investments in basic research in this field, with the aim of developing new and more efficient therapeutic and diagnostic tools.

In June last year, INBRAIN received a first-seed investment from a syndicate of investors led by Asabys Partners (through Sabadell-Asabys Health Innovation Investment) and Alta Life Sciences, including the Institut Català de Finances (ICF), Finaves (IESE Business School) and BStartUp. The most recent investment was co-led by Asabys Partners and Alta Life Sciences, and joined by Vsquared Ventures, a DeepTech-focused early-stage venture capitalist based in Munich; TruVenturo GmbH, Germany’s most successful tech and life science company builders; and CDTI, at the Spanish Ministry of Science and Innovation.

Cinzia Spinato, Graphene Flagship Business Developer for Biomedical Applications, said: “INBRAIN is leading the way in the field of graphene-based implantable brain devices, and I hope that this success will raise the interest of new stakeholders and corporates towards the opportunities graphene offers in the healthcare domain. I remember when INBRAIN was born, and it is impressive how they have grown so fast: transforming a laboratory technology into a product – an outstanding milestone. This investment will be fundamental to speed up the development of graphene-based medical devices, which will be tested on patients much earlier than everyone expected.”

Technological transformation

INBRAIN Neuroelectronics is bringing a complete technological transformation to the treatment of neurological diseases. Its brain implantable intelligent systems are based on graphene electrodes, which allow miniaturisation to nanoscale fabrication, with the potential to reach single-neuron resolution. The extraordinary properties of graphene – which is light, biocompatible, flexible and extremely conductive – are harnessed in much smaller devices that are safer to implant and can be programmed, upgraded and recharged wirelessly.

Driven by artificial intelligence, the implant can learn from the brain of each patient and trigger adaptive responses to deliver personalised neurological therapy. In addition, the use of big data management will permit remote monitoring of the device and data processing.

The technology has already been validated in in vitro and in vivo, and biocompatibility and toxicity tests have been successful. Studies on large animals have been completed and the investment will bring the technology to human patients, in collaboration with key neurosurgical and neurological groups in Europe.

“This substantial investment exemplifies the growing interest and ever-expanding opportunities to exploit graphene and layered materials in the biomedical domain. Due to its unique properties, graphene has the potential to transform this application area. The Graphene Flagship has chosen biomedical applications as a focus area for commercialisation, and continues to support efforts to foster new innovations – from research to the factory floor, now and into future.”
— Kari Hjelt, Graphene Flagship Head of Innovation

The Graphene Flagship, Funded by the European Commission, aims to secure a major role for Europe in the ongoing technological revolution, helping to bring graphene innovation out of the lab and into commercial applications.

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References

Reference:

Invisible tattoo

Ideal platform for implantable sensors

Disruptive technology based on graphene

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