Category: Medical Research & Technology

New X-Ray Tool to Spy into Virus’ Cellular Subversion

A new X-Ray tool called the Compact Cell-Imaging Device (CoCID) will seek to answer the questions of how viruses penetrate cells, and disrupt and subvert cellular processes to produce more virus copies.

In order to advance research into viral diseases, the aim of the project is to develop a particularly suitable cell-imaging method – which has so far been of limited access to researchers – for extensive application in medical research.

A particularly high-performance method of cell-imaging is soft X-ray microscopy (SXM), explained Dr Venera Weinhardt from the Centre for Organismal Studies of Heidelberg University. A physicist specialising in innovative X-ray procedures, she is head of the Molecular Virology division at the Department of Infectious Diseases of Heidelberg University Hospital. “SXM makes use of the special properties of the soft X-ray spectrum in order to look into the interior of a single intact cell and generate three-dimensional images of its whole internal structure. That also reveals the changes induced by viral infections,” explained Dr Weinhardt. 
Thus, soft X-ray microscopy is distinct from methods like electron microscopy, which can visualise individual parts of a cell but not the whole interior.

Professor Ralf Bartenschlager, a Molecular Virologist at the Ruprecht-Karls-Universität Heidelberg commented, “As a virologist working on how SARS-CoV-2 interacts with and alters its host cell, we will greatly benefit from the development of a soft X-ray microscope that allows us to gain unprecedented insights into this intimate interaction. We have previously used several imaging technologies to address the question of host cell reprogramming by viruses, but each technique has its limitations.”

Since the illumination required for this type of microscopy comes from huge particle accelerators called synchrotrons, currently SXM can only be performed at five research stations in the entire world. The main feature of CoCID therefore lies in further developing a miniaturised soft X-ray approach which has been patented by SiriusXT, a spin-out company from University College Dublin. The breakthrough technology will reduce the size of the X-ray source from a football-field sized synchrotron, instead using a laser-produced plasma (LPP) device that can fit on a bench.

“The SXM microscope developed by SiriusXT performs just as well but is many times smaller, less expensive, and still very fast.” said Dr Weinhardt.

Heidelberg researchers are particularly interested in the potential of the new technology in researching SARS-CoV-2. Prof Bartenschlager’s working group is mainly concerned with how the virus reprograms its host cells. He said that SXM images created under the leadership of Dr Weinhardt at Lawrence Berkeley National Laboratory in California are already promising in this respect.

Three-dimensional images of cells infected with SARS-CoV-2 were generated thanks to a cooperation agreement with the European Molecular Biology Laboratory (EMBL) in Heidelberg.

“Through working with these images we have a pretty good idea of what factors play a role with imaging in connection with the virus-infected cells and we can pass these findings on to the CoCID consortium. As soon as the soft X-ray prototype from Dublin is up and running we will also deliver samples of infected cells, enable a direct comparison with available images and provide support in interpreting data,” said Prof Bartenschlager.

According to the Heidelberg researchers, a soft X-ray microscopy available for daily use should have distinct advantages over current techniques, such as being much faster. Prof Bartenschlager said: “We can’t afford long waits or a time-intensive method when it comes to novel viruses such as SARS-CoV-2, which we learn something new about and which changes on a daily basis.”

Source: News-Medical.Net

New Bioluminescent System Illuminates Biological Processes

Scientists at the Federal University of São Carlos (UFSCar) have developed a new bioluminescent system that can enable greatly improved imaging of biological and pathological processes in organisms.

Luciferases are enzymes that catalyse the oxidation of luciferins present in organisms such as fireflies, which results in bioluminescence in the visible light spectrum. Images of cell cultures and live animal models are made using the luciferin-luciferase system found in fireflies. For example, this can show the structure and activity of tumours, or follow the viral process in cells, helping physicians develop treatments.

“We obtained a novel luciferin-luciferase system that produces far-red light at the wavelength of 650 nanometres and emits the brightest bioluminescence ever reported in this part of the spectrum,” said principal investigator Professor Vadim Viviani, biochemist at UFSCar. “It’s a highly promising result for bioluminescence imaging of biological and pathological processes in mammalian tissues.”

“Red bioluminescence is preferred when imaging biological or pathological processes in mammalian tissues because haemoglobin, myoglobin and melanin absorb little long-wavelength light. Detection is best of all in the far red and near-infrared bands, but bioluminescent systems that naturally emit far red light don’t exist,” Prof Viviani added.

“Some genetically modified forms of luciferase and synthetic analogs of natural luciferins are produced commercially. In conjunction, they produce light at wavelengths as long as 700 nanometers, but the light produced by these artificial systems is generally much weaker and more short-lived than light from natural bioluminescent systems.”

Prof Viviani and collaborators genetically modified luciferase from the Railroad worm Phrixothrix hirtus, the only luciferase that naturally emits red light, and combined with luciferin analogues synthesised by colleagues at the University of Electro-Communications in Tokyo. The resulting luciferin-luciferase generates a much more efficient far-red bioluminescence.

“Our best combination produces far-red at 650 nanometres, three times brighter than natural luciferin and luciferase, and roughly 1000 times brighter than the same luciferase with a commercial analog,” Viviani said.

“Besides the long-wavelength and intense brightness, our combination has better thermal stability and cell membrane penetrability. Above all, it produces more lasting continuous bioluminescence, taking at least an hour to decay and significantly facilitating the real-time imaging of biological and pathological processes.”

Source: News-Medical.Net

Journal information: Viviani, R. V, et al. (2021) A Very Bright Far-Red Bioluminescence Emitting Combination Based on Engineered Railroad Worm Luciferase and 6′-Amino-Analogs for Bioimaging Purposes. International Journal of Molecular Sciences. doi.org/10.3390/ijms22010303.

Telemedicine Is as Satisfactory as In-person Follow-Up for Knee Surgery

Following arthroscopic knee surgery, patients are as satisfied with telemedicine follow-ups as they are with in-person follow-up, according to a new study published in The Journal of Bone & Joint Surgery.

“Patient satisfaction with overall care is equivalent between telemedicine and office-based follow-up after an arthroscopic meniscal surgical procedure in the immediate postoperative period,” wrote Christina P Herrero, MD, and colleagues of NYU Langone Health.

The study recruited 122 patients who underwent arthroscopic surgery on the meniscus in the knee, which is one of the most common orthopaedic surgical procedures. Of these patients, 88% had a removal of the meniscus (meniscectomy), with the rest undergoing meniscal repair procedures.
Patients were randomly assigned to either office-based or telemedicine follow-up, scheduled for 5 to 14 days postoperatively. During both types of follow-up visits, the surgeon spoke to the patient about the surgical findings, pain the patient might be experiencing, and the postoperative recovery period, as well as performing a physical examination that included range-of-motion testing.

The telemedicine follow-ups were performed using the patient’s home computer or mobile device via a telemedicine program that was compliant with privacy rules. Surgeons of course were unable to physically feel or touch the knee during telemedicine follow-ups. However they could still conduct a visual assessment of wound healing, drainage, and swelling. 

Overall satisfaction ratings were nearly identical between groups. The surveys showed average patient satisfaction scores (on a 0-to-10 scale) were 9.77 in office-based follow-up and 9.79 for telemedicine follow-up. In both groups, only about 20% of patients said they would have preferred the other type of visit. There was also similar improvement observed in pain scores between groups: from about 5 (out of a maximum of 10) on the day of the surgery to 3 at the follow-up visit.

Telemedicine has become all the more crucial in the COVID pandemic to minimise contact, but the levels of satisfaction shown indicate that it may be a promising standard mode of care in the future, especially for cases where access to physical follow-up consultation may be difficult for the patients. 

“Telemedicine may be a reasonable alternative to office-based follow-up after knee arthroscopy,” Dr Herrero and coauthors concluded. “[Our] study only evaluated the first postoperative visit, but future studies may benefit from expanding the use of telemedicine to longer-term follow-ups or to additional surgical procedures.”

Source: News-Medical.Net

Journal information: Herrero, C. P., et al. (2021) Patient Satisfaction Is Equivalent Using Telemedicine Versus Office-Based Follow-up After Arthroscopic Meniscal Surgery. The Journal of Bone & Joint Surgery. doi.org/10.2106/JBJS.20.01413.

New Smart Speakers That Can Remotely Monitor Heartbeat


Smart speaker services like Amazon’s Alexa have shown that they can be adapted to monitor the breathing of babies, and recent development has enabled them to detect heartbeats without contacting the skin.

“Heart rhythm disorders are actually more common than some other well-known heart conditions. Cardiac arrhythmias can cause major morbidities such as strokes, but can be highly unpredictable in occurrence, and thus difficult to diagnose,” explained co-senior author Dr Arun Sridhar, assistant professor of cardiology at the UW School of Medicine. “Availability of a low-cost test that can be performed frequently and at the convenience of home can be a game-changer for certain patients in terms of early diagnosis and management.”

Instead of listening to the heartbeat, the smart speaker emits a continuous sound which bounces off the patient’s body. Changes in the received sound are associated with motions in the body from a heartbeat.
“The motion from someone’s breathing is orders of magnitude larger on the chest wall than the motion from heartbeats, so that poses a pretty big challenge,” said lead author Anran Wang, a doctoral student in the Allen School. “And the breathing signal is not regular so it’s hard to simply filter it out. Using the fact that smart speakers have multiple microphones, we designed a new beam-forming algorithm to help the speakers find heartbeats.”

Beam-forming is a technology where an array of emitters or receivers can change the direction in which a signal is emitted or received. Applications of such technology include directing sound only in one direction, such as a person watching TV while another wants quiet while they read,
Much in the way AI systems sort out sounds to identify human speech, the algorithm developed by the team can pick up heartbeats. As this does not produce the usual peaks seen in heartbeat monitors, this also requires processing the heartbeat further to extract the inter-beat interval.
“With this method, we are not getting the electric signal of the heart contracting. Instead we’re seeing the vibrations on the skin when the heart beats,” Mr Wang said.

The researchers tested their prototype smart speaker system on 26 healthy participants and 24 patients with hospitalised with a variety of cardiac conditions. The team compared the smart speaker’s inter-beat interval with one from a standard heartbeat monitor. Of the nearly  2,300 heartbeats measured for the healthy participants, the smart speaker’s median inter-beat interval was within 28 milliseconds of the standard monitor. With cardiac patients, the median inter-beat interval measured by the smart speaker was within 30 milliseconds of the standard.

The technology is currently set up for spot checks; a person concerned about their heart rhythm could sit in front of a smart speaker for a reading. In the future, the researchers hope that the system could be set up to monitor heartbeats for long periods, such as when they are sleeping, helping to diagnose conditions like sleep apnoea.

Source: Medical Xpress

Faster 3-D Bioprinting A Step Closer to Printing Whole Organs

With the demonstration of a new type of more rapid 3-D bioprinting, University at Buffalo engineers have taken a step closer to the fabrication of whole organs.

In a video of the process, a hand emerges over a matter of seconds from a vat of liquid almost as if out of a science fiction movie. In reality, the video was sped up from its original duration of 19 minutes, but even this is a quantum leap ahead of the six or so hours such a process previously took. 
“The technology we’ve developed is 10-50 times faster than the industry standard, and it works with large sample sizes that have been very difficult to achieve previously,” said co-lead author Ruogang Zhao, PhD, associate professor of biomedical engineering.

The new method involves a 3-D printing technology called stereolithography and hydrogels. Hydrogels have applications in wound dressings, contact lenses and hygiene products, as well as scaffolds for tissue engineering.

Scaffolds are particularly important in 3-D bioprinting, and the team has spent a great deal of its time and effort on these in order to come up with an optimised solution for its fast, accurate 3-D printing technique.
“Our method allows for the rapid printing of centimeter-sized hydrogel models. It significantly reduces part deformation and cellular injuries caused by the prolonged exposure to the environmental stresses you commonly see in conventional 3-D printing methods,” said the other co-lead author, Chi Zhou, PhD, associate professor of industrial and systems engineering.

This method is readily suited for the printing of cells with embedded networks of blood vessels. It is expected that this emerging technology will be key to producing whole 3-D printed organs and tissue.

Source: Medical Xpress

Journal information: Nanditha Anandakrishnan et al, Fast Stereolithography Printing of Large‐Scale Biocompatible Hydrogel Models, Advanced Healthcare Materials (2021). DOI: 10.1002/adhm.202002103
https://medicalxpress.com/news/2021-03-rapid-3d-method-3d-printed.html

Combination Nanoparticle Therapy Shows Promise as Antiviral

Researchers have developed a new nanoparticle combination as a broad-spectrum anti-RNA virus treatment. 

The results of their study have been published on the bioRxiv preprint server. Note that as a preprint, this paper has not yet been peer reviewed.
Non-specific antivirals offer a number of attractive advantages. Their broad spectrum activity suppresses mutations, and would they also readily be at hand for future outbreaks. Nanoparticles are one possibility, with reduced toxicity.

Silver nanoparticles (AgNPs) are well-established as antibacterial and antiviral agents, and are the subject of many exotic biomedical applications. The mechanism of AgNPs is thought to be through physiochemical destruction of the microbial surface, with internal disruption from free Ag+ ions and reactive oxide species. Graphene oxide (GO) also has anti microbial properties. With its high surface area, GO also acts as a drug carrier.

The researchers produced seven different material combinations using three different methods: reduction with silver salt, direct addition of Ag nanospheres, and direct addition of Ag nanospheres to thiolised graphene.
To test the materials against seasonal-type infections as well as the kind of virus that could be expected from a future pandemic, the researchers tested the nanoparticles with influenza A virus (IAV) and human coronavirus (HCoV) OC43. IAV is an enveloped virus of the orthomyxovirus family with a segmented single-stranded RNA genome; it causes flu pandemics. HCoV-OC43 is an enveloped betacoronavirus with a single-stranded RNA genome associated with the common cold in humans.

Two of the GO-AgNP materials showed rapid, potent antiviral activity in solution against the viruses. The remaining five materials possessed a range of modest to no antiviral effects against IAV, the researchers reported. They observed a synergistic effect between the AgNPs and GO, with mechanism of action possibly being rapid disruption of the viral envelope. With high levels of antiviral agents, the combination of AgNPs with GO was found to show greater antiviral performance and lower toxicity.

“Our finding that graphene oxide/silver nanoparticle ink can rapidly prevent in vitro infection with two different viruses is exciting, and suggests that the ink has the potential to be used in a variety of applications to help reduce the spread of viruses in the environment,” said co-author Dr Meredith J Crane.

Source: News-Medical.Net

Journal information: Graphene oxide/silver nanoparticle ink formulations rapidly inhibit influenza A virus and OC43 coronavirus infection in vitro, Meredith J. Crane, Stephen Devine, Amanda M. Jamieson, bioRxiv 2021.02.25.43

Researchers Study Enzyme Processes for New Drugs

Traditional discovery has produced drugs that effectively target proteins directly involved with disease, but options are starting to run out and researchers are looking to more complex and obscure interactions for drug targets.

So far, drug discovery has used the ‘small molecule’ approach, where a specific protein is targetted in a cancer cell to shut it down and bring down the cancer cell as a whole. Up until this point, traditional drugs have only been able to target proteins that are involved in the disease that also have activities that are amenable to the small molecule approach, leaving a vast number of proteins unaddressed. Many of these other proteins may be involved in disease processes behind the scenes.

“It’s starting to get to the point where we’ve kind of taken traditional drug discovery as far as we can, and we really need something new,” explained University of Nevada, Las Vegas biochemist Gary Kleiger.

“Cancer cells are clever,” Kleiger said. “They can evolve very, very quickly. So, a drug might be working at first—targeting an enzyme and telling that enzyme, ‘stop doing your activity,’ which can stop the cancer cells from growing. Those cancer cells appear to lie dormant, but all the while there are still little things that happen that eventually enable those cancer cells to bypass that drug.” Therefore, in order to stay ahead of cancer’s capacity to evolve drug resistance, it is necessary to target many additional disease-causing proteins, and thus, limiting the landscape of druggable proteins is a serious disadvantage.

The new approach by investigated by Kleiger and collaborators uses a family of human enzymes called ubiquitin ligases found in human cells. Of about 20 000 known proteins in the human body, some 5-10% are enzymes.

Kleiger’s team uses cutting edge cryo electron microscopes that can image the ubiquitin ligases when they’re at work. To test their hypotheses, Kleiger and collaborators measure the activity of ‘mutated’ enzymes that should now be defective in their activities.

Kleiger compared the process to how a 50 000 year old society might view a bicycle. They could identify its purpose and general properties, but could test the importance of a certain gear; if it was bent, the bicycle would no longer function. “We can do that at the molecular level with the enzymes,” he said.

Source: Medical Xpress

Journal information: Daniel Horn-Ghetko et al, Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly, Nature (2021). DOI: 10.1038/s41586-021-03197-9

Battery Backups Can Protect People Dependent on Medical Equipment

A battery. Photo by Danilo Alvesd on Unsplash.

In countries prone to blackouts from extreme weather events (and in some cases solar flares) battery backups could provide a viable alternative to keep the medical support systems for vulnerable family members functioning. As climate change is set to increase the frequency and severity of weather-related blackouts, a study from the Columbia University Mailman School of Public Health examined the value of battery backups.

Millions of people are reliant on home medical equipment – the elderly, ill people, many of whom are poor or otherwise vulnerable. Medical equipment such as oxygen concentrators, nebulisers, ventilators, and dialysis and sleep apnoea machines often have no backup power in case of an outage.

In a 2019 wildfire which caused power outages, many vulnerable residents reported complications, such as one man who awoke, unable to breathe when his sleep apnoea breathing machine stopped functioning.
Community centres such as schools are often turned to for services when power fails, such as using their refrigerators to store food, but many do not have backup power.

“Climate change coupled with aging energy infrastructure is driving extreme weather-related power outages, as we’ve seen recently in Texas,” said study co-author Diana Hernández, PhD, Associate Professor of Sociomedical Sciences, Columbia University, “The technology to improve resiliency and energy independence exists, and it needs to be made more accessible to those who could most benefit. Battery storage units, particularly those powered by the sun, are a critical tool to help vulnerable individuals and communities survive the climate crisis.”

In the US territory of Puerto Rico, following the widespread destruction of the electrical grid by Hurricane Maria, many residents used solar panels instead of diesel generators due to ease of use, low cost, and not emitting fumes that exacerbate asthma and other lung conditions

A review of literature showed that blackouts can result in negative health consequences ranging from carbon monoxide poisoning, temperature-related illness, gastrointestinal illness, and mortality to cardiovascular, respiratory, and hospitalisations for kidney disease, especially for individuals dependent on electrically powered medical equipment.

Beyond electrical backup, in the US, older adults, poorer families, and individuals of non-Hispanic Black and Hispanic race/ethnicity are also less likely to have emergency supplies of food, water and medicine in the event of disaster.

Overall, the researchers found that more work is needed to better define and capture the relevant exposures and outcomes. “There is urgent need for data to inform disaster mitigation, preparedness, and response policies (and budgets) in an increasingly energy-reliant world,” said first author Joan Casey, PhD, assistant professor of environmental health sciences at Columbia Mailman School.

Eskom in South Africa is already facing a shortfall due to users abandoning its services for solar power generation, forcing tariff changes and increases. An uptake of battery backups to complement the solar panels may greatly alleviate vulnerabilities of people dependent on medical equipment in an uncertain power supply environment, as well as improving resilience to natural disasters, without the health hazards of generators.

Source: News-Medical.Net

Journal information: Mango, M., et al. (2021) Resilient Power: Battery storage as a home-based solution to address climate-related power outages for medically vulnerable populations. Futures. doi.org/10.1016/j.futures.2021.102707.

Novel Magnetic Technique Detects Malaria in Blood

A new magnetic method has been developed that can detect malaria, leading to faster, accurate and cheap diagnosis of the deadly disease.

An international study field-tested this new tool in Papua New-Guinea, in the hopes of helping the fight against this disease, which had 229 million reported cases in 2019, with 700 000 deaths a year.

“Malaria is easily treated but it is actually hard to diagnose, and because of that there can be over-treatment, which we have seen can lead to the spread of drug-resistant malaria,” said Dr Stephan Karl, a Senior Research Fellow in Malaria and Vector Biology at James Cook University’s Australian Institute of Tropical Health and Medicine.

“Improving malaria diagnosis, especially through the development of practical methods for resource-limited places, is important and timely,” he said.

An international team including the University of Augsburg’s Professor Istvan Kezsmarki, with the PNG Institute of Medical Research and the Burnet Institute, came up with the magnetic detection method, called rotating-crystal magneto-optical detection (RMOD).

When malaria parasites break down blood, the haeme molecules are aggregated by the parasites into biocrystals called haemezoin, which contain magnetic iron. This iron can is detectable by the RMOD method.

“I’ve studied the magnetic properties of malaria infected blood since 2006, and we engaged with Professor Kezsmarki’s team in 2013 to demonstrate the sensitivity of this test using human malaria parasites,” Dr Karl said.

A field study was successfully conducted, involving almost 1000 suspected malaria patients in a high-transmission area of Papua New-Guinea.

“After years of in-lab optimisation of the device, in collaboration with Dr. Karl we demonstrated the great potential of RMOD in fast and reliable malaria field tests performed in Papua New-Guinea,” Prof Kezsmarki said.

“We showed that RMOD performs well in comparison to the most reliable existing method..It’s very promising, as RMOD testing can be conducted after a short training session and provides test results within 10 minutes. From a funding perspective the cost is very low since no expensive reagents are used,” said Dr Karl.

Dr Karl said the aim was to refine the design until a test could be done by a simple button push.

Source: Medical Xpress

Journal information: L. Arndt et al, Magneto-optical diagnosis of symptomatic malaria in Papua New Guinea, Nature Communications (2021). DOI: 10.1038/s41467-021-21110-w

Neural Network Matches Dermatologists’ Assessment of Skin Lesions

Researchers have developed an AI-based tool that can use smartphone camera pictures to spot suspicious pigmented lesions (SPLs) with an accuracy close to that of professional dermatologists.

Such technology would hardly put dermatologists out of work; on the contrary, there is a great need for readily available skin cancer screening. In the US, there are only 12 000 practising dermatologists, who would need to see over 27 000 patients each per year in order to screen the entire population for SPLs which could lead to cancer. Computer-aided diagnosis (CAD) has thus been developed over previous years to help assist in diagnosis, but thus far had failed to spot melanomas in a meaningful way. Such CAD programs only analyse individual SPLs, while dermatologists compare other lesions on the same patient to reach a diagnosis, called ‘ugly duckling’ criteria.

This shortcoming has been addressed in a new CAD system that uses convolutional deep neural networks (CDNNs) developed by researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Massachusetts Institute of Technology (MIT).

The new system was able to distinguish SPLs from non-suspicious lesions in photos of patients’ skin at ~90% accuracy, and established an ‘ugly duckling’ criteria which could match three dermatologists’ consensus 88% of the time.

“We essentially provide a well-defined mathematical proxy for the deep intuition a dermatologist relies on when determining whether a skin lesion is suspicious enough to warrant closer examination,” said first author Luis Soenksen, PhD, a Postdoctoral Fellow at the Wyss Institute who is also a Venture Builder at MIT. “This innovation allows photos of patients’ skin to be quickly analyzed to identify lesions that should be evaluated by a dermatologist, allowing effective screening for melanoma at the population level.”

The researchers used a database of 33 000 images to train the system, which also included background elements and non-skin elements. These extraneous elements were left in so that the CDNN would be able to use normal images taken by consumer-grade cameras. The images contained SPLs and non-suspicious skin lesions identified by three certified dermatologists.
The software then developed a ‘map’ of how far away a lesion was from the others in terms of similarity, giving an ‘ugly duckling’ criteria. To test the software, they used 135 photos from 68 patients, which assigned an ‘oddness’ score to each lesion. This was then compared to dermatologists’ assessments of those lesions, matching individual dermatologists 88% of the time and their consensus 86% of the time
“This high level of consensus between artificial intelligence and human clinicians is an important advance in this field, because dermatologists’ agreement with each other is typically very high, around 90%,” said co-author Jim Collins, PhD, of the Wyss Institute, who is also the Termeer Professor of Medical Engineering and Science at MIT. “Essentially, we’ve been able to achieve dermatologist-level accuracy in diagnosing potential skin cancer lesions from images that can be taken by anybody with a smartphone, which opens up huge potential for finding and treating melanoma earlier.”

Source: Medical Xpress

Journal information: “Using deep learning for dermatologist-level detection of suspicious pigmented skin lesions from wide-field images” Science Translational Medicine, 2021.