The AI tool, developed by researchers at Stanford University and detailed in a paper published June 7 in JAMA Network Open, highlights areas of a brain scan that are likely to contain an aneurysm.

“There’s been a lot of concern about how machine learning will actually work within the medical field,” said Allison Park, a Stanford graduate student in statistics and co-lead author of the paper. “This research is an example of how humans stay involved in the diagnostic process, aided by an artificial intelligence tool.”

This tool, which is built around an algorithm called HeadXNet, improved clinicians’ ability to correctly identify aneurysms at a level equivalent to finding six more aneurysms in 100 scans that contain aneurysms. It also improved consensus among the interpreting clinicians. While the success of HeadXNet in these experiments is promising, the team of researchers — who have expertise in machine learning, radiology and neurosurgery — cautions that further investigation is needed to evaluate generalizability of the AI tool prior to real-time clinical deployment given differences in scanner hardware and imaging protocols across different hospital centers. The researchers plan to address such problems through multi-center collaboration.

Augmented expertise

Combing brain scans for signs of an aneurysm can mean scrolling through hundreds of images. Aneurysms come in many sizes and shapes and balloon out at tricky angles — some register as no more than a blip within the movie-like succession of images.

“Search for an aneurysm is one of the most labor-intensive and critical tasks radiologists undertake,” said Kristen Yeom, associate professor of radiology and co-senior author of the paper. “Given inherent challenges of complex neurovascular anatomy and potential fatal outcome of a missed aneurysm, it prompted me to apply advances in computer science and vision to neuroimaging.”

Yeom brought the idea to the AI for Healthcare Bootcamp run by Stanford’s Machine Learning Group, which is led by Andrew Ng, adjunct professor of computer science and co-senior author of the paper. The central challenge was creating an artificial intelligence tool that could accurately process these large stacks of 3D images and complement clinical diagnostic practice.

To train their algorithm, Yeom worked with Park and Christopher Chute, a graduate student in computer science, and outlined clinically significant aneurysms detectable on 611 computerized tomography (CT) angiogram head scans.

“We labelled, by hand, every voxel — the 3D equivalent to a pixel — with whether or not it was part of an aneurysm,” said Chute, who is also co-lead author of the paper. “Building the training data was a pretty grueling task and there were a lot of data.”

Following the training, the algorithm decides for each voxel of a scan whether there is an aneurysm present. The end result of the HeadXNet tool is the algorithm’s conclusions overlaid as a semi-transparent highlight on top of the scan. This representation of the algorithm’s decision makes it easy for the clinicians to still see what the scans look like without HeadXNet’s input.

“We were interested how these scans with AI-added overlays would improve the performance of clinicians,” said Pranav Rajpurkar, a graduate student in computer science and co-lead author of the paper. “Rather than just having the algorithm say that a scan contained an aneurysm, we were able to bring the exact locations of the aneurysms to the clinician’s attention.”

Eight clinicians tested HeadXNet by evaluating a set of 115 brain scans for aneurysm, once with the help of HeadXNet and once without. With the tool, the clinicians correctly identified more aneurysms, and therefore reduced the “miss” rate, and the clinicians were more likely to agree with one another. HeadXNet did not influence how long it took the clinicians to decide on a diagnosis or their ability to correctly identify scans without aneurysms — a guard against telling someone they have an aneurysm when they don’t.

To other tasks and institutions

The machine learning methods at the heart of HeadXNet could likely be trained to identify other diseases inside and outside the brain. For example, Yeom imagines a future version could focus on speeding up identifying aneurysms after they have burst, saving precious time in an urgent situation. But a considerable hurdle remains in integrating any artificial intelligence medical tools with daily clinical workflow in radiology across hospitals.

Current scan viewers aren’t designed to work with deep learning assistance, so the researchers had to custom-build tools to integrate HeadXNet within scan viewers. Similarly, variations in real-world data — as opposed to the data on which the algorithm is tested and trained — could reduce model performance. If the algorithm processes data from different kinds of scanners or imaging protocols, or a patient population that wasn’t part of its original training, it might not work as expected.

“Because of these issues, I think deployment will come faster not with pure AI automation, but instead with AI and radiologists collaborating,” said Ng. “We still have technical and non-technical work to do, but we as a community will get there and AI-radiologist collaboration is the most promising path.”

Some premature babies are born with severely underdeveloped gastrointestinal tracts or can develop diseases like necrotizing enterocolitis, which attacks the intestines. In severe cases, surgical removal of the affected bowels (intestines) must be performed. This can have dire consequences.

Most nutrient and water absorption occurs in the small intestine, so if patients are not left with enough healthy tissue, they can suffer from serious complications like malnutrition or dehydration — also known as short bowel syndrome. In order to get the proper nutrients, patients may have to be fed through a feeding tube or intravenously- through a needle into the bloodstream. In the most severe cases of short bowel syndrome, small intestine transplant from donor tissue is the only answer; but this, too, comes with its own list of problems. Babies must be big enough for this procedure, which often means they need to wait several months. Even then, the road is not an easy one. Patients must take anti-rejection medications, which have their own side effects and the success rate of transplantation is only about fifty percent.

With such challenges, the future seems bleak for these babies. To Dr. Grikscheit, this is not acceptable. She wants more for her patients and she envisions a world in which missing portions of intestines can be grown.

Scientists like Dr. Grikscheit investigate growth of new tissue from stem cells to treat babies with severe intestinal impairments. “Stem cell therapies would really improve upon current options,” she says. “Right now, these babies can either get a transplant, or live on IV nutrition, which really impacts the way they can interact with the world and develop. There has to be a better way.”

The Cell Stem Cell article was written by Dr. Grikscheit and colleagues as part of INTENS, a European consortium that fosters research to treat children with intestinal failure through tissue engineering. Tissue engineering is the process of producing new tissue in the laboratory from stem cells. The publication describes the progress researchers have made as well as the challenges scientists face in bringing stem cell therapy to patients.

Stem cells have the capability of developing into any cell type, making them ideal starting material for organ repair. The paper discusses two main ways in which stem cells could potentially treat babies with these intestinal issues. Stem cells can either be taken from the patient’s own intestine or “off the shelf” — from a stock source of stem cells that can be engineered into intestinal tissue. The two pathways each offer distinct advantages to patients and the treatment type could depend on the condition each child faces.

Research in this field is showing promise for future therapy. Recent progress has allowed researchers to generate larger amounts of intestinal tissue than ever before.

“We’re not yet at the stage of delivering this therapy to babies but we’re developing the road map,” says Dr. Grikscheit. “We’re getting closer.”

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The group led by Professor Martina Havenith, Chair of Physical Chemistry II, and Professor Dominik Marx, Chair of Theoretical Chemistry, from Ruhr-Universität Bochum, together with the team led by Dr. Britta Redlich from Radboud University, Nijmegen, describes the results in the journal Science Advances, published online in advance on 7 June 2019.

Understanding how complex molecules were formed

If hydrochloric acid comes into contact with water molecules under normal conditions, such as at room temperature, the acid immediately dissociates: it releases its proton (H+), one chloride ion (Cl-) remains. The research team wanted to find out whether the same process also takes place at extremely low temperatures below ten Kelvin, i.e. below minus 263.15 degrees Celsius. “We would like to know whether the same acid-alkali chemistry as we know on Earth also exists in the extreme conditions in interstellar space,” explains Martina Havenith, Speaker for the Cluster of Excellence Resolv. “The results are crucial for understanding how more complex chemical molecules formed in space — long before the first precursors of life came into existence.”

In order to replicate the extremely low temperatures in the laboratory, the researchers had the chemical reactions take place in a droplet of superfluid helium. They monitored the processes using a special type of infrared spectroscopy, which can detect molecular vibrations with low frequencies. A laser with especially high brightness, as is available in Nijmegen, was needed for this. Computer simulations enabled the scientists to interpret the experimental results.

It comes down to the order

First of all, the researchers added four water molecules, one after the other, to the hydrochloric acid molecule. The hydrochloric acid dissociated during this process: it donated its proton to a water molecule, and a hydronium ion was created. The remaining chloride ion, the hydronium ion and the three other water molecules formed a cluster.

However, if the researchers first created an ice-like cluster from the four water molecules and then added the hydrochloric acid, they yielded a different result: the hydrochloric acid molecule did not dissociate; the proton remained bonded to the chloride ion.

“Under the conditions that can be found in interstellar space, the acids are thus able to dissociate, but this does not necessarily have to happen — both processes are two sides of the same coin, so to speak,” summarises Martina Havenith.

Chemistry in space is not simple

The researchers assume that the result can also be applied to other acids, i.e. it represents the basic principle of chemistry under ultracold conditions. “Chemistry in space is by no means simple; it might even be more complex than chemistry under planetary conditions,” says Dominik Marx. After all, it depends not only on the mixing ratios of the reacting substances but also on the order in which they are added to each other. “This phenomenon needs to be taken into consideration in future experiments and simulations under ultracold conditions,” says the researcher.

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The technique measures the speed and action of the sperm flagellum, or tail, which provides vital information for understanding whether sperm in an ejaculate have the potential to reach and fertilise the egg.

It was developed by a University of Birmingham team led by Professor Dave Smith in the School of Mathematics, in partnership with the University’s Centre for Human Reproductive Science and is published today in the journal Human Reproduction.

Professor Smith explains: “We have all heard of ‘sperm count’, and indeed the tools available to understand sperm — manual counting with a microscope — have not changed much since the 1950s. However, think of the amount of technology — camera, computing, connectivity — that we all now have access to. This project is about harnessing these 21st century technologies to address male fertility problems.”

Current methods of analysing sperm for male fertility have been restricted to either counting the number of sperm produced, or tracking the head of the cell and there is limited understanding of what a healthy swimming sperm looks like.

Meurig Gallagher, lead author of the study, says: “Sperm have an incredibly challenging task — they must travel distances of several thousand times their own body length through the female reproductive tract in search of an egg. This journey whittles a population of many million cells down to under a hundred. The flagellum is responsible for propulsion and navigation, so it’s really vital that we understand what success looks like — how a healthy tail moves and how it consumes energy.”

Using a combination of rapid, high-throughput digital imaging, mathematics and fluid dynamics to detect and track sperm in samples, the team have developed a free-to-use software package called FAST (flagellar capture and sperm tracking). They hope clinical research teams worldwide will start to use this to better understand how sperm motility relates to fertility.

This improved understanding will help researchers and clinicians develop new interventions to tackle male fertility problems.

Gemma Cupples, of the School of Mathematics, developed the system’s mathematical model to understand the amount of energy required for sperm to swim effectively. “The new model enables us to measure miniscule forces that are impossible to measure experimentally,” she explains. “The technique has lots of potential for other important problems, for example understanding how bacteria spread, and how fluids are transported around in tiny spaces in the body such as the brain.”

Jackson Kirkman Brown MBE, of the University’s Centre for Human Reproductive Science, led the clinical strategy. “Diagnostic techniques are crude and there are still no drugs available for treating male infertility,” he says. “We know that sperm motility is a major factor and so being able to analyse the movement of the sperm in detail will ultimately help us to identify appropriate treatments or lifestyle changes to tackle male fertility problems, giving couples clearer answers and enabling better decisions.

“Importantly, the better diagnoses this technique should enable will mean that patients can also be better assigned the correct treatment — be that an inexpensive and ‘easy’ treatment such as washing the sperm and injecting into the womb, or more invasive and complex treatments such as IVF or ICSI — a process similar to IVF in which sperm is injected directly into the harvested egg.”

The work is funded by the EPSRC Rapid Sperm Capture Healthcare Technologies Challenge Award and the National Institute for Health Research.

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The researchers surveyed survivors two years after the 2010 earthquake in Haiti. Results show that 94% reported experiencing subsequent insomnia symptoms after the disaster. Two years later, 42% showed clinically significant levels of post-traumatic stress disorder (PTSD), and nearly 22% had symptoms of depression. There were significant positive correlations between sleep disturbances and peritraumatic distress (i.e., emotional reaction during and immediately after the event), PTSD, and symptoms of depression. Resilience did not appear to be a buffer against sleep disturbance.

“This is one of the first epidemiological studies to investigate the prevalence of sleep disturbances among survivors of the 2010 Haiti earthquake,” said lead author and principal investigator Judite Blanc, Ph.D., an NIH T32 postdoctoral fellow in the Center for Healthful Behavior Change within the Division of Health and Behavior in the Department of Population Health at NYU School of Medicine. “Our study underscores the strong association between common trauma-related disorders and comorbid sleep conditions among a group of survivors.”

The study involved 165 participants with a mean age of about 31 years; 52% were men. Participants were living in Port-au-Prince, Haiti, one of the areas affected by the 2010 earthquake. According to the authors, it was the most devastating earthquake in the country’s history, killing more than 200,000 people and displacing more than 1 million residents.

Measures included demographic factors, the Peritraumatic Distress Inventory, the PTSD Checklist Specific, the Beck Depression Inventory, and the Connor-Davidson Resilience Scale. Spearman correlations and multilinear regressions were used to explore associations among resilience, PTSD, depression, and sleep disturbances.

“Findings from our study highlight the need to assess and treat sleep issues among disaster survivors, as they are highly prevalent after a natural disaster and are related to mental health conditions,” said Blanc. “Our work supports the importance of sleep in disaster preparedness programs globally.”

Blanc added that sleep is often neglected in the aftermath of traumatic events, but in these situations, sleep should be considered an important target of mental and physical health interventions.

“Our results make the case that sleep health should be a major component of all public and global health programs and specifically in humanitarian crises,” said Blanc.

The research abstract was published recently in an online supplement of the journal Sleep and will be presented Tuesday, June 11, in San Antonio at SLEEP 2019, the 33rd annual meeting of the Associated Professional Sleep Societies LLC (APSS), which is a joint venture of the American Academy of Sleep Medicine and the Sleep Research Society.

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The new compound, which was tested in an animal model of melanoma, could make current chemotherapies more powerful. It works by thwarting cancer’s ability to survive, evolve, and adapt to the DNA damage created by traditional chemotherapy drugs like cisplatin.

“Chemotherapies are often effective the first time around, but then the cancers mutate and become resistant to that drug, and the next, and the next,” said senior study co-author Pei Zhou, Ph.D., a professor of biochemistry at Duke University School of Medicine.

“It reminds me of Boggarts, those shapeshifting creatures from Harry Potter that morph from one scary thing to another. The beauty of this approach is that you essentially freeze the Boggart in its current form, so you can kill it off for good.”

The study was published June 6 in Cell.

In their simplest form, cancer cells are normal cells that are growing out of control. Each time these cells divide, the DNA within them must replicate to generate new copies to go inside each new cell. The first chemotherapy drugs were based on the rationale that rapidly growing cancer cells would be more sensitive to damage to their DNA. Drugs like cisplatin are designed to damage DNA, causing the sensitive replication machinery normally tasked with copying each strand to stall. If DNA replication is stalled for too long, cell division halts, and cells die.

The strategy is brutal and effective, even curative in some cases. But long-term, it often fails, as cancer cells figure out a way to proliferate even in the presence of DNA damage.

“The cancer cells often swap out the high fidelity replication machinery, which usually does the copying, with a sloppy replacement that covers up the lesions and moves on,” said Zhou. “As a result, the cells survive, but with mutations in their DNA.”

Because this process, known as translesion synthesis, is a major cause of cancer drug resistance, it has become a major area of study in cancer research. Scientists have identified a key protein involved, named Rev1, and have even disrupted it through genetic means — works done in the laboratories of Graham C. Walker and Michael T. Hemann at MIT, both senior co-authors of this study. However, attempts to do the same with small molecules had never succeeded, presumably because the protein lacked an obvious binding pocket that a potential drug could exploit.

In this study, Zhou and his collaborators at Duke, MIT, and the University of Rhode Island decided to try their luck at finding a small molecule to block or inhibit Rev1. They screened 10,000 small molecule compounds, and were surprised to find that one — a molecule called JH-RE-06 — appeared to do the trick.

The researchers used a technique called x-ray crystallography to visualize the unexpected interactions between Rev1 and JH-RE-06. They found that when Rev1 interacts with JH-RE-06, it pairs up or dimerizes with another copy of itself, creating a binding pocket where there wasn’t one before. When Rev1 is locked up in this dimer, it can no longer help cancer cells survive and attain their shape-shifting powers.

The researchers then tested the new molecule in human cancer cell lines and showed that it enhanced the ability of several forms of chemotherapy to kill cells, while also suppressing their ability to mutate in the presence of DNA-damaging drugs. Finally, they tested it in a mouse model of human melanoma. They found that not only did the tumors stop growing in mice treated with a combination of cisplatin and JH-RE-06, but also that those mice survived longer.

Senior study co-author Jiyong Hong, PhD, a professor of chemistry at Duke, said that they are currently creating versions of JH-RE-06 that have enhanced pharmacologic properties that could make it an even more attractive drug. “This is a great proof of principle that it is possible to target this protein, but we have a lot of work to do to turn this lead compound into a viable candidate that we can take to the clinic.”

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The NIST setup, which occupies just a few square feet of table space, has potential applications such as disease diagnosis, identification of chemicals used in manufacturing, and biomass energy harvesting. The work is described in the June 7 issue of Science Advances.

Optical frequency combs measure exact frequencies, or colors, of light. Various comb designs have enabled the development of next-generation atomic clocks and show promise for environmental applications such as detecting methane leaks. Biological applications have been slower to develop, in part because it’s been hard to directly generate and measure the relevant infrared light.

To showcase biological applications, the NIST team used the new apparatus to detect “fingerprints” of NIST’s monoclonal antibody reference material, a protein made of more than 20,000 atoms that is used by the biopharmaceutical industry to ensure the quality of treatments.

“For the first time our frequency combs have simultaneous coverage across the entire infrared molecular fingerprint region,” project leader Scott Diddams said. “Other key advantages are speed, resolution and dynamic range in acquiring data.”

Mid-infrared light is an especially useful research probe because molecules usually rotate and vibrate at these frequencies. But until now it’s been difficult to probe this region due to a lack of broadband or tunable light sources and efficient detectors such as those available for visible and near-infrared light, the part of the infrared spectrum closest to visible light.

The new NIST apparatus overcomes these problems. Simple fiber lasers generate light spanning the entire range used to identify molecules — that is, mid-infrared to far-infrared wavelengths of 3-27 micrometers (frequencies of approximately 10-100 terahertz). The amounts of light absorbed at specific frequencies provide a unique signature of a molecule. The new system is innovative in detecting the electric fields of the absorbed light using photodiodes (light detectors) operating in the near-infrared range.

“A unique feature is that we detect signals in real time by rapidly sampling the infrared electric field with a near-infrared laser,” Diddams explained. “This has two advantages: It shifts the detection from the infrared to the near-infrared where we can use inexpensive telecommunications photodiodes, and we no longer suffer from the limitations of infrared detectors, which require cryogenic (liquid nitrogen) cooling.”

The researchers detected signature vibrations of three bands of amides (chemical groups containing carbon, oxygen, nitrogen and hydrogen) in the monoclonal antibody reference material. Amide bands in proteins are used to determine the folding, unfolding and aggregating mechanisms. Specific features of the detected bands indicated that the protein has a sheet structure, agreeing with previous studies. Sheets connect chemical groups in a flat arrangement.

In addition to biological applications, the new apparatus might be used to detect interactions between infrared light and condensed matter for quantum computing approaches that store data in molecular vibrations or rotations. In addition, when combined with novel imaging techniques, the tabletop system could obtain nanometer-scale images of samples that currently require the use of a much larger synchrotron facility.

Coauthors of the new paper include researchers from the University of Campinas, in Brazil, and the Institute of Photonic Sciences, in Spain. Funding was provided by the Defense Advanced Research Projects Agency, the National Research Council and the Air Force Office of Scientific Research.