Keeping one step ahead of earthquakes

by Nick Klenske, Horizon: The EU Research & Innovation Magazine

As technologies continue to improve, earthquake-prone cities will be better prepared. 

Credit: © Marco Iacobucci Epp, Shutterstock

While accurately predicting earthquakes is in the realm of science fiction, early warning systems are very much a reality. As advances in research and technology make these systems increasingly effective, they're vital to reducing an earthquake's human, social and economic toll.

Damaging earthquakes can strike at any time. While we can't prevent them from occurring, we can make sure casualties, economic loss and disruption of essential services are kept to a minimum.

Building more resilient cities is key to withstanding earthquake disasters. If we had a better idea of when earthquakes would strike, authorities could initiate local emergency, evacuation and shelter plans. But unfortunately, this is not the case.

"Because earthquakes occur on faults, we know where they will occur. The problem is that we don't know how to predict when an earthquake will strike," explained Quentin Bletery, from the Research Institute for Development (IRD) in France. He is a researcher at the Géoazur laboratory at Université Côte d'Azur.

"Successful earthquake prediction must provide the location, time and magnitude of a future event with high accuracy, [something] which as of now, can't be done," added Johannes Schweitzer, Principal Research Geophysicist at NORSAR, an independent research foundation specialized in seismology and seismic monitoring.

Potential of AI to improve the accuracy and speed of early warning systems

Earthquake early warning (EEW) systems are evolving rapidly thanks to advances in computer power and network communication.

EEW systems work by identifying the first signals generated by an earthquake rupture before the strongest shaking and tsunami reach populated areas. These signals follow the origin of the earthquake and can be recorded seconds before the seismic waves.

A promising, recently identified early signal is the prompt elasto-gravity signal (PEGS), which travels at the speed of light but is a million times smaller than seismic waves, and therefore, often goes undetected.

According to Bletery, artificial intelligence (AI) could play a key role in identifying this signal. With the support of the EARLI project, he is leading an effort to develop an AI algorithm capable of doing exactly that.

"Our AI system aims to increase the accuracy and speed of early warning systems by enabling them to pick up an extremely weak signal that precedes even the fastest seismic waves," said Bletery.

Albeit still in its very early stages, if the project succeeds, Bletery says public authorities will have access to nearly instantaneous information about an earthquake's magnitude and location. "This would allow them to take such immediate mitigation efforts as, for example, shutting down infrastructure like trains and nuclear power plants and moving people to earthquake- and tsunami-safe zones," he noted.

Statistical technique to enhance seismic resilience

Another approach to improve seismic seismic resilience and reduce human losses is operational earthquake forecasting (OEF). TURNkey, led by NORSAR, aims to improve the effectiveness of this statistical technique used to study seismic sequences to provide timely warnings.

"OEF can inform us about changing seismic hazards over time, enabling emergency managers and public authorities to prepare for a potentially damaging earthquake," explained Ivan Van Bever, TURNkey project manager. "What OEF can't do, is provide warnings with a high level of accuracy."

In addition to improving existing methods, TURNkey is developing the "Forecasting—Early Warning—Consequence Prediction—Response' (FWCR) platform to increase the accuracy of earthquake warnings and ensure that all warning-related information is sent to end-users in a format that is both understandable and useful.

"The platform will forecast and issue warnings for aftershocks and will improve the ability for users to estimate both direct and indirect losses," said Van Bever

Better prepared than ever

The platform is currently being tested at six locations across Europe: Bucharest (Romania), the Pyrenees mountain range (France), the towns of Hveragerdi and Husavik (Iceland), the cities of Patras and Aigio (Greece), and the port of Gioia Tauro (Southern Italy). It is also being tested in Groningen province (Netherlands), which is affected by induced seismicity—minor earthquakes and tremors caused by human activity that alters the stresses and strains on the Earth's crust.

Johannes Schweitzer, who is the project coordinator, is confident the multi-sensor-based earthquake information system will prove capable of enabling early warning and rapid response. "The TURNkey platform will close the gap between theoretical systems and their practical application in Europe," remarked Schweitzer. "In doing so, it will improve a city's seismic resilience before, during and after a damaging earthquake."

"As these technologies and systems continue to improve, they could reduce an earthquake's human, social and economic toll," added Bletery.

Earthquake-prone cities will be better prepared than ever before. At the very least these new systems will give people a heads up to drop, cover and hold on during an earthquake.DeepShake uses machine learning to rapidly estimate earthquake shaking intensity

Provided by Horizon: The EU Research & Innovation Magazine 

Laboratory will illuminate formation, composition, activity of comets

New experiments will measure the properties of comet material in space-like conditions.

Peer-Reviewed Publication

AMERICAN INSTITUTE OF PHYSICS

 

IMAGE: THE NEW CHAMBER, WHICH WILL SIMULATE SPACE-LIKE CONDITIONS AND HAS 14 ASSOCIATED INSTRUMENTS TO MEASURE COMET PROPERTIES. view more 

CREDIT: KREUZIG ET AL.

WASHINGTON, November 3, 2021 -- Comets are icy and dusty snowballs of material that have remained relatively unchanged since they first formed billions of years ago. Studying the small bodies provides clues about the formation of the solar system.

In Review of Scientific Instruments, by AIP Publishing, researchers from the Technische Universität Braunschweig, the Austrian Academy of Science, the University of Bern, the German Aerospace Center, and the Max Planck Institute for Solar System Research developed a laboratory to simulate comets in space-like conditions.

The goal of the international research group, the Comet Physics Laboratory (CoPhyLab), is to understand the internal structure of comets, as well as how their constituent materials form and react. While comets are made of ice and dust, the composition and ratios of that material remain a mystery.

Many of the lab's future experiments will involve creating sample comet materials with differing compositions. By testing those materials in the space-like chamber, the researchers can compare each sample to what has been observed on actual comets.

To accomplish this, the scientists place a sample in their chamber, then pump it down to low pressures and cool it down to low temperatures. One window of the chamber lets in radiation from an artificial star, which heats the comet material much like it would in space.

"Before [this project], every group was using different samples. That made it very hard to compare if what they were seeing was the same as what we were seeing," said author Christopher Kreuzig. "A major goal of this project is to establish a comparable standard for comet experiments where everyone is using the same equipment and production protocol for the sample material."

Combining 14 instruments into one chamber allows the scientists to measure the comet material's evolution, as well as the conditions inside the experiment, all at once.

In space, radiation from the sun causes ice to evaporate and particles to fly away from comets, creating a tail that is visible on Earth. In the chamber, high-speed cameras track any particles that fly away from the sample. The chamber also uses a unique cooling system to accommodate a scale that can detect if those same particles land near the sample and track gas evaporation in real time.

"Underneath our sample sits a scale, which is capable of measuring the weight of the sample over the whole experiment time," said Kreuzig. "You can really see how much water ice or CO2 ice we lose over time due to evaporation."

The team completed construction of the lab and is now optimizing their sample production. They are planning the next big experiment run for early 2022.

###

The article "The CoPhyLab comet-simulation chamber" is authored by Christopher Kreuzig, Guenter Kargl, Antoine Pommerol, Joerg Knollenberg, Anthony Lethuillier, Noah Salomon Molinski, Thorben Gilke, Dorothea Bischoff, Clément Feller, Ekkehard Kührt, Holger Sierks, Nora Hänni, Holly Capelo, Carsten Güttler, David Haack, Katharina Otto, Erika Kaufmann, Maria Schweighard, Wolfgang Macher, Patrick Tiefenbacher, Bastian Gundlach, and Jürgen Blum.  The article appeared in Review of Scientific Instruments on Nov. 2, 2021 (DOI: 10.1063/5.0057030 and can be accessed at https://aip.scitation.org/doi/full/10.1063/5.0057030.

ABOUT THE JOURNAL

Review of Scientific Instruments publishes novel advancements in scientific instrumentation, apparatuses, techniques of experimental measurement, and related mathematical analysis. Its content includes publication on instruments covering all areas of science including physics, chemistry, materials science, and biology. See https://aip.scitation.org/journal/rsi.

###

---

JOURNAL

Review of Scientific Instruments

DOI

10.1063/5.0057030 

ARTICLE TITLE

The CoPhyLab comet-simulation chamber

ARTICLE PUBLICATION DATE

2-Nov-2021

Cannabis use disorder rising significantly during pregnancy

Columbia and Weill Cornell researchers found cannabis use disorders increased 150 percent in prenatal hospitalizations from 2010 to 2018

Peer-Reviewed Publication

COLUMBIA UNIVERSITY IRVING MEDICAL CENTER

As more states legalize cannabis (now 37) for medical or recreational purposes its use during pregnancy is increasing, along with the potential for abuse or dependence. 

A new study, co-led by researchers from Columbia University and Weill Cornell Medicine, has captured the magnitude and issues related to cannabis use disorders during pregnancy by examining diagnostic codes for more than 20 million U.S. hospital discharges. Most of those hospitalizations were for childbirth.

The study, “Association of Comorbid Behavioral and Medical Conditions with Cannabis Use Disorder in Pregnancy,” published in the online edition of JAMA Psychiatry Nov. 3, found that the proportion of hospitalized pregnant patients identified with cannabis use disorder—defined as cannabis use with clinically significant impairment or distress—rose 150 percent from 2010 to 2018.

“This is the largest study to document the scale of cannabis use disorder in prenatal hospitalizations,” said Claudia Lugo-Candelas, PhD, assistant professor of clinical medical psychology in Columbia’s Department of Psychiatry and one of the study’s co-authors. She notes the study found that pregnant patients with the condition had sharply higher levels of depression, anxiety, and nausea—results warranting clinical concern.  

“It’s a red flag that patients may not be getting the treatment they need,” Lugo-Candelas said.

Cannabis legalization has likely lessened fears about its risks in pregnancy. Some pregnant patients use cannabis instead of prescribed medications, thinking it’s a safer choice. Both the American Academy of Pediatrics (AAP) and the American College of Obstetricians and Gynecologists (ACOG) have recommended against using cannabis while pregnant, chiefly because of known and unknown fetal effects. Concerns for maternal effects focus on smoking or vaping risks, not mental health.

The study identified 249,084 hospitalized pregnant patients with cannabis use disorder and classified them into three sub-groups: those with cannabis use disorder only; those with use disorders for cannabis and other substances, including at least one controlled substance; and those with cannabis use disorder and other substances (alcohol, tobacco) not related to controlled substances. Data from hospitalized pregnant patients without any substance use disorders were analyzed for comparison.

Those with the cannabis condition were more likely to be younger (ages 15 to 24), Black non-Hispanic, and covered by Medicaid rather than private insurance.

Patients’ records were analyzed for depression, anxiety, trauma, and ADHD, and a broader category of mood-related disorders. Medical conditions measured included chronic pain, epilepsy, multiple sclerosis, nausea, and vomiting.

All disorder sub-groups had elevated rates of nearly every factor studied. Patients with cannabis use disorder alone had levels of depression and anxiety three times higher than patients with no use conditions. Mood-related disorders affected 58 percent of cannabis disorder patients but only 5 percent of those without any substance use disorders. 

“The least other substance use you have, the more that cannabis use makes a difference,” Lugo-Candelas said. “That’s really striking.”

Nausea was also high in the cannabis use disorder hospitalizations. Whether that was due to patients using cannabis to mitigate nausea, or due to cannabis use, which can cause a vomiting syndrome, or a symptom of pregnancy is unknown. Study co-author Angélica Meinhofer, PhD, assistant professor of population health sciences at Weill Cornell Medicine, noted that many states allow medical use of cannabis for nausea and vomiting.

Screening for cannabis use during pregnancy could help, but state mandatory reporting requirements may deter some clinicians from asking about use. Better patient education could reduce the problem and get treatment to patients sooner, especially for those identified with co-occurring cannabis dependency and psychiatric disorders.  

“Hopefully these findings will motivate better conversations between pregnant patients and their health care providers,” said Meinhofer.

The authors emphasize they aren’t arguing for or against cannabis use in pregnancy. The science on prenatal effects of the disorder is still largely unknown, although frequent use has been linked to low birth weight and other adverse outcomes. Their study, the researchers say, instead underscores the need to further explore the disorder and its links to psychiatric and medical conditions.

The rising rate of cannabis use by pregnant patients shows that such investigations are needed now. “This is a population that’s showing a level of distress that is very, very high,” said Lugo-Candelas. “Care and attention need to be rolled out.”

###

Katherine M. Keyes, PhD, MPH, associate professor of epidemiology at Columbia’s Mailman School of Public Health, and Jesse Hinde, PhD, Community Health Research Division, RTI International, were also on the study’s research team.

---

JOURNAL

JAMA Psychiatry

DOI

10.1001/jamapsychiatry.2021.3193 

METHOD OF RESEARCH

Systematic review

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Association of Comorbid Behavioral and Medical Conditions With Cannabis Use Disorder in Pregnancy

ARTICLE PUBLICATION DATE

3-Nov-2021

Disclaimer: AAAS and EurekAlert! 

How does the brain create our perception of reality?

New findings explore how patterns of brain activity shape the way we perceive the world

Reports and Proceedings

SOCIETY FOR NEUROSCIENCE

WASHINGTON, D.C. — New findings from studies in both people and animals are revealing clues about how sensory information and cognitive processes interact in the brain to produce our perception of the world. The findings were presented at Neuroscience 2021, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.

Sensory inputs, such as sights, sounds, and touches, yield rich information about the external world. But our perception and interpretation of sensations are heavily shaped by cognitive processes such as attention, expectation, and memory. A better understanding of the neural basis of perceptual phenomena will help clarify both ordinary experiences — such as the ability to pick a single voice out of a noisy background — and disorders in which perception is altered — such as attention-deficit/hyperactivity disorder, autism, schizophrenia, and Alzheimer’s disease.

Today’s new findings show:

• In mice, a specific type of brain cell called a PV neuron improves the ability to distinguish a target sound from background noise (i.e., the cocktail party problem) (Kamal Sen, Boston University).
• The feeling of ownership over one’s body while experiencing an event strengthens the memory representation of that event in the hippocampus, a brain region involved in learning and memory (Heather Iriye, Karolinska Institute, Sweden).
• In humans and monkeys, imagining an object’s movement activates motion-sensitive areas of the brain, suggesting that both species can simulate versions of the world in similar ways (David Sheinberg, Brown University).
• A novel technique involving non-invasive transcranial magnetic stimulation (TMS) informed by real-time scalp EEG recordings enhanced human visual perception by modulating communication between frontal and visual brain regions (Nitzan Censor, Tel-Aviv University, Israel).

“The neuroscience findings presented today demonstrate the importance of comparative brain studies in long-standing issues in human perception and cognition,” said Sabine Kastner, a professor at Princeton University who studies visual perception and attention. “These advances show how research in different model systems can come together to inform our understanding of the human brain, from the neurobiological mechanisms of perception to our subjective perceptual experiences.”

This research was supported by national funding agencies including the National Institutes of Health and private funding organizations. Find out more about sensory perception and the brain on BrainFacts.org.

Mechanisms of Perception Press Conference Summary

• Patterns of brain activity at different levels, from individual cells to multi-region networks, are revealing how cognitive processes shape perceptions of sensory information.
• Animal studies can explore the mechanistic underpinnings of perceptual phenomena, while functional imaging studies in humans allow for the investigation of subjective experiences.

PV Neurons Enhance Cortical Coding in the Cocktail Party Problem

Kamal Sen, kamalsen@bu.edu, Abstract P442.10

• The brain mechanisms that enable a listener to select and follow a specific sound in a noisy environment — sometimes called the cocktail party problem — are poorly understood and may be impaired in people with disorders such as hearing impairment and autism.
• In mice, activity of a specific cell type in the auditory cortex, called the PV neuron, improved the brain’s ability to select target sounds amid competing sounds.
• PV neurons enhanced the timing and patterns of cortical neuron firing in response to target sounds, offering a potential strategy for designing better hearing-assistive devices.

Body Ownership and the Neural Processes of Memory Encoding and Reinstatement

Heather Iriye, heather.iriye@ki.se, Abstract P505.02

• The feeling of body ownership — the perception of one’s body as one’s own — during an experience is thought to contribute to how accurately and vividly we are able to remember and reexperience events.
• Researchers combined virtual reality with brain imaging to manipulate participants’ sense of body ownership within immersive videos using a perceptual full-body illusion.
• The more participants could remember about events experienced with body ownership, the stronger the representation of that event in the hippocampus one week later.
• Insights into how to optimize memory formation and preserve the ability to relive past experiences could guide interventions for cognitive disorders such as Alzheimer’s disease.

The Neural Bases of Simulation in the Primate Brain

David Sheinberg, David_Sheinberg@brown.edu, Abstract P775.01

• Perception depends on both information received from our senses and sophisticated cognitive processes such as simulation — internally manipulating rich mental models of the world to imagine experiences one has never had.
• The design of a novel simulation condition, where a ball falls through an obstacle filled space, revealed that animals, like people, appear to use internal simulation to solve this task.
• Functional magnetic resonance imaging showed that simulation of movement by monkeys activates motion-sensitive areas of the brain even though no external motion is being sensed.
• The findings may have implications for the detailed study and treatment of psychiatric disorders in which simulated experiences become confused with reality, such as schizophrenia and post-traumatic stress disorder.

Closed-loop EEG-TMS Modulation of Frontal-occipital Communication Enhances Visual Perception

Nitzan Censor, censornitzan@tauex.tau.ac.il, Abstract P767.09

• Visual perception is shaped by coordinated communication between frontal and visual brain regions.
• Researchers used a novel combination of non-invasive transcranial magnetic stimulation (TMS) of frontal regions and real-time scalp electroencephalography (EEG) recordings of brain activity in visual regions to synchronize activity between the regions.
• The TMS-EEG procedure enhanced participants’ performance on a visual detection-attention task.
• These findings suggest visual perception can be augmented by real-time modulation of communication between distant brain regions.  

###

About the Society for Neuroscience

The Society for Neuroscience is the world's largest organization of scientists and physicians devoted to understanding the brain and nervous system. The nonprofit organization, founded in 1969, now has nearly 37,000 members in more than 90 countries and over 130 chapters worldwide.

New commentary paper highlights costs of defects in surgical care and calls for elimination of defects in value

A well-designed and well-executed holistic approach to eliminating defects in surgical care through creation of Centers of Excellence has potential to simultaneously decrease costs and increase value

Peer-Reviewed Publication

UNIVERSITY HOSPITALS CLEVELAND MEDICAL CENTER

CLEVELAND – A commentary, published in the Nov. 3 issue of the journal NEJM Catalyst Innovations in Care Delivery, highlights how defects in surgical care could be diminished or eliminated for the benefit of patients and to lower costs in American health care spending.

“While prior reports have commented on individual defects in surgical care, we believe that the current article is the first to summarize the opportunity to reduce defects in surgical care,” said author David W. Dietz, MD, Chief, Division of Colorectal Surgery, and Vice President of System Surgery Quality, University Hospitals Cleveland Medical Center.

Using colorectal surgery to provide examples and national estimates of the costs of defects in surgical care, the paper summarizes a holistic approach to eliminating defects in surgical care and offers a framework for centers of excellence for removing them.

“Defects in health care are common and can be defined as behaviors, based on known evidence, that needlessly reduce the quality of care and patient experience or add to the annual total costs of care,” said Dr. Dietz.

“We are now entering a new era in medicine and surgery in which the focus will be elevated from the quality of care to its value,” he said. “High-value health care is achieved when excellent outcomes, including patient experience, are achieved at reasonable costs.  As surgery accounts for nearly half of all Medicare spending, surgeons will have a critical role in this journey.”

Co-author Peter Pronovost, MD, estimates the U.S. health care system spends $1.4 trillion annually—one-third of health care costs—on defects.  At his own institution, University Hospitals in Cleveland, where he is the Chief Clinical Transformation Officer, he found that focused efforts to reveal and reduce defects improved quality and reduced Medicare costs by 9 percent. Dr. Pronovost is also Professor, schools of Medicine, Nursing, and Management, Case Western Reserve University.

In their new paper, Drs. Dietz and Pronovost estimate that defects in colorectal surgery cost the American health care system more than $12 billion.  The authors discuss eight areas (or domains) of defects that waste money and/or contribute to lower value in care for colorectal surgery patients.

They are:

• Difficulty in Accessing Care, where patients may find navigating health systems difficult and unable to find information about the quality of surgeons or hospitals. “While this defect may or may not drive up costs, it results in low-value care by compromising patient experience and quality of life. For example, patients with rectal cancer who are treated by a non-specialist surgeon are much more likely to end up with a permanent colostomy,” said Dr. Pronovost.

• Difficulty Supporting Shared Decision-Making – Under the current fee-for-service system in the U.S. health system, surgeons have pressure to see more patients, making it difficult for them to spend adequate time answering questions and discussing treatment alternatives. While researchers have developed patient decision aids for diseases such as ulcerative colitis and colorectal cancer, these aids are rarely used in clinical practice. This situation leads to less-satisfactory outcomes.

• Inappropriate Care - One study estimates that 10 percent to 20 percent of all wasteful spending in U.S. health care is for overtreatment, overuse, and unnecessary care, accounting for $70 billion to $200 billion annually. For virtually every procedure studied, 30 percent are unnecessary if clinicians use rigorous appropriateness criteria. These services land squarely in the realm of no-value care because the patient cannot gain clinical benefits.

• Low-Value Site of Care - Many surgical procedures are performed at expensive inpatient facilities when they could be performed at an ambulatory center for 50 percent less. 

• Care at Low-Volume Hospitals by Low-Volume Surgeons - Outcomes of many major surgical procedures are strongly correlated with the annual volume performed at the hospital and by the surgeon. Yet many patients continue to be treated by low-volume hospitals and providers, even when a high-volume option is less than 30 miles away. When treated by low-volume providers, patients with rectal cancer are more likely to undergo abdominoperineal resection, to end up with a permanent colostomy, and to have worse survival.

• Care with Avoidable Complications - Colorectal surgery procedures are associated with some of the highest rates of postoperative complications across the country. A recent study showed that 70 percent of patients have at least one complication, with an associated cost increase of nearly 40 percent. The most serious complication of colorectal surgery—anastomotic leak—increases the cost of hospitalization by $8,000. A reduction in the rate of anastomotic leak from 15 percent to 10 percent nationally would save $20.4 million annually. If 75 percent of anastomotic leaks could be avoided after colorectal surgery, $32.1 million in health care costs could be saved annually in U.S.

• Avoidable Post-Acute Care - Discharge to post-acute care is a common practice for patients undergoing any major surgery. Reasons for post-acute care include advanced age, poor functional status, and preventable postoperative complications. One study showed significant variability between hospitals in terms of post-acute care spending for patients managed with colectomy.

• Preventable Readmissions - Readmissions after surgery represent potentially low-quality care and increased costs to the health system. Yet readmissions are also indicative of the patient’s health: either it is deteriorating or the patient gained no clinical benefit from the procedure. Such circumstances represent no-value care scenarios. Approximately 14 percent of patients who have undergone colorectal surgery are readmitted after being discharged. Commons reasons for readmission include surgical site infections, small bowel obstruction, and dehydration in patients undergoing ileostomy. One study examined readmissions after colorectal surgery from 2013 to 2016 and showed that 40 percent were preventable. The median cost per stay was $8,885 (based on 2002–2008 data); thus, $300 million in cost-savings could be achieved per year by preventing unnecessary readmissions.

“Given the abundance of opportunities presented, a ‘whack-a-mole’ approach to address them individually seems inefficient and overwhelming,” said Dr. Pronovost. “However, a holistic approach through the creation of Centers of Excellence (COEs), if well designed and well executed, can address all of these defects”

Dr. Pronovost said, “COEs are a systematic attempt to design surgical care to eliminate all or most of these defects.  In COEs, we provide frictionless access; we provide patient navigation; we use explicit appropriateness criteria to ensure patients will benefit from the procedure; we ensure the procedure is done at the highest value site of service by a surgeon and at a hospital that has high volume; we use standard protocols, yet personalize when needed to eliminate preventable harm; we ensure patients go home rather than to a post-acute facility when possible.   As a result; quality and experience increase and cost decrease.”  University Hospitals has created COEs, for example, for joint replacement surgery, spine surgery, and atrial fibrillation ablation and is creating one for colorectal surgery.  

“If we are to finally improve the value of surgical care in the U.S., we need to ensure that surgeons are engaged in the process and that principles for quality improvement are also applied to identify and eliminate all defects in value in surgical care,” he said.

Other authors of the paper are William V. Padula, PhD, MS, Assistant Professor, Department of Pharmaceutical & Health Economics, School of Pharmacy; Fellow, Leonard D. Schaeffer Center for Health Policy & Economics, University of Southern California, Los Angeles; and Hanke Zheng, MS, Graduate Research Assistant, Department of Pharmaceutical & Health Economics, School of Pharmacy, University of Southern California, Los Angeles.

###

About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of 23 hospitals (including 5 joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, Oxford University and the Technion Israel Institute of Technology. The main campus also includes the UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,000 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn, Facebook and Twitter. For more information, visit UHhospitals.org.

 

---

JOURNAL

NEJM Catalyst

METHOD OF RESEARCH

Literature review

SUBJECT OF RESEARCH

Not applicable

ARTICLE TITLE

Costs of Defects in Surgical Care: A Call to Eliminate Defects in Value

Combating antibiotic resistance

As bacterial infections impervious to drugs rise, so does the need to develop better antibiotics

Peer-Reviewed Publication

HARVARD MEDICAL SCHOOL

As long as antibiotics have existed, so too has antibiotic resistance—the inevitable result as infectious bacteria continually evolve to evade the very drugs designed to kill them.

Today, antibiotic resistance is considered a major global health threat. In the United States, The Centers for Disease Control and Prevention estimates that every year, at least 2.8 million people develop infections resistant to antibiotics, leading to more than 35,000 deaths. Yet, in recent decades, antibiotic development has been slow, and no new classes of antibiotics have reached the market. Meanwhile, widespread use of the limited number of antibiotics currently available has spurred more bacterial strains to develop resistance, with additional strains already resistant to available antibiotics being discovered, often in hospitals. This situation is expected only to worsen over time, resulting in more drug-resistant bacterial infections and deaths.

Maofu Liao, an associate professor of cell biology in the Blavatnik Institute at Harvard Medical School, spoke with Harvard Medicine News about antibiotic resistance and the challenges of developing new antibiotics.

Liao explained how his team’s research on protein structures in bacteria could inform antibiotic design and described a new pipeline his lab is establishing to improve the process.

In a newly published study in Science, Liao and colleagues demonstrated that their pipeline can effectively identify compounds that interfere with essential proteins in bacteria and thus may have potential as antibiotics.

HM News: What are some of the most pressing challenges with currently available antibiotics?

Liao: One issue is that most drug development efforts depend on industry, but antibiotics are time-consuming and expensive to develop—and often aren’t necessarily required for treatment and aren’t taken by patients on a regular basis. It’s hard to make the business case to industry that it’s worthwhile to develop new antibiotics when so much effort and money are required, and profit isn’t predictable or immediate. A second issue is the way we use antibiotics. For a long time, we have relied on single-use antibiotics, or a limited combination of antibiotics. This makes it easy for bacteria to acquire resistance. They can then transfer that capability to other bacteria that have not been exposed to antibiotics. So, we are using very limited tools that bacteria can easily overcome.       

Another critical issue is how we develop antibiotics. With few exceptions, our efforts to identify new antibiotics mostly rely on chemical screens against bacterial growth. People do a screen and hope to find some magical compound that can kill the bacteria with great efficacy. Once they have that, they hand the compound to chemists who optimize it and hopefully develop it into a clinically useful antibiotic. Such screens cannot target specific proteins in bacteria, and may exclude compounds that have the potential to attack crucial bacterial proteins. Moreover, for antibiotics developed through such screens, we often don’t know the underlying mechanism of how they work, or why they stop working when resistance occurs. This is a critical gap in our current approach.

HM News: What are you studying in the realm of antibiotic resistance?

Liao: I have a longstanding interest in studying how proteins work, so I come into the field on the protein mechanism side. Inside humans, or any living organisms, there are many proteins that do many different things. In bacteria, some of these proteins are doing essential work—so if the proteins get disrupted, the bacteria are not happy and may even die. That’s something we’d like to exploit. First, we want to understand how these essential proteins inside bacteria work and then we want to use this information to direct our effort to kill the bacteria with antibiotics.

HM News: Can you provide more detail about the bacteria you study?

Liao: Most of our work is on E. coli, which is a model organism related to many pathogenic bacteria. E. coli is a type of Gram-negative bacteria, which means it has an extra membrane in addition to the regular membrane around the cell. That extra outer membrane is vital for keeping the microbe alive. It prevents a lot of things from entering the cell, including antibiotics, and plays a key role in antibiotic resistance. The outer membrane is made of lipids, but many of these lipid molecules are attached to long chains of polysaccharides, or sugars—so the membrane looks hairy, but those hairs are actually sugar chains. These are large, strange lipid molecules called lipopolysaccharides that have to be synthesized inside the cell and then transported to the outer membrane where they are assembled. We are studying the proteins involved in transporting these lipids from inside the cell to the outer surface. The proteins involved in the transport process are essential for E. coli survival and growth. If we can somehow interfere with the function of these transport proteins, we may affect bacterial growth and survival.

HM News: You are using a technique called Cryo-EM in your research. What are the benefits of this technique?

Liao: Cryo-EM is a microscopy technique used in structural biology, which is a field that aims to see small things in high resolution. Traditional structural biology relied on methods like X-ray crystallography to obtain high-resolution details of protein structure. However, with X-ray crystallography you have to put your protein in crystal contact instead of in solution, which makes it difficult to observe all the different conformations, or shapes, of the protein—only some of which may be relevant. Cryo-EM is more flexible because it doesn't require crystal contact. You freeze your protein sample in ice, put it into the microscope, and take many, many images. Those images can be put together and processed to obtain high-resolution structures of the protein in its different conformations. This method helps us obtain critical insights into how transporter proteins in E. coli work. We are able to look at the entire protein–lipid complex in high resolution to see how the protein interacts with its lipid substrate in a lot of detail. 

HM News: How can insights from cryo-EM improve antibiotic development?

Liao: We are trying to build an entirely new pipeline for antibiotic development. The pipeline starts with a chemical screen to find a compound that can stop the activity of essential proteins in bacteria. Once we have that, we use cryo-EM to obtain the high-resolution structure of the target protein bound to the compound. Then we know which pocket the compound binds on the protein and we gain high-resolution information about the binding pocket. We use the structural information about that so-called druggable pocket to do a virtual screen, potentially using artificial intelligence, to find other compounds with other chemical backbones—or scaffolds—that bind to the same pocket on the protein. So, we ask the question: What other compounds with other scaffolds can take advantage of this pocket that worked for the first compound? Next, we use cryo-EM to determine the structure of the protein bound to any new compound that was identified, and confirm the compound’s effect on protein activity and bacterial growth. We do that so we can validate our prediction and get more detailed information about how every part of the new compound interacts with the pocket; which parts are more important, which parts are less important. We also get information about the potential variations of the druggable pocket when the protein is bound to the new compound, so we can better understand the interplay between the protein and compound. This gives us a rational way to further optimize the compound as it is developed into an antibiotic. In our recent paper in Science, we successfully used this pipeline to identify a completely different compound that had the same effect on an essential transporter protein as our starting compound.

HM News: What is the long-term goal for your pipeline?

Liao: We are still doing the initial work to demonstrate the power of our pipeline, but as we focus on these essential transporter proteins, we hope this information can be used to develop better antibiotics. During our research, we realized that knowing the mechanism of a compound and having high-resolution information about how the compound interacts with a target protein really breaks open many possibilities of antibiotic drug development. It allows us to use more rational approaches to develop antibiotics efficiently. Our goal is to change the way we develop antibiotics. We would like to show that new ideas and new technologies can transform antibiotic discovery into a more systematic, rational, and robust process.

I hope that in the future, by changing the way we develop antibiotics, humans can eventually win the race of antibiotic resistance. I think we should develop a wide range of broad-spectrum and narrow-spectrum antibiotics: We should have multiple drugs to target multiple proteins inside bacteria and we should have multiple drugs to target the same essential protein through different mechanisms, such as different drug pockets. If we have a large array of useful antibiotics, bacteria should not be able to develop resistance so easily. Plus, then we can combine different antibiotics for different patients based on their particular disease and infection conditions to get the best results. First, we need the tools, then we can have clever ways to use them. But if we don’t have the tools in hand, there’s really nothing we can do.

###

 

---

JOURNAL

Science

DOI

10.1126/science.abi9009 

ARTICLE TITLE

Distinct allosteric mechanisms of first-generation MsbA inhibitors

ARTICLE PUBLICATION DATE

23-Sep-2021

OLDER DRUG CHEAPER TOO

Popular heart failure drug no better than older drug in sickest patients

Study suggests older drug may be safer for an advanced form of heart failure

Peer-Reviewed Publication

WASHINGTON UNIVERSITY SCHOOL OF MEDICINE

A new study led by researchers at Washington University School of Medicine in St. Louis suggests that a widely used heart failure drug named sacubitril/valsartan is no better than valsartan alone in patients with severe heart failure. The study also provides evidence that the treatment with valsartan may be slightly safer for patients with advanced heart failure.

The study was published online Nov. 3 in JAMA Cardiology.

Heart failure is one of the leading causes of hospitalization in the United States, with about two heart failure hospitalizations occurring every minute. It is often triggered by damage to the heart from, for example, a heart attack or a viral infection. A complex clinical syndrome, heart failure leads to increased retention of salt and water by the kidneys. This results in a buildup of fluid in the lungs, causing shortness of breath and fatigue. The body’s response to heart damage is to activate hormonal regulatory systems that attempt to restore normal blood flow to vital organs. Over time, these hormonal systems can lead to secondary damage to the heart and the circulation, resulting in worsening heart failure. Most drugs used to treat heart failure block the harmful effects of high levels of the compensatory hormones.

The study, called the LIFE trial, focused on advanced heart failure patients with reduced pumping capacity, referred to as Heart Failure with a Reduced Ejection Fraction (HFrEF).

“Patients with the most severe heart failure are often not included in clinical trials because they’re so severely ill they don’t qualify to participate,” said first author and Washington University cardiologist Douglas L. Mann, MD, the Tobias and Hortense Lewin Professor of Medicine. “We wanted to study these patients because their condition is so much worse than that of patients with mild or moderate heart failure. It’s basically a different disease. Because medical therapies are limited in these patients, the only treatment options are cardiac transplantation or left ventricular assist devices. Our hope was that treatment with sacubitril/valsartan would prevent the need to transplant patients or use expensive mechanical circulatory assist devices.”

The combination drug sacubitril/valsartan was shown to be more effective than the standard of care — treatment with an angiotensin converting enzyme inhibitor — in a previous large clinical trial involving more than 8,000 heart failure patients with a reduced ejection fraction, but only 60 patients in that trial (less than 1%) had severe disease.

The current LIFE trial included 335 patients with advanced heart failure with a reduced ejection fraction. On average, these patients’ hearts pumped only one-third of the blood volume they should have been pumping. Such patients have chronic shortness of breath and fatigue, even at rest while receiving optimal medical therapy. Half were randomly assigned to receive sacubitril/valsartan along with standard medical therapy for heart failure; the other half received valsartan alone plus standard medical therapy. Neither patients nor researchers knew which patients were in each group. Both drugs are pills taken by mouth. The duration of the study was 24 weeks.

To compare the effectiveness of the drugs, the researchers measured changes in a biomarker that is easily detectable in the blood, called N-terminal pro-Brain Natriuretic Peptide (NT-proBNP). Levels of the biomarker were measured before the patients started treatment and at various times over 24 weeks of therapy. Levels of the biomarker reflect the amount of congestion that heart failure patients have. Decreased levels are associated with improved heart failure symptoms, and increased levels reflect worsening heart failure and increased likelihood of death. The major finding was that there was no statistically significant difference in levels of the biomarker over 24 weeks in the patients taking sacubitril/valsartan, as compared to patients receiving valsartan. This finding was observed across all of the subgroups that were examined.

Compared with valsartan alone, the sacubitril/valsartan treatment group also did not show any improvement in the total number of days alive, days out of the hospital and days that were free from complications of heart failure. Sacubitril/valsartan and valsartan also showed no differences in heart failure hospitalizations, deaths from cardiovascular causes or deaths from any cause. There was a statistically significant increase in potassium levels in the patients receiving sacubitril/valsartan; however, the elevated potassium levels were not life-threatening.

“The findings of the trial were really surprising to us,” said Mann, also a professor of cell biology & physiology. “In every other trial involving sacubitril/valsartan, the drug showed a benefit over the standard of care, including lowering NT-proBNP levels. Even though we didn’t have a large enough sample size in the trial to see clinically meaningful differences in the endpoints between the two groups, every clinical outcome that we measured favored treatment with valsartan alone. Since the results of the trial did not show significant differences in favor of one treatment strategy over the other, we cannot say that valsartan is better than sacubitril/valsartan for patients with advanced heart failure. But as a doctor, I often have to make treatment decisions for my patients based on clinical trial evidence that does not clearly show statistically significant differences between treatment groups. For the most severe heart failure patients, sacubitril/valsartan does not appear to provide an advantage over valsartan, which is a generic drug that is far less expensive to use and was not associated with elevated potassium levels and thus is easier to monitor over time.”

The researchers speculate that the severity of heart failure in the patients in the trial may have resulted in a loss of the beneficial effects of neprilysin inhibition, which would explain why sacubitril/valsartan was no different than valsartan. Experimental and clinical studies have shown that the excessive activation of hormonal systems in severe advanced heart failure can override the drugs that are used to block these systems in order to restore normal balance.

“The evidence suggests that sacubitril/valsartan helps heart failure patients with mild or moderate heart failure but is no better than valsartan for patients with severe disease,” Mann said. “Although we were not able to show a benefit for sacubitril/valsartan in the LIFE trial, we believe that results of the trial will be helpful to the clinicians who provide care for this vulnerable population of advanced heart failure patients. We clearly need to do a better job of preventing heart failure from progressing to an advanced stage, and we need more research to develop better medical therapies for the patients who do progress to advanced stages.”

Lead collaborators on this national clinical trial include researchers at Harvard Medical School and Duke University.

###

This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH), grant numbers U10 HL084904, U10 HL110297, U10 HL110342, U10 HL110309, U10 HL110262, U10 HL110338, U10 HL110312, U10 HL110302, U10 HL110336 and U10 HL110337. Novartis Pharmaceutical Corp. provided the drugs used in the study and partial funding through its investigator-initiated trial program CLCZ696BUS04T.

Mann serves on the steering committee for the PARADISE-MI trial (comparing sacubitril/valsartan to enalapril) for Novartis.

Mann DL, et al for the LIFE Investigators. Effect of treatment with sacubitril/valsartan in patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA Cardiology. Nov. 3, 2021.

Washington University School of Medicine’s 1,700 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, consistently ranking among the top medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

---

JOURNAL

JAMA Cardiology

DOI

10.1001/jamacardio.2021.4567 

METHOD OF RESEARCH

Randomized controlled/clinical trial

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial

ARTICLE PUBLICATION DATE

3-Nov-2021

COI STATEMENT

Mann serves on the steering committee for the PARADISE-MI trial (comparing sacubitril/valsartan to enalapril) for Novartis.