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Aging and Alzheimer's leave the brain starved of energy. Now scientists think they've found a way to aid the brain's metabolism — in mice. PM Images/Getty Images hide caption

Shots - Health News

This metabolic brain boost revives memory in alzheimer’s mice.

September 2, 2024 • An experimental cancer drug that helps the brain turn glucose into energy was able to reverse memory loss in a mouse model of Alzheimer’s disease.

A drug that restores brain metabolism could help treat Alzheimer's

A squat lobster in the genus Sternostylus, thought to be a newly identified species, was photographed along the Nazca Ridge off the coast of Chile. ROV SuBastian/Schmidt Ocean Institute hide caption

A newly mapped underwater mountain could be home to 20 new species

August 30, 2024 • Researchers who led the 28-day expedition along the nearly 2-mile tall seamount hope the discoveries made will inform future policies safeguarding the understudied, high-seas region.

Corn rootworm is known as the 'billion dollar bug' for how much damage it causes to corn crops in the United States. Researcher Emily Bick is tackling the problem by eavesdropping on this and other insects. Lina Tran hide caption

How listening to the sounds of insects can help detect agricultural pests

August 30, 2024 • From Indonesia to Wisconsin, farmers all over the world struggle with a huge problem: pests. On top of that, it's tough for farmers to identify where exactly they have the pests and when. Reporter Lina Tran from NPR member station WUWM in Milwaukee joins host Emily Kwong to tell the story of how researchers in the Midwest are inventing new forms of pest detection that involve eavesdropping on the world of insects. Plus, hear what aphid slurping sounds like.

A white-browed sparrow weaver inspects a roost under construction, after just receiving some grass brought by another member of its group. Maria Cristina Tello-Ramos hide caption

When birds build nests, they're also building a culture

August 29, 2024 • Nest-building isn’t just instinct. Birds can learn from others, letting groups within one species develop their own distinctive nest-building traditions.

Shells, composed mostly of invasive zebra mussels pile up at Sleeping Bear Dunes National Lakeshore in Michigan. The Nonindigenous Aquatic Nuisance Species Control and Prevention Act of 1990 and the United States Geological Survey's Nonindigenous Aquatic Species database were created in response to this mussel. corfoto/Getty Images hide caption

Here's what's missing from the invasive species narrative

August 28, 2024 • At first glance, the whole narrative of aquatic invasive species may seem straightforward: A bad non-native species comes into a new ecosystem and overruns good native species. But the truth? It's a little more complicated. To tear down everything we thought we knew about invasive species and construct a more nuanced picture, host Emily Kwong talks to experts Ian Pfingsten, who works on the United States Geological Survey's Nonindigenous Aquatic Species Database, and Nicholas Reo, a Canada Excellence Research Chair in Coastal Relationalities and Regeneration.

Many people get into their phones when they're bored, then scroll through social media in the hopes of alleviating that boredom. But new research suggests that swiping from video to video might increase boredom, not alleviate it. Tippapatt/Getty Images hide caption

Scrolling might make you MORE bored, not less

August 23, 2024 • Have you ever scrolled through a TikTok without finishing it? Switched between YouTube videos halfway through one or the other? Pressed "fast forward" on a Netflix episode that just wasn't holding your interest? That habit is called "digital switching" — and it might be causing the exact thing you're trying to avoid: boredom. Emily and Regina break that and more of the week's news down with the help of All Things Considered 's Ailsa Chang.

Invasive cane toads like this one have fanned out across Australia, killing numerous predators in their wake, including freshwater crocodiles. Joshua Prieto/SOPA Images/LightRocket via Getty Images hide caption

To save wild crocodiles in Australia, scientists gave them food poisoning

August 16, 2024 • Freshwater crocodiles die every year in Australia from eating poisonous cane toads that humans introduced to the continent. Now scientists have found a way to teach the crocs to avoid the toxic toads.

Saving freshwater crocodiles — by teaching them to not eat poisonous toads

Conservation biologist Gliselle Marin carefully untangles a bat from a net in Belize during the annual Bat-a-thon. Her fanny pack is decorated with printed bats. Luis Echeverría for NPR hide caption

Goats and Soda

This scientist has a bat tat and earrings. she says there's a lot to learn from bats.

August 12, 2024 • Gliselle Marin joins the “Bat-a-thon,” a group of 80-some bat researchers who converge on Belize each year to study these winged mammals.

A scientist in Belize hopes bats can galvanize locals to protect their forests

Researchers glued cameras and tracking instruments to small pieces of neoprene, that they then glued to the fur of the sea lions Nathan Angelakis hide caption

Scientists attach video cameras to sea lions to map the ocean floor

August 9, 2024 • How do you study unmapped areas of the ocean and identify critical habitat for an endangered species? You include the study animal in the scientific process! Researchers from the University of Adelaide fitted endangered Australian sea lions with cameras and tracking devices to better understand where they spent their time. The information could help scientists protect critical sea lion habitat and could give researchers a new tool for mapping the ocean.

"Everything that we are as human beings is in our brain," Dr. Theodore Schwartz says. Brian Marcus /Penguin Randomhouse hide caption

Health Care

For this brain surgeon, the operating room is 'the ultimate in mindful meditation'.

August 5, 2024 • Dr. Theodore Schwartz has been treating neurological illnesses for nearly 30 years. He says being a brain surgeon requires steady hands — and a strong bladder. His new book is Gray Matters.

New blood tests that help detect Alzheimer's disease are opening up a new era in diagnosis and treatment, doctors say. Marcus Brandt/picture alliance/Getty Images hide caption

New blood tests can help diagnose Alzheimer's. Are doctors ready for what's next?

August 2, 2024 • A new generation of blood tests can help diagnose Alzheimer’s disease. But many doctors don’t yet know how to use them.

Alzheimer's blood tests

Some researchers say the African coral tree has a racial slur embedded in its name. This month, scientists at an international meeting voted to have that epithet removed. tree-species/Flickr hide caption

Some plant names can be racist. Scientists are looking to rename them

July 31, 2024 • An international group of researchers has voted to modify the scientific names of more than 200 plant species whose names carry a derogatory word.

Researchers are revising botanical names to address troubling connotations

A key protein called Reelin may help stave off Alzheimer's disease, according to a growing body of research. GSO Images/The Image Bank/Getty Images hide caption

A protein called Reelin keeps popping up in brains that resist aging and Alzheimer’s

July 29, 2024 • Early in life, the protein Reelin helps assemble the brain. Later on, it appears to protect the organ from Alzheimer’s and other threats to memory and thinking.

Alzheimer's resilience

There are over eight hundred species of leeches, but researchers estimate that only ten percent of all leeches are terrestrial. Auscape/Contributor/Getty Images hide caption

We hate to tell you this, but there are leeches that can jump

July 29, 2024 • Generally, we at Short Wave are open-minded to the creepies and the crawlies, but even we must admit that leeches are already the stuff of nightmares. They lurk in water. They drink blood. There are over 800 different species of them. And now, as scientists have confirmed ... at least some of them can jump!

Two chimpanzees groom each other — a behavior that can involve several gestures. Anup Shah/Getty Images hide caption

What chimpanzee gestures reveal about human communication

July 26, 2024 • Chimpanzees are humans' closest living relatives. But does much of their communication resembles ours? According to a new study published earlier this week in the journal Current Biology , chimpanzees gesture back-and-forth in a similar way to how humans take turns speaking. The research presents an intriguing possibility that this style of communication may have evolved before humans split off from great apes, and tells researchers more about how turn-taking evolved.

Project RattleCam lets people observe rattlesnakes with a live webcam. Scott Boback hide caption

Watch a livestream of Colorado’s ‘mega den’ of pregnant rattlesnakes

July 24, 2024 • On a rocky hillside in Colorado is a “mega den” of hundreds of rattlesnakes — along with cameras livestreaming the whole thing.

 Pregnant Rattlesnakes Webcam

Glyptodonts were giant, armadillo-like shelled mammals that went extinct about 10,000 years ago. A study reveals that cut marks on a glyptodont fossil in South America could have been made by humans a little over 20,000 years ago. Daniel Eskridge/Stocktrek Images/Science Source hide caption

When did humans get to South America? This giant shelled mammal fossil may hold clues

July 23, 2024 • A fossil of an armadillo-like mammal appears to bear cut marks from butchering by humans, suggesting people were living in South America at least 20,000 years ago, even earlier than once thought.

Ancient Armadillos

Once completed, India's National River Linking Project will transfer an estimated 200 billion cubic meters of water around the country each year. STRDEL / Stringer/Getty Images hide caption

India's plan to reroute rivers could have unintended consequences on rainfall

July 19, 2024 • More than a hundred years ago, a British engineer proposed linking two rivers in India to better irrigate the area and cheaply move goods. The link never happened, but the idea survived. Today, due to extreme flooding in some parts of the country mirrored by debilitating drought in others, India's National Water Development Agency plans to dig thirty links between rivers across the country. It's the largest project of its kind and will take decades to complete. But scientists are worried what moving that much water could do to the land, the people — and even the weather. Host Emily Kwong talks to journalist Sushmita Pathak about her recent story on the project.

In 2022, a large, unexpected rogue wave struck the Viking Polaris, breaking windows. One passenger died and others were injured. Alexis Delisi/AFP/Getty Images hide caption

Rogue waves can strike without warning. These scientists found a way to predict them

July 18, 2024 • Scientists have created a new tool that can give 5 minutes advance warning of a dangerous rogue wave in the ocean.

A study finds that psilocybin can desynchronize networks in the brain, potentially enhancing its plasticity. Sara Moser/Washington University School of Medicine in St. Louis hide caption

A scientist took a psychedelic drug — and watched his own brain 'fall apart'

July 18, 2024 • Scientists scanned the brains of people who took psilocybin, including a member of the research team. The scans showed how the drug disrupts key networks, potentially enhancing brain plasticity.

A prominent brain scientist took psilocybin as part of his own brain study

Crows can be trained to count out loud much in the way that human toddlers do, a study finds. Andreas Nieder/Universal Images Group Editorial hide caption

Crows can count out loud like human toddlers — when they aren't cheating the test

July 18, 2024 • A study finds that carrion crows can be taught to count and make vocalizations that indicate the number counted, much in the same way that human toddlers do.

Crows can count vocally like toddlers, research shows

An image released by the FDA shows bottles containing tianeptine and other compounds. Authorities have urged gas station store owners and others not to sell the products, with names like Neptune's Fix, Za Za and Tianaa, citing serious health risks. FDA hide caption

8 things to know about the drug known as 'gas station heroin'

July 14, 2024 • For decades, tianeptine was used to treat depression, even though no one knew how it worked. But it turns out it's a type of opioid, and the U.S. is facing a spike in abuse of "gas station heroin."

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News Release

Thursday, May 25, 2023

Large study provides scientists with deeper insight into long COVID symptoms

NIH-funded research effort identifies most common symptoms, potential subgroups, and initial symptom-based scoring system – with aim of improving future diagnostics and treatment.

Initial findings from a study of nearly 10,000 Americans, many of whom had COVID-19, have uncovered new details about long COVID, the post-infection set of conditions that can affect nearly every tissue and organ in the body. Clinical symptoms can vary and include fatigue, brain fog, and dizziness, and last for months or years after a person has COVID-19. The research team, funded by the National Institutes of Health, also found that long COVID was more common and severe in study participants infected before the 2021 Omicron variant.

The study, published in JAMA , is coordinated through the NIH’s Researching COVID to Enhance Recovery (RECOVER) initiative, a nationwide effort dedicated to understanding why some people develop long-term symptoms following COVID-19, and most importantly, how to detect, treat, and prevent long COVID. The researchers hope this study is the next step toward potential treatments for long COVID, which affects the health and wellbeing of millions of Americans.

“Americans living with long COVID want to understand what is happening with their bodies,” said ADM Rachel L. Levine, M.D., Assistant Secretary for Health. “RECOVER, as part of a broader government response, in collaboration with academia, industry, public health institutions, advocacy organizations and patients, is making great strides toward improving our understanding of long COVID and its associated conditions.”

Researchers examined data from 9,764 adults, including 8,646 who had COVID-19 and 1,118 who did not have COVID-19. They assessed more than 30 symptoms across multiple body areas and organs and applied statistical analyses that identified 12 symptoms that most set apart those with and without long COVID: post-exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, heart palpitations, issues with sexual desire or capacity, loss of smell or taste, thirst, chronic cough, chest pain, and abnormal movements.

They then established a scoring system based on patient-reported symptoms. By assigning points to each of the 12 symptoms, the team gave each patient a score based on symptom combinations. With these scores in hand, researchers identified a meaningful threshold for identifying participants with long COVID. They also found that certain symptoms occurred together and defined four subgroups or “clusters” with a range of impacts on health.

Based on a subset of 2,231 patients in this analysis who had a first COVID-19 infection on or after Dec. 1, 2021, when the Omicron variant was circulating, about 10% experienced long-term symptoms or long COVID after six months. The results are based on a survey of a highly diverse set of patients and are not final. Survey results will next be compared for accuracy against an array of lab tests and imaging.

To date, more than 100 million Americans have been infected with SARS-CoV-2, the virus that causes COVID-19. As of April, the federal government’s Household Pulse survey estimates that about 10% of adults infected with the virus continue to experience and suffer from the many symptoms termed together as long COVID. Patients and researchers have identified more than 200 symptoms associated with long COVID.

“This study is an important step toward defining long COVID beyond any one individual symptom,” said study author Leora Horwitz, M.D., director of the Center for Healthcare Innovation and Delivery Science, and co-principal investigator for the RECOVER Clinical Science Core, at NYU Langone Health. “This approach — which may evolve over time — will serve as a foundation for scientific discovery and treatment design.” The researchers explain studying the underlying biological mechanisms of long COVID is central to advancing informed interventions and identifying effective treatment strategies.

In addition to establishing the scoring system, the researchers found that participants who were unvaccinated or who had COVID-19 before the Omicron strain emerged in 2021 were more likely to have long COVID and more severe cases of long COVID. Further, reinfections were also linked to higher long COVID frequency and severity, compared to people who only had COVID-19 once.

“While the score developed in this study is an important research tool and early step toward diagnosing and monitoring patients with long COVID, we recognize its limitations,” said David C. Goff, M.D., Ph.D., director of the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute, part of NIH. Goff serves as an epidemiology lead for NIH RECOVER. “All patients suffering from long COVID deserve the attention and respect of the medical field, as well as care and treatment driven by their experiences. As treatments are developed, it will be important to consider the complete symptom profile.”

The ongoing RECOVER research serves as the foundation for planned clinical trials, whose interventions are rooted in many of the symptoms outlined in this study. RECOVER clinical trials are expected to begin enrolling patient participants in 2023.

This research was funded by NIH agreements OT2HL161841 , OT2HL161847 , and OT2HL156812 . Additional support came from grant R01 HL162373 . For more information on RECOVER, visit https://recovercovid.org .                                                                 

About RECOVER : The National Institutes of Health Researching COVID to Enhance Recovery (NIH RECOVER) Initiative is a $1.15 billion effort, including support through the American Rescue Plan Act of 2021, that seeks to identify how people recuperate from COVID-19, and who are at risk for developing post-acute sequelae of SARS-CoV-2 (PASC). Researchers are also working with patients, clinicians, and communities across the United States to identify strategies to prevent and treat the long-term effects of COVID – including long COVID. For more information, please visit recovercovid.org .

HHS Long COVID Coordination : This work is a part of the National Research Action Plan (opens pdf), a broader government-wide effort in response to the Presidential Memorandum directing the Secretary for the Department of Health and Human Services to mount a full and effective response to long COVID. Led by Assistant Secretary for Health Admiral Rachel Levine, the Plan and its companion Services and Supports for Longer-term Impacts of COVID-19 (opens pdf) report lay the groundwork to advance progress in the prevention, diagnosis, treatment, and provision of services for individuals experiencing long COVID.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

NIH…Turning Discovery Into Health ®

Thaweethai T, Jolley SE, Karlson EW, et al. Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection.  JAMA.  Published online May 25, 2023. doi: 10.1001/jama.2023.8823

Change Note

On May 31, 2023, a statistic in the seventh paragraph on the percentage of adults continuing to experience symptoms of COVID-19 was updated from 6% to 10%.

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The universe had a secret life before the Big Bang, new study hints

The secrets of black holes and dark matter could lie before the Big Bang, a new study of "bouncing" cosmology hints.

The Big Bang may not have been the beginning of the universe, according to a theory of cosmology that suggests the universe can “bounce” between phases of contraction and expansion. If that theory is true, then it could have profound implications about the nature of the cosmos, including two of its most mysterious components: black holes and dark matter.

With this in mind, a recent study suggests that dark matter could be composed of black holes formed during a transition from the universe's last contraction to the current expansion phase, which occurred before the Big Bang. If this hypothesis holds, the gravitational waves generated during the black hole formation process might be detectable by future gravitational wave observatories, providing a way to confirm this dark matter generation scenario.

Observations of stellar movements in galaxies and the cosmic microwave background — an afterglow of the Big Bang — indicate that about 80% of all matter in the universe is dark matter , a substance that doesn't reflect, absorb or emit light. Despite its abundance, scientists have not yet identified what dark matter is made of.

In the new study, researchers explored a scenario where dark matter consists of primordial black holes formed from density fluctuations that occurred during the universe's last contraction phase, not long before the period of expansion that we observe now. They published their findings in June in the Journal of Cosmology and Astroparticle Physics .

The bouncing cosmos

The traditional cosmological view of the universe suggests that it started from a singularity, followed by a short period of extremely rapid expansion, called inflation. However, the authors behind the new study analyzed a more exotic theory, known as non-singular matter bouncing cosmology, which posits that the universe first underwent a contraction phase. This phase ended with a rebound due to the increasing density of matter, leading to the Big Bang and the accelerated expansion we observe today.

Related: The universe could stop expanding 'remarkably soon', study suggests

In this bouncing cosmology, the universe contracted to a size about 50 orders of magnitude smaller than it is today. After the rebound, photons and other particles were born, marking the Big Bang. Near the rebound, the matter density was so high that small black holes formed from quantum fluctuations in the matter’s density, making them viable candidates for dark matter.

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"Small primordial black holes can be produced during the very early stages of the universe, and if they are not too small, their decay due to Hawking radiation [a hypothetical phenomenon of black holes emitting particles due to quantum effects] will not be efficient enough to get rid of them, so they would still be around now," Patrick Peter , director of research at the French National Centre for Scientific Research (CNRS), who was not involved in the study, told Live Science in an email. "Weighing more or less the mass of an asteroid , they could contribute to dark matter, or even solve this issue altogether."

— Cosmic 'superbubbles' might be throwing entire galaxies into chaos, theoretical study hints

— 'Immortal' stars at the Milky Way's center may have found an endless energy source, study suggests

— Giant 'rogue waves' of invisible matter might be disrupting the orbits of stars, new study hints

The scientists' calculations show that this universe mode's properties, such as the curvature of space and the microwave background, match current observations, supporting their hypothesis.

To further test their predictions, the researchers hope to make use of next-generation gravitational wave observatories.The scientists calculated the properties of the gravitational waves produced during black hole formation in their model and found that they could be detected by upcoming gravitational observatories like the Laser Interferometer Space Antenna (LISA ) and the Einstein Telescope . These detections could confirm whether primordial black holes are indeed dark matter; however, it could take more than a decade before either facility sees first light.

"This work is important in the sense that it provides a natural way of forming small yet still present black holes forming dark matter in a framework which is not the usual one based on inflation," Peter said. "Other works currently investigate the behavior of such tiny black holes around stars, potentially leading to a way of detecting them in the future."

Andrey got his B.Sc. and M.Sc. degrees in elementary particle physics from Novosibirsk State University in Russia, and a Ph.D. in string theory from the Weizmann Institute of Science in Israel. He works as a science writer, specializing in physics, space, and technology. His articles have been published in  Elements ,  N+1 , and  AdvancedScienceNews .

'Immortal' stars at the Milky Way's center may have found an endless energy source, study suggests

Earth's upper atmosphere could hold a missing piece of the universe, new study hints

Horse domestication didn't happen the way we think it did

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Credit: Johns Hopkins University

Study inspired by curious 15-year-old could advance search for novel antibiotics

New bacteria found in raw honey could benefit the fight against legionnaires' disease and antibiotic resistance, according to new johns hopkins medicine research.

By Alexandria Carolan

Equipped with a suitcase full of honey, high school sophomore Carson Shin contacted university after university, hoping to work with expert biochemists to investigate the sticky substance's antimicrobial properties.

The only problem? Scientists seemed wary of collaborating with a 15-year-old.

Image caption: Carson Shin

Shin couldn't have predicted that, five years later, he would co-author a Johns Hopkins Medicine report showing that dormant and previously undescribed bacteria found in raw honey produce antibiotics that can kill the bacterial pathogen Legionella . The pathogen can be found in potable water and causes Legionnaires' disease, a life-threatening pneumonia that kills one in 10 people infected with it.

The published report not only offers a first step in the development of new antibiotics for Legionella , but has the potential to aid in the fight against antibiotic resistance, says senior author Tamara O'Connor , assistant professor of biological chemistry at Johns Hopkins University School of Medicine.

Shin reached out to O'Connor in the spring of 2019, beginning a summer internship with the professor that he hoped would uncover a novel antimicrobial property of honey.

"Carson showed tremendous initiative and was very inquisitive," O'Connor says. "It's exciting to have any student join the lab who demonstrates this level of intellectual engagement in science."

Initially, Shin and O'Connor exposed Legionella to raw, unpasteurized honey, to test whether the natural substance could kill the bacteria. Surprisingly, honey had little effect on Legionella . However, in the course of these experiments, they identified several different bacteria in the honey that, in response to Legionella , produced and secreted antibiotics that were lethal to the pathogen.

"We found the right conditions for the honey bacteria to thrive, allowing us to tap into a resource we didn't know was there," Shin says.

In nature, O'Connor says, "bacteria figure out ways to outcompete one another, which often involves releasing toxic molecules that kill their competitors." The honey bacteria Shin and O'Connor isolated "recognize Legionella as competition and launch a deadly response."

The honey bacteria were identified as members of the Bacillus and Lysinibacillus genera of bacteria. This is not surprising, O'Connor says, because bacilli produce spores that are protected from the antimicrobial properties of honey. These bacteria are commonly found in raw honey, explaining why it is recommended to eat only pasteurized honey, she says.

Upon sequencing the genomes of two of the bacterial isolates, strain AHB2 and strain AHB11 , the researchers identified them as members of the species Bacillus safensis . Previously, the ability for this group of bacteria to produce antibacterial molecules was not well-documented.

Further experiments revealed how specific the response of honey bacteria to Legionella was.

"Remarkably, the bacteria in honey only produce these antibacterial molecules in response to Legionella species, as none of the other bacterial pathogens we exposed them to elicited this response," O'Connor says.

Image caption: Tamara O'Connor

While other pathogens did not cause honey bacteria to produce these antibiotics, many were susceptible to them, O'Connor says. These results suggest antibacterial molecules produced by honey could target other harmful pathogens and could be used as broad-spectrum antibiotics. While these preliminary findings offer the identification of new antibacterial molecules, more research is needed to determine their potential for developing viable therapeutics, O'Connor says.

Antimicrobial resistance is one of the largest threats to global public health, contributing to nearly 5 million deaths in 2019, according to the World Health Organization—creating a dire need for the development of new antibiotics to treat bacterial infections.

Similar studies of the biowarfare between microorganisms have led scientists to identify many antimicrobial molecules, says O'Connor. The vast majority of antibiotics prescribed by physicians originate from natural products, she says.

"The ability to tap into these resources by identifying new bacteria and the conditions that cause them to produce antibacterial molecules is critical in the fight against antibiotic resistance," she says.

Young scientists like Shin are crucial to combat antibiotic resistance, O'Connor says.

"Carson exemplifies how the curiosity of an aspiring young scientist can lead to exciting new discoveries," she says.

Shin, who is beginning his senior year of college this fall at the University of Pennsylvania, said his experience at Johns Hopkins influenced his decision to study anthropology. Before reaching out to O'Connor, Shin had looked into raw honey's historic and ancient role in traditional medicines of the Egyptians, Greeks, and Islamic countries over thousands of years.

"Our research stems from studying culture. You can learn valuable information about medicine from cultures across the world and across time," Shin says.

The research was supported independently by the Department of Biological Chemistry and the Johns Hopkins University School of Medicine .

Posted in Health

Tagged antibiotics , department of biological chemistry , bacteria

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Rethinking Addiction as a Chronic Brain Disease

Some researchers argue that the roles of social environment and personal choice have to be considered in order to make progress in treating people addicted to drugs.

By Jan Hoffman

Qué comer para una vida larga y saludable

No hay ninguna fórmula mágica, pero algunos patrones de alimentación están más asociados a una vida más larga que otros.

By Alice Callahan

How to Eat for a Long and Healthy Life

There’s no one-size-fits-all approach, but certain dietary patterns are more associated with longer lives than others.

Dialysis May Prolong Life for Older Patients. But Not by Much.

In one recent study, the challenging regimen added 77 days of life after three years. Often, kidney disease can be managed in other ways.

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La República Democrática del Congo se enfrenta a la viruela símica sin vacunas, pruebas ni tratamientos

El país, que está en el centro de la emergencia de salud global, batalla hasta para diagnosticar casos y proporcionar los servicios médicos básicos.

By Stephanie Nolen

Eliyahu Rips, Who Claimed to Find Secret Codes in the Torah, Dies at 75

His work provided the basis for the worldwide best seller “The Bible Code,” but he later rejected the book as unscientific.

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James Bjorken, 90, Dies; Physicist Who Helped Prove That Quarks Exist

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An Obesity Drug Prevents Covid Deaths, Study Suggests

People taking Wegovy were not protected from infection. But in a large trial, their death rates were markedly lower, for reasons that are not clear.

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Imperiled by Volcanic Eruptions, Iceland Scoops Up Answers From the Deep

Earth scientists are working to determine the course of future lava flows in Iceland’s southwestern corner one bucketful at a time.

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Author of ‘White Fragility’ Faces Accusations of Plagiarism

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• Mackenzie Wildman 16 , PhD   ; 
• Stephen H Friend 2, 4 , MD, PhD  

1 4YouandMe, Seattle, WA, United States

2 Department of Psychiatry, University of Oxford, Oxford, United Kingdom

3 Crohn's & Colitis Foundation, New York, NY, United States

4 Section of Urology and Renal Transplantation, Virginia Mason Francisan Health, Seattle, WA, United States

5 MindMed Inc, New York, NY, United States

6 Tufts University School of Medicine, Boston, MA, United States

7 Department of Paediatrics, University of Toronto, Toronto, ON, Canada

8 Department of Pediatric Hematology/Oncology, Schneider Children's Medical Center of Israel, Petach-Tikva, Israel

9 Department of Pediatrics, University of Toronto, Toronto, ON, Canada

10 Gasteroentology Unit, Oxford University Hospitals NHS Foundation Trust and Biomedical Research Centre, Oxford, United Kingdom

11 The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, United States

12 Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States

13 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States

14 Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada

15 Evidation Health Inc, Santa Mateo, CA, United States

16 Sage Bionetworks, Seattle, WA, United States

Corresponding Author:

Sarah M Goodday, MSc, PhD

2901 3rd Ave

Seattle, WA, 98121

United States

Phone: 1 (206) 928 8243

Email: [email protected]

Background: Wearable digital health technologies and mobile apps (personal digital health technologies [DHTs]) hold great promise for transforming health research and care. However, engagement in personal DHT research is poor.

Objective: The objective of this paper is to describe how participant engagement techniques and different study designs affect participant adherence, retention, and overall engagement in research involving personal DHTs.

Methods: Quantitative and qualitative analysis of engagement factors are reported across 6 unique personal DHT research studies that adopted aspects of a participant-centric design. Study populations included (1) frontline health care workers; (2) a conception, pregnant, and postpartum population; (3) individuals with Crohn disease; (4) individuals with pancreatic cancer; (5) individuals with central nervous system tumors; and (6) families with a Li-Fraumeni syndrome affected member. All included studies involved the use of a study smartphone app that collected both daily and intermittent passive and active tasks, as well as using multiple wearable devices including smartwatches, smart rings, and smart scales. All studies included a variety of participant-centric engagement strategies centered on working with participants as co-designers and regular check-in phone calls to provide support over study participation. Overall retention, probability of staying in the study, and median adherence to study activities are reported.

Results: The median proportion of participants retained in the study across the 6 studies was 77.2% (IQR 72.6%-88%). The probability of staying in the study stayed above 80% for all studies during the first month of study participation and stayed above 50% for the entire active study period across all studies. Median adherence to study activities varied by study population. Severely ill cancer populations and postpartum mothers showed the lowest adherence to personal DHT research tasks, largely the result of physical, mental, and situational barriers. Except for the cancer and postpartum populations, median adherences for the Oura smart ring, Garmin, and Apple smartwatches were over 80% and 90%, respectively. Median adherence to the scheduled check-in calls was high across all but one cohort (50%, IQR 20%-75%: low-engagement cohort). Median adherence to study-related activities in this low-engagement cohort was lower than in all other included studies.

Conclusions: Participant-centric engagement strategies aid in participant retention and maintain good adherence in some populations. Primary barriers to engagement were participant burden (task fatigue and inconvenience), physical, mental, and situational barriers (unable to complete tasks), and low perceived benefit (lack of understanding of the value of personal DHTs). More population-specific tailoring of personal DHT designs is needed so that these new tools can be perceived as personally valuable to the end user.

Introduction

Wearable digital health technologies (DHTs) [ 1 , 2 ] and mobile apps facilitate the remote, real-world assessment of health including objective signs of disease that are typically confined to health care visits and health care provider interpretation. These specific categories of DHTs, herein referred to as “personal DHTs,” hold promise for transforming health research through the new ability to capture high-resolution, high-frequency, in-the-moment health-related multimodal information in decentralized ways. Through the provision of personal DHTs in clinical care, individuals could be better empowered to navigate their health outside the health care system with greater accessibility, agency, and accuracy than currently possible [ 1 , 2 ]. One of the largest challenges in the future of digital health that involves the use of personal DHTs is end-user engagement. While direct comparisons of engagement in personal DHT research are challenging due to the heterogeneous reporting of retention and adherence factors, and a lack of consensus on a definition of “engagement” [ 3 - 6 ], accumulating evidence supports that so far engagement in the use of personal DHTs has been poor. Specifically, retention in personal DHT research studies and the use of health-related apps is low across diverse populations and applications [ 7 - 9 ]. Further, there is evidence of attrition biases in personal DHT research resulting in insufficient representation of minority populations [ 7 ]. In addition to poor retention, personal DHT research studies have low adherence to completing active app-based tasks resulting in large amounts of missing data. This missing data problem results in challenges in artificial intelligence models from insufficient volumes of data to follow individual patterns, and limits app-based context “label” data. This “label” data is crucial for validating passively collected information from personal DHTs, particularly given the early state of the field and as the utility of certain approaches such as knowledge graphs and large language models emerge.

Several personal DHTs health research studies have started to surface [ 7 - 12 ], resulting in the identification of barriers to engagement. These barriers include technical problems with the technology and in collecting the data, usability, privacy concerns, and digital literacy. Many of these barriers point to a need to retain a human element in the research process, and to include an aspect of co-designing with end users. Emerging personal DHT research studies that show better engagement retain some form of “human-in-the-loop” (regular contact with research staff) and co-design or end-user approach [ 11 - 15 ]. Among these studies, retention rates of 80% and higher have been observed, while average adherence to wearable device use and daily app surveys have been shown to be >90% and 70%, respectively [ 11 - 15 ].

The promise of digital health rests on the assumption that end users can be engaged in the long-term use of personal DHTs for health monitoring, yet this remains to be seen among most existing research applications. There have been increasing international calls for the inclusion of patients in the design and conduct of health research [ 16 - 18 ], and this seems particularly relevant for digital health research where the patient is the end user of these new remote tools. In this paper, we report on engagement across 6 unique personal DHT health research studies that adopted different aspects of a participant-centric design, but each with distinct population and design features. The objective is to describe how participant engagement techniques and different personal DHT designs affect participant adherence, retention, and overall engagement in personal DHT health research.

Study Design

In total, 6 personal DHT research studies are included in this quantitative and qualitative analysis of engagement that span diverse populations including a frontline health care population (the stress and recovery in frontline health care workers study) [ 11 ]; a conception, pregnancy, and postpartum population (Better Understanding the Metamorphosis of Pregnancy [BUMP] study) [ 19 ]; and populations with different diseases including Crohn disease (stress in Crohn: forecasting symptom transitions study), Li-Fraumeni syndrome (stress and LFS: a feasibility study of wearable technologies to detect stress in families with LFS), and patients with pancreatic and central nervous system (CNS) tumors (help enable real-time observations [HERO] in pancreatic [PANC] and CNS tumors studies) [ 20 ].

All of these studies were conducted by 4YouandMe—a US-based nonprofit (charitable) organization. 4YouandMe specializes in open-source research into the application of personal DHTs for health and wellness [ 20 ]. 4YouandMe has a particular focus on leveraging personal DHTs to empower the patient in navigating their unique disease or life transitional period. These 6 studies were included in this analysis as they reflect all of the completed studies by 4YouandMe at the time of this analysis. Characteristics of these studies can be found in Table 1 and additional methodological detail can be found in Multimedia Appendix 1 . All studies involved the use of a bespoke study smartphone app built by 4YouandMe and the use of the Oura smart ring, the Garmin smartwatch, the Apple smartwatch, an Empatica smartwatch, and the Bodyport Cardiac Scale. Details of these devices can be found in Multimedia Appendix 2 ).

a MSSM: Mount Sinai School of Medicine.

b HERO-CNS: help enable real-time observations—central nervous system.

c CNS: central nervous system.

d HERO-PANC: help enable real-time observations—pancreatic cancer.

e n=24, 2 unknown.

f Until withdrawal, progression, death, or study completion (October 31, 2022).

g LFS: Li-Fraumeni syndrome.

h BUMP: Better Understanding the Metamorphosis of Pregnancy.

i BUMP-C: Better Understanding the Metamorphosis of Pregnancy—Conception.

Ethical Considerations

All included studies were approved by the local institutional research ethics boards (REB) at their local sites ( Multimedia Appendix 1 ): stress and recovery in frontline health care workers study (institutional review board [IRB], Advarra [4UCOVID1901, Pro00043205]), BUMP study (IRB Advarra Pro00047893), stress in Crohn (Oxford site: Hampshire-A IRAS ID: 269286, Mount Sinai School of Medicine [MSSM] site: IRB of MSSM: GCO 19-1543 | IRB-19-02298), stress and LFS (Sick Kids: REB: 1000072240), HERO-CNS (John Hopkins Medicine IRB IRB00253818), and HERO-PANC (University Hospital Network REB: 20-5211).

Statistical Analysis

Definitions of adherence in digital health research studies are heterogeneous [ 3 - 6 ]. Consistent criteria for adherence across all included studies were attempted. While many different wearable features could be used as the basis for the use of the device, features that were most reliably monitored were selected. For studies using the Oura smart ring, daily adherence was defined as at least one sleep data event present for the prior night. The Oura ring was only expected to be worn at night for many of the included studies, which is why sleep data were used as the indicator for adherence. For studies using the Garmin smartwatch, daily adherence was defined as step data present for that day. For the Empatica smartwatch, daily adherence was defined as at least one data event (worn properly in a day). Adherence to the Bodyport Cardiac Scale was defined as the proportion of days where a weight event was present divided by the total number of expected follow-up days. Adherence to in-app task completion was defined as the proportion of tasks completed when prompted in the app divided by the total number of tasks that should have been completed over study follow-up. For example, all included studies had a daily survey. In a study with a minimum of 4 months of follow-up expected from participants, the total number of expected daily surveys is approximately 120. For a weekly app survey, the total number of expected surveys for a 4-month study follow-up would be 16. Adherence to biweekly check-in calls was defined as the proportion of calls completed divided by the total number of expected calls over study follow-up. Medians and ranges are described since the adherence distributions were nonnormally distributed. All adherence estimations were performed only among retained participants.

Differences in adherence and retention by sociodemographic characteristics were estimated using χ 2 , Fisher exact, Mann-Whitney U , and ANOVA tests where appropriate among studies that have sufficient sample sizes (stress and recovery, BUMP, and stress in Crohn). Survival probabilities using the Kaplan-Meier approach were calculated to display the probability of retention over the course of each included study. Retention (total proportion of participants completing the study among all enrolled) is also reported. Additional information on how retention was calculated for each unique study can be found in Multimedia Appendix 3 .

Description of Included Studies

Study design characteristics of all studies are described in Table 1 . All studies included the use of at least one wearable device plus a study app that involved daily, as well as intermittent surveys (daily question prompts, validated questionnaires) and active tasks (cognitive active or physical function tasks [eg, walk tests], video diaries). In all included studies, participants were required to use their own Android or iPhone smartphone for study activities. Recruitment mechanisms differed across studies with some including remote recruitment through digital advertisements on social media, professional organizations and newsletters, and patient portals (stress and recovery, and BUMP), while others recruited patients in-person through specialty clinics (stress in Crohn, HERO studies, and stress and LFS). The daily burden of app active tasks across studies ranged from 2 to 7 minutes. Study follow-up periods across studies ranged from 4 to 18 months. Across all studies except the stress and LFS study, participants were offered to keep some of the study wearable devices (most often the ring and the watch). Further, 2 studies included the option for modest financial compensation (BUMP and stress in Crohn).

All studies included an engagement strategy that centered around a biweekly phone check-in with a consistent engagement specialist that served the purpose of supporting participants, helping them with onboarding, resolving potential technological problems, and discussing and collecting study experience feedback. Additionally, all included studies implemented different strategies that focused on working with participants as co-designers. These strategies included making app changes that were driven by direct participant feedback during active follow-up, offering a “your data” section in the app that allowed participants to track key symptoms over time, hosting optional investigator-participant Zoom calls where participants could meet the study team, receive study updates, preliminary results, and could offer more feedback, and inviting participants to contribute to and be listed as coauthors on published work.

Adherence by Study Population

Median adherence in engagement phone check-in calls, wearable device use, daily app survey completion, and in-app active tasks can be found in Table 2 . Median adherence varied across study populations. The stress in Crohn–MSSM site had a lower adherence on the engagement check-in calls (50%) compared to other studies, many of which had 100% adherence on these calls ( Table 2 ). This study site is herein referred to as the low-engagement cohort. In this low-engagement cohort, median adherence to completing daily app surveys, to wearing the Empatica smartwatch, and to using the Bodyport Cardiac Scale were lower than all other study cohorts that included these studies’ activities (except the BUMP-postpartum cohort). Further, median adherence to using the Oura smart ring was lower in the low-engagement cohort compared to other cohorts except for the postpartum and severely ill cancer populations.

The HERO studies included the most severely ill participants including patients with active diagnoses of CNS and pancreatic tumors. Some HERO participants were undergoing chemotherapy, some had therapy-related complications, some had infections, and some had progressive, life-threatening tumor growth. While the total number of participants in these studies was low, these studies showed low adherence on the daily survey (<55%) and wearable device use (<65% HERO-CNS only). Interestingly, HERO-PANC participants exhibited high wearable device use median adherence (83.3%, IQR 51%-93.2%, Oura and 95.5%, IQR 75.2%-99.2%, Garmin), despite the health status of this population. Further, median adherence to in-app cognitive active tasks was higher among the HERO studies compared to most other studies. Engagement check-in call adherence was also high in the HERO studies. Among the BUMP postpartum cohort, there was consistently lower adherence on all study tasks except for the engagement check-in calls compared to other studies, particularly in comparison to the BUMP prenatal cohort. Specifically, median adherence to the Oura ring, Garmin smartwatch use, and the Bodyport Cardiac Scale in the BUMP-prenatal cohort compared to the BUMP postpartum cohort dropped from 87.2% (IQR 68.7%-96.7%) to 55% (IQR 5.5%-83.7%), 96.7% (IQR 82.9%-100%) to 62.5% (IQR 12.3%-96.4%), and 74.7% (IQR 52%-87.3%) to 33.1% (IQR 8.9%-67.7%), respectively ( Table 2 ).

a BUMP-C: Better Understanding the Metamorphosis of Pregnancy—Conception.

b BUMP: Better Understanding the Metamorphosis of Pregnancy.

c BUMP-POST: Better Understanding the Metamorphosis of Pregnancy—Postpartum.

d SINC: stress in Crohn.

e MSSM: Mount Sinai School of Medicine.

f HERO-CNS: help enable real-time observations—central nervous system.

g HERO-PANC: help enable real-time observations—pancreatic cancer.

h LFS: Li-Fraumeni syndrome.

i ES: engagement specialist.

j Not available.

k EBT: emotional bias test.

Adherence by Study Activity

There were differences in adherence rates across different study activities. Adherence to wearable device use was consistently higher across studies compared to in-app activities, which is not surprising given the passive nature of these devices. Excluding the postpartum and HERO-CNS study, median adherence to Oura ring use was >80% across all studies, and as high as 99% (IQR 94.9%-99.6%; stress in Crohn-Oxford site; Table 2 ). There were also differences in adherence across specific wearable devices. Garmin and Apple smartwatch adherence was >95% in BUMP pregnant individuals and HERO-PANC participants, while median adherence for the Empatica Watch was lower among the studies that used this device (stress in Crohn-Oxford, 72.5%, IQR 37.1%-96.8%; stress in Crohn-MSSM, low-engagement cohort, 26%, IQR 6.2%-64.1%; and stress in LFS, 86.8%, IQR 0.7%-0.9%). Median adherence to the Bodyport Cardiac Scale was 74.7% (IQR 52%-87.3%) among BUMP pregnant individuals and 79.5% (IQR 52.7%-88.4%) in HERO-PANC participants ( Table 2 ). Excluding the postpartum and HERO study populations and the low-engagement cohort, in-app daily survey adherence was >60% for all studies ( Table 2 ). Finally, adherence to in-app active tasks was lower in general compared to other activities such as wearable device use or in-app surveys. Tasks that involved walking (gait and walk task) or speaking (video diaries) showed lower adherence compared to other active tasks (eg, cognitive and emotional bias tasks; Table 2 ).

Adherence by Study Recruitment and Engagement Strategy

There did not appear to be any meaningful difference in median adherence rates across study activities by study recruitment methods (in-clinic vs remote) or follow-up time. Further, 2 studies that included modest financial compensation in addition to engagement strategies showed higher adherence rates compared to some of the other studies (ie, BUMP and stress in Crohn), but the impact of compensation is difficult to disentangle from other study characteristics such as population differences, and these studies did not show superior adherence rates compared to the stress and recovery study that did not offer financial compensation.

The median proportion of participants retained in the study across the 6 studies was 77.2% (IQR 72.6%-88%; Table 3 ). The probability of staying in the study stayed above 80% for all studies during the first month of study participation and stayed above 50% for the entire active study period across all studies ( Multimedia Appendix 4 ).

b Only includes participants who were enrolled in the Better Understanding the Metamorphosis of Pregnancy—Conception-specific app.

c BUMP: Better Understanding the Metamorphosis of Pregnancy.

d MSSM: Mount Sinai School of Medicine.

e HERO-CNS: help enable real-time observations—central nervous system.

f HERO-PANC: help enable real-time observations—pancreatic cancer.

g Help enable real-time observations—pancreatic cancer has unique factors to consider when interpreting the proportion retained until study completion, since the study aimed to monitor patients until they developed progressive disease or died, or the study end date (October 31, 2022; see Multimedia Appendix 3 ).

Adherence and Retention by Participant Sociodemographic Characteristics

Median adherence for the Oura smart ring, a smartwatch (Garmin, Apple, and Empatica), and the Bodyport Cardiac Scale was lower among younger participants compared to older participants across most studies ( Multimedia Appendix 5 ). Specifically, Oura smart ring adherence was significantly lower in those aged 18-25 years compared to those aged ≥26 years in the BUMP study ( P =.03) and stress in Crohn-MSSM studies ( P =.02), and was lower in the BUMP-C and stress and recover studies, but this difference was not statistically significant at P =.59 and P =.08, respectively. Median adherence for Apple smartwatch use was significantly lower in those aged 18-25 years compared to those aged ≥26 years in the BUMP study ( P =.02), while median adherence for Garmin smartwatch use was lower but not statistically significant ( P =.06). Median adherence for the Bodyport Cardiac Scale was significantly lower in those aged 18-25 years compared to those aged ≥26 years in BUMP ( P <.005) and stress in Crohn-MSSM ( P <.006).

In the BUMP study, Black or African American ethnicity had significantly higher median adherence to completing the in-app daily survey compared to other race or ethnicity groups ( P =.01). This trend was observed in the stress and recovery study ( P =.07) and the stress in Crohn-MSSM study ( P =.24), although the difference was not statistically significant. In contrast, median adherence to Oura smart ring, smartwatch, and Bodyport Cardiac Scale use was lower among Black or African American individuals compared to other race or ethnicity groups, although these differences were not statistically significant ( Multimedia Appendix 5 ).

Retention did not significantly differ by age group or gender ( Multimedia Appendix 6 ).

Retention likelihood was significantly different by race or ethnicity groups in BUMP-C ( P <.001) and BUMP ( P= .001). Specifically, participants of White ethnicity were more likely to stay in the study in both BUMP-C and BUMP, while participants reporting their race or ethnicity as either unknown or not reporting this item were less likely to be retained ( Multimedia Appendix 6 ).

Barriers to Engagement (Qualitative Synthesis of Participant Feedback)

Figure 1 describes key themes that impacted participant retention, adherence, and overall engagement that cut across all included studies. These themes include participant burden and forgetfulness, digital literacy, physical and mental barriers, personal and altruistic benefits, and privacy and confidentiality. Qualitative feedback from participants, research staff, and investigators across these 5 themes is summarized in Multimedia Appendix 7 . The top three barriers to engagement in active study tasks were (1) participant burden and in particular fatigue with the repetitiveness of tasks; (2) physical or mental and situational barriers that prevented the ability to complete tasks; and (3) personal and altruistic benefit, namely the perception that the use of the personal DHTs was not personally useful for a health benefit or a lack of understanding as to why and how certain features (eg, heart rate variability) could be useful to track for health benefit. Qualitative feedback from participants in the 2 cohorts demonstrating lower adherence (HERO-PANC and BUMP post partum) suggested that while participants were highly engaged, they were either too ill, distracted, or tired to complete many of the study activities while navigating a serious illness or the early postpartum period.

Principal Findings

Evidence across 6 unique and diverse studies involving the longitudinal use of personal DHTs supports that participant-centric engagement strategies aid in participant retention and maintaining good adherence in some populations. These strategies centered around (1) human contact with an engagement specialist as often as every 2 weeks, (2) investigator-participant meetings during active study follow-up, (3) offering returned symptom data in the app, (4) inviting participants to contribute as coauthors in published work, and (5) real-time modifications to the study app based on participant feedback.

In the majority of included studies, the probability of staying in the study stayed above 90% for the first month and stayed above 50% for active study periods for all studies. Lower retention or adherence was observed among studies that included a severely ill cancer population and a postpartum population. Barriers to participation in these cohorts were largely the result of physical and situational roadblocks. Excluding studies of a severely ill and postpartum population and the low-engagement cohort in the stress in Crohn study, adherence to Oura smart ring and Garmin smartwatch use was 80% and as high as 99% in some cohorts, while adherence to the Bodyport Cardiac Scale was 75% in a pregnant population. This supports that different populations can successfully be engaged in the use of active app assessments and wearable devices in the long term with adequate support.

Retention and adherence rates observed in these studies are higher than typically reported by other personal DHT research studies [ 7 - 9 , 12 , 13 , 21 ]. For example, a review of 8 large app-based DHT research studies in the United States reported that the probability of staying in the study dropped to or below 50% after the first 4 weeks of participation for all included studies [ 7 ]. Further, across the 8 included studies in this review, >50% of participants did not engage with the app for at least 7 days. Another large app-based study in the United States, the Warfighter Analytics Using Smartphones for Health study that collected daily active and passive app data reported a median retention of 45.2% (38/84 days), while the probability of staying in the study hit 50% at approximately 5.5 weeks [ 10 ]. A large app-based study in the United Kingdom (cloudy with a chance of pain study) involving daily active app assessments reported that 64% of participants fell into the low engagement or no engagement categories after baseline [ 12 ]. The RADAR study [ 14 ], a multinational study involving active and passive assessments from an app, and a Fitbit reported comparable retention results among participants with major depression to those reported here. This study reported a retention rate of 54.6% for 43 weeks of study participation; however, the probability of staying in the study stayed above 75% for the first several months of participation (~6 months). While the active app assessments in this study only included assessments every 2 weeks as opposed to daily assessments, this study additionally included aspects of a participant-centric design, which may have contributed to the higher reported retention [ 15 ].

Taken together, in comparison to other published personal DHT research studies, the 6 studies included in this paper reflect higher levels of engagement. Importantly, the included studies in this analysis involved high burden designs in comparison to other studies that request, for example, weekly or biweekly active tasks of participants [ 14 ] or only involve the use of a smartwatch. Specifically, across the included studies here, participants were expected to complete on average 4.6 (SD 1.62) minutes a day of app activities in addition to continuously using multiple wearable devices.

While different variations of participant-centric strategies were used across the 6 included studies, a key common feature was a biweekly check-in call with an engagement specialist. These calls served the purpose of providing support and building rapport with participants, working through onboarding and technological issues with study devices, tracking adherence, and receiving study-related feedback from participants. Numerous challenges arise in the conduct of remote, personal DHT research, and without frequent check-in and semiregular data monitoring by research staff, knowledge of these issues is a black box. The most significant drop in retention in personal DHT research studies tends to be during the first few weeks of participation [ 7 ]. These early onboarding weeks are crucial in working with participants to ensure they can get into a rhythm of participation. The passive sensing nature of personal DHTs has much potential to inform new objective measures of health, however, are not always intuitively understood as personally important for unique diseases (eg, heart rate variability or phone screen time). Personal DHT studies allow for “light touch” research approaches that enable data collection without traditional research coordinator contact, but this may come with a cost that inadvertently creates a less engaging study environment for participants and limits the opportunity to help participants understand the value in their participation. Of the included 6 studies, 1 cohort had much lower engagement on the check-in calls (50% adherence) compared to other included studies and, in turn, consistently demonstrated lower adherence to study-related activities. Still, even with extensive engagement designs, populations that had physical, mental, and situational barriers to study task completion (ie, severely ill, postpartum mothers) showed lower adherence to wearable device use and active smartphone tasks compared to other study populations. Top reported barriers to engagement included participant burden, physical, mental, and situational barriers, and low perceived value of personal DHTs for health care. These engagement barriers have been reported in previous literature [ 8 , 9 ] relating to DHT research and in the use of DHT interventions. However, the conveyed importance of the perceived value of the approach among participants in the current analysis is noteworthy. Given the foreign nature of personal DHTs for many individuals, particularly older populations, further work is needed to co-design and educate end users on the potential value of self-monitoring unique health-related data.

Irrespective of the engagement approach, adherence to in-app surveys and tasks was lower than wearable device use, which is not surprising given the higher burden related to in-app activities. The self-reported information captured from frequent or momentary in-app assessments is extremely valuable as context information. This context information or “label” data is useful for validating objectively captured information, yet remains the most difficult to capture in sufficient detail. Further, certain in-app activity adherences were consistently lower than others. Namely, activities that required the user to be active (walk in a straight line or complete a video diary) were low across studies. Still, adherence to daily in-app surveys was >60% for all studies excluding the postpartum and HERO study populations.

Limitations

This quantitative and qualitative analysis compared observational data across different digital health studies. However, no true comparison cohort that did not include engagement strategies was included. Therefore, the inferred casualty of participant check-ins with engagement specialists on retention and adherence rates cannot be not concluded. We are formally testing whether the biweekly check-in significantly increases adherence and retention in an ongoing study with an appropriate comparison arm without check-in support (NCT05753605). One of the included studies (stress and recovery) was conducted during the early 2020 COVID-19 pandemic. There is some evidence that engagement in research was higher during the early pandemic time periods [ 22 ]. It cannot be ruled out that the higher observed retention and adherence in this study compared to others was not due to this potential time period bias. The stress in the Crohn-Oxford site included a population of patients some of whom were already engaged in the use of web-based monitoring of symptoms. In turn, this could have contributed to the high retention and higher adherence observed at this site compared to the other stress in the Crohn-MSSM site. The results presented on barriers to engagement were primarily qualitative and collected from conversations with participants, research staff, and investigators across studies.

Conclusions

Globally, mobile apps are used for a variety of purposes in everyday life, while the use of smartwatches for activity monitoring is gaining increasing popularity. However, the use of these tools for health remains a challenge. These findings support that human support via phone and other participant-centric engagement strategies centered on giving back to participants and working with them as co-designers can support sufficient retention and adherence in personal DHT research across diverse populations. This has implications for the utility and potential necessity of a digital support worker in digital health care, as highlighted by others [ 23 ]. A power of personal DHTs is enabling the patient to be in control of their health through self-monitoring, but this new role comes with a responsibility. This important shift in role from doctor to patient outlines how crucial it is to include patients in the early design phase of personal DHT health research. Further work is needed to inform app designs that support habitual forming activities around task completion so that app-related activities become a part of participants’ daily routine and are perceived as personally valuable.

Acknowledgments

The stress and recovery study was supported in part by the Bill & Melinda Gates Foundation (INV-016651). The stress in Crohn study was funded by the Leona M. and Harry B. Helmsley Charitable Trust (1911-03376). The help enable real-time observation (HERO)–central nervus system study was funded by the Mark Foundation for Cancer Research through an ASPIRE award (19-024-ASP). The HERO–pancreatic cancer study was funded by the Mark Foundation for Cancer Research through an ASPIRE award (19-024-ASP), Pancreatic Cancer Canada, the Princess Margaret Cancer Foundation, and 4YouandMe. The Better Understanding the Metamorphosis of Pregnancy (BUMP) study was funded by 4YouandMe and Sema4 along with supplemental in-kind contributions from coalition partners (Evidation Health, Vector Institute, Cambridge Cognition, and Bodyport). The stress and LFS study was funded by in-kind contributions from 4YouandMe, SickKids Hospital, and the Vector Institute.

Conflicts of Interest

CB is a consultant for Depuy Synthes, Bionaut Labs, Galectin Therapeutics, Haystack Oncology, and Privo Technologies. CB is a cofounder of Belay Diagnostics and OrisDx. DRK is an officer, employee, and shareholder of MindMed; a consultant at Tempus, Nightware, and Limitless; and board member of Sonara. RPH is an advisory board member at Bristol Meyers Squibb. MH is an advisory board member for Servier, AnHeart, and Bayer; steering committee member for Novartis; honoraria from Novartis; data safety monitoring committee member for Advarra and Parexel. RG received a graduate scholarship from Pfizer and provided consulting or advisory roles for Astrazeneca, Tempus, Eisai, Incyte, Knight Therapeutics, Guardant Health, and Ipsen. The others declare no conflicts of interest.

Study descriptions.

Study wearable devices.

Retention calculations.

Probability of retaining in the study across studies.

Median adherence to study activities stratified by sociodemographic characteristics.

Sociodemographic differences in participants who were retained versus not retained.

Qualitative feedback from participants, research staff, and investigators surrounding barriers to engagement in digital health research, summarized across 6 unique studies.

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Abbreviations

Edited by G Eysenbach, T de Azevedo Cardoso; submitted 06.03.24; peer-reviewed by C Godoy Jr; comments to author 05.04.24; revised version received 12.04.24; accepted 29.05.24; published 03.09.24.

©Sarah M Goodday, Emma Karlin, Alexa Brooks, Carol Chapman, Christiana Harry, Nelly Lugo, Shannon Peabody, Shazia Rangwala, Ella Swanson, Jonell Tempero, Robin Yang, Daniel R Karlin, Ron Rabinowicz, David Malkin, Simon Travis, Alissa Walsh, Robert P Hirten, Bruce E Sands, Chetan Bettegowda, Matthias Holdhoff, Jessica Wollett, Kelly Szajna, Kallan Dirmeyer, Anna Dodd, Shawn Hutchinson, Stephanie Ramotar, Robert C Grant, Adrien Boch, Mackenzie Wildman, Stephen H Friend. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 03.09.2024.

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Deep Learning Models for Lung Nodule Segmentation: A Comparative Study

• Original Article
• Published: 03 September 2024

Cite this article

• Aliya Orazalina 2 ,
• Heechul Yoon   ORCID: orcid.org/0000-0002-9328-5900 1 ,
• Sang-II Choi 2 &
• Seokhyun Yoon 1  

Lung nodule detection is clinically crucial but challenging and time-consuming. The development of automated segmentation approaches could be helpful. To assess the capability of deep learning methods for lung diagnosis, this paper compares recent deep learning models and evaluates their performance. We implemented several preprocessing steps, including windowing, thresholding, and resizing, to improve the image quality, adjust the image dimension suitable for the network, and focus on specific areas of interest within an image. The evaluation was conducted on the Lung Image Database Consortium (LIDC) dataset using Dice similarity coefficient (DSC) and Hausdorff distance (HD) metrics with model complexity parameters for a multifaceted comparison of the models. The experiments showed that the highest accuracy among the five chosen models (97.80% DSC and 1.29 HD) was reached by the Connected-UNets model, which also has the highest computational complexity. In this paper, we quantitatively evaluated and compared 5 deep learning models namely Salient Attention UNet, Connected-UNets, DDANet, UTNet, and EdgeNeXt. The evidence-based overview of current deep learning achievements for the clinical community investigated in this study can be useful to the research community in developing a new model and, thus, designing computer-aided detection and diagnosis (CAD) systems.

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Acknowledgements

This research was supported by the National Research Foundation of Korea grant funded by the Korea government (MSIT) (NRF-2022R1C1C1012107). This research was partially supported by the Institute of Information and communications Technology Planning and Evaluation (IITP) grant funded by the Korea government (MSIT) (No. RS-2022-II220101). This research was also partially supported by the Technology Innovation Program (No. 20022442 and No. 20024893) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea).

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Orazalina, A., Yoon, H., Choi, SI. et al. Deep Learning Models for Lung Nodule Segmentation: A Comparative Study. J. Electr. Eng. Technol. (2024). https://doi.org/10.1007/s42835-024-02032-1

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DOI : https://doi.org/10.1007/s42835-024-02032-1

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Recent developments in cancer research: Expectations for a new remedy

1 Department of Surgery and Science, Kyushu University, Fukuoka Japan

Qingjiang Hu

Yuta kasagi, masaki mori.

Cancer research has made remarkable progress and new discoveries are beginning to be made. For example, the discovery of immune checkpoint inhibition mechanisms in cancer cells has led to the development of immune checkpoint inhibitors that have benefited many cancer patients. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiome, immunotherapy. and organoids. Exosomes research will lead to further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods. Microbiome are important in understanding the disease. Immunotherapy is the fourth treatment in cancer therapy. Organoid biology will further develop with a goal of translating the research into personalized therapy. These research areas may result in the creation of new cancer treatments in the future.

Cancer research has made remarkable progress and new discoveries are beginning to be made. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiomes, immunotherapy, and organoids.

1. INTRODUCTION

The cancer research field has developed significantly through use of new equipment and technology. One example of new technology is Next‐Generation Sequencing (NGS). Also known as high‐throughput sequencing, NGS is the catch‐all term used to describe a number of different modern nucleic acid sequencing technologies. These methods allow for much quicker and cheaper sequencing of DNA and RNA compared with the previously used Sanger sequencing, and as such have revolutionized the study of genomics and molecular biology. NGS also allows for easier detection of mutations in cancer samples, leading to development of many new agents that can be used to treat patients. For example, if the RAS gene status is detected as wild type in a colorectal cancer patient, then an anti‐EGFR antibody, such as cetuximab or panitumumab, can be used for treatment.

A liquid biopsy, also known as fluid biopsy or fluid phase biopsy, is the sampling and analysis of non‐solid biological tissue, primarily blood. 1 It is being used as a novel way to detect cancer. Like a traditional biopsy, this type of technique is mainly used as a diagnostic and monitoring tool for diseases, and also has the added benefit of being largely noninvasive. Therefore, liquid biopsies can be performed more frequently, allowing for better tracking of tumors and mutations over a duration of time. This technique may also be used to validate the effectiveness of a cancer treatment drug by taking multiple liquid biopsy samples in the span of a few weeks. It may also prove to be beneficial for monitoring relapse in patients after treatment.

Novel devices and drugs have also been developed and used for cancer treatment. For surgery procedures, robotic‐assisted laparoscopic surgery has evolved and made it possible to visualize the fine movement of the forceps in three dimensions. This method is now used in esophageal, gastric, and rectal cancer surgeries in Japan. 2 , 3 , 4

Recently, immunotherapy became an additional method for treating cancer patients. The discovery of the immune checkpoint by Dr Honjo led to the development of immune checkpoint inhibitors. 5 Despite these developments, gastrointestinal cancers are still a major problem in need of new treatment methods. In this review, we introduce and describe four new areas of cancer research that may contribute to cancer treatment in the future: exosomes, microbiome, immunotherapy, and organoids.

2. AN APPLICATION OF EXOSOME RESEARCH IN CANCER THERAPY

An exosome is a small particle that is secreted by cells. Its size can range from 50 to 150 nm and has a surface consisting of proteins and lipids that originate from the cell membrane. Additionally, proteins and nucleic acids, such as DNA, microRNAs, and mRNAs, can be found inside the exosome as its “cargo.” 6 Recently, many researchers have discovered that exosomes are involved in the mechanisms of various diseases. As mentioned above, various functional compounds, such as microRNAs, mRNAs, and proteins, can be contained within exosomes. 7 , 8 Many cells use secretion of exosomes to communicate with one another, and these exosomes can even reach distant cells. Cancer cells can also secrete exosomes that contain molecules beneficial to cancer growth. For example, microRNAs found in cancer exosomes can modulate gene expression to induce angiogenesis in the tumor microenvironment, which supports metastasis. 9 Exosomes released from cancer cells can also reportedly break the blood‐brain barrier, which makes it contribute to brain metastasis. 10 , 11 Cancer cells themselves are similarly affected by the exosomes secreted by the surrounding normal cells. 12 In one case, the exosomes secreted by bone marrow‐delivered mesenchymal stem cells can force cancer cells into a dormant state. 13 These dormant cancer cells become resistant to chemotherapy and are involved in long‐term disease recurrence. Thus, exosomes are deeply involved in cancer proliferation, invasion, and metastasis, as well as in the formation of the tumor microenvironment and pre‐metastatic niche. 13 Further research on cancer‐related exosomes is ongoing.

Knowledge of exosomes can be applied to cancer treatment. If the secretion of exosomes from cancer cells can be prevented, then signal transduction supporting the formation of the tumor microenvironment and pre‐metastatic niche can be blocked. Work focusing on the removal of cancer exosomes is now ongoing. 14

Exosomes can also be utilized for cancer diagnosis. Exosomes secreted by many cell types are found in various body fluids, such as blood and urine. Capturing and analyzing exosomes from cancer cells can be used to detect the presence of disease. 15 Obtaining blood or urine from patients is not very invasive or painful. Since many molecules, such as various proteins, DNA, and microRNAs, can be found in exosomes from normal cells, it is important to distinguish them from cancer‐related ones. If exosomes are to be used for cancer diagnosis, then specific biomarkers need to be discovered. Additionally, the development of a method to detect these exosomes must be done. Currently, exosome detection methods for exosomes abundantly found in the serum of colorectal and pancreatic cancer patients, as well as exosomes found in the urine of bladder cancer patients, are being developed. 16 , 17 Thus, further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods, is significantly affected by exosome research.

3. MICROBIOME IN CANCER RESEARCH

A large number of microorganisms inhabit the human body. These microorganisms include bacteria, viruses, and fungi. Among them, bacteria have the most important relationship with the human body. Bacteria can live anywhere within the human body, including the digestive tract, respiratory system, and oral cavity. 18 , 19 , 20 In particular, bacteria in the digestive tract are rich in type and number, 21 with possibly 1000 types and more than 100 trillion individual bacterial cells present. 22 , 23 The overall population of various bacteria found in the human intestine is referred to as the “intestinal flora.” Recently, the terms “microbiota” or “microbiome” have also been widely used.

Recent advancements with NGS have led to a much more precise understanding of the intestinal microbiome. 24 The bacteria in the human microbiome mainly belong to four phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteri. Of these, Firmicutes and Bacteroidetes are the most dominant species. It is reported that microbiome vary depending on age and race. 25 , 26 Dysbiosis is a condition in which the diversity of the microbiome is reduced. Dysbiosis is reportedly involved in various diseases such as inflammatory bowel disease, colorectal cancer, obesity, diabetes, and allergic diseases. 27 , 28 , 29 For example, bacteria such as Atopobium parvulum and Actinomyces odontolyticus increase in number during the early stages of colorectal cancer (adenomas or intramucosal cancers) and decrease in number during cancer progression. 30 This suggests that a specific microbiome is associated with early stages of colorectal cancer development, which may be useful knowledge for early cancer detection.

Various studies have also been conducted to elucidate the relationship between the microbiome and the human immune system. 31 The IgA antibody, which is one of the most important elements in the intestinal immune system, is believed to play a role in the elimination of pathogens and maintenance of the intestinal environment. The IgA antibody recognizes, eliminates, and neutralizes pathogenic bacteria and toxins. It also maintains a symbiotic relationship by recognizing and binding to the normal microbiome of the host. 32 Mice lacking a microbiome have reduced production of the IgA antibody. A microbiome is required for IgA antibody differentiation. Recent studies have identified W27IgA antibodies that have the ability to bind to various bacteria. 33 Oral administration of a W27IgA antibody to enteritis model mice suppressed enteritis by altering the microbiome. This W27IgA antibody can recognize a part of the amino acid sequence of serine hydroxymethyl transferase, which is a metabolic enzyme involved in bacterial growth. The W27IgA antibody can suppress the growth of E coli by binding to them. However, the W27IgA antibody does not bind to bacteria that suppress enteritis, such as bifidobacteria and lactic acid bacteria. 33 Thus, the microbiome is deeply involved in human intestinal immunity. Recently, it is having been established that the microbiome is not only involved in intestinal immunity, but also in the systemic immune system.

As the analysis of the microbiome progresses, the pathophysiology of various diseases, such as cancers, and its relationship with the regulatory function of the human immune system will be further elucidated. It has been demonstrated that F nucleatum plays a role in the development and progression of colon adenomas and colorectal cancer. It is also related to lymph node metastases and distant metastasis. 34 , 35 Also, microbiome is associated with hepatocellular carcinoma. 36 Studying microbiome will give us some clue in the development and remedy for gastrointestinal cancers (Table  1 ).

Gastrointestinal cancer and their related microbiome

4. THE RISE OF IMMUNOTHERAPY IN CANCER TREATMENT

For many years, surgery, chemotherapy, and radiation therapy were the main methods of cancer treatment. In addition to these therapies, immunotherapy has recently attracted great attention worldwide (Table  2 ). 37 , 38 Under normal circumstances, a cancer antigen will activate the patient's immune system to attack the cancer cells. However, sometimes the immune system does not recognize the cancer cells as non‐self, or it simply fails to attack them. This can result in the development and progression of cancer.

Immune checkpoint inhibitors

Although therapies that activate the immune system against cancer cells have been studied for a long time, the use of the patient's own immune system for cancer treatment was not established. Recently, the effectiveness of both immune checkpoint inhibition therapy and chimeric antigen receptor (CAR)‐T cell therapy has proved to be promising. 39 , 40 Immunotherapy has moved to the forefront of cancer treatment strategies.

There are two major reasons why proving the efficacy of cancer immunotherapies was difficult for some time. First, cancer immunity is strongly suppressed. Signal transduction from immune checkpoint compounds, such as PD‐1 and CTLA4, strongly inhibits cytotoxic T cells (CTLs). 38 This checkpoint mechanism can prevent the immune system from attacking cancer cells. The development of immune checkpoint inhibitors has arisen from the discovery of this mechanism. Inhibition of immune checkpoint molecules with neutralizing antibodies can release the suppression of cancer‐specific CTLs, activate immunity, and promote cancer elimination. The effectiveness of immune checkpoint antibodies has been confirmed and clinically applied to many solid cancers such as melanoma, 41 lung cancer, 42 urothelial cancer, 43 gastric cancer, 44 and esophageal cancer. 45 In addition to PD‐1 and CTLA4, new immune checkpoint molecules, such as LAG3, TIGIT, and SIRPA, are also being actively studied. 46 , 47 , 48 Although this therapy is promising, the cancer cases who respond to these therapies are limited. This is because use of this therapy requires the presence of cancer‐specific CTLs in the patient's body. To maximize the therapeutic effect, it is desirable to select appropriate cases and develop useful biomarkers.

The second difficulty for immunotherapy is that T cells do not recognize specific cancer cell antigens and immune accelerators are too weak. One goal of CAR‐T cell therapy is to strengthen the immune accelerator by administering CTLs to the patient's body that recognize specific cancer cell‐specific antigens. A CAR is prepared by fusing a single chain Fv (scFv), derived from a monoclonal antibody that recognizes a specific antigen expressed by cancer cells, with CD3z and costimulatory molecules (CD28, 4‐1BB, and others). Next, the CAR is introduced to the T cells obtained from a cancer patient and CAR‐T cells are made. CAR‐T cells recognize the specific antigen of the cancer cells and are activated to damage these cells. CAR‐T cells recognize cancer‐specific antigens with high antibody specificity and attack the respective cancer cells with strong cytotoxic activity and high proliferative activity. CAR‐T therapy is effective in blood cancers such as B‐cell acute lymphoblastic leukemia and myeloma. 49 , 50 While CAR‐T cell therapy has a high therapeutic effect, a frequent and serious adverse event called cytokine release syndrome has been observed in some patients. 51 , 52 The development of a technique for suppressing the occurrence of cytokine release syndrome is anticipated. In addition, the development of CAR‐T cell therapies for solid tumors is ongoing.

Recently, there was new progress made in treating gastrointestinal cancer patients. For MSI‐H colorectal cancer, the combination therapy with nivolumab and ipilimumab was approved. From the nivolumab plus ipilimumab cohort of CheckMate‐142, progression‐free survival rates were 76% (9 months) and 71% (12 months); respective overall survival rates were 87% and 85% which were quite high. This new treatment will benefit MSI‐H colorectal cancer patients. 53

Thus, it is expected that further understanding of cancer immune mechanisms and the development of various immunotherapies will contribute to great progress in cancer treatment.

One problem for immunotherapy is that there is no certain predictive biomarker. It was thought that the expression of PD‐1 or PD‐L1 would predict the effect. However, this was not the case. To find a new biomarker, we assessed the cytolytic activity (CYT) score. The CYT score is a new index of cancer immunity calculated from the mRNA expression levels of GZMA and PRF1. We are now evaluating CYT score in gastric cancer patients (data not published). The development in the biomarker search will benefit many gastrointestinal cancer patients.

5. ADVANTAGES FOR USING ORGANOIDS IN CANCER RESEARCH

The three‐dimensional (3D) organoid system is a cell culture‐based, novel, and physiologically relevant biologic platform. 54 An organoid is a miniaturized and simplified version of an organ that is produced in vitro in 3D and shows realistic microanatomy. With only one to a few cells isolated from tissue or cultured cells as the starting material, organoids are grown and passaged in a basement membrane matrix, which contributes to their self‐renewal and differentiation capacities. 54 , 55 The technique used for growing organoids has rapidly improved since the early 2010s with the advent of the field of stem cell biology. The characteristics of stem, embryonic stem cells (ES cells), or induced pluripotent stem cells (iPS cells) that allow them to form an organoid in vitro are also found in multiple types of carcinoma tissues and cells. Therefore, cancer researchers have applied ES cells or iPS cells in their field. 56 , 57 , 58

Organoid formation generally requires culturing stem cells or their progenitor cells in 3D. 54 , 55 The morphological and functional characteristics of various types of carcinoma tissue have been recapitulated in organoids that were generated from single‐cell suspensions or cell aggregates. These suspensions or aggregates were isolated from murine and human tissues or cultured cells, as well as from cancer stem cells propagated in culture. The structures of the organoids show the potential of cancer stem cell self‐renewal, proliferation, and differentiation abilities, and also provide insights into the roles of molecular pathways and niche factors that are essential in cancer tissues. 56 , 57 , 59 , 60 , 61 , 62 The organoid system also has been utilized for studying multiple biological processes, including motility, stress response, cell‐cell communications, and cellular interactions that involve a variety of cell types such as fibroblasts, endothelial cells, and inflammatory cells. These interactions are mediated via cell surface molecules, extracellular matrix proteins, and receptors in the microenvironment under homeostatic and pathologic conditions.

Although the organoid system is a complex and not effortless procedure that requires specific media, supplements, and many tricky techniques, 58 , 63 application of this system has been extended to a variety of cell types from different carcinomas (colorectal, pancreatic, prostate, breast, ovary, and esophageal cancers). 56 , 57 , 59 , 60 , 61 An organoid is generally induced within a few days to weeks, and is faster and less costly than the murine xenograft assay. Furthermore, applying novel genetic manipulations (e.g. CRISPR‐Cas9) can be carried out in the organoid system. 64 , 65

Kasagi et al modified keratinocyte serum‐free medium to grow 3D organoids from endoscopic esophageal biopsies, immortalized human esophageal epithelial cells, and murine esophagi. Esophageal 3D organoids serve as a novel platform to investigate regulatory mechanisms in squamous epithelial homeostasis in the context of esophageal cancers. 64

We anticipate that many experimental results that utilize the organoid system will be published in the future.

The 3D organoid system has emerged in the past several years as a robust tool in basic research with the potential to be used for personalized medicine. 66 By passaging dissociated primary structures to generate secondary 3D organoids, this system can be performed using live tissue pieces obtained from biopsies, operative‐resected specimens, or even frozen tissues. This method has the potential to transform personalized therapy. For example, in the case of cancer recurrence, an effective chemotherapy can be selected by testing the chemotherapeutic sensitivity of cancer‐derived organoids from an individual patient's tissue stocks. In many cases, a patient's organoid accumulation is helpful for testing the sensitivity of novel therapeutic agents for treating carcinoma. 66 Hence, it appears that organoid biology will further develop with a goal of translating the research into personalized therapy.

6. SUMMARY AND FUTURE DIRECTIONS

This review describes four new cancer‐related studies: exosomes, microbiome, immunotherapy, and organoids (Figure  1 ).

The summary of the four cancer research areas. In this figure the summary of the four cancer research areas is shown: exosome, microbiome, immunotherapy, and organoid research

Since exosomes are released in blood or urine, if the capturing system is established, it will be a less invasive test to diagnose cancer. In the present, the presence of circulating tumor DNA (ctDNA) is one of the tools to detect the minimal residual disease. However, since ctDNA is only DNA, it is difficult to spread to cancer research. In that respect, as exosomes include not only DNA but also other nucleic acids and proteins, this will be a new tool for cancer research such as the diagnosis of early cancer.

Microbiome may lead to improved cancer diagnosis and treatment. Detecting a specific microbiome in a gastrointestinal tract may predict a specific cancer. And changing microbiome in some way may result in preventing cancer development.

Organoids may help address the problem of drug resistance, and also lead to the development of personalized therapy. However, producing organoids takes time and testing the drug resistance may take more time. If we could overcome these problems, the research into organoids can contribute to overcoming cancer.

As shown in Table  3 , many new studies and findings are reported into this field of research. These four novel cancer research areas will make many contributions to the diagnosis and treatment of cancer.

Recent studies on exosome, microbiome, immunotherapy, and organoids

Conflict of Interest: All the authors have no conflict of interest to disclose.

ACKNOWLEDGMENTS

We thank Dr Hirofumi Hasuda and Dr Naomichi Koga for their help in preparing this manuscript. We also thank J. Iacona, PhD, from Edanz Group for editing a draft of this manuscript.

Ando K, Hu Q, Kasagi Y, Oki E, Mori M. Recent developments in cancer research: Expectations for a new remedy . Ann Gastroenterol Surg . 2021; 5 :419–426. 10.1002/ags3.12440 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

• Introduction
• Conclusions
• Article Information

eTable 1. Classification of Indications

eTable 2. Dechallenge and Rechallenge With Semaglutide

eTable 3. Dechallenge and Rechallenge With Liraglutide

eTable 4. Sex, Median Age and Dose (IQR) for Suicidal Ideation ADRs by Drug and Indication

eTable 5. Coreported Psychiatric Reactions for Semaglutide

eTable 6. Coreported Psychiatric Reactions for Liraglutide by Indication

eTable 7. Number of Cases, Noncases, Other Adverse Drug Reactions (ADRs) and Total Number of Other Reports in the Database for Semaglutide

eTable 8. Number of Cases, Noncases, Other Adverse Drug Reactions (ADRs) and Total Number of Other Reports in the Database for Liraglutide

eTable 9. Disproportionality Analysis of Semaglutide-Associated Suicidal Ideation Compared With All Other Drugs in the Database in Female and Male Patients Separately

eTable 10. Number of Semaglutide-Associated Cases of Adverse Drug Reactions (ADRs) by Year

eTable 11. Number of Liraglutide-Associated Cases of Adverse Drug Reactions (ADRs) by Year

eReferences.

Data Sharing Statement

• GLP-1 Receptor Agonists and Suicidality JAMA Network Open Invited Commentary August 20, 2024 Francesco Salvo, MD, PhD; Jean-Luc Faillie, MD, PhD

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Schoretsanitis G , Weiler S , Barbui C , Raschi E , Gastaldon C. Disproportionality Analysis From World Health Organization Data on Semaglutide, Liraglutide, and Suicidality. JAMA Netw Open. 2024;7(8):e2423385. doi:10.1001/jamanetworkopen.2024.23385

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Disproportionality Analysis From World Health Organization Data on Semaglutide, Liraglutide, and Suicidality

• 1 The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, New York
• 2 Department of Psychiatry, Zucker School of Medicine at Northwell/Hofstra, Hempstead, Glen Oaks, New York
• 3 Department of Psychiatry, Psychotherapy and Psychosomatics, Hospital of Psychiatry, University of Zurich, Zurich, Switzerland
• 4 Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
• 5 Institute of Primary Care, University of Zurich and University Hospital Zurich, Zurich, Switzerland
• 6 WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation, Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy
• 7 Pharmacology Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
• 8 Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
• Invited Commentary GLP-1 Receptor Agonists and Suicidality Francesco Salvo, MD, PhD; Jean-Luc Faillie, MD, PhD JAMA Network Open

Question   Are glucagon-like peptide-1 receptor agonists semaglutide and liraglutide, which were originally introduced for the treatment of type 2 diabetes and are frequently prescribed due to their weight loss properties, associated with disproportionately increased reporting of suicidality?

Findings   This disproportionality analysis through the case-control design based on the World Health Organization global database collecting suspected adverse drug reactions, identified a disproportionality signal of suicidal ideation with semaglutide, which remained significant when comparing semaglutide with dapagliflozin and metformin and in the subgroup of patients with coreported use of antidepressants and benzodiazepines.

Meaning   A detected signal of semaglutide-associated suicidal ideation warrants urgent clarification.

Importance   Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have gained use primarily due to their weight-reduction effects, although a regulatory review was undertaken for potential suicidality concern.

Objectives   To evaluate potential signals for suicidal and self-injurious adverse drug reactions (ADRs) associated with the GLP-1 RAs semaglutide and liraglutide.

Design, Setting, and Participants   Disproportionality analysis through the case-control design using the World Health Organization (WHO) global database of suspected ADRs. Participants were clinical patients worldwide experiencing an ADR suspectedly attributable to semaglutide or liraglutide in the database from inception to August 30, 2023. Data were analyzed from September to December 2023.

Exposure   Treatment with semaglutide or liraglutide regardless of indication or treatment duration.

Main Outcomes and Measures   Reporting odds ratio (ROR) and the bayesian information component (IC) with 95% CIs were calculated as measures of disproportionate reporting of suicidal and self-injurious ADRs associated with semaglutide and liraglutide compared with all other medications. Sensitivity analyses were conducted including patients with coreported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators. A disproportionality signal was considered when the lower limits of the ROR and IC were above 1 and 0, respectively.

Results   A total of 107 (median [IQR] age 48 [40-56] years; 59 female patients [55%]) and 162 (median [IQR] age 47 [38-60] years; 100 female patients [61%]) cases of suicidal and/or self-injurious ADRs were reported between November 2000 and August 2023 with semaglutide and liraglutide, respectively. Significant disproportionality was detected only for semaglutide-associated suicidal ideation (ROR, 1.45; 95% CI, 1.18-1.77; IC, 0.53; 95% CI, 0.19-0.78), which remained significant in patients with coreported use of antidepressants (ROR, 4.45; 95% CI, 2.52-7.86; IC, 1.96; 95% CI, 0.98-2.63) and benzodiazepines (ROR, 4.07; 95% CI, 1.69-9.82; IC, 1.67; 95% CI, 0.11-2.65), when compared with dapagliflozin (ROR, 5.56; 95% CI, 3.23-9.60; IC, 0.70; 95% CI, 0.36-0.95), metformin (ROR, 3.86; 95% CI, 2.91-5.12; IC, 1.20; 95% CI, 0.94-1.53) and orlistat (ROR, 4.24; 95% CI, 2.69-6.69; IC, 0.70; 95% CI, 0.36-0.95).

Conclusions and Relevance   This study using the WHO database found a signal of semaglutide-associated suicidal ideation, which warrants urgent clarification.

Over the past decade, obesity trends have reached epidemic standards. 1 In this context, the understanding of glucagon-like peptide-1 (GLP-1)–based mechanisms and related anorectic properties of GLP-1 receptor agonists (RAs) have revolutionized the treatment of obesity. 2 In addition to enhancing glucose-dependent insulin release, GLP-1 RAs may reduce glucagon secretion as well as gastric emptying. 2 Originally introduced for the treatment of type 2 diabetes, the effect of GLP-1 RAs on weight loss soon caught research attention. 3 The weight loss properties of liraglutide and semaglutide quickly went viral on social media, leveraging their promotion as lifestyle drugs not just for patients with diabetes 4 and leading to a global shortage. 5 Currently, it is estimated that approximately 10% of patients with type 2 diabetes in the US are prescribed GLP-1 RAs. 6 Accordingly, regulatory authorities over the world have urged health care professionals to direct available supplies to patients with type 2 diabetes who are inadequately managed with other medications over off-label prescriptions. 7 , 8 Despite the promising potential of GLP-1 RAs, serious concerns have been raised about their safety. 9 , 10 On July 3, 2023, a series of reports for suicidal or self-harming thoughts associated with liraglutide or semaglutide triggered an ongoing review by the European Medicines Agency (EMA). 11 Previously, in the approval trials, 9 of the 3384 patients treated with liraglutide (0.27%) had reported suicidal ideation compared with 2 of 1941 patients allocated to the placebo group (0.10%). 12 On the other hand, no patients using semaglutide for obesity had developed suicidal ideation, 13 , 14 and no mental health differences were observed in adolescents, with a lower percentage of participants in the semaglutide group than in the placebo group reporting psychiatric adverse events (7% vs 15%). 15

The EMA-led investigation might have a global impact, given that liraglutide and semaglutide are administered to more than 20 million people per year. 11 This investigation was expected to be completed in November 2023, but ultimately updated in April 2024 after requesting further clarifications. 16 In the meantime the British Medicines and Healthcare Products Regulatory Agency and the US Food and Drug Administration (FDA) also announced a similar investigation. 17 So far both EMA and FDA declared that they did not find any clear demonstration of a relationship between GLP-1 RAs and suicide based on the available evidence, although the FDA investigation is still ongoing. 18 , 19

Marketing companies stated that warnings about suicidal behavior and ideation are formally required for medications prescribed for chronic weight management affecting the central nervous system. 20 The first 2 pharmacovigilance studies on the topic only included partial data from the US, 21 , 22 and a report from the EMA pharmacovigilance database did not assess disproportionality. 23 Typically, patients with suicidality are excluded from clinical trials; therefore, the reports from clinical trials may be less precise in capturing the risk of suicidal or self-injurious adverse drug reactions (ADRs) in later practice. In this context, we aimed to assess suicidal and/or self-injurious ADRs associated with liraglutide or semaglutide at a global level, using a World Health Organization (WHO) database of individual case safety reports (ICSRs).

This case-control study was conceived as a disproportionality analysis of the WHO Vigibase, a consolidated tool for postmarketing surveillance. In the past, large-scale ICSR databases attracted interest for early detection and characterization of emerging safety issues. 24 - 26

All procedures and analyses adhered to the Uppsala Monitoring Centre (UMC) caveat agreement for reporting standards and were in accordance with the Helsinki declaration for ethical principles in medical research. As the data were anonymized and all analyses were descriptive, an ethical review from the Zurich Cantonal ethics board was not required. Additionally, per the Common Rule, because all data in the database are anonymized, patient informed consent was not required. This study was reported according to The Reporting of A Disproportionality Analysis for Drug Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV) guideline. 27 - 29

We conducted a comprehensive search for reports of suicidal or self-injurious ADRs associated with liraglutide and semaglutide within the WHO global ICSRs database, which is the largest pharmacovigilance archive worldwide containing over 28 million reports of suspected ADRs from 140 member countries. On August 30, 2023, we selected all deduplicated ICSRs recorded in the database from inception. Reports for semaglutide were recorded between July 2011 and August 2023, whereas for liraglutide, reports were collected between November 2000 and August 2023. Database services are offered by the UMC, which manages the database. 30 , 31 Drugs recorded on the reports are coded using the WHO drug dictionary 32 and ADRs are classified according to the Medical Dictionary for Regulatory Activities (MedDRA), version 23.1. 33 Two authors (C.G. and G.S.) identified ADRs involving liraglutide and/or semaglutide as suspected or interacting drugs to identify any report of suicidal and/or self-injurious ADRs as classified in the “suicide/self-injury” standardized MedDRA query (SMQ) of the MedDRA classification. Such SMQs include any ADR related to suicidal and/or self-injurious thoughts and events. 34 Cases were all reports of suicidal and/or self-injurious ADRs, whereas controls were all other reports of suspected ADRs. We included liraglutide-related or semaglutide-related reports.

Descriptive statistics on demographic and clinical characteristics (in medians and IQRs) of reported cases were provided. We compared the percentage of female patients, age, and dose between patients prescribed GLP-1 RAs for different indications. We grouped indications into the following categories: diabetes, weight management, possible off-label indication, and others. The classification of indications is detailed in eTable 1 in Supplement 1 . Comparisons of demographic and clinical characteristics were performed using χ 2 tests, Wilcox, Kruskal-Wallis, or Fisher tests. We also explored psychiatric symptoms coreported with the suicidal and/or self-injurious ADRs of interest. Two-sided P values less than .05 were considered significant.

We performed disproportionality analysis using 2 consolidated measures when at least 3 reports were recorded: first, we estimated reporting odds ratio (ROR) 35 and the bayesian information component (IC), 36 with 95% CIs. We applied well-established thresholds to define signals of disproportionate reporting, that is, lower limit of the 95% CI greater than 1 and greater than 0 for ROR and IC, respectively. Additional details about disproportionality analysis are reported in the eMethods in Supplement 1 .

For suicidal and/or self-injurious ADRs that had a signal of disproportionate reporting in the main disproportionality analysis, we performed sensitivity analyses to explore potential confounders. The following sensitivity analyses were conducted: (1) selecting only cases with coreporting of use of antidepressants and (2) only cases with coreporting of use of benzodiazepines as a proxy of depressive and anxiety disorders that can increase the risk of suicidal and/or self-injurious behaviors and ideation. Moreover, we repeated the aforementioned analyses by (3) excluding reports with coreporting of antidepressants and (4) benzodiazepines. To additionally mitigate the risk of confounding by indication and channeling bias, we performed 3 other sensitivity analyses using other drugs prescribed for the same indications (obesity and type 2 diabetes) as comparators; specifically we selected (5) dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, and (6) metformin, considering their well-established role in the treatment of type 2 diabetes coupled with their favorable impact on body weight 37 , 38 ; and (7) orlistat, considering its indication for obesity and weight loss.

We also assessed the disproportionality of reporting in female and male patients separately. Last, to assess the trend of reporting over time, we reported the number of reports by year for all ADRs of interest and for each ADR with disproportionate reporting. Data were analyzed from September to December 2023.

As of August 30, 2023, of the 36 172 078 total reports in the database, we identified a total of 107 (median [IQR] age, 48 [40-56] years; 59 female patients [55%]; median [IQR] treatment duration, 24.0 [2.3-61.0] days [data from 28 reports]) unique, deduplicated cases of suicidal and/or self-injurious ADRs associated with semaglutide (107 of the 30 527 total reports [0.35%]) and 162 (median [IQR] age, 47 [38-60] years; 100 female patients [61%]; median [IQR] treatment duration, 46.0 [14.0-99.0] days [data from 33 reports]) cases associated with liraglutide (162 of 52 131 total reports [0.31%]). Demographic and clinical characteristics of the cases are reported in Table 1 by GLP-1 RA.

Regarding indications for use, the main reason for prescription was a possible off-label use (34 patients for semaglutide [31.8%] and 55 for liraglutide [33.9%]), followed by weight management (28 for semaglutide [26.2%] and 40 for liraglutide [24.7%]), diabetes (26 for semaglutide [24.3%] and 33 for liraglutide [20.4%]), and in 1 case for polycystic ovary syndrome for each GLP-1 RA (1 for semaglutide [0.9%] and 1 for liraglutide [0.6%]). Semaglutide-associated cases were reported by consumers in almost half of the reports (52 cases [48.6%]). Liraglutide-associated cases were mainly reported by health professionals (103 cases [63.6%]).

Regarding outcomes following dechallenge and rechallenge, both for semaglutide (eTable 2 in Supplement 1 ) and liraglutide (eTable 3 in Supplement 1 ), suicidal ideation resolved after drug discontinuation in 62.5% of the cases. In the semaglutide-associated reports of suicidal and/or self-injurious ADRs, the most common comedications included antidiabetics (17 patients [15.9%]) and antidepressants (14 patients [13.1%]), with higher percentages for liraglutide (49 patients [30.3%] and 30 patients [18.5%], respectively) ( Table 1 ).

Suicidal and/or self-injurious ADRs associated with semaglutide and/or liraglutide are presented in Table 2 . Suicidal ideation, intentional overdose, and suicide attempt ranked highest for semaglutide (94 patients [88%], 7 patients [6.5%], and 7 patients [6.5%], respectively), whereas for liraglutide suicidal ideation, completed suicide, and suicide attempt ranked highest (116 patients [71.6%], 19 patients [11.7%], and 16 patients [9.9%], respectively). Seven reactions (6.5%) were fatal for semaglutide and 24 (14.8%) for liraglutide. In Table 2 we report the number and percentage of each ADR by indication. For reports of suicidal ideation, we reported older age for patients prescribed liraglutide for diabetes compared with off-label and weight management, as well as a lower percentage of female patients prescribed liraglutide for diabetes compared with off-label and weight management (eTable 4 in Supplement 1 ).

The list of coreported psychiatric symptoms for semaglutide and liraglutide is reported in eTable 5 and eTable 6 in Supplement 1 . For liraglutide there were 91 cases in which suicidal and/or self-injurious ADRs were reported without any other psychiatric symptoms, 50 cases in which 1 psychiatric symptom was coreported, and 21 in which 2 or more other psychiatric symptoms were reported. Table 2 shows the number of cases in which suicidal and/or self-injurious ADRs were reported alone by indication. In half of these cases the drug was taken off-label both for semaglutide and liraglutide ( Table 2 ).

We detected a significant disproportionality only for semaglutide-associated suicidal ideation compared with all medications (ROR, 1.45; 95% CI, 1.18-1.77; IC, 0.53; 95% CI, 0.19-0.78) ( Table 3 ). Data on duration for semaglutide treatment were available in 26 patients reporting suicidal ideation, with a mean (range) duration of 80.39 (0 to 610) days between semaglutide treatment initiation and suicidal ideation occurrence. We did not find signals for any other ADR of interest ( Table 3 ). Numbers of cases and controls are reported in eTable 7 and eTable 8 in Supplement 1 .

The first sensitivity analysis including cases with comedications with antidepressants showed a disproportionate reporting of semaglutide-associated suicidal ideation compared with all medications (ROR, 4.45; 95% CI, 2.52 to 7.86; IC, 1.96; 95% CI, 0.98 to 2.63). The second sensitivity analysis including cases with comedications with benzodiazepines showed a disproportionate reporting of semaglutide-associated suicidal ideation compared with all medications (ROR, 4.07; 95% CI, 1.69 to 9.82; IC, 1.67; 95% CI, 0.11 to 2.65). Reporting was not disproportionate when excluding reports with comedications with antidepressants (ROR, 1.28; 95% CI, 1.03 to 1.60; IC, 0.36; 95% CI, −0.10 to 0.63), but remained disproportionate when excluding reports with comedications with benzodiazepines (ROR, 1.40; 95% CI, 1.13 to 1.72; IC, 0.48; 95% CI, 0.13 to 0.73). The fifth sensitivity analysis showed a disproportionate reporting of semaglutide-associated suicidal ideation compared with dapagliflozin (ROR, 5.56; 95% CI, 3.23 to 9.60; IC, 0.70; 95% CI, 0.36 to 0.95). The sixth sensitivity analysis showed a disproportionate reporting of semaglutide-associated suicidal ideation compared with metformin (ROR, 3.86; 95% CI, 2.91 to 5.12; IC, 1.20; 95% CI, 0.94 to 1.53). The seventh sensitivity analysis showed a disproportionate reporting of semaglutide-associated suicidal ideation compared with orlistat (ROR, 4.24; 95% CI, 2.69 to 6.69; IC, 0.70; 95% CI, 0.36 to 0.95). The analysis of disproportionality for suicidal ideation in female and male patients separately yielded disproportionate reporting in men (ROR, 1.51; 95% CI, 1.09 to 2.08; IC, 0.58; 95% CI, 0.03 to 0.97), whereas in female patients, although the lower limit of the 95% CI of the ROR was greater than 1 (ROR, 1.35; 95% CI, 1.02 to 1.77) the lower limit of the 95% CI of the IC was less than 0 (IC, 0.42; 95% CI,−0.05 to 0.75) (eTable 9 in Supplement 1 ).

From marketization year till August 2023, there was a slight increase in the proportion of suicidal ADRs reported for both drugs. The increase was from 0% (2017) to 0.8% (2023) for semaglutide and from 0.09% (2014) to 0.4% (2023) for liraglutide (eTable 10 and eTable 11 in Supplement 1 ).

In this disproportionality analysis of the world’s largest ICSRs database using a case-control design, we found a significant disproportionality only for semaglutide-associated suicidal ideation compared with other medications. The number of reports showed a gradual increase over the years, which may indicate a widening therapeutic scope in obesity and accumulating clinical experience.

To our knowledge, no previous reports investigated the association between semaglutide and suicidal ideation using this database. In our sensitivity analyses, the disproportionality remained significant when focusing on coreported antidepressants or benzodiazepines, suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide. When repeating the analysis after excluding cases in which antidepressants were coreported, we did not detect a disproportionality signal. In contrast, when repeating the analysis after excluding cases in which benzodiazepines were coreported, the disproportionality remained significant. This is consistent with an interaction between baseline psychopathology and semaglutide effects and warrants further investigation. Although EMA stated that no update to the product information is warranted, based on these findings, we believe that a precaution of use in patients with psychiatric disorders or psychological lability could be added in the semaglutide package insert. Remarkably, the FDA label of semaglutide for obesity warned to monitor for depression or suicidal thoughts. 39

One study using the FDA pharmacovigilance database suggested disproportionate reporting for suicidal ideation and suicidal depression for semaglutide and liraglutide, 21 whereas another study did not detect an association between suicidality and GLP-1 RAs. 22 Likewise, a cohort study using electronic health records did not detect higher risks of suicidal ideation in patients with obesity or diabetes treated with semaglutide compared with non–GLP-1 RAs. 40 Compared with this study, in our analysis we also included patients with potential off-label prescription of GLP-1 RAs. Thus, our analysis may be generalized to patients receiving GLP-1 RAs without a diagnosis of diabetes or obesity, thus further confirming the complementary nature of studies based on ICSRs disproportionality analysis and longitudinal observational design.

Evidence from bariatric studies suggests that a history of depression or anxiety is a predictor of suicide risk postoperatively, providing context for this interplay 41 ; authors discussed this association in light of the emerging frustration due to high expectations of bariatric surgery outcomes in patients with limited resources to deal with mental distress. 41 Of note, the pivotal trials of semaglutide in obesity had different exclusion criteria for mental disorders, such as major depressive disorder within 2 years before screening, diagnosis of severe psychiatric disorders, and history of suicide attempts. 13 , 15 An alternative hypothesis may consider very rapid weight loss related to adjustment problems such as inability to eat as expected and ultimately exacerbated mental distress in highly vulnerable patients. 41 Due to lack of data on GLP-1 RA–related changes of baseline weight or BMI, we could not test for either hypothesis.

Although comorbidity with depression is high in patients with diabetes, 42 the coreporting between antidepressants and antidiabetics was negligible. Furthermore, the signal of semaglutide remained when comparing with dapagliflozin, metformin, and orlistat, mitigating the risk of confounding by indication for diabetes and obesity. Therefore, patients with diabetes and/or obesity without psychiatric comorbidities may not be at high risk of semaglutide-associated suicidal ideation. Although ADR incidence cannot be calculated using the spontaneous reporting system, this ADR is likely to be rare and would probably not substantially alter the benefit-risk profile of semaglutide in approved therapeutic settings. However, the observed high proportion of cases due to possible off-label use and a recently published postmarketing signal of misuse or abuse 43 call for urgent clarification of patient-related and drug-related risk factors; cohort studies and large registries should be stratified by therapeutic indication, sex, and history of mental disorders, and data from off-label use should be retrieved.

Despite the large number of cases, we did not detect any signals for liraglutide-associated suicidal and/or self-injurious ADRs. Pooled data from phase 2 and 3 trials on liraglutide vs placebo for weight management identified a potential risk for suicidal ideation. 12 Nine of 3384 participants in the liraglutide group vs 2 of 1941 in the placebo group reported suicidal ideation or behavior during the trial (0.27% vs 0.10%). 12

The results of this study should be interpreted in light of several limitations. 25 First, we need to consider barriers to reporting and missing information. Second, the well-known inability to infer causality does not allow us to attribute any reactions to the effect of a drug. Third, the lack of denominator does not allow us to estimate the incidence of ADRs. Fourth, selection and collider bias, 44 as well as confounding by indication and channeling bias, although partially mitigated by our sensitivity analyses, may have played a role as people with treatment-resistant diabetes or obesity might reflect a subgroup of patients with more severe conditions including higher risk of mental distress. Additional adjustments for potential confounders, such as alcohol or substance misuse, were limited by the relatively small number of reports found. In the absence of more details about off-label prescribing, we were not able to further qualify the extent to which prescribing was off-label and its impact on the results. Fifth, the lack of treatment outcomes, such as weight change, did not allow different hypotheses to be considered. Sixth, the high proportion of cases with missing data on medication dose precluded a dose-response analysis. Seventh, because of the absence of information on the sociodemographic profile of the reporters, it is impossible to account for volunteer bias. Eighth, it is not possible to exclude the chance that, for instance, suicidal ideation may have preexisted. Ninth, data on treatment duration until ADR were provided only in a small number of reports. Additionally, since disproportionality measures are interdependent, the lack of statistically significant disproportionality should not be automatically interpreted as a safety endorsement. Several factors may influence the reporting pattern and the ability to detect disproportionality, including known and widely reported ADRs such as gastrointestinal ADRs.

Our findings are relevant to the general reader seeking up-to-date information. This relevance arises from the expectation that personal or anecdotal reports may continue to gain popularity on social media platforms without knowledge about risks. 45 One consequence of this trend may be the increase in off-label use of semaglutide, which is a public health concern that has led to the illegal trade in semaglutide pens, some of which are counterfeit. 46 Recently, a public warning about fake counterfeit semaglutide pens was issued in the United Kingdom and the US. 46 , 47 Considering the risk of suicidal ideation in people taking semaglutide off-label, authorities should consider issuing a warning to inform about this risk.

In this disproportionality study of an ADR database, we reported a disproportionality signal of suicidal ideation with semaglutide, but not for liraglutide, particularly among patients with coreported antidepressant use, a proxy for affective disorders (a notable exclusion criteria of premarketing clinical trials).

Accepted for Publication: May 21, 2024.

Published: August 20, 2024. doi:10.1001/jamanetworkopen.2024.23385

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2024 Schoretsanitis G et al. JAMA Network Open .

Corresponding Author: Georgios Schoretsanitis, MD, PhD, The Zucker Hillside Hospital, Behavioral Health Pavilion, 75-59 263rd St, Glen Oaks, NY 11004 ( [email protected] ).

Author Contributions: Drs Schoretsanitis and Gastaldon had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Schoretsanitis, Weiler, Raschi, Gastaldon.

Drafting of the manuscript: Schoretsanitis, Gastaldon.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Schoretsanitis, Gastaldon.

Administrative, technical, or material support: Barbui.

Supervision: Schoretsanitis, Barbui, Raschi.

Conflict of Interest Disclosures: Dr Schoretsanitis reported receiving personal fees from HLS, Dexcel, Saladax, and Thermo Fisher outside the submitted work. Dr. Weiler reported being a member of the Human Medicines Expert Committee of Swissmedic. No other disclosures were reported.

Disclaimer: The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. While the authors used data from VigiBase, the World Health Organization (WHO) global database of individual case safety reports, as a source of information, the conclusions do not represent the opinion of the Uppsala Monitoring Centre (UMC) or the WHO.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: The authors acknowledge the UMC, which provided and gave permission to use the data analyzed in the present study. The authors are also indebted to Dr Leonie Heron, PhD, Institute for Social and Preventive Medicine, University of Bern, Bern, Switzerland, who helped in editing this article. She was not compensated for her services.

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Study: Transparency is often lacking in datasets used to train large language models

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In order to train more powerful large language models, researchers use vast dataset collections that blend diverse data from thousands of web sources.

But as these datasets are combined and recombined into multiple collections, important information about their origins and restrictions on how they can be used are often lost or confounded in the shuffle.

Not only does this raise legal and ethical concerns, it can also damage a model’s performance. For instance, if a dataset is miscategorized, someone training a machine-learning model for a certain task may end up unwittingly using data that are not designed for that task.

In addition, data from unknown sources could contain biases that cause a model to make unfair predictions when deployed.

To improve data transparency, a team of multidisciplinary researchers from MIT and elsewhere launched a systematic audit of more than 1,800 text datasets on popular hosting sites. They found that more than 70 percent of these datasets omitted some licensing information, while about 50 percent had information that contained errors.

Building off these insights, they developed a user-friendly tool called the  Data Provenance Explorer that automatically generates easy-to-read summaries of a dataset’s creators, sources, licenses, and allowable uses.

“These types of tools can help regulators and practitioners make informed decisions about AI deployment, and further the responsible development of AI,” says Alex “Sandy” Pentland, an MIT professor, leader of the Human Dynamics Group in the MIT Media Lab, and co-author of a new open-access paper about the project .

The Data Provenance Explorer could help AI practitioners build more effective models by enabling them to select training datasets that fit their model’s intended purpose. In the long run, this could improve the accuracy of AI models in real-world situations, such as those used to evaluate loan applications or respond to customer queries.

“One of the best ways to understand the capabilities and limitations of an AI model is understanding what data it was trained on. When you have misattribution and confusion about where data came from, you have a serious transparency issue,” says Robert Mahari, a graduate student in the MIT Human Dynamics Group, a JD candidate at Harvard Law School, and co-lead author on the paper.

Mahari and Pentland are joined on the paper by co-lead author Shayne Longpre, a graduate student in the Media Lab; Sara Hooker, who leads the research lab Cohere for AI; as well as others at MIT, the University of California at Irvine, the University of Lille in France, the University of Colorado at Boulder, Olin College, Carnegie Mellon University, Contextual AI, ML Commons, and Tidelift. The research is published today in Nature Machine Intelligence .

Focus on finetuning

Researchers often use a technique called fine-tuning to improve the capabilities of a large language model that will be deployed for a specific task, like question-answering. For finetuning, they carefully build curated datasets designed to boost a model’s performance for this one task.

The MIT researchers focused on these fine-tuning datasets, which are often developed by researchers, academic organizations, or companies and licensed for specific uses.

When crowdsourced platforms aggregate such datasets into larger collections for practitioners to use for fine-tuning, some of that original license information is often left behind.

“These licenses ought to matter, and they should be enforceable,” Mahari says.

For instance, if the licensing terms of a dataset are wrong or missing, someone could spend a great deal of money and time developing a model they might be forced to take down later because some training data contained private information.

“People can end up training models where they don’t even understand the capabilities, concerns, or risk of those models, which ultimately stem from the data,” Longpre adds.

To begin this study, the researchers formally defined data provenance as the combination of a dataset’s sourcing, creating, and licensing heritage, as well as its characteristics. From there, they developed a structured auditing procedure to trace the data provenance of more than 1,800 text dataset collections from popular online repositories.

After finding that more than 70 percent of these datasets contained “unspecified” licenses that omitted much information, the researchers worked backward to fill in the blanks. Through their efforts, they reduced the number of datasets with “unspecified” licenses to around 30 percent.

Their work also revealed that the correct licenses were often more restrictive than those assigned by the repositories.   

In addition, they found that nearly all dataset creators were concentrated in the global north, which could limit a model’s capabilities if it is trained for deployment in a different region. For instance, a Turkish language dataset created predominantly by people in the U.S. and China might not contain any culturally significant aspects, Mahari explains.

“We almost delude ourselves into thinking the datasets are more diverse than they actually are,” he says.

Interestingly, the researchers also saw a dramatic spike in restrictions placed on datasets created in 2023 and 2024, which might be driven by concerns from academics that their datasets could be used for unintended commercial purposes.

A user-friendly tool

To help others obtain this information without the need for a manual audit, the researchers built the Data Provenance Explorer. In addition to sorting and filtering datasets based on certain criteria, the tool allows users to download a data provenance card that provides a succinct, structured overview of dataset characteristics.

“We are hoping this is a step, not just to understand the landscape, but also help people going forward to make more informed choices about what data they are training on,” Mahari says.

In the future, the researchers want to expand their analysis to investigate data provenance for multimodal data, including video and speech. They also want to study how terms of service on websites that serve as data sources are echoed in datasets.

As they expand their research, they are also reaching out to regulators to discuss their findings and the unique copyright implications of fine-tuning data.

“We need data provenance and transparency from the outset, when people are creating and releasing these datasets, to make it easier for others to derive these insights,” Longpre says.

“Many proposed policy interventions assume that we can correctly assign and identify licenses associated with data, and this work first shows that this is not the case, and then significantly improves the provenance information available,” says Stella Biderman, executive director of EleutherAI, who was not involved with this work. “In addition, section 3 contains relevant legal discussion. This is very valuable to machine learning practitioners outside companies large enough to have dedicated legal teams. Many people who want to build AI systems for public good are currently quietly struggling to figure out how to handle data licensing, because the internet is not designed in a way that makes data provenance easy to figure out.”

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Mobile phones are not linked to brain cancer, according to a major review of 28 years of research.

A systematic review into the potential health effects from radio wave exposure has shown mobile phones are not linked to brain cancer. The review was commissioned by the World Health Organization and is published today  in the journal Environment International .

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New Study Shows Over 10% of Medicare Beneficiaries Have Diagnoses Indicating Dementia

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Dementia DataHub website fills a critical epidemiological data gap

CHICAGO, September 3, 2024 – In the first comprehensive count of all Medicare beneficiaries of all ages with documented diagnosis of some form of dementia, a new study published today in JAMA Network Open estimated that millions of Americans in Medicare had diagnostic evidence of dementia. The study, conducted by researchers at NORC at the University of Chicago and George Washington University’s Milken Institute School of Public Health, estimated that in 2019, 5.4 million Medicare beneficiaries had diagnoses indicating likely or highly likely dementia, and an additional 2.6 million people had diagnoses indicating possible dementia. 

The study, “Case Definition for Diagnosed Alzheimer Disease and Related Dementias in Medicare,” developed and applied a new case definition of claims-based dementia identification informed by a systematic review of previous definitions used across the research community. Dementia causes progressive deterioration in memory, language, and bodily function and ultimately results in death. The study used a new diagnostic and drug code case definition based on a systematic review of previous research. 

“This new case definition for identifying dementia is novel in that it was driven by researcher consensus and data analysis,” said Kan Gianattasio , the first author of the study and a research scientist in Health Care Evaluation at NORC at the University of Chicago. “It is an important first step toward our goal of developing a refined national surveillance system that can be used by public health researchers and practitioners, policymakers, and medical professionals for dementia monitoring and research purposes.”   

The project team used the case definition developed in the paper to create the Dementia DataHub , a public website that provides detailed geographic and demographic data on different types of diagnosed dementia in Medicare at the national, state, and county level. The Dementia DataHub currently includes estimates for beneficiaries enrolled in Medicare in 2020. 

According to the study:

• Approximately 9.1 percent of all Medicare beneficiaries, and 10.9 percent of beneficiaries ages 65 and older with Part A and B coverage, had diagnostic evidence of at least likely dementia.
• 4.3 percent of all beneficiaries and 4.8 percent of those ages 65 and older with Part A and B coverage had diagnostic evidence that could possibly indicate dementia. 
• Beneficiaries with diagnostic evidence of dementia were older, frailer, had greater proportions of dual Medicaid eligibility and long-term care utilization, were more likely to die in 2019, and incurred greater all-cause Medicare expenditures than those without diagnostic evidence of dementia. 

The authors caution that their research includes only people who received documentation for a diagnosis or prescription drug through Medicare; prior research has indicated that as many as up to 61 percent of dementia patients in the United States are undiagnosed.

According to the Dementia DataHub:

• Rates of diagnosed dementia varied by state and U.S. county. In 2020, Puerto Rico (10.6 percent), Florida (8.2 percent), Texas (8.1 percent), Connecticut (8.0 percent), and New York (7.9 percent) had the highest burden of “highly likely” dementia among their Medicare beneficiaries.
• Idaho (5.3 percent), Montana (5.1 percent), Vermont (5.0 percent), Wyoming (4.9 percent), and Alaska (4.9 percent) had the lowest burden (excluding territories other than Puerto Rico). 

Research regarding the reasons for differences in diagnosis rates by demographics and geography is ongoing. 

The Dementia DataHub draws data from Medicare, which provides nearly universal health coverage for people ages 65 and older, and coverage for selected groups younger than 65 such as those who qualify because of disability. NORC and its collaborating organizations analyzed Medicare fee-for-service claims and Medicare Advantage encounter data to measure the scope and outcomes of Alzheimer’s and related dementias (ADRD). Among Medicare beneficiaries enrolled in 2020, over 8.1 million were coded as having some form of diagnosed dementia.

“We developed the Dementia DataHub to provide the research community and the public with data visualizations and tools to explore the epidemiology of diagnosed dementia in the United States,” said David Rein , program area director in NORC’s Public Health Analytics Program Area and principal investigator of the grant that supports the project. “The DataHub provides the first counts and statistics on diagnosed dementia prevalence, incidence, all-cause Medicare payments, mortality, and COVID-19 infection, at the national, state, and county levels, and uses the internet to facilitate the use of these data. We hope our work can help others better understand regional and demographic variation in diagnosed dementia and use the information to reduce the impact of dementia on individuals and families nationwide.”

The Dementia DataHub is a joint effort led by NORC at the University of Chicago, with intellectual and technical support from George Washington University’s Milken Institute School of Public Health and KPMG LLP. The DataHub is funded by the National Institute on Aging, part of the National Institutes of Health, through Grant R01-AG-075730. The content of both the paper and the DataHub is solely the responsibility of the project team and does not necessarily represent the official views of the National Institutes of Health.

“We needed a nationwide dementia surveillance system to really understand the scope of the dementia epidemic, direct critical support to those in need, address disparities, and create informed policy solutions,” said Dr. Melinda Power, the director of George Washington University’s Institute for Brain Health and Dementia, and co-investigator on the project. “The Dementia DataHub fills that need.” 

Multidisciplinary experts from across NORC contributed to building a website that presents our findings via visually appealing and easily accessible interactive maps and dashboards, allowing users to delve deep while safeguarding individual privacy. The DataHub also contains a summary of the website’s data that will eventually be updated to include the drivers and determinants of geographic variation in dementia outcomes. 

“The prevalence of Alzheimer’s and related dementias is rising fast, and the impact is not equitable. Policymakers and advocates need the best data possible to track and fight back against this disease. The Dementia Datahub provides all of us with actionable insights that can enable us to fight back against Alzheimer’s with greater efficiency, effectiveness, and precision. Together with our National Alzheimer’s Disease Index, this information enables us to better execute on our mission to end the disease—for everyone, everywhere,” said Russ Paulsen, chief operating officer of UsAgainstAlzheimer’s, a leading Alzheimer’s not-for-profit working on prevention, early detection and diagnosis and equal access to treatments for ADRD. UsAgainstAlzheimer’s has been briefed about the Dementia DataHub but was not involved with project.  

Dementia DataHub Case Definitions

• Highly Likely Dementia:  A patient having a dementia-specific diagnosis code on at least two separate dates over a three-year period.
• Likely Dementia:  A patient having a dementia-specific diagnoses code indicating dementia on only one date over three-year period.
• Possible Dementia:  A person having diagnosis codes that may indicate dementia over a three-year period, or a prescription drug inidcated for dementia without a corresponding dementia diagnosis code.
• Any Dementia:  The sum of highly likely dementia, likely dementia, and possible dementia.

The portal’s public use files provide the granular data researchers and others need to better investigate and understand ADRD and its scope and to more effectively plan public health services as the nation prepares for a potential surge in cases. In the future, the Dementia DataHub will include additional indicators, data sources, and more.

Visit: Case Definition for Diagnosed Alzheimer Disease and Related Dementias in Medicare

JAMA Article

Explore the Dementia DataHub website

Dementia DataHub

About NORC at the University of Chicago

NORC at the University of Chicago conducts research and analysis that decision-makers trust. As a nonpartisan research organization and a pioneer in measuring and understanding the world, we have studied almost every aspect of the human experience and every major news event for more than eight decades. Today, we partner with government, corporate, and nonprofit clients around the world to provide the objectivity and expertise necessary to inform the critical decisions facing society.

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New study finds promising approach for reducing brain inflammation

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A new study by researchers at the Azrieli Centre for Autism Research (ACAR) has uncovered a promising approach for reducing brain inflammation. 

Glial cells, which support and protect neurons, can become overactive during injury and brain inflammation. This overactivity may contribute to chronic neurodegeneration and worsen brain disorders. Understanding how this process, called reactive gliosis, is controlled could help scientists better understand brain diseases and improve treatments.  

The study, published in the open-access journal Cell Reports , found that removing a gene linked to autism, CHD8, from certain brain cells called astrocytes, reduces over-reactivity during brain injury and inflammations in experimental mouse models. 

Researchers found that adult mice with the CHD8 gene removed from astrocytes experienced less brain inflammation and alleviated symptoms compared to mice with the gene. Removing the gene changed how DNA is packaged and transcribed in astrocytes, leading to changes in the activity of other genes necessary for the growth and communication of these brain cells with others. 

The team was eager to explore how their discovery could be applied in real-world treatments. Further work showed they could reduce astrocyte reactivity directly in the brain using CRISPR, a specific gene-editing technology that is revolutionizing biomedical research. These results suggest that targeting the CHD8 gene in astrocytes in the adult brain could be a promising approach for reducing brain inflammation and treating related brain disorders.  

This study was led by Platon Megagiannis, a PhD student in the Integrated Program in Neuroscience of McGill University, in the lab of Yang Zhou . Contributing labs include those of Guy Rouleau, Stefano Stifani, and Keith Murai from ACAR; Neville Sanjana from the New York Genome Center; Gene Yeo and Trey Ideker from the University of California San Diego; and Guoping Feng at MIT.

Read the research paper

Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes.  Megagiannis, Platon et al. Cell Reports, Volume 43, Issue 8, 114637. DOI: 10.1016/j.celrep.2024.114637

Yang Zhou (left) and Platon Megagiannis.

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