Liquid biopsies provide breakthrough in diagnosing retinoblastoma

8541 Melinda A. Smith, PhD
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Looking Ahead: A New Frontier in Retinoblastoma

How to biopsy the unbiopsy-able: Retinoblastoma research study to go international.
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Just a handful of years ago, retinoblastoma had the medical field stumped. This aggressive eye cancer affects babies and young children and can lead to loss of vision. Unfortunately, the only way to diagnose the disease is through a doctor’s exam. Unlike with most cancers, oncologists can’t directly sample or biopsy the cancer.

Enter Jesse Berry, MD, Associate Professor of Ophthalmology and Dermatology (Clinical Scholar) at the USC Roski Eye Institute, and the Director of Ocular Oncology and the Retinoblastoma Program at Children’s Hospital Los Angeles. Dr. Berry was a full-time clinician who turned to research in hopes of finding a better way to diagnose this pediatric cancer. She decided to examine the aqueous humor, which is the fluid inside the eye. What began as a question–can we arrive at a diagnosis using the aqueous humor?–grew into a full research program.

It turns out that these liquid biopsies contain more than a yes or no diagnosis of retinoblastoma.

“We use a tiny amount of fluid,” says Dr. Berry. “It’s only 100 microliters, about half the size of a pea. But we get a trove of information, things that were impossible to see before. We can see genetic mutations, chromosomal abnormalities. We can diagnose retinoblastoma at a molecular level.” This arms oncologists with a very specific map of each child’s disease.

The results have been so promising that Dr. Berry is taking her research to the next level. She has received funding from the National Cancer Institute of the National Institutes of Health (NIH) to oversee an international study on liquid biopsies for retinoblastoma. “Our studies have shown that some markers in the aqueous humor might mean a more severe disease,” she says. “Now we have a chance to really study this in a much, much larger patient population.”

Set to begin this summer, the study involves 18 sites internationally, including the largest retinoblastoma center in Canada. All study samples will be sent to and processed by Dr. Berry’s team and the Center for Personalized Medicine. The study is the first of its kind.

Children will be followed for a minimum of two years, so researchers can examine samples for possible cancer recurrence. Because tumors return in approximately 50% of retinoblastoma patients, this information can be lifesaving.

“We know that detecting a cancer as early as possible gives a child the best chance,” says Dr. Berry. “In continuing to take biopsies from these children, we can treat any recurrences early on, even before they’re visible to a clinician upon examination.”


Innovation in Under a Decade
To put into perspective how quickly and exponentially this research has grown, one need only to look at Dr. Berry’s NIH awards. A mere five years ago, she proposed to study the aqueous humor for liquid biopsy. Now, as her five-year grant comes to a close, much has changed, thanks to Dr. Berry’s determination and the work of CHLA’s Center for Personalized Medicine. “We now have a test in-house, where we can sample a patient’s aqueous humor, and within days we know whether or not the child has retinoblastoma, and the exact mutations and molecular profile of their cancer.”

What’s next?

The results of Dr. Berry’s forthcoming study will help shape the next phase of her research. “Right now, we’re in this position where we see very strong data,” she says, “and we need to ensure that what we’re seeing is also represented in the international population.” Then, says Dr. Berry, the team has plans to develop a clinical trial to evolve the standard of care for diagnosing and treating retinoblastoma–and link specific treatments to the information identified in the liquid biopsy.


This story originally appeared on the website of Children’s Hospital Los Angeles and has been reprinted with their permission.

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Entrepreneur turns to USC online health administration program to help launch startup


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Entrepreneur Turns to USC EMHA Program to Help Found Health Care Startup

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Entrepreneur Turns to USC EMHA Program to Help Found Health Care Startup
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When Ryan Nazar, MD launched Practical Healthcare, a startup aimed at empowering patients and building a community, he was on a mission to improve patient satisfaction, especially when it came to difficult disease and injury diagnoses.

But while Nazar had plenty of medical experience as a board-certified disability medicine physician, he knew he needed to advance his health care management and leadership skills to ensure his new company was a success. That’s why he turned to the Executive Master of Health Administration (EMHA) online program from the USC Price School of Public Policy.

Nazar, who attended medical school at University of Kentucky College, graduated in 2011 and decided to pursue neurosurgery, heading to Toronto for an internship and later Louisville for his residency. It was at that time, he said, the seeds for Practical Healthcare were sowed.

A patient from his residency was struggling to recover from a neck injury, despite the fact that she continually wore a brace. When Nazar deepened the physician-patient dialogue and asked how she wanted to tackle the treatment, she chose to remove the brace.

After doing so, she was finally able to recover. Inspired by the power of patient storytelling, Nazar soon published a peer-reviewed study outlining the disadvantages of legacy neck brace treatment, which “immobilized” patients’ necks and “recreated” the injuries.

“[The study] went on to us developing a 3D-printed cervical collar that I took to market. That was my foot out of the door of practicing clinical medicine,” he explained.

From there, Nazar continued to work in the medical startup space, ultimately settling into the business side of health care. While he was confident in the career pivot, Nazar sought an advanced degree to help him thrive in a leadership position.

“I [applied] to USC to obtain the EMHA to develop that skillset and gain the connections to really have a bigger impact on patient care and health care delivery,” he said.

Nazar was particularly drawn to the program’s group-based, problem-solving learning models, allowing him to gain “collective knowledge” from both the instructors and fellow cohort members.

“[It] created the sense that … I’m going to come here and have connections for the rest of my career and life that I can depend on and grow,” he said.

Although he graduated in 2019, Nazar said the program and his USC connections continue to influence how he approaches his work at Practical Healthcare as well as the industry at large. Being able to hone in on patient care within the EMHA was especially important for Nazar, as it helped maximize his impact on the health care field.

“[The program] allows you to specialize in different fields within health care. [It focuses on] what you value, and then it allows you, rather than putting your energy everywhere, to focus it in one area where you can make an impact, where you can break through the health care inertia,” Nazar said.

When Nazar completed the EMHA program, he was well-positioned to become a true leader in the health care startup space and launch the company he had long dreamed of: Practical Healthcare, which he described as “the first social media platform purpose-built for patient empowerment,” one that’s essentially a combination of LinkedIn, Reddit and Pinterest with “a medical twist.”

“Through the EMHA program, I discovered the power of storytelling, the value of learning from classmates and the importance of crowdsourcing solutions from peers[.] I honed my process improvement skills. These principles have deeply influenced Practical Healthcare, where we see patients as experts and foster a network of personalized treatments …. We aim not to disrupt health care, but to empower the resources already within our system[,]” he recently shared on LinkedIn.

Simply put, Practical Healthcare is for patients who feel a “one-size-fits-all approach” doesn’t tackle the unique medical issues they may have. Instead of having dissatisfied patients turn to social media platforms for advice, which can lead to misinformation or a lack of qualified assistance, they can utilize Practical Healthcare, where they can network with other patients with similar issues and values to get support.

A newsfeed function ensures these patients are getting up-to-date, trusted medical information aligned with their needs. There are also empowerment tools that allow patients to feel more confident in taking control of their health care journeys.

It’s an exciting moment for Nazar, who stresses he couldn’t have achieved the success he has at Practical Healthcare without USC Price. It’s why he strongly encourages other people interested in health care leadership to explore the EMHA online program. For those potential new students, he advises using their time at USC to truly define and pursue their goals.

“I think for anyone coming into the EMHA program, listen to yourself first and foremost. Realize that you can write your own story while at USC and take advantage of that. Whatever you choose to do, make sure that it’s something that aligns with you and that you’re following your success and your vision,” he said.

Learn more about the Executive Master of Health Care Administration online program today.

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Older adults with mild cognitive impairment may struggle with everyday decision-making

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Older adults with mild cognitive impairment may struggle with everyday decision making

Researchers from the Keck School of Medicine of USC found that the condition, which can be a precursor to dementia, was linked to worse decision-making abilities.
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Mild cognitive impairment (MCI) is a form of cognitive ability loss that can precede Alzheimer’s disease or other types of dementia. People with MCI have some trouble with memory and thinking, but can largely lead independent lives.

Past research suggests that adults with MCI may have worse judgment than those without when it comes to making financial and health care decisions. But how and when does age-related decline affect day-to-day decision making, and how can families and communities support older adults in balancing autonomy and safety?

A new study, funded in part by the National Institutes of Health, has now analyzed decision making more holistically and in a broader population of older adults. The researchers found that participants with MCI performed significantly worse on a test of four types of decision-making abilities compared to older adults who were cognitively healthy. The results were just published in the Journal of Alzheimer’s Disease.

“This additional evidence helps replicate our earlier studies and makes us more confident that older adults with MCI might have trouble with certain types of decisions,” said corresponding author Duke Han, PhD, director of neuropsychology in the Department of Family Medicine and a professor of family medicine, neurology, psychology and gerontology at the Keck School of Medicine of USC.

That could indicate that adults with MCI might want to seek support on certain types of decisions, including financial matters or whether it’s safe to continue driving. But the researchers note an important caveat: Adults with MCI can still do many things on their own.

“The study does not imply that older adults with MCI are incapable of making good decisions independently,” said Laura Fenton, a doctoral student in clinical psychology at the USC Dornsife College of Letters, Arts and Sciences and the paper’s first author. “While those with MCI may benefit from additional resources, assistance during decision making or both, it will be important to strike a balance between support and respect for autonomy.”

Measuring decision making

To explore the link between MCI and decision-making, the researchers tested participants enrolled in the Advancing Understanding of Transportation Options (AUTO) study, an analysis of decision-making in driving among older adults led by Marian E. Betz, MD, MPH, professor of emergency medicine at the University of Colorado.

The present analysis included data from 301 older adults with an average age of 77.1 years, spread across three sites (Denver, Indianapolis and San Diego). Using data from multiple regions makes the findings more broadly applicable, Han said.

Han and his colleagues tested decision-making with a modified assessment known as the Short Portable Assessment of Capacity for Everyday Decision making (SPACED). Older adults answered questions about a hypothetical scenario: A family member received a past due notice from the electric company and needed to decide whether to pay the bill or leave the country to avoid the problem. The participants were asked to explain the problem and discuss advantages, disadvantages and potential consequences of the two proposed solutions. Trained raters then gave scores for four kinds of decision-making abilities based on the coherence of each answer — understanding, appreciation, comparative reasoning and consequential reasoning.

Participants with MCI scored an average of 2.17 points lower on the SPACED than those without. Among cognitively healthy individuals, 79.9% received a perfect score on the SPACED; among those with MCI, 57.1% scored perfectly.

A broad approach

Because the SPACED assesses multiple components of decision making, the study’s findings could have broad implications for choices about finances, health care, end-of-life issues and more.

“One of the main takeaways is that if someone is starting to experience cognitive impairment, it’s not a bad idea to seek out additional help in these areas,” Han said.

In future research, Han and his colleagues aim to increase the racial and ethnic diversity of participants to ensure that findings accurately capture the experience of older adults across the United States.

About this study

In addition to Han, Fenton and Betz, the study’s other authors are Carolyn G. DiGuiseppi, Rachel L. Johnson, Ryan A. Peterson, Christopher E. Knoepke and Daniel D. Matlock from the University of Colorado; Nicole R. Fowler from the Indiana University School of Medicine; Linda Hill and Ryan Moran from the University of California San Diego; and Jason Karlawish from the University of Pennsylvania.

This work was supported by the National Institutes of Health [R01AG059613, UL1 TR002535, K23 HL153892] and the Colorado Clinical and Translational Sciences Institute.

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COVID-19, flu and respiratory syncytial virus (RSV) vaccines — what you need to know

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COVID-19, Flu and RSV vaccines — what you need to know
Keck Medicine of USC experts discuss new recommendations for staying healthy and safe during the respiratory virus season
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LOS ANGELES — Over the last few years, the nation has been through multiple rounds of COVID-19 vaccinations. This fall, the COVID-19 vaccine will be offered annually. The flu shot will also be recommended, as well as a newly approved vaccine for respiratory syncytial virus (RSV), a virus that is especially harmful to infants and older adults.
What can we expect from the vaccines, how important are they and can you get them at the same time? Keck Medicine of USC experts have the answers.
How COVID-19 vaccinations are changing this fall
The updated COVID-19 vaccine is designed as a single annual dose that will target the Omicron subvariant XBB.1.5, which is responsible for the majority of cases today. This formula should also offer protection against the new XBB substrains that have recently emerged.
The vaccine will be offered by Pfizer, Moderna and a newcomer, Novavax.
We are still awaiting final approval and recommendations for the vaccine from the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC). At that time, health officials will also make recommendations about who is eligible for the vaccine.
The U.S. Government COVID-19 Vaccine Distribution Program, which provided free vaccinations, will end. However, insurance should pick up the cost for COVID-19 vaccines, and for those uninsured or underinsured, the CDC is launching the Bridge Access Program for COVID-19 vaccines. The CDC will partner with state and local programs to provide and distribute the free vaccines.
— Edward Jones-Lopez, MD, MS, is an infectious disease expert with Keck Medicine of USC. He is available for interviews in English and Spanish.

Why COVID-19 vaccines are still needed
Research shows about 75% of Americans have retained at least some immunity from a prior infection of the virus. However, immunity fades over time and the individual risk of getting COVID-19, despite some immunity, is varied and inconsistent. The protection offered by vaccines also fades over time.
Despite advances in treating COVID-19, it still can be a difficult and deadly disease that can lead to hospitalization, long-term symptoms or death. The side effects of the vaccine have proven to be minimal, so it is recommended that everyone who is eligible gets vaccinated, especially as we are coming off a summer surge and there may be future outbreaks over the holidays.
If you have any concerns about the vaccine due to a health condition, consult your health care provider. Additionally, while most people can wait until the new COVID-19 vaccine is released rather than getting the still-available 2022 vaccine, if you feel your health requires a vaccination now, you should also talk to your health care provider.
— Earl Strum, MD, is the medical director of Employee Health Services for Keck Medicine of USC and clinical professor of population and public health science with the Keck School of Medicine of USC.

Timing your vaccines safely and effectively

It is recommended that everyone six months or older be vaccinated against influenza every year. The best time to get the flu shot is September or October, so you will be inoculated in plenty of time before the high-flu season of the holidays.
It is safe to get the flu shot at the same time as your COVID-19 vaccine. For some people, one or both vaccines may result in mild flu-like symptoms that should pass within a few days. For those concerned about soreness at the site of the jab, consider getting one shot in one arm and one in the other arm to avoid overtaxing one limb. Also, if a local reaction does occur, you will know which vaccine was responsible. If not insured, you can find a free flu shot at a local health clinic, pharmacy or even grocery store.
RSV is a highly contagious virus that causes infections of the lungs and breathing passages, particularly among the young and old. The CDC recommends adults 60 years and older receive a single dose of the RSV vaccine in consultation with their health care provider. Additionally, the FDA just approved the RSV vaccine for use in pregnant individuals to protect infants from the virus.
Clinical trials have shown that there are minimal side effects of the vaccine, and any mild symptoms far offset the possible serious complications RSV can cause. Talk to your health care provider should you have any questions or concerns about this new vaccine, including payment/insurance options.
While co-administration of the RSV vaccine with other vaccines is in accordance with general best practice guidelines for immunization, recommendations have not yet been made whether or not this vaccine should be taken at the same time as the COVID-19 and flu vaccines.
— Krist Azizian, PharmD, MHA, is the chief pharmacy officer for Keck Medicine of USC.


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Alzheimer’s gene associated with increased fertility in Amazonian women

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Alzheimer’s gene associated with increased fertility in Amazonian women

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Alzheimer’s gene associated with increased fertility in Amazonian women
Allele associated with increased risks for dementia and heart disease is linked to earlier age of first birth as well as shorter intervals between births in a Bolivian indigenous community.
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gust 18, 2023 | Print
In a quest to determine how a gene associated with increased Alzheimer’s risk is surviving natural selection, a group of researchers from multiple universities including USC have discovered that the APOE-?4 allele is associated with increased fertility in women.

Previous research revealed that the Apolipoprotein-?4 (APOE-?4) allele increases the risk for a variety of diseases in aging populations, specifically Alzheimer’s and cardiovascular disease. And yet, despite its negative effects, this allele remains prevalent in approximately 20% of the human population.

In the new paper, the authors worked alongside the Tsimane (Chi-mahn-eh) community in Bolivia, a forager-horticultural society, to look at the effects of the allele through an evolutionary, anthropological lens. To do so, lead author Benjamin Trumble, an associate professor of evolutionary anthropology at Arizona State University, headed to the Bolivian Amazon lowlands where the Tsimane live.

The Tsimane Health and Life History Project (co-directed by Trumble, Hillard Kaplan of Chapman University, Michael Gurven of UC Santa Barbara, and Jonathan Stieglitz of the Institute for Advanced Study in Toulouse, France) has a longstanding relationship with the Tsimane to collect demographic and biomedical data and help provide medical care — a relationship that has been in effect for over 20 years. With over 17,000 people living across 90 villages, their hunter-farmer lifestyle is more similar to human life prior to the Industrial Revolution than modern cities, offering a unique glimpse into health and aging without modern-day influences.

Several researchers at USC have been involved with the Tsimane Health and Life History Project (THLHP), including University Professor and ARCO/William F. Kieschnick Chair in the Neurobiology of Aging Caleb Finch, a corresponding author of the new study. Finch has researched APOE alleles and their associations with health risks for more than 30 years; in a 2017 study, he and his colleagues discovered that APOE-?4 was associated with higher fertility in women exposed to high pathogen levels in rural Ghana.

“APOE-?4 was first recognized in the 1980s for its association with high blood cholesterol and more heart attacks,” Finch said. “That set many of us to thinking that maybe there was a reproductive advantage to having high lipids during pregnancy.”

For this particular study, the researchers collected data from 795 Tsimane women, ranging in age from 13 to 90 years old. The team of researchers not only retrieved genetic data to determine which alleles are present for each individual, but also information about their fertility, including age of first birth, how long between births and total number of live births.

When looking at the data, the researchers found that Tsimane women with the presence of one APOE-?4 allele had an increase of 0.5 births, compared with those without the APOE-?4 allele. The number of live births increased even more when there was the presence of two copies of the APOE-?4 allele. These women had an average increase of two live births compared with those without this specific allele.

“What we found in this population was that women began reproducing almost a year earlier if they had the APOE-?4 allele, and they had shorter interbirth intervals. Those two things combined allow them to have about half an additional kid if they have one copy or two additional kids if they have two copies,” Trumble explained.

This advantageous effect on fertility could help to explain how an allele that has such a negative impact in one’s later life through the increased chances of developing Alzheimer’s or cardiovascular disease has not been weeded out by natural selection — the advantages take place in one’s early to mid-life years, and therefore are passed along to their offspring.

“Genes that are associated with diseases that occur after the age of reproduction, or after reproduction has already started, are in ‘selection’s shadow.’ There have been a lot of arguments about the APOE-?4 allele — that it may be an example of selection’s shadow, that you don’t develop Alzheimer’s until after you’ve already had all your kids,” Trumble said.

Other smaller studies have shown other advantageous aspects of the APOE-?4 allele, including that children in Brazil are able to handle environmental pathogens and parasites, such as Giardia, better than those without the allele, which resulted in better cognitive functions and higher growth rates.

Even with these benefits of the APOE-?4 allele that have been discovered, there is still the major deleterious effect of the increased risk of Alzheimer’s and cardiovascular disease in the later stages of life. Interestingly, this negative effect of the allele is mostly seen in Westernized nations. The Tsimane, for instance, have the lowest rates of dementia and Alzheimer’s in the world, despite having the same 20% prevalence of the APOE-?4 allele in their population.

What can this mean for understanding and treating the negative effects of the allele in areas affected the most?

“We need to better understand global variation, and in particular, we need to kind of think outside the box and move beyond our focus on ‘this allele causes X disease’ and that’s just how it is,” Trumble said. “Instead, we need to take a step back and say, ‘What about in different environments? What about in the environments in which humans evolved?’ Because that actually opens up a whole other possibility for prevention or treatment by being able to mimic some of the aspects of that lifestyle. If we aren’t seeing the same associations between APOE-?4 and some outcome, then maybe (we need to) kind of take a step back and say, ‘OK, what are the differences?'”

Further research into the APOE alleles will also include the study of their “gene neighbors,” separated genes that modify the activity of the different alleles, which may shed more light on how APOE-?4 improves fertility, Finch said.

“This is a deep, robust study that shows APOE-?4 has a major set of benefits to reproduction,” Finch said. “The next phase of the work with the Tsimane is to look at these other genes to see how they interact or modify the effects of APOE-?3 and APOE-?4.”

“Apolipoprotein-?4 is associated with higher fecundity in a natural fertility population” was released August 9, 2023 in Science Advances. In addition to Trumble, Gurven, Finch, Kaplan, and Stieglitz, coauthors included Mia Charifson of New York University; Tom Kraft of the University of Utah; Angela R. Garcia, Stephanie V. Koebele, and Kenneth Buetow of Arizona State University; Daniel K. Cummings and Paul Hooper of Chapman University; Amanda J. Lea of the Canadian Institute for Advanced Research; Daniel Eid Rodriguez of the Universidad de San Simon, Bolivia; Bret Beheim and Riana Minocher of the Max Planck Institute for Evolutionary Anthropology, Germany; Maguin Gutierrez of the Tsimane Gran Consejo, Bolivia; Gregory S. Thomas of UC Irvine; and Margaret Gatz of USC.

The Tsimane Health and Life History Project is a large interdisciplinary team effort, combining anthropologists, cardiologists, neurologists and gerontologists, as well Bolivian physicians and Tsimane anthropologists. The project was funded by the National Institutes of Health, National Institute on Aging (R01AG054442). Other funders of this study included the National Science Foundation (1748282) and Agence Nationale de la Recherche (ANR-17-EURE-0010).

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Gift to expand understanding, clinical management of migraine, other debilitating neurological pain


USC Dornsife receives gift to expand the understanding and clinical management of migraine and other debilitating neurological pain

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USC Dornsife receives gift to expand the understanding and clinical management of migraine and other debilitating neurological pain
Arnold and Roberta Mahler aim to break down research silos, accelerate treatment progress and bring hope to patients and families.
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Roberta “Bobbi” Mahler ’66 knows firsthand that the pain associated with migraine disease is not just physiological. Living with chronic neurological pain can also be emotionally distressing, impacting both migraine sufferers and those who care for them.
Mahler’s daughter first developed debilitating headaches at age 14, in 1988. As her daughter’s physical and mental anguish worsened over time and treatments proved inadequate, Mahler felt powerless to help her.
Her desire to spare other migraine patients and their families such suffering now underlies the generous gifts that she and her husband, Arnold Mahler, have made to the USC Dornsife College of Letters, Arts and Sciences and the Keck School of Medicine of USC.
In Spring 2022, the Mahlers donated $2 million to USC Dornsife to establish endowed funds aimed at furthering the understanding of neurological pain and its clinical management through collaborative endeavors between researchers at both USC schools. Several weeks later, they bequeathed a third of their estates to establish an endowed professorship in headache and neuralgia medicine at Keck School of Medicine.
“Anyone who has experienced … being in a helpless position of watching a loved one suffering intense pain will be able to relate to my desire to improve our medical professions’ knowledge and understanding and their practices related to neurological ailments and pain management,” says Bobbi Mahler.
Gift aims to overcome barriers to treatment
Mahler notes that when her daughter first began experiencing migraine over three decades ago, doctors dismissed her complaints. “No matter where we took her, they said, ‘It’s all in her head,'” she recalls.
In the ensuing decades, “there’s been a lot of progress in the field, and doctors … recognize it as a real issue,” she says. “But not enough has happened, in large part from a lack of collaboration and grant acquisition between departments and schools within individual universities.”
Though high-profile individuals, including tennis star Serena Williams, have been publicly vocal about their struggles with migraine in recent years, research shows that stigma remains a barrier to treatment for many of the 47 million Americans who live with migraine.
Other studies indicated that the dearth of federal funding for migraine research and of medical specialists who treat migraine has meant that the pace of research on effective treatments has been slow, and treatments, data and clinical studies are not universally shared and discussed.
With their gifts, the Mahlers aim to support research and clinical advancements that pierce such barriers.
“We want to elevate and escalate the speed of progress,” says Mahler. “We want help for migraine sufferers sooner, better, faster.”
Collaboration targets pain
In their careers, both Arnold and Bobbi Mahler served in leadership roles that taught them the value of bringing experts together to solve complex problems. Bobbi Mahler, who majored in international relations and earned her teaching credential at USC Dornsife, had a long career as an elementary school administrator and superintendent.
“I learned that the best things get done in the best ways when you have all the forces contributing,” says Mahler, who now coaches educational administrators.
Arnold Mahler developed a similar view through his work running an international acquisitions and mergers business.
The couple came to believe that the best way to accelerate understanding and treatment of neurological pain is to dissolve institutional divisions between researchers and medical clinicians. “You work it out like a jigsaw puzzle together,” says Bobbi Mahler.
When approaching USC with their idea for the endowed funds, “we insisted on a commitment to an intentional and consistent venue for the sharing of knowledge and practice between clinicians and researchers,” she says. “As a result of what we wanted, it became evident we needed to establish two endowments, not one.”
Transformative gifts boost powerful research
With $1.5 million of their gift going to USC Dornsife, the couple established the Mahler Family Endowed Fellowship Fund, which provides fellowships to graduate students and postdoctoral researchers to pursue fundamental or translational research related to neurological pain, from molecular mechanism to brain function.
The remaining $500,000 of their gift established the Mahler Family Endowed Research Fund, which will support collaborative research activities of the USC Dornsife Pain Center.
Their bequest to Keck School of Medicine, currently valued at about $2 million, will establish the Dr. Roberta and Arnold Mahler Endowed Professorship in Headache and Neuralgia Medicine. The holder of the professorship will oversee collaborative efforts between the USC Department of Neurology at Keck School of Medicine and USC Dornsife.
Should the bequest ultimately exceed $2 million, the remainder will establish the Dr. Roberta and Arnold Mahler Translational Science Fund, whose purpose will be to support a program manager responsible for assisting in the formal collaboration efforts between the two USC schools.
“These transformative gifts represent a lasting commitment to USC for the Mahlers, whose estates will leave a legacy of impact for years to come,” said Alexandra Lohse, senior director of development and planned giving at USC Dornsife.
Research to end migraine is “all about hope”
While the endowments will afford scholars and students enhanced opportunities to teach, learn and generate impactful research, the ultimate beneficiaries of the gifts will be patients who struggle with neurological pain. Patients who become subjects of the collaborative research and clinical activities “will receive and contribute to advanced effective treatment of neurological diseases and chronic pain,” says Mahler.
Finding new ways to safely and reliably relieve migraine promises to transform the sense of hopelessness that many patients and families feel.
“They will be able to live fuller, happier and more productive lives,” she says. “It’s all about hope.”
The Mahlers also wish to inspire additional donations to USC that expand research and treatment funding for migraine and other chronic neural pain conditions that prevent people from living full and satisfying lives.
“Our dream is that others who have an interest in collaborative, multidisciplinary problem-solving in the world of medical research will also contribute to these efforts to whatever degree they can,” says Mahler.
Mahler notes that seeing her and her husband’s vision for the endowments come to fruition is very gratifying. “Not too many people can be this lucky to see a dream start to be fulfilled,” she says.

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Transformative gifts provide vital support for much-needed migraine and neurological pain research.
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Exposure to air pollution early in pregnancy increases risk of gestational diabetes, study finds

Exposure to air pollution early in pregnancy — and even shortly before conception — increases a woman’s risk of developing gestational diabetes, according to a new USC study out in The Lancet Regional Health — Americas.

Gestational diabetes usually goes away after childbirth, but it can cause problems during pregnancy. For the mother, it increases the risk of high blood pressure and preeclampsia. For the baby, it can lead to larger birth weight, a higher chance of delivery by cesarean section and greater risk of obesity in the future.

“Interestingly, we found gestational diabetes risk wasn’t associated with long-term air pollution exposure but was associated with air pollution in a relatively short but critical periconceptional window, from five weeks before to five weeks after conception,” said first author Zhongzheng “Jason” Niu, a postdoctoral fellow in population and public health science at the Keck School of Medicine of USC. “During the menstrual cycle, in preparation for pregnancy, a woman’s body goes through significant physiological changes, especially in how it handles glucose to support fetal growth. This dynamic period of metabolic adaptation may increase the mother’s susceptibility to environmental insults.”

For the study, researchers drew 617 participants from the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) study, an ongoing prospective pregnancy cohort study established in 2015. Participants, predominately Hispanic, were patients at clinical sites that serve low-income populations in Los Angeles.

Niu and his colleagues correlated residential addresses with EPA ambient air quality data. Specific pollutants on the watchlist were those typically associated with traffic: fine particle pollutants PM2.5 and PM10 as well as nitrogen dioxide and ozone.

Study focuses on gestational diabetes and air pollution

Of the 617 participants, 60 developed gestational diabetes. The study found that exposure to air pollutants during the critical periconceptional window was associated with an increased risk of gestational diabetes, by 5.7% for PM2.5, 8.9% for PM10 and 15% for nitrogen dioxide.

The researchers also found the association between air pollution and gestational diabetes was more pronounced among study participants experiencing prenatal depression. Prenatal depression, already a concern for its potential impact on both mother and child, appears to amplify the effects of air pollution exposure.

“Our research indicates that women with symptoms of prenatal depression are even more vulnerable to the adverse effects of air pollution,” said senior author Shohreh Farzan, an associate professor of population and public health sciences at the Keck School of Medicine. “This underscores the importance of developing more holistic health care approaches that consider both mental and environmental factors during pregnancy. Addressing prenatal depression not only benefits maternal mental health but may also buffer against environmental risks like air pollution.”

Unclear what connects gestational diabetes and ambient air pollution

The mechanism connecting ambient air pollution and gestational diabetes remains unclear, researchers say, but an interplay among impaired glucose metabolism, inflammation and hormonal changes could be to blame. Prenatal depression, with disrupted immune and hormonal functions, could make the case worse.

One theory is that air pollution exposures trigger oxidative stress in the respiratory tract, Farzan said, leading to chronic inflammation throughout the body, with exhausted antioxidant defenses over time. This disrupts insulin signaling pathways and limits glucose-consuming cells from healthy intake of circulating glucose.

“We suspect air pollution, particularly for exposure in a defined period of the eight weeks from last menstrual period through the first few weeks of pregnancy, could disrupt physiological adaptations during early pregnancy that may predispose the pregnant women to an increased risk of gestational diabetes,” said Farzan. “Even though the overall levels of air pollution observed in the study were within guidelines, these levels still present significant health risks. This underscores the need to reevaluate the adequacy of existing air quality standards to ensure the well-being of expectant mothers and their unborn children.”

In addition to Niu and Farzan, other authors are Rima Habre, Tingyu Yang, Brendan H. Grubbs, Sandrah P. Eckel, Jill Johnston, Genevieve F. Dunton, Theresa M. Bastain, Carrie V. Breton, Laila Al-Marayati, all of Keck School of Medicine; Claudia M. Toledo-Corral of Keck School of Medicine and California State University, Northridge; Nathana Lurvey of Eisner Health, Los Angeles; and Fred Lurmann and Nathan Pavlovic of Sonoma Technology Inc.

The work was supported by NIH grants P50MD015705, P50 ES026086, UH3OD023287, P30ES007048, R01ES027409 and EPA grant 83615801-0.

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Linked through mission, L.A. and USC bring medicine and housing to the homeless via Street Medicine

With more than 76,000 people living on the streets of Los Angeles and neighboring cities, homelessness looms large in the region’s public consciousness.

“The homeless population is probably something that everyone in this room thinks about every morning that they wake up,” USC President Carol L. Folt said, nodding at L.A. Mayor Karen Bass and more than 260 medical professionals and advocates attending the 5th annual California Street Medicine Symposium on Friday.

The homeless population is probably something that everyone in this room thinks about every morning that they wake up.

Carol L. Folt, USC president

Folt and Bass met for a “fireside chat” at the symposium, which also drew more than 160 virtual attendees. Their joint appearance symbolized a growing collaboration between the city — as Bass works intensely to house and provide services to the unhoused — and the university, whose Street Medicine teams are providing daily, mobile care to thousands of homeless people and training other teams around the state.

“We really must set the pathway for ending homelessness,” Bass said. “That has to be our orientation.

“I drive down a street and I see a tent and I think I have no right to think that I can’t move forward and I can’t do things,” Bass said.

Folt noted the mayor’s background in health care. Bass, a former physician’s assistant and nurse, has encountered the tragic realities of daily life in L.A. in the emergency room.

“Working in the emergency room, you have a different viewpoint,” Bass said, noting that her constant exposure to medical emergencies give her confidence that it is possible to solve homelessness.

“When people come up to me all freaked out about homelessness or other issues, I think, ‘Do you have a pulse?’ We can manage this,” Bass said. “It helps to lower the temperature and calm people down and say: We can do this. We are the richest country in the world. We can do this.”

L.A. funding for USC Street Medicine program

Earlier this summer, the L.A. City Council approved $4 million in new funding for USC Street Medicine. Co-directed by Brett Feldman and Corinne Feldman, the program operates four full-time teams who wind their way through L.A. streets, to stop and provide medical care to unhoused people throughout the city.

USC Street Medicine teams consist of physicians, physician assistants, medical assistants and nurses, as well as a social worker and psychiatrist “who meet people where they are at,” said Brett Feldman, explaining the program’s mobile model of health care in the streets. Feldman runs the program with Corinne Feldman, a fellow physician, who oversees education and training. They are married — a power couple of Street Medicine who provide not only medical aid but compassion and love to people who may feel they have none. Through their annual symposium, they connect with and train other street medicine teams from across California, which is home to an estimated 30 such teams.

“Heart speaks to heart, as you say, Brett,” Folt said after he introduced her to the crowd.

Feldman noted that with Folt’s leadership, the university allowed USC Street Medicine to lead legislation, AB 369, to seek reimbursements for street medicine care. After some effort, the university, USC Street Medicine and the Street Medicine Institute pivoted the effort instead to change Medicare rules.

They succeeded.

In June, the federal Centers for Medicare and Medicaid Services officially recognized that medical care can be delivered on the street. The decision makes it possible for street medicine teams to be reimbursed for services, removing a significant obstacle to treatment.

Taking medical care to the streets

The Street Medicine teams provide on-site primary care and treatment for psychiatric disorders and substance use disorders, dispensing medications, tending wounds and performing blood draws. Through their work, the medical teams become very close to many of the patients, helping many rise from hardship, while seeing others stumble, fall or, sadly, pass on. All the same, the teams are there to aid them.

Each team cares for approximately 400 patients a year and provides around 2,500 patient visits per year. The program has been shown to decrease hospitalizations by over 70%.

Working with unhoused patients also intricately links these teams to the city’s efforts. The teams serve as a conduit to housing, with almost 40% of all people seen being placed in transitional or permanent housing, including the mayor’s Inside Safe program.

Months earlier, after Bass was sworn in as mayor, she declared a state of emergency in L.A. for homelessness. The move freed up funds and other resources for the city to launch the Inside Safe program to house the unhoused in motels.

We are dispelling the myth that people want to be in the street.

Karen Bass, Los Angeles mayor

“Inside Safe — it’s not rocket science,” Bass said. “It’s spending a few days going out and asking people if they want housing. We are dispelling the myth that people want to be in the street. People don’t want to be in the street. I never believed they did.”

Bass explained that the two missions — housing and medicine — go hand in hand. “The day you come out of the tent is the day you should have a full physical and mental health assessment,” Bass said, adding that is why she wanted the city to collaborate with USC Street Medicine.

Caring for the unhoused forges for many of the physicians a transcendent connection between the teams and their patients. Patients often list the providers on their documents as their first phone call or surviving kin, underscoring their profound relationship.

After the fireside chat, Corinne Feldman acknowledged that the teams who have devoted themselves to the mission of street medicine endure trauma and grief, losing patients to illness, violence and injustice. (See below.)

She invited attendees to pluck a ribbon from the bowls she had set on the tables, and to write with markers the names of patients whom they loved and lost. The ribbons will be gathered and made into a wreath that will hang on the wall of USC Street Medicine’s offices.

“We invite you today to let suffering speak,” she said.

‘Remembrance’ by Corinne Feldman

Corinne Feldman read this to the audience after the fireside chat.

“In my experience, one of the most disorienting parts of this work has been the inexplicable loss of precious life to the streets — passings which are often unceremonious, unnoticed, uncounted and unaccounted for.

“And when they are counted, lives are reported as aggregated numbers, metrics or costs — nameless and faceless.

“The lives of those who were unsheltered and the street-based teams who have come to know them are intricately interwoven. The nature of street-based work is bidirectionally rehumanizing and humbling.

“The teams witness the complexity, intolerability and devastation often borne by nearly always choosing between two impossible choices.

“And in many instances, it is a team member that is listed in a medical chart as next of kin, are the recipient of final phone calls or are the hand-holder of a terminally ill person who didn’t want to die alone.

“So, what we are often left with is unexpressed love. The tension between holding it all in, and letting it all out. In other words, grief.

What if grief was no longer expected to be a solitary burden to carry alone … but rather something that could be collected, shared and held by many hands?

Corinne Feldman, USC Street Medicine

“But what if grief was no longer expected to be a solitary burden to carry alone, layered one by one onto a tiny, but sturdy, frame until it breaks, but rather something that could be collected, shared and held by many hands?

“Collective grief is justice. It is community. And it is loud because it stands in the way of the belief that no one cared anyway. That no one would miss them. No one loved them and therefore no one would grieve.

“Philosopher Cornell West teaches that in order to become a ‘prisoner of hope,’ we must ‘wrestle with despair.’ Hope is a product of witness, of being in the mess. Hope is not the product of being a spectator.

“And from that vantage point, we must be unwavering in letting suffering speak, in order to hear truth.

“So, we invite you today, to let suffering speak. To remember. First by participating in a collective remembrance project. On your tables, you will find ribbon and markers. We invite you to write the name of a person, whether patient, family, friend or neighbor, who has died on our streets.

“If you are joining us virtually, we welcome those names to be put in the chat and we will write the names for you. These ribbons will be collected today and placed on a remembrance wreath that will be displayed in the division of Street Medicine at USC and brought yearly to this symposium so we may continue to honor those who have departed.”

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People can’t recover the ability to hear — or maybe they can


August 14, 2023 at noon Pacific Time
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A deafened adult cannot recover the ability to hear, because the sensory hearing cells of the inner ear don’t regenerate after damage. In two new studies, partially funded by the National Institutes of Health and published in the Proceedings of the National Academy of the Sciences (PNAS), USC Stem Cell scientists explain why this is the case and how we might be able to change it.


“In the non-sensory supporting cells of the inner ear, key genes required for conversion to sensory cells are shut off through a process known as ‘epigenetic silencing.’ By studying how the genes are shut off, we begin to understand how we might turn them back on to regenerate hearing,” said John Duc Nguyen, the first author of one of the papers. Nguyen now works at the biotech company Genentech and earned his PhD in the USC Stem Cell laboratory of Neil Segil, who passed away from pancreatic cancer in 2022.


The second paper explored when and how the ability to form sensory hearing cells is gained in the inner ear in the first place and describes two specific genes that could be useful for regenerating hearing in adults.


“We focused on the genes Sox4 and Sox11 because we found that they are necessary for forming sensory hearing cells during development,” said the paper’s first author Emily Xizi Wang, who also conducted her research as a PhD student in the Segil Lab, and works at the biotech company Atara Biotherapeutics.


Gage Crump, a co-author on both papers and the interim chair of USC’s Department of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine of USC, added: “These two papers are not only great science, but also a clear example of Neil Segil’s enduring legacy as an exceptional mentor to the next generation of stem cell researchers.”


Silencing isn’t golden


One important way that genes are shut off or “silenced” involves chemical compounds called methyl groups that bind to DNA and make it inaccessible–the focus of Nguyen’s paper. When the DNA that instructs a cell to become a sensory hearing cell is methylated, the cell cannot access these instructions.


Through their experiments with non-sensory supporting cells extracted from the inner ears of mice, Nguyen and his colleagues confirmed that DNA methylation silences genes that promote conversion into sensory hearing cells, including the gene Atoh1 that is known to be a master regulator of inner ear development.


An enzyme called TET can remove methyl groups from the DNA, thus reversing the gene silencing and restoring the capacity of supporting cells to convert into sensory hair cells. Accordingly, when the scientists blocked the activity of TET, the supporting cells retained their DNA methylation and therefore could not convert into sensory hair cells in the Petri dish.


Intriguingly, in a separate experiment, the researchers tested the extent of gene silencing in supporting cells from a chronically deafened mouse. They found that gene silencing was partially reversed, meaning that the supporting cells had the capacity to respond to signals to transform into sensory hearing cells. This finding has important implications: the loss of sensory hearing cells itself might partially reverse gene silencing in supporting cells in chronically deaf individuals. If so, the supporting cells of chronically deaf individuals might already be naturally primed to convert into sensory hearing cells.


Segil’s longtime collaborator Andrew K. Groves from the Baylor College of Medicine served as the paper’s corresponding author.


Knocking their Sox off


In the second paper, Wang and her colleagues explored when and how the progenitor cells of the inner ear gain the ability to form sensory hearing cells.


The scientists pinpointed when progenitor cells acquire this ability: between days 12 and 13.5 of embryonic development in mice. During this window, the progenitor cells acquire the capacity to respond to signals from the master regulator gene Atoh1 that triggers the formation of sensory hearing cells later during development.


What primes the progenitor cells to respond to Atoh1 are two additional genes, Sox4 and Sox11, that change the state of these cells.


In embryonic mice lacking Sox4 and Sox11, progenitor cells in the inner ear failed to develop into sensory hearing cells. Specifically, a loss of Sox4 and Sox11 made the cells’ DNA inaccessible–an effect similar to DNA methylation. With their DNA inaccessible, the progenitor cells couldn’t respond to signals from Atoh1.


On the flip side, high levels of Sox4 and Sox11 activity stimulated mouse progenitor cells and supporting cells to form sensory hearing cells in a Petri dish.


More promising still, in mice with damaged sensory cells in the inner ear, high levels of Sox4 and Sox11 activity increased the percentage of vestibular supporting cells that converted into sensory receptor cells–from 6 percent to 40 percent.


“We’re excited to continue exploring the mechanisms by which cells in the inner ear gain the ability to differentiate as sensory cells during development and how these can be used to promote the recovery of sensory hearing cells in the mature inner ear,” said the paper’s corresponding author Ksenia Gnedeva, who completed her postdoctoral training in the Segil Lab and is now an assistant professor in the USC Tina and Rick Caruso Department of Otolaryngology – Head and Neck Surgery, and the Department of Stem Cell Biology and Regenerative Medicine.


About the studies


Juan Llamas from the Segil lab and Tuo Shi from the Crump lab are co-authors of both studies. For Wang and Gnedeva’s paper, additional co-authors include Talon Trecek, Litao Tao, and Welly Makmura from the Segil lab.


Both studies were supported by the National Institutes of Health (NIH grant RO1 DC015829), as well as a Hearing Restoration Project Consortium award from the Hearing Health Foundation. Nguyen and Groves’ study received support from three additional NIH grants (F31 DC018703, T32 HD060549, and RO1 DC014832), and Wang and Gnedeva’s study received support from two additional NIH grants (R21 DC016984 and T32DC009975).

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Helping older adults in times of extreme heat


Helping Older Adults in Times of Extreme Heat

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Helping Older Adults in Times of Extreme Heat
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As the summer of 2023 appears poised to be the hottest on record, caregiving expert Donna Benton shares how caregivers can help vulnerable older adults stay healthy despite the heat.

“It is predicted that this is not just going to be our hottest summer, but we’re going to have more extreme weather events, so we need to be prepared,” says Benton, research associate professor at the USC Leonard Davis School of Gerontology and director of the USC Family Caregiver Support Center (FCSC). “There are things that caregivers can do to make sure that an older adult is safe during these type of heat emergencies that we’re witnessing more.”

Check in and prepare
Simply checking in with loved ones, friends, or neighbors and making some quick preparations can be hugely beneficial, Benton says.

“It’s nice to have a checklist of things that you can do,” she says. “Can you make sure the person has enough water in their house? Are you aware of where the cooling centers are? If you have an extra fan and that person doesn’t have one, can you loan them a fan? [Is there] a list of their doctors, so that if you need to call the doctor and describe what’s going on, they can tell you the next steps to do if somebody’s feeling ill?”

This is especially important for people living alone, Benton adds: “It’s important if you can at least have one other person who checks on you on a regular basis. That way, if there’s an emergency, you should have somebody who knows.”

Know who’s at risk
Older people are at heightened risk during heat waves, especially in low-income communities, Benton explained.

“The highest-risk people during this climate change are people who are ill; a lot of older adults already have some illnesses,” she says. “People who are in low income areas [may not] have accessible ways of cooling their home. … Older adults are more vulnerable during extreme heat and other natural disasters because they may have physical limitations so that they can’t get out of the home.”

New training program for caregivers
The Los Angeles Caregiver Resource Center, a program of the FCSC, is partnering with UCLA to launch HeatWise, a training program for informal caregivers on helping older adults prepare for heatwaves and recognizing the signs of heat-related illness. The HeatWise program was proposed by UCLA student Nikolas Wianecki and was named a winner of the 2023 Health Equity Challenge, a competition presented by the UCLA Center for Health Policy Research, The MolinaCares Accord, and the California Health Care Foundation.

Benton says the HeatWise program will feature online and printed toolkits with checklists, resources, and lists of symptoms all related to heat as well as workshops to help caregivers learn how to respond to heat emergencies.

“[The toolkit] be easy to read, with things you can rip out and fill in so that you have your checklist ready and you can individualize it,” she says. “It’s really an exciting project.”

Watch below as Donna Benton shares how to help older adults in times of extreme heat.

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As the summer of 2023 appears poised to be the hottest on record, caregiving expert Donna Benton (@donnabentonphd) shares how caregivers can help vulnerable older adults stay healthy despite the heat. #Heatwave #Caregivers
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