Blocking Zika: New antiviral may treat and prevent infection, a Stanford study suggests

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Image of the surface of the Zika virus by Purdue University/courtesy of Kuhn and Rossmann research groups

The Zika virus, which made headlines in 2016 following an outbreak in South America, is transmitted by mosquitos and can cause serious birth defects and neurological problems. Researchers are searching for antiviral treatments or effective vaccines to address this global health threat, but there are currently no approved treatments.

Now, Stanford researchers are taking a different approach — investigating cellular factors of humans that are essential for Zika to propagate. One of those factors is a type of protein called Hsp70, which helps proteins fold correctly and performs a wide range of housekeeping and quality-control functions in cells.

Based on a series of experiments in mosquito and human cells, the Stanford study found that certain Hsp70 proteins are required in multiple steps of the Zika virus’ lifecycle. By blocking Hsp70 with an Hsp70 inhibitor drug, the researchers were able to prevent virus replication, as recently reported in Cell Reports.

One advantage of targeting the human host protein to thwart Zika is that it is less likely to promote drug resistance, Judith Frydman, PhD, senior author of the paper and a professor of genetics and of biology at Stanford, told me.

“The emergence of drug-resistant variants is a major obstacle for the development of antiviral therapies,” she continued. “We hypothesize that because Hsp70 is required for several different steps in the Zika virus cycle, it would be difficult for Zika to acquire enough mutations to develop resistance to the Hsp70 inhibitors. This opens the way to both therapeutic and prophylactic use of these drugs for short courses of treatment without losing effectiveness due to resistance.”

In addition, the team found that the Hsp70 inhibitors showed negligible toxicity to the host cells at the concentrations needed to fully block virus production. They demonstrated this lack of toxicity in both human cells and mice.

“The virus has a much higher demand for Hsp70 than the host cellular processes,” Frydman said. “We can exploit the viral ‘addiction’ to Hsp70 for treatment to prevent the virus from producing the proteins it needs to replicate and infect cells. But most importantly, we show Hsp70 inhibitors can be administered to animals at therapeutically effective doses. To my knowledge, this is the first drug that actually works for Zika-infected animals, protecting them from lethal infection and disease symptoms.”

The researchers believe their new approach could serve to create broad-spectrum antivirals that work against other existing and emerging viruses. In fact, this class of drugs could also treat other insect-borne viruses including Dengue virus and Yellow Fever, Frydman said.

“Our findings provide new strategies to develop a novel class of antivirals that will not be rendered ineffective by the emergence of drug resistance,” Frydman said. “This unique property of targeting host factors used for viral protein folding therapeutically may close a fundamental gap in antiviral drug development.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

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A look back at the military’s influence on American nutrition

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Image of early 1940s poster by Office for Emergency Management, Office of War Information, Domestic Operations Branch, Bureau of Special Services

If you think of our military’s influence on food, you may picture MREs — meals, ready-to-eat — which are the main operational food rations for the U.S. Armed Forces. You may even have some MREs in your earthquake supply bin.

But according to Hannah LeBlanc, a history of science doctoral candidate at Stanford, the U.S. military has had a more fundamental and far-reaching impact on American nutrition than MREs. In fact, she argues, American nutrition was profoundly altered during the mid-1900s when the U.S. government poured funding into nutrition research. The legacies from this research include the food pyramid, recommended dietary allowances and much more.

LeBlanc’s dissertation reveals that the government hired nutritionists and issued propaganda films about nutrition because they needed healthy soldiers to fight in World War II at a time when many men were physically weakened from malnutrition during the Great Depression. And the government studied physiology in hopes of improving their soldiers’ physical endurance and food processing to preserve food longer.

Nutrition was also viewed as a national security issue during the Cold War — combating hunger as a means to protect our democracy. LeBlanc explained in a recent Stanford news release, “If you’re hungry, communism’s promises of food and well-being are going to be appealing.”

LeBlanc came to these conclusions by delving into a dozen archives throughout the U.S. for primary sources, such as military memos, government budgets and propagandistic nutrition films.

LeBlanc’s advisor, Londa Schiebinger, PhD, argues in the news release that this work can act as a reminder to pay attention to who is funding and directing our research: “Since the 1950s, there’s been this idea that science is merely objective. And, yes, we discover truth in science, but research priorities are very much determined by society.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

How yellow fever shaped 19th-century New Orleans: A Q&A

Stanford historian explains how frequent yellow fever epidemics in nineteenth-century Louisiana generated cultural and social norms in its fatal wake.

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I was intrigued when I came across the Stanford profile of Kathryn Olivarius, PhD, a historian of 19th-century America. Her research primarily explores how epidemic yellow fever disrupted society in the antebellum South, generating cultural and social norms in its fatal wake. To learn more, I spoke with her recently.

As a historian, what got you interested in fellow fever?

“When I embarked on my PhD, I wanted to write about how slavery changed in Louisiana after 1803 with the Louisiana Purchase, as the region shifted from Spanish and French to American rule. But while sitting in Tulane’s archives and perusing letters, diaries, plantation ledgers and ship manifests, what impressed me the most was how much people spoke about disease. And the disease they feared the most was undoubtedly yellow fever  — a disease that struck antebellum New Orleans at epidemic levels nearly every third summer.

Yellow fever victims experienced a sudden onset of headache, back pains, jaundice, nausea and chills. Within days, they oozed blood through their external orifices, writhed in pain and vomited up partly coagulated blood. About half of all people who contracted yellow fever in the 19th century died, while the survivors gained lifetime immunity.

In my view, yellow fever played a critical role in Louisiana’s asymmetrical social organization, on the schedule and character of the cotton market, on capitalism itself and on the entire system and ideology of racial slavery. So I decided to focus on the disease for my PhD and my forthcoming book.”

How did the disease impact the social structure of 19th-century Louisiana?

“Antebellum New Orleans sat at the heart of America’s slave and cotton kingdoms. But it was also the nation’s necropolis, the city of the dead, with yellow fever routinely killing about 8 percent of its population between July and October. In some neighborhoods — particularly those with high densities of immunologically-naive recent immigrants from Germany, Ireland and the American North — yellow fever deaths could reach 20 or even 30 percent.

These repeated epidemics generated a hierarchy of ‘acclimated’ survivors who leveraged their immunity for social, economic and political power and ‘unacclimated’ recent immigrants who languished in social and professional purgatory. Until whites could prove they were acclimated, they struggled to find steady, well-paid employment, housing, spouses and a political voice. From the employer’s perspective, it wasted time and money to train someone for a detail-oriented job only to watch him sicken and die by the autumn.”

How did this affect slavery?

“Because of the disease, the commercial-civic elite of New Orleans argued that they required large-scale black slavery — publicly proclaiming that black people were naturally immune to the disease based on spurious and racially-specific visions of medicine and biology. It became a powerful proslavery argument with many whites claiming that black slavery was natural, even humanitarian, as it distanced white people from labor, spaces and activities that would kill them. Some even argued black immunity signaled divine sanction for widespread slavery, with God creating black slaves specifically to labor in the cane and sugar fields of the Mississippi Valley.

But in private, most slavers would not buy an unacclimated slave. The slave market essentially shut down in August, September and October in order to protect the health of potential buyers and their valuable slave property. This inconsistency suggests that the widespread belief in black immunity was less a reflection of biological reality but instead a social tool, a means to epidemiologically-justify racial slavery.”

Do you believe anything similar is happening today?

“Yellow fever still kills thousands of people each year. It’s endemic in 47 countries, mostly in Africa and Central and South America. The Intergovernmental Panel on Climate Change’s report released last year also suggests that Americans may become more familiar with this disease again as ecologies change and mosquito populations migrate. Zika, spread by the same mosquito as yellow fever, has been an increasing problem in recent years.

In terms of the social impact of disease, there are certainly modern analogues of societies in the midst of terrifying epidemics rationalizing mass death or singling out certain marginalized groups as the cause. The most obvious comparison in the U.S. is probably HIV/AIDS in the 1980s with gay people, intravenous drug users and Haitians who were blamed for the disease’s spread and who faced severe discrimination on the basis of their alleged-vulnerability.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Blood test may detect early signs of lung-transplant rejection

New blood test measures the DNA fragments of lung transplant donors in the blood of recipients, in hopes of preventing organ rejection and saving lives.

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Image by kalhh

After receiving a lung transplant, patients face the likely chance that their body’s immune system will reject the transplanted organ. Rejection can happen at any time due to a variety of factors such as a lung infection or an injury to the lungs during transplant surgery. The most deadly type of rejection is chronic lung allograft rejection (CLAD), which develops slowly and often silently without obvious symptoms.

Now, researchers have developed a simple blood test that detects tissue graft injury within the first three months after lung transplant surgery. After further validation, this non-invasive test could identify patients with a high risk of CLAD or death due to graft failure, allowing doctors to intervene early and possibly prevent chronic rejection.

“This test solves a long-standing problem in lung transplants: detection of hidden signs of rejection,” said Hannah Valantine, MD, co-leader of the study and a senior investigator at the National Heart, Lung, and Blood Institute, in a recent news release. “We’re very excited about its potential to save lives, especially in the wake of a critical shortage of donor organs.”

Valantine is also a Stanford professor of medicine and Kiran Khush, MD, associate professor of medicine, is a co-senior author.

The new test measures the amount of DNA fragments circulating freely in a patient’s bloodstream. Since the lung donor and recipients have different genomes, the test can identify and quantify the fragments from both people. If there are a lot more donor DNA fragments, this indicates that the organ is injured.

As recently reported in EBioMedicine, the researchers regularly monitored blood samples from 106 lung transplant patients during the first three months after surgery at several institutions, including Stanford. After dividing the patients into three groups based on the level of donor-derived DNA fragments in their blood, the team found that patients with higher levels were six times more likely to subsequently develop transplant organ failure or die than those with lower levels. And many of these high-risk patients didn’t have symptoms.

“We showed for the first time that donor-derived DNA is a predictive marker for chronic lung rejection and death, and could provide critical time-points to intervene, perhaps preventing these outcomes,” Valantine said in the release. “Once rejection is detected early via this test, doctors would then have the option to increase the dosages of anti-rejection drugs, add new agents that reduce tissue inflammation, or take other measures to prevent or slow the progression.”

The researchers expect commercial versions of the blood test to be available for clinical use soon. They are also planning future studies to evaluate the blood test for other solid organ transplants.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

On the importance of including pregnant women in clinical trials: A Q&A

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Photo by StockSnap

As a research scientist, I’ve negotiated the complex nature of getting approval to image human subjects. So I know firsthand that it is common to exclude pregnant women from clinical trials. Although this practice is well-intentioned, it is also misguided — according to an opinion piece recently published in JAMA. To learn more, I spoke with one of the authors, Heather Byers, MD, a clinical assistant professor in pediatrics at Stanford.

Why are pregnant women excluded from clinical trials?

“Historically, women in general were excluded from clinical trials because men were thought to be a more homogenous group without hormonal cycles and other sex-based variables that might impact the medical conditions under study.

In addition, pregnant women are still classified as a ‘vulnerable’ population for all research studies, so investigators must take additional steps to enroll them to ensure minimum risk.

Also, the lack of data about what pregnant women can safely be exposed to leads to more uncertainty. So many investigators choose to exclude them, even if they might benefit from the study intervention.”

Why is this a problem?

“Excluding them is a problem because women don’t stop getting sick or stop having chronic medical conditions just because they are pregnant. The average woman is exposed to four medications during her pregnancy and over 80 percent of medications haven’t been studied in a like population. This forces pregnant women to take medications on an “off-label” basis — meaning, the medications weren’t studied or approved for use in pregnant women — because there’s no other option. Pregnant women deserve better. It’s a matter of justice.”

What are the barriers and how can we overcome them?

“First, we advocate reclassifying pregnant women from ‘vulnerable’ to ‘scientifically complex.’ Pregnancy doesn’t alter a woman’s capacity for autonomous decision-making. Indeed, a pregnant woman frequently makes complex medical decisions for herself and her fetus that reflect her family’s values.

Another barrier for medical investigators is the perceived legal risk regarding a potential adverse outcome in the fetus or mother. As we discuss in the JAMA Viewpoint, this barrier could be addressed by standardizing the informed consent process.

Finally, federal regulations don’t define ‘acceptable risk’ to the woman or fetus and this uncertainty is perceived as a risk in itself. But in some cases, pregnant women may accept the uncertainty and risk.

For example, it was imperative to reduce mother-to-child transmission of HIV. So obstetricians reluctantly included pregnant women with HIV in their study of antiretroviral treatments, since the risk of the drugs were thought to be low and the potential benefit high. And the effectiveness of this study helped transform the AIDS epidemic.”

Is progress being made?

“Although progress has been slow, there has been an increased effort to enroll pregnant women. Several high-profile clinical trials involving pregnant women recently completed and institutions like the National Institutes of Health are working to change their polices. For example, the NIH Task Force on Research Specific to Pregnant Women and Lactating Women recently issued a report that summarizes the current gaps in knowledge and provides recommendations for continued progress.”

How did you become involved?

“I first became interested in this subject as a medical student during my rotation at NIH with Pamela Stratton, MD, one of the obstetricians involved in the study of antiretrovirals to prevent vertical transmission of HIV.

Later, as an obstetrics resident, I was frustrated by the lack of information to share with my patients regarding the risk and clinical impact of various medications, vaccines and medical conditions in pregnancy. Every anecdotal story  — such as my patient who was hospitalized in intensive care for months with influenza because she’d been too afraid to get the flu vaccine earlier in her pregnancy — is one too many. The fear of uncertain risk can be dangerous. There should be a better way.

One thing that has changed is the rise of social media and patient support group accessibility. Although this should not replace the controlled setting of a clinical trial, partnerships between motivated patient advocacy groups and medical investigators can be a powerful tool for obtaining information about risk and benefits going forward.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Jamming with the Midnight Rounds: A Q&A

Photo by Victoria Bruzoni of Midnight Rounds band, from left to right: James Wall, Matias Bruzoni, Raji Koppolu, Yasser El-Sayed, Garret Vygantas, Jon Palma and Jeff Linnel

The next time you listen to music at a nearby pub or Bay Area event, double check to see who is playing. You just might see one of your Stanford physicians.

At a division holiday party in 2009, pediatric surgeon Matias Bruzoni, MD, on vocals, piano and guitar and nurse practitioner Raji Koppolu on vocals played acoustic versions of popular songs. Soon after, two more pediatric surgeons joined and the band Midnight Rounds was born. Over the years, the band has expanded to include piano, guitar, bass, percussion, drums, violin and vocals. I spoke with Bruzoni to learn more.

What is the origin of the name, Midnight Rounds?

“Our bass and guitar player James Wall, MD, and his family generously turn their guest house into a music studio whenever we need to practice. We all have very tight schedules due to our professional work, so once a week we practice late at night — many times going past midnight. As providers, we also make rounds every day to see our patients, so our drummer Yasser El-Sayed, MD, suggested we call ourselves Midnight Rounds.”

What kind of music do you play?

“Our repertoire includes oldies, country, 80’s, 90’s and more modern pop songs. We particularly enjoy creating mashups of songs, flipping back and forth between songs and adding our own twist. For instance, we like playing “Free” sung by the Zac Brown Band mashed up with “Into the Mystic” by Van Morrison and “Lodi” by Creedence Clearwater Revival mashed up with “Sloop John B” by the Beach Boys. Another favorite song is “Dixieland Delight” by Alabama, which features Jonathan Palma, MD, playing violin.”

Where do you play?

“We play in many different venues including weddings, wineries, local pubs, holiday parties, pumpkin festivals and wherever we’re invited. It varies, but we average a couple of events per month. We play quarterly at the Pioneer Saloon in Woodside — we’ll be there on January 12.

We sometimes make a little money during our performances at places like Pioneer. We decided as a group to donate the proceeds to different charity organizations that benefit women and children’s health.”

Is there any relation between playing in the band and medicine?

“For us, the band is a perfect excuse to get together outside of regular working hours. We feel this strengthens our relationships with each other in the hospital. It’s also a healthy way to recharge our batteries, avoid burn-out and thus take better care of our patients.

In addition, we’ve gotten to know a lot of people that work at Stanford — nurses, OR staff, social workers, interpreters and other docs like anesthesiologists — who come to our gigs. Our strongest crew are the NICU nurses and social workers, who follow us wherever we go. I think our patients definitely benefit, because teamwork is essential to patient care.

I also think performing under pressure is a great exercise since it is very similar to what we do every day here at the hospital. You get nervous even if you’re doing an acoustic session in front of 10 people, since you want to sound good. When I interview residents for positions here at Stanford, I pay a lot of attention to whether they excel in athletics or music, which gives me an idea on how well they can perform under pressure.”

Describe a favorite moment with the band.

“There are times when we have our kids sing or play an instrument with us. And that’s a very special moment. For instance, the other day we played at a pumpkin patch. People were playing games and stuff, not paying much attention to the band. But everyone went dead silent when my daughter came up to sing a Justin Bieber song. And then they started taping it. It was really magical.”

What’s next?

“We’re thinking about writing some original songs as an experiment. But mostly we just want to build up our repertoire. We started with maybe five songs and now we have about 50 songs that we can we can play — some of them without even practicing. We usually practice tow to three new songs for every new gig. Our band members have very different musical tastes, which makes it fun to blend all them together.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Medical students turn to peer-support groups for assistance: A Q&A

Photo by rawpixel

School can be overwhelming, especially medical school. But Stanford Medicine offers many different forms of mental health support, including a peer-to-peer support program for medical students called Ears 4 Peers. To learn more, I spoke with Dina Wang-Kraus, MD, a Stanford psychiatry and behavioral sciences resident and co-founder of the program.

What inspired you to start the Ears 4 Peers program?

“In 2012, I was a first-year medical student and I was noticing that a significant number of my classmates were experiencing compassion fatigue and burnout. We were encouraged to reach out to the counseling and psychology services but there was some hesitancy, either from busy schedules or anxieties surrounding stigma. So, Norma Villalon, MD, and I decided to found a peer-to-peer support program. I started a similar program in college at Johns Hopkins, called A Place to Talk.

The hope was to have near-peers — those who were just walking in your shoes — provide support. Our goal was to bridge the distance students often feel when in a competitive, challenging situation. We may have been adults in our mid-twenties to forties, but we were only in the infancy of our training.

Rebecca Smith-Coggins, MD, is our faculty adviser and leader. From day one, she’s believed in our cause.”

What are some issues the program addresses?

“We receive calls regarding issues like academic stress, interpersonal relationship conflicts, imposter syndrome, intimate partner violence, Stanford Duck syndrome and suicidal thoughts. We also receive calls from students feeling lonely, disconnected and homesick, especially around finals, holidays and medical board exams. And some students call hoping to be referred for additional support.”

How are Ears 4 Peers mentors selected and trained?

“Ears 4 Peers mentors are nominated by their peers or self-nominated. They complete an application to tell us more about themselves, what draws them to this type of work and what they hope to gain from the experience.

We’re very lucky to have the support of Alejandro Martinez, PhD, the Associate Dean of Students for the Stanford undergraduate campus. He and his team designed a curriculum specifically for Stanford School of Medicine.”

What role do you play in the program now?

“As a resident, I’ve transitioned out of being an official Ears 4 Peers mentor but I continue to remain actively involved in near-peer mentoring for medical students. Two years ago as an intern in psychiatry, I worked with Jessi Gold, MD, to inaugurate Stanford’s  Medical Student Reflection Groups. Each group is made up of four to 10 medical students who commit to joining for six to 12 months. We meet every other week, and groups are facilitated by psychiatry residents trained in group therapy and psychotherapy. As resident physicians, we remain near-peers; however, we’re able to facilitate a different kind of support and personal growth given our psychiatry training.

Stanford students are welcome to reach out to me at sdwangkraus@stanford.edu to learn more.”

What advise can you give medical students and residents?

“I recall medical school to be an exhilarating time, but it also felt like I was drinking from Niagara Falls, one cup at a time. There were times when I felt overwhelmed and even burnt out.

We see a lot of beauty and humility in medicine, but there are also times when we see a lot of tragedy and suffering. Having peer-support, knowing that I was not alone, was empowering and liberating — and it continues to be.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.