A new take on virtual education can promote breastfeeding

 Mentor mothers using MOVIE videos during a training session (Photo by Maya Adam). 

Feeding infants formula with invisible pathogens can cause life-threatening diarrhea, and introducing solid foods too early can result in nutrient deficiencies. For reasons like these, the World Health Organization and UNICEF recommend feeding infants only breast milk for the first six months, when possible.

But this guideline is rarely followed in developing countries with limited access to health care and education. In South Africa, for instance, less than a third of new mothers exclusively breastfeed for that long.

Now, Stanford Medicine researchers are trying to improve breastfeeding outcomes in South Africa by developing and testing an educational video series. These videos discuss topics such as the health benefits of breastfeeding and what to do if breastfeeding isn’t possible. After running a 19-month study, they found that video-based counseling using computer tablets can promote breastfeeding in under-resourced settings as effectively as in-person counseling.

The study was led by Maya Adam, MD, a clinical assistant professor of pediatrics and the director of Health Media Innovation at Stanford. Adam and the research team partnered with health care workers from Philani Maternal Child Health and Nutrition Trust who shared the video series — called the Philani MObile Video Intervention for Exclusive breastfeeding (MOVIE) — with new and expecting mothers in their South African communities.

“Thankfully, more and more mothers even in the hardest-to-reach communities are gaining access to mobile technology,” said Adam. This access opens up the opportunity to promote breastfeeding in these communities by designing entertaining, educational content and delivering it on mobile devices, she said.

Details of the study were published September 28 in PLOS Medicine.

Entertainment education

To create the videos, Adam collaborated with Stanford’s Digital Medic team in South Africa to harness the power of “entertainment-education.” The idea is to draw learners in with dramatic narratives, compelling visuals and soundtracks, Adam said.

The 13 videos are short: four minutes or less. A local South African artist illustrated the health and motivational messages and other local women narrated them. For example, one animated video depicts the story of a mother explaining to her daughter why she breastfed against her own mother’s advice. These illustrations were interspersed with personal narratives from three South African celebrities and four community mothers.

“Some videos were more geared towards the early newborn phase, like the common challenges video. And some were geared towards later phases, like the one aimed at supporting moms who need to return to work,” said Adam.

To test the video series’ ability to provide effective education and encourage breastfeeding, Adam’s team ran a controlled trial involving 84 community health workers, or “mentor mothers,” from the Philani Maternal Child Health and Nutrition Trust. Each mentor recruited and counseled a group of mothers in her community, with 1502 mothers participating in the study.

The mentors were randomly assigned to either the control or intervention group. One half, the traditional mentors, used only face-to-face breastfeeding counseling, while the intervention mentors spent part of their home visits showing Stanford’s videos on tablets that the study provided. The videos were viewed a total of 6,435 times during the visits.

As good as face-to-face

Throughout the study, all mentor mothers counseled their clients on infant feeding during regular home visits starting in the last trimester of pregnancy and lasting until the baby was 5 months old. The intervention mentors chose specific videos to meet the client’s needs.

Each time a baby turned 1 month old or 5 months old, the mentors surveyed the mother’s feeding practices and maternal knowledge.

The researchers observed no significant differences between breastfeeding outcomes for both mentor groups. For example, overall, about 54% of all participants reported during the 5-month survey that they were breastfeeding exclusively. The similarity of these outcomes suggests that the videos were as effective as traditional counseling when used to replace part of the home visit.

However, the videos had the benefit of allowing intervention mentors to do other health-related tasks for the families, including monitoring other children’s growth, updating and keeping medical records and completing referral forms, Adams said.

Mentor mothers also reported that carrying a tablet increased their credibility within the community, said Adam.  “My hope is this research will help policymakers and funders see the great potential in equipping community health workers of all levels with mobile devices,” said Adam. “The mentors are heroes, fighting for their communities at the frontlines of health. They deserve to have the technological tools they need.”

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

New approach effectively relieves chronic low back pain

Anyone with an aching back knows just how debilitating that pain can be. Now, Stanford Medicine researchers may have good news for the 500 million people worldwide experiencing low back pain.  

Stanford pain psychologist Beth Darnall, PhD, has developed a single-session, two-hour class called Empowered Relief, which aims to rapidly equip patients with pain management skills. The first randomized, controlled clinical trial suggests this new method may be as effective at reducing chronic low back pain as weeks of traditional therapies, a paper in JAMA Network Open recently reported.    

Empowered Relief stems from a traditional therapy called cognitive behavioral therapy, which relies on the interconnection between thoughts, feelings, physical sensations and actions. Both treatments can help patients identify and change thoughts and behaviors that increase their pain, as well as learn coping skills to better control pain response and improve quality of life.

“The problem is CBT isn’t broadly accessible,” said Darnall. “There are only a small number of behavioral specialists, and yet millions of Americans live with ongoing pain. And many under-served communities in the U.S. don’t know how to find a trained therapist.”

Another major barrier, said Darnall, is time commitment — cognitive behavioral therapy patients attend a two-hour group session each week for two to three months.

To address this problem, Darnall combined what she believed were the most critical skills from cognitive behavioral therapy, such as identifying unhelpful and stressful thought patterns, with information about the science of pain, mindfulness principles, and the relaxation response. With the help of an instructor, patients then translate their new skills and knowledge into a personalized plan to manage their pain at home.

“The goal is to align our treatments with what’s feasible for patients and make it broadly accessible,” Darnall said. It’s possible, she said, to teach 85 people in a one-and-done Empowered Relief class. And if taught weekly, 680 patients could be treated in eight weeks, compared with 10-15 who could be treated during that time with cognitive behavioral therapy.

Pain treatment with lasting effects

Darnall conducted the clinical study with Sean Mackey, MD, PhD, professor of anesthesiology, perioperative and pain medicine at Stanford. In it, 263 adults with chronic low back pain — most of whom had this pain for more than five years and almost half of whom had additional chronic pain conditions — were randomly assigned to eight cognitive behavioral therapy sessions, one Empowered Relief session or one traditional health education session, which acted as a control. (In health education, participants learned basic information, such as the definition and warning signs of back pain, but not actionable skills or the neurobiology of pain.)

For three months after the treatment, the participants reported information about their pain, such as its intensity and whether it disturbed their sleep. According to patient reporting, Darnall’s course relieved pain as effectively as cognitive behavioral therapy and better than the health education session.

“I was pleasantly surprised that people’s back pain improved as well as their sleep, depression and anxiety symptoms,” said Mackey. “I can easily see this integrating with standard medical care to provide benefits for many patients.”

The results are promising, but the study will need to be replicated in a larger and more diverse population, said Darnall.

The success of the course doesn’t mean cognitive behavioral therapy will be eliminated, Darnall said. Instead, the researchers want to determine how to match individual patients with treatment options that work best for them. That, she said, could inform pain treatment protocols, resource allocations and other medical decision-making.

Now, Darnall’s team is expanding access to the Empowered Relief program to help address existing disparities in pain care. The class is already available in five languages and seven countries to treat chronic pain — and the team has certified 300 healthcare clinicians around the world as Empowered Relief instructors.

“I hope expanded, online access to the course will provide more equitable access to evidence-based pain care for people living in rural areas, prisons and other settings that lack trained pain professionals,” she said.

Photo by Sasun Bughdaryan

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

How to talk with someone about COVID-19 vaccine hesitancy

With less than half of the United States fully vaccinated, you’ve probably wondered, “How should I talk to hesitant friends or family members about getting their COVID-19 shot?” Now, Stanford Medicine researchers specializing in health education have developed guidelines to help facilitate those awkward conversations.

“We’re trying to find common ground between different audiences to create guidelines that catalyze conversation about vaccination, not stifle it,” said Rachelle Mirkin, MPH, administrative director of health education, engagement and promotion at Stanford Health Care, who led the effort.

Moreover, these conversations either aren’t happening or they’re often ineffectively divisive, said Emilie Wagner, a healthcare strategy consultant who teaches at Stanford and who helped Mirkin and Nicole Altamirano, program manager for digital experience strategy, conduct the research. “There’s so much tension that people don’t want to risk a relationship. Yet, if it goes unaddressed, the tension just naturally mounts.”

The team wanted to understand why some people are reluctant to adopt COVID-19 prevention measures — including wearing a mask, social distancing and being vaccinated — and wanted to learn how to facilitate better communication with vaccine-hesitant individuals.

So far, they’ve discovered that traditional messages — such as the need to protect yourself and others or the enticement of getting kids back to school — don’t move the needle when it comes to persuading hesitant people to get a vaccine. Having a personal, empathetic conversation with people works better than presenting statistics and facts at them.

Needing a new approach

Mirkin and her team conducted an extensive literature review of vaccine hesitancy, using the information to create a list of 25 talking points they thought might sway those who are vaccine hesitant.

They then interviewed health care providers, hospital administrators and a small group of older white adults who were vaccine hesitant, but only regarding COVID-19. Somewhat surprisingly, these participants weren’t generally against vaccines, said Mirkin. Some had already received a two-part shingles vaccines, which can have significant side effects including fatigue, muscle pain and fever.

But when it came to COVID-19 shots, the traditional messaging did not resonate with the target group, said Wagner.

“They had a response for everything,” she said. “They thought the vaccine wasn’t a means for returning to normal. It wasn’t their responsibility to keep others safe. And they believed the risk of the vaccine outweighed the risk of COVID.”

So, the team switched from drawing on knowledge to drawing on empathy. Instead of focusing primarily on facts, they suggest having open-ended conversations that validate feelings and personalize the vaccine experience. And they recommend talking about how everyday life is easier once you’re vaccinated.

According to Wagner, they found that the appeal of hassle-free travel can motivate this group to get vaccinated. Visiting with grandkids can also nudge older adults into getting their shots. But generally, it takes a combination of incentives. The researchers also realized that many short conversations over time are needed. “It takes persistence, so talking with friends and family members can be more effective than a single conversation with a provider,” Wagner said.  

To share their approach more broadly, the researchers translated their new strategy into two practical guides — one for health care providers and one for friends and family — and are now disseminating them.

“We need to make space for these discussions,” Mirkin explained. “The more non-judgmental conversations you have with an individual, the more likely they are to protect themselves and others from COVID.”

Encouraging vaccine acceptance, one group at a time

Mirkin’s team is also trying to understand the drivers of vaccine acceptance in two other groups: Latino Spanish speakers and Pacific Islanders. They are working with community partners to create social media campaigns, including Facebook ads, Twitter and Instagram posts, as well as public service announcements. So far, the Latino public service announcements have been picked up by Telemundo, a Spanish-language television network, and the Facebook ads have more than 3 million hits.

Based on initial data, the main issue for Latinos and Pacific Islanders is access to personal protective equipment — such as masks — COVID-19 testing and vaccines, Mirkin said. “In general, the concerns are very logistics-based, whereas the Caucasian hesitant group is philosophically- and identity-based,” she said.

Vaccine acceptance is often complicated by a larger erosion of trust of science and health care systems that have failed many people, especially those of color, said Mirkin. “As an academic medical center, we have to understand what’s going on to begin to reshape the conditions to help rebuild trust.”

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

Photo by Mattia Ascenzo  

Lung Organoids: A Novel Way to Model COVID Infection

Calvin Kuo, MD, PhD, with Shannon Choi, MD, PhD, a student in the Kuo lab. Courtesy Steve Fisch

A year into the pandemic, we’ve all heard the stories. A patient is a little short of breath but appears to have a mild case of COVID-19. The next day, she deteriorates so rapidly that she’s rushed to intensive care, put on a ventilator, and hooked up to a dialysis machine to prevent kidney failure. Her overzealous immune system has gone rogue, attacking healthy cells instead of just fighting off the virus.

What triggers this devastating immune response, called a cytokine storm? Researchers are still struggling to identify the underlying processes that initiate a COVID infection and subsequent cytokine storm.

Biologists use advanced technologies and cell cultures in petri dishes to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus strain responsible for COVID-19, identifying its key characteristics such as the famous crownlike spikes on their surfaces. But these short-lived cultures don’t act like real organs. And scientists are limited by their samples.

“When you analyze samples from patients, they’re often at the end stage of the disease, and many of the samples are from autopsy. You can’t understand the initiation process because the tissue is essentially destroyed,” says Calvin Kuo, MD, PhD, professor of hematology.

Understanding how the disease develops and testing potential treatments require better ways to model this coronavirus.

Miniature Organs in a Dish

Kuo’s laboratory develops organoids—three-dimensional miniature organs grown in a petri dish that mimic the shape, structure, and tissue organization of real organs.

Grown from human tissue samples using precisely defined ingredients, these organoids are little spheres of gel up to 1 millimeter in diameter. Healthy tissue samples are mechanically minced and enzyme digested to get to single cells, and then the organoids are grown from single stem cells. They last about six months, significantly longer than the few-weeks lifetime of traditional cell cultures.

Kuo initially developed organoids to study stem cell biology and model cancer. His team was the first to use organoids to convert normal tissues to cancer, as previously reported in Nature Medicine.

But he was passionate about using organoids to model infectious diseases. In 2015, he led a National Institute of Allergy and Infectious Diseases U19 research program, recently renewed for an additional five years, in collaboration with Stanford researchers Manuel Amieva, MD, professor of pediatrics and of microbiology and immunology; Harry Greenberg, MD, the Joseph D. Grant Professor in the Stanford University School of Medicine and professor of microbiology and immunology; Elizabeth Mellins, MD, professor of pediatrics; and Sarah Heilshorn, PhD, professor of materials science and engineering. Focusing mainly on the gastrointestinal tract, this multidisciplinary team provided proof of principle that organoids could model infectious diseases.

“With an organoid system, you can start at the infection and look at the very earliest events that occur after infection. And those can give insights as to what needs to be blocked therapeutically,” Kuo explains.

Distal Lung Organoids

After the initial success with gastrointestinal organoids, Ameen Salahudeen, MD, PhD, a hematology and oncology postdoctoral fellow working in Kuo’s lab, led efforts to expand this work by developing distal lung organoids. He partnered with lung stem cell expert Tushar Desai, MD, associate professor of pulmonary, allergy, and critical care medicine at Stanford.

The distal lung is composed of terminal bronchioles and alveolar air sacs, where inhaled air passes through the tiny ducts from the bronchioles into the elastic air sacs. It performs essential respiratory functions that can be compromised by inflammatory or infectious disorders, such as COVID-19 pneumonia.

“Growing distal lung cultures in a pure way that doesn’t require any supporting feeder cells and is in a chemically defined media had not been possible,” Kuo says. “We were able to do this very beautifully—to grow alveoli at the terminal bronchioles as long-term human cultures.”

The team developed two types of distal lung organoids. Both were made from human distal lung samples provided by Stanford cardiothoracic surgeon Joseph Schrager, MD.

They grew the first type, alveolar organoids, from single alveolar type 2 (AT2) stem cells. AT2 cells have several important functions that together help control the immune response to decrease lung injury and repair. The scientists then induced the AT2 cells to produce alveolar type 1 (AT1) cells, which are the thin-walled cells lining the alveolar air sacs; they are essential for the lung’s gas-exchange function.

“The second type are the basal organoids, which grow from single basal stem cells. They give rise to the mucus-secreting club cells and the ciliated cells with beating hair. And we can see the beating hair under the microscope—it’s quite dramatic,” describes Kuo. “That’s a very nice reproduction of the differentiation and function of the lung.” The team also grows a mixture of alveolar and basal organoids.

They selected these organoid types to determine which cell types in the bronchioles and alveoli were infectible—in hopes of identifying the different mechanisms for how viruses cause respiratory compromise.

Initially, they tested the distal lung organoids using the H1N1 influenza virus, collaborating with Stanford molecular virology expert Jeff Glenn, MD, PhD.

The team fluorescently labeled the virus and infected the lung organoids, demonstrating that the virus replicated in both basal and alveolar organoids. Next, they did more sophisticated PCR-based testing to show that the virus replicated its genome.

COVID-19 Model

“But then the COVID-19 pandemic hit, so we initiated a fabulous collaboration with infectious disease expert Catherine Blish, MD, PhD, in the Department of Medicine, to infect our lung organoids with SARS-CoV-2. This was driven by a talented MD-PhD student in my lab, Shannon Choi,” says Kuo. “She worked with Arjun Rustagi, an infectious disease fellow in Catherine Blish’s lab, who infected the organoids in a biosafety-level-3 lab.”

Another partnership was critical, though. An important coronavirus receptor, called angiotensin-converting enzyme 2, or ACE2, resides inside the lung organoids. But ACE2 needed to be on the outside of the organoid to get the infection going.

Luckily, Amieva previously devised a way to flip intestinal organoids inside out. Working together, Choi and Amieva turned the lung organoids inside out.

As reported in Nature in November 2020, the team demonstrated that the coronavirus infected their distal lung organoids, including the alveolar air sacs, where COVID-19 pneumonia originates. They also identified a new airway subpopulation as a COVID-19 virus target cell.

“Everyone knew basal cells were stem cells in the lung, but they thought they were all equivalent. Using our organoids, we discovered an unknown basal cell subpopulation containing the stem cell activity. And then we showed this subpopulation actually existed in human lungs in very interesting anatomic locations,” Kuo says.

COVID-19 Applications

According to Kuo, their distal lung organoids have three major applications for COVID-19.

They are using them to screen potential coronavirus therapeutic antibodies and to understand how these treatments work. Although initially focused on COVID-19, this screening will likely expand to other kinds of lung infections in the future.

Because the distal lung with the alveoli is the site of the COVID-19 pneumonia, they also plan to use the organoids to identify the underlying biological mechanisms behind coronavirus infection. Finally, they plan to extend their organoid system to incorporate immune cells and understand more complex processes. In particular, they plan to model the dreaded cytokine storm.

Overall, Kuo emphasizes that this organoid research represents a huge team effort involving many investigators with wide-ranging expertise from various departments at Stanford, as well as an “interesting evolution of events.” “Now we have a human experimental system to model SARS-CoV-2 infection of the distal lung with alveoli, which is the site of the lung disease that kills patients,” he summarizes. “We know patients die because of severe pneumonia and lung failure. We can now recapitulate this in the dish. So, we can study how it works, and also test drug treatments.” 

This is a reposting of my feature article in the recent Stanford Medicine Annual Report. Check it out to see videos of these lung organoids.

Innovative Antibody Treatment Proves Safe and Effective for Immune Disorders

Many blood and immune disorders could be cured by transplanting healthy blood stem cells from a matched donor. But first the patients need a pretreatment procedure to eliminate their own blood stem cells, making room in the bone marrow for the donor cells to take their place.

The problem is that the standard pretreatments—chemotherapy or radiation—are very toxic. Doctors don’t want to give them to vulnerable children, such as those with a rare genetic disorder called severe combined immunodeficiency (SCID).

Infants with SCID have compromised immune systems that struggle to fight off even common infections caused by viruses and fungi. These babies have many chronic and life-threatening problems, including frequent lung infections, chronic diarrhea, and recurrent sinus infections.

Judy Shizuru, MD, PhD, reviews data with Wendy Pang, PhD

“Without treatment, SCID infants usually die from infections within the first two years of life. Blood stem cell transplants are the only definitive cure for this disease,” says Judith Shizuru, MD, PhD, professor of blood and marrow transplantation and cellular therapy and of pediatrics. “But transplants usually involve chemotherapy, and we don’t want to give these agents to these children because they’re particularly susceptible to the damaging short-term and long-term effects—including growth defects, neurological problems, and increased risk of cancers. This is especially true for certain subtypes of SCID.”

Instead, SCID patients are often given a blood stem cell transplant without pretreating with chemotherapy to create space in their bone marrow. But then the donors’ self-renewing blood stem cells may not fully engraft, so the kids can’t robustly regenerate their immune systems. These children have to rely on regular intravenous immunoglobulin infusions to boost their immune response, and the effectiveness of donor immune cells can wane over time.

The great need for a less toxic pretreatment for blood stem cell transplants inspired Shizuru to initiate a Stanford study testing a novel antibody pretreatment in SCID patients—in collaboration with Rajni Agarwal-Hashmi, MD, associate professor of pediatrics, and other stem cell transplantation and regenerative medicine specialists at Stanford and UC-San Francisco.  

Targeting Blood Stem Cells

The novel pretreatment uses the JSP191 antibody to target a protein called CD117, found on the surface of blood stem cells. The antibody binds to this protein, which then blocks CD117 from binding to a stem cell factor critical for keeping blood stem cells alive. When the interaction between CD117 and the essential stem cell factor is interrupted, the patient’s blood stem cells are depleted—making space for the donor’s healthy cells to engraft.

“It’s not like chemotherapy or radiation,” says Shizuru. “It’s a targeted way to deplete the blood stem cells without damaging normal healthy cells.”

The Stanford team chose SCID patients for their first human JSP191 clinical trial in part because these children have a unique biology—they lack lymphocytes, so they are less likely to immunologically reject the blood stem cells from a donor. Since immune suppressive medications aren’t necessary, the researchers can more easily see if the antibody therapy clears space in the bone marrow and the transplant works.

Initially, the clinical trial studied older children and adults with SCID whose first blood stem cell transplant had failed, so that they could evaluate whether JSP191 therapy was safe and well tolerated. The participants ranged in age from 3 years old to mid-30s, but most were between 11 and 13 years old. According to Shizuru, many of these kids had chronic infections and also wanted to be liberated from having intravenous immunoglobulin infusions.  

Rajni Agarwal-Hashmi, MD

Promising Results

The results are very promising, as Shizuru reported in 2019 at the American Society of Hematology annual conference. The antibody safely created room in the patients’ bone marrow, allowing healthy donor stem cell engraftment without common side effects like transfusion reactions, treatment-related toxicities, or bone marrow suppression.

“The wonderful thing about the antibody JSP191 is it’s super-safe. This conditioning agent doesn’t affect the DNA or any other organ, as far as we can tell,” explains Shizuru. “We give it as a onetime, really low dose. And it’s not showing any side effects. It’s an amazing drug.” 

The study’s clinicians even remarked that the re-transplant kids looked bored in the hospital because the expected complications didn’t happen, says Shizuru. “The patients’ counts didn’t drop. They didn’t have increased infections. They didn’t need blood transfusions,” she says. “So, we decided to give the antibody as an inpatient treatment and then do everything else as outpatient after 48 hours.”

The results were promising from the start. The first participant pretreated with JSP191 was a 3-year-old girl with chronic diarrhea and infections. After about a year, she no longer had diarrhea and started going to school for the first time. In fact, her family was infected with COVID-19 and she did fine, as Shizuru learned during a public discussion.

Expanding the Clinical Trial

Based on the safety and success of the first phase, the JSP191 trial expanded to include infants newly diagnosed with SCID. Two infants have received the antibody pretreatment followed by a blood stem cell transplant.

The first infant did really well, demonstrating signs that his donor cells may fully restore his immune function. The second infant’s response was more complicated; the researchers determined that she had some immune function that may have rejected the maternal stem cells. She subsequently underwent another transplant without the antibody agent, using a mix of chemotherapies.  

After their initial success, Shizuru’s team expanded the use of JSP191 to include other vulnerable populations—older adults with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). AML is a type of leukemia in which DNA mutations cause the rapid growth of abnormal cells that build up in the bone marrow. Although it starts in the bone marrow, AML often quickly moves to the blood and sometimes spreads to other parts of the body. MDS are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells. Both AML and MDS primarily occur in people over 65 years old.

This adult study is based on the preclinical work of Wendy Pang, MD, PhD, who was a postdoctoral fellow in the Shizuru laboratory. She showed that the disease-causing MDS and AML stem cells express CD117, so they can be targeted by JSP191. Further, the team observed synergistic eradication of stem cells when these anti-CD117 antibodies were combined with low-dose radiation.

The ongoing clinical trial utilizing JSP191 combined with low-dose radiation is led by Lori Muffly, MD, assistant professor of blood and marrow transplantation and cellular therapies. The preliminary results are encouraging based on the first six participants, who were older adults (64–74 years old) with AML or MDS. The researchers observed no side effects associated with JSP191, and the patients’ blood stem cell transplants were successful.

“We transplanted our first SCID babies and then opened the trial up to older patients with AML and MDS. So, now we’re covering the full spectrum for this targeted therapy: from a 3-month-old infant with SCID to a 74-year-old with AML,” Shizuru says.

The JSP191 project has now moved to a biotechnology company, Jasper Therapeutics. Shizuru expects that in the future, the studies will expand to include sickle cell disease, a group of inherited red blood cell disorders, where the JSP191 antibody can help to engraft the donor cells.

“In terms of pretreatment, there’s been no innovation on transplant agents in decades. People have been innovating on transplant by simply reducing the dose of chemotherapies, but we haven’t seen a successful new agent,” explains Shizuru. “The development of JSP191 leverages our understanding of the biology of blood stem cells by targeting a critically important molecule. JSP191 antibody is now the platform agent.”

This is a reposting of my feature article in the recent Stanford Medicine Annual Report.

Behind the scenes with a co-director of The Pride Study

In our “Behind the Scenes” series, Stanford Medicine physicians, nurses, researchers and staff members share a glimpse of their daily lives.

For Stanford obstetrician/gynecologist Juno Obedin-Maliver, MD, MPH, there is no typical day. Part of what she loves about her job is that every day is different.

Obedin-Maliver practices the full spectrum of gynecology, including outpatient, inpatient, operative and emergency services. She also co-directs The PRIDE Study, which is a national prospective, longitudinal cohort of sexual and/or gender minority people — including but not limited to lesbian, gay, bisexual, transgender and queer people.

I was excited to speak with her about how she fits all of this into her day — both before and during the COVID-19 pandemic.

Pre-COVID morning routine

I get up between 5 a.m. and 6:15 a.m. I usually make some tea and have breakfast before getting my three-year-old son up, dressed and fed. Then, either my partner or I take him to school. Next, I head down to Stanford from San Francisco where I live.

Organizing the workweek

I see patients about 30% of the time, and the rest of the time I do research. Days that I don’t see patients are a mix of research writing and meetings — with overnight calls or surgery kind of sprinkled in here and there.

Part of my research team is at Stanford, part at the University of California San Francisco and part at our office in the Oakland City Center. So, I have meetings with folks all over the Bay, and also all over the country, because we have collaborators and stakeholders across the United States.

The PRIDE Study

The main focus of  The PRIDE Study is understanding the relationship between being a sexual and/or gender minority person and a person’s health. And we think about health broadly: physical health, mental health, social health and wellbeing. We want to understand in more detail the well-documented health disparities among sexual and gender minority people, but also their health resiliency. We’ve enrolled about 18,000 people in the study.

I’m also working to build an LGBTQ+ program at Stanford, which will include clinical care, research and education.

Juno Obedin-Maliver, MD, MPH, and Mitchell Lunn, MD, co-direct The PRIDE Study, a national prospective, longitudinal cohort of sexual and/or gender minority people.
Most productive time of the day

My most productive time is in the morning at home. I usually triage my email — deleting spam, putting actionable items on my to-do list and putting anything that requires significant time on my calendar. And if I get up at 5 am, I can get an hour of uninterrupted writing in before my son wakes up, which is awesome.

Evening ritual

I get home between 6 p.m. and 7:30 p.m., then I just hang out with my son and my partner. We give him dinner and a bath, read him books and get him to sleep. And then we have our own dinner. Sometimes we just hang out until bedtime. And sometimes, unfortunately, we get back on the computer to work.

In the evening, I like to meditate, if only for 10 minutes. I remember what I’m grateful for. And I generally read a novel before I go to bed. Right now, I’m reading a book called The Hakawati by Rabih Alameddine. It’s pretty great. I try to get to sleep by 10 or 10:30 p.m.

My day during the pandemic

I still see patients one day a week, and it’s a mix of in-person and video visits in the clinic. I also work some shifts on labor and delivery.

In terms of research, my team is still rocking and rolling, despite the challenges of COVID-19 and systemic violence around the country. I’m very luck to work with an inspiring team dedicated to equity and justice.

Professionally, it’s been a productive time, and we’ve published a number of papers. We’ve also launched a survey about the impact of COVID-19 for LGBTQ+ people, and a related survey about respiratory symptoms, and have had a few thousand responses already. The pandemic seems to be exacerbating systems of inequality, and that’s certainly true for LGBTQ+ — and even more so for LGBTQ+ people of color and those who are economically disadvantaged. As we enter Pride Month, we are also about to launch our fourth annual questionnaire on June 8, and celebrate having over 18,000 participants.

Having a 3-year-old at home and splitting his care throughout the day with my partner has been a big challenge though. Our kiddo misses his friends and school, as we all do. In many ways, we’re closer than ever, and have had a lot of opportunities to do crafts and bake — and we’re growing food on our porch (tomatoes, lettuce, peppers, chard and strawberries!).

On the other hand, trying to still fit in a full work day is a struggle; it means working before he is up and long after he goes to sleep, and unfortunately more screen time for him than ever before. That being said, we’re so lucky to be healthy, have access to food and have jobs that allow us to work at least some of the time from home while still being of service.

Photos by Steve Fisch

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

Physicians re-evaluate use of lead aprons during X-rays

When you get routine X-rays of your teeth at the dentist’s office or a chest X-ray to determine if you have pneumonia, you expect the technologist to drape your pelvis in a heavy radioprotective apron. But that may not happen the next time you get X-rays.

There is growing evidence that shielding reproductive organs has negligible benefit; and because a protective cover can move out of place, using it can result in an increased radiation dose to the patient or impaired quality of diagnostic images.

Shielding testes and ovaries during X-ray imaging has been standard practice since the 1950s due to a fear of hereditary risks — namely, that the radiation would mutate germ cells and these mutations would be passed on to future generations. This concern was prompted by the genetic effects observed in studies of irradiated fruit flies. However, such hereditary effects have not been observed in humans.

“We now understand that the radiosensitivity of ovaries and testes is extremely low. In fact, they are some of the lower radiation-sensitive organs — much lower than the colon, stomach, bone marrow and breast tissue,” said  Donald Frush, MD, a professor of pediatric radiology at Lucile Packard Children’s Hospital Stanford.

In addition, he explained, technology improvements have dramatically reduced the radiation dose that a patient receives during standard X-ray films, computerized tomography scans and other radiographic procedures. For example, a review paper finds that the radiation dose to ovaries and testes dropped by 96% from 1959 to 2012 for equivalent X-ray exams of the pelvis without shielding.

But even if the radioprotective shielding may have minimal — or no — benefit, why not use it just to be safe?

The main problem is that so-called lead aprons — which aren’t made of lead anymore — are difficult to position accurately, Frush said. Even following shielding guidelines, the position of the ovaries is so variable that they may not be completely covered.  Also,  the protective shield can obscure the target anatomy. This forces doctors to live with poor-quality diagnostic information or to repeat the X-ray scan, thus increasing the radiation dose given to the patient, he said.

Positioning radioprotective aprons is particularly troublesome for small children.

“Kids kick their legs up and the shield moves while the technologists are stepping out of the room to take the exposure and can’t see them. So the X-rays have to be retaken, which means additional dose to the kids,” Frush said.

Another issue derives from something called automatic exposure control, a technology that optimizes image quality by adjusting the X-ray machine’s radiation output based on what is in the imaging field. Overall, automatic exposure control greatly improves the quality of the X-ray images and enables a lower dose to be used.  

However, if positioning errors cause the radioprotective apron to enter the imaging field, the radiographic system increases the magnitude and length of its output, in order to penetrate the shield.

“Automatic exposure control is a great tool, but it needs to be used appropriately. It’s not recommended for small children, particularly in combination with radioprotective shielding,”  said Frush.

With these concerns in mind, many technologists, medical physicists and radiologists are now recommending to discontinue the routine practice of shielding reproductive organs during X-ray imaging. However, they support giving technologists discretion to provide shielding in certain circumstances, such as on parental request. This position is supported by several groups, including the American Association of Physicists in MedicineNational Council on Radiation Protection and Measurements and American College of Radiology.

These new guidelines are also supported by the Image Gently Alliance, a coalition of heath care organizations dedicated to promoting safe pediatric imaging, which is chaired by Frush. And they are being adopted by Stanford hospitals.

“Lucile Packard Children’s revised policy on gonadal shielding has been formalized by the department,” he said. “There is still some work to do with education, including training providers and medical students to have a dialogue with patients and caregivers. But so far, pushback by patients has been much less than expected.”

Looking beyond the issue of shielding, Frush advised parents to be open to lifesaving medical imaging for their children, while also advocating for its best use. He said:

“Ask the doctor who is referring the test: Is it the right study? Is it the right thing to do now, or can it wait? Ask the imaging facility:  Are you taking into account the age and size of my child to keep the radiation dose reasonable?”

Photo by Shutterstock / pang-oasis

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

Physicists curate list of COVID-19 projects to join

As we continue to deal with the global COVID-19 pandemic, biomedical researchers are racing to understand the virus that causes the disease, to evaluate its spread, and to develop tests, treatments and vaccines.

Physicists are volunteering to assist in these efforts, using their skills in data analytics, machine learning, simulation, software, computing, hardware development and project management. And an organization called Science Responds is helping to match them with projects that need their support.

As Savannah Thais, a postdoctoral researcher in high-energy physics and a co-founder of Science Responds, reported at the April meeting of the American Physical Society, physicists are assisting with a variety of types of projects, divided into the following categories:

Epidemiology

Epidemiology is the branch of medical science that studies public health problems and events in order to understand what causes them, how they are distributed among populations and possible ways to control them. Epidemiologists investigate diverse problems including pollution, foodborne illnesses, natural disasters and infectious diseases such as COVID-19.

Science Responds is connecting physicists with epidemiological projects that are working to model how the virus that causes COVID-19 might spread. Physicists hope to help address a major problem that the experts making these models face: incorporating data from a multitude of dissimilar sources.

Thais says physicists have the background and experience needed to provide epidemiologists this kind of support.

“We don’t think physicists should be building their own epidemiological models from scratch, because they don’t have the domain expertise of an epidemiologist or biologist about infectious diseases,” she says. But “physicists can be most effective by providing their computing and statistics skills to interdisciplinary research.”

One epidemiology project Science Responds encourages volunteers to join is HealthMap, which displays data about COVID-19 cases across the globe over time via an openly accessible website and mobile app. HealthMap integrates and filters data from diverse, publicly available sources—including online news aggregators and reports from governments and agencies such as the World Health Organization—and then creates intuitive visualizations of the state of the outbreak by location.

Other modeling projects use analyses of the genomic features of previously studied viruses to help estimate unreported COVID-19 cases; integrate health and hospital resource data to inform localized risk predictions; and incorporate information from previous animal and human outbreaks to improve model accuracy.

Diagnosis

An important part of dealing with an epidemic is determining who has the disease, but shortages of testing supplies have made diagnosis a challenge. Science Responds promotes projects that are trying to address this gap in different ways.

Some projects use artificial intelligence to process visual or audio data. The project CAD4COVID, for example, builds off an existing technology that has been highly successful in diagnosing tuberculosis through the analysis of chest X-rays. The project COVID Voice Detector, on the other hand, is collecting audio recordings to develop an AI that can recognize signs of COVID-19 infection in a patient’s voice.

Other projects are building tools to predict who is likely to experience the most severe effects of COVID-19. These machine-learning-based efforts identify indicators such as markers that appear in blood tests or specific features from lung biopsies to predict the likelihood of long-term hospitalization or death.

Treatments and cures

The race to develop COVID-19 vaccines and treatments begins with understanding the physical structure of the virus. On this front, Science Responds collaborators are providing key support for an effort called Folding@Home, which uses computer simulations to map out the proteins the SARS-CoV-2 virus uses to reproduce and suppress a patient’s immune system. Physicists are helping to develop the protein-folding simulations, but they are also playing a pivotal role in looking for help from anyone with a computer that Folding@Home can use remotely to run folding simulations.

In addition, physicists are helping process the massive amount of data related to the SARS-CoV-2 genome. They’re hoping to identify molecules that are important to the growth and spread of the virus and to understand its mutations.

Science Responds collaborators are also aiding efforts to use machine learning to identify drugs that could be repurposed to treat COVID-19. For example, they are using natural-language-processing algorithms to comb through a massive database of scholarly articles, called CORD-19, for relevant ideas. Other projects are using deep-learning-based models with existing data to predict how commercially available drugs will interact with the virus.

Supporting hospitals and healthcare systems

Science Responds participants are volunteering on projects to support frontline workers who are providing medical care to COVID-19 patients. These efforts include developing models to help predict hospital overload and to allow for the sharing of resources such as mechanical ventilators and personal protective equipment.

One example is the CHIME project, which gathers information on hospital resources and predicts when the needs of patients will exceed an institution’s capacity. CHIME has already been deployed in several hospitals, including the University of Pennsylvania Health System.

Another project in this area is COVID Care Map, which is using open-source data to map existing supplies of hospital beds, ventilators and other resources needed to care for COVID-19 patients such as available staff.

Other projects highlighted by Science Responds are aimed at improving telehealth. Enhanced at-home care could reduce the spread of COVID-19 by eliminating unnecessary hospital visits and improving access to care for rural areas.

Researchers are helping to develop AI-based chatbots that can be used to assess possible infections, educate patients and call on human providers when necessary. Other projects are working to combine in-home sensors and cameras with AI-assisted technologies to remotely monitor the health of vulnerable populations.

Socio-economic response

Finally, Science Responds volunteers are also working to address what they call “second-order effects,” not directly related to healthcare.

Some projects deal with infodemiology, research into what we can learn from user-contributed, health-related content on the internet. Researchers are analyzing millions of real-time tweets related to COVID-19 to answer questions like: How are people reacting to the outbreak? How is Twitter being used to pass on vital information? How is Twitter being abused to spread false information, panic and hate?

Physicists with data-analysis and data-engineering expertise can volunteer for projects aimed at bringing attention to at-risk populations. Thais leads a project that is developing a COVID-19 Vulnerability Index, an AI-based predictive model used to identify communities at high risk of socio-economic and health impacts associated with the spread of COVID-19.

The index looks at a wide range of measures, such as whether community members have access to home Wi-Fi, whether they are affected by non-COVID health issues such as diabetes, and whether healthcare resources are available to them.

Are you a physicist looking to volunteer? Thais recommends checking out the Science Responds website, which lists projects organized by their required skills, highlights available data sources, computing resources and funding opportunities, and provides instructions for getting connected.

Illustration by Sandbox Studio, Chicago with Ana Kova

This is a reposting of my news feature, courtesy of Symmetry magazine.

 

Nerve interface provides intuitive and precise control of prosthetic hand

Current state-of-the-art designs for a multifunctional prosthetic hand are restricted in functionality by the signals used to control it. A promising source for prosthetic motor control is the peripheral nerves that run from the spinal column down the arm, since they still function after an upper limb amputation. But building a direct interface to the peripheral nervous system is challenging, because these nerves and their electrical signals are incredibly small. Current interface techniques are hindered by signal amplitude and stability issues, so they provide amputees with only a limited number of independent movements. 

Now, researchers from the University of Michigan have developed a novel regenerative peripheral nerve interface (RPNI) that relies on tiny muscle grafts to amplify the peripheral nerve signals, which are then translated into motor control signals for the prosthesis using standard machine learning algorithms. The research team has demonstrated real-time, intuitive, finger-level control of a robotic hand for amputees, as reported in a recent issue of Science Translational Medicine.

“We take a small graft from one of the patient’s quadricep muscles, or from the amputated limb if they are doing the amputation right then, and wrap just the right amount of muscle around the nerve. The nerve then regrows into the muscle to form new neuromuscular junctions,” says Cindy Chestek, an associate professor of biomedical engineering at the University of Michigan and a senior author on the study. “This creates multiple innervated muscle fibers that are controlled by the small nerve and that all fire at the same time to create a much larger electrical signal—10 or 100 times bigger than you would record from inside or around a nerve. And we do this for several of the nerves in the arm.”

This surgical technique was initially developed by co-researcher Paul Cederna, a plastic surgeon at the University of Michigan, to treat phantom limb pain caused by neuromas. A neuroma is a painful growth of nerve cells that forms at the site of the amputation injury. Over 200 patients have undergone the surgery to treat neuroma pain.

“The impetus for these surgeries was to give nerve fibers a target, or a muscle, to latch on to so neuromas didn’t develop,” says Gregory Clark, an associate professor in biomedical engineering from the University of Utah who was not involved in the study. “Paul Cederna was insightful enough to realize these reinnervated mini-muscles also provided a wonderful opportunity to serve as signal sources for dexterous, intuitive control. That means there’s a ready population that could benefit from this approach.”

The Michigan team validated their technique with studies involving four participants with upper extremity amputations who had previously undergone RPNI surgery to treat neuroma pain. Each participant had a total of 3 to 9 muscle grafts implanted on nerves. Initially, the researchers measured the signals from these RPNIs using fine-wire, nickel-alloy electrodes, which were inserted through the skin into the grafts using ultrasound guidance. They measured high-amplitude electromyography signals, representing the electrical activity of the mini-muscles, when the participants imagined they were moving the fingers of their phantom hand. The ultrasound images showed the participants’ thoughts caused the associated specific mini-muscles to contract. These proof-of-concept measurements, however, were limited by the discomfort and movement of the percutaneous electrodes that pierced the skin.

Next, the team surgically implanted permanent electrodes into the RPNIs of two of the participants. They used a type of electrode commonly used for battery-powered diaphragm pacing systems, which electrically stimulate the diaphragm muscles and nerves of patients with chronic respiratory insufficiency to help regulate their breathing. These implanted electrodes allowed the researchers to measure even larger electrical signals—week after week from the same participant—by just plugging into the connector. After taking 5 to 15 minutes of calibration data, the electrical signals were translated into movement intent using machine learning algorithms and then passed on to a prosthetic hand. Both subjects were able to intuitively complete tasks like stacking physical blocks without any training—it worked on the first try just by thinking about it, says Chestek. Another key result is that the algorithm kept working even 300 days later.

“The ability to use the determined relationship between electrical activity and intended movement for a very long period of time has important practical consequences for the user of a prosthesis, because the last thing they want is to rely on a hand that is not reliable,” Clark says.

Although this clinical trial is ongoing, the Michigan team is now investigating how to replace the connector and computer card with an implantable device that communicates wirelessly, so patients can walk around in the real world. The researchers are also working to incorporate sensory feedback through the regenerative peripheral nerve interface. Their ultimate goal is for patients to feel like their prosthetic hand is alive, taking over the space in the brain where their natural hand used to be.

“People are excited because this is a novel approach that will provide high quality, intuitive, and very specific signals that can be used in a very straightforward, natural way to provide high degrees of dexterous control that are also very stable and last a long time,” Clark says.

Read the article in Science Translational Medicine.

Illustration of multiple regenerative peripheral nerve interfaces (RPNIs) created for each available nerve of an amputee. Fine-wire electrodes were embedded into his RPNI muscles during the readout session. Credit: Philip Vu/University of Michigan; Science Translational Medicine doi: 10.1126/scitranslmed.aay2857

This is a reposting of my news brief, courtesy of Materials Research Society.

Why do viruses like the coronavirus sometimes steal our sense of smell?

When you catch a severe cold, your nose stuffs up, you can’t smell anything and food tastes funny. Fortunately, most people regain their sense of smell once the cold runs its course. But for others, the complete (anosmia) or partial (hyposmia) loss of the sense of smell is permanent.

I spoke with Zara Patel, MD, a Stanford associate professor of otolaryngology, head and neck surgery, and director of endoscopic skull base surgery, to learn more about her research on olfactory disorders. In particular, we discussed her recent study on the possible association between post-viral olfactory loss and other cranial neuropathies, which are disorders that impair your nerves and ultimately your ability to feel or move. She also described how her work pertains to the COVID-19 pandemic.  

How does a virus impair someone’s sense of smell?

A variety of viruses can attack the cranial nerves related to smell or the mucosal tissue that surrounds those nerves. Cranial nerves control things in our head and neck — such as the nerves that allow us to speak by using our vocal cords, control our facial motion, hear and smell.

For example, COVID-19 is just one type of disease caused by a coronavirus. There are many other types of coronaviruses that cause colds and upper respiratory illnesses, as well as rhinoviruses and influenza viruses. Any of these viruses are known to cause inflammation, either directly around the nerve in the nasal lining or within the nerve itself. When the nerve is either surrounded by inflammatory molecules or has a lot of inflammation within the nerve cell body, it cannot function correctly — and that is what causes the loss or dysfunction of smell. And it can happen to anyone: young and old, healthy and sick.

How did your study investigate olfactory loss?

In my practice, I see patients who have smell dysfunction. But I’m also a sinus and skull base surgeon, so I have a whole host of other patients with sinus problems and skull-based tumors who don’t have an olfactory loss. So we did a case-control study to compare the incidence of cranial neuropathies — conditions in which nerves in the brain or brain stem are damaged — in two patient groups. Ninety-one patients had post-viral olfactory loss and 100 were controls; and they were matched as closely as possible for age and gender.

We also looked at family history of neurologic diseases — such as Alzheimer’s disease, Parkinson’s disease and stroke.

What did you find?

Patients with post-viral olfactory loss had six-times higher odds of having other cranial neuropathies than the control group — with an incidence rate of other cranial nerve deficits of 11% and 2%, respectively. Family history of neurologic diseases was associated with more than two-fold greater odds of having a cranial nerve deficit. Although we had a small sample size, the striking difference between the groups implies that it is worthwhile to research this with a larger population.

Our findings suggest that patients experiencing these pathologies may have inherent vulnerabilities to neural damage or decreased ability of nerve recovery — something beyond known risk factors like age, body mass index, co-morbidities and the duration of the loss before intervention. For example, there may be a genetic predisposition, but that is just an untested theory at this point.

How does this work pertain to COVID-19?

Smell loss can be one of the earliest signs of a COVID-19 infection. It can sometimes be the only sign. Or it can present after other symptoms. Although it may not affect every patient with COVID-19, loss of smell and taste is definitely associated with the disease. In some countries, including France, they’ve used this as a triage mechanism. People need to know that these symptoms can be related to the COVID-19 disease process so they aren’t going about their lives like normal and spreading the virus.

The pandemic also might impact how we treat patients with olfactory dysfunction in general. When someone has a viral-induced inflammation of the nerve, we sometimes treat it with steroids to decrease the inflammation. But treating COVID-19 patients with steroids might be a bad idea because of its effect on the inflammatory processes going on in their heart and lungs.

What advice do you have for people who have an impaired sense of smell?  

First, if you lose your sense of smell and it isn’t coming back after all the other symptoms have gone away, seek care as soon as possible. If you wait too long, there is much less that we can do to help you. Interventions, including olfactory training and medications, are more effective when you are treated early.

Second, if you lose your sense of smell or taste during this pandemic and you don’t have any other symptoms, contact your doctor. The doctor can decide whether you need to be tested for COVID-19 or whether you need to self-isolate to avoid being a vector of the virus in your family or community.

Image by carles

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