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How Stem Cells Decide Their Fate

Source: Memorial Sloan Kettering - On Cancer
Date: 08/13/2019
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Stem cells are defined by their ability to differentiate into other, more specialized cell types. When one stem cell divides into two (which are then called daughter cells), three things can happen to the new cells: Both cells can continue being stem cells, both cells can differentiate into a new cell type, or the cells can go their separate ways, with one maintaining the properties of a stem cell and the other becoming something new.

“It may be surprising, but as much as stem cells have been studied, we don’t know much about how they make this commitment when they divide,” says Michael Kharas, who is in the Sloan Kettering Institute’s Molecular Pharmacology Program. Dr. Kharas led a team from SKI, in collaboration with investigators at Weill Cornell Medical College, that discovered new details about how dividing stem cells choose what to become. Their findings were published August 13 in Cell Reports.

Dr. Kharas’s lab uses human and mouse blood (hematopoietic) stem cells to study how certain types of leukemia develop.

Knocking Out an Important Protein

When both daughter cells are the same cell type, this is called symmetric division. That’s true whether they continue being stem cells or become something new. When one cell stays a stem cell and the other differentiates, it’s called asymmetric division. This happens about 30 percent of the time.

“The beauty of asymmetric division is that you’re maintaining your stem cell numbers,” Dr. Kharas explains. “If every time a stem cell divides, it loses its identity as a stem cell, you will eventually deplete all the stem cells. But if all the cells remain stem cells, you’ll never get the variety of cell types you need to form an entire blood system.”

Previous work in the Kharas lab has focused on a protein called MUSASHI-2. The researchers found that when MUSASHI-2 is knocked out in blood stem cells, the cells lose their “stemness.” They are more likely to differentiate and become nonstem cells. Additionally, they have less of the asymmetric type of division.Targeting RNA-binding proteins has been identified as a new approach in the development of drugs for leukemia.

In the new study, the investigators — led by first authors Yuanming Cheng and Hanzhi Luo, of Dr. Kharas’s lab, and Franco Izzo from Weill Cornell — focused on a different protein: METTL3. Both MUSASHI-2 and METTL3 are RNA-binding proteins, but the METTL3 protein is the key enzyme that can add chemicals called methyl groups to specific RNA nucleotides. This process is called methylation, and it decorates RNA with marks called m6A. 

Ultimately, this helps regulate the stability of the RNAs and the efficiency of protein production. Targeting RNA-binding proteins has been identified as a new approach in the development of drugs for leukemia.

Taking a Closer Look at Stem Cells

To study the role of m6A, the researchers compared the blood-forming systems of mice that had METTL3 knocked out and those that did not, to see how blood development was affected. They found that the mice without the protein seemed to have an accumulation of blood stem cells, suggesting that the cells were unable to become more specialized cells. 

To get a better look at what was going on, the lab of Dan Landau at Weill Cornell studied the cells with a type of analysis called single-cell RNA sequencing (RNA seq). RNA seq enables researchers to determine which genes are being expressed, or turned on, in cells. This revealed that there were actually fewer stem cells than originally thought. But some of the cells seemed to be stuck in an intermediate state between stem cell and differentiated cell that the scientists had never seen before.

“These stem cells had reduced ability to symmetrically differentiate. Based on these findings, we believe that METTL3 — and therefore, RNA methylation — controls this specific type of division in hematopoietic stem cells,” Dr. Kharas notes. “This research suggests a general mechanism for RNA methylation in controlling how stem cells regulate their fate when they divide.”

Implications for Cancer Treatment and Beyond

Dr. Kharas explains that there are two main implications for this new finding.

Many researchers and pharmaceutical companies are focused on developing new leukemia drugs that target the RNA methylation process. “It’s important to know how these drugs might work and what unintended consequences they may have,” he says.

But perhaps more interesting to the researchers who worked on the project are the implications for understanding the division and differentiation of hematopoietic stem cells.

“Now that we have identified this new population of cells in our lab, we may be able to use them as a model to understand the intricate steps that happen when a stem cell decides to differentiate,” Dr. Kharas concludes. “It may eventually provide a new approach for growing large numbers of stem cells for the development of cell therapies.”

Dr. Kharas is a scholar of the Leukemia and Lymphoma Society. The MSK team was funded by a National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Career Development Award, an NIH/NIDDK grant (R01-DK101989-01A1), an NIH/National Cancer Institute grant (1R01CA193842-01), a Kimmel Scholar Award from the Sidney Kimmel Foundation, a V Scholar grant from the V Foundation for Cancer Research, a Geoffrey Beene Award from the Geoffrey Beene Cancer Research Center at MSK, an Alex’s Lemonade Stand ‘A’ Award Grant, and funding from the Starr Cancer Consortium. Dr. Luo is supported by a New York State Stem Cell Science training award. The Weill Cornell team received funding from a Burroughs Wellcome Fund Career Award for Medical Scientists, an American Society of Hematology Scholar Award, and the Leukemia and Lymphoma Society Translational Research Program.

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Salk team reveals clues into early development of autism spectrum disorder

Source: Salk Institute
Date: 01/07/2019
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Neurons from people with autism exhibit different patterns of growth and develop at a faster rate

Autism spectrum disorder (ASD) is a relatively common developmental disorder of communication and behavior that affects about 1 in 59 children in the US, according to the Centers for Disease Control and Prevention. Despite its prevalence, it is still unclear what causes the disease and what are the best ways to treat it.

Researchers at the Salk Institute compared stem cells created from individuals with ASD against stem cells created from those without ASD to uncover, for the first time, measurable differences in the patterns and speed of development in the ASD-derived cells.

The findings, published January 7, 2019, in the journal Nature Neuroscience, could lead to diagnostic methods to detect ASD at an early stage, when preventive interventions could potentially take place.

“Although our work only examined cells in cultures, it may help us understand how early changes in gene expression could lead to altered brain development in individuals with ASD,” says Salk Professor Rusty Gage, the study’s senior author and president of the Institute. “We hope that this work will open up new ways to study neuropsychiatric and neurodevelopmental disorders.”

For the study, the researchers took skin cells from eight people with ASD and five people without ASD and turned them into pluripotent stem cells—cells that have the ability to develop into any cell type. They then coaxed the stem cells to develop along the path of becoming neurons by exposing them to certain chemical factors.

By using molecular “snapshots” from different developmental stages in the stem cells, the team was able to track genetic programs that switched on in a certain order as the stem cells developed into neurons. This revealed key differences in the cells derived from people with ASD. For instance, the Salk team observed that the genetic program associated with the neural stem-cell stage turned on earlier in the ASD cells than it did in the cells from those without ASD. This genetic program includes many genes that have been associated with higher chances of ASD. In addition, the neurons that eventually developed from the people with ASD grew faster and had more complex branches than those from the control group.

“It’s currently hypothesized that abnormalities in early brain development lead to autism, but the transition from a normally developing brain to an ASD diagnosis is blurred,” says first author Simon Schafer, a postdoctoral fellow in the Gage lab. “A major challenge in the field has been to determine the critical developmental periods and their associated cellular states. This research could provide a basis for discovering the common pathological traits that emerge during ASD development.”

“This is a very exciting finding, and it encourages us to further refine our methodological framework to help advance our understanding of the early cell biological events that precede the onset of symptoms,” adds Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. “Studying system dynamics could maximize our chance of capturing relevant mechanistic disease states.”

The researchers say the experiments in this study will lead to more dynamic approaches for studying the mechanisms that are involved in ASD predisposition and progression.

They next plan to focus on the creation of brain organoids, three-dimensional models of brain development in a dish that enable scientists to study the interactions between different types of brain cells.

“The current diagnostic methods are mostly subjective and occur after the emergence of behavioral abnormalities in young children,” Schafer says. “We hope these studies will serve as a framework for developing novel approaches for diagnosis during an early period of child development—long before behavioral symptoms manifest—to have the maximum impact on treatment and intervention.”

Other researchers on the paper were Apua C. M. Paquola, Shani Stern, Monique Pena, Thomas J. M. Kuret, Marvin Liyanage, Abed AlFatah Mansour, Baptiste N. Jaeger, Maria C. Marchetto and Jerome Mertens of Salk; David Gosselin of Université Laval in Quebec City, Canada; Manching Ku of the University of Freiburg in Freiburg, Germany; and Christopher K. Glass of the University of California San Diego.

This work was funded by The James S. McDonnell Foundation, G. Harold & Leila Y. Mathers Charitable Foundation, JPB Foundation, the March of Dimes Foundation, National Institutes of Health (NIH) grants MH095741 and MH090258, The Engman Foundation, Annette C. Merle-Smith, The Paul G. Allen Family Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust. It was also supported by NIH grant P30 014195, the German Research Foundation (DFG) and the Chapman Foundation.

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Research confirms nerve cells made from skin cells are a valid lab model for studying disease

Source: Salk Institute
Date: 01/15/2019
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Salk and Stanford team shows that induced neuronal cells derived from fibroblasts are similar to neurons in the brain, on the epigenomic level

The incidence of some neurological diseases—especially those related to aging, such as Alzheimer’s and Parkinson’s diseases—is increasing. To better understand these conditions and evaluate potential new treatments, researchers need accurate models that they can study in the lab.

Researchers from the Salk Institute, along with collaborators at Stanford University and Baylor College of Medicine, have shown that cells from mice that have been induced to grow into nerve cells using a previously published method have molecular signatures matching neurons that developed naturally in the brain.

The study, published in eLife on January 15, 2019, opens the door for better ways to model an individual patient’s disease. This technique would enable researchers to study how neurological conditions develop, as well as to test new therapies. The new technology also could help to advance research into gene therapies that are derived from a patient’s own cells.

“This research is charting the path for the most optimal way of creating neurons in the lab,” says Salk Professor Joseph Ecker, one of the study’s two senior authors. “By taking these cells and reprogramming them into neurons, you can potentially learn new things about how these diseases function on a cellular level, especially diseases driven by genetic changes.”

The cells used in the study, called fibroblasts, make up most of the connective tissue in animals and play an important role in wound healing. Researchers have been studying how to transform fibroblasts into neuron cells in laboratory dishes, but until now they didn’t know whether these newly created neurons accurately corresponded to neurons that had grown naturally in the brain.

The technique for inducing the fibroblasts to grow into neurons with the matching epigenome was developed by Stanford’s Marius Wernig, the paper’s co-senior author. With this method, making induced neuronal cells does not involve pluripotent intermediates. Instead, the cells are directly converted from fibroblasts to neurons.

“An important question in cellular engineering is how to know the quality of your product,” says co-first author Chongyuan Luo, a postdoctoral fellow in Ecker’s lab. “If we’re making neurons from fibroblasts, we want to know how they compare with neurons in the brain. We are particularly interested in looking at these cells at the level of the epigenome.”

The epigenome is made up of chemicals that attach to DNA and regulate when genes get turned on and translated into proteins. Differences between the epigenomes of induced and naturally grown neurons could result in different features of induced neurons that might make them less accurate models of neuronal behavior.

Using a technique developed in the Ecker lab called MethylC-seq, the researchers looked at every place in the genome where chemical groups called methyl groups are attached. They confirmed that these induced neurons have epigenomes that match neurons in the brain.

“This research was done in mouse cells, but we plan to use the same technology to study induced neurons made with human cells,” explains Ecker, who is director of Salk’s Genomic Analysis Laboratory and a Howard Hughes Medical Institute investigator. Ecker plans to also collaborate with colleagues to apply the technology to look at human cells to better understand age-related cognitive decline.

Other researchers on the paper were Rosa Castanon and Joseph R. Nery of Salk; Sean M. Cullen and Margaret A. Goodell of Baylor College of Medicine; and Qian Yi Lee, Orly L. Wapinski, Moritz Mall, Michael S. Kareta and Howard Y. Chang of Stanford.

The work was supported by the National Institutes of Health (grants P50-HG007735 and R01 DK092883), the California Institute for Regenerative Medicine (grant RB5-07466) and the Howard Hughes Medical Institute.

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Key enzyme found in plants could guide development of medicines and other products

Source: Salk Institute
Date: 09/06/2019
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Salk research explains how plants are able to efficiently manufacture the compounds they use to adapt to stress

Plants can do many amazing things. Among their talents, they can manufacture compounds that help them repel pests, attract pollinators, cure infections and protect themselves from excess temperatures, drought and other hazards in the environment.

Researchers from the Salk Institute studying how plants evolved the abilities to make these natural chemicals have uncovered how an enzyme called chalcone isomerase evolved to enable plants to make products vital to their own survival. The researchers’ hope is that this knowledge will inform the manufacture of products that are beneficial to humans, including medications and improved crops. The study appeared in the print version of ACS Catalysis on September 6, 2019.

“Since land plants first appeared on earth approximately 450 million years ago, they have developed a sophisticated metabolic system to transform carbon dioxide from the atmosphere into a myriad of natural chemicals in their roots, shoots and seeds,” says Salk Professor Joseph Noel, the paper’s senior author. “This is the culmination of work we’ve been doing in my lab for the past 20 years, trying to understand plant chemical evolution. It gives us detailed knowledge about how plants have developed this unique ability to make some very unusual but important molecules.”

Previous research in the Noel lab looked at how these enzymes evolved from non-enzyme proteins, including studying more primitive versions of them that appear in organisms such as bacteria and fungi.

As an enzyme, chalcone isomerase acts as a catalyst to accelerate chemical reactions in plants. It also helps to ensure the chemicals that are made in the plant are the proper form, since molecules with the same chemical formula can take two different variations that are mirror images of each other (called isomers).

“In the pharmaceutical industry, it’s important that the drugs being made are the correct version, or isomer, because using the wrong one can lead to unintended side effects,” says Noel, who is director of Salk’s Jack H. Skirball Center for Chemical Biology and Proteomics and holds the Arthur and Julie Woodrow Chair. “By studying how chalcone isomerase works, we can learn more about how to accelerate the manufacture of the correct isomers of pharmaceuticals and other products that may be important to human health.”

In the current study, the investigators used several structural biology techniques to investigate the enzyme’s unique shape and how its shape changes as it interacts with other molecules. They pinpointed the part of chalcone isomerase’s structure that allowed it to catalyze reactions incredibly fast while also ensuring it makes the proper, biologically active isomer. These reactions lead to a host of activities in plants, including converting primary metabolites like phenylalanine and tyrosine into vital specialized molecules called flavonoids.

It turned out that one particular amino acid, arginine, that was one of many amino acids linked together in chalcone isomerase sat in a location, shaped by evolution, that allowed it to play the key role in how chalcone isomerase reactions were catalyzed.

“By doing structural studies and computer modeling, we could see the very precise positions of arginine within the enzyme’s active site as the reaction proceeded,” says first author Jason Burke, a former postdoctoral research in Noel’s lab who is now an assistant professor at California State University San Bernardino. “Without that arginine, it doesn’t work the same way.”

Burke adds that this type of catalyst has been long sought by organic chemists. “This is an example of nature already solving a problem that chemists have been looking at for a long time,” he adds.

“By understanding chalcone isomerase, we can create a new toolset that chemists will be able to use for the reactions they’re studying,” Noel says. “It’s absolutely vital to have this kind of foundational knowledge to be able to design molecular systems that can carry out a particular task even in the next generation of nutritionally dense crops capable of transforming the greenhouse gas carbon dioxide into molecules essential for life.”

Other researchers on the paper were James La Clair, Ryan Philippe, Joseph Jez, Marianne Bowman, Gordon Louie, and Katherine Woods of Salk; Anna Pabis, Marina Corbella, and Shina Kamerlin of Uppsala University in Sweden; George Cortina of the University of Virginia; Miriam Kaltenbach and Dan Tawfik of the Weizmann Institute of Science in Israel; and Andrew Nelson of the University of Texas at Austin.

This work was also supported by the Howard Hughes Medical Institute, United States National Science Foundation grant EEC-0813570, the Wenner-Gren Foundations, European Research Council ERC grant agreement 30647, and a Wallenberg Academy Fellowship from the Knut and Alice Wallenberg Foundation. The Swedish National Infrastructure for Computing provided the computer time for the simulations conducted in this study.

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Novel technique helps explain why bright light keeps us awake

Source: Salk Institute
Date: 10/15/2019
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Researchers discover a way to make electron microscopy more detailed and precise by visualizing the activation of brain circuits over long distances

In recent decades, scientists have learned a great deal about how different neurons connect and send signals to each other. But it’s been difficult to trace the activity of individual nerve fibers known as axons, some of which can extend from the tip of the toe to the head. Understanding these connections is important for figuring out how the brain receives and responds to signals from other parts of the body.

Researchers at the Salk Institute and UC San Diego are reporting a novel technique for tracing these connections and determining how neurons communicate. The team used this technique to uncover details about how the brain responds to light signals received by the retina in mice, published October 15, 2019, in Cell Reports.

“This study is a breakthrough because no one could figure out how to study these connections before,” says Salk Professor Satchidananda Panda, co-corresponding author of the paper. “This new technique has enabled us to go well beyond the limitations of electron microscopy.”

The new method makes use of several different laboratory techniques to understand a type of neuron called intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells, which are found in the retina, in the back of the eye, express a protein called melanopsin that senses blue light.

The Salk and UCSD teams used a virus to deliver a protein called a mini-singlet oxygen-generating protein (mini-SOG) to the ipRGCs, so that the cells could be viewed in more detail under election microscopy. The system was designed to tether the mini-SOG to the membranes of the light-sensitive cells so that the entire neuron, including its long axons that reach out to different parts of the brain, can be easily tracked under both light and electron microscope.

“Thanks to development and application of new genetically introduced probes for correlated multiscale light and electron microscopic imaging, our Salk and UCSD-based research teams were able to follow the small processes emanating from nerve cells over centimeters, all the way from the retina to multiple places where they connect to brain regions critical to circadian rhythms, eye reflexes and vision,” says Mark Ellisman, distinguished professor of neurosciences at UC San Diego and adjunct professor at Salk, who co-led the work. “We were able to obtain unprecedented three-dimensional information about the machinery required for these neuronal cells to signal the next neurons in the complex circuits.”

Most of the previous work with mini-SOGs has been done in cell lines, and using them in mice, to map how neurons from the retina wire the brain, was a first, according the researchers. The method enabled them to glean new information about the connections between ipRGCs and different parts of the brain.

The ipRGCs are known to connect to many brain regions that regulate very different tasks. The cells tell one part of the brain how bright it is outside so that our pupil can rapidly close—in less than a second. The same ipRGCs also connect to the master clock in the brain that regulates our sleep-wake cycle. “However, it takes several minutes of bright light to make us fully awake,” Panda says. “How the same ipRGCs do these very different tasks with different time scales was not clear until now.”

The investigators found that the difference has to do with the way that light detected by the retina reaches the brain. By delivering the mini-SOG to the eyes of the mice, they were able to trace the signal to the part of the brain that constricts the pupil in response to light.

“These connections were much stronger—similar to water pouring out of a garden hose,” Panda says. “Whereas the connection between the ipRGCs and the master clocks were weaker—more like drip irrigation.” Because the ipRGCs deliver the light signal to the circadian center through this slower drip system, it takes longer for any meaningful information to reach and reset the brain clock.

“This research helps explain why, when you get up in the night to get a drink of water and turn on the light for a few seconds, you’re usually able to go right back to sleep,” Panda says. “But if you hear a noise outside and end up walking around your house for half an hour with the lights on, it’s much harder. There will be enough light signal reaching the master clock neurons in the brain that ultimately wakes up the rest of the brain.”

Panda says that the new technique will be useful for studying other neural connections, as the researchers can essentially use the same viruses to express mini-SOGs in any neuron and ask how different neurons make connections to different appendages.

“These findings and methods open new opportunities for brain researchers studying the long-distance wiring of brains in normal and in animal models of human disease,” adds Ellisman.

Other researchers on the paper were Luis Rios, Hiep Le, Yu Hsin Liu, Masatoshi Hirayama, Ludovic Mure, and Megumi Hatori of Salk and Keun-Young Kim, Alex Perez, Sébastien Phan, Eric Bushong, Thomas Deerinck, Maya Ellisman, Varda Lev-Ram, Suyeon Ju, Sneha Panda, Sanghee Yoon, and Mark Ellisman of the University of California at San Diego.

The research was supported by National Institutes of Health grants EY 016807, P41GM103412, RO1 GM086197, and RO1 NS027177.

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Proactive Psychiatric Consultations Benefit MICU Patients

Source: Brigham and Women's Hospital - On a Mission
Date: 01/03/2019
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Preexisting mental illness and substance abuse disorders are common in patients being treated in intensive care units (ICUs), as is delirium. There is increasing appreciation for the impact of these conditions on overall health outcomes, length of hospital stay and mortality.

Proactive psychiatric consultation has demonstrated improved outcomes in the general hospital setting. Accordingly, Brigham and Women’s Hospital has launched and studied an innovative proactive psychiatric consultation model in the intensive care setting. In this model, a psychiatrist is embedded with the medical ICU (MICU) team and participates in daily walk rounds, rather than the standard approach of having psychiatric consultations conducted only when called by the primary care team.

“These are patients who are critically ill and at their most vulnerable,” said Nomi Levy-Carrick, MD, MPHIL, an associate psychiatrist in the Brigham’s Department of Psychiatry. “The idea is that if you can identify any psychiatric conditions or delirium early in the course of their treatment, you are more likely to be able to bring an informed approach to managing those issues. In that way, you can help to support patients as they navigate this critical period.”

A 2018 study published in Psychosomatics by Dr. Levy-Carrick and her colleagues at the Brigham found that including proactive psychiatric consultation for patients in the ICU led to shorter hospital stays, particularly for those who needed to be on ventilators as part of their care. In the study, two MICUs at the Brigham were randomized to either proactive or conventional psychiatric consultation models.

Due to the study’s positive results, this program remains active at the Brigham. It is managed in cooperation with the critical care medicine and nursing staffs in the ICU.

Beyond what was shown in the study, there are many other ways that patients can benefit from proactive psychiatric consultation. One situation is in the case of delirium, which is common in the ICU setting.

“We’re able to help alleviate their agitation, including through the use of medication, to minimize distress,” Dr. Levy-Carrick said. “Many people come to the ICU already taking a variety of psychotropic medications. We can help manage these medications in the context of the broader medical complexity. We make sure that these drugs are either continued or discontinued in ways that can improve the patient’s overall outcome.”

One built-in component of this model is that it takes into account the possible role of trauma in psychiatric health and recovery. “We’ve recognized that someone’s prior exposure to trauma impacts their ability to tolerate hospitalizations,” Dr. Levy-Carrick said. “At the same time, medical procedures themselves can be potentially traumatic. It’s important that we find ways to mitigate that to prevent the progression of any kind of pathology related to their experience of hospitals.”

Another important part of this program is that members of the psychiatry team continue to follow patients after they are moved to a regular medical floor, and even beyond.

“We follow these patients longitudinally from the point of critical illness through medical stabilization. We also have the opportunity to see them again after they’ve gone home through our Critical Illness Recovery Program,” Dr. Levy-Carrick said. “It provides us with an increased opportunity to be able to help these patients, many of whom may have longer-term psychiatric and other medical needs.”

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Research Efforts Focus on Link Between Hormonal Contraceptives and HIV Infection

Source: Brigham and Women's - On a Mission
Date: 02/20/2019
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According to the World Health Organization, more than half of all married or in-union women of reproductive age use some form of contraception. Additionally, the number of women around the globe who either use contraception or have an unmet need for family planning is expected to grow by more than 900 million over the next decade.

One popular form of birth control is injectable hormonal contraceptives, predominantly the progestin-only form known as depot medroxyprogesterone acetate (DMPA, Depo-Provera®). Yet growing evidence has linked this form of contraception to an increased risk of HIV acquisition and transmission. Researchers at Brigham and Women’s Hospital are focused on determining the underlying causes for this connection and getting the word out about this important public health issue, which affects both women and men.

“This situation is particularly concerning because DMPA is the most commonly used contraceptive method in sub-Saharan Africa, the region that bears an estimated 70 percent of the global HIV infection burden,” said director of the Laboratory of Genital Tract Biology at Brigham and Women’s Hospital and Harvard University. “Our research provides a biologic explanation for the risks and variations in vulnerability to the potential adverse effects of hormonal contraception.”

Work coming out of Dr. Fichorova’s lab also has contributed to the understanding of inflammation and dysbiosis in women and newborns. Other research has looked at how bacteria, protozoan parasites and viruses act in concert to modify human host immunity. In 2018, Dr. Fichorova’s team received an Innovation Award from the Brigham Research Institute to translate their research and recently filed inventions into a novel live biotherapeutic for treatment of vaginal dysbiosis to prevent these conditions.

For the past five years, much of Dr. Fichorova’s research has focused on understanding how and why certain types of hormonal contraceptives change a woman’s biological defenses against infections—and HIV infection in particular. “If we can unveil the molecular pathways that lead to a predisposition to infection, we can discover novel drug targets for preventive medicine,” she said. “At the same time, we hope to lift a significant barrier to the rational design of new, safer contraceptive technologies.”

In one study, Dr. Fichorova and her colleagues analyzed cervical swabs and other data taken from more than 800 women enrolled in family planning clinics in Uganda and Zimbabwe. A major finding was that DMPA was associated with cervical immune imbalance and biomarkers of inflammation that were also associated with higher risk of HIV seroconversion in these women in the next three months.

The team also found higher shedding of HIV in those who seroconverted, thus suggesting pathways for both higher acquisition and transmission of the virus. They showed that DMPA had even broader immune-suppressive effects when acting on the background of abnormal vaginal microbiota characterized by lower abundance of lactobacilli and overgrowth of potentially pathogenic residential bacteria, a condition most often diagnosed as bacterial vaginosis. The data suggested that not only sexually transmitted infections such as herpes but also non-sexually transmitted reproductive tract infections and dysbiosis can make women more vulnerable to the side effects of DMPA.

To a lesser extent, changes in the cervical immune environment were also found in women taking a type of oral contraceptive where another synthetic progestin (levonorgestrel) was combined with synthetic estrogen.

Dr. Fichorova’s lab also has brought to the spotlight the fact that certain species of lactobacilli act as a sentinel of good health in the female reproductive tract, emphasizing the importance of treating conditions that are not sexually transmitted, such as bacterial vaginosis and yeast infections. Non-sexually transmitted vaginal bacteria prevalent in bacterial vaginosis can ascend to the uterus and cause placental epigenetic changes and systemic perinatal inflammation, leading to serious adverse reproductive and child health outcomes.

“Research enabling the design of safer contraceptive technologies is urgently needed. Women of reproductive age should not have to face impossible choices between preventing an unplanned pregnancy and preventing a devastating infection,” Dr. Fichorova concluded. “Understanding, properly diagnosing and treating non-sexually transmitted vaginal dysbiosis should be promoted as a powerful tool for prevention of contraceptives’ side effects as well as adverse pregnancy outcomes.”

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Assessing Older Trauma Patients to Ensure They Get the Specialized Care They Need

Source: Brigham and Women's - On a Mission
Date: 02/13/2019
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When an older person suffers a trauma resulting in multiple broken bones and other injuries, often due to a fall or car accident, ensuring he or she gets appropriate care can be challenging. This is especially true when health care providers don’t have training or experience in geriatrics.

For that reason, Brigham and Women’s Hospital established a program whereby every person aged 65 or above who is admitted for trauma receives a frailty assessment. Frailty is a complex syndrome that’s usually related to age. It is characterized by physical decline and increased vulnerability to external insults such as trauma, infections and other acute illnesses.

“We are possibly the only hospital in the country that has trained our surgical residents to do these frailty assessments at the time of admission,” said Samir Tulebaev, MD, of the Brigham’s Division of Aging, who developed the Geriatric Co-Management Service. “We’ve created a system in which the patients who may need extra care are identified right away. That’s important, because people who are frail are less likely to recover if they don’t get the care they need.”

Any trauma patient who is identified as frail is put into the Frailty Identification and Care Pathway. This program, which was launched in 2016, includes a comprehensive geriatric assessment by Dr. Tulebaev or one of the other two geriatricians on the team.

During this assessment, patients are screened in a number of areas. Experts review a list of all the medications patients regularly take in order to identify anything that may cause harmful interactions or other complications. Patients are also screened for cognitive impairments, psychiatric problems such as depression and the presence of delirium. Nutritional assessments and physical therapy consultations are performed as well.

In addition to physical health, familial and social structures are crucial for the patient’s well-being and recovery after trauma. “A patient’s social domain is just as important as their physical domain,” Dr. Tulebaev said. “That’s something we always take into account. If you’re lacking in family or other social support, that will negatively influence your health.”

Taking care of frail trauma patients is a team effort. “This program is inherently multidisciplinary,” Dr. Tulebaev explained. “When we developed the protocol, we sat down and brainstormed with everyone who is involved in the frailty pathway. This includes nurses, physician assistants, nursing assistants and physical therapists. That’s a big part of what’s made it so successful.”

In May 2018, nurses at the Brigham received Magnet designation from the American Nurses Credentialing Center (ANCC). The Magnet Recognition Program honors organizations where nursing leaders play a key role in improving patient outcomes. The ANCC cited the Geriatric Co-Management Service as one of the factors that set the Brigham nurses apart and led to the designation.

Nurses have also begun to take the Frailty Identification and Care Pathway into other parts of the hospital. “When we developed the program, we envisioned it partly as a research project. And we have begun to show that it does make a difference in measures like readmission rates to the Intensive Care Unit,” Dr. Tulebaev said.

“This has been one of the most important and rewarding programs I’ve ever been a part of,” said Brigham trauma surgeon Zara Cooper, MD, who helped develop the frailty pathway. “Once we recognized that our frail older trauma patients had unique needs that weren’t being addressed, hundreds of clinicians rallied together to learn primary geriatrics and provide care in a person-centered way. This is the wave of the future.”

“One of the things that’s special about our program is that it’s so clinically oriented,” Dr. Tulebaev concluded. “We’re engaged with patients and their family members, as well as with our colleagues. This helps us to make extremely valuable contributions to the care of our patients.”

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Brigham Otolaryngologist Takes His Expertise to Haiti

Source: Brigham and Women's - On a Mission
Date: 02/13/2019
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The expertise of the physicians and surgeons at Brigham and Women’s Hospital benefits patients well beyond New England. Through Partners in Health, the Boston-based nonprofit health care organization, specialists from the Brigham travel to hospitals in developing countries around the globe, offering patient care as well as training for local doctors.

Over the past decade, Brigham otolaryngologist Anthony A. Prince, MD, has made a number of trips with his colleague, Robert Boucher, MD, MPH, to Hôpital Universitaire de Mirebalais (HUM), in Mirebalais, Haiti. At HUM, he works with local otolaryngologists and general surgeons in providing a range of surgical services to treat head and neck disorders. On their most recent trip in November 2018, Dr. Prince and Dr. Boucher treated children, adolescents and adults for problems including sinonasal masses, thyroid goiters and malignant salivary tumors.

HUM is a modern, 300-bed facility that delivers primary care services to about 185,000 people and sees as many as 700 patients every day in the outpatient setting. As a university hospital, it also provides training and education for the next generation of Haitian nurses, medical students and resident physicians. Many other members of the Brigham community spend time at HUM, offering training and patient-care services in internal medicine, general surgery, pediatrics, and obstetrics and gynecology.

“Haiti has a population about the size of New York City—more than 10 million people—but there are only about 20 fully trained otolaryngologists in the whole country,” Dr. Prince said. “Access to otolaryngology services is quite limited for a variety of reasons, including lack of providers, cost and geographic distance to clinics and hospitals. Due to these constraints, many patients end up presenting with advanced disease. This can make treatment challenging and surgeries complex.”

At HUM, Dr. Prince and his U.S.-based colleagues support and supplement the care provided by the university’s sole otolaryngologist, who is available at HUM only on a part-time basis. Their support of HUM’s otolaryngology services includes donating surgical equipment and supplies that allow the team to safely perform a broad spectrum of head and neck surgical procedures, some of which were not possible in this part of Haiti a few years ago.

“It’s very busy, but it’s rewarding at the same time, especially seeing patients after surgery and knowing that we’ve made a difference in their lives,” Dr. Prince said. “Many of these patients have waited a long time to have these surgeries.”

Due to the lack of otolaryngology specialists in Haiti, transfer of surgical skills is an additional and important goal of Dr. Prince’s visits. During each visit, he teaches, advises and assists general-surgery resident physicians as well as the local otolaryngologist in contemporary head and neck surgical techniques.

“There are cases where they feel uncomfortable doing these procedures, but I think it’s helpful that I’m able to provide that level of expertise for them, as well as to help with their surgical volumes,” Dr. Prince said. “As the number of general-surgery training programs in Haiti far outnumber the sole otolaryngology training program, it is important that we take opportunities to transfer current head and neck surgery techniques to the general surgery trainees.”

Dr. Prince and his colleagues hope to eventually work with trainees in the country’s sole otolaryngology residency and training program in Port-au-Prince, which is about a 90- minute trip via winding, mountainous roads. For now, however, they’re focused on working with the local otolaryngologist and general surgeons to develop surgical plans for the more complicated cases. Eventually, Dr. Prince would like to bring some of Haiti’s otolaryngologists to Boston so that they can receive further training at the Brigham.

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Longitudinal Walk-In Urgent Care Psychiatric Clinic Offers a New Model of Care

Source: Brigham and Women's Hospital - On a Mission
Date: 11/12/2019
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Arranging psychiatric care can be a logistical challenge. Appointments usually need to be scheduled months in advance, and missed visits may result in removal from patient rolls. This situation is often a critical obstacle to care, especially because people who require psychiatric care are likely to struggle to deal with these sorts of challenges.

The Challenge of Access to Care

This situation was the impetus for the creation of the urgent care clinic for psychiatry at Brigham and Women’s Hospital. It was launched in 2017 to make it easier for people to get care when they need it.

“Access to psychiatry is difficult pretty much everywhere you go,” said David S. Kroll, MD, of Brigham and Women’s Department of Psychiatry, who leads the program. “There are parts of the country where there literally is no psychiatrist within hundreds of miles. Even in Boston, where we have a relatively high concentration of psychiatrists, it can be difficult for patients to see them, in part because psychiatric care is just very time-intensive.”

Dr. Kroll explained that although historically the Brigham has been well-equipped to provide excellent psychiatric care to patients who are able to adhere to the basic expectations of the clinic, too many people were being kept out of psychiatry because of the difficulty in keeping appointments. He and his colleagues decided that a walk-in clinic would be an innovative way to address this challenge.

The Longitudinal Urgent Care Psychiatry (LUCY) clinic is currently open three afternoons a week for walk-in visits. A handful of psychiatrists share in clinical duties. Anyone who gets primary care through another Brigham doctor is eligible to participate; having a previous relationship with the Department of Psychiatry is not required. The clinic also has social workers on staff who can manage crises, help patients schedule regular follow-ups and provide limited therapy when needed.

“When we opened our doors to walk-ins, we basically told people, ‘You can come in for anything you need,’” Dr. Kroll said. “If it’s an urgent care visit, that’s fine. If there’s an expectation that you will continue to get your care primarily on a walk-in basis, that’s fine too.” He added that although a consistent structure to appointments is ideal, when the alternative is no care at all, the walk-in clinic provides a valuable service.

A Major Innovation for the Field of Psychiatry

In the two years that the clinic has been open, it has seen 350 patients—250 of whom previously did not have any access to psychiatric care. Additionally, 60 percent of those patients sought follow-up, either through another urgent care visit or through a scheduled appointment with another psychiatrist in the clinic.

“We’re still working on a formal outcomes study, but anecdotally the clinic appears to have reduced the way that some patient groups have traditionally used emergency rooms,” Dr. Kroll said. He added that while the clinic sees a disproportionate number of Medicare and Medicaid patients, the psychiatrists working in the clinic tend to be more productive, in part because many appointments are shorter than average. “From a fee-per-service perspective, it works out pretty well,” he said.

Plans are in place to expand social work and therapy services and to increase the number of doctors who are available during clinic hours.

“Other programs have tried different kinds of walk-in clinics,” Dr. Kroll concluded. “But ours is unique in that we’re planning for long-term management of patients within this urgent care framework.”