Choose Your News
For the first time, investigators in the Division of Infectious Diseases at the University of North Carolina School of Medicine have determined how antiretroviral therapy (ART) affects the way HIV disseminates and establishes infection in the female reproductive tract. These observations have significant implications for future HIV prevention, vaccine and cure studies. A recent HIV prevention clinical trial demonstrated 93 percent protection against secondary heterosexual transmission when infected partners received early ART. Vaginal transmission accounts for the majority of new HIV infections worldwide. Globally, 35 million people are living with HIV and 2.1 million are newly infected each year. These findings were published in the Journal of Clinical Investigation on Monday, Feb. 8.
“Surprisingly, it does not matter how a woman is exposed to HIV – vaginally, rectally, etc. – the virus goes very quickly to the female reproductive tract,” said J. Victor Garcia, PhD, study co-author, and a professor of medicine in the Center for AIDS Research, the Institute for Global Health & Infectious Diseases, and the Division of Infectious Diseases at UNC. “Your body’s CD4 T cells, which are the cells HIV infects, also migrate to the female reproductive tract shortly after exposure. It is like putting more kindling on a smoldering fire.”
Using humanized mouse models, Garcia and his team also noticed that CD8 T cells, the cells in the body that fight infection, are delayed in getting to the female reproductive tract. This delay allows HIV to establish itself not only in the female reproductive tract, but also in cervicovaginal secretions.
“Your CD8 T cells, which are supposed to protect you, are not arriving in the female reproductive tract in time,” said Garcia. “When we think about potential vaccines against HIV, this is important information to have.”
Yet, when ART is taken regularly, the likelihood of transmission rapidly declines.
“Once ART was introduced into our models, the number of infected cells in the female reproductive tract and cervicovaginal secretions vastly decreased,” said Angela Wahl, PhD, study co-author and an assistant professor of medicine in the Division of Infectious Diseases at UNC School of Medicine. “However, even on therapy, there is still residual virus in the female reproductive tract, just not enough to transmit infection. And these remaining infected cells are persistently making HIV RNA. This has implications for cure research and indicates that the female reproductive tract could represent a potential reservoir for HIV during therapy.”
Dr. Garcia, Dr. Wahl and their team in the Division of Infectious Diseases at UNC School of Medicine collaborated with scientists in UNC’s Department of Biostatistics as well as the Department of Infectious Diseases at Aarhus University Hospital in Denmark. This study was funded through the National Institute of Allergy and Infectious Diseases within the U.S. National Institutes of Health.
By Bradley Allf, Features Writer, UNC’s Institute for Global Health & Infectious Diseases
When someone mentions global health, a lot of people think about disease. Whether it’s medical professionals on the front lines of the latest outbreak of infection or researchers developing a new cancer treatment, when we hear “global health” we tend to think of the medical field. But some people that work to improve global health, such as UNC Professor Dinesh Manocha, PhD, don’t wear scrubs or lab coats. In fact, the only “people” featured in Manocha’s work at all are made up entirely of pixels and binary code. Yet the work Manocha has been doing in the field of crowd simulation is having a big impact on global health.
Manocha, who works in the Department of Computer Science along with his collaborator Professor Ming C. Lin, PhD, and graduate students, aims to better understand how crowds move through space.
“Basically, we are trying to do a lot of mathematical models to see how people behave in different settings,” says Manocha. And it’s a hard problem… but if you have good data, like video data, we can learn from it and then give a better prediction of human behavior.”
By analyzing real-world videos of crowds, he and his team are able to model how a group of people will likely move through a particular space— like a stadium, mall or street-crossing. One need only look back to last September to understand the potential human health benefits of such insight.
It was the last day of the yearly Islamic tradition of Hajj, where millions of pilgrims converge on the Saudi Arabian city of Mecca for a weeklong series of rituals. It is the largest annual gathering of people on earth.
On this particular day, with temperatures soaring near record levels, a mass of people crushed together at the intersection of streets 204 and 223 in Mina, for reasons still unclear. In total, more than 700 people died that day as a result of the “Mina Stampede” as it has come to be called (though some reports suggest the death toll is as high as 2,400). Manocha was contacted shortly afterward by researchers from Saudi Arabia who wanted to know how to prevent such a tragedy from happening again.
This wasn’t the first time Manocha has been approached about using his research to improve crowd safety during Hajj. Since 2011, his group has been working with a team at the Hajj Research Institute of Umm Al-Qura University, Saudi Arabia, to better predict the movement of pilgrims as they perform the various rituals of Hajj. One of their main results was designing a “Virtual Tawaf Simulator,” which can predict the pedestrian flow of pilgrims under different circumstances in the area that surrounds the Grand Kaaba. This was perhaps the very first demonstration of crowd simulation technology being used to predict the movement of tens or hundreds of thousands of people in a dense setting.
By better understanding how crowds move through space, the research Manocha and his team are doing can inform new ideas for improving crowd safety, such as changing the layout of a space or building. That could be a huge step toward making crowds, like those that gather for Hajj, safer.
The Science Behind Crowd Movement
So what does this research look like specifically?
Professor Manocha offers to show me some of the simulations his group is working on. He turns on a computer and pulls up a video showing a crowded city street corner.
“So this is a very famous crossing in Tokyo called ‘Shibuya.’ And this happens at five o’clock. Suddenly, all the lights go red and you see masses of people walking like this, like this– and I’ve been there,” says Manocha. “It’s one of the most congested human crowds.”
He plays the video and I watch an astounding number of people making their way across the street. “People follow their own patterns, they make lanes, and formations. And we’re getting similar patterns here,” Manocha says, pointing to a second video playing beside the first.
This is the simulation. Manocha and his team recreated the physical parameters of Shibuya and then placed one of their simulated crowds into that environment to see how it would move. The pixelated people in the video are obviously computer-generated, but the natural way the crowd moves across the street? Less so. Just like in the real video, each person walks with their own intentionality. Some move quickly, others move more slowly. Some follow the main channels while others carve out a slightly different path. The people even cluster in certain areas in a very similar way in both videos.
Manocha’s team is able to produce such accurate crowd movement patterns because the models that they have designed take into account all sorts of dimensions that affect human movement. These include parameters like collision-avoidance, reaction to the environment, and even personality.
Another such parameter is cultural background. His research has shown that crowd dynamics can change depending on the culture of the people in the crowd.
“Crowds in Asia are very different from crowds in America,” Manocha says. “So we use cultural factors. And other research groups have done experiments, like for example in Asia or in India, there’s not a big notion of personal space. People just move fast and if other pedestrians come close, you may not slow down.” On the other hand, in many Western nations dense crowds move more slowly because those cultures tend to want more personal space.
Such is the breadth of Manocha’s work. He and his team must draw information from all sorts of areas to inform their research because human behavior is governed by more than just a desire to move efficiently from place to place. In another video created by Manocha’s team, one can watch how stress impacts the movement of a crowd. A group of people under a moderate amount of stress is shown to move quickly to its destination. But under a high stress level– the example given in the video is the stress created by a loud alarm– crowd movement breaks down as people clump together, preventing efficient movement.
Such examinations of culture and stress are not the typical bread and butter of computer science research. As Manocha says, “This is a very multi-disciplinary field, from math, to physics, to psychology, to computer vision, to parallel computing, et cetera– all kinds of ideas come in the picture.”
Predicting Crowds in Chapel Hill
And this expanded scope of inquiry lends itself to broader applicability. Beyond just Hajj, the research has implications for gatherings of people at any scale. Even the local crowds that gather in Chapel Hill on Franklin Street, say for Halloween or after a big sporting victory, pose significant threats to human health and could thus potentially benefit from some of the insight Manocha’s research holds for improving crowd management.
“I’ve seen crowd rush in events downtown that have been created by firecrackers; I’ve seen it created by guns being shot. I’ve seen it created by really violent and bloody fights.”
That’s Interim Fire Chief of Chapel Hill, Matt Sullivan talking about his experiences coordinating crowd management on Franklin Street. I’m talking with him to try and understand what crowd management looks like on the ground level. According to Sullivan, planning for these crowds is a huge undertaking, requiring months of planning, multiple fire and police departments, and even a weather eye on the performance of the UNC basketball team.
All this is necessary because of the inherent risks associated with such large crowds. Chief Sullivan and his fire team, as well as the police and EMS personnel that make up Chapel Hill’s Crowd Management Team, must contend with all sorts of problems that arise from these crowds: violence, alcohol poisoning, fires and sexual harassment. But one risk they are always acutely aware of is crowd rush. That is, the rapid movement of a mass of people in a crowd.
Unfortunately, in such an event there is little that emergency personnel would be able to do to stop the rush. During crowd rush, emergency personnel are trained not to resist the crowd’s movement.
“When something like that occurs, the responders get out of the way, and there’s specific ways they are trained to get out of the way,” says Sullivan. “They want to get behind a big immovable object– get behind a big tree or in an alcove– and let the rush come by.”
Trying to stop a crowd rush, beyond just being useless, would be dangerous for both responders and the people in the crowd.
Instead, decreasing the dangers of a rush is all about preparation. For example, before the event begins police and fire teams set up barricades around the event perimeter to limit traffic, among other reasons. But they are careful to use only flimsy barricades. Small, lightweight structures are crucial for safe crowd management, as they allow crowds to swell past the barriers should a rush occur.
“We can’t bring in heavy concrete blocks and barriers,” Sullivan says. “We have got to have stuff that can be thrown away pretty easily and quickly so that people can move. So while it has to be secure, if an incident occurred we have got to be able to open up the perimeter to flush people out.”
This is an idea Manocha himself is interested in. Previously, his team worked on a project where they accurately simulated the movement of a crowd exiting a stadium. One of the next goals of this project is to predict how stadium barricades impact the movement of a dense crowd. Such a project could inform safer policies for utilizing these barricades during crowd events, which might one day change how local police and fire departments deal with the threat of crowd rush.
I am reminded of other ideas Manocha has worked on throughout my conversation with Chief Sullivan. For example, Sullivan says that one important part of being prepared for crowd rush is to have a set of scripted statements that can be sent out over the PA system to control a crowd.
“So a PA won’t say ‘hey you all stop running.’ No, there are scripted messages that they have prepared when something goes bad. It’s like when a tornado is coming you don’t say ‘hey folks a tornado is coming!”’ Sullivan continues, “We’re looking at things you can do operationally not to increase panic.”
As discussed above, Manocha’s research has shown that panicked, stressed out crowds tend to bunch tightly, constricting movement and increasing the dangers of crushing or other crowd disasters. Using calm scripted messages over the PA allows Sullivan and his team to reduce the stress levels in a crowd and thereby decrease the threat it poses.
Thus, the research conducted by Manocha and his collaborators has the potential to impact crowd management policy at multiple scales, from local to global. This is important because the issues associated with crowds will only grow as our world becomes more urban.
Dr. Armin Seyfried is a leading researcher on pedestrian dynamics at the Jülich Supercomputing Centre and a close collaborator with Manocha. He attests to the effects of urbanization on crowd management.
“Worldwide[,] cities are growing. In particular in Europe we are confronted with the problem that the process happens in the context of a historical urban structure with often limited space,” Seyfried says. “More and more we have problems that there is no space to expand transport infrastructures…”
Seyfried provides historical city centers, in which modification or removal is typically out of the question, as an example of one of the factors limiting the infrastructure changes cities can put in place to accommodate growing crowds. As our urban centers expand and begin pushing against the walls of this limited space, a better understanding of crowd dynamics will be vital to ensuring that these areas are safe.
For Manocha, the application of his research to real-world problems that pose risks to human health is the most rewarding aspect of the work.
“If our research results can be used to improve the lives of others, that is one of the major fulfilling aspects of this research,” he says. “My entire team of students and collaborators would love to develop technologies that can be used by others, or used to improve the lives of others by designing better spaces for pedestrian flows and reducing the chances of a crowd disaster.”
So while he may not study medicine or public health, Manocha’s work is undoubtedly tackling a serious global health issue, and it has the potential to lead to safer communities—from Chapel Hill to Mecca.
By Morag MacLachlan, Communications Director, UNC’s Institute for Global Health & Infectious Diseases (IGHID)
It’s called a kissing bug, and its bite can sometimes mean the kiss of death.
“It feeds on blood to mature and it will bite you, usually on your face,” says Natalie Bowman, MD, MPH, Assistant Professor of Medicine and an Infectious Diseases Specialist at UNC. “The insect will then poop and that is what is infectious. The parasite Trypanosoma cruzi, or T. cruzi, is in the bug’s feces. If you rub the bite, the parasite then gets into your system from the cut in your skin.”
The parasite causes Chagas disease, named after the Brazilian physician Carlos Chagas who discovered T. cruzi in 1909. Bowman says it is estimated that 6-7 million people worldwide are living with Chagas disease. Although the kissing bug is the main mode of transmission, the disease can be transmitted from mother to child during pregnancy. It can also be passed during a blood transfusion, which is why the US began testing its blood supply in 2007 for the disease. This screening has yielded nearly 1,500 positive tests in 43 states.
“When first infected, a small amount of people will develop a fever, but most people have no symptoms,” Bowman says. “For the majority of people – about 70-90 percent – the disease will lay dormant in the body. For the 10-30 percent who develop chronic Chagas disease, heart failure and deadly gastrointestinal issues can occur. This is a prime example of why I pursued a career in infectious diseases. A lot of medicine is about understanding your own body’s dysfunction. But ID is the interaction between a person and the outside world coming into your body. In this case, it’s you versus the bugs!”
It is unclear why the parasite resides in the kissing bug, an insect related to stinkbugs. Eleven species of the kissing bug are found in 28 states in the US. However, the parasite T. cruzi is only found in bugs in 10 of these states. It is estimated that 300,000 people in the US have been infected, according to a research study published in the Journal of Clinical Infectious Diseases in 2009. Bowman has treated two people at UNC hospitals for Chagas disease – a woman who was diagnosed while pregnant and a man whose brother also had been infected by the parasite and developed heart disease. The drugs to treat Chagas disease – nifurtimox and benznidazole – are not approved by the FDA, but patients can gain access to the treatment through the Centers for Disease Control and Prevention (CDC). Yet, the problem is much more prevalent in Central and South America.
Drunk from the Cold
Chagas disease can be traced back throughout the ages. Bowman says it has been isolated in samples from 9000-year-old mummies on the west coast of South America. European explorers and colonists dating back to the 16th and 17th centuries recorded symptoms in line with Chagas disease, including enlarged colon and difficulty swallowing. Due to his health problems later in life, some scientists even believe famous evolution theorist Charles Darwin contracted Chagas disease during his voyage to South America in the 1800s on the HMS Beagle.
To this day, the parasite and the disease are much more common in Central and South America. In fact, Chagas diseases causes thousands of deaths in the Americas annually and more morbidity and mortality than any other parasitic disease, including malaria. In Peru, where Bowman has conducted research since she was a medical student, the insect host for the parasite is called chirimacha. Bowman says chirimacha means “drunk from the cold” in Quechua and is an appropriate name for the bug as it comes out at night to feed.
Like many illnesses, Chagas disease is associated with poverty. A lack of routine insecticide spraying and poorly constructed homes allow for the chirimacha bug to easily access people in Central and South American while they sleep. In Bolivia, the number of people living with Chagas disease is staggering.
“Bolivia is the epicenter for Chagas disease,” Bowman says. “In some rural Bolivian villages, 80-90 percent of people have it. And if you are also co-infected with HIV, it is usually fatal. Up to 80 percent of people living with HIV and untreated reactivation Chagas disease die.”
In addition to treating patients, Bowman’s research focuses on the intersection of HIV and parasitic diseases like Chagas disease. People who are living with HIV and Chagas disease often develop a chagoma – or a parasitic mass in the brain. Jon Juliano, MD, MSPH, Assistant Professor of Medicine at UNC and an infectious disease specialist, serves as a mentor on Bowman’s K award investigating the pathogenesis of T. Cruzi in people living with HIV in Bolivia.
“Chagas disease is really a neglected tropical disease. Very few people research this globally,” Juliano says. “But this is not just a third world problem. As more and more people from Central and South America move north, we will begin to see more cases in the US.”
Research Dictates Clinical Care
Bowman spent two summers in medical school in Peru working with Bob Gillman, MD, a Professor of International Health at Johns Hopkins studying the epidemiology of Chagas disease in the Peruvian city of Arequipa. Prior research in Brazil and Argentina showed treating children with benznidazole and nifurtimox yielded cure rates of nearly 60 percent. Yet treating people who had developed heart disease from Chagas disease had very little effect. This means treating people before symptoms start leads to better clinical outcomes, Bowman says.
Bowman also tagged along with an insecticide spray team in Arequipa, Peru, where animal pens and walls of homes were treated, reducing transmission. Educating people about the bug and parasite as well as routine screening of pregnant women also helps decrease the number of people who contract the disease.
And her research continues in the hopes that it will improve clinical care. Bowman has a study comparing Chagas disease with other neurological, opportunistic infections. For example, in people living with HIV, the symptoms of Chagas disease are often mistaken for toxoplasmosis – a disease that results from infection with the Toxoplasma gondii parasite and causes flu-like symptoms. By the time the clinician realizes the toxoplasmosis drugs are not working and that the real culprit may be Chagas disease, it is often already too late for the patient. Building off of this information, Bowman is now focused on developing ways for clinicians in South and Central America to distinguish between different infections using limited diagnostic resources.
“Natalie is one of the first researchers to use modern molecular tools to study this ancient scourge,” says Steve Meshnick, MD, PhD, Professor and Associate Chair of the Department of Epidemiology at UNC and a mentor on Bowman’s K award. “Her work is helping elucidate the genetic diversity of the parasite, how the disease is spread and how it causes disease in people with HIV.”
She is also studying the microbiome of the kissing bug.
“We will examine the feces of 50-60 bugs in Peru for this study,” Bowman says. “We are trying to understand why a parasite would want to live inside the kissing bug. This is why I like infectious diseases. There is a mystery to it. I get to be a detective and figure out how to provide better clinical care for people.”
By Hannah Webster, Communications Intern, UNC Eshelman School of Pharmacy
Olena Northrup, a fourth-year doctor of pharmacy student at the UNC Eshelman School of Pharmacy, hails from Ukraine, so she did not expect that visiting neighboring Moldova for a few weeks to share perspectives on different health care systems to be completely novel. However, she said she found that her time in Moldova was unlike anything she had experienced before: a professional and personal journey that will affect her as a future health professional.
“It was interesting to observe the availability of pharmacy services from being virtually nonexistent in hospitals to a pharmacist’s ability to give medical advice and recommend a therapy course, which included the frequent use of herbal remedies,” she said.
Through the School’s Global Pharmacy Scholars Program, Northrup and fellow student Chandler Gurley spent three and a half weeks 5,000 miles away in Chisinau, the capital of Moldova. This is the pilot year for a program that focuses on Eastern European pharmacy education and the use of herbal medicines.
“There is a strong prevalence of general public caution towards medication use in Moldova. Patients usually prefer to start with an alternative route and try herbal medications,” Northrup said. “When you are immersed in the culture, you understand their perspective and why things are done a certain way, so I think it definitely benefits student pharmacists as people and as professionals to go to a different country.”
Moldova lies to the northeast of Europe’s Balkan Peninsula between Ukraine and Romania and has a population of 3.56 million. After the breakup of the Soviet Union in 1991, the Moldovan government established a social-service program to supplement the income of citizens during the transition from a command to a market economy. The Social Security Fund supplies those in need with medical payments and housing and food subsidies.
“It is difficult to zero in on a specific highlight during my time in Moldova,” Northrup said. “But I enjoyed discovering the differences and similarities of the health care system, the role and responsibilities of the pharmacists in various settings and the impact on delivery of patient care.”
The Global Pharmacy Scholars Program at the UNC Eshelman School of Pharmacy gives students the opportunity to complete clinical rotations in a unique learning setting while growing personally from an international experience. From England to Zambia, Japan to Malawi, the GPS program enables students to learn about health care issues in various countries, exposes them to different cultures and health care systems, extends scholarship opportunities available to students and faculty and develops the next generation of global leaders in pharmacy.
Northrup and Gurley are fourth-year doctor of pharmacy students based at the pharmacy school’s satellite campus in Asheville. They both agreed that participating in the GPS has been one of their most influential experiences as pharmacy students.
The plan to add the Nicolae Testemițanu State University of Medicine and Pharmacy in Chisinau, Moldova, to the GPS program has been in the works for several years, but the idea stems back almost two decades. Amanda Corbett, Pharm.D., is a clinical associate professor in the pharmacy school and serves as the global pharmacology coordinator for the UNC Institute of Global Health and Infectious Diseases. She spent two weeks in Moldova with Gurley and Northrup.
“I had actually been to Moldova in 1997 and did medical work there, so I had an interest in the culture and the health care system, but I also had an interest in pharmacognosy or plant-based medicine, and that is a big effort that happens specifically in Moldova,” Corbett said.
The relationship between the UNC Eshelman School of Pharmacy and the Nicolae Testemițanu State University of Medicine and Pharmacy was developed with the hope of both institutions benefitting. Moldova’s students and educators would learn about U.S. clinical pharmacy education, and UNC students and educators would learn about Moldovan herbal medicine and community pharmacy.
“When they were talking about international rotations, I was really excited because I’m from that part of the world and helping a country over there to develop clinical pharmacy is really exciting,” Northrup said. “Moldova as a country has great hospitality, and their interest in herbal medicine is very interesting.”
Gurley said learning about the curriculum and the institution’s educational priorities was a meaningful experience.
“Their school of pharmacy is very chemistry-based, almost like a graduate program in chemistry and not clinical at all. There’s no patient interaction in their curriculum,” she said.
Northrup said the most significant aspect of the rotation was being asked to critique hospital services. In Moldova, there is almost no hospital experience built into the pharmacy curriculum, so the hospital asked the students for information about their clinical education at the UNC Eshelman School of Pharmacy.
“We were presented with the task to evaluate Medpark International Hospital services in accordance with the European Joint Commission standards and present our findings and recommendations to the head clinicians and administrative staff,” she said. “It made me see what becoming a professional means: clarifying expectations, starting somewhere, researching and figuring out what needs to be done, asking for feedback and then repeating.”
But aside from providing information, Northrup said they gained substantial knowledge from their time there as well. They visited community pharmacies and distribution centers and learned about the pharmacists’ roles and responsibilities in Moldova. They also had the opportunity to tour herbal cultivation centers where pharmacy students participate in growing, harvesting and preserving herbal drugs.
“They really emphasize herbal medicinal plants,” Gurley said. “It was such an interesting experience, just to see a different perspective of medicine.”
Northrup said the students were also challenged to think critically about how culture affects medicinal use. People in Moldova generally prefer herbal and alternative medicine routes before using traditional medication. Gurley said by being immersed in the culture, it is much easier to understand medical preferences different from those in the United States.
“In terms of learning, it was very much more of a life experience than a pharmacy experience. Just seeing how their culture affects pharmacy and how they go about life in general,” Gurley said. “The people there are some of the most grateful and thankful people I have ever met in my entire life.
Northrup said the most beneficial thing she learned was how significant cultural competence is when working as a health professional.
“The Moldova rotation was an exciting and culturally-diverse experience for me,” Northrup said. “It undeniably presents great opportunities for future UNC students to grow as well-rounded, compassionate and culturally competent pharmacists.”
Listen: Our Dr. Myron Cohen Tells Innovate Raleigh UNC, GSK Company Will Bring Top Minds Together to Cure HIV