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Scientists use advanced imaging to map uncharted area of genome

Using advanced imaging techniques, researchers at the University of Colorado Anschutz Medical Campus have mapped a previously uncharted region of the human genome that gives rise to a variety of disease, setting the stage to potentially test for the conditions in the future.

The study, published Sept. 3 in the journal Genome Research, was conducted by scientists at CU Anschutz led by Tamim Shaikh, PhD, the University of California San Francisco (UCSF) led by Pui-Yan Kwok MD, PhD and KU Leuven in Belgium led by Joris Vermeesch, PhD.

Dr. Tamim Shaikh, PhD, professor of pediatrics in the section of Genetics and Metabolism at CU School of Medicine.
Dr. Tamim Shaikh, PhD, professor of pediatrics in the section of Genetics and Metabolism at CU School of Medicine.

The research upends the view of many that the human genome was fully mapped in 2001 with the completion of the Human Genome Project.

“We have realized over time that this is not entirely true, as there are numerous gaps that remain in the reference human genome sequence,” said Shaikh, one of the senior authors of the study.  Shaikh is a professor of pediatrics in the section of Genetics and Metabolism at University of Colorado School of Medicine. “These gaps are present in regions that are unmappable and often `invisible’ to past and most current sequencing technologies.”

The researchers focused on a region on Chromosome 22, known as 22q11. There were numerous gaps in the sequence of this chromosome due to unmappable genetic sequences known as low copy repeats or LCRs.

LCRs are a significant source of genetic instability and can break chromosomes. That leads to a loss or gain of large pieces of DNA which can cause serious diseases. The loss of DNA in 22q11 leads to the 22q11 deletion syndrome resulting in symptoms which may include intellectual disability, dysmorphic features, heart defects, seizures, Autism spectrum disorders and schizophrenia.

Using two state-of-the-art genome mapping technologies known as fiber FISH and Bionano optical mapping, the researchers were able to see long DNA molecules and discover an unprecedented and extreme level of variability between individuals and populations. These differences can be hundreds of thousands to over two million base pairs of DNA.

“The large differences between people cannot be assessed without the mapping technologies deployed in this study,” said Dr. Pui-Yan Kwok, Henry Bachrach Distinguished Professor at UCSF, a collaborator of Dr. Shaikh who co-authored the paper. “Our approach brings clarity to the organization of the highly complex region studied.”

Shaikh agreed.

“You are mapping these chromosomal fragments back to the genome to see what is different,” Shaikh said. “We looked at over 150 apparently healthy people. We found the region in question was drastically different in each person.”

Some people carried far less and some far more DNA in this part of the genome.

Children with the 22q11 deletion syndrome and their parents were also tested to determine if their 22q11 LCRs were different.

“Now we can start asking questions like, `Is someone with more or  less DNA more disposed to have a child with disease?’” Shaikh asked. “If so, then it might be possible to genetically test parents before they have children.”

Shaikh said this region of the genome is constantly evolving.

“If you look from one generation to the next you may see changes within the same family,” he said. “That is pretty incredible.”

The study was funded multiple sources including a grant from the National Institutes of Health to Shaikh and Kwok.

 

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Health care workers unprepared for magnitude of climate change

An epidemic of chronic kidney disease that has killed tens of thousands of agricultural workers worldwide, is just one of many ailments poised to strike as a result of climate change, according to researchers at the University of Colorado Anschutz Medical Campus.

“Chronic kidney disease is a sentinel disease in the era of climate change,” said

Dr. Cecilia Sorensen
Dr. Cecilia Sorensen, lead author of the article in the New England Journal of Medicine.

Cecilia Sorensen, MD, of the Colorado School of Public Health and the University of Colorado School of Medicine. “But we can learn from this epidemic and choose a wiser path forward.”

The article was published today in the New England Journal of Medicine.

Lead author Sorensen and her colleague, Ramon Garcia-Trabanino, MD, said chronic kidney disease of unknown origin or CKDu is now the second leading cause of death in Nicaragua and El Salvador. The death toll from the disease rose 83% in Guatemala over the past decade.

The exact cause of the disease, which hits agricultural workers in hot climates especially hard, remains unknown. It doesn’t align with typical chronic kidney disease which is usually associated with diabetes and hypertension.

“What we do know for certain is that CKDu is related to heat exposure and dehydration,” Sorensen said, adding that exposure to pesticides, heavy metals, infectious agents and poverty may also play a role.

Sugar cane workers in Central America, who often toil in 104-degree heat in heavy clothing, are often victims of the illness.  Sorensen said there is evidence that constant exposure to high temperatures can result in chronic kidney damage.

“They can’t say it’s too hot, they don’t want to go work in the fields,” she said. “If they don’t work, they don’t eat that night.”

The disease is also showing up in the U.S. in places like Florida, California and Colorado’s San Luis Valley.

And the hotter it gets, Sorensen said, the more likely it will increase along with other diseases.

“When it gets hotter, we see more people in emergency rooms with cardiovascular disease,” said Sorensen, who is an emergency department physician at CU Anschutz and a member of the CU Consortium for Climate Change & Health. “We are seeing average global temperatures gradually creep up but one of the biggest risks are heat waves.”

She said U.S. public health officials are not prepared for the kinds of heat waves seen in Europe in 2003 that killed over 70,000 people.

“We are way behind the curve on this compared to Europe,” she said. “We are also seeing Lyme disease in places we never saw it before because the winters are no longer cold enough to kill off the ticks that carry it.”

She said the mosquitos that carry diseases like Zika, dengue fever and Chikungunya are now showing up in the U.S.

“If we are to address both the CKDu and other climate-related diseases, we will have to integrate environmental information into clinical and public health practice and build robust early-warning systems focused on vulnerable communities and climate-sensitive diseases…so we can respond rapidly,” she said. “We believe physicians have the opportunity to change the course of the future.”

 

 

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Researchers discover why intense light can protect cardiovascular health

Researchers at the University of Colorado Anschutz Medical Campus have found that intense light amplifies a specific gene that bolsters blood vessels and offers protection against heart attacks.

“We already knew that intense light can protect against heart attacks, but now we have found the mechanism behind it,” said the study’s senior author Tobias Eckle, MD, PhD, professor of anesthesiology at the University of Colorado School of Medicine.

The study was published today in the journal Cell Reports.

Tobias Eckle, MD, PhD, professor of anesthesiology
Tobias Eckle, MD, PhD, professor of anesthesiology

The scientists discovered that housing mice under intense light conditions for one week `robustly enhances cardio protection’, which resulted in a dramatic reduction of cardiac tissue damage after a heart attack. They also found that humans could potentially benefit from a similar light exposure strategy.

In an effort to find out why, they developed a strategy to protect the heart using intense light to target and manipulate the function of the PER2 gene which is expressed in a circadian pattern in the part of the brain that controls circadian rhythms.

By amplifying this gene through light, they found that it protected cardiovascular tissues against low oxygen conditions like myocardial ischemia, caused by reduced oxygen flow to the heart.

They also discovered that the light increased cardiac adenosine, a chemical that plays a role in blood flow regulation.

Mice that were blind, however, enjoyed no cardio protection indicating a need for visual light perception.

Next, they investigated whether intense light had similar effects on healthy human volunteers. The subjects were exposed to 30 minutes of intense light measured in lumens. In this case, volunteers were exposed to 10,000 LUX, or lumens, on five consecutive days. Researchers also did serial blood draws.

The light therapy increased PER2 levels as it did in mice. Plasma triglycerides, a surrogate for insulin sensitivity and carbohydrate metabolism, significantly decreased. Overall, the therapy improved metabolism.

Eckle has long known that light plays a critical role in cardiovascular health and regulating biological processes. He pointed out that past studies have shown an increase in myocardial infarctions during darker winter months in all U.S. states, including sunnier places like Arizona, Hawaii and California. The duration of the light isn’t as important as the intensity, he said.

“The most dramatic event in the history of earth was the arrival of sunlight,” Eckle said. “Sunlight caused the great oxygen event. With sunlight, trillions of algae could now make oxygen, transforming the entire planet.”

Eckle said the study shows, on a molecular level, that intensive light therapy offers a promising strategy in treating or preventing low oxygen conditions like myocardial ischemia.

He said if the therapy is given before high risk cardiac and non-cardiac surgery it could offer protection against injury to the heart muscle which can be fatal.

“Giving patients light therapy for a week before surgery could increase cardio protection,” he said. “Drugs could also be developed that offer similar protections based on these findings. However, future studies in humans will be necessary to understand the impact of intense light therapy and its potential for cardio protection.”

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CU Anschutz researchers win grant to commercialize miniature microscope

A team of researchers from the University of Colorado Anschutz Medical Campus has received a grant to commercialize a miniature microscope that fits on the head of a mouse and can peer deeply inside the living brain.

The microscope, known as the 2P-FCM, uses an electrowetting lens mounted on the head of a freely moving mouse where a high-powered, fiber optic light can actually view and control neural activity as it happens. The lens is liquid and can change shape when electricity is applied.

Emily Gibson and Diego Restrepo examined the miniature microscope they developed with two professors from CU Boulder. The team won a $2 million NIH Brain Initiative grant to refine and expand the use of the instrument.
Emily Gibson and Diego Restrepo working on the miniature microscope that allows them to see inside a living brain.

“We can image deep into the brain which makes it very attractive to a lot of neuroscience researchers,” said Emily Gibson, PhD, assistant professor of bioengineering at CU Anschutz who helped create the microscope.  The initial demonstration of the 2P-FCM was published in Scientific Reports (Ozbay et al., 2018).

Gibson and her colleague Diego Restrepo, PhD, professor of cell and developmental biology at the University of Colorado School of Medicine, along with Karl Kilborn, co-president of 3i (Intelligent Imaging Innovations, Inc.) in Denver, won the $394,260 Small Business Innovation Research (SBIR) grant.

The microscope was first deployed to the University of Paris. Based on that success, it will next be used at New York University and Duke University.

The company 3i, founded by Karl Kilborn, along with Colin Monks, a former PhD student of CU Anschutz, and Abraham Kupfer, a former investigator at National Jewish, will produce the microscope. The company’s manufacturing efforts will be guided by Baris Ozbay, PhD, who helped create the prototype while working in Gibson’s lab and now works at 3i.

In 2016, Restrepo and Gibson along with Juliet Gopinath, PhD, associate professor in electrical, computer and energy engineering at CU Boulder and Victor Bright, PhD, professor of mechanical engineering at CU Boulder won a $2 million grant, spread over three years, from the National Institutes of Health (NIH) and the National Institute of Neurological Disorders and Stroke (NINDS). It was part of the NIH’s new BRAIN initiative aimed at revolutionizing the understanding of the human brain.

The money was partly used to optimize the microscope and deploy it in different neuroscience labs.

The device represents a breakthrough in the way scientists can observe brain activity. The microscope is attached to a thin fiber optic cable and mounted on a mouse’s head, allowing it to wander freely. Scientists can then observe complex neural processes within the brain.

“This can also be used to monitor brain responses to social and behavioral interactions,” Restrepo said. “To do that, you need an animal that is moving around and interacting with its environment.”

Kilborn, 3i co-president, said the goal of the BRAIN initiative was to ensure that new technologies developed academically made their way into as many laboratories as possible.

“This SBIR will help 3i disseminate the pioneering work done at CU Anschutz in the laboratories of Emily Gibson and Diego Restrepo, along with collaborators at CU Boulder in the laboratories of Victor Bright and Juliet Gopinath, which has also been funded, in part, by the BRAIN Initiative,” he said.  We are excited by the experimental potential of this new technology and believe the grant represents a positive example of how academia and industry can work together to advance research in neuroscience.”

The microscope will allow scientists to investigate a wide range of subjects.

Some of those involved with the project are studying the neural basis of vocal learning in songbirds, decision-making in non-human primates and the neural basis of social bonding among prairie voles.

“This microscope has been getting a lot of attention,” Gibson said. “The idea is to turn it into an easy-to-use commercial product and make it available to labs around the world. For me, that is what is most rewarding about this work.”

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Scientists demonstrate the advantages of diverse populations when compiling genetic data

AURORA, Colo. (June 19, 2019) – Relying strictly on genetic data from those of European descent, rather than more diverse populations, can exacerbate existing disease and increase health care disparities, according to new research.

The research letter was published today in the journal Nature.

“There have been numerous discoveries in human genetics over the last few decades that have told us a lot about biology, but most of the work is being done on those of European descent,” said the study’s first author Christopher Gignoux, PhD, MS, associate professor at the Colorado Center for Personalized Medicine at the University of Colorado Anschutz Medical Campus. “By limiting our focus, we are limiting our understanding of the human genetics underlying complex traits. The PAGE Study gives us an overdue opportunity to look at what we can find when studying a large number of groups together.”

Associate Professor Chris Gignoux of the Colorado Center for Personalized Medicine.
Associate Professor Chris Gignoux of the Colorado Center for Personalized Medicine at CU Anschutz.

This was borne out in the study which examined thousands of individuals in the U.S. of non-European ancestry. The Population Architecture using Genomics and Epidemiology study (PAGE) was developed by the National Human Genome Research Institute and the National Institute on Minority Health and Health Disparities to conduct and empower genetic research in diverse populations.

Researchers genotyped 49,839 people and found a number of genetic variants replicated from studies strictly of European descent. But PAGE investigators found dozens of discoveries that would not have been possible in a single population study. This included both complex traits and in Mendelian, or monogenic disorders.

“In light of differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and health care disparities,” the study said. “Critical variants can be missed if they have a low frequency or are completely absent in European populations…” Especially rare variants.

 

Kathleen Barnes, PhD, director of the Colorado Center for Personalized Medicine at CU Anschutz
Kathleen Barnes, PhD, director of the Colorado Center for Personalized Medicine at CU Anschutz

Gignoux said the success of precision medicine and genomics means recruiting people from underrepresented populations for genetic studies. Right now, those genomic databases lack critical diversity despite the fact that many of in underrepresented groups have the greatest health burden and stand to benefit the most from being included.

“The Colorado Center for Personalized Medicine on the Anschutz Medical Campus is committed to personalized medicine here in our state and region that will benefit ALL people, regardless of who you are or where you came from,” said Kathleen Barnes, PhD, director of the Colorado Center for Personalized Medicine. “Initiatives like PAGE, and the work summarized in this manuscript by Chris Gignoux and colleagues, show us the way forward in achieving our goals of inclusion. It also illuminates just how important genetic diversity is in our understanding of the architecture of genetic disease. These approaches can now feed into our personalized ancestry information resource for patients interested in their own ancestry, as well as benefit our research and clinical community.”

Gignoux agreed.

“With studies of diverse groups we got a better overall picture of the genetic architecture which show the underpinnings of disease,” Gignoux said. “We want to understand how genetics can improve and ameliorate disease rather than make it worse.”

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Cochrane US Network opens affiliate at CU Anschutz

The Cochrane US Network, made up of some of the country’s leading institutions in the research and practice of evidence-based medicine, announced Tuesday the opening of 11 new affiliates across the country including one at the University of Colorado Anschutz Medical Campus.

These new affiliates will join Cochrane’s 70 other groups around the world to promote evidence-informed decision making in health care by supporting and training systematic review authors and users of Cochrane Reviews, as well as working with clinicians, professional associations, policymakers, patients, health care provider organizations and the media to encourage the dissemination and use of Cochrane evidence.

Robert Dellavalle, MD, PhD, MSPH, professor of dermatology at the CU School of Medicine
Robert Dellavalle, MD, PhD, MSPH, professor of dermatology at the CU School of Medicine

“Cochrane is a leading evidence-based medicine organization, so it’s a very big deal to be a site that is tied to that effort,” said Robert Dellavalle, MD, PhD, MSPH, a professor of dermatology at the University of Colorado School of Medicine, who will lead the CU Anschutz affiliate. “Cochrane is known for having some of the best methodology for doing systematic review of evidence and they are highly cited in the field.”

The Cochrane US Network is made up of the existing Cochrane US West Associate Center based at Oregon Health & Science University; three Cochrane Review Groups producing systematic reviews in neonatal health, fertility regulation and urological conditions; three US satellites of Cochrane Review Groups focusing on eyes and vision, pregnancy and childbirth and musculoskeletal disease; one field specializing in complementary medicine. The 11 new affiliate institutions include:

  • AcademyHealth
  • American College of Physicians
  • Central Michigan University
  • Cornell University
  • Mayo Clinic Evidence-based Practice Center
  • Penn Medicine Center for Evidence-based Practice
  • RTI International – University of North Carolina Evidence-based Practice Center
  • Texas Christian University
  • University of Chicago Medicine
  • University of Colorado Anschutz Medical Campus
  • University of Maryland School of Medicine

Mark Wilson, Cochrane CEO, said: “I am delighted to see such a prestigious and committed group of US institutions and leaders in evidence-informed health care join Cochrane’s global family of collaborators.”

“Many of these researchers and clinicians are leaders in the field, and I am excited by the expertise, innovation and knowledge they will bring to our mission of delivering trusted evidence into health policy and clinical decision-making,” Wilson said. “The US health system is the largest and most sophisticated in the world, yet suffers from huge inequalities in health outcomes and tremendous wastefulness.”

Wilson believes a vibrant Cochrane Network promoting greater use of evidence showing what health interventions work and what don’t can make a real difference.

“I hope that this new – already extensive – network will grow further and welcome many more partners in the years to come,” he said.

These new Cochrane affiliates each have their own specific areas of expertise and focus. Collectively, the Network will focus on producing high quality evidence on priority topics for the US; providing training to systematic review authors and health care practitioners, policymakers and others in the interpretation of Cochrane Reviews. It will also raise the general awareness around Cochrane evidence to make well-informed health and health care decisions.  The new Network will build on the work of the former US Cochrane Center based at Johns Hopkins University.

“The establishment of the US Network is an important development for Cochrane as well as the health care community in the U.S.,” said Marguerite Koster, co-chair of the Cochrane Governing Board. “Coordination and collaboration are core values of the Network because we strongly believe we can add value by working together as a consortium. I very much look forward to the start of the network and to seeing it develop and grow as a platform for anyone interested in evidence-informed health and health care in the US.”

A formal launch of the new ‘Cochrane US Network’ was held today in Washington DC. During the launch meeting Cochrane CEO, Mark Wilson, and Governing Board co-chair, Marguerite Koster, introduced the US Network. Additionally, representatives from the Network will introduce their institutions and planned work, and speak to the value of being part of the Network.

The Cochrane US Network is part of Cochrane, a global independent network of researchers, professionals, patients, careers and people interested in health. Cochrane produces reviews which study all of the best available evidence generated through research and make it easier to inform decisions about health. Cochrane is a not-for profit organization with over 65,000 members and supporters from more than 130 countries working together to produce credible, accessible health information that is free from commercial sponsorship and other conflicts of interest. Cochrane’s work is recognized as representing an international gold standard for high quality, trusted information.

 

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Chronic kidney disease epidemic may be result of high heat, toxins

farm workers

A mysterious epidemic of chronic kidney disease among agricultural workers and manual laborers may be caused by a combination of increasingly hot temperatures, toxins and infections, according to researchers at the University of Colorado Anschutz Medical Campus.

The study was published today in the New England Journal of Medicine.

Professor Lee Newman, MD, MA
Professor Lee Newman, MD, MA

In recent years, chronic kidney disease has emerged as a major illness among workers in hot climates. It was first identified in the 1990s by clinicians treating sugar cane workers in Central America. In 2012, it claimed roughly 20,000 lives and has now been identified in California, Florida and in Colorado’s San Luis Valley.

But the exact cause has been hard to determine.

“We looked at all the available literature on the subject and asked, `What do we know today? Where are the gaps?” said the study’s lead author Lee Newman, MD, MA, director of the Center for Health, Work & Environment  and professor in the  Dept. of Environmental & Occupational Health at the Colorado School of Public Health. “We were hoping to synthesize everything we know so far for a framework for moving forward.”

The disease is more prevalent in sugar cane workers and other agricultural employees including cotton and corn workers, shrimp farmers and miners. It is less common at higher elevations.

Newman and study co-author Richard Johnson, MD, of

the University of Colorado School of Medicine, said the disease could be caused by heat, a direct health impact of climate change, as well as pesticides like glyphosate.

“Some pesticides are nephrotoxic, and these could possibly contaminate the water supply,” Johnson said. “Indeed, there are studies showing the epidemic in Sri Lanka is greatest in areas where there are shallow wells in which toxins might become concentrated.”

Dr. Rick Johnson of CU Anschutz
Professor Richard Johnson, MD

Sri Lankan farmers exposed to glyphosate showed an increased risk for chronic kidney disease. Still, the levels in wells were very low and studies in Central America turned up little glyphosate. Along with pesticides, the researchers looked at heavy metals as a possible culprit. Lead and cadmium, known to cause kidney injury, have been reported in the soils of Sri Lanka and Central America.

Other potential causes include infectious diseases that can hurt the kidneys such as the hanta virus and leptospirosis, common in sugar cane workers. Genetic factors are also a possibility.

“The common factors are heat exposure and heavy labor,” Newman said.

Heat stress and persistent dehydration can cause kidney damage.

The disease is moving into the U.S. with agricultural workers in Florida, California’s Central Valley and Colorado’s San Luis Valley reporting incidences of the illness.

“This is not the usual kidney disease we see in the U.S.,” Newman said. “It is not caused by high blood pressure or diabetes. The usual suspects are not the cause.”

Johnson pointed out that CU Anschutz has two major efforts underway that are investigating worker health and the impact of climate change on disease.

“This disease is not confined to the southern hemisphere, it is coming here and in fact it is already here,” Johnson said. “It is my opinion that climate change plays a role in this epidemic.”

Those impacted are mostly agricultural workers, the people who grow and harvest the world’s food.

“They are the people who feed the planet,” Johnson said. “If climate change continues like this who is going to feed us?”

Newman and Johnson believe the epidemic is caused by a combination of heat and some kind of toxin and they recognize the need to take preventative action immediately.  That means ensuring workers get adequate breaks, drink enough fluids and spend time in the shade. It also means maintaining a clean water supply, free of chemicals toxic to the kidneys.

“When clinicians detect clusters of patients with chronic kidney disease who work for the same employer or in similar jobs,” the authors said, “they should contact occupational health and safety and public health professionals to promote investigations of workplace conditions.”

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New disease discovered by CU Anschutz researchers

A new immunodeficiency disease caused by a novel genetic mutation has been identified by researchers at the University of Colorado Anschutz Medical Campus providing unique insights into cell biology.

The findings were published last week in The Journal of Experimental Medicine.

Elena Hsieh, MD, assistant professor of pediatrics and microbiology, immunology at the CU School of Medicine and CHCO.
Elena Hsieh, MD, assistant professor of pediatrics and microbiology, immunology at the CU School of Medicine and CHCO.

The researchers made the discovery while investigating why an infant was suffering from inflammatory bowel disease along with other conditions including eczema, food allergies, lung disease, and persistent CMV (cytomegalovirus) infection.

“Other than a specialized elemental formula, he was unable to eat any food and his gut inflammation persisted despite numerous therapies,” said the study’s co-author Cullen Dutmer, MD, an assistant professor of pediatrics specializing in allergy and immunology at the University of Colorado School of Medicine and Children’s Hospital Colorado (CHCO).

The young boy’s sister suffered from similar problems, and their collective symptoms were consistent with an immune dysregulation syndrome.  Patients suffering from these syndromes have poorly functioning immune systems which can result in serious, recurrent, or unusual infections, as well as autoimmune/inflammatory complications affecting the gastrointestinal tract, skin, lungs, and circulating blood cells.  This defective (or dysregulated) immune system may also lead to increased risk for cancer.

Cullen Dutmer, MD, an assistant professor of pediatrics specializing in allergy and immunology at the University of Colorado School of Medicine and Children’s Hospital Colorado
Cullen Dutmer, MD, assistant professor of pediatrics specializing in allergy and immunology at the CU School of Medicine and CHCO.

The researchers found that the siblings had the first known human defect in a gene called IL2RB (encoding interleukin-2 receptor beta, IL-2Rb), resulting in decreased numbers of immune cells called regulatory T cells which prevent autoimmunity. At the same time, the children had an accumulation of ‘natural killer’ cells which, if functioning normally, help protect against viral infections and cancer.

“But the mutation meant the natural killer cells were incapable of maturing properly and could not clear CMV, resulting in a persistent and debilitating infection,” said study co-author Elena Hsieh, MD, assistant professor of pediatrics and microbiology, immunology at the CU School of Medicine and CHCO.

“We tracked this disease down to a single gene and that is a fairly rare event,” Hsieh said. “Prior to our findings, there had been no documented cases of a mutation in this particular gene leading to human disease.”

Ross Kedl, PhD, professor of immunology and microbiology at the CU School of Medicine
Ross Kedl, PhD, professor of immunology and microbiology at the CU School of Medicine

Dutmer said it’s likely that others suffer from this condition but it has never been identified.

“Although clearly a rare disease, it has likely been missed in other children,” he said. “Now that it is out there, we know to look for it.”

Study co-author Ross Kedl, PhD, professor of immunology and microbiology at the CU School of Medicine agreed.

“The discovery also means that the defect could be addressed through gene therapy,” Kedl said. “We could feasibly go in, manipulate the gene, and get it back in the right sequence.”

Recent advancements in identifying genetic causes of immunodeficiency diseases have led to innovative treatments.  Gene therapy, a therapeutic approach that corrects specific genetic defects, is emerging as a viable treatment option for some immunodeficiency diseases.

A recent study showcased the use of gene therapy to treat severe combined immune deficiency or SCID caused by mutations in the gene IL2RG (Mamcarz et al., New England Journal of Medicine 2019).

“Identifying the underlying genetic causes of immunodeficiency diseases and other disorders can reveal targets for promising personalized treatment strategies like gene therapy,” Dutmer and Hsieh said. “That would allow for therapeutic interventions that are uniquely tailored to meet the needs of the individual.”

Kedl noted that this discovery illustrates the ‘bench-to-bedside’ research capacities on the CU Anschutz Medical Campus and in its graduate training programs.

One of the first authors of the study, Isabel Fernandez, is an MD/PhD student the CU School of Medicine, pursuing a PhD in Immunology in the Kedl lab. Her co-first author is Ryan Baxter, MS, who is a research assistant in the Hsieh lab.

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Prove it: National telehealth research network greenlighted

The University of Colorado Anschutz Medical Campus is part of a team of researchers that has received a grant of $3.6 million for the SPROUT-CTSA Collaborative Telehealth Research Network.

This five-year grant will support the development of telehealth research efforts, metric development, identification of best practices and the development of collaborative policy and advocacy materials across the country. It builds on work underway as part of the SPROUT (Supporting Pediatric Research on Outcomes and Utilization of Telehealth) collaborative, an established network of institutions and pediatric providers operating within the American Academy of Pediatrics (which is a sub awardee of the grant).

Photo
Christina Olson, MD, assistant professor of pediatrics.

The Medical University of South Carolina (MUSC) is the primary awardee of the grant. Institutions that are part of this collaborative effort include the University of Colorado Anschutz Medical CampusChildren’s Hospital Colorado, University of Pennsylvania – Children’s Hospital of Philadelphia (CHOP) and Mercy Clinic in St. Louis, Missouri.

“At the national level, there is no academic authority currently spearheading multicenter telehealth research studies,” said Christina Olson, MD, assistant professor of pediatrics and site primary investigator at the University of Colorado Anschutz Medical Campus – Children’s Hospital Colorado. “We have piecemeal efforts happening in terms of research, national policy development and payer guidelines. This network will provide tools, resources and guidance to accelerate the development of telehealth studies across the country. We will support champions of telehealth to become champions of research as well.”

“This is a huge step forward in the development of safe and impactful telehealth programs across the country,” said primary investigator for the grant S. David McSwain, MD, MUSC Children’s Health physician and MUSC associate professor of pediatric critical care and chief medical information officer.  “Academic research into the real impact of telehealth services is a critical component of developing and growing programs with the greatest potential to improve our health care system. Many physicians and other health care providers are hesitant about incorporating telehealth into their practices because it’s difficult to separate the theoretical benefits from the real value.”

In 2015, McSwain collaborated with a small group of pediatric physicians across the country to form SPROUT, which has since completed and published the nation’s first broad assessment of pediatric telehealth infrastructure across the country.

“That was a critical starting point,” said John Chuo, MD, associate professor of clinical pediatrics, co-chair of SPROUT and site primary investigator at CHOP. “When we started SPROUT, we realized that we couldn’t conduct studies on pediatric telehealth unless we actually knew which institutions were providing which types of services, and that information wasn’t available anywhere. So we made that our first investigation.”

While much anecdotal or small-scale evidence exists about the benefits of telehealth, including cost reduction, improved quality of care in some patient populations and improved access to care for some rural and underserved populations, barriers to fully demonstrating the gains made via telehealth care delivery persist. For example, there are few best practices in existence for conducting multisite telehealth research involving patient care outcomes, limited access to research trials for rural populations and limitations to care access for special populations such as children or the elderly.

The grant is funded by a Collaborative Innovation Award through the National Center for the Advancing Translational Science (NCATS), a branch of the National Institutes of Health. The program will operate in collaboration with CTSA (Clinical and Translational Science Award) sites across the country to facilitate research development and support current and future telehealth researchers to develop projects and apply for funding. CU’s Colorado Clinical and Translational Sciences Institute (CCTSI) and its partner, Children’s Hospital Colorado are one of these CTSA sites. As opposed to supporting a specific clinical research study, this grant seeks to establish an easily accessible support structure around telehealth research: tools, resources, guidance, collaboration, education and advocacy materials that will be valuable to anyone across the country who wants to study telehealth programs.

“We expect this network to become the preeminent source for evidence-based policy and outcomes data,” said Brooke Yeager McSwain, RRT, health policy consultant for the project and manager of the South Carolina Children’s Telehealth Collaborative. “Our national and state legislators have seen the benefits of telehealth for certain populations and regions. We have to demonstrate to them that this works across the country and has the potential to dramatically impact health care delivery models, particularly in value-based care.”

Alison Curfman, MD, medical director of Pediatrics at Mercy Virtual and a co-investigator of the grant, spends much of her time thinking about better ways to partner with children and their families for overall better health. “We have to ensure that children have access to every type of care that they need at the right time, no matter where they live. The technology is here. The commitment of the early-adopters is here. Our next frontier is proving to other pediatric providers across the health care spectrum that telehealth is about so much more than convenience.”

Guest contributor: Wendy Meyer, Colorado Clinical and Translational Sciences Institute.

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Sexual behavior may influence gut microbiome

A person’s sexual behavior could affect their microbiome and immune system, potentially elevating their risk of HIV infection, according to a new study from researchers at the University of Colorado Anschutz Medical Campus.

The study was published last week in the journal PLOS Pathogens.

Brent Palmer, PhD, associate professor of medicine in the Division of Allergy and Clinical Immunology at the CU School of Medicine
Brent Palmer, PhD, associate professor of medicine in the Division of Allergy and Clinical Immunology at the CU School of Medicine

The microbiome, a community of microbes in the gut, play a major role in driving and shaping the human immune system. But recent studies have shown that men who have sex with men (MSM) have very distinct microbiomes compared with men who have sex with women (MSW), regardless of HIV-infection status.

CU Anschutz researchers wanted to know whether this altered microbiome induces T cell activation associated with HIV transmission risk and increased disease severity.

To study this they took stool samples of 35 healthy men – men who had sex with men and men who had sex with women – and transplanted them into mice. The mice who received the MSM stool samples showed increased evidence of activation of CD4+ T cells, which would put them at a higher risk of HIV if they were human.

They also isolated immune cells from the intestines of HIV negative individuals and exposed them to bacteria from MSM and MSW feces. Human gut derived immune cells exposed to MSM fecal bacteria were more likely to be infected by HIV virus in vitro. This was again linked with increased immune activation by these fecal bacteria.

“These results provide evidence for a direct link between microbiome composition and immune activation in HIV-negative and HIV-positive MSM, and a rationale for investigating the gut microbiome as a risk factor for HIV transmission,” said the study’s senior author Brent Palmer, PhD, associate professor of medicine in the Division of Allergy and Clinical Immunology at the CU School of Medicine.

Exactly why the microbiome of men who have sex with men is so distinct remains unknown. Some have theorized that diet may promote inflammation and thereby activate T cells.

“There is a unique microbiome associated with men who have sex with men that drives immune activation in the gut that may also drive higher levels of HIV infection,” Palmer said. “But we still don’t know exactly why this is.”

Yet understanding this microbiome is important, Palmer said, because it could directly affect the immune system of high-risk men and lead to an increased risk of HIV infection.

The study co-authors include Sam X. Li, PhD, and Catherine Lozupone, PhD, of the University of Colorado Anschutz Medical Campus.

 

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