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Physicians’ book ‘Enviromedics’ explores link between climate change and human health

The adverse impacts to human health from global warming are undeniable and on track to worsen, without significant interventions, in the coming decades.

Jay Lemery, MD, of CU Anschutz
Jay Lemery, MD

This is the view of Jay Lemery, MD, associate professor of medicine in the CU School of Medicine, and the wider scientific community. Lemery co-authored a recently published book, “Enviromedics: The Impact of Climate Change on Human Health” with Paul Auerbach, MD, professor of emergency medicine at Stanford University School of Medicine.

Lemery, who is also section chief of the Wilderness and Environmental Medicine Section in the SOM’s Department of Emergency Medicine, has a strong interest in the interplay of the environment and human health.

Asked why he and Auerbach wrote the book, Lemery said, “It’s clear there’s been a conspicuous absence of physicians and health care providers engaging in the dialogue on climate change and its impact on human health. We also felt the science was being politicized and risk assessments for most Americans were skewed. So we wanted to take a step back and weigh in from the physicians’ point of view, essentially saying, ‘We know sickness – this is what we do every day,’ and point to what we see coming down the pike.”

The book takes the reader to the bedside, providing vignettes of the sicknesses physicians are seeing across the globe. The book’s message is clear: Climate change is and will be a driver to make these health problems worse.

‘Changes in vector-borne diseases’

Lemery chatted with Today about “Enviromedics” and the dire prognosis for the planet and its inhabitants if climate change continues unchecked.

Today: What are the effects of climate when it comes to human biology? What are physicians seeing in that regard?

Lemery:

  • Extreme heat events are real and becoming more prevalent and intense. We’re seeing heat illness, heat stress – acute conditions – but we also see things like chronic kidney disease spiking in vulnerable places, like among field workers in central America and south Asia. We’re seeing pre-existing health conditions – diabetes, heart disease, congestive heart failure – all exacerbated by extreme heat. In general, we’re seeing exacerbations of chronic disease with vulnerable populations – the very old, the very sick, the very young.
  • We’re also seeing changes in vector-borne diseases – infectious diseases like malaria, dengue, even Zika – and the range of these diseases is increasing in altitude and latitude. Also, the life cycles of the vectors – the mosquitoes and ticks that carry the diseases – are being altered by climate change.
  • After extreme weather events, we see not only the trauma from flooding and extreme damage to infrastructure – causing hundreds of deaths like this summer with the hurricanes – but also the breakouts of water-borne disease. This happens after the fact, when water supplies, sewage systems and food-growth areas are all mixed and spread out after these weather events.
  • We’re seeing degraded air quality over huge swaths; even in the U.S., huge swaths of the American West have been affected all summer from wildfires, which are now more intense and long-lasting than anytime in the historical record.
  • For people who suffer from allergies, the aero-allergen seasons are longer and the pollen counts are higher than we’ve ever seen.
  • From the sea-level rise caused by global warming, we’re seeing higher storm surges, and there’s been a slow erosion, particularly of low-lying areas in the low-lying nations in the Pacific and Indian oceans. These are communities, and in some cases nations, that are looking at the best science and saying, ‘We probably won’t have a home in 100 years.’ So we are now actually seeing migrations of people who are resettling in places like Australia and New Zealand.
  • There are also force multipliers. Food security is affected by extreme weather; extreme precipitation events, extreme drought events and extreme heat events all disrupt food supply. In poverty-stricken areas, when the food supply is disrupted, food insecurity and the consequential malnutrition or even starvation becomes more at risk than it was previously.

‘We know this is coming’

Today: Someone may say, “Even though you’re a scientist, you’re not a climatologist, you’re not a meteorologist. Why should we listen to you on the subject of climate change?” If someone were to say that to you, what would be your response?

Book "Enviromedics"
Jay Lemery, MD, associate professor of medicine in the CU School of Medicine, co-authored “Eviromedics: The Impact of Climate Change on Human Health.”

Lemery: That’s exactly right. It’s time that we as physicians, as health care providers, as the people who deal with injury and sickness and even death, step forward and say, ‘This is the same thing. What we’re seeing and what we can anticipate as drivers of morbidity and mortality, we know this is coming.’ So it’s important to hear it from your doctor, from those of us who wear the metaphorical white coat, and say, ‘This is a big deal.’ We’ve spent a lot of time delivering altruistic-oriented messages – ‘Save the whales’ or ‘Love mother Earth’ – or abstract messages – like ‘There’s 400 parts per million of carbon dioxide in the atmosphere’ – but I don’t think those messages have worked.

We need to bring it back to a simple message: This is about the health of your parents, your kids’ risk of asthma and other health issues that affect the people you love. This comes down to the very basic health issues of humanity – and if that’s not a fulcrum for change, I’m not sure what is. That’s why we wrote the book.

Today: Where does the science stand on the direct link to these kinds of health issues right now?

Lemery: The science is pretty clear, and frankly no one is really debating this anymore: Human-caused climate change is driving a lot of these health issues. Now, some of them are direct, but many more are indirect. So, where public health was tenuous as first, force multipliers are making the situation worse. I think it’s important to understand that the data is clear, and the people who spend their careers studying this across all spectrums of environmental earth science have been saying the same thing: This is real; the change is real; and the historical record has never shown anything near this. It’s beyond historical fluctuations.

‘Trajectories going up across all metrics’

 Today: Will climate change affect people in the next five or 10 years, or the next 50 years? How fast will these effects get worse?

Also written by Dr. Lemery

In 2015, Jay Lemery, MD, co-authored “Global Climate Change and Human Health” with George Luber, PhD.

Lemery: We’re seeing the effects now. This summer has seen some of the strongest storms on record in the Atlantic basin. In the last few years, we’ve seen absolutely the most extreme storms on record. We know that the heat waves we’re seeing now are all beyond historical precedent. The majority of the warmest years on record have been in the last 10 to 20 years. Meanwhile, the Arctic sea ice is at its lowest point on average than has ever been recorded.

The fact that these effects are cumulative is very worrisome. We know that the data tell us that if we stop producing carbon now, it will be a long, long time before the Earth equalizes. And of course we’re not stopping carbon production, so I think the trends we’re seeing are going to worsen and last centuries into the future. To what degree will be the trajectory? I think that’s being postulated as varied, but, unfortunately, the trajectories are going up across all metrics.

Editor’s note: Matthew Kaskavitch, digital engagement strategist, contributed to this report. 

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Study to probe impact of marijuana legalization

Does legalizing recreational marijuana in a state lead its residents to use it, or other substances, more? How does legalization impact careers, family life and mental health? Are some people more vulnerable to its negative impacts than others?

These are some of the questions University of Colorado researchers hope to help answer via a sweeping new $5.5-million study of 5,000 twins funded by the National Institute on Drug Abuse (NIDA). It is the first and only study of its kind in the nation.

“Increasing numbers of states are legalizing recreational marijuana, but we know almost nothing about the health and social consequences of this dramatic and rapid shift in public policy,” says John Hewitt, director of the Institute for Behavioral Genetics at CU Boulder and a co-principal investigator of the study. “There is clear need for solid scientific evidence, and the experiment now unfolding in Colorado provides a rare opportunity to accumulate such evidence.”

Results of marijuana legalization

For the study, Hewitt and co-principal investigator Christian Hopfer, MD, a professor of psychiatry at CU Anschutz Medical Campus, will collaborate with colleagues at the University of Minnesota to study 1,250 sets of twins ages 23 to 29 there, where recreational use remains prohibited, and 1,250 sets of twins in Colorado, where it has been legal since 2014.

As part of several ongoing longitudinal studies of twins, the researchers have already been following the participants for 15 to 20 years, collecting data on their use of marijuana, alcohol and other drugs in adolescence, as well as about their psychological health and social functioning. Via phone and internet surveys over five years, they’ll now collect data from the twins again looking at changes in behavior from prior to legalization to after legalization in the Colorado cohort.

By including twins living in Minnesota, the researchers can control for factors – aside from legalization – that might influence outcomes regardless of what state one lives in. In addition to looking at how frequently subjects are using marijuana, the researchers will also look at the methods by which people are using it (edibles, dabbing, smoking, etc.) and how potent – in terms of THC levels – it is.

“There is a big cultural change of how marijuana is being used as a result of legalization,” says Hewitt. “Dabbing is just as legal as smoking your grandmother’s grass, but the consequences could be very different.”

Long-term studies of twins

“Some people will be fine. Some people may benefit. But for a subset of people, we suspect there will be adverse consequences.”

They’ll also ask questions about whether participants – all at an important developmental window of life full of role transitions – are fulfilling their career goals, how their relationships with their family members are, and any legal or psychological challenges they may be facing.

By looking at pairs of twins, including identical twins (who are genetically identical) and fraternal twins (who are not genetically identical), they’ll also be able to explore what genetic or environmental factors may play a role in making some people more vulnerable than others to any negative impacts of legalization.

“Some people will be fine. Some people may benefit. But for a subset of people, we suspect there will be adverse consequences,” Hewitt says.

Health impacts of marijuana use

The researchers note that in the past 15 years the prevalence of past-year adult marijuana use has doubled in the United States, yet little is known about how much is too much and which populations should be advised to abstain.

“If you go to a doctor’s office, there are established guidelines for what you might call safe and appropriate use for alcohol. But doctors have no idea what they should be telling patients when it comes to marijuana use,” says Hopfer.

By pulling the data together, the researchers hope to ultimately paint a more accurate picture of how usage changes as a result of legalization and how those changes may impact health in the long run.

Minnesota department of psychology researchers Scott Vrieze, Matt McGue and Bill Iacono are also principal investigators on the project.

Guest Contributor: Lisa Marshall

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Second University of Colorado vaccine approved by FDA for shingles

The Centers for Disease Control’s Advisory Committee on Immunization Practices recommended new treatment practices Wednesday for shingles based on a vaccine initially developed at the University of Colorado Health Sciences Center, now the University of Colorado Anschutz Medical Campus.

Paul Tabor, Associate Director of CU Innovations at the University of Colorado Anschutz, said, “The Shingrix vaccine is an important advance in the prevention of a very painful disease that affects millions of people each year and disproportionally impacts patients over 50 years old.”

Shingrix received approval by The Food and Drug Administration last week and is the second vaccine approved to prevent Shingles. The existing drug treatment, Zostavax, also was developed at the University of Colorado and has been prescribed in the US since 2006.

Dr. Abbas Vafai

According to the CDC, one in three people in the US will contract shingles during their lifetime. Shingles is caused by the Varicella Zoster virus, which also causes chicken pox. It presents as a painful, itchy rash that is particularly debilitating for the elderly and people with weak immune systems. It causes blisters that last for several weeks and cause shooting, burning pain.

The virus remains latent in the body, even if contracted as chicken pox in youth, to present as shingles later in life.

“We are proud that this breakthrough was initially discovered and developed at the University of Colorado,” said Kimberly Muller, Managing Director of CU Innovations. “It is a powerful example of how CU, CU Innovations and its partners translate cutting-edge research into products that significantly improve lives.”

Shingrix is a recombinant plasmid vaccine based upon a truncated Varicella-Zoster virus glycoprotein which is effective at immunizing humans against shingles. It stimulates an immune response that can be more powerful and longer lasting than current therapies. The technology was developed by former CU professor of neurology and microbiology Abbas Vafai in the 1980s.

“It was a long road to get here, but the obstacle was because it is a unique vaccine,” Vafai said. “The vaccine involves single-gene genetic engineering. The vaccine contains a single viral protein purified in the lab – not the whole virus.”

The CU Board of Regents was granted two patents related to Shingrix, both now assigned to a commercial partner.

Don Elliman, Chancellor of the University of Colorado Anschutz Medical Campus, said, “The CU Anschutz Medical Campus has a history of rigorous research and innovation, as the development of these vaccines illustrates. The pace of these innovations is only quickening. Last year alone, more than 20 patents were granted, six more start-up companies were formed and invention disclosures increased by 125%. We’re continuing the CU Anschutz tradition of translating research into practice, leading to important discoveries that improve lives.”

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Scientists develop new theory of molecular evolution

Researchers from the University of Colorado Anschutz Medical Campus and the University College London have developed a new theory of molecular evolution, offering insights into how genes function, how the rates of evolutionary divergence can be predicted, and how harmful mutations arise at a basic level.

“Molecules are the basis of all life and we wanted to find out why molecules evolve the way they do,” said study co-author David Pollock, PhD, professor of biochemistry and molecular genetics at the CU School of Medicine.

Professor David Pollock, PhD, is co-author of the new study
Professor David Pollock, PhD, is co-author of the new study

Pollock and fellow author Richard Goldstein, Ph.D., professor of infection and immunity at University College London, published the study October 23, 2017 in the journal Nature Ecology and Evolution.

Their theory of evolutionary mechanics transforms evolving molecular systems into a framework where the tools of statistical mechanics can be applied, opening a novel window into how protein evolution works.

“The approach rests on understanding proteins as integrated systems,” said Goldstein. “Too often we ignore interactions between different parts of a protein, but we know that changes in one part of the protein affect subsequent changes in other parts. It turns out this is really important for understanding why these molecules evolve the way they do.”

Proteins constantly change as mutations become fixed or eliminated depending on the protein structure, function and stability. This depends on amino acid interactions throughout the protein that cause evolution at one site to alter the chance of evolution at other sites.

The scientists discovered that they could predict rates of protein evolution based on their biochemical properties.

“This was a real surprise,” Pollock said. “Our theory accounts for well-known population genetics effects such as strength of selection and effective population size, but they drop out of the final equations that predict the rate of molecular evolution.”

For years, researchers have run up against problems with standard models of molecular evolution used in studying the evolutionary relationships among species. This led to difficulties in reconstructing important evolutionary events in ancestral organisms.

These patterns of molecular convergence were found to change regularly over evolutionary time in ways that indicated continually fluctuating constraints in different parts of proteins.

“This flips around the usual idea that the amino acids will adjust to the requirements of the rest of the protein,” Goldstein said. “But we couldn’t explain exactly why this happened, or whether there was any regularity to the process.”

But once the system was placed into a statistical mechanics framework, the magnitude of amino acid entrenchment was seen as central to understanding rates of evolutionary divergence.

The researchers said that the strength of selection in protein evolution is balanced by the sequence entropy of folding, the number of sequences that provide a protein with a given degree of stability.

“We like to think of the other amino acids as a bunch of kids jumping down on a memory foam mattress while you try to walk on it,” Pollock said. “Most of the time your feet are sunk into the mattress and you can’t step forward, but every so often the kids will create a dent in the mattress that allows you to step ahead.”

The title of the paper is “Sequence entropy of folding and the absolute rate of amino acid substitutions.”

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Enough vitamin D when young associated with lower risk of diabetes-related autoimmunity

Getting enough vitamin D during infancy and childhood is associated with a reduced risk of islet autoimmunity among children at increased genetic risk for type 1 diabetes, according to a study published this week in the journal Diabetes.

The study’s lead author, Jill Norris, MPH, PhD, of the Colorado School of Public Health, and her co-authors examined the association between vitamin D levels in the blood and islet autoimmunity. Islet autoimmunity, detected by antibodies that appear when the immune system attacks the islet cells in the pancreas that produce insulin, is a precursor to type 1 diabetes.

Professor Jill Norris, PhD, MPH, is lead author of the study.
Professor Jill Norris, PhD, MPH, is lead author of the study.

“For several years there has been controversy among scientists about whether vitamin D lowers the risk of developing of islet autoimmunity and type 1 diabetes,” said Dr. Norris.

Type 1 diabetes is a chronic autoimmune disease that is increasing by 3-5 percent annually worldwide. The disease is now the most common metabolic disorder in children under age 10. In younger children, the number of new cases is particularly high. And the risks seem to be greater at higher latitudes, further north from the equator.

Vitamin D represents a candidate protective factor for type 1 diabetes as it regulates the immune system and autoimmunity. Moreover, vitamin D status varies by latitude. But associations between vitamin D levels and islet autoimmunity have been inconsistent. This may be due to different study designs, population variation in vitamin D levels, or a failure to account for the combined effect of exposure and underlying genetic variation in the vitamin D pathway.

The findings are part of The Environmental Determinants of Diabetes in the Young (TEDDY) study, a large, multi-national study funded by the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases.

TEDDY’s effort began in 2004 with children from six clinical centers: three in the U.S. (Barbara Davis Center for Childhood Diabetes at CU Anschutz, the Pacific Northwest Research Institute in Seattle, and Augusta University in Georgia) and three in Europe (Universities of Turku, Oulu, and Tampere in Finland, Helmholtz Zentrum München in Germany, and Lund University in Sweden). The aim of the study is to search for triggers and protective factors for type 1 diabetes in 8,676 children with elevated type 1 diabetes risk.

The TEDDY children were followed with blood samples drawn every three to six months from infancy, to determine the presence of islet autoimmunity, as well as levels of vitamin D.

The authors compared 376 children who developed islet autoimmunity with 1,041 children who did not.  The authors found that in children with a genetic variant in the vitamin D receptor gene, vitamin D levels in infancy and childhood were lower in those that went on to develop islet autoimmunity compared with those that did not develop autoimmunity.

This study is the first to show that higher childhood vitamin D levels are significantly associated with a decreased risk of IA.

“Since this association does not prove cause-and-effect, we look to future prospective studies to confirm whether a vitamin D intervention can help prevent type 1 diabetes,” Dr. Norris said.

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New service offers fast, standardized results for eating disorder experts

Eating disorder researchers at the University of Colorado Anschutz Medical Campus have developed a new procedure that takes detailed patient questionnaires and generates a fast, standardized score for mental health professionals.

The service is available free to doctors, psychologists and other health professionals working with patients who have eating disorders.

Dr. Guido Frank, associate professor of psychiatry, is an expert in eating disorders

“Despite all the research, the fact is we still have limited treatments available in the field of eating disorders,” said Guido Frank, MD, eating disorder expert and associate professor of psychiatry and neuroscience at the University of Colorado School of Medicine. “But if we clinicians use similar validated assessments across disciplines and providers, the field of eating disorders will be more cohesive and more evidence-based.”

Frank and his fellow researchers, developed a web-based service where therapists can sign in patients. The patients fill out questionnaires developed for those with disorders like anorexia nervosa, bulimia and binge eating. Using a computer program, the questionnaire is automatically scored with a number that health care providers can use to understand the nature of the illness. The scoring process keeps the patients anonymous.

“The therapist receives the results and can discuss them with the patient,” Frank said. “It is purely a free service in the hopes that it will help.”

Frank said the system is unique in offering a standardized scoring method while bringing the latest science to practitioners in the field.

“Sometimes the work we do is hard to translate into the real world so we trying to close that research gap,” he said. “This shared knowledge, I believe, will help us  personalize treatment and provide evidence-based interventions that are tailored to individual needs.”

Here is the general /primary link to the service portal: Know Your Client/Know Your Patient

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Training cells as cancer killers

With the August approval by the Food and Drug Administration of a new therapy to treat young patients with a form of leukemia, the University of Colorado Anschutz Medical Campus is positioned to contribute to a revolution in patient care.

The therapy, from Novartis, carries an exotic name that is bound to become more familiar in the days ahead: chimeric antigen receptor T cell, or CAR-T. It’s not a drug or radiation, but rather a new line of attack that relies on reengineering a patient’s own cells to recognize, attack and kill cancer cells. The target in the Novartis therapy is acute lymphoblastic leukemia (ALL), the most common form of cancer in children.

The trial of the therapy, called Kymriah, targeted ALL patients 25 years or younger with high-risk leukemia who relapsed after standard therapy, including bone marrow transplants and chemotherapy, or whose disease was resistant to treatment. More than 80 percent achieved remission within one month of therapy.  The longest TCAR treated patient is more than five years from treatment and she remains in remission.

“It’s a tremendous leap forward,” said Lia Gore, MD, head of Pediatric Hematology, Oncology and BMT at Children’s Hospital Colorado. “It’s a landmark change in how we will treat disease, in this case cancer.”

Children’s Colorado is one of 30 or so hospitals nationwide approved to administer the Kymriah therapy. Treatment will not be available outside an approved center.

Seek and destroy

Gore is principal investigator in a separate trial of a similar immunotherapy from Kite Pharmaceutical. Like Kymriah, the Kite therapy takes a page from nature’s book to turn the tables on cancer.  Both treatments target a protein called CD19 that ALL cells commonly express. Clinicians harvest T-cells, key building blocks of the body’s immune system, from the patient then send them to a facility where they are genetically modified, grown, and expanded in the lab under special conditions. In effect, the T-cells are retrained to seek, identify and destroy an enemy – in this case the cancer cells marked by CD19.

The manufacturing facility grows the reengineered cells by the millions, then ships them back to hospital clinicians, who infuse them back into the patient in a process similar to a blood transfusion. The cells grow and expand in the patient, and the immune system uses its newly weaponized T-cells to not only fight the cancer but in an encouraging number of cases rid itself of it.

“It works somewhat like a vaccine, in that the body mounts an immune response to the cancer cells,” Gore said.

Promising as it may be, don’t look for immunotherapy clinics to sprout in strip malls. Nor is the treatment, or the body’s response to it, akin to routine vaccination.

“It requires a high level of expertise,” Gore said, including teams to collect the blood cells, equipment to store and ship them, a dedicated lab to generate the cells and return them to clinicians to infuse the reengineered cells, and expertise to manage patients who receive the therapy – which is not without risks of its own.

One serious side effect of the therapy, for example, is cytokine release syndrome, a reaction to the specialized T-cells that can drive dangerously high fevers, low blood pressure, fluid retention, and neurologic problems, Gore said. The reaction is “evidence that the immune system has been activated to try to fight the cancer cells,” she added – a good thing – but it will frequently require intensive care.

Patients who receive the therapy also require extensive follow-up care, noted Kelly Maloney, MD,  program leader for Leukemia/Lymphoma at Children’s Colorado. Maloney manages follow-up care for several patients who participated in the Novartis trial at other hospitals. The follow-up includes monitoring blood counts as well as liver and kidney function, and providing follow-up reports to the trial-site hospitals. Patients also require lifetime immunoglobulin infusion therapy to replace healthy infection-fighting cells that are killed along with cancer cells by the CAR T-cells, Maloney explained.

New hope

While the complexities make for a clinical challenge, the selection of Children’s Hospital Colorado as an approved site for the Kymriah therapy is an exciting prospect for young patients and their families, Maloney said. Kymriah has produced remarkable remission numbers in kids who have frequently relapsed, leaving them with slim hopes of recovery, she said.

“For years and years, we’ve seen kids relapse after their first remissions,” said Maloney, who finished her fellowship training in 1998. These tough cases have required bone marrow transplants and multiple, increased doses of chemotherapy in attempts to turn the tide.

“In the past, with these multiply relapsed patients, there was nothing left for us to offer,” Maloney said. “It’s easier to have glimmers of hope now for families. The therapy is likely to move earlier in therapy in some patients so it’s not going to come with second and third and fourth relapses. It’s going to move up to a targeted, first-relapse therapy.”

Growing Cells
Cells in a biosafety hood in the Verneris Lab. The flasks contain T cells and natural killer cells that have been growing in the laboratory under various conditions for two or three weeks.

“The future is very bright for these patients,” agreed Michael Verneris, MD, program leader of BMT and Cellular Therapy at Children’s Colorado. Verneris was the local principal investigator for the Novartis trial at the University of Minnesota before moving to Colorado late last year.

The 80-plus-percent remission rates for the trial patients are especially notable because their conditions were so grave, Verneris said. “Kids enrolled in this trial had life spans that we measured in weeks and months,” he said.

Home-grown, natural-born killers

The Anschutz Medical Campus is poised to become a bigger player in the burgeoning immunotherapy field, Verneris said. For example, it’s home not only to the researchers and clinicians who will drive new therapies forward but also to the biotechnology facilities capable of growing the massive stocks of blood cells necessary to administer the therapies.

Those players include Children’s Hospital Colorado – and, on the adult side, UCHealth University of Colorado Hospital – the University of Colorado School of Medicine; Clinimmune Labs, a massive blood collection, processing and storage facility owned by CU; and the Gates Center for Regenerative Medicine, which is supported by the CU, UCHealth, and Children’s Hospital Colorado. The center conducts the stem cell research and biomanufacturing that helps to drive the development of immunotherapies and other cell-based approaches to treating disease.

The search for the next-generation of cancer therapies is also underway in Verneris’s lab on the fourth floor of Research Complex 1 North on the CU Anschutz campus. He and his colleagues are working to transform simple skin cells into cancer-fighting warriors. The technology, developed about a decade ago, involves genetically reprogramming the cells to return them to their embryonic state. At this point, these induced pluripotent stem cells (iPSCs), as they’re called, are blank slates awaiting an identity through genetic prodding.

Jessica Lake, MD
Jessica Lake, MD, a pediatric hematology/oncology/bone marrow transplant fellow at CU, counts natural killer cells before an experiment in the Verneris Lab.

Verneris is working to create white blood cells called natural killers (NKs) from iPSCs.  In the body, NK cells live up to their name. Their mission is to seek out and destroy invaders that attack healthy cells. In the lab, Verneris and his team are growing their own NKs from iPSCs and testing their cancer-killing power. The goal: create a potent weapon that can be mass-manufactured and infused in patients – an “off-the-shelf” therapy, as he describes it.

“Companies are charging toward this,” Verneris said. “It’s an incredibly exciting time.”

Wide application – and more questions

For Gore, the immunotherapy approach has great power because it can be broadly applied. Researchers are already looking at using it to fight acute myeloid leukemia, a form more aggressive than ALL, with a lower survival rate, she said. It’s being investigated to treat brain tumors, sarcomas and other cancers. Kymriah focused on CD19 because the protein is common in this type of leukemia, and therefore a good therapeutic target, Gore said, “but there are antigens on the surface of every cell.” Many of them could one day find themselves in the crosshairs of a patient’s newly charged immune system.

For now, however, a central question and challenge from the Novartis trial remains. Why did the Kymriah therapy work much better for some patients than others? It turns out, Verneris said, that in some, the CAR T-cells did not “persist.” That is, they worked well initially in killing the cancer cells, but then diminished in number, allowing cancer cells to reclaim the battlefield.

“The question is, where did they go in the body?” Verneris said. “We want them to stay in the blood.”

For that reason, Kymriah cannot be called a cure for everyone, Gore added. It’s a problem that requires ongoing research. One possible confounding factor, Gore said, is leukemia and other cancer cells’ ability to mutate and develop their own resistance mechanisms to fight off the CAR T-cells.

Because of these uncertainties and the quest for new knowledge about the disease and the people it strikes, clinicians and researchers will monitor Kymriah patients for at least 15 years, Gore said. “We need to evaluate its long-term effects.”

Paying the price

Another uncertainty and source of controversy is the cost of the therapy, pegged at $475,000 to hospitals directly.  This charge does not represent the total cost to patients and insurers for receiving this therapy, Gore said, although Novartis has said the charge will be dropped if it doesn’t work in the first month.

Maloney acknowledged the issue of cost will be a point of contention but emphasized that it plays no role in her clinical decision making.

“My job as a physician is to provide the best therapy for my patients,” she said. “I can’t put the decision on a cost-benefit ratio. All my patients’ lives are precious and they all deserve the best chance of survival.”

A further complication is that some patients will require a bone marrow transplant after CAR-T therapy and some will not, Gore added. The cost of a transplant is roughly $150,000 to $200,000 at the low end, but complications and long-term care can drive that to $1 million and higher, she said. If, on the other hand, a patient doesn’t need a transplant after the CAR-T therapy, “the overall cost [of the therapy] is probably going to be less over a lifetime.”

For Verneris, that points to the need to identify as accurately as possible which CAR T-cell therapy patients will likely also need a transplant.

“We know that some patients have been in remission up to five years with CAR-T. They are probably cured,” he said. But for patients who had shorter remissions, the “door opens to BMT,” he added. “The challenge is figuring out who needs the transplant and who doesn’t.”

These questions don’t dampen the excitement that immunotherapy is generating in the pediatric hematology world at large or, especially, at Children’s Hospital Colorado, Maloney said.

“Having more access [to CAR T-cell therapy] and having a family able to stay local is super-important for the psycho-social part – having people around them who can support them for what can be a tough therapy at times,” she said.

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Program reduces high ED use, increases primary care visits for most vulnerable patients

Researchers at the University of Colorado Anschutz Medical Campus  have found that a community-based program aimed at high users of hospital emergency departments (EDs), reduced ED visits and hospital admissions,  while increasing use of primary care providers.

“Many programs have tried to tackle the problem of high utilizers of hospital emergency departments. These are usually people who are on Medicaid,” said the study’s first author Roberta Capp, MD, an assistant professor of emergency medicine at the University of Colorado School of Medicine. “But this is the first program to show that care coordination actually works.”

The study was published October 2, 2017 in the journal Health Affairs http://bit.ly/2fJUIaq.

Dr. Roberta Capp, assistant professor of emergency medicine, is the first author on the study.
Dr. Roberta Capp, assistant professor of emergency medicine, is the first author on the study.

Capp and her fellow researchers implemented and evaluated Bridges to Care (B2C), an ED-initiated, community-based program. It was one of four sites funded by a Center for Medicare and Medicaid Innovations grant.

The program was led by Rutgers University Center for State Health Policy and developed in collaboration with four Colorado stakeholders including an urban academic hospital, a network of 13 local federally qualified health centers, a mental health clinic and a community advocacy organization.

Researchers compared participants in the B2C program, which focused on Medicaid eligible high ED users, with patients who had received standard care with respect to ED utilization, hospital admission and primary care use.

High ED users were identified as adults who had two or more ED visits or hospital admissions within the last 180 days.

During the six months after B2C enrollment, the participants had 29.7 percent fewer ED visits and 30 percent less hospitalizations. At the same time, they had 123 percent more primary care visits than the control subjects.

“There is a perspective from multiple stakeholders that high users of the ED are difficult patients,” Capp said. “But this study shows that patients use the ED because of there are serious barriers to care.

ED care makes up 5 – 6 percent of all healthcare expenses.

Previous studies have shown that providing care-coordination services and better access to primary care can reduce waste in healthcare spending. A number of programs addressing low-income, high users of EDs have been implemented with mixed results. Most were hospital-based with little community involvement.

But Capp said the B2C intervention is the first aimed at high users of EDs to combine active outreach in the ED with multidisciplinary, community-based services.

It offers intensive medical, behavioral health and social care coordination services. That includes providing a care coordinator, a health coach, a behavioral health specialist, a community health worker and frequent home visits.

Each patient was given a personally tailored, 60-day care plan that included, but was not limited to assistance with getting housing resources, refugee services, access to transportation, help with applying for insurance and disability benefits, setting up primary and specialty care and filling prescriptions.

“We believe that our success stems from bringing together different healthcare systems, breaking down silos between disciplines and focusing on continuity of care in the outpatient setting,” Capp said.

The study shows just how intense the services offered to this population must be to reduce their reliance on EDs. One reason is that they often have chronic diseases, including mental illness.

“We learned that active outreach in the ED is key to ensuring successful high utilizer and enrollment and engagement,” the study said.

For example, early in the study, the team used call back lists and enrolled only 80 patients in seven to eight months, but when a community health worker was embedded in the ED, enrollment over the same period of time tripled.

“For a program like B2C to be effective, behavioral health services must be provided to high utilizers to ensure comprehensive, multidisciplinary care,” Capp said.

She hopes federal lawmakers examining the Affordable Care Act will evaluate the program as a more cost efficient way of providing high quality care to the most vulnerable.

Co-authors of the study from CU Anschutz include Benjamin Honigman, MD, professor of emergency medicine; Jennifer Wiler, MD, associate professor of emergency medicine and Richard Lindrooth, PhD, professor in the department of health systems, management and policy.

 

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CU Researchers win prestigious $2 million NIH grant for Brain study

Researchers from the University of Colorado Anschutz Medical Campus and the University of Colorado Boulder have won a $2 million grant allowing them to refine a unique microscope they have developed while expanding its use to other scientists across the country.

“We will deploy a fiber-coupled, two photon miniature microscope to the laboratories of four users studying neural activity to understand vocal learning, decision making, social interactions and neural development in various species,” said Diego Restrepo, PhD, professor of cell and developmental biology and director of the Center for NeuroScience at the University of Colorado School of Medicine.

This miniature microscope allows researchers to see inside the living brain.
This miniature microscope allows researchers to see inside the living brain.

Restrepo along with Emily Gibson, PhD, assistant professor of bioengineering at CU Anschutz, 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 have collaborated on the development of the microscope and share the grant. CU Anschutz’s Baris Ozbay, PhD, also helped create the microscope.

The $2 million grant, spread over three years, comes from the National Institutes of Health (NIH) and the National Institute of Neurological Disorders and Stroke (NINDS). It is part of the NIH’s new BRAIN initiative aimed at revolutionizing the understanding of the human brain.

It goes to researchers developing innovative technologies that show how individual cells and complex neural circuits interact in both time and space. That knowledge will hopefully lead to cures, treatments and prevention of brain disorders.

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 examine 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.

The microscope, known as the 2P-FCM, uses an electrowetting lens mounted on the head of a live 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.

Gibson said the microscope is unique because it allows deeper brain imaging by using two-photon excitation with longer wavelengths to reduce light scattering in tissue.

“Our 2P-FCM is the only miniature, head-mounted microscope that provides dynamic focus capability in real time to image different brain areas and cells in different layers of the brain to get a more complete picture of neuron interactions,” she said. “This grant will allow us to take our proof-of-concept design that we have demonstrated in my lab and begin to disseminate it for widespread use in the neuroscience community.”

Bright and Gopinath at CU Boulder spearheaded the development of the electrowetting lens.

“My group developed fluid-based, electrowetting tunable optical components for focusing and scanning the laser beam in the microscope,” Bright said.  “I have been working with Juliet Gopinath on the tunable fluid-based optics for eight years. We started working on the microscope concept with Diego Restrepo and Emily Gibson about five to six years ago.”

Gopinath has focused on the design and characterization of the adaptive optical elements that allow for 3-D imaging.

“I think that the technology I develop will actually be used to benefit society and have a direct impact on quality of life,” she said. “I also think this intersection of neuroscience and engineering is wonderful.”

The grant will allow the researchers to incorporate new holographic optogenetic stimulation into the microscope to record and modulate brain activity in awake animals.

It also offers four other scientists the chance to use the microscope to study neural activities in animals besides mice:

  • Richard Mooney, professor of neurobiology at Duke University, will study the neural basis of vocal learning in songbirds.
  • Bijan Pesaran, associate professor of neuroscience at New York University, will examine decision making in non-human primates.
  • Ethan Hughes, assistant professor of cell biology at CU Anschutz, will study the dynamics of myelination. Myelin protects neurons and helps them conduct signals more efficiently.
  • Zoe Donaldson, assistant professor behavioral neuroscience – molecular, cellular and developmental biology at CU Boulder, will investigate the neural basis of social bonding among prairie voles.
From the left: Diego Restrepo, Emily Gibson of CU Anschutz with Juliet Gopinath and Victor Bright of CU Anschutz.
From the left: Diego Restrepo and Emily Gibson of CU Anschutz with Juliet Gopinath and Victor Bright of CU Boulder.

Last year, the team received a $600,000 grant from the National Science Foundation to use the microscope to reconnect neural communication between parts of the brain where it had been severed.

The Denver company 3i (Intelligent Imaging Innovations, Inc.) is working on the commercial release of the microscope.

The Brain Initiative grant number is U01 NS099577.

 

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Despite efforts, barriers to emergency contraceptives remain

Efforts to win greater access to emergency contraceptives (EC) saw some success in 2013 after the U.S. Food and Drug Administration removed age restrictions on over-the-counter sales of the levonogestrel drug Plan B.

But a new study shows those needing EC can still encounter cost and availability barriers.

Laura Borgelt, PharmD, professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences
Laura Borgelt, PharmD, professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences

Researchers at the University of Colorado School of Medicine discovered this when they asked 633 Colorado pharmacies in 2014 about EC access. They found EC completely accessible to just 23 percent of those who use them.

They report their findings in the latest issue of the journal Women’s Health Issues, “Barriers to Single-Dose Levonorgestrel-Only Emergency Contraception Access in Retail Pharmacies.” The study was selected by the editor of Women’s Health Issues as an Editor’s Choice article for the September/October 2017 edition.

Women’s Health Issues is the official journal of the Jacobs Institute of Women’s Health, which is based in the Department of Health Policy and Management at Milken Institute School of Public Health (Milken Institute SPH) at the George Washington University.

Study author Van (Mimi) Chau, a student at CU School of Medicine, under the mentorship of Carol Stamm, MD, along with colleagues that included Laura Borgelt, PharmD,  a professor at the  University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences  used the Little Blue Book 2014, which physicians use for referrals, to identify Colorado pharmacies, and then had three researchers call the pharmacies posing as women seeking levonogestrel-only emergency contraception (LNG-EC). Chau was part of the University’s Leadership, Education, Advocacy and Development (LEADS) track while she worked on the project.

Study says barriers to emergency contraceptives remain
Study says barriers to emergency contraceptives remain

They asked each pharmacy whether they had LNG-EC in stock, whether it was located on the shelf or had to be requested from the pharmacy, whether a generic version was available, how much the product cost, and whether any additional documentation — such as proof of age or a prescription — was required to purchase the drug. The authors defined EC as being “completely accessible” at a pharmacy if the responding employee reported having it available on store shelves that day for purchase without presenting an ID or prescription. Accessibility is important because EC must be taken within 120 hours of intercourse, and research suggests it is most effective within the first 24 hours.

Chau and her colleagues found that 87 percent of pharmacies reported having LNG-EC in stock, but it was only completely accessible at 23 percent of the stores surveyed. Of the stores with the drug in stock, 42 percent reported it was behind the counter — i.e., had to be requested from a pharmacy employee — and 56 percent told callers an ID or prescription was required for purchase. Independent pharmacies were significantly less likely to have EC in stock (58 percent of independent stores vs. 90 percent of chain stores and 100 percent of 24-hour stores) or demonstrate complete access (10 percent vs. 25 percent and 15 percent), the authors report.

Requiring EC purchasers to request the drug from a pharmacy employee and present additional documentation are potentially substantial barriers, the authors note, because people may find it embarrassing to interact with an employee about reproductive healthcare and may lack the requested documents. Adolescents may not have identification or may not meet the age limit pharmacy employees believe to be in place.

When considering why pharmacy employees report outdated policies for documentation and behind-the-counter access, the authors point out that the age cutoff for LNG-EC products changed four times before being lifted completely, and suggest “delays in updating store policies or lag in information dissemination may explain the variability in knowledge among pharmacy staff about FDA regulations and requirements.”

“Although federal policy restrictions on LNG-EC have been removed, this study demonstrates that retail pharmacy-level policies can still create tangible hindrances in obtaining appropriate health care,” Chau and her co-authors write.

The study, “Barriers to Single-Dose Levonorgestrel-Only Emergency Contraception Access in Retail Pharmacies,” has been published in the September/October issue of Women’s Health Issues.

Guest contributor: Contact for this story is Jackie Brinkman.

 

 

 

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