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New arrival bolsters Cardiothoracic Surgery team

The recent addition of Jay Pal, MD, PhD, to the Division of Cardiothoracic Surgery at the University of Colorado School of Medicine both maintains and deepens its expertise in treating heart failure and other serious cardiac problems. It’s also gained a guy who would rather focus on teamwork than individual achievement.

Pal joined the team June 19 after nearly four years with the University of Washington in Seattle, where he honed his skills in heart transplant surgery and implantation of left ventricular assist devices (LVADs) and other mechanical tools that support circulation in heart failure patients. He’s successfully retrieved and transplanted donor organs from remote areas in Alaska, pushing the boundaries of time for safe transplant. He’s developed expertise in less invasive techniques for LVAD surgery. For patients with acute cardiac problems, Pal has worked extensively with methods of short-term circulatory support, such as extracorporeal membrane oxygenation (ECMO).

Joe Cleveland
Pal takes over as surgical director of the Mechanical Circulatory Support Program from Joseph Cleveland, MD, who remains active with the CT team as a surgeon and research leader.

These and other skills strengthen not only the cardiothoracic (CT) surgery team but also the Heart Failure Program at CU and UCHealth University of Colorado Hospital. They also contributed to Pal’s selection as surgical director of CU’s Mechanical Circulatory Support Program. He takes over from Joseph Cleveland, MD, who has headed the program since its inception in 2001.

Don’t expect Pal to focus on these accomplishments when he talks about what motivates him, though.

“As a surgeon, caring for patients with heart failure requires good collaboration with management by my cardiology colleagues,” Pal said. “Physicians tend to work in silos, but heart failure requires multispecialty care by skilled specialists and nurses in the ORs, ICUs and clinics. That reflects my personality. I have something to learn from everyone. It’s foolish to think I can do anything alone.”

New shoes

Pal’s arrival fills a vacancy created about a year and a half ago with the departure of Ashok Babu, MD, for Saint Thomas Heart in Nashville. With last year’s addition of Muhammad Aftab, MD, the CT surgery team is positioned to rebuild its annual LVAD volume to its past peak of 50 or so, Cleveland said. It performed 36 such procedures last year.

Amrut Ambardekar
Cardiac Transplantation Program Director Amrut Ambardekar, MD, welcomes the experience and expertise that Pal brings to CU and University of Colorado Hospital.

“The number of cardiac surgeries we do has been increasing generally,” added Amrut Ambardekar, MD, director of CU’s Cardiac Transplantation Program. “Jay not only fills a void in staffing but will allow us to grow to the next level.”

With Pal taking on the surgical director’s administrative duties, Cleveland will also have more time to pursue his research interests while maintaining his surgical schedule. He’s principal investigator for the clinical trial of the HeartMate 3 LVAD, which in late August received FDA approval as a short-term LVAD for patients awaiting heart transplant. Cleveland said he also plans to increase the CT surgery team’s involvement with CU’s Structural Heart Program, which offers minimally invasive procedures that are increasingly in demand, such as transcatheter aortic valve replacement (TAVR).

Cleveland said he’s confident that he can take on these new challenges, thanks to Pal’s mix of experience in areas both familiar and new to the CU program.

“We wanted someone who is mid-career who can, at the same time, bring outside ideas and help to make us better,” Cleveland said. “Jay also impressed us as thoughtful and collaborative, someone who would be a good colleague.”

Extending ECMO

The ECMO program promises to be another beneficiary. The technique involves providing mechanical circulation support for patients with acute heart and/or lung damage from heart attacks, arrhythmias, or viral infections, for example. The machine boosts circulation and breathing, giving injured organs a chance to rest and heal, sometimes as a bridge to an LVAD or transplant.

“There is an urgent need in Denver and beyond for care for people who get very sick, very quickly,” Pal said. “These patients would otherwise die. With aggressive care, we can salvage their organs and their lives.”

Ambardekar said the number of ECMO cases grew from 40 in fiscal year 2016 (which ended June 30, 2016) to 50 in fiscal year 2017. The program also earned the ELSO Gold Level Award of Excellence for excellence in patient care, training, education and other criteria for measuring and evaluating organizations that use ECMO to treat patients.

Longer reach

Pal also promises to help the Transplant Program extend its reach in retrieving donor hearts for patients on its waiting list. The traditional “upper limit” for bringing a heart from the field to the surgical table is four hours, Pal said. But he and his colleagues at the University of Washington often pushed beyond that boundary, sometimes flying from Seattle to deep into the Alaskan interior or far down the coast to Southern California to get and bring back a lifesaving heart. They regularly kept the organs viable for six hours and more, he said.

One key to the success was a new technique that keeps the donor heart perfused with warm blood during transport. Even more important, Pal said, was donor selection and timing. “It’s important to have healthy young donors,” he noted. “The surgery must also then be expeditious. The distance should be a minor factor in our decision making.”

His experience should help the CU team expand the area it travels for donor organs, Ambardekar said. “We’ve generally not gone more than 1,000 miles, but Jay is used to traveling longer distances,” he said. “For our patients waiting for a transplant, the farther we can go for organs, the better.”

That capability also promises to be important because the United Network for Organ Sharing (UNOS) is preparing to implement changes to its adult heart allocation system. One of them will expand the geographic area available to institutions to procure hearts for its sickest patients.

As Pal put it, “The number of people with heart failure is growing, but the donor population is still relatively fixed. That means our ability to get hearts to those who will benefit the most is paramount.”

Cutting down on cutting open

Meanwhile, Pal also has experience with surgical alternatives to opening the sternum for implantation of LVADs. Instead, surgeons make a much smaller incision in the chest wall. The idea isn’t about saving time – in fact, the procedure is more difficult and takes longer than opening the chest, Pal said. It’s aimed at sparing patients who get LVADs as a bridge to heart transplant a second sternotomy when they receive their new hearts, he said.

Cleveland said he’s done one of the less-invasive procedures, but having it more available as an option for patients is important for the CT surgery team as a whole. “We want to bring in new techniques as we move forward,” he said.

A considerable number of patients at UCH stand to benefit from having the choice. Half of the patients who received heart transplants in 2016 were those who received LVADs as a bridge, Ambardekar noted.

“Ultimately the transplants for those patients could be better, safer, faster and involve less bleeding” if they have a minimally invasive procedure to implant their LVADs, he said.

In touch with outreach

The ultimate goal all these procedures is to help patients live better lives, and that requires educating and staying connected, not only with them, but with their providers. University of Washington is in a bigger and more competitive market than Denver – at least in terms of the availability of tertiary and quaternary care – but like their Denver colleagues, Seattle specialists serve patients from a large swath of thinly populated rural communities in the eastern portion of Washington. Pal is familiar with the importance of reaching out to community cardiologists to help them care for their heart failure patients and keep them close to home as much as possible.

Pal plans to join Cleveland, Ambardekar and others on trips to places like Greeley and Cheyenne, Wyoming to meet with primary care providers and cardiologists. They offer tips on treating heart failure and explain the basics of operating, monitoring and maintaining LVADs. Cleveland said he and his team have also hosted groups of community cardiologists at UCH to observe how patients are selected to receive LVADs and transplants. Community providers with questions can also call in to a 24-hour help line staffed by the hospital’s Mechanical Circulatory Support Program coordinators.

“It’s two-way communication,” Cleveland said. “Patients know we are not here to supplant their community providers. We’re here to help manage complex medical situations.”

“My goal is to help patients not just live longer, but to go back to doing the things they want,” Pal said. “It’s not about our program getting all the patients. It’s about serving as a resource for patients and their providers.”

Still a relative newcomer to the Rocky Mountain region, Pal said he looks forward to skiing, camping and hiking with twin daughters Aliana and Isabella (not quite 3 years old) and wife, Angela. While he points to the similarities between the clinical programs in Washington and Colorado, he’s looking forward to experiencing one difference as autumn in Seattle and Denver approaches.

“The sunshine here is quite nice,” he said.

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Researchers find creosote bush could treat Giardia and brain-eating amoeba infections

Compounds produced by the creosote bush, a desert shrub common to American Southwest, exhibit potent anti-parasitic properties against two deadly parasites responsible for Giardia infections (Giardia lamblia) and the amoeba that causes an often-lethal form of encephalitis (Naegleria fowleri), according to researchers at the Skaggs School of Pharmacy and Pharmaceutical Sciences at CU Anschutz and UC San Diego.

Daniel LaBarbera, PhD, associate professor of drug discovery and medicinal chemistry at Skaggs School of Pharmacy and Pharmaceutical Sciences.
Daniel LaBarbera, PhD, associate professor of drug discovery and medicinal chemistry at Skaggs School of Pharmacy and Pharmaceutical Sciences.

The findings, published online this month in PLOS Neglected Tropical Diseases, may give scientists the chance to widen their arsenal of antimicrobial agents effective against deadly parasitic infections. The current standard treatment for both infections involve antibiotics and anti-parasitic drugs.

The World Health Organization estimates giardiasis, a diarrheal illness, is linked to approximately 846,000 deaths worldwide each year. Infection usually occurs through ingestion of contaminated water or food. Though rarely lethal in the United States, it’s estimated there are more than a million cases of giardiasis in the country annually. Infections due to N. fowleri, sometimes called the `brain eating amoeba,’ are much less common than Giardia.

Compounds from the creosote bush may fight two deadly parasitic infections.
Compounds from the creosote bush may fight two deadly parasitic infections.

“However, it is a far deadlier parasite that is found in warm fresh waters and infects the central nervous systems of their victims through the nasal passages causing lethal brain damage known as primary amoebic meningoencephalitis (PAM),” said principal investigator Dan LaBarbera, PhD, associate professor of drug discovery and medicinal chemistry at the Skaggs School of Pharmacy and Pharmaceutical Sciences at CU Anschutz.

Due to its rapid infection cycle and high mortality rate, the CDC has been given special approval to provide the drug miltefosine to clinicians as a treatment option for N. fowleri infection. But it is still not FDA approved and has limited availability in the U.S. This new compound potentially provides a less expensive, more effective treatment option.

Scientists from CU Anschutz and UC San Diego collaborated as part of the Skaggs Scholars program, which matches investigators from Skaggs-funded schools of pharmacy with complementary expertise to discover potential drug breakthroughs. UC San Diego scientists provided expertise in parasitology, while the CU Skaggs School of Pharmacy provided expertise in natural products, compound libraries and active compounds from plants. The researchers investigated these tropical diseases because of their occurrence in Mexico and South America and found indigenous peoples treating infections with creosote compounds.

“The significance and intrigue about our study is that it shows the value of prospecting for new medicines from plants traditionally used by indigenous people as medicine,” said co-principal investigator Anjan Debnath, Ph.D., an assistant adjunct professor at Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego.

The creosote bush (Larrea tridentata), is a tough evergreen bush with small waxy leaves, yellow flowers and a distinctive turpentine-like scent. Native Americans in both the United States and Mexico have long used the plant for a variety of ailments, including intestinal complaints. There is also an existing body of scientific work documenting the plant’s pharmacologically active compounds, notably nordihydroguaiaretic acid (NDGA). NDGA has antiviral, antibacterial, anti-inflammatory and anticancer properties.  The study is the first to show that NDGA and five other compounds are active against both pathogenic parasites.

In other studies, NDGA has been shown to be a neuroprotective agent. It protects human monocytes and other cells and tissues through its powerful antioxidant activity.

“In our study the creosote natural product, NDGA, proved to be a more potent anti-parasitic agent against N. fowleri compared to miltefosine,” LaBarbera said. “Therefore, NDGA may lead to a more effective drug therapy option for N. fowleri infection.”

This research was funded in part, by a grant from The ALSAM Foundation and National Institutes of Health.

 

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Major communication gaps between doctors and home health care nurses revealed

Researchers at the University of  Colorado Anschutz Medical Campus have found serious gaps in communication between physicians and home health care agencies (HHC) responsible for caring for often elderly patients discharged from hospitals. The problem, the study said, can contribute to hospital readmissions.

The research, published today in the Journal of General Internal Medicine, cites an array of communication challenges between HHC agencies and physicians following hospital discharge.

Dr. Christine Jones, assistant professor of medicine and lead author of the study.
Dr. Christine Jones, MD, MS, assistant professor of medicine and lead author of the study.

The study cited frequent discrepancies in medication lists, confusion over who was responsible to write patient care orders, inaccessible hospital records and resistance from clinicians and staff for accountability.

Led by Christine D. Jones, MD, MS, assistant professor at the University of Colorado School of Medicine, the researchers conducted six focus groups with HHC nurses from six different agencies in Colorado to ask about their general experience with caring for patients after discharge from any of their referring hospitals.

“We found that communication breakdowns can have consequences for patients,” said Jones, lead author of the study. “These are some of our most fragile patients, most are over 65, and more seamless communication is needed.”

Some of the HHC nurses interviewed complained of a lack of accountability, medical errors and difficulty in reaching doctors.

“As a general rule, I’ve been told you’re not to contact the hospitals. I actually got in trouble for contacting the hospital, trying to find out, get more information, trying to track a doctor down,” one nurse said in a focus group.

Another nurse said even if they reach a primary care physician, they often say they didn’t know the patient was in the hospital and they don’t have a report on them.

“The communication between the hospital and the primary care providers is just as bad as it is for us because the PCP’s don’t have the information,” the nurse said.

Dr. Jones said another complicating factor is that insurance often requires doctors to order HHC services. So if a nurse practitioner is providing primary care for a patient, obtaining HHC immediately becomes more difficult.

The researchers found another serious problem when it came to ordering medication. HHC nurses and staff said most of the medication lists they receive are incorrect due to the number of doctors and specialties involved.

“As hospitalists, we need to think about what happens beyond the hospital walls and how we can support our patients after discharge, especially when it comes to home health care patients who can be very vulnerable.” Jones said.

She noted that the study did not focus on any one specific hospital, but hospitals in general.

The study proposes a series of solutions to these problems including the following:

  • Hospitals and primary care physicians could provide HHC agencies direct access to Electronic Medical Records and direct phone lines to doctors.
  • Enact laws allowing nurse practitioners and physician’s assistants to write HHC orders. A bill was under consideration to do this but was not acted upon by Congress.
  • Clearly establishing accountability for hospital clinicians to manage HHC orders until a primary care physician can see a patient and help HHC nurses with questions.
  • Create better communication methods with PCPs to ensure safer transitions

“Our findings suggest that improvements to accountability and communication could address patient needs and goals, avoid medication discrepancies and ultimately improve safety for patients and HHC nurses,” Dr. Jones said.

 

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Immune system may keep body from neutralizing HIV-1 virus

Researchers at the University of  Colorado Anschutz Medical Campus have discovered that a process protecting the body from autoimmune disease appears to prevent it from creating antibodies that can neutralize the HIV-1 virus, a finding that could possibly help lead to a vaccine that stimulates production of these antibodies.

Dr. Raul Torres, professor of immunology and microbiology at CU Anschutz
Raul Torres, PhD, professor of immunology and microbiology at the University of Colorado School of Medicine.

The study, led by Raul M. Torres, PhD, professor of immunology and microbiology at the University of Colorado School of Medicine, was published Tuesday in The Journal of Experimental Medicine.

Torres and his team sought to better understand how the body’s own immune system might be getting in the way of neutralizing the HIV-1 virus.

They knew that some patients infected with HIV-1 developed what are known as ‘broadly neutralizing antibodies,’ or bnAbs, that can protect against a wide variety of HIV-1 strains by recognizing a protein on the surface of the virus called Env. But the patients only develop these antibodies after many years of infection.

Because of shared features found in a number of HIV-1 bnAbs, researchers suspected the inability or delayed ability to make these type of protective antibodies against HIV was due to the immune system suppressing production of the antibodies to prevent the body from creating self-reactive antibodies that could cause autoimmune diseases like systemic lupus erythematosus.

At the same time, patients with lupus showed slower rates of HIV-1 infection. Scientists believe that’s because these autoimmune patients produce self-reactive antibodies that recognize and neutralize HIV-1.

The process by which the body prevents the creation of antibodies that can cause autoimmune disease is known as immunological tolerance.

Torres wanted to break through that tolerance and stimulate the production of antibodies that could neutralize HIV-1.

“We wanted to see if people could make a protective response to HIV-1 without the normal restraint imposed by the immune system to prevent autoimmunity,” Torres said.

The researchers first tested mice with genetic defects that caused lupus-like symptoms. They found that many of them produced antibodies that could neutralize HIV-1 after being injected with alum, a chemical that promotes antibody secretion and is often used in vaccinations.

Next, they treated normal mice with a drug that impairs immunological tolerance and found that they began producing antibodies capable of neutralizing HIV-1. The production of these antibodies was increased by alum injections. And if the mice were also injected with the HIV-1 protein Env, they produced potent broadly neutralizing antibodies capable of neutralizing a range of HIV-1 strains.

In every case, the production of these HIV-neutralizing antibodies correlated with the levels of a self-reactive antibody that recognizes a chromosomal protein called Histone H2A. The researchers confirmed these antibodies could neutralize HIV-1.

“We think this may reflect an example of molecular mimicry where the virus has evolved to mimic or look like a self protein,” Torres said.

Torres suggested that the difficulty in developing a vaccine against HIV-1 may be because of the ability of the virus to camouflage itself as a normal part of the body.

“But breaching peripheral immunological tolerance permits the production of cross-reactive antibodies able to neutralize HIV-1,” Torres said.

Since the research was done on animals, scientists must still determine its relevance for HIV-1 immunity in humans.

“The primary consideration will be determining whether immunological tolerance can be temporarily relaxed without leading to detrimental autoimmune manifestations and as a means to possibly elicit HIV-1 bnAbs with vaccination,” he said.

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National study shows interventions like telephone calls can reduce suicides

In perhaps the largest national suicide intervention trial ever conducted, researchers at the University of  Colorado Anschutz Medical Campus and Brown University found that phone calls to suicidal patients following discharge from Emergency Departments led to a 30 percent reduction in future suicide attempts.

The study was published recently in JAMA Psychiatry.

The year-long trial, which involved 1,376 patients in eight locations nationwide, provided suicidal patients with interventions that included specialized screening, safety planning guidance and follow-up telephone calls.

Dr. Michael Allen, professor of psychiatry and emergency medicine at the Helen and Arthur E. Johnson Depression Center at CU Anschutz, co-authored the study.
Dr. Michael Allen, professor of psychiatry and emergency medicine at the Helen and Arthur E. Johnson Depression Center, co-authored the study.

“People who are suicidal are often disconnected and socially isolated,” said study co-author Dr. Michael Allen, MD, professor of psychiatry and emergency medicine at the Helen and Arthur E. Johnson Depression Center at CU Anschutz. “So any positive contact with the world can make them feel better.”

Allen is also medical director of Rocky Mountain Crisis Partners in Denver which has already implemented a similar program where counselors call suicidal patients following their discharge from Emergency Departments (EDs).

Suicide is the 10th leading cause of death in the U.S. In 2015, there were 44,193 deaths by suicide nationally. Over one million people attempt to take their own life every year.

Colorado routinely ranks among the top 10 states for suicide with about 1,000 deaths a year. Last year, it was number seven in the country. The state Legislature has set a goal of reducing suicides by 20 percent by 2024.

Allen said simply handing a suicidal patient a psychiatric referral when discharged isn’t enough.

“We call them up to seven times to check on them after discharge,” he said. “If they aren’t there we leave a message and call again. For many, this telephone call is all they get.”

The crisis center has worked with 17 of Colorado’s 88 EDs and is hoping to increase that number and eventually go statewide.

“We don’t need more brick and mortar buildings, we can reduce suicide risk by simply calling people on the phone,” Allen said.

Dr. Emmy Betz, associate professor of emergency medicine.
Dr. Emmy Betz, associate professor of emergency medicine.

His colleague and study collaborator Dr. Emmy Betz agreed.

“Telephone follow-up programs offer a great way to help bridge an ED visit to outpatient mental health care and hopefully save lives,” said Betz, an associate professor of emergency medicine at CU Anschutz who has conducted extensive research on suicide. “It would be great to see such programs become more widely implemented. Suicide is a leading cause of death, especially in Colorado, and a shortage of inpatient and outpatient mental health care options make innovative approaches like telephone counseling even more attractive.”

The study was led by Brown University and Butler Hospital psychologist Ivan Miller.

Miller, a professor of psychiatry and human behavior at the Warren Alpert Medical School of Brown University, said he was encouraged that they were able to impact suicide attempts among this population with a relatively limited intervention.

While suicide prevention efforts such as hotlines are well known, published controlled trials of specific interventions are much rarer, Miller said.

“We were happy that we were able to find these results,” he said.

This report was one of several from the Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE) study led by Miller, Professor Edwin Boudreaux of the University of Massachusetts and Dr. Carlos Camargo of Massachusetts General Hospital and Harvard University.

Dr. Betz was the principal investigator for Colorado’s ED-SAFE site.

The trial took place in three phases to create three comparison groups. In the first phase, 497 patients received each ED’s usual treatment as a control group. In phase two universal screening was implemented and 377 patients received additional attention in the ED. In the third phase, 502 patients received the experimental intervention.

Those patients received the same Phase 2 care including additional suicide screening from ED physicians, suicide prevention information from nurses and a personal safety plan they could fill out to prepare for times when they might begin harboring suicidal thoughts again.

Over the next year, they also received periodic phone calls from trained providers at Butler Hospital in Providence, R.I., who would discuss suicide risk factors, personal values and goals, safety and future planning, treatment engagement, and problem solving.

The number of suicide attempts and the proportion of people attempting suicide declined significantly in the intervention group compared to treatment as usual. The middle group, which received only additional screening, did not show a significant drop compared to the treatment as usual group.

“This is a remarkably low cost, low tech intervention that has achieved impressive results,” Dr. Allen said.

 

 

 

 

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Scientists use high tech microscope to find clue to an autoimmune disease

Using a unique microscope capable of illuminating living cell structures in great detail, researchers at the University of  Colorado Anschutz Medical Campus have found clues into how a destructive autoimmune disease works, setting the stage for more discoveries in the future.

The scientists were trying to visualize antibodies that cause neuromyelitis optica (NMO), a rare autoimmune disorder that causes paralysis and blindness. Using a custom STED (Stimulated Emission Depletion) microscope built at CU Anschutz, they were able to actually see clusters of antibodies atop astrocytes, the brain cell target of the autoimmune response in NMO.

Dr. Jeffrey Bennett, MD, PhD, is senior author of the study.
Dr. Jeffrey Bennett, MD, PhD, is senior author of the study.

“We discovered that we could see the natural clustering of antibodies on the surface of target cells. This could potentially correspond with their ability to damage the cells,” said Professor Jeffrey Bennett, MD, PhD, senior author of the study and associate director of Translational Research at the Center for NeuroScience at CU Anschutz. “We know that once antibody binds to the surface of the astrocyte, we are witnessing the first steps in the disease process.”

When that domino effect begins, it’s hard to stop. But Bennett said the ability to see the antibodies on the brain cells offers a chance to develop targeted therapies that do not suppress the body’s immune system like current treatments for the disease do.

“By applying this novel approach we can see firsthand how these antibodies work,” said the study’s lead author, John Soltys, a current student in the Medical Scientist Training Program at CU Anschutz. “We are looking at the initiation of autoimmune injury in this disease.”

The breakthrough was made possible with the STED microscope, a complex instrument that uses lasers to achieve extreme precision and clarity. It was built by physicist Stephanie Meyer, PhD, at CU Anschutz. This is the first time it has been used in a research project here.

“This would have been impossible to see with any kind of normal microscope,” said study co-author Professor Diego Restrepo, PhD, director of the Center for NeuroScience.  “We are inviting other scientists with research projects on campus to use the STED microscope.”

According to Meyer, lower resolution microscopes are blurrier than the STED due to diffraction of light. But the STED’s lasers illuminate a smaller area to acquire a higher resolution image . Unlike electron microscopes, STED users can see entire living cells at super high resolution, as they did in this study.

Restrepo said there are only a handful of STEDs in the nation and just one in Colorado.

The researchers said the discovery is the result of a unique partnership between clinical neurology, immunology and neuroscience coming together to solve a fundamental question of how antibodies can initiate targeted injury in an autoimmune disease.

“These are the building blocks that we can use to carry our research to the next level,” Bennett said.

The study was published this week in Biophysical Journal.

 

 

 

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States can lower risk of measles outbreak by strengthening exemption policies

States with weaker non-medical exemption policies for vaccinations can reduce the likelihood of a measles outbreak 140 to 190 percent by strengthening them, a new study from the University of Colorado Anschutz Medical Campus shows.

Researchers said the magnitude of those outbreaks can also be cut in half by strengthening exemption policies for children.

“In the year 2000 measles was no longer being transmitted in the U.S.,” said the study’s lead author Melanie Whittington, PhD., a health services researcher. “Compare that to 2015 when we had over 150 cases in the first three months. Suddenly measles is an issue again despite having an effective vaccine.”

Jonathan Campbell, associate professor at the CU Skaggs School of Pharmacy and Pharmaceutical Sciences
Jonathan Campbell, associate professor at the CU Skaggs School of Pharmacy and Pharmaceutical Sciences, is senior author of the paper.

Whittington and her colleagues, including the study’s senior author Jonathan Campbell, PhD, associate professor of clinical pharmacy at the CU Skaggs School of Pharmacy and Pharmaceutical Sciences, wanted to find out why.

Using mathematical models, they simulated the magnitude, likelihood and cost of a measles outbreak under different non-medical vaccine exemption policies.

Every state has such policies. Those with “easy” exemption policies typically only require a parent signature on a standardized form. States with “medium” exemption policies require parents to obtain a form from a health department and/or attend an educational session on vaccinations, or write a statement of objection. Finally, states with “difficult” exemption policies require parents to get a standardized form or statement of objection notarized.

The researchers, using data from the Centers for Disease Control and Prevention’s National Immunization Study, found easier non-medical vaccine exemption policies to be associated with a greater risk for outbreaks of vaccine-preventable diseases.

The state they modeled was Colorado, which has one of the lowest vaccination rates for measles. Only 87.4 percent of children between the ages of 19-35 months are covered. And 5 percent of kindergartners report an exemption.

“We modeled an environment where the population had low vaccination coverage and then simulated measles outbreaks under different exemption policies,” said Whittington. “We found that a state like Colorado is 140 to 190 percent more likely to experience an outbreak with an easy exemption policy than if it had a medium or difficult non-medical exemption policy.  The outbreak size can also be reduced nearly by half with stronger policies.”

While the researchers focused on measles, strengthening exemption policies could benefit other vaccine-preventable diseases, such as mumps.

“There is a tradeoff here,” said Campbell, who specializes in pharmaceutical outcomes research. “It’s a trade between freedom and risk. Are we willing to give up a small piece of freedom that nudges us toward vaccination in order to halve the risk of a detrimental outbreak of a preventable disease?  I think Colorado should be willing to make that trade.”

The researchers urged the strengthening of non-medical exemption policies as a way to increase vaccination coverage.

“We are not saying you can’t have non-medical exemptions,” Campbell and Whittington said. “But if we strengthen them, we can improve health and reduce the economic impact of a potential outbreak.”

The study was published online this month in Academic Pediatrics.

The co-authors include Allison Kempe, MD, MPH; Amanda Dempsey, MD, PhD and Rachel Herlihy, MD, MPH.

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Data Science to Patient Value initiative strives to maximize big data

Jean Kutner, MD
Jean Kutner, MD, is one of the leaders of the Data Science to Patient Value initiative

When Jean Kutner, MD, MSPH, provides care for patients, she wishes she could spend more time talking with patients about their health and the care they want to receive—and not spending her time on a computer, trying to sort through volumes of health records.

“That’s probably not a good use of our valuable and limited time together,” said Kutner, a general internist and palliative care specialist, chief medical officer of University of Colorado Hospital and associate dean for clinical affairs at the University of Colorado School of Medicine (SOM).

Despite her occasional frustration, Kutner is not against technology—far from it. She wants to unlock its potential to create effective care personalized for each patient.

Kutner co-leads the Data Science to Patient Value (D2V) initiative, a new multidisciplinary program at the University of Colorado Anschutz Medical Campus. The initiative, supported with a $20 million grant from the SOM’s Transformational Research Funding program, has big ambitions.

“Our work could revolutionize how we think about how health care is provided, the patient experience, and how we make decisions,” Kutner said. “Our goal is to make CU Anschutz a leader in the intersection between data and value and the application of cutting-edge data science to the value equation.”

Personalizing big data

Right now, the volume of clinically relevant data in health records and from other sources can be overwhelming. Initiatives like D2V could fix that and develop technologies that create a new era in health care. Kutner thinks in the future supercomputers will help diagnose and treat patients, and that will lead to real improvements in their health and maximize the doctor-patient relationship.

“This is personalized medicine focused on a patient’s goals and values, and not necessarily on their genome,” Kutner said.

She gives the hypothetical example of a patient just discharged from the hospital. In a few years, a doctor could use an activity tracker like a Fitbit to see if the patient exercises and gets out of the house. The doctor would look for signs the patient is not recovering or has developed other health problems.

Kutner said the clinical team could see the data and reach out to the patient, checking on their status and, if necessary, asking the patient to come in to be evaluated. Before the visit, a supercomputer could analyze the patient’s data and compare it to data collected from tens of millions of other people. The analysis could create a personalized risk profile with suggestions for a custom treatment plan based on proven therapies. At the start of the next appointment, a doctor could see that information in single user-friendly dashboard.

“With all that data already synthesized, I could get the most value out of face-to-face time with a patient and help them make decisions about their treatment,” Kutner said. “That would be my ideal world.”

Physicians would still have important roles, Kutner said. The doctor and patient would use their time together to talk about what problems are arising and focus on their patients’ priorities. They would work together to get back on track.

Value from the patient’s perspective

While D2V is working on technological innovation in fields such as medical informatics, biostatistics and data visualization, Kutner said it also will address the more philosophical question of how to define value. It is not a simple question.

“If I’m a patient, I might define value differently than an insurer or a health care provider,” Kutner said. Patients can have unsatisfactory experiences despite being what doctors might consider success stories.

D2V will address that disconnect by including stakeholders such as patient advocates and experts in public health and the insurance industry. Kutner believes that will keep the project focused on the ultimate goal, which is improving care.

Building technology and a team

D2V started work in 2016 by recruiting experts from across CU Anschutz. Kutner wants to take advantage of CU Anschutz’s collaborative environment and current faculty members, researchers and staff.

“We have unique expertise here. We have outstanding data scientists. We have people who do world-leading work in care decision making and understanding stakeholder perspectives,” Kutner said. “We need to connect them behind a common goal.”

D2V also recruits researchers from around the world, with more people hired each month. Guest speakers from other leading institutions have given seminars to spark ideas.

Eight pilot projects are underway. They include a team trying to improve the databases that track children who have severe asthma attacks. That project’s goal is to test whether risk profiles can help create personalized predictions of when children might suffer attacks.

D2V will fund an additional six pilot projects in 2017 and is accepting project proposals through March 15.

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Even after treatment, brains of anorexia nervosa patients not fully recovered

Even after weeks of treatment and considerable weight gain, the brains of adolescent patients with anorexia nervosa remain altered, putting them at risk for possible relapse, according to researchers at the University of Colorado Anschutz Medical Campus.

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

The study, published last week in the American Journal of Psychiatry, examined 21 female adolescents before and after treatment for anorexia and found that their brains still had an elevated reward system compared to 21 participants without the eating disorder.

“That means they are not cured,” said Guido Frank, MD, senior author of the study and associate professor of psychiatry and neuroscience at the University of Colorado School of Medicine. “This disease fundamentally changes the brain response to stimuli in our environment. The brain has to normalize and that takes time.”

Brain scans of anorexia nervosa patients have implicated central reward circuits that govern appetite and food intake in the disease. This study showed that the reward system was elevated when the patients were underweight and remained so once weight was restored.

The neurotransmitter dopamine might be the key, researchers said.

Dopamine mediates reward learning and is suspected of playing a major role in the pathology of anorexia nervosa. Animal studies have shown that food restriction or weight loss enhances dopamine response to rewards.

With that in mind, Frank, an expert in eating disorders, and his colleagues wanted to see if this heightened brain activity would normalize once the patient regained weight.

Study participants, adolescent girls who were between 15 and 16 years old, underwent a series of reward-learning taste tests while their brains were being scanned.

The results showed that reward responses were higher in adolescents with anorexia nervosa than in those without it. This normalized somewhat after weight gain but still remained elevated.

At the same time, the study showed that those with anorexia had widespread changes to parts of the brain like the insula, which processes taste along with a number of other functions including body self-awareness.

The more severely altered the brain was, the harder it was to treat the illness, or in other words, the more severely altered the brain, the more difficult it was for the patients to gain weight in treatment.

“Generalized sensitization of brain reward responsiveness may last long into recovery,” the study said. “Whether individuals with anorexia nervosa have a genetic predisposition for such sensitization requires further study.”

Frank said more studies are also needed to determine if the continued elevated brain response is due to a heightened dopamine reaction to starvation and whether it signals a severe form of anorexia among adolescents that is more resistant to treatment.

In either case, Frank said the biological markers discovered here could be used to help determine the likelihood of treatment success. They could also point the way toward using drugs that target the dopamine reward system.

“Anorexia nervosa is hard to treat. It is the third most common chronic illness among teenage girls with a mortality rate 12 times higher than the death rate for all causes of death for females 15-24 years old,” Frank said. “But with studies like this we are learning more and more about what is actually happening in the brain. And if we understand the system, we can develop better strategies to treat the disease.”

The study co-authors include Marisa DeGuzman, BA, BS, Megan Shott, BS, Tony Yang, MD, PhD and Justin Riederer, BS.

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Common antioxidant may guard against development of liver disease

A common antioxidant found in human breast milk and foods like kiwi fruit can protect against nonalcoholic fatty liver disease (NAFLD) in the offspring of obese mice, according to researchers at the  University of Colorado Anschutz Medical Campus.

“Pyrroloquinoline quinone, or PQQ, is a natural antioxidant found in soil and many foods and enriched in human breast milk,” said the study’s lead author Karen Jonscher, PhD, an associate professor of anesthesiology and a physicist at CU Anschutz. “When given to obese mouse mothers during pregnancy and lactation, we found it protected their offspring from developing symptoms of liver fat and damage that leads to NAFLD in early adulthood.”

Dr. Karen Jonscher
Karen Jonscher, PhD, associate professor of anesthesiology and a physicist at CU Anschutz.

The study, published online last week in the Journal of the Federation of American Societies for Experimental Biology, is the first to demonstrate that PQQ can protect offspring of obese mothers from acceleration of obesity-induced liver disease.

NAFLD is the most common liver disease in the world, affecting 20-30 percent of all adults in the U.S. and over 60 percent of those who are obese. It heightens the risk of cardiovascular disease, type 2 diabetes and liver cancer.

Scientists have found that mice fed a high fat, Western-style diet give birth to offspring with a higher chance of getting the disease.

“We know that infants born to mothers with obesity have a greater chance of developing NAFLD over their lifetime, and in fact one-third of obese children under 18 may have undiagnosed fatty liver disease that, when discovered, is more likely to be advanced at the time of diagnosis,” Jonscher said. “The goal of our study, which we carried out using a mouse model of obese pregnancy, was to determine whether a novel antioxidant given to mothers during pregnancy and breastfeeding could prevent the development of NAFLD in the offspring.”

Jonscher and her colleagues fed adult mice healthy diets or Western-style diets heavy on fat, sugar and cholesterol. They gave a subset of both groups PQQ in their drinking water.

Their offspring were kept on the diets for 20 weeks. Those fed a Western diet gained more weight than those on a healthy diet. PQQ did not change the weight gain but it did reduce the fat in the livers, even before the mice were born. The antioxidant also reduced inflammation in the livers of mice fed the Western diet. The researchers found that PQQ protected adult mice from fatty liver, even when it  was stopped after three weeks when the mice quit breastfeeding.

Jonscher believes the antioxidant may work by impacting pathways critical to the early onset of diseases associated with maternal obesity, high fat diets and inflammation.

PQQ is found in human breast milk, soy, parsley, celery, kiwi and papaya. It’s also found in soil and interstellar dust. Jonscher said it could possibly be used as a prenatal or lactation supplement to protect children of obese mothers from developing liver and cardiovascular disease in adulthood, but cautioned that pregnant women should always consult their doctor before taking any supplement.

“Perhaps supplementing the diet of obese pregnant mothers with PQQ, which has proven safe in several human studies, will be a therapeutic target worthy of more study in the battle to reduce the risk of NAFLD in babies,” Jonscher said.

 

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