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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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Researchers say climate change may accelerate infectious disease outbreaks

Aside from inflicting devastating natural disasters on often vulnerable communities, climate change can also spur outbreaks of infectious diseases like Zika , malaria and dengue fever, according to a new study by researchers at the University of  Colorado Anschutz Medical Campus.

“Climate change presents complex and wide-reaching threats to human health,” said Cecilia Sorensen, MD, lead author of the study and the Living Closer Foundation Fellow in Climate and Health Policy at CU Anschutz. “It can amplify and unmask ecological and socio-political weaknesses and increase the risk of adverse health outcomes in socially vulnerable regions.”

When natural disasters strike such places, she said, the climatic conditions may make the public health crisis significantly worse.

Dr. Cecilia Sorensen, lead author of the study and the Living Closer Foundation Fellow in Climate and Health Policy at CU Anschutz.
Dr. Cecilia Sorensen, lead author of the study and the Living Closer Foundation Fellow in Climate and Health Policy at CU Anschutz.

The researchers said these vulnerabilities can happen anywhere. After Hurricane Katrina hit New Orleans, cases of West Nile disease doubled the next year. Climate change in Africa appears to be increasing cases of malaria. And the recent destruction in Houston, Florida and Puerto Rico due to hurricanes may usher in more infectious diseases in the years ahead.

The study focused specifically on a magnitude 7.7 earthquake that struck coastal Ecuador in April 2016, coinciding with an exceptionally strong El Niño event. El Niños are associated with heavy rainfall and warmer air temperatures. They are also linked to outbreaks of dengue fever.

Sorensen, a clinical instructor in emergency medicine at CU Anschutz, was in Ecuador with her co-authors working with the Walking Palms Global Initiative. They were operating a mobile health clinic after the disaster.

“We were seeing all of these viral symptoms in the wake of the quake,” she said. “We noticed a huge spike in Zika cases where the earthquake occurred. Prior to this, there were only a handful of Zika cases in the whole country.”

In fact, the researchers found the number of Zika cases had increased 12-fold in the quake zone.

Zika virus is transmitted by mosquitos. Symptoms are usually mild but the infection can cause major abnormalities and even death in a developing fetus.

Warmer temperatures and increased rainfall from the El Niño, along with a devastated infrastructure and an influx of people into larger cities, likely caused the spike in Zika cases, Sorensen said.

Natural disasters like Hurricane Katrina can spur outbreaks of infectious disease.
Natural disasters like Hurricane Katrina can spur outbreaks of infectious disease.

“We saw so many people affected by the earthquake that were sleeping outside without any shelter from mosquitoes, so we were worrying that the region’s changing climate could facilitate the spread of diseases,” she said. “Natural disasters can create a niche for emerging diseases to come out and affect more people.”

Sorensen’s team reviewed the existing research on the link between short-term climate changes and disease transmission. They applied those findings to explain the role of the earthquake and El Niño in the Zika outbreak.

They suggest El Niño created ideal conditions for Zika-carrying mosquitos to breed and make more copies of the Zika virus. The warmer temperatures and increased rainfall from El Niño have previously been associated with a higher likelihood of dengue outbreaks. Warmer temperatures can also accelerate viral replication in mosquitoes and influence mosquitos’ development and breeding habits.

At the same time, the El Niño event brought warmer sea-surface temperatures, which have been shown to correlate with outbreaks of mosquito-transmitted diseases. Estimates from remote sensing data in coastal Ecuador show that sea-surface temperatures were higher than average from 2014-2016.

The team also believes an increase in water scarcity after the earthquake indirectly benefited mosquito development. The quake damaged municipal water systems, forcing people to store water in open containers outside their homes. These served as additional habitats for mosquito larvae.

The new findings could be used by governments to identify and protect vulnerable communities before natural disasters happen, Sorensen said.

“One idea is to develop disease models that can use existing climate models to predict where these vectors will show up due to climate variability,” she said. “Applying these new models to areas that have pre-existing social vulnerabilities could identify susceptible regions, allowing us to direct healthcare resources there ahead of time.”

The study was published October 12 in GeoHealth, a publication of the American Geophysical Union.

The co-authors of the study from CU Anschutz include Emilie Calvello-Hynes, MD, assistant professor of emergency medicine and Jay Lemery, MD, associate professor of emergency medicine and chief of wilderness and environmental medicine.

The other co-authors include: Mercy J. Borbor-Cordova, Faculty of Naval Engineering, Oceanic Sciences and Natural Resources, Escuela Superior Politecnica del Litoral, Guayaquil, Ecuador; Avriel Diaz, Dept. of Evolution, Ecology and Environmental Biology, Columbia University; Anna M. Stewart-Ibarra, Department of Public Health and Preventative Medicine, SUNY Upstate Medical University, Syracuse, NY.

This paper is a collaboration of the University of Colorado Consortium for Climate Change and Health.

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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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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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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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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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