Using advanced imaging techniques, researchers at the University of Colorado Anschutz Medical Campus have mapped a previously uncharted region of the human genome that gives rise to a variety of disease, setting the stage to potentially test for the conditions in the future.
The study, published Sept. 3 in the journal Genome Research, was conducted by scientists at CU Anschutz led by Tamim Shaikh, PhD, the University of California San Francisco (UCSF) led by Pui-Yan Kwok MD, PhD and KU Leuven in Belgium led by Joris Vermeesch, PhD.
The research upends the view of many that the human genome was fully mapped in 2001 with the completion of the Human Genome Project.
“We have realized over time that this is not entirely true, as there are numerous gaps that remain in the reference human genome sequence,” said Shaikh, one of the senior authors of the study. Shaikh is a professor of pediatrics in the section of Genetics and Metabolism at University of Colorado School of Medicine. “These gaps are present in regions that are unmappable and often `invisible’ to past and most current sequencing technologies.”
The researchers focused on a region on Chromosome 22, known as 22q11. There were numerous gaps in the sequence of this chromosome due to unmappable genetic sequences known as low copy repeats or LCRs.
LCRs are a significant source of genetic instability and can break chromosomes. That leads to a loss or gain of large pieces of DNA which can cause serious diseases. The loss of DNA in 22q11 leads to the 22q11 deletion syndrome resulting in symptoms which may include intellectual disability, dysmorphic features, heart defects, seizures, Autism spectrum disorders and schizophrenia.
Using two state-of-the-art genome mapping technologies known as fiber FISH and Bionano optical mapping, the researchers were able to see long DNA molecules and discover an unprecedented and extreme level of variability between individuals and populations. These differences can be hundreds of thousands to over two million base pairs of DNA.
“The large differences between people cannot be assessed without the mapping technologies deployed in this study,” said Dr. Pui-Yan Kwok, Henry Bachrach Distinguished Professor at UCSF, a collaborator of Dr. Shaikh who co-authored the paper. “Our approach brings clarity to the organization of the highly complex region studied.”
“You are mapping these chromosomal fragments back to the genome to see what is different,” Shaikh said. “We looked at over 150 apparently healthy people. We found the region in question was drastically different in each person.”
Some people carried far less and some far more DNA in this part of the genome.
Children with the 22q11 deletion syndrome and their parents were also tested to determine if their 22q11 LCRs were different.
“Now we can start asking questions like, `Is someone with more or less DNA more disposed to have a child with disease?’” Shaikh asked. “If so, then it might be possible to genetically test parents before they have children.”
Shaikh said this region of the genome is constantly evolving.
“If you look from one generation to the next you may see changes within the same family,” he said. “That is pretty incredible.”
The study was funded multiple sources including a grant from the National Institutes of Health to Shaikh and Kwok.
In contrast to the science fiction portrayal of evil computers plotting to overthrow humankind, artificial intelligence (AI) in fact seems poised to help improve human health in a multitude of ways, including flagging suspicious moles for dermatologist follow-up, monitoring blood volume in military field personnel and tracking flu outbreaks via Twitter.
The Colorado Clinical and Translational Science Institute (CCTSI) recently held the 7th annual CU-CSU Summit on the topic of “AI and Machine Learning in Biomedical Research”, with over 150 researchers, clinicians and student attendees from all three CU campuses and CSU.
Ronald Sokol, MD, CCTSI director, said, “The purpose of the CCTSI is to accelerate and catalyze translating discoveries into better patient care and population health by bringing together expertise from all our partners.” Rather than individual campuses operating in silos, the annual Summit brings together clinicians, basic and clinical researchers, post-doctoral fellows, mathematicians and others to highlight ongoing research excellence, establish collaborations and increase interconnectivity of the four campuses.
This year’s conference on AI hit capacity for registration, including attendance by more mathematicians and with more poster submissions than the preceding six events. “The topic of AI in research is everywhere. No one knows exactly what is going to happen,” Sokol said, referencing the many privacy and ethics concerns about AI use in research. “I’m here to learn too – I’m not sure I understand it all.”
Living up to the ‘hype’
Lawrence Hunter, director of the Computational Bioscience program at CU Anschutz, framed AI as having the potential to change the way people practice medicine. “There’s a lot of hype, so we need to be careful how we talk about it,” Hunter said.
What, specifically, is AI doing for biomedical research in Colorado? Michael Paul, PhD, assistant professor of Information Science from CU Boulder, uses social monitoring through sites like Twitter and Google to track and predict public health, including yearly flu rates and Zika virus outbreaks. The Centers for Disease Control (CDC) is typically considered the gold standard for public health information, but Paul points out that CDC data is always at least two weeks behind. In contrast, Google Trends provides a daily population snapshot: as a fictional example, ‘1 million people in Colorado searched for ‘flu symptoms on September 15, 2019’.
Social media sources like Twitter can be mined for tweets containing terms like ‘flu’ within a specific geographic area or demographic group of interest. Using Twitter, researchers can distinguish between “I have the flu” vs. “I hope I don’t get the flu”, whereas Google data cannot make this distinction.
Steve Moulton, MD, trauma surgeon, director of Trauma and Burn Services at Children’s Hospital Colorado and CU School of Medicine and co-founder of Flashback Technologies, Inc, used a machine learning system originally designed to help robots navigate unfamiliar terrain in outdoor, unstructured environments to create a new patented handheld medical device called the CipherOx, which was granted FDA clearance in 2018.
The CipherOx, developed in partnership with the Defense Advanced Research Projects Agency (DARPA) from the United States Department of Defense, monitors heart rate and oxygen saturation and estimates blood volume through a new AI-calculated number called the compensatory reserve index (CRI), which indicates how close a patient is to going into shock due to blood loss or dehydration. While designed to be used in military field operations, the CipherOx can also be used to monitor patients en route to the hospital and postpartum women. Of note, Moulton’s pilot studies were funded by the CCTSI.
AI use in machine learning can be broken into three broad categories: supervised, unsupervised and reinforcement learning. In supervised learning, AI systems learn by being trained to make decisions. For example, in 2016 Google developed an AI-based tool to help ophthalmologists identify patients at risk for a diabetes complication known as diabetic retinopathy that can result in blindness. The Google algorithm learned from a set of images diagnosed by board-certified ophthalmologists and built a set of criteria for making yes vs. no decisions.
In unsupervised learning, AI relies on probabilities to evaluate complex datasets; predictive text on your cellphone is an example of this. In biomedical research, an example of unsupervised learning is using AI to analyze drug labels to find common safety concerns among drugs that treat similar conditions.
Finally, reinforcement learning, like Google’s AlphaZero, the world’s best machine chess player, allows AI to try a lot of options to maximize reward while minimizing a penalty. In reinforcement learning, an AI program can fully explore a hypothetical space without causing trouble. Reinforcement learning in biomedical research can be useful when AI is given a narrow range of choices, for example, predicting best patient response within a narrow range of possible drug doses.
Human mistakes vs. AI mistakes
According to Lawrence Hunter from CU Anschutz, a major problem with AI in healthcare is not proving how good AI is, but paying attention to where it fails. “With 92% correct AI, that gives us confidence that the system is accurate, but we have to be really careful about the other 8% because the kinds of errors AI makes are different (and can be more severe) than the kinds of errors humans make,” he said.
Matt DeCamp, associate professor with the Center for Bioethics and Humanities from CU Anschutz, gave an example of this phenomenon: when AI was used to classify pictures, a picture of a dragonfly was alternatively identified as a skunk, sea lion, banana and mitten. “Some mistakes are easily detected (dragonfly doesn’t equal sea lion),” DeCamp said, “but other mistakes closer to the realm of reasonable may challenge how risks are evaluated by Institutional Review Boards (IRB),” the panels of scientists and clinicians responsible for evaluating patient risks in clinical trials.
THE AI LANDSCAPE
Matt DeCamp, associate professor with the Center for Bioethics and Humanities from CU Anschutz, framed the AI landscape:
Up to $6 billion anticipated for AI investment into biomedical research by 2021
At least 14 recent AI-related FDA approvals in past two years, mostly in imaging, ophthalmology and pathology
55 active or pending clinical trials using the term “deep learning”
141 startup biotech companies using AI
Insurance companies actively using AI to review records and optimize care for chronic conditions
In examples like Google’s system for helping ophthalmologists catch patients at risk of blindness, AI has been heralded as increasing patient access, particularly in rural areas and for patients with limited mobility, and decreasing costs for providers and hospitals. While potential for using AI to improve human health is high, DeCamp echoed Hunter’s comments and cautioned against automatic acceptance of AI superiority. “It’s possible that an AI system could be better on average, but remember that being better on average can obscure systematic biases for different subpopulations. And that is an issue of justice.”
Challenges and concerns
Some issues relative to AI use in biomedical research involve patient privacy. For example, a lawsuit made headlines this summer when a patient at the University of Chicago claimed that his privacy was violated in breach of contract and consumer protection law as a result of data sharing between the university and Google. Michael Paul from CU Boulder said that recent studies regarding use of recreational drug brings up obvious concerns about how to balance public health research with privacy, since Twitter exists in a public space.
Truly informed consent is also an ethical concern, given the ‘black box’ nature of AI algorithms. DeCamp from CU Anschutz clarified, “Black box, meaning that the algorithmic workings are not only unknown, but may be in principle unknowable.”
Just because we can, should we?
Matt DeCamp said that as an ethicist, AI raises big questions. “What is an appropriate use of AI in the first place? Just because we can, does that mean we should? For example, there’s interest in developing robot caregivers. Should we? Would computer-generated poetry be ‘real’ poetry?” Patients may fear further de-personalization of health care in a system that can already seem impersonal at times.
Long-lasting effects of AI are even more uncertain. Will AI change the way we think or act toward each other? DeCamp highlighted research from sociologist Sherry Turkle, PhD, from the Massachusetts Institute of Technology that validates this possibility. In summary of Turkle’s research, DeCamp said, “Computers don’t just change what we do, but also what we think.”
Guest contributor: Shawna Matthews, a CU Anschutz postdoc
Getting ready to catch a morning flight to Chicago in February 2018, Emily Daniels felt a strange tightness in her chest. She noticed a shortness of breath. Taking her mother’s advice, she called her obstetrician who said she should go to the ER.
She remembers thinking, “Emergency room … is that really necessary?” Nonetheless, Emily went to an ER near her home in Lakewood and re-booked for a 5 p.m. flight, thinking she’d still make her business trip. After an initial test, doctors advised a CT scan, which revealed two blood clots in Emily’s lungs and a mass in the bottom of her right lung.
“Cancer didn’t even register in my mind,” she said. “What could that (mass) be? I’m young, healthy, no history of disease, never smoked.”
The doctor said it could be lymphoma, a virus or lung cancer and said she should remain in the hospital. Adding to the urgency: Emily was 33 weeks pregnant with her second child.
‘Fight for our kids’
A subsequent biopsy confirmed the mass was cancerous and additional scans showed cancer in Emily’s bones and right adrenal gland. Stage IV lung cancer.
“Initially, it was shocking, devastating,” she said. “But we (along with her husband Brian) also knew we couldn’t wallow in our sadness. We had a 3 ½-year-old girl (Paige) and a baby on the way, so we were going to fight for our kids.”
Emily stayed in the hospital and delivered her baby, Brady, but her diagnosis precluded the new-mother things, like nursing and a quick release from the hospital, she enjoyed with Paige. What should have been a celebratory time felt overshadowed by a startling and grim diagnosis.
She remembers the trip home from the hospital with Brian – Paige was at home with Emily’s parents – where “we pulled over on the side of the road and broke down.”
Pivotal decision for personalized care
Brian Daniels, a former football standout at the University of Colorado, consulted a handful orthopedic doctors he knew from his playing days. Their advice: Get an appointment with Ross Camidge, MD, PhD, professor and director of thoracic oncology, at the CU Anschutz Medical Campus. “He’s one of the best in the world with this targeted therapy,” Emily said. “It was a no-brainer … this is where I needed to do my treatment.”
The decision has proven to be pivotal, as Camidge, in collaboration with Robert Doebele, MD, PhD, associate professor of medicine, CU School of Medicine, eventually devised a completely novel and personalized treatment that has, for more than eight months, stopped the spread of Emily’s cancer.
However, before making this major discovery, which will be presented at next week’s World Conference on Lung Cancer in Barcelona, Emily’s medical team worked through their clinical bag of tricks in a very short time. In the ensuing battle, it was readily apparent that Emily’s cancer did not play by the normal rules.
In basic terms, the cancer battle comes down to exposure and attack: identifying the genetic pathways that enable cancer to grow, and developing therapies that inhibit those pathways.
BREAKTHROUGH ON WORLD STAGE
Camidge and Doebele are co-authors on the report about the living-cell line that gave doctors insight into Emily Daniels’ cancer and resulted in her novel, personalized treatment regimen that will be presented at the World Conference on Lung Cancer in early September.
Soon after Emily was first seen in the lung cancer multi-disciplinary clinic at the CU Cancer Center Camidge quickly discovered that she had ALK-positive non-small cell lung cancer. Over a decade ago, Camidge was on the clinical-trial forefront that developed the first treatment for lung cancers driven by acquired changes in the anaplastic lymphoma kinase (ALK) gene, causing the cells to grow abnormally fast and aggressively.
A few years later, the initial drug was replaced by more effective ones; Camidge co-led an international trial in 2017 that established alectinib as the initial go-to therapy for this sub-type of lung cancer.
In late-February 2018, Emily started on alectinib and initially responded well to the four pills taken in the morning and four more in the evening. But in just a couple months, her cancer was progressing again.
Another biopsy, tested with the CU Colorado Molecular Correlates Laboratory’s cutting-edge assays, did not show any identifiable reason for the cancer’s resistance. Camidge tried another ALK inhibitor, brigatinib – a drug he also helped develop and one that showed great promise for longer-duration disease control.
However, within a month, Emily’s cancer was progressing again.
Living cells are key to breakthrough
In June 2018, the addition of a specific chemotherapy regimen, identified by Camidge in 2011 as being particularly effective in ALK-positive lung cancer, helped stop her cancer – but only for 3 ½ months. The team then applied another CU-developed treatment strategy: weeding the garden – or radiotherapy treatment of “oligo-progression” as Camidge’s team coined it – whereby they kept Emily on her drug treatments while treating individual spots of cancer with highly focused radiation.
However, nothing completely slowed the cancer. “My colleague Dr. Bob Doebele had this idea that not everything driving resistance in a cancer cell can be found just by looking with the already-established tests,” Camidge said.
Doebele knew there were only a certain number of interrogations that could be done on the kind of preserved pieces of tissue from biopsies like the one sent to the Colorado Molecular Correlates lab. So when the biopsy of Emily’s cancer was taken, as part of a CU research protocol, some of her cancer was sent directly to Doebele’s lab to see if live cancer cells could be grown from it.
“When Bob grows it and it’s living, he can poke it and see which signaling pathways go up and down,” Camidge said. “He was able to deduce that Emily’s cancer had become dependent on another signaling pathway, separate from the ALK side of things.”
That pathway is called MET, and it essentially acts as a second driver of Emily’s cancer.
‘Responded like a dream’
Importantly, all of the known ways of activating MET, the methods doctors test for it in preserved cancer tissue, showed normal results. The key difference were the living cells.
“Entirely because Dr. Doebele was able to grow the cells in a lab, we were able to say for the first time to a patient, ‘Look, your cancer cells have tons of MET signaling going on,’” Camidge said. “In the living cell lines, if we put on a MET inhibitor as well as an ALK inhibitor, they get really unhappy.
“Emily is technically the only patient I know of that has this exact mechanism resistance,” he said.
‘I just have to have hope and believe that the doctors are going to keep coming up with new things.’ – Emily Daniels
Based on Doebele’s data, which will be highlighted at the Barcelona conference, Camidge added crizotinib, a licensed drug designed for other purposes but which can function as a MET inhibitor, to Emily’s treatment.
What has been her response to this targeted-therapy regimen — one that’s been applied to a handful of patients, if that, in the world? Emily started the regimen last December and “she has responded like a dream,” Camidge said.
Emily, 33, is enjoying every day with her children, watching Paige head off to kindergarten and hearing Brady utter his first words. In August, she and Brian took a long-planned trip to the French Alps and coastal Italy. Every chance Emily gets, she logs a several-mile run, does yoga or lifts weights.
She has also become an advocate for other people battling the disease. She and Brian organized a golf tournament – Links for Lungs – which tees off again on Sept. 11. Last year’s debut tournament raised over $130,000 for the Lung Cancer of Colorado Fund.
“It’s important for me to be an advocate for research and be the face of lung cancer,” she said. “This can happen to anyone – it’s not just smokers and older people.”
‘Truly cutting edge’
Emily said she need not look beyond the CU Anschutz Medical Campus and UCHealth University Hospital for her care. “The research is truly cutting edge,” she said. “They’re doing things at the hospital that they’re not doing at other places. The research that Dr. Doebele and Dr. Camidge are doing truly saved my life and gives me unique treatment options.”
‘Here we are at the cutting edge again. Our whole team lives there and we’re comfortable with it.’ – Dr. Ross Camidge
Camidge is impressed by the way Emily has turned her disease into a positive as she reaches out to other lung cancer patients. “Even though she’s hit many bumps in the road, her attitude is kind of like, ‘Yeah, it’s just another one,’” he said. “So she’s actually much more inspiring to them – not necessarily because things have gone well, but because she’s dug in there… It’s like, she can really say to other lung cancer patients, ‘We’ve been through it, and I know what you’re going through.’”
Emily knows she’ll never be completely cancer free; she has to stay on treatment to control the disease. The important thing is to keep moving forward. “I just have to have hope and believe that the doctors are going to keep coming up with new things,” she said. “I want see Paige go to kindergarten, and Brady grow up and play football and do all the things a parent wants to do with their kids.”
Camidge said all indications show that the combination therapy is working in Emily’s case, but they must remain vigilant.
The next move is to develop a clinical trial with a MET inhibitor that is better at getting into the brain than crizotinib. “The brain is known to be a problem area for crizotinib to reach,” he said. “So we are not waiting to react; we are working on developing the next generation of MET-ALK combinations for Emily and anyone else who needs them.”
The research into cancer’s vulnerabilities, to ideally overcome the disease, grows ever stronger, thanks to the fundraising efforts of people like the Daniels and the novel clinical trials taking place at academic medical centers such as CU Anschutz.
“Here we are at the cutting edge again,” Camidge said. “But that’s OK. Our whole team lives there and we’re comfortable with it.”
“We already knew that intense light can protect against heart attacks, but now we have found the mechanism behind it,” said the study’s senior author Tobias Eckle, MD, PhD, professor of anesthesiology at the University of Colorado School of Medicine.
The study was published today in the journal Cell Reports.
The scientists discovered that housing mice under intense light conditions for one week `robustly enhances cardio protection’, which resulted in a dramatic reduction of cardiac tissue damage after a heart attack. They also found that humans could potentially benefit from a similar light exposure strategy.
In an effort to find out why, they developed a strategy to protect the heart using intense light to target and manipulate the function of the PER2 gene which is expressed in a circadian pattern in the part of the brain that controls circadian rhythms.
By amplifying this gene through light, they found that it protected cardiovascular tissues against low oxygen conditions like myocardial ischemia, caused by reduced oxygen flow to the heart.
They also discovered that the light increased cardiac adenosine, a chemical that plays a role in blood flow regulation.
Mice that were blind, however, enjoyed no cardio protection indicating a need for visual light perception.
Next, they investigated whether intense light had similar effects on healthy human volunteers. The subjects were exposed to 30 minutes of intense light measured in lumens. In this case, volunteers were exposed to 10,000 LUX, or lumens, on five consecutive days. Researchers also did serial blood draws.
The light therapy increased PER2 levels as it did in mice. Plasma triglycerides, a surrogate for insulin sensitivity and carbohydrate metabolism, significantly decreased. Overall, the therapy improved metabolism.
Eckle has long known that light plays a critical role in cardiovascular health and regulating biological processes. He pointed out that past studies have shown an increase in myocardial infarctions during darker winter months in all U.S. states, including sunnier places like Arizona, Hawaii and California. The duration of the light isn’t as important as the intensity, he said.
“The most dramatic event in the history of earth was the arrival of sunlight,” Eckle said. “Sunlight caused the great oxygen event. With sunlight, trillions of algae could now make oxygen, transforming the entire planet.”
Eckle said the study shows, on a molecular level, that intensive light therapy offers a promising strategy in treating or preventing low oxygen conditions like myocardial ischemia.
He said if the therapy is given before high risk cardiac and non-cardiac surgery it could offer protection against injury to the heart muscle which can be fatal.
“Giving patients light therapy for a week before surgery could increase cardio protection,” he said. “Drugs could also be developed that offer similar protections based on these findings. However, future studies in humans will be necessary to understand the impact of intense light therapy and its potential for cardio protection.”
AURORA, Colo. (July 30, 2019) – A pair of new journal articles by researchers at the University of Colorado School of Medicine indicate that both genetic and environmental factors play significant roles in the onset of vitiligo, an autoimmune disease that results in the loss of color in blotches of skin.
The findings also show that while the tools for scientific understanding of the genetic basis of a complex disease like vitiligo have advanced, there are still many other as-yet-unidentified factors that contribute to vitiligo’s onset.
Spritz and his co-authors reviewed two types of vitiligo cases – simplex and multiplex. In most instances, vitiligo appears in individuals with no family history of the disease, which are referred to as the simplex cases. In the multiplex cases, there are other family members with vitiligo.
“The paper could be called a first chapter to the ‘vitiligo instruction manual,’” Spritz said. “We found that the vitiligo genetic risk score is higher in the multiplex families than in the simplex cases, and the more affected relatives in the family the higher the risk score. That means that vitiligo in multiplex families and simplex cases is basically the same, but that the families with multiple affected relatives have higher genetic risk. That means that the same treatments probably will be effective in both types of cases.”
That finding complicates the ability of scientists and physicians who want to predict who might be affected by vitiligo. Simplex cases and multiplex cases seem to mostly involve the same underlying genetic variants, with different patients just having different combinations of genetic risk variants. Such a finding complicates the use of predictive personalized medicine to diagnose and treat complex diseases, Spritz said, because there doesn’t appear to be genetically-defined patient subgroups with different underlying biology who might thus respond differentially to personalized treatments.
In addition to Spritz, the authors of the article are Genevieve H.L. Roberts, a PhD candidate in human medical genetics and genomics at CU Anschutz Medical Campus at the time of writing the article; Subrata Paul, a PhD candidate in statistics at CU Denver; Daniel Yorgov, PhD, assistant professor of applied statistics at Purdue University Fort Wayne; and Stephanie Santorico, PhD, professor and director of statistical programs at the Colorado School of Public Health.
“Vitiligo converted from being principally a pediatric-onset to principally an adult-onset disease over the period 1970-2004,” Spritz said. “That is amazing. Our genes haven’t changed over that period of time; altered genes or even gene effects don’t seem to be the cause. This must reflect some beneficial environmental change that somehow delays or reduces vitiligo triggering in people who are genetically susceptible. What was it? We don’t know.”
The authors write that one or more environmental changes seem to have altered triggering of vitiligo and delayed disease onset, with a similar pattern both in North America and in Europe. “While this apparently beneficial change provides an extraordinary inroad to discover vitiligo environmental triggers, the number of potential candidates is enormous,” Spritz and his colleagues write.
Among just a few of the possibilities in the United States: The Clean Air Acts of 1963 and 1970, the Nuclear Test Ban Treaty of 1963, the Water Quality Act of 1969, the establishment of the Occupational Safety and Health Administration in 1970. Globally, sunscreens with sun protection factor ratings were introduced in 1974. Even eating habits may contribute. The authors note that yogurt consumption became more common in the early 1970s, which potentially altered the gut microbiome for many people.
In addition to Spritz, the authors of the letter in Journal of Investigative Dermatology, are Ying Jin, MD, PhD, senior instructor of pediatrics, and Stephanie Santorico, PhD, professor and director of statistical programs at the Colorado School of Public Health.
Guest contributor: Mark Couch, School of Medicine.
AURORA, Colo. (July 24, 2019) – Physicians in the United States may prescribe opioids more frequently to patients during hospitalization and at discharge when compared to their physician peers in other countries, according to a recently published study led by researchers from the University of Colorado School of Medicine.
The study reviewed prescribing practices at 11 academic hospitals in eight countries – the United States, Canada, Spain, Italy, Taiwan, South Korea, the United Kingdom, and New Zealand. The four hospitals in the United States were the University of Colorado Hospital, Denver Health, Hennepin Healthcare in Minneapolis, and Legacy Health in Portland, Oregon.
“Compared with patients hospitalized in other countries, a greater percentage of those hospitalized in the US were prescribed opioid analgesics both during hospitalization and at the time of discharge, even after adjustment for pain severity as well as several other factors like how ill the patients were,” wrote the authors of the article that was published online today in the Journal of Hospital Medicine.
The first author of the article is Marisha Burden, MD, associate professor of medicine at the CU School of Medicine and head of the Division of Hospital Medicine.
The study is important because the epidemic misuse of opioid medications has led to addiction and premature death in many communities across the country.
For the newly published study, the researchers approached 1,309 eligible patients and 981 of them consented to the study. Five hundred three were in the United States and 478 were from other countries. Seventy-nine percent of the patients in U.S. hospitals who experienced pain were prescribed opioids during hospitalization, compared with 51 percent of patients at the sites in other countries.
In addition to prescribing practices, the authors note that the patients’ perception of pain and the cultural biases toward pain medication may have affected the prescribing practices.
“While we observed that physicians in the US more frequently prescribed opioid analgesics during hospitalizations than physicians working in other countries, we also observed that patients in the US reported higher levels of pain during their hospitalization,” Burden and her co-authors wrote. “Our study also suggests that reducing the opioid epidemic in the US may require addressing patients’ expectations regarding pain control in addition to providers’ inpatient analgesic prescribing patterns.”
Mothers living near more intense oil and gas development activity have a 40-70% higher chance of having children with congenital heart defects (CHDs) compared to those living in areas of less intense activity, according to a new study from researchers at the Colorado School of Public Health.
“We observed more children were being born with a congenital heart defect in areas with the highest intensity of oil and gas well activity,” said the study’s senior author Lisa McKenzie, PhD, MPH, of the Colorado School of Public Health at the University of Colorado Anschutz Medical Campus. At least 17 million people in the U.S. and 6% of Colorado’s population live within one mile of an active oil and gas well site.
The study was published today in the peer-reviewed journal Environment International.
The researchers studied 3,324 infants born in Colorado from 2005-2011. They looked at infants with several specific types of CHDs.
Researchers estimated the monthly intensity oil and gas well activity at mother’s residence from three months prior to conception through the second month of pregnancy. This intensity measure accounted for the phase of development (drilling, well completion, or production), size of well sites, and production volumes.
They found mothers living in areas with the most intense levels of oil and gas well activity were about 40-70% more likely to have children with CHDs. This is the most common birth defect in the country and a leading cause of death among infants with birth defects. Infants with a CHD are less likely to thrive, more likely to have developmental problems and more vulnerable to brain injury.
Animal models show that CHDs can happen with a single environmental exposure during early pregnancy. Some of the most common hazardous air pollutants emitted from well sites are suspected teratogens – agents that can cause birth defects – known to cross the placenta.
The study builds on a previous one that looked at 124,842 births in rural Colorado between1996-2009 and found that CHDs increased with increasing density of oil and gas wells around the maternal residence. Another study in Oklahoma that looked at 476,000 births found positive but imprecise associations between proximity to oil and gas wells and several types of CHDs.
Those studies had several limitations including not being able to distinguish between well development and production phases at sites, and they did not confirm specific CHDs by reviewing medical records.
The limitations were addressed in this latest study. Researchers were able to confirm where the mothers lived in the first months of their pregnancy, estimate the intensity of well activity and account for the presence of other air pollution sources. The CHDs were also confirmed by a medical record review and did not include those with a known genetic origin.
“We observed positive associations between odds of a birth with a CHD and maternal exposure to oil and gas activities…in the second gestational month,” the study researchers said.
The study data showed higher levels of CHDs in rural areas with high intensities of oil and gas activity as opposed to those in more urban areas. McKenzie said it is likely that other sources of air pollution in urban areas obscured those associations.
Exactly how chemicals lead to CHDs is not entirely understood. Some evidence suggests that they may affect the formation of the heart in the second month of pregnancy. That could lead to birth defects.
McKenzie said the findings suggested but did not prove a causal relationship between oil and gas exploration and congenital heart defects and that more research needs to be done.
“This study provides further evidence of a positive association between maternal proximity to oil and gas well site activities and several types of CHDs,” she said. “Taken together, our results and expanding development of oil and gas well sites underscore the importance of continuing to conduct comprehensive and rigorous research on health consequences of early life exposure to oil and gas activities.”
The study co-authors include William Allshouse, PhD, BSPH and Stephen Daniels, MD, PhD, both of the University of Colorado Anschutz Medical Campus. The study was funded by a grant from the American Heart Association.
The microscope, known as the 2P-FCM, uses an electrowetting lens mounted on the head of a freely moving mouse where a high-powered, fiber optic light can actually view and control neural activity as it happens. The lens is liquid and can change shape when electricity is applied.
“We can image deep into the brain which makes it very attractive to a lot of neuroscience researchers,” said Emily Gibson, PhD, assistant professor of bioengineering at CU Anschutz who helped create the microscope. The initial demonstration of the 2P-FCM was published in Scientific Reports (Ozbay et al., 2018).
Gibson and her colleague Diego Restrepo, PhD, professor of cell and developmental biology at the University of Colorado School of Medicine, along with Karl Kilborn, co-president of 3i (Intelligent Imaging Innovations, Inc.) in Denver, won the $394,260 Small Business Innovation Research (SBIR) grant.
The microscope was first deployed to the University of Paris. Based on that success, it will next be used at New York University and Duke University.
The company 3i, founded by Karl Kilborn, along with Colin Monks, a former PhD student of CU Anschutz, and Abraham Kupfer, a former investigator at National Jewish, will produce the microscope. The company’s manufacturing efforts will be guided by Baris Ozbay, PhD, who helped create the prototype while working in Gibson’s lab and now works at 3i.
In 2016, Restrepo and Gibson along with Juliet Gopinath, PhD, associate professor in electrical, computer and energy engineering at CU Boulder and Victor Bright, PhD, professor of mechanical engineering at CU Boulder won a $2 million grant, spread over three years, from the National Institutes of Health (NIH) and the National Institute of Neurological Disorders and Stroke (NINDS). It was part of the NIH’s new BRAIN initiative aimed at revolutionizing the understanding of the human brain.
The money was partly used to optimize the microscope and deploy it in different neuroscience labs.
The device represents a breakthrough in the way scientists can observe brain activity. The microscope is attached to a thin fiber optic cable and mounted on a mouse’s head, allowing it to wander freely. Scientists can then observe complex neural processes within the brain.
“This can also be used to monitor brain responses to social and behavioral interactions,” Restrepo said. “To do that, you need an animal that is moving around and interacting with its environment.”
Kilborn, 3i co-president, said the goal of the BRAIN initiative was to ensure that new technologies developed academically made their way into as many laboratories as possible.
“This SBIR will help 3i disseminate the pioneering work done at CU Anschutz in the laboratories of Emily Gibson and Diego Restrepo, along with collaborators at CU Boulder in the laboratories of Victor Bright and Juliet Gopinath, which has also been funded, in part, by the BRAIN Initiative,” he said. We are excited by the experimental potential of this new technology and believe the grant represents a positive example of how academia and industry can work together to advance research in neuroscience.”
The microscope will allow scientists to investigate a wide range of subjects.
Some of those involved with the project are studying the neural basis of vocal learning in songbirds, decision-making in non-human primates and the neural basis of social bonding among prairie voles.
“This microscope has been getting a lot of attention,” Gibson said. “The idea is to turn it into an easy-to-use commercial product and make it available to labs around the world. For me, that is what is most rewarding about this work.”
AURORA, Colo. (June 19, 2019) – Relying strictly on genetic data from those of European descent, rather than more diverse populations, can exacerbate existing disease and increase health care disparities, according to new research.
The research letter was published today in the journal Nature.
“There have been numerous discoveries in human genetics over the last few decades that have told us a lot about biology, but most of the work is being done on those of European descent,” said the study’s first author Christopher Gignoux, PhD, MS, associate professor at the Colorado Center for Personalized Medicine at the University of Colorado Anschutz Medical Campus. “By limiting our focus, we are limiting our understanding of the human genetics underlying complex traits. The PAGE Study gives us an overdue opportunity to look at what we can find when studying a large number of groups together.”
This was borne out in the study which examined thousands of individuals in the U.S. of non-European ancestry. The Population Architecture using Genomics and Epidemiology study (PAGE) was developed by the National Human Genome Research Institute and the National Institute on Minority Health and Health Disparities to conduct and empower genetic research in diverse populations.
Researchers genotyped 49,839 people and found a number of genetic variants replicated from studies strictly of European descent. But PAGE investigators found dozens of discoveries that would not have been possible in a single population study. This included both complex traits and in Mendelian, or monogenic disorders.
“In light of differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and health care disparities,” the study said. “Critical variants can be missed if they have a low frequency or are completely absent in European populations…” Especially rare variants.
Gignoux said the success of precision medicine and genomics means recruiting people from underrepresented populations for genetic studies. Right now, those genomic databases lack critical diversity despite the fact that many of in underrepresented groups have the greatest health burden and stand to benefit the most from being included.
“The Colorado Center for Personalized Medicine on the Anschutz Medical Campus is committed to personalized medicine here in our state and region that will benefit ALL people, regardless of who you are or where you came from,” said Kathleen Barnes, PhD, director of the Colorado Center for Personalized Medicine. “Initiatives like PAGE, and the work summarized in this manuscript by Chris Gignoux and colleagues, show us the way forward in achieving our goals of inclusion. It also illuminates just how important genetic diversity is in our understanding of the architecture of genetic disease. These approaches can now feed into our personalized ancestry information resource for patients interested in their own ancestry, as well as benefit our research and clinical community.”
“With studies of diverse groups we got a better overall picture of the genetic architecture which show the underpinnings of disease,” Gignoux said. “We want to understand how genetics can improve and ameliorate disease rather than make it worse.”
A University of Colorado Cancer Center study presented at the American Society for Clinical Oncology (ASCO) Annual Meeting 2019 shows that while 73 percent of surveyed oncology providers believe that medical marijuana provides benefits for cancer patients, only 46 percent are comfortable recommending it. Major concerns included uncertain dosing, limited knowledge of available products and where to get them, and possible interactions with other medications.
Survey respondents included 48 specialized oncologists, 47 physicians, 53 registered nurses, 17 pharmacists, and 7 “other” oncology providers. Seventy-nine percent reported that educational programs both during training and as continuing medical education courses could increase their comfort level with medical marijuana prescribing. Interestingly, 68 percent of providers reported receiving information about medical marijuana from their patients – the next most common sources of information were news media (accessed by 55 percent of providers), and other providers (53 percent).
“We asked and most providers didn’t train in a state where medical marijuana was legal. We need to adapt our healthcare education to include this, and also offer trainings on medical marijuana to current providers,” Glode says.
Providers also reported legal and regulatory concerns, especially providers working in academic medical centers who expressed uncertainty whether recommending medical marijuana could jeopardize federal funding (marijuana remains a U.S. Drug Enforcement Agency Schedule 1 drug). Providers felt as if additional clinical data describing the effectiveness of medical marijuana and endorsed guidelines describing the conditions and situations in which it should be used would increase their comfort in prescribing.
“Still, the biggest issue that providers saw is the lack of certainty in dosing,” Glode says. “The issue is it’s not regulated – a dispensary might say a product has this much THC and this much CBD, but no one is testing that for sure. Limited data suggest that patients should start low and slow, no more than 10mg of THC in a dose, but we don’t know that’s what patients are really getting. Then from a consumption perspective, inhalation and smoking is the least preferred due to possible damage to the lung. So many doctors recommend edibles, oils, and tinctures, but we still don’t have good data comparing dosage across these forms.”
Glode and study colleagues including Stephen Leong, MD, hope to expand the survey to gather a more nationally representative sample.
“Knowledge is an issue,” Glode says. “If we could do a better job educating our healthcare providers, it might be used more often and potentially more safely.”