Newswise — Researchers have gained a greater understanding of the biology of staphylococcus skin infections in mice and how the mouse immune system mobilizes to fight them. A study appears this week in the Proceedings of the National Academy of Sciences of the United States of America. Community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) typically causes skin infections but can spread throughout the body to cause invasive infections such as sepsis, and possibly death. These CA-MRSA bacteria are becoming increasingly resistant to multiple antibiotics, making them especially difficult to treat. In healthy people, the body’s natural immune defenses typically keep CA-MRSA infections in the skin, and appropriate antibiotics can effectively treat them. However, patients who are immunocompromised have difficulty fighting the bacteria, which can become invasive and cause life-threating infections. “While the human immune responses that protect against S. aureus infections have remained elusive, we have as a start determined in mice that protective immunity against MRSA is orchestrated by specific immune cells called gamma/delta T cells, which upon infection travel from the lymph nodes to the infected skin to initiate the protective host response,” says Lloyd Miller, M.D., Ph.D., an associate professor of dermatology at the Johns Hopkins University School of Medicine. Miller notes that CA-MRSA and other multidrug resistant bacteria are becoming a bigger problem in health care, as most antibiotics no longer work against these infections and few new antibiotics are being developed in the pipeline. In the case of CA-MRSA, sometimes only two or three oral antibiotics remain that can treat these infections. Miller and his team are working to understand the specific details of the mouse immune system’s MRSA-fighting program to develop a way to probe the human immune system to develop alternative immune-based treatments that could work along with antibiotic regimens, or eliminate the need for antibiotics altogether. In their previous research, Miller and his team discovered that a cytokine protein called IL-17 is critical for turning on the host defense against staph infections. However, until know, they did not know which cell produced it, particularly which type of T cell. Also, there are two types of IL-17, one called IL-17A and the other IL-17F, but the researchers didn’t know if one or the other or both are required to mount the host response against CA-MRSA. So they teamed up with colleagues at the National Institutes of Health (NIH) who had engineered mice that would glow different colors depending on which form of IL-17 the mouse was making. The researchers then injected MRSA in the skin of these mice and found that the infected skin glowed green and red. They concluded this to mean that both types of IL-17 are involved in the immune response to the bacteria.  “We were fairly certain that IL-17 was being made by T cells but we didn’t know if it was the T cells that are normally in the skin or T cells that were migrating from the lymph nodes to the site of infection,” says Miller. Using the same glowing mice, the team asked what would happen if it blocked T cells from leaving the lymph nodes and treated the mice with FTY720 (fingolimod), a drug normally used to treat multiple sclerosis by keeping T cells from mobilizing from lymph nodes and minimizing inflammatory responses. After administering FTY720 to the mice that had an MRSA infection, the researchers saw no glowing, which informed them that the IL-17 seen at the site of the MRSA infection in the skin was made solely by T cells that had migrated from the lymph nodes. The researchers then extracted cells from the infection site as well as cells from the lymph nodes both before and after infecting the mice with MRSA. They labeled these cells with different colors depending on the types of proteins found on the surface of each cell. In mice without MRSA, a particular type of T cells called gamma/delta T cells expanded dramatically after infecting the mice with MRSA. The team then set out to determine which exact cells were expanding. Working with colleagues at the University of California, Davis, the team determined the genetic sequences of all of the T cell receptors in the mouse lymph nodes before and after infecting the mice with MRSA. They found that only one type of gamma/delta T cell clone expanded with a specific T cell receptor. What’s called the V gamma 6/Vdelta 4(+) expanded from 2% to over 20% to fight MRSA. “We think that this one single gamma/delta T cell clone is mediating the protective IL-17 response in mice,” says Miller. “What’s more is that these results really relied on having the latest technologies available to scientists today. We couldn’t have figured this out 10 years ago, for example. “While it is not known if there is an exact parallel cell type in humans, we’re encouraged that we can find something similar, which means we could be well on our way to developing new T cell-based therapies against MRSA.” Next steps for this team involve examining the T cell responses in humans to determine if a similar mechanism exists. Other authors on this paper include Mark Marchitto, Carly Dillen, Haiyun Liu, Robert Miller, Nathan Archer, Roger Ortines, Martin Alphonse, Alina Marusina, Advaitaa Ravipati, Yu Wang, Angel Byrd, Bret Pinsker, Isabelle Brown, Emily Zhang, Shuting Cai, Nathachit Limjunyawong and Xinzhong Dong of Johns Hopkins; Alexander Merleev, Scott Simon and Emanual Maverakis of the University of California, Davis; Michael Yeaman of the University of California, Los Angeles; Wei Shen and Scott Durum of the National Institutes of Health and Rebecca O’Brien of National Jewish Health. This work was supported by the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (R01AR069502 and R01AR073665), the National Institute of Allergy and Infectious Diseases (R21AI126896 [L.S.M.], U01AI124319 [to MRY] and R01AI129302 [to SIS]), and federal funds from the National Cancer Institute under Contract Number HHSN261200800001E (MRA) (to S.D.) and the Office of the National Institutes of Health Director (1DP2OD008752 [to EM]).
Newswise — PITTSBURGH, May 14, 2019 – The same sources thought to inflict oxidative stress on cells—pollution, diesel exhaust, smoking and obesity—also are associated with shorter telomeres, the protective tips on the ends of the chromosomal shoelace.  A new study from the University of Pittsburgh, published today in Molecular Cell, provides the first smoking gun evidence that oxidative stress acts directly on telomeres to hasten cellular aging.  “Telomeres consist of hundreds of guanine bases, which are sinks for oxidation,” said senior author Patricia Opresko, Ph.D., professor of environmental and occupational health at the Pitt Graduate School of Public Health and UPMC Hillman Cancer Center. “Is it just a coincidence? Or could it be true that oxidizing those guanines in the telomeres is really contributing to shortening?”  To find out for sure, Opresko needed some way to inflict oxidative stress on telomeres and nowhere else.  So, she enlisted the help of Marcel Bruchez, Ph.D., professor of biological sciences and chemistry and director of the Molecular Biosensors and Imaging Center at Carnegie Mellon University. Bruchez developed a method for zeroing in on the telomeres using a special light-activated molecule that latches onto the telomere and delivers localized free radicals—the molecular agent of oxidative stress—on command.  “One of the main challenges to targeting oxidative damage to specific loci in living cells has been achieving precise temporal and dose-control of this damage,” Bruchez said. “By combining telomere targeting with our optochemogenetic generation of singlet oxygen, we are able to selectively control when and how hard the oxidative stress is applied specifically at the telomere sites.”  The researchers repeatedly exposed cultured cancer cells to this targeted oxidation procedure, mimicking conditions of environmental oxidative stress and inflammation, and, indeed, they saw the telomeres break and shorten with each cell division, despite repair efforts by the telomere lengthening enzyme telomerase.  As the DNA repair machinery tried to fix the broken telomeres, the ends of the chromosomes often fused together, destabilizing the genome and preventing cells from dividing properly.  Whereas telomere shortening spells bad news for healthy cells, Opresko said, the flipside is that targeting telomeres might offer a way to fight cancer. With short enough telomeres, cancer cells would stop dividing.  “If we can understand what causes telomere shortening and how cells compensate for that,” Opresko said, “then we’ll be in a better position to design intervention strategies that protect telomeres in healthy cells and target telomeres in cancer cells.”  Other authors on this study include Elise Fouquerel, Ph.D., Ryan Barnes, Ph.D., Shikhar Uttam, Ph.D., and Simon Watkins, Ph.D., all of Pitt.  This work was supported by grants from the National Institutes of Health (K99ES027028, R01ES022944, R01CA207342, R01ES02842, R21/R33ES025606 and R01EB017268).
Many in their 50s and early 60s buy supplements or do puzzles in hopes of protecting brain health, but may miss out on effective strategies Newswise — ANN ARBOR, MI – Many Americans in their 50s and early 60s are worried about declining brain health, especially if they have loved ones with memory loss and dementia, a new national poll finds. But while the majority of those polled say they take supplements or do puzzles in an effort to stave off brain decline, very few of them have talked with their doctors about evidence-based ways to prevent memory loss. As a result, they may miss out on proven strategies to keep their brains sharp into their later years, says the poll team from the University of Michigan. In all, nearly half of respondents to the National Poll on Healthy Aging felt they were likely to develop dementia as they aged, and nearly as many worried about this prospect. In reality, research suggests that less than 20 percent of people who have reached age 65 will go on to lose cognitive ability from Alzheimer’s disease, vascular dementia or other conditions. Despite the brain-related concerns of so many respondents, only five percent of the entire group, and 10 percent of those who said they had a family history of dementia, said they had talked with a healthcare provider about how to prevent memory problems. At the same time, 73 percent said they do crossword puzzles or brain games, or take supplements, to try to keep their minds sharp. Neither strategy has been shown to have a beneficial effect by major research studies. The poll, carried out by the U-M Institute for Healthcare Policy and Innovation with support from AARP and Michigan Medicine, U-M’s academic medical center, asked 1,028 adults aged 50 to 64 a range of brain health questions. “While many people in this age range expressed concerns about losing memory, and say they take active steps to prevent it, most haven’t sought advice from medical professionals, who could help them understand which steps actually have scientific evidence behind them,” says Donovan Maust, M.D., M.S., a U-M geriatric psychiatrist who helped design the poll and analyze the results. “Many people may not realize they could help preserve brain health by managing their blood pressure and blood sugar, getting more physical activity and better sleep, and stopping smoking.” Maust worked with poll director Preeti Malani, M.D., U-M dementia researcher Kenneth Langa, M.D., PhD, and the poll team. Effects of experience The team found stark differences in perceptions and viewpoints between the one-third of poll respondents who said they had a family history of dementia, or had served as a caregiver to a loved one with dementia, and those without such experience or family links. For instance, 73 percent of those with a family history of dementia said they themselves were somewhat or very likely to develop the condition as they aged – compared with just 32 percent of those with no family history. The gap between the two groups was nearly as large when the research team asked if poll respondents were worried about developing dementia later in life. “Staying mentally sharp is the number one concern for older adults,” says Alison Bryant, Ph.D., senior vice president of research for AARP. “According to the Global Council on Brain Health, people should concentrate on those things we know can improve brain health—eating a healthy diet, getting adequate sleep, exercising, and socializing with friends and family.”   Attitudes toward dementia research Differences also emerged between those who had dementia in their families, and those without, when the researchers asked respondents if they’d consider taking part in dementia-related research. Seventy-one percent of those with a family history of dementia said they’d be willing to give researchers a sample of their DNA, compared with 51 percent of the other respondents. Nearly twice as many of those with a family history said they’d take part in a test of a new medicine aimed at preventing dementia, or a new treatment for people diagnosed with dementia. The poll also suggests that researchers searching for better ways to prevent, diagnose or treat dementia may have to work hard to attract participants. Thirty-nine percent of those who wouldn’t be willing to give a DNA sample said it was because they didn’t want their DNA to be stored in a repository. Similarly, 37 percent of those who said they wouldn’t take part in studies of new prevention or treatment strategies expressed concerns about being a “guinea pig”, and one-fifth worried about potential harms. Healthy lives, healthy attitudes The poll also shows that a greater percentage of adults in their 50s and early 60s who say they get adequate sleep and exercise, ate healthily and were active socially at least several times a week felt their memory was just as sharp now as it was when they were younger, compared to those who do not engage in these healthy behaviors as frequently. But those who said their health was fair or poor, or who reported that they didn’t often engage in healthy lifestyle practices, were much more likely to say that their memory had declined since their younger years. In all, 59 percent of those polled said their memory was slightly worse than it used to be. “For anyone who wants to stay as sharp as possible as they age, the evidence is clear: focus on your diet, your exercise, your sleep and your blood pressure,” says Malani. “Don’t focus on worrying about what might happen, or the products you can buy that promise to help, but rather focus on what you can do now that research has proven to help.” The National Poll on Healthy Aging results are based on responses from a nationally representative sample of 1,028 adults aged 50 to 64 who answered a wide range of questions online. Questions were written, and data interpreted and compiled, by the IHPI team. Laptops and Internet access were provided to poll respondents who did not already have them. A full report of the findings and methodology is available at, along with past National Poll on Healthy Aging reports
Newswise — Researchers at UC Davis Health and UC San Francisco have found a way to teach a computer to precisely detect one of the hallmarks of Alzheimer’s disease in human brain tissue, delivering a proof of concept for a machine-learning approach to distinguishing critical markers of the disease. Amyloid plaques are clumps of protein fragments in the brains of people with Alzheimer's disease that destroy nerve cell connections. Much like the way Facebook recognizes faces based on captured images, the machine learning tool developed by a team of University of California scientists can “see” if a sample of brain tissue has one type of amyloid plaque or another, and do it very quickly. The findings, published May 15 in Nature Communications, suggest that machine learning can augment the expertise and analysis of an expert neuropathologist. The tool allows them to analyze thousands of times more data and ask new questions that would not be possible with the limited data processing capabilities of even the most highly trained human experts. “We still need the pathologist,” said Brittany N. Dugger, PhD, an assistant professor in the UC Davis Department of Pathology and Laboratory Medicine and lead author of the study. “This is a tool, like a keyboard is for writing. As keyboards have aided in writing workflows, digital pathology paired with machine learning can aid with neuropathology workflows.” In this study, she partnered with Michael J. Keiser, PhD, an assistant professor in UCSF’s Institute for Neurodegenerative Diseases and Department of Pharmaceutical Chemistry, to determine if they could teach a computer to automate the laborious process of identifying and analyzing tiny amyloid plaques of various types in large slices of autopsied human brain tissue. For this job, Keiser and his team designed a “convolutional neural network” (CNN), a computer program designed to recognize patterns based on thousands of human-labeled examples. To create enough training examples to teach the CNN algorithm how Dugger analyzes brain tissue, the UCSF team worked with her to devise a method that allowed her to rapidly annotate or label tens of thousands of images from a collection half a million close-up images of tissue from 43 healthy and diseased brain samples. Like a computer dating service that allows users to swipe left or right to label someone’s photo “hot” or “not,” they developed a web platform that allowed Dugger to look one-at-a-time at highly zoomed-in regions of potential plaques and quickly label what she saw there. This digital pathology tool — which researchers called “blob or not” — allowed Dugger to annotate more than 70,000 “blobs,” or plaque candidates, at a rate of about 2,000 images per hour. The UCSF team used this database of tens of thousands of labeled example images to train their CNN machine-learning algorithm to identify different types of brain changes seen in Alzheimer’s disease. That includes discriminating between so-called cored and diffuse plaques and identifying abnormalities in blood vessels.  The researchers showed that their algorithm could process an entire whole-brain slice slide with 98.7% accuracy, with speed only limited by the number of computer processors they used. (In the current study they used a single graphics card like those used by home gamers.) The team then performed rigorous tests of the computer’s identification skills to make sure its analysis was biologically valid. “It’s notoriously hard to know what a machine-learning algorithm is actually doing under the hood, but we can open the black box and ask it to show us why it made its predictions,” Keiser explained. Keiser emphasized that the machine learning tool is no better at identifying plaques than Dugger, the neuropathologist who trained the computer to find them in the first place. “But it’s tireless and scalable,” he said. “It’s a co-pilot, a force multiplier that extends the scope of what we can accomplish and lets us ask questions we never would have attempted manually. For example, we can look for rare plaques in unexpected places that could give us important clues about the course of the disease. To promote use of the tool, the researchers have made it and the study data publicly available online. This has already generated interactions with other researchers who have evaluated the data and the algorithms in their own labs. In the future, the researchers hope that such algorithms will become a standard part of neuropathology research, trained to help scientists analyze vast amounts of data, tirelessly seeking out patterns that could unlock new insights into causes and potential treatments for the disease.  “If we can better characterize what we are seeing, this could provide further insights into the diversity of dementia,” Dugger said. “It opens the door to precision medicine for dementias.” She added, “These projects are phenomenal examples of cross-disciplinary translational science; neuropathologists, a statistician, a clinician, and engineers coming together, forming a dialogue and working together to solve a problem.” Other study authors included: Charles DeCarli, Lee-Way Jin and Laurel Beckett from UC Davis; Ziqi Tang of UCSF and Tsinghua University in Beijing, China, and Kangway V. Chuang of UCSF. The study was funded by an NIH P30 AG010129, Paul G. Allen Family Foundation Distinguished Investigator Award and the China Scholarship Council. The authors declare no conflicting interests.
Newswise — In experiments with pregnant mice infected with the Zika virus, Johns Hopkins Medicine researchers report they have successfully used a long-standing immunosuppressive drug to diminish the rate of fetal deaths and birth defects in the mice’s offspring. The U.S. Food and Drug Administration-approved medicine, anakinra, once commonly used to treat rheumatoid arthritis and other autoimmune diseases in newborns and adults, has largely been replaced by more effective drugs. However, in the Zika-infected mouse experiments, the drug appears to interfere with inflammation in the pregnant animals’ placentas, the researchers say. There also is evidence the drug directly reduces inflammation in fetal brains. A report on the findings was published in the April issue of the Journal of Clinical Investigation Insights. “Until now, the focus of research has been on finding vaccines and antiviral drugs, but our study strongly suggests that the placental immune response should not be overlooked as a target for treatment,” says Irina Burd, M.D., Ph.D., associate professor of gynecology and obstetrics and director of the Integrated Research Center for Fetal Medicine at the Johns Hopkins University School of Medicine. “Using an FDA-approved drug already shown to be safe in infants shortens the time that we may be able to quickly start clinical trials and get a potentially effective preventative measure approved and available to help decrease the harmful effects of Zika.” According to the U.S. Centers for Disease Control and Prevention, 10% of babies born in the U.S. to women with a Zika infection during pregnancy develop fetal brain birth defects that range from slow head growth to microcephaly, a condition marked by a very small head due to brain abnormalities. Zika can be spread by infected mosquitos or unprotected sex from an infected person, and is passed from a pregnant woman to her unborn child. Pregnant women with Zika are also at increased risk for miscarriage. In Burd’s earlier work in 2014 in the American Journal of Reproductive Immunology with mouse models of newborn brain injury, she found that anakinra protected newborn mice from brain damage when the pregnant mothers were treated with inflammatory protein, notably interleukin-1beta. For this study, the researchers first wanted to see how Zika may affect the placenta in pregnant mice with the virus to try to figure out the cause behind the fetal deaths and birth defects. They compared pregnant mice infected with strains of Zika found in Nigeria, Puerto Rico and Brazil to pregnant mice not infected with the virus. They found that mice with Zika turned on the gene that makes the protein for interleukin-1beta at higher levels in the placenta compared to non-infected mice. They also found higher levels in the placenta of the interleukin-1beta protein. Because Zika causes early overproduction of interleukin-1beta, the researchers turned to the drug anakinra to test its potential for alleviating the damaging effects to fetal mice of mothers with Zika. The researchers injected mice placentas with either 10 milligrams per kilogram of anakinra or with fluid without the drug. After eight days of in utero exposure to the virus, 1.8% of the 322 mice infected with Zika but not given the drug had birth defects such as contracted limbs with tightened muscles, kinked tails, and fused fingers and toes. None of the mice given the drug showed signs of these birth defects. Comparable to the defects shown in the mice, human babies with microcephaly-caused defects may have limb contractures. The researchers say it is important to note that the defects noted in the mice may vary from humans because each species develops differently.  The researchers also say that more fetal mice treated in utero with anakinra survived to full-term birth compared to untreated mice. In the pregnant mice with Zika, 39.2% of the mothers had fetal deaths. In mice with Zika given the drug in utero, 20.8% of the mothers had fetal deaths. Next, the researchers wanted see if the drug protected the brains of the mice born to mothers with Zika from inflammation. The researchers took mice immune system cells from the brain, called microglia, and infected them with Zika. After a day, microglia with Zika had made more cells, showing that the Zika was causing inflammation. They treated microglia infected with Zika with anakinra, and after 24 hours there were fewer microglia, suggesting that the drug protected the brain cells from inflammation. Five days after birth, the mice born treated with anakinra completed neurological and physical assessments that tested balance, movement, vision, depth perception and coordination. For example, in the coordination test, the mice were put on their backs and researchers measured how long it would take them to flip over. Mice given the drug flipped over to become upright about one second faster on average than mice without treatment, which the researchers say was significant for this kind of test. The researchers believe the drug was responsible for reversing the neurodevelopmental abnormalities that caused longer performance times. “Currently, there is no cure for Zika, but our study suggests that there may be FDA-approved medications like anakinra that have the potential to combat some of the worst effects of the virus,” says Sabra Klein, Ph.D., associate professor of molecular microbiology and immunology at the Johns Hopkins University Bloomberg School of Public Health. “ “Future studies are urgently needed to determine the possible benefits of such a drug in people,” says Burd. “More and more countries are affected by Zika. And it would be great for us to continue doing this research with the same rigor and funding so we can continue to fight this not only in the United States but, globally.” Other researchers who participated in the study included Jun Lei, Meghan Vermillion, Bei Jia, Han Xie, Li Xie, Michael McLane, Jeanne Sheffield, Andrew Pekosz and Amanda Brown of the Johns Hopkins University School of Medicine and Bloomberg School of Public Health. This work was supported by funds from the Johns Hopkins Integrated Research Center for Fetal Medicine, Sheikh Abdullah Bugshan Fund, Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases, ABOG/AAOGF Bridge Funding Award, the National Institutes of Health Office of the Director (T32 OD011089) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development grant for training veterinarians for careers in biomedical research (R01HD097608). The researchers report no conflicts of interest.
Results of a first-in-humans trial presented at AATS 99th Annual Meeting indicates the safety of a novel treatment for ischemia reperfusion injury where none has existed to-date. Newswise — TORONTO – May 5, 2019 – A new study, presented today at the American Association for Thoracic Surgery’s 99thAnnual Meeting, shows that a potential treatment for ischemia- reperfusion injury is safe for humans.  Building upon three decades of preclinical animal studies, this NIH-funded trial demonstrated, for the first time, the safety of Regadenoson (an adenosine 2A receptor agonist) in human lung transplant patients.  Ischemia-reperfusion injury is a major source of morbidity and mortality in lung transplant patients, and contributes to the less than optimal survival rates in lung transplant recipients.  Adenosine 2AR agonists like Regadenoson offer a potentially novel treatment for this common inflammatory complication where none exists today.  Researchers found no dose limiting toxicities in the non-randomized trial and no 30-day mortality.  The TCV lab at University of Virginia, under the direction of Dr. Irving Kron, has spent three decades studying the efficacy of A2AR agonists for lung transplant in rodents and large animals.  In humans, Regadenoson, (LexiscanTM), is clinically approved as a bolus for myocardial imaging, but its safety profile in the high risk lung transplant population as an infusion had not been established. This clinical trial was designed to assess the safety of regadenoson in human lung transplant recipients as a prequel to an efficacy trial. “It is gratifying to see this research move from bench to bedside, with decades of work culminating in a clinical trial,” said Senior Author, Dr. Christine Lau, Professor of Surgery in the Division of Thoracic & Cardiovascular Surgery at the University of Virginia. “As the field of lung transplants evolves rapidly, we continue to see ischemia-reperfusion injury, making the potential of a new treatment an exciting development.” With safety established, the next step for testing efficacy is a multi-institutional, randomized trial.  Additionally, because the treatment appears effective whether the drug is given to the donor lung or the recipient, future trials will use ex-vivolung profusion to administer the drug only to the donor lung, eliminating any risk to the patient. Presenting author Dr. Joshua A. Boys, MD explained, “This treatment has the potential to be the next big thing in the world of lung transplants. With further study, this can quickly move from a quality of life improvement therapy to one that greatly improves survival for the long term.”
Credit: Lesion photo courtesy of Kelly Nelson, National Cancer Institute, and photomicrograph courtesy of Markus Schrober and Elaine Fuchs, The Rockefeller University A macro and micro look at skin cancer: (left) A leg with a squamous cell carcinoma lesion and (right) a colorized photomicrograph of the cancer at the cellular level. Mohs micrographic surgery, the subject of a new paper from Johns Hopkins Medicine, is one of the most effective techniques for treating this type of malignancy.   Newswise — Sometimes a little gentle peer persuasion goes a long way toward correcting a large problem. That’s the message from researchers at Johns Hopkins Medicine and seven collaborating health care organizations which report that a “Dear Colleague” performance evaluation letter successively convinced physicians nationwide to reduce the amount of tissue they removed in a common surgical treatment for skin cancer to meet a professionally recognized benchmark of good practice. In a study published in the journal JAMA Dermatology, the researchers reported an immediate positive change in surgical behavior — an improvement that was sustained for one year — for 83 percent of the physicians notified that they were excising more-than-necessary amounts of tissue on a regular basis during Mohs micrographic surgery (MMS). The surgery is considered the most effective technique for treating many basal cell and squamous cell carcinomas, the two most common types of skin cancer. “This study demonstrates the tremendous power of physicians within a specialty to create peer-to-peer accountability and of using that accountability to reduce unnecessary treatment and lower health care costs,” says Martin A. Makary, M.D., Ph.D., senior author of the study, professor of surgery at the Johns Hopkins University School of Medicine and an authority on health care quality. He also serves as principal investigator of Improving Wisely, a national project to lower medical costs in the United States by implementing measures of appropriateness in health care. The new study, part of the Improving Wisely effort, was supported by a grant from the Robert Wood Johnson foundation. MMS, developed by Frederic Mohs at the University of Wisconsin in the 1930s, is a specialized technique for the treatment of skin cancer, the most common malignancy in the United States at greater than 5.4 million cases annually. Performed as an outpatient procedure, MMS is designed so that the surgeon can methodically remove cancerous tissue on the surface and all of its “roots” — extensions of the tumors that may exist under the skin or lie along blood vessels, nerves and cartilage. The surgery is conducted in stages, with stage 1 involving the removal of the visible cancer and a thin layer of surrounding tissue. The excised sample is then cut into sections, stained and examined microscopically while the patient waits. If residual cancer is found, the surgeon can elect right then to remove more tissue in successive stages. The process is repeated as many times as necessary. The American College of Mohs Surgery (ACMS) considers a surgeon’s annual mean stages per MMS case to be the measure of quality and appropriateness for the technique. Using that metric, the organization defines physicians whose practices are two standard deviations or more beyond the overall average as outliers who are performing excessive stages in MMS procedures. Because previous studies suggest that MMS practices vary widely among surgeons, the study by Makary, his team and the ACMS had two aims: evaluate outlier practice patterns using a big-data approach and then, test whether a peer-to-peer notification could change the behavior of surgeons not meeting the appropriateness standard. “This was an important goal because overuse of stages per case burdens patients with unnecessary and time-consuming surgical resections, and taxes the health care system with avoidable costs,” says Christine Fahim, Ph.D., M.Sc., one of the study authors, a postdoctoral fellow at the Johns Hopkins University School of Medicine and the Johns Hopkins Bloomberg School of Public Health, and implementation and intervention design lead for Improving Wisely. In their paper, the researchers describe how they used Medicare Part B claims to choose their study population of 2,329 U.S. surgeons who each performed more than 10 MMS procedures between Jan. 1 and Dec. 31, 2014. The claim forms included the number of stages done in each case, so individual and overall annual averages were easily calculated. Outliers and inliers (surgeons whose MMS performance was within the accepted range of appropriateness defined by the ACMS) were identified by their performances before they became part of the study population (as measured between Jan. 1, 2016, and Jan. 31, 2017). The study population was then divided into four groups: (1) 53 outliers, each of whom would receive an intervention letter indicating his or her performance, and urging an improvement in practice, (2) 87 outliers, each of whom would not receive an intervention, (3) 992 inliers who would receive a straightforward performance evaluation letter, and (4) 1,197 inliers who would not receive a letter. The intervention groups received their letters in February 2017. Each surgeon’s MMS performance, defined as annual mean stages per case, was measured pre-intervention (between Jan. 1, 2016, and Jan. 31, 2017) and post-intervention (between March 1, 2017, and March 31, 2018). The notified outlier group demonstrated a pre- to post-intervention decrease in mean stages per case from 2.55 to 2.31, with 44 of the 53 surgeons (83 percent) improving their MMS behavior. The non-notified outliers dropped from 2.56 to 2.46, with 69 percent making positive changes. The researchers attribute the drop by non-notified outliers to two factors: an awareness campaign by ACMS around the time the intervention letters went out and possible communications between surgeons who received the letters and their colleagues who did not. The performance of the inlier groups, as expected, remained statistically about the same. The researchers also estimated that the relatively inexpensive ($150,000 or about $144 per surgeon) peer-to-peer intervention saved $11 million in Medicare costs during the study period. “We observed an immediate and sustained improvement in quality with a simple intervention based on the spirit of physicians helping one another,” Makary says. “The low cost to implement the program relative to the significant savings achievable suggests that this model could be applied to other areas of medicine with broad financial implications. More importantly, we found that even small improvements in a physician’s performance can positively impact the many patients he or she treats.” The lead and corresponding author of the JAMA Dermatology paper is John Albertini of the Wake Forest University School of Medicine (Winston-Salem, North Carolina). Along with Makary and Fahim, the Johns Hopkins University School of Medicine (Baltimore, Maryland) co-authors are: Susan Hutfless, Peiqi Wang, Angela Park, Heidi Overton, William Bruhn, Tim Xu and Aravind Krishnan. Other co-authors are: Thomas Stasko, University of Oklahoma (Oklahoma City, Oklahoma); Allison Vidimos, Cleveland Clinic (Cleveland, Ohio); Barry Leshin, also at Wake Forest; Elizabeth Billingsley, Penn State Health (Hershey, Pennsylvania); Brett Coldiron, University Hospital (Cincinnati, Ohio); Richard Bennett, Bennett Surgery Center (Santa Monica, California); and Victor Marks, ACMS (Milwaukee, Wisconsin). The authors have declared no conflicts of interest.
Newswise — Among the most well-known disease carrying bugs in Texas are mosquitos, spiders, cockroaches and ticks. But the Kissing Bug is a serious, lesser known threat to Texans. While it has a cute name, many folks don’t know there’s a not-so-cute, deadly parasite the bug can transmit. Texas State Assistant Professor Dr. Paula Stigler Granados has spent several years researching Chagas disease, a “silent killer” carried through many Kissing Bugs. Dr. Stigler Granados recently shared what the disease means, especially for migrants, as well as those who may contract the disease locally without realizing it.  What is Chagas Disease? “The disease itself is interesting and complex,” explained Dr. Stigler Granados. Caused by a parasite called T. Cruzi, Chagas disease manifests itself in two stages: acute and chronic. During the acute phase of eight to 12 weeks, people may experience mild flu-like symptoms, itchiness at the site of the bite, or no symptoms at all. Once the acute phase is over, the person enters into the chronic stage, which can either be with or without symptoms. The beginning chronic stage of Chagas can last for years or even decades with no symptoms at all, hence the name “silent killer”. Many people will never know they have encountered a kissing bug or even know they have the disease. However, if the disease isn’t found and treated before the person develops symptoms, they may go on to develop symptoms and the disease will often be untreatable and fatal. Symptoms include irreversible cardiac complications (including heart failure) and sometimes intestinal issues such as megaesophagus and megacolon. Only 30-40% of infected individuals will go on to ever develop symptoms, while 60% can live out their lives with no complications.  Who is most at risk? The insects and the disease are more prevalent in Latin American countries partly due to climate and poorer living conditions. However, the insects are common in the southern U.S. and Chagas disease has been documented in the U.S. as early as the 1930’s.  Because Texas is an entry point for many migrants from areas where Chagas is more prevalent means consideration should be given on how to treat persons coming from higher risk areas. When people coming from Latin American countries are able to be seen by local physicians, the doctors aren’t often familiar with the disease and treatment options that are available. When time is of the essence, treatment cannot wait. Chagas disease is a relatively slow moving disease and is not contagious. It cannot be transmitted from animal to human or human to human, except it can be passed from mother to fetus. Pregnant women coming from endemic areas are encouraged to know their status to prevent passing on the disease to their children. Additionally, Texas residents are still at risk, regardless of where they come from. More than 60% of Kissing Bugs in the state have been found to carry the parasite. Although not commonly found in urban areas, they are attracted to any areas where they can easily access a blood meal. Rats nests, animal kennels, wooded areas and debris piles are all good living conditions for kissing bugs.  How is research changing the conversation? As Dr. Stigler Granados shared, “not everyone is talking about this disease- one of the biggest barriers is lack of awareness amongst the health communities in the United States.” Research, such as Dr. Stigler Granados’ recent study on healthcare gaps for patients, help connect the dots. Because Chagas is a zoonotic disease, animals can contract the disease as well. Veterinarians who are seeing the disease more often than physicians and are more familiar with the disease can actually help communities better understand their risks.  With such a huge lack of awareness in the U.S. about the disease, one of Dr. Stigler Granados’  biggest concerns is congenital transmission. If most pregnant women are seeking health care, it’s a great opportunity to implement a screening program to catch the disease early. Right now, she’s advocating for more physicians to  screen pregnant mothers in an effort to better understand prevalence. There are newly available effective and inexpensive treatment options for both the infants and the moms, making it a win-win situation when it is caught early.  “Once we start raising awareness with one audience of health professionals and mothers, we can work on providing greater education to others,” added Dr. Stigler Granados. She’s hoping to get approval on a grant to implement screening newborns, which would be a big milestone to help with understanding prevalence and leading to better diagnosis and treatment.
Newswise — The neuropeptide oxytocin blocks enhanced drinking in alcohol-dependent rats, according to a study published April 16 in the open-access journal PLOS Biology led by Drs. Tunstall, Koob and Vendruscolo of the National Institutes of Health, and Drs. Kirson and Roberto of The Scripps Research Institute. Targeting the oxytocin system, the authors note, may provide novel pharmaceutical interventions for the treatment of alcohol-use disorder. Administering oxytocin can decrease consumption, withdrawal symptoms, and drug-seeking behavior associated with several drugs of abuse, and shows promise as a pharmacological approach to treat drug addiction. But first, researchers need to understand how oxytocin mediates these effects in animal models. To address this question, Tunstall and colleagues tested the hypothesis that oxytocin administration could normalize the maladaptive brain changes that occur in alcohol dependence and thereby reduce alcohol drinking in an established rat model of alcohol dependence. The authors investigated oxytocin’s effects on dependence-induced alcohol consumption and altered signaling of the inhibitory neurotransmitter GABA in the central nucleus of the amygdala (CeA) -- a key brain region in the network affected by alcohol dependence. The experiments demonstrated that oxytocin administered systemically, intranasally or into the brain blocked excess drinking in alcohol-dependent but not in normal rats. Moreover, oxytocin blocked GABA signaling in the CeA. Taken together, these results provide evidence that oxytocin likely blocks enhanced drinking by altering CeA GABA transmission. These results provide evidence that aberrations in the oxytocin system may underlie alcohol use disorder and that targeting this system, possibly by intranasal administration, could prove a promising therapy in people who misuse alcohol.
Novel strategy could be useful component of comprehensive smoking cessation plan, study says WASHINGTON -- Smokers who are trying to quit may not always have to reach for a piece of nicotine gum to stave off a craving. Deliberately inhaling a pleasant aroma may be enough to reduce the urge to light up, at least temporarily, and could be used as part of an effective smoking cessation strategy, according to research published by the American Psychological Association. “Despite disappointing relapse rates, there have been few new approaches to smoking cessation in general and to craving relief in particular,” said lead author Michael Sayette, PhD, of the University of Pittsburgh. “Using pleasant odors to disrupt smoking routines would offer a distinct and novel method for reducing cravings, and our results to this end are promising.” The research was published in the. While smoking rates have fallen over the past 50 years, approximately 40 million Americans still smoke, according the U.S. Centers for Disease Control and Prevention. Most adult smokers want to quit and at least half report trying in the past year, yet half of those who try relapse within two weeks. “Even with nicotine replacement, relapse is common. New interventions are urgently needed to help the millions who wish to quit but are unable,” said Sayette. The researchers recruited 232 smokers, ages 18 to 55, who were not trying to quit at the time and were not using any other nicotine delivery system, such as gum or vaping. They were asked not to smoke for eight hours prior to the experiment and were required to bring a pack of their preferred cigarettes and a lighter with them. Upon arrival, the people first smelled and rated a number of different odors generally considered to be pleasant (e.g., chocolate, apple, peppermint, lemon or vanilla) as well as one unpleasant chemical odor, tobacco from the participant’s preferred brand of cigarettes and one blank (no odor). They were then asked to light a cigarette and hold it in their hands, but not smoke it. After 10 seconds, the participants verbally rated their urge to smoke on a scale of 1 to 100 before extinguishing the cigarette and putting it in an ashtray. The participants then opened a container that held either the scent they had rated most pleasurable, the scent of tobacco or no scent and sniffed it once before again rating their urge to smoke. They continued to sniff the container they were given for the next five minutes, rating their urge to smoke every 60 seconds. The average craving score just after lighting the cigarette was 82.13. Regardless of what odor they smelled, all participants experienced a decreased urge to smoke after sniffing the container, but the average craving scores for those who smelled pleasant odors dropped significantly more (19.3 points) than those who smelled tobacco (11.7 points) or received the blank (11.2 points). The researchers were not surprised by the findings, as they confirmed and extended results from a much smaller, exploratory study they had previously conducted, according to Sayette. “These days, replicating prior findings is not something I take for granted, and extending the research by showing that we can maintain the effect for as long as five minutes suggests it might offer enough time for a smoker to decide to avoid or leave their high-risk situation,” he said. Sayette believes that part of the reduction seen in all three conditions may be due to smokers extinguishing the cigarette and removing temptation. As for why pleasant aromas achieved a greater reduction in cravings, he thinks they may work by distracting smokers from thoughts of their craving to memories linked to these olfactory cues (e.g., peppermint reminded some of the smokers of childhood Christmas holidays spent at a grandparent’s home), but more research would need to be done to confirm his hypothesis.   “Our research suggests that the use of pleasant odors shows promise for controlling nicotine cravings in individuals who are trying to quit smoking,” said Sayette, who noted that additional research needs to be done to see if this strategy could prove useful alone or in combination with other approaches to smoking cessation. Article:  “Pleasant Olfactory Cues Can Reduce Cigarette Cravings,” by Michael Sayette, PhD, Mary Marchetti, BS, Lea Martin, PhD, and Molly Bowdring, MS, University of Pittsburgh, and Rachel Herz, PhD, Brown University. Journal of Abnormal Psychology. Published online April 15, 2019. Full text of the article is available from the APA Public Affairs Office and at Contact: Michael Sayette can be reached via email at or by phone at (412) 624-8799.