Large genome study leads to better understanding of high blood pressure Photo by Jeff Bowen (12/04/2018) A large international genetic study that included several VA researchers has identified more than 500 new gene locations that affect blood pressure. The project is the largest genetic study of blood pressure to date, involving more than 1 million participants. It included data from VA’s Million Veteran Program. By comparing participants’ genetic data, researchers identified 535 new locations on the human genome that influence blood pressure. The researchers calculate that the new findings increase the knowledge of inheritable blood pressure traits by 27 percent. They call the findings “an important step forward” in understanding how genes affect blood pressure. (Nature Genetics, October 2018) Program improved headaches-tbi staff interactions with residents Photo for illustrative purposes only. ©iStock/monkeybusinessimages (12/04/2018) A training program improved interactions between staff and VA community living center residents, in a study by researchers at several VA facilities. The intervention centered on observations, huddles, and a focus on the positive. Researchers surveyed 62 residents and 308 staff members after the staff behavioral change program. Results showed increased communication and decreased negative staff intervention with residents after the training. Staff members credited the program with helping them to understand the importance of engagement and improving the quality of their interactions with residents. (Gerontologist, July 13, 2018) White matter damage could explain chronic headaches after TBI Photo: ©iStock/wenht (12/04/2018) Researchers with the VA San Diego Healthcare System have identified white matter abnormalities in the brains of patients with mild traumatic brain injury that may help explain their chronic headaches. The study used brain imaging data from 12 patients with TBI and chronic headache, compared with healthy controls. The TBI patients had abnormalities of the white matter in two brain tracts: the left superior longitudinal fasciculus, and the right anterior thalamic radiation. These tracts link different parts of the brain. This disruption of communication within the brain could be partly responsible for chronic headaches often experienced by patients with TBI, say the researchers. (Molecular Pain, Oct. 16, 2018) Mouse study: Aspirin may slow multiple sclerosis Photo by Jerry Daliege (11/29/2018) Low-dose aspirin could suppress multiple sclerosis symptoms and slow the disease, according to a mouse study by Jesse Brown VA Medical Center researchers. Mice with a condition similar to MS were given small doses of aspirin orally. Mice given aspirin show reduced symptoms for both relapsing-remitting and chronic forms of the disease. The aspirin also seems to have prevented destruction to the myelin sheath in the spinal cord caused by destructive T-cells. The researchers found that aspirin reversed the depletion of regulatory T-cells that occurs in MS, which may have helped stop other T-cells from attacking nerve fibers. While more study is needed, the results suggest that low-dose aspirin regimens could help patients with MS, say the researchers. (Science Signaling, Nov. 27, 2018) Rural, urban ICUs perform similarly in VA system Photo: ©iStock/PeopleImages (11/29/2018) Rural intensive care units (ICUs) in VA facilities perform similarly to their urban counterparts, found an Iowa City VA Health Care System study. Researchers looked at data on nearly 10,000 rural patients and almost 66,000 urban patients. They found that patients treated at rural ICUs had similar mortality rates, despite rural locations having lower-complexity facilities. Rural patients were less likely to have respiratory illnesses and more likely to have sepsis than urban patients, and they had higher illness severity scores. Rural patients also had fewer inter-hospital transfers and shorter ICU length of stay. The results indicate that being part of a national health care system may have benefits for rural facilities that should be explored outside the VA system, according to the researchers. (Journal of Critical Care, Oct. 19, 2018) Study explains gene mutation’s link to ALS Photo: ©iStock/imaginima (11/29/2018) Researchers at the VA Lexington Medical Center and University of Kentucky have shown how a gene mutation may contribute to the development of amyotrophic lateral sclerosis (ALS). Mutation to a gene called fused in sarcoma (FUS) are known to contribute to some cases of inherited ALS. The researchers showed that this mutation can suppress protein translation and interfere with how RNA functions in the body. The mutated proteins generated by the FUS gene disrupt an RNA quality-control pathway, which damages neuronal maintenance and function. Because this mutation suppresses how proteins are translated within cells and disrupts how RNA regulates cell activity, it likely contributes to the motor cell death seen in ALS. According to the researchers, the results will add to the understanding of both how this specific mutation can lead to inherited ALS, and more generally how ALS develops. (Proceedings of the National Academy of Sciences, Nov. 19, 2018) Patients more likely to use psychotropic medication in suicide attempts when they have a prescription Photo: ©iStock/DNY59 (11/21/2018) People at high risk for suicide who had a psychotropic medication prescription were more likely to use that type of drug in suicide attempts than those without a prescription, found a study including a Rocky Mountain Regional VA Medical Center researcher. The study looked at health insurance data for nearly 23,000 people who had attempted suicide. Those who had prescription access to a psychotropic drug were 1.7 times more likely to use that drug to attempt suicide than those without a prescription. People with antipsychotic or mood stabilizer prescriptions had the highest odds of using their prescription drug in a suicide attempt. Antianxiety drugs were the most common class of drugs used, regardless of prescription status, accounting for 59 percent of overdose attempts. The results show that people at risk for suicide with psychotropic prescriptions should be targeted for safety interventions, say the researchers. (Journal of Clinical Psychiatry, Nov. 6, 2018) High cholesterol linked to lower risk of death in chronic kidney disease patients Photo: ©iStock/lbodvar (11/21/2018) High cholesterol was linked to lower risk of death in chronic kidney disease patients, but higher risk of death in other patients, in a VA Long Beach Healthcare System study. Researchers looked at data on more than 2 million Veterans. They found that, in patients with chronic kidney disease, patients with cholesterol levels higher than 200 mg/dL had lower risk of all-cause death. However, patients without chronic kidney disease had a higher risk of death from cardiovascular conditions when their cholesterol was above 200 mg/dL. More research is needed to explore the seemingly paradoxical relationship between chronic kidney disease and cholesterol, according to the researchers. (American Heart Association Scientific Sessions, Nov. 10, 2018) Reasons for trauma-focused therapy drop-out Photo: ©iStock/asiseeit (11/21/2018) Minneapolis VA Healthcare System researchers explored why some Veterans with PTSD drop out of prolonged exposure and cognitive processing therapy, the two main forms of psychotherapy that VA uses to treat the condition. About one-third of Veterans who begin prolonged exposure and cognitive processing therapy do not complete treatment. Researchers interviewed 60 patients who completed treatment and 68 who did not to look for differences. They found differences between the groups in the strength of the working relationship between patient and therapist, patients’ ability to cope with increased distress, and internal motivation. Treatment buy-in, logistical factors such as transportation, and beliefs about treatment did not appear to influence the drop-out rate. (Annual Meeting of the International Society for Traumatic Stress Studies, Nov. 9, 2018) Diabetes prevention program equally effective online and in person Photo: ©iStock/Wand_Prapan (11/14/2018) Diabetes prevention programs delivered in person and online can be similarly effective for both older and younger Veterans, found a VA Ann Arbor Healthcare System study. Researchers looked at data from 378 Veterans enrolled in a weight management program either in-person or online. Over 70 percent of participants completed eight or more sessions within six months. A higher percentage of the online group completed at least eight sessions. Both online and in-person groups saw similar weight loss. Weight loss was the same for both younger participants and participants 65 or older. The results show that online programs may be an good way for diabetes prevention programs to reach older adults, say the researchers. (Diabetes Care, Oct. 30, 2018) Benzodiazepine use linked to greater hospitalization, suicide risk in those with PTSD Photo: ©iStock/happyphoton (11/14/2018) Patients with PTSD who were prescribed benzodiazepines, such as Valium or Xanax, had higher health care utilization and suicide risk than similar patients not given the drugs, in a study by VA Salt Lake City Health Care System researchers. They looked at data on more than 240,000 Veterans with PTSD. About 7 percent of those were prescribed benzodiazepines during the 14 years examined in the study. Patients prescribed benzodiazepines had more hospitalizations, as well as outpatient and mental health visits, than those not on the drug. Benzodiazepines users had a significantly greater risk of death from suicide, and were more likely to have suicide attempts or suicidal thoughts. The study strengthens the evidence against use of the drugs in Veterans with PTSD, according to the researchers. (Journal of Clinical Psychiatry, Oct. 23, 2018) Household paints likely to contain rash-causing allergen Photo: ©iStock/gece33 (11/14/2018) Household paints frequently contain isothiazolinones, despite claims on safety data sheets, according to a study featuring Minneapolis VA Medical Center researchers. Isothiazolinones are commonly used as preservatives in household products, but can cause allergic reactions. The researchers tested 47 common paints. All 47 contained at least one isothiazolinone. Concentration varied based on the type of isothiazolinone present. Isothiazolinones were present even in paint specifically advertised as being preservative-free. Safety data sheets, which are supposed to disclose potential allergens, were inaccurate and insufficient to warn against possible contact dermatitis, say the researchers. (Dermatitis, Oct. 20, 2018) Omega-3 fatty acids boost neurological health after stroke in mice Photo: ©iStock/BlackJack3D (11/07/2018) Omega-3 fatty acids were shown to improve neurological health after stroke, in a mouse study by VA Pittsburgh Health Care System researchers. The researchers gave mice food supplements of omega-3 polyunsaturated fatty acids, including from fish oil, for 35 days after a stroke. Mice given omega-3 had better cognitive function and neurovascular healing than those not on the supplements. Omega-3 was not as effective at improving cognitive function in older animals as in younger animals, although older animals did improve some. The results suggest that omega-3 fatty acid could be a promising therapy after stroke, say the researchers. (Neurobiology of Disease, Sept. 12, 2018) Battlefield acupuncture effective in both groups and individually Photo by Robert Turtil (11/07/2018) Battlefield acupuncture was effective in treating back pain in both group and individual settings, in a West Haven VA Medical Center study. In battlefield acupuncture, needles are placed in specific sites in the ear to influence the nervous system. The researchers treated 284 Veterans with back pain in either a group or individual setting, for a total of close to 800 treatment sessions. Patients self-reported a decrease in pain after 82 percent of treatments. Patients reported no change after 10 percent of treatments, and reported increased pain after 8 percent of the sessions. Both group and individual treatment had similar rates of effectiveness. The results confirm that battlefield acupuncture could be a useful treatment to relieve pain, whether administered in a group or individually. (Medical Acupuncture, Oct. 1, 2018) Study reveals how lungs protect against damage from cigarette smoke ©iStock/bagi1998 (11/07/2018) A study by VA Pittsburgh Healthcare System researchers explored mechanisms that protect the lungs from oxidants and how smoking can damage these processes. The researchers looked at two parts of the lungs’ defense system: an enzyme called GPx3 and a hormone receptor called PPAR-gamma. They found that GPx3 expression was decreased in the lungs of patients with chronic obstructive pulmonary disease (COPD). The study showed that PPAR-gamma responds to oxidative stress from cigarette smoke by increasing GPx3 production, which helps protect the lungs from damage. However, the researchers also found that cigarette smoke makes the relationship between GPx3 and PPAR-gamma less effective. They believe that the results could be useful in the development of more effective treatments for COPD. (Free Radical Biology and Medicine, October 2018)
Police Killings of Unarmed Black Americans Affect Mental Health of Black Community First Study to Show Mental Health “Spillover Effects” from Deaths of Unarmed Black Americans Newswise — PHILADELPHIA — Black Americans are nearly three times more likely to be killed by police than their white counterparts, with even larger disparities among those who are unarmed. The trend is also harming the mental health of the black community, according to new research published in The Lancet from the Perelman School of Medicine at the University of Pennsylvania and the Boston University School of Public Health. “These deaths don’t just have immediate consequences for the families and friends. There’s a true mental health spillover effect for those not directly involved,” said Atheendar S. Venkataramani, MD, PhD, an assistant professor of Medical Ethics and Health Policy in Penn’s Perelman School of Medicine, and co-lead author of the study. In a national survey of nearly 40,000 black Americans who were interviewed within three months following at least one death of a black American at the hands of police in their state, the team found that police killings of unarmed black Americans were associated with worse mental health among other black Americans in the United States general population. “Addressing this problem will require interventions to reduce the prevalence of police killings as well as programs that mitigate the adverse mental health effects in communities when these events occur,” said co-lead author Jacob Bor, ScD, SM, an assistant professor at the Boston University School of Public Health. “More broadly, the findings indicate that events widely perceived to reflect structural racism cause significant harm to the mental health of black Americans. Efforts to reduce health disparities should explicitly target structural racism.” Structural racism is described as policies, laws, practices, and other norms entrenched in institutions that can harm a certain racial group and perpetuate racial inequities. The researchers combined newly released data on police killings between 2013 and 2016 from the Mapping Police Violence Project database with data from the U.S. Behavioral Risk Factor Surveillance System (BRFSS) of over 103,000 black Americans. BRFSS is a nationally-representative, telephone-based, random-digit dial survey of adults ages 18 years and older. The primary exposure was the number of police killings of unarmed black Americans occurring in the three months prior to the person being surveyed. Exposure included word of mouth and news stories in print, radio, television, and/or social media. To measure mental health outcomes, the researchers asked respondents: “Now thinking about your mental health, which includes stress, depression, and problems with emotions, for how many days during the past 30 days was your mental health not good?” Researchers then compared the number of poor mental health days experienced by black Americans surveyed after a police killing of an unarmed person to that of black Americans residing in the same state surveyed before that event. Overall, the study suggests the police killings could contribute 1.7 additional poor mental health days per person ever year, or 55 million more poor mental health days every year among black Americans in the United States. To contextualize those numbers, the authors point to diabetes, which is responsible for an estimated 75 million poor mental health days among black Americans. “Our estimates therefore suggest that the population mental health burden from police killings among black Americans is nearly as large as the mental health burden associated with diabetes,” they wrote. The study shows, for the first time, that police killings of unarmed black Americans have a “meaningful, population-level impact” on the mental health of other black Americans. “The effects are likely even larger than what we estimated,” said Venkataramani, pointing to the fact that more high-profile cases of police killings that grabbed national media attention could have exerted mental health effects among black Americans living in other states, as well. Importantly, the researchers saw no spillover mental health effects among white respondents, nor among respondents of either race in response to police killings of unarmed whites or of armed black Americans. This striking specificity points to the importance of structural racism as a key mechanism underlying the study findings, and a driver of population health, more generally, the authors said: “[P]olice killings of unarmed black Americans are perceived by many as manifestations of structural racism and as implicit signals of the lower value placed on black lives by law enforcement and legal institutions – as well as by society at large.” Co-authors of the study include David R. Williams, PhD, of the Harvard T.H. Chan School of Public Health, and Alexander C. Tsai, of Massachusetts General Hospital. ### Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise. The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $405 million awarded in the 2017 fiscal year. The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation’s first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine, and Princeton House Behavioral Health, a leading provider of highly skilled and compassionate behavioral healthcare. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2017, Penn Medicine provided more than $500 million to benefit our community.
In rare occurrences, forceful manipulation of the neck is linked to a damaging side effect: vision problems and bleeding inside the eye. For those in the habit of getting their neck adjusted by a chiropractor, the University of Michigan Kellogg Eye Center has an interesting case to know about: High velocity neck manipulation has been shown to result in stress on the eye and lead to spotty vision. The risk is rare, but one that Yannis Paulus, M.D., a retina specialist at Kellogg, reports on in the American Journal of Ophthalmology Case Reports. The energetic thrusts and rotations sometimes performed in high-velocity neck manipulation have been linked to damage to the blood vessels in the retina. Resulting abnormal bleeding inside the eye may also cause vision loss. This was the case for a 59-year-old woman who experienced a “tadpole” shaped spot in her vision while driving home from a chiropractor visit — with her sight worsening the next day. She had just received cervical spine manipulation using the high-velocity technique to help with her headaches. The woman’s vision returned to normal in about two weeks without treatment. She was referred to Kellogg Eye Center by her optometrist who co-authored the case report. Because the cells of the retina are so sensitive, even small injuries to the blood vessels can translate to vision problems. That’s why Paulus encourages patients to report their alternative medicine pursuits — and for physicians to actively listen and inform them of possible related side effects. Risks from chiropractic treatment Cardiovascular experts have been outspoken about health risks of chiropractic treatment. High-velocity neck manipulation has been associated with a certain type of stroke, or vertebral artery dissection, which led the American Heart Association to issue a warning statement in 2014. The short, rapid movements of neck manipulation may cause a small tear in the artery walls in the neck. The artery wall injury can result in a stroke if a blood clot forms at the site and later breaks free to block a blood vessel in the brain. Eye problems can follow, including double vision or central retinal artery occlusion, a blockage of the artery carrying oxygen to the nerve cells in the retina at the back of the eye. But the case at Kellogg suggests a new complication: direct damage to structures in the eye due to the force of neck adjustments. It’s the first case report of chiropractic care leading to multiple preretinal hemorrhages, authors say. Other possible complications are disrupting the vitreous humor — the clear, gel-like substance that fills the eye between the lens and the retina. The high-velocity technique may have induced a posterior vitreous detachment, or PVD, which occurs when the vitreous humor pulls away from the retina. No specific treatment is needed for PVD. Most patients no longer notice flashes in their vision after three months and “floaters” tend to improve, according to the American Society of Retina Specialists. Complications from PVD are rare but can be serious and in some cases require urgent treatment such as laser treatment to seal the retinal tear or surgery for a retinal detachment. Although the connection to chiropractic care is considered a temporal association, the timing of the patient’s eye symptoms following the chiropractic visit is hard to ignore. Paulus didn’t rule out future chiropractic visits for the patient but notes that “her chiropractor may need to modify techniques used during her visits.”
Newswise — In a proof-of-principle study, researchers at Johns Hopkins report that a certain liver immune cell called a macrophage contains only defective or inert HIV-1 copies, and aren’t likely to restart infection on their own in HIV-1-infected people on long-term antiretroviral therapy (ART). The study, the investigators say, strongly suggest that defective or inert HIV-1 can remain in the liver macrophages for up to ten years without functioning as an HIV-1 “reservoir” that can replicate the virus at high levels. A report of the findings was published online on Sept. 10 and in the Oct. issue of the Journal of Clinical Investigation. “Our study was the first, to our knowledge, in which purified liver tissue macrophages from HIV-1 infected people taking ART directly tested the idea that tissue macrophages are a long-lived active HIV-1 reservoir,” says Ashwin Balagopal, M.D., an associate professor in the Division of Infectious Diseases at the Johns Hopkins University School of Medicine. According to the U.S. Centers for Disease Control and Prevention (CDC), 36.7 million people worldwide and 1.1 million people in the U.S. are infected with HIV-1. Commonly, ART is successfully used to suppress the replication of HIV-1 and stop or control the progression of acquired immunodeficiency syndrome (AIDS) in humans. The virus infects the body’s immune system cells, commonly forming a persistent, and reservoir in humans in so-called resting memory CD4+ T white blood cells. Macrophages work with T cells normally to envelop and clear tissues of microbes and debris. The inability to completely wipe out pools of infectious HIV-1 has for decades frustrated efforts to completely cure the infection. And it means that the interruption or discontinuation of ART at any time re-activates HIV-1 replication, spreading the virus to new cells. As a result, Balagopal says, investigators are increasingly focused more specifically on the location and biology of these HIV-1 reservoirs. To determine if liver macrophages were a true source of infection-capable HIV-1 reservoirs after ART, liver tissue samples were taken from nine HIV-1 infected persons, seven of whom underwent liver transplantation at the Johns Hopkins Hospital and would have otherwise had their livers discarded. Eight of the nine persons were on ART for periods ranging from eight to 140 months. The sample group included only adults whose demographic information is considered exempt from human subject research because all samples were obtained strictly for scientific reasons or postmortem, and would otherwise have been discarded. The Johns Hopkins School of Medicine institutional review approved this study protocol. Using lab techniques that both measure HIV-1 containing T cells and separate out the liver macrophages, the researchers found HIV-1 to be present in the macrophages even after exposure to longstanding virus-suppressing ART. However, Balagopal said that when his team tried to simulate virus “rebound” from the liver macrophages in the laboratory, they found only “fragments of HIV-1 in small quantities, without robust growth of full-length, infectious virus.” The researchers found that HIV-1 was in the liver macrophages of one subject who took ART for 11.7 years. They concluded that while liver macrophages might harbor HIV-1 for a long time, it’s unlikely these viruses could continue an infection on their own, unlikely to function as a reservoir, because the viruses were not able to replicate. Balagopal cautioned that their study results still affirm the need to address liver macrophage infection, because even if inert, these cells may be able to produce portions of viral proteins that can misdirect the immune system. “These results contribute an important piece in our efforts to understand the role of non-T cells, such as macrophages, as HIV-1 cellular reservoirs in individuals on long-term ART, but also may help the research community focus on additional cure strategies," Abraham Kandathil, Ph.D., a research associate in the Division of Infectious Diseases at Johns Hopkins University School of Medicine who performed all of the key experiments. In the future, Kandathil says, more research is needed to determine if the inert HIV-1 infected liver macrophages have any functional significance in people taking ART because expression of defective HIV-1 proteins can confuse the immune system and cause tissue inflammation. “To find a comprehensive HIV-1 cure, it’s important to identify all of the relevant HIV-1 reservoirs in the body, since it’s possible that the virus hides in the DNA of numerous cell types and each may require different strategies to get a cure,” says Balagopal. Balagopal noted that their study was limited by the small number of liver macrophages and human samples studied, as well as the small number of CD4+ T cells in the liver cell cultures that may have prevented the researchers’ ability to detect them. Other authors on this paper include Sho Sugawara, Christine M. Durand, Jeffrey Quinn, Jaiprasath Sachithanandham, Andrew M. Cameron, and Justin R. Bailey of the Johns Hopkins University School of Medicine along with Ashish Goyal and Alan S. Perelson from Los Alamos National Laboratory. This research is supported by grants from the National Institute of Allergy and Infectious Diseases (K08 AI 081544, R56 AI 118445, R01 AI024333, R01 AI116868, and P01 AI131365), the National Institute on Drug Abuse (R01 DA 016078), the National Institutes of Health Office of the Director (R01 OD 011095 and 108707-54-RKRL ) and amfAR, the Foundation for AIDS Research (108814-55-RGRL). The authors have declared that no conflict of interest exists.
More than 1 in 10 people aged 50-64 have had genetic tests ordered by a doctor or ordered directly. Many more want to – but also worry about worrying Newswise — ANN ARBOR, MI – Only a small percentage of people in their 50s and early 60s have had their DNA tested – either for medical reasons, to learn their ancestry or out of curiosity – but far more have an interest in getting such tests done, according to a new poll. One in 10 have taken genetic tests offered directly to consumers, and one in 20 have taken genetic tests ordered by a doctor, according to new findings from the National Poll on Healthy Aging. More than half expressed interest in getting DNA tests to guide medical care, understand health risks or know their ancestry. Still, the poll finds, that desire to know more about their risk of disease or heritage comes with a grain of salt. Two thirds of those polled said they thought genetic testing could lead them to worry too much about their future health. The poll of 993 adults between the ages of 50 and 64 was conducted by the University of Michigan Institute for Healthcare Policy and Innovation, and sponsored by AARP and Michigan Medicine, U-M’s academic medical center. It comes at a time when the U.S. Food and Drug Administration has approved several disease-specific tests to be marketed directly to the public, instead of requiring a physician to order them. The poll also asked respondents their interest in testing to learn their genetic risk for three later-life disorders: Alzheimer’s disease, Parkinson’s disease or macular degeneration. Around two-thirds had at least some interest in each test. Scott Roberts, Ph.D., a professor from the U-M School of Public Health who has studied use of genetic testing, including direct-to-consumer testing, worked on the poll’s design and analysis. He notes that even those who get direct-to-consumer genetic tests mainly to learn about their ancestral heritage could end up being “blindsided” by findings showing that they have a high risk of diseases such as Alzheimer’s. “Compared to previous findings in the general adult population, this age group appears to be a little more lukewarm about their views of the benefits versus the risks of genetic testing overall,” he says. “The majority said they might be interested in knowing their risk for specific conditions, but on other hand they were worried about potential psychological distress from the results.” Roberts points out that the accuracy of any genetic test is not 100 percent. He also notes that testing ordered by physicians often comes with a chance to meet with a genetic counselor – a specially trained clinician who can help patients decide whether to get tested, prepare them for handling the results, and help them understand what the results do and don’t mean. By contrast, direct-to-consumer testing often comes with none of these services, and individuals who buy DNA tests directly may encounter difficulty in interpreting them, or getting access to a genetic counselor after they receive their results. Genetic counselors are already in high demand for clinical cases, and their appointment times are prioritized for those who have a clinical reason for DNA testing, including family history of a serious genetic illness. “Patients may not think about the downstream effects of direct-to-consumer genetic testing. An unexpected positive result may lead to several additional tests that may or may not be covered by insurance,” says Preeti Malani, M.D., director of the poll and a professor of internal medicine at the U-M Medical School who has special training in geriatric medicine. Experience with testing The five percent of the poll respondents who had already had a genetic test ordered by their physician said it was done either because the physician suggested it or because they had wanted to find out more about their risk of disease or how best to manage a current condition. Ten percent had had a direct-to-consumer test. More than 70 percent of them said they were interested in learning more about their ancestry, and just under half said they were just curious about their genetic make-up. Just over one in 10 said they got tested to find out more about their health in general, or their risk of a particular disease. Combining the two types of genetic testing, 14 percent had had either kind. “We’re living in an era when advances like DNA testing are providing an amazing amount of useful health information,” says Alison Bryant, Ph.D., senior vice president of research for AARP. “As genetic testing becomes even more sophisticated and common among older adults, the challenge will be to ensure that people understand the benefits and limitations of these tests.” Future of genetic testing Roberts, who specializes in genetic testing for Alzheimer’s disease, notes that 70 percent of poll respondents had an interest in learning their Alzheimer’s risk. Newer clinical trials of drugs that aim to prevent, delay or slow progression of memory loss and other cognitive problems are actually looking to enroll people who have a higher-than-usual genetic risk of Alzheimer’s. So those who elect to buy such a test, or whose doctors order one for them because of family history, may now have an action they can take based on their results. “Before, there wasn’t much we could recommend, but now there are more research opportunities to take part in, and we know more about health behaviors earlier in life that can affect the risk of Alzheimer’s and other forms of dementia later in life,” he says. Poll respondents seemed to understand how genetic testing provides a potential window into the future, both for their own health risks (90 percent agreed with this idea) or for those of their children and grandchildren (86 percent). But 41 percent said that a genetic test wasn’t necessary if they already know what disease risks run in their family. The poll results are based on answers from a nationally representative sample of 993 people ages 50 to 64. The poll respondents 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 it. A full report of the findings and methodology is available at www.healthyagingpoll.org, along with past National Poll on Healthy Aging reports.
Highlights The blood pressure–lowering medication ramipril reduced protein excretion—or proteinuria—in children with chronic kidney disease. Greater reductions in proteinuria during the first months of treatment were linked with a lower risk of kidney disease progression. Newswise — Washington, DC (June 21, 2018) — In a study of children with chronic kidney disease (CKD), blood pressure medications reduced protein excretion in the urine, which was linked with a lower risk of disease progression. The findings, which appear in an upcoming issue of the Journal of the American Society of Nephrology (JASN), provide valuable information for monitoring and treating pediatric patients with CKD. The excretion of protein in the urine, or proteinuria, indicates an increased risk for kidney and heart problems, and it is known in adult patients that this risk can be lowered with medications called angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers. Both types of drugs cause blood vessel relaxation and a decrease in blood pressure. It has not been clear, however, whether these medications benefit children with proteinuria. To investigate, Sophie van den Belt, MD, PhD (University Medical Center Groningen, in The Netherlands) and her colleagues analyzed data from the Effect of Strict Blood Pressure Control and ACE inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) trial. This trial investigated whether intensified blood pressure control can delay the progression of chronic kidney disease (CKD) in children with the condition. In total, 280 children with CKD stage 2–4 received a fixed dose of the ACE inhibitor ramipril and were subsequently randomized to conventional or intensified blood pressure control with antihypertensive medications. The average initial proteinuria lowering was 40.2% in the conventional blood pressure control group and 46.7% in the intensified blood pressure control group. Due to the similar initial proteinuria change in the 2 study arms, the groups were combined for further analysis. The investigators found that ramipril therapy lowered proteinuria by an average of 43.5%. Also, a higher degree of proteinuria lowering during the first months of treatment was linked with a lower risk of CKD progression. “The results indicate that a higher initial proteinuria reduction with ACE inhibition is independently associated with long-term preservation of renal function in children with CKD. This finding suggests that proteinuria lowering is an important target in the management of pediatric CKD,” said Dr. van den Belt. Study co-authors include Hiddo Lambers Heerspink, PharmD, PhD, Valentina Gracchi, MD, PhD, Dick de Zeeuw, MD, PhD, Elke Wühl, MD, PhD, and Franz Schaefer, MD, PhD, for the ESCAPE trial group. Disclosures: The ESCAPE study was supported by grants of the Boehringer Ingelheim Stiftung, the European Commission (5th Framework Programme QLRT-2001-00908, the Kuratorium für Dialyse und Nierentransplantation e.V., Neu-Isenburg, and the Baxter Extramural Grant Program. The study protocol was developed exclusively by the participants. Onsite monitoring of study data collection was performed by an independent clinical research organization (Omnicare Clinical Research). Aventis Pharmaceuticals supplied ramipril and financed the GCP audit. Dr. Schaefer reports serving as a paid advisor for Abbvie, Astellas, and Bayer. No other potential conflicts of interest relevant to this article were reported. The article, entitled “Early proteinuria lowering by ACE inhibition predicts renal survival in children with chronic kidney disease,” will appear online at http://jasn.asnjournals.org/ on June 21, 2018, doi: 10.2215/ASN.2018010036. The content of this article does not reflect the views or opinions of The American Society of Nephrology (ASN). Responsibility for the information and views expressed therein lies entirely with the author(s). ASN does not offer medical advice. All content in ASN publications is for informational purposes only, and is not intended to cover all possible uses, directions, precautions, drug interactions, or adverse effects. This content should not be used during a medical emergency or for the diagnosis or treatment of any medical condition. Please consult your doctor or other qualified health care provider if you have any questions about a medical condition, or before taking any drug, changing your diet or commencing or discontinuing any course of treatment. Do not ignore or delay obtaining professional medical advice because of information accessed through ASN. Call 911 or your doctor for all medical emergencies. Since 1966, ASN has been leading the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients. ASN has more than 18,000 members representing 112 countries. For more information, please visit www.asn-online.org or contact the society at 202-640-4660.
MEDICAID EXPANSION HAS HELPED LOW-INCOME KIDNEY FAILURE PATIENTS GET ON THE TRANSPLANT WAITLIST BEFORE STARTING DIALYSIS
Highlights In states that expanded Medicaid under the Affordable Care Act to cover more low-income individuals, there was an increase in the number of Medicaid beneficiaries who were preemptively waitlisted to receive a kidney transplant. Medicaid expansion was associated with greater gains racial and ethnic minorities in being listed pre-emptively on the transplant waitlist compared with whites. Newswise — Washington, DC (June 21, 2018) — New research indicates that Medicaid expansion under the Affordable Care Act has helped to place many low-income individuals with chronic kidney disease (CKD) on the kidney transplant waiting list before starting dialysis. In addition, after expansion, there were larger gains in pre-emptive listing for minorities with Medicaid coverage than for whites. The findings appear in an upcoming issue of the Clinical Journal of the American Society of Nephrology (CJASN). Kidney transplantation is considered more cost-effective than dialysis, and preemptive wait-listing—or placing patients on the kidney transplant waiting list before they require dialysis—can help minimize the time that patients will eventually need to spend on dialysis before receiving a kidney transplant. Access to the kidney transplant waiting list is generally contingent on having health insurance coverage, however. Medicare provides a health insurance safety net once individuals develop kidney failure and require dialysis, but prior to Medicaid expansion under the Affordable Care Act, no similar safety net existed for low income individuals with advanced CKD who were not yet on dialysis. Studies are needed to determine whether Medicaid expansion under the Affordable Care Act has provided opportunities for low-income individuals with CKD to get the care they need. To investigate, Meera Nair Harhay, MD, MSCE, FASN (Drexel University College of Medicine) and her colleagues examined information from the United Network of Organ Sharing database on adults listed for kidney transplantation before dialysis dependence in 2011–2013 (pre–Medicaid expansion) and 2014–2016 (post–Medicaid expansion). “We explored whether Medicaid expansion, in offering an option for health insurance coverage for low-income individuals in the United States, would be associated with an increase in the number of Medicaid beneficiaries on the kidney transplant waiting list,” said Dr. Harhay. The team found that after states expanded Medicaid to cover more low-income individuals, there was an increase in preemptive listings of Medicaid beneficiaries. States that fully implemented Medicaid expansion on January 1, 2014 had a 59% relative increase in Medicaid-covered preemptive listings from the pre-expansion to post-expansion period, compared with an 8.8% relative increase among Medicaid non-expansion states. From the pre- to post-expansion period, the adjusted proportion of listings with Medicaid coverage decreased by 0.3 percentage-points among non-expansion states and increased by 3.0 percentage-points among expansion states. Also, more of the new racial/ethnic minority listings from expansion states were Medicaid beneficiaries, as compared with the new white listings. In addition, Medicaid beneficiaries on the waiting list from Medicaid expansion states were more likely to be employed and functionally independent than Medicaid beneficiaries on the waiting list from non-expansion states. The authors noted that additional studies are needed to determine whether long-term transplant outcomes differ among candidates who were listed with expanded Medicaid coverage compared with those with other coverage options. In an accompanying editorial, Nitender Goyal, MD and Daniel Weiner, MD, MS (Tufts Medical Center) note that policies that improve access to care can have a tremendous impact on the delivery of medical care. “Harhay and colleagues elegantly quantified this by describing the effects of access to Medicaid on preemptive kidney transplant listing. Much harder to quantify but likely far more numerous are the patients who, because of earlier diagnosis and treatment of their kidney disease may never need to be listed for a kidney transplant, but rather will be able to maintain kidney health with better access to medical care,” they wrote. Study co-authors include Ryan M. McKenna, PhD, Suzanne M. Boyle, MD, Karthik Ranganna, MD, Lissa Levin Mizrahi, MD, Stephen Guy, MD, Gregory E. Malat, PharmD, Gary Xiao, MD, David J. Reich, MD, and Michael O. Harhay, PhD. Disclosures: The authors reported no financial disclosures. The article, entitled “Association Between Medicaid Expansion Under the Affordable Care Act and Preemptive Listings for Kidney Transplantation,” will appear online at http://cjasn.asnjournals.org/ on June 21, 2018, doi: 10.2215/CJN.00100118. The editorial, entitled “The Affordable Care Act, Kidney Transplant Access and Kidney Disease Care in the United States,” will appear online at http://cjasn.asnjournals.org/ on June 21, 2018. The content of this article does not reflect the views or opinions of The American Society of Nephrology (ASN). Responsibility for the information and views expressed therein lies entirely with the author(s). ASN does not offer medical advice. All content in ASN publications is for informational purposes only, and is not intended to cover all possible uses, directions, precautions, drug interactions, or adverse effects. This content should not be used during a medical emergency or for the diagnosis or treatment of any medical condition. Please consult your doctor or other qualified health care provider if you have any questions about a medical condition, or before taking any drug, changing your diet or commencing or discontinuing any course of treatment. Do not ignore or delay obtaining professional medical advice because of information accessed through ASN. Call 911 or your doctor for all medical emergencies. Since 1966, ASN has been leading the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients. ASN has more than 18,000 members representing 112 countries. For more information, please visit www.asn-online.org or contact the society at 202-640-4660.
Newswise — ANN ARBOR, Mich. — Philosophers have pondered the nature of consciousness for thousands of years. In the 21st century, the debate over how the brain gives rise to our everyday experience continues to puzzle scientists. To help, researchers in the University of Michigan Medical School Center for Consciousness Science are working to identify areas of the brain that help us wake up, a basic building block of everyday consciousness. In the search for what controls our overall level of consciousness, researchers have traditionally focused on structures in the lower part of the brain. These structures include the brainstem (which regulates vital functions like breathing, blood pressure and heartbeat); the hypothalamus (which is involved in sleep and controlling bodily functions); and the thalamus (which relays information from the senses). George Mashour, M.D., Ph.D., professor in the Department of Anesthesiology and director of the center, decided to look at different areas of the cortex, the upper part of the brain, for its ability to control the level of consciousness. Recent research in nonhuman primates provides evidence that the prefrontal cortex has a switchboard-like relationship with other areas of the brain, helping to ignite awareness of visual information. “There has been a debate that has recently intensified as to whether or not the prefrontal cortex — versus areas farther back — plays a role in generating conscious experience. We thought that we’d target some of these different areas in the front and back of the brain to see which ones had the ability to control the level of consciousness,” he says. The key to ignition? Because anesthesia is used to temporarily eliminate conscious experience during medical procedures, it provides the perfect opportunity to test hypotheses about consciousness. Mashour and lead-author Dinesh Pal, Ph.D., also of the Department of Anesthesiology, anesthetized rats with a common anesthetic used in humans. “We wanted to see what had the causal power to take an unconscious brain receiving ongoing anesthesia and wake it up,” says Pal. To test this, they targeted two neurotransmitters that are associated with wakefulness: acetylcholine and norepinephrine. The team exposed the anesthetized rats’ prefrontal and parietal cortex to drugs that ramped up the effect of the neurotransmitters and measured their brain activity and behavior. When exposed to an acetylcholine-receptor activator, their brain waves, normally slow during sleep and anesthesia, sped up. But rats were able to start behaving as though they were awake only with prefrontal cortex stimulation, all while continuing to receive the same level of anesthesia that is used clinically for surgery in humans. These findings were published in the journal Current Biology. Mashour says their new study “suggests that the prefrontal cortex also has the potential to play a role in coordinating the level of consciousness, possibly through the cholinergic system.” Clinically, these results could be explored for applications in people with disorders of consciousness, such as coma or vegetative states. “Let’s say you have a patient in a coma: Could the prefrontal cortex be a site that is modulated to help coordinate events to help improve level of consciousness?” Mashour asks. The implications of this possibility are significant because of the relative accessibility of the prefrontal cortex. “It’s very difficult and dangerous to directly intervene at the level of arousal centers in the brainstem because of its location, small size and nearby vital functions. Maybe the prefrontal cortex is an accessible gateway to some of those other arousal systems that could be leveraged in a clinical setting outside of anesthesia,” he says. This work was funded by the National Institutes of Health (R01GM098578), and the Department of Anesthesiology, University of Michigan Medical School, Ann Arbor. Physiology doctoral student Jon Dean was co-first author of the article.
EMBARGOED AJPH RESEARCH: PROP. 47 AND DRUG ARRESTS, TEEN SELF-INJURY, LGBQ SUBSTANCE ABUSE, WOMEN’S TOBACCO USE, PUBLIC HOUSING AND ASTHMA
American Journal of Public Health August Issue research highlights: Proposition 47 reduced racial disparities in California drug possession arrests Newswise — In the month following passage of Proposition 47 in California, absolute black–white disparities in monthly felony drug arrests decreased from 81 to 44 per 100,000 and continued to decrease over time. During the first year after enactment, felony drug arrests fell by an estimated 51,985 among whites, 15,028 among blacks, and 50,113 among Latinos. Researchers concluded that reducing criminal penalties for drug possession can reduce racial/ethnic disparities in criminal justice exposure and has implications for improving health inequalities linked to social determinants of health. The study used data on all drug arrests made in California from 2011 to 2016, comparing racial/ethnic disparities in drug arrests between whites, blacks and Latinos, immediately and 1 year after policy changes, controlling for secular and seasonal trends. [Author Contact: Alyssa C. Mooney, Department of Epidemiology and Biostatistics, San Francisco, CA. “Racial/Ethnic Disparities in Arrests for Drug Possession After California Proposition 47, 2011–2016.”]. Teenagers at high risk of self-injury; higher among girls As much as 30 percent of girls in some areas of the United States self-harm without the intention of suicide. This research found rates of boys reporting purposefully hurting themselves without wanting to die over the past 12 months ranged from 6.4 percent (in Delaware) to 14.8 percent (in Nevada). Rates for girls varied from 17.7 percent (in Delaware) to 30.8 percent (in Idaho). Rates of self-injury declined with age and varied by race and ethnicity. Depression; suicidal thoughts, plans and attempts; sexual minority status; being electronically bullied; and smoking and substance use were associated with non-suicidal self-injury. [Author Contact: Martin A. Monto, Department of Sociology and Social Work, University of Portland, Portland, OR. “Nonsuicidal Self-Injury Among a Representative Sample of US Adolescents, 2015.”]. LGBQ adolescents at substantially greater risk of substance abuse Researchers found that LGBQ adolescents were 1.12 times as likely as heterosexual adolescents to report any lifetime substance abuse and 1.27 times more likely to report past 30-day substance use. LGBQ adolescents had significantly greater risk for alcohol, tobacco and other illicit drugs. LGBQ adolescents were more than 3.5 times as likely to use methamphetamines, more than 2.7 times as likely to use hallucinogens and more than 2.6 times as likely to use steroids or ecstasy. Study authors conclude policymakers should invest in prevention and early intervention resources to address substance use risks among LGBQ adolescents. [Author Contact: John W. Ayers, Graduate School of Public Health, San Diego State University San Diego, CA. " Substance Use Among Lesbian, Gay, Bisexual, and Questioning Adolescents in the United States, 2015."]. Women’s cigarette use decreased; blunt use increased over time This analysis of data from the U.S. National Survey on Drug Use found among all women, cigarette use decreased, blunt use increased and cigar use remained stable between 2006 and 2016. Among pregnant women, smoking prevalence was highest in the first trimester. From 2006 to 2016, pregnant women were less likely to smoke cigarettes, cigars and blunts than were nonpregnant women, with declines in use occurring from first to third trimesters. Across all years, the likelihood of pregnant women having smoked cigarettes in the past 30 days (14.5 percent) was lower than in nonpregnant women (26.4 percent). Similarly, the likelihood of pregnant women having smoked cigars (1.2 percent) was lower than in nonpregnant women (3.4 percent). The likelihood of pregnant women having smoked blunts (1.8 percent) was lower than in nonpregnant women (4.0 percent). The likelihood of blunt smoking is increasing among reproductive-aged women, with use in the second and third trimesters increasing since 2013. Researchers concluded that pregnancy is an opportunity for mothers to reduce or discontinue tobacco use. [Author Contact: Victoria H. Coleman-Cowger, Battelle, Baltimore, MD." Cigar and Marijuana Blunt Use Among Pregnant and Nonpregnant Women of Reproductive Age in the United States, 2006–2016."]. Residents of public housing and rental assistance twice as likely to have asthma This research found the rate of asthma was 2.02 and 2.34 times higher among public housing development residents and rental assistance renters, respectively, than among homeowners in Boston. Researchers observed smoking-related effect modification. This heightened asthma rate remained consistent when researchers compared the rate with non-public housing renters who were eligible for subsidized housing according to income. Smoking was found to modify the association between housing status and current asthma, and the associations of public housing residents and rental assistance residents were highest in magnitude among ever-smokers. [Author Contact: Amar J. Mehta, Research and Evaluation Office, Boston Public Health Commission, Boston, MA "Subsidized Housing and Adult Asthma in Boston, 2010–2015."]. Uninsured and minorities less likely to receive smoking cessation help from health clinics Researchers found that odds of receiving counseling and medication from a health clinic to help quit smoking were lower among uninsured patients and those of a race/ethnicity other than non-Hispanic White. The odds of receiving smoking cessation help were also lower among patients with diabetes. The odds of receiving smoking cessation assistance were higher for older patients, those with comorbidity, women and those with more visits. Authors concluded that disparities in smoking cessation assistance exist in health clinic settings. [Author Contact: Steffani R. Bailey, PhD, Oregon Health & Science University, Department of Family Medicine, Portland, OR "Disparities in Smoking Cessation Assistance in US Primary Care Clinics."]. Find a full list of AJPH research papers published online below: Austerity Policies and Mortality in Spain after the Financial Crisis of 2008. Human Experimentation In Public Schools: How Schools Served As Sites Of Vaccine Trials In The Twentieth Century Did Reducing Criminal Penalties for Drug Possession in California Affect Racial Disparities in Drug Arrests? Prevention of Underage Drinking on California Indian Reservations Using Individual- And Community-Level Approaches Substance Use Among Lesbian, Gay, Bisexual And Questioning Adolescents In The United States, 2015 Community And Street-Scale Supports For Walking In The US Virgin Islands Before The 2017 Hurricanes Childhood Experiences Of Sexual Violence, Pregnancy, And Marriage Associated With Child Sex Trafficking Among Female Sex Workers In Two US-Mexico Border Cities. Industry Support Of Patient Advocacy Organizations: The Case For Sunshine Subsidized Housing And Adult Asthma: Findings From A Population-Based Health Survey In Boston Non-Suicidal Self-Injury Among A Representative Sample Of U.S. Adolescents, 2015 Cigar And Marijuana "Blunt" Use Among Pregnant And Non-Pregnant Women Of Reproductive Age In The United States, 2006-2016 Early Childhood Caries: Determinants Of Country Level Prevalence And Data Availability Disparities In Smoking Cessation Assistance In US Primary Care Clinics Homeless Children Seeking Shelter In An Urban Pediatric Emergency Department After State Housing Policy Change HPV Knowledge And Vaccine Awareness, Intention, And Uptake Among Adult Inmates In Kansas When Inclusion Excludes: Epidemiological Reframing Of Behavioral Diagnoses And Home Experiences Of Deaf Children Toward Real-Time Infoveillance Of Twitter Health Messages: Practical Considerations For Data Collection, Management, And Human Coding. Incarceration And Health Of Sexual And Gender Minority Persons Compliance In 2017 With Federal Calorie Labeling In 90 Chain Restaurants And 10 Retail Food Outlets Prior To Required Implementation The articles above will be published online June 21, 2018, at 4 p.m. ET by AJPH under “First Look.” “First Look” articles have undergone peer review, copyediting and approval by authors but have not yet been printed to paper or posted online by issue. AJPH is published by the American Public Health Association, and is available at www.ajph.org. Complimentary online access to the Journal is available to credentialed members of the media. Address inquiries to Megan Lowry at APHA, 202-777-3913, or email her. A single print issue of the Journal is available for $35 from the Journal’s Subscriptions Department. If you are not a member of the press, a member of APHA or a subscriber, online single-issue access is $30, and online single-article access is $22 at www.ajph.org. For direct customer service, call 202-777-2516, or email us. To stay up-to-date on the latest in public health research, sign up for new content email alerts. ### The American Journal of Public Health is the monthly journal of the American Public Health Association. APHA champions the health of all people and all communities. We strengthen the public health profession. We speak out for public health issues and policies backed by science. We are the only organization that influences federal policy, has a nearly 150-year perspective and brings together members from all fields of public health. Visit www.apha.org.
Newswise — BIRMINGHAM, Ala. – A surprising form of cell-to-cell communication in glioblastoma promotes global changes in recipient cells, including aggressiveness, motility, and resistance to radiation or chemotherapy. Paradoxically, the sending cells in this signaling are glioblastoma cells that are undergoing programmed cell death, or apoptosis, according to research by a team at institutes in the United States, Russia and South Korea. The dying cancer cells send their signals by means of extracellular vesicles induced and released during apoptosis. These vesicles — small, membrane-bound blobs known as exosomes — carry components that alter RNA splicing in the recipient glioblastoma cells, and this altered splicing promotes therapy resistance and aggressive migration. This mechanism thus becomes a possible target for new therapies to treat glioblastoma, a primary brain cancer, and the mechanism may apply to other cancer types as well. “Clinically, our data may provide the rationale to the molecular targeting of RNA splicing events or specific splicing factors for novel cancer therapies,” said Ichiro Nakano, M.D., Ph.D., leader of the international studybeing published in Cancer Cell. “This may lead to decreased acquisition of therapy resistance, as well as reduction in the migration of cancer cells.” Nakano is an academic neurosurgeon at the University of Alabama at Birmingham who conducts both brain tumor translational research and clinical brain tumor surgery. He is professor of neurosurgery in the UAB School of Medicine and a senior scientist for the UAB Comprehensive Cancer Center. Glioblastoma exhibits invasive behavior, abrupt growth and poor patient survival. As the number of the cancer cells rapidly increases, abundant apoptotic tumor cells are intermingled with neighboring proliferating tumor cells. The apoptotic cells can account for up to 70 percent of the tumor cell population. The discovery of this unusual cell-to-cell communication began with a simple experiment — injecting a combination of lethally irradiated human glioblastoma cells, which makes them apoptotic, and “healthy” glioblastoma cells into a mouse xenograft model. This combination led to much more aggressive tumor growth, as seen in brain scans, compared to “healthy” glioblastoma cells or irradiated glioblastoma cells alone. The combination was also more therapy-resistant. The UAB researchers and colleagues found that, after induction of apoptosis, glioblastoma cells shed significantly higher numbers of exosomes with larger average sizes. Those apoptotic exosomes, when combined with “healthy” glioblastoma cells, significantly increased tumor growth in the xenograft model and cell motility in bench experiments. Also, while the “healthy” glioblastoma cells alone had a clear border between the tumor and adjacent normal tissue in the xenograft, the glioblastoma cells co-injected with apoptotic exosomes invaded into adjacent brain tissue. Exosomes shed by non-apoptotic cells did not have these effects. To discover the mechanism underlying these changes, the researchers looked at what was inside the apoptotic exosomes. The vesicles were enriched with spliceosomal proteins and several U snRNAs — parts of the cellular machinery that remove introns from pre-messenger RNA. These are normally confined to the nuclei of cells; but the Nakano team found that, as the glioblastoma cells underwent apoptosis, the spliceosomal proteins were transported out of the nucleus to the cell cytoplasm, where they could be packaged into vesicles for release. Glioblastoma cell subtypes include the proneural subtypes and the mesenchymal subtype. Recent data have shown that, after therapy, glioblastoma cells shift from the less aggressive proneural subtype to the more aggressive and therapy-resistant mesenchymal subtype. The researchers found that apoptotic exosomes induced substantial alternate RNA splicing in recipient cells that resembled the splicing patterns found in the mesenchymal glioblastoma subtype. Part of this was caused by the splicing factor RBM11, which is encapsulated in the vesicles. The researchers found that exogenous RBM11 caused upregulation of endogenous RBM11 in the recipient cells and activated glycolysis. Overexpression of RBM11 increased the migration of glioblastoma cells. They also found that RBM11 altered RNA splicing to produce an isoform of the protein cyclinD1 that promotes DNA repair and an isoform of the protein MDM4 that has significantly higher anti-apoptotic activity. These changes can make the cells more therapy-resistant. Examination of the Cancer Genome Atlas database showed that elevated expression of those two isoforms is associated with poor prognoses for glioblastoma patients. Finally, the Nakano-led team looked at paired glioblastoma specimens of primary and recurrent tumors from matched patients. In most of the 43 pairs of matched samples, the RBM11 protein levels were substantially higher in the recurrent glioblastoma compared to the original, untreated tumors. In two other patient cohorts, they found that the higher RBM11 levels correlated with poor post-surgical survival for glioma patients. Beside Nakano, co-authors of the paper, “Apoptotic cell-derived extracellular vesicles promote malignancy of glioblastoma via intercellular transfer of splicing factors,” are Marat S. Pavlyukov, Hai Yu, Soniya Bastola, Mutsuko Minata, Suojun Zhang, Jia Wang, Svetlana Komarova, Jun Wang, Shinobu Yamaguchi and Heba Allah Alsheikh, UAB Department of Neurosurgery; Victoria O. Shender, Ksenia Anufrieva, Nadezhda V. Antipova, Georgij P. Arapidi, Vadim Govorun, Nikolay B. Pestov and Mikhail I. Shakhparonov, the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Yeri Lee, Yong Jae Shin and Do-Hyun Nam, Sungkyunkwan University School of Medicine, Seoul, Korea; Ahmed Mohyeldin, Junfeng Shi and L. James Lee, Ohio State University, Columbus, Ohio; Dongquan Chen, UAB Division of Preventive Medicine; Sung-Hak Kim, Chonnam National University, Gwangju, Korea; and Evgeniy G. Evtushenko, Lomonosov Moscow State University, Moscow, Russia. This work was supported by NIH grants NS083767, NS087913, CA183991 and CA201402; Russian Foundation for Basic Research grants 16-04-01414, 16-04-01209 and 17-29-06056; and Russian Science Foundation grants 17-75-20205 and 16-14-10335; and by the Scholarships of the President of the Russian Federation SP-4811.2018.4. At UAB, Nakano surgically cares for brain tumor patients. For any questions about his clinical program, call 205-996-2098 during working hours or 205-572-9703 at night or on weekends.