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.
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.
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.
Newswise — CHAPEL HILL, NC – When cells grow and divide to ensure a biological function – such as a properly working organ – DNA must be unwound from its typical tightly packed form and copied into RNA to create proteins. When this process goes awry – if too little or too much RNA is produced – then the result could be diseases such as cancers. UNC School of Medicine researchers have discovered that a protein called Spt6, previously known to have a key role in making RNA and repackaging DNA after RNA copying, also facilitates RNA degradation so that cells have just the right amount of RNA for the creation of proteins. The discovery, published in Molecular Cell, represents a revolutionary new understanding of gene expression control and suggests a potential target for treating cancers and other diseases. “By revealing and understanding this mechanism, we can start to think about targeting parts of it therapeutically in diseases in which Spt6 isn’t working properly,” said study senior author Brian D. Strahl, PhD, the Oliver Smithies Investigator, Professor, and Vice Chair in the Department of Biochemistry & Biophysics at UNC-Chapel Hill. Every human cell carries a large amount of DNA – called the genome – composed of roughly 3.5 billion letters that assemble into the genetic code. Researchers have been studying how large genomes fit into the tiny confines of cells. We know that proteins called histones carefully organize and package DNA in cells. Much like wrapping yarn around its spool, the DNA wraps around the histones to be condensed into a smaller space. Although histones help to keep DNA packaged, this packaging creates a barrier to “reading” the genetic information housed within DNA. The DNA needs to be “opened” much like a book needs to be opened for the pages to be read – except that “opening DNA” is a little complicated. Accessing DNA information is a highly controlled process that involves temporarily removing the histones so the genetic code can be copied into RNA and the RNA can then be used to create proteins. Normally, cells destroy the copied RNA “messages” once they are no longer needed. Diseases such as cancer may arise when the ability of cells to either produce or destroy the messages goes awry. When a gene is copied into a strand of RNA, the DNA in and around the gene must be loosened from its normal tightly wound configuration. Scientists have known that Spt6 has the crucial job of helping DNA become tightly re-wound when the copying process is completed. But that’s not its only function. “Spt6 seems to be a bit like a Swiss Army Knife,” said Strahl, a member of the UNC Lineberger Comprehensive Cancer Center. “Spt6 has many functions, from helping the cell create messenger RNAs, to putting histones back onto the DNA after they were removed. Our study now shows that Spt6 also helps control how much of the messenger RNA remains after it’s copied from DNA.” The first thing Strahl’s lab investigated was how Spt6 binds to RNA Polymerase II, which is the enzyme machine that copies DNA into RNA. The function of this Spt6-Polymerase II interaction has been unclear. So the Strahl lab wanted to determine whether a non-binding version of Spt6 still performed its DNA-histone rewrapping function. “To our surprise, we found that Spt6 was still able to get to genes, although at sub-optimal levels,” Strahl said. “But Spt6 still did its job of adding back histones.” Although Spt6 still functioned, the researchers witnessed a big problem: the RNA amounts were extremely high, and these high RNA amounts did not occur because there was more copying with the defective form of Spt6. “It dawned on us that there is more to Spt6 function than just re-wrapping the DNA around histones and facilitating RNA Polymerase copying of DNA,” said first author Raghuvar Dronamraju, PhD, research assistant professor in Strahl’s lab. The researchers measured the amounts of all the RNAs in cells that had the mutant form of Spt6 and found abnormal amounts of many RNAs. This suggested there was a loss of the usual control mechanism that maintained just the right amount of each RNA. It wasn’t clear at first how the disruption of Spt6’s binding to the polymerase caused RNA misregulation, but further experiments revealed a completely unexpected mechanism. Normally, RNAs in the process of being made are exposed to enzymes that protect or degrade them so that the cumulative actions of these enzymes create a precise amount of RNA that a cell needs for protein synthesis. The UNC scientists found that the form of Spt6 that could not bind to RNA Polymerase II disrupted this balance between RNA protection and RNA degradation, specifically the degradation side. They found that many RNAs survived in cells longer than they normally would have, allowing the RNA levels to rise to abnormal levels. Strahl’s team went further and connected the dots to show that Spt6 interacted with one of the cell’s major RNA degradation machineries – a protein complex called Ccr4-Not. Strahl’s team showed that Spt6 used its interaction with RNA Polymerase II to recruit Ccr4-Not during gene expression to ensure the proper balance of enzymes that protect and degrade RNA. Moreover, the researchers discovered that mutant Spt6 did not affect the levels of all RNAs. A large number of affected RNAs encode proteins that control cell division. Ordinarily, RNAs that contribute to cell division are rapidly degraded as cells pass from one part of the cell division cycle to another. But the abnormal failure to remove these RNAs in the mutant Spt6 cells caused the cells to develop profound growth and cell division defects. The study by the Strahl lab thus revealed a previously unknown, fundamental mechanism of RNA degradation, and the results suggest that defects in the RNA degradation function of Spt6 may underlie some diseases, particularly cancers, which feature uncontrolled cell division. “Given Spt6 in humans is sometimes found mutated or misregulated in cancers, it will be important to examine this RNA control mechanism further to determine whether its failure contributes to cancer,” Strahl said. His team will turn to researching this with the hope that future studies could identify new therapeutic targets to treat human disease. The researchers still have many questions about Spt6’s involvement in regulating RNAs. But already it’s apparent that Spt6’s influence on RNA stability represents “a new twist in transcription,” as Strahl calls it. This research was performed with baker’s yeast, a classic basic science organism that researchers use to investigate the intricate details of how cells perform and control many biological functions. Importantly, the yeast studies can be extended to human cells because the same proteins occur in yeast and humans. Other co-authors are Austin Hepperla, Yoichiro Shibata, PhD, Alexander Adams, Terry Magnuson, PhD, and Ian Davis, PhD. The National Institutes of Health and the Corn-Hammond Fund for Pediatric Oncology funded this research.
Newswise — AMES, Iowa – Setbacks are to be expected when pursuing a goal, whether you are trying to lose weight or save money. The challenge is getting back on track and not giving up after a difficulty or crisis, says a marketing professor in Iowa State University’s Ivy College of Business. José Rosa, John and Deborah Ganoe Faculty Fellow, is part of a research team working on practical ways to help people stick to health-related goals – specifically, prescribed regimens for medical ailments that require significant lifestyle changes. The work is personal for Rosa. His diabetic sister nearly died when her blood sugar hit dangerously high levels, and she struggles with poor vision and health, he said. Staying committed to a long-term health goal is challenging, because it may feel as if there is no light at the end of the tunnel, Rosa said. If your goal is to lose 20 pounds, there is a defined timeframe and a point to celebrate achieving your goal. However, if you are diabetic and need to cut certain foods from your diet or change your daily routine to exercise more, the goal has a different feel, Rosa said. “These are some of the most difficult goals we face, because the effort has to become a way of life. If you’re a diabetic, you have to be thinking about your diet every time you eat,” Rosa said. “In many ways, it is sacrificial. You must endure this cost and the reward is health.” Unfortunately, the reward is not immediate and often difficult to realize with certain ailments, such as diabetes or high blood pressure. As we age, other health issues can complicate the outcome of the initial goal and appear as if our efforts are not paying off. This makes it harder to stick to the goal, Rosa said, even though we know giving up can have serious consequences. Rosa and Richard Vann, lead author and assistant professor at Penn State Behrend in Erie, Pennsylvania; and Sean McCrea, associate professor at the University of Wyoming, conducted five experiments to understand how crisis influences motivation and commitment to the goal. They found a setback or difficulty often prompts people to reassess the cost-benefits of the goal and consider quitting. The results are published online in the journal Psychology & Marketing. Setback can snowball The experiments simulated a series of situations in which some participants faced an action crisis. They then answered several questions to determine how they would react. Rosa says an action crisis may be related or unrelated to the goal, but it is a point during goal pursuit when circumstances change, causing us to question whether the goal really matters. Once that questioning begins, we shift our mindset from implementation to evaluation. We renegotiate the importance of the outcomes and may determine it is no longer worth it, Rosa said. The researchers refer to that decision to quit as “taking the off ramp,” which can snowball into other problems. “We know it’s hard to get back on once people take the off ramp. This causes some people to feel like failures and stop trying all together. In some situations, the off ramp leads to behaviors that cause another crisis or a significant decline,” he said. For example, Rosa says a man with high blood pressure stops taking his medication and suffers a heart attack, or a diabetic woman has an insulin reaction causing her to black out and crash her car. Intervention to prevent renegotiation Researchers are now using data from the experiments to develop and test interventions for patients on prescribed health regimens. Rosa says the goal is to provide specific instructions for patients to follow and help shift their mindset from renegotiation or evaluation back to implementation. The potential benefit of such an intervention extends beyond the individual patient, Rosa said. From a marketing perspective, it is an issue of consumption and making health care more effective for patients. Rosa says the right intervention will help patients stay on track, lessening the risk for additional health issues and lowering health care costs.
Newswise — JUPITER, FL – June 21, 2018 – About half of all drugs, ranging from morphine to penicillin, come from compounds that are from—or have been derived from—nature. This includes many cancer drugs, which are toxic enough to kill cancer cells. So how do the organisms that make these toxic substances protect themselves from the harmful effects? Scientists on the Florida campus of Scripps Research have uncovered a previously unknown mechanism—proteins that cells use to bind to a toxic substance and sequester it from the rest of the organism. “Thanks to this discovery, we now know something about the mechanisms of resistance that’s never been known before for the enediyne antitumor antibiotics,” says study senior author Ben Shen, PhD, professor and co-chair of the Scripps Research Department of Chemistry. The work has important implications for understanding how human cancer cells develop resistance to natural product-based chemotherapies. Furthermore, the microbiome may play a role in drug resistance. The study was published today in the journal Cell Chemical Biology. “This mechanism could be clinically relevant for patients getting these drugs, so it’s very important to study it further,” says Shen. Natural products—chemical compounds produced by living organisms—are considered one of the best sources of new drugs and drug leads. “They possess enormous structural and chemical diversity compared with molecules that are made in the lab,” Shen says. Natural products may come from flowers, trees or marine organisms such as sponges. One of the most common sources, however, is soil-dwelling bacteria. Shen’s lab is focused on a class of natural products called enediynes. These compounds come from bacteria called actinomycetes, which are naturally found in the soil. Two enediyne products are already FDA approved as cancer drugs and are in wide use. But patients who take them often develop resistance. After a period of months or years, tumors can stop responding to the chemotherapy and begin growing again. While how patients develop resistance to these drugs remains largely unknown, scientists have uncovered two mechanisms that bacteria use to protect themselves from enediynes. “Mechanisms of self-resistance in antibiotic producers serve as outstanding models to predict and combat future drug resistance in a clinical setting,” says Shen. In the new study, researchers report a third, previously undiscovered resistance mechanism. It involves three genes called tnmS1, tnmS2 and tnmS3, which encode proteins that allow bacteria to resist the effects of a type of enediynes called tiancimycins. Shen’s lab is currently studying tiancimycins, which hold great promise for new cancer drugs. The proteins work by binding to tiancimycins and keeping them separate from the rest of the organism. After discovering these genes in actinomycetes and how they work, the investigators studied how widespread these genes are in other microorganisms. They were surprised to find that in addition to actinomycetes, the genes were also present in several microorganisms commonly found in the human microbiota, the collection of microorganisms that naturally inhabit the human body. “This raises a lot of questions that no one has ever asked before,” Shen says. “I can rationalize why the producing organism would have these genes, because it needs to protect itself from its own metabolites. But why do other microorganisms need these resistance genes?” He notes that it may be possible for gut microbes to pass the products of these genes on to their host—humans—which could contribute to drug resistance. “These findings raise the possibility that the human microbiota might impact the efficacy of enediyne-based drugs and should be taken into consideration when developing new chemotherapies,” Shen says. “Future efforts to survey the human microbiome for resistance elements should be an important part of natural product-based drug discovery programs.” Other authors of the study, “Resistance to Enediyne Antitumor Antibiotics by Sequestration,” were Chin-Yuan Chang, Xiaohui Yan, Ivana Crnovcic, Thibault Annaval, Jeffrey D. Rudolf, Dong Yang and Hindra, of Scripps Research, George N. Phillips, Jr. of Rice University, and Changsoo Chang, Boguslaw Nocek, Gyorgy Babnigg and Andrzej Joachimiak of Argonne National Laboratory. This research was funded by the National Institutes of Health (grants GM098248, GM109456, GM121060, GM094585, CA078747, GM115575 and CA204484) and the Department of Energy, Office of Biological and Environmental Research (grant DE-AC02-06CH11357). About Scripps Research Scripps Research is one of the world's preeminent independent, not-for-profit organizations focusing on research in the biomedical sciences. Scripps Research is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
Unusually High Levels of Herpesviruses Found in the Alzheimer’s Disease Brain, Mount Sinai Researchers Report Networks identified for developing new therapies to treat Alzheimer’s disease Newswise — NEW York, NY (June 21, 2018) Two strains of human herpesvirus—human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) —are found in the brains of people with Alzheimer’s disease at levels up to twice as high as in those without Alzheimer’s, researchers from the Icahn School of Medicine at Mount Sinai report. Using evidence from postmortem brain tissue from the Mount Sinai Brain Bank, the research team also identified previously unknown gene networks that will both offer new testable hypotheses for understanding Alzheimer’s pathology and reveal novel potential targets for new drugs that may arrest Alzheimer's disease progression, and could potentially prevent the disease if administered early enough. This is the first study to use a data-driven approach to study the impact of viruses on Alzheimer’s and to identify the role of HHV-6A and HHV-7 in the disease. This is also the first evidence that integration of HHV genomes into human brain genomes may play a role in the etiology of Alzheimer’s. These viruses can cause encephalitis and other chronic conditions. Results of the study will be published online in Neuron, at 11 am EDT on Thursday, June 21. The research team initially performed RNA sequencing on four brain regions in more than 600 samples of postmortem tissue from people with and without Alzheimer’s to quantify which genes were present in the brain, and whether any were associated with the onset and progression of Alzheimer’s. Through a variety of computational approaches, the team uncovered a complex network of unexpected associations, linking specific viruses with different aspects of Alzheimer’s biology. They examined the influence of each virus on specific genes and proteins in brain cells, and identified associations between specific viruses and amyloid plaques, neurofibrillary tangles, and clinical dementia severity. To evaluate the robustness of their findings, the team incorporated a further 800 RNA sequencing samples collected by the Mayo Clinic and Rush Alzheimer’s Disease Center, observing a persistent increase of HHV-6A and HHV-7 abundance in samples from individuals with Alzheimer’s, thus replicating their main findings in two additional, independent, geographically dispersed cohorts. Every 65 seconds, someone in the United States develops Alzheimer’s. In 2018, the costs of providing care to individuals with Alzheimer’s and other dementias are expected to total more than $277 billion. By mid-century, a new diagnosis will occur every 33 seconds, and costs are expected to exceed $1 trillion annually. Despite the dire public health implications, Alzheimer’s remains the only Top 10 cause of mortality in the United States for which no disease-modifying treatments are available. This study has been enabled by the extensive molecular profiling of several large patient cohorts, generated in the course of the National Institute on Aging (NIA) Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD). AMP-AD is a precompetitive partnership among government, industry, and nonprofit organizations that focuses on discovering novel, clinically relevant therapeutic targets and on developing biomarkers to help validate existing therapeutic targets. This multisector partnership is managed by the Foundation for the NIH. The combined funding support for this five-year endeavor is $185.2 million. Through the generation of this large, “multi-omic” resource, the team was able to perform their investigation of viral activity in Alzheimer’s in an entirely data-driven manner. The term “multi-omic” is used as shorthand to imply that data from genes, proteins, fats, and other tissue components are all assessed and then represented qualitatively and quantitatively in a complex mathematical model. “This study represents a significant advancement in our understanding of the plausibility of the pathogen hypothesis of Alzheimer’s,” said the study’s senior author, Joel Dudley, PhD, Director of the Institute for Next Generation Healthcare at the Icahn School of Medicine at Mount Sinai. “Our work identified specific biological networks that offer new testable hypotheses regarding the role of microbial defense and innate immune function in the pathophysiology of Alzheimer’s. If it becomes evident that specific viral species directly contribute to an individual’s risk of developing Alzheimer’s or their rate of progression once diagnosed, then this would offer a new conceptual framework for understanding the emergence and evolution of Alzheimer’s at individual, as well as population, levels.” Dr. Dudley notes that this study could potentially translate to the identification of virus, or virus-related, biomarkers that could improve patient risk stratification and diagnosis, as well as implying novel viral targets and biological pathways that could be addressed with new preventative and therapeutic drugs. As with any complex set of findings, they will need to be confirmed in additional patient cohorts, and further studies to specifically address a causal role for viruses are now being conducted by the research team. “This is the most compelling evidence ever presented that points to a viral contribution to the cause or progression of Alzheimer’s,” said one of the study’s authors, Sam Gandy, MD, PhD, Professor of Neurology and Psychiatry and Director of the Center for Cognitive Health and NFL Neurological Care at Mount Sinai. “A similar situation arose recently in certain forms of Lou Gehrig’s disease. In those patients, viral proteins were discovered in the spinal fluid of some Lou Gehrig’s patients, and patients with positive viral protein tests in their spinal fluid showed benefit when treated with antiviral drugs.” Other Mount Sinai authors of the study include co-first authors Ben Readhead, MBBS, and Jean-Vianney Haure-Mirande, PhD. Other Mount Sinai authors include Vahram Haroutounian, PhD, Professor of Psychiatry and Neurobiology and Director of the NeuroBioBank; Mary Sano, PhD, Director of Alzheimer’s Disease Research; Noam Beckmann, PhD candidate; Eric Schadt, PhD, Dean for Precision Medicine and Professor of Genetics and Genomic Sciences; and Michelle Ehrlich, MD, Professor of Neurology, Pediatrics, and Genetics and Genomics Sciences. Postmortem brain tissue was collected through the NIH-designated NeuroBioBank (NBB) System that contributes to support of the Mount Sinai VA/Alzheimer’s Disease Research Center Brain Bank (AG005138). The Dudley Laboratory at the Icahn School of Medicine at Mount Sinai has an institutional partnership with Banner-ASU Neurodegenerative Disease Research Center. Postmortem brain tissue was collected through the NIH-designated NeuroBioBank (NBB) System that contributes to support of the Mount Sinai VA/Alzheimer’s Disease Research Center Brain Bank (AG005138). Dr. Vahram Haroutunian from the Mount Sinai School of Medicine is Director of the NeuroBioBank. Additional postmortem data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, R01 NS080820, Cure PSP Foundation, and support from Mayo Foundation, U24 NS072026, P30 AG19610, Michael J. Fox Foundation for Parkinson’s Research P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute. Additional work performed in this study was supported by U01 AG046170, R56AG058469, and philanthropic financial support was provided by Katherine Gehl. About the Mount Sinai Health System The Mount Sinai Health System is New York City’s largest integrated delivery system encompassing seven hospital campuses, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai’s vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The System includes approximately 7,100 primary and specialty care physicians; 10 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report’s “Best Medical Schools”, aligned with a U.S. News & World Report’s “Honor Roll” Hospital, No. 13 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report’s “Honor Roll” of top U.S. hospitals; it is one of the nation’s top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in four other specialties in the 2017-2018 “Best Hospitals” issue. Mount Sinai’s Kravis Children’s Hospital also is ranked in six out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology and 50th for Ear, Nose, and Throat, while Mount Sinai Beth Israel, Mount Sinai St. Luke’s and Mount Sinai West are ranked regionally. For more information, visit http://www.mountsinai.org/, or find Mount Sinai on Facebook, Twitter and YouTube.