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. 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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.
New Haven, Conn. — Summer is here, but enjoying longer and sunnier days outdoors means your skin is vulnerable to sunburn. Experts at Yale Cancer Center (YCC) and Yale School of Medicine (YSM) say unless you take the right precautions, sun exposure (even if you don't get scorched) can damage your skin, causing wrinkles, age spots and even skin cancer. Just one sunburn during your youth doubles your chances of developing melanoma, the deadliest form of skin cancer. “Since skin cancer is the most common form of cancer in the United States—one in five people will be diagnosed with it in their lifetime—it’s important to practice sun safety before heading outdoors,” said Michael Girardi, MD, director of the Phototherapy Unit at YCC and professor of dermatology at YSM. “There is concern that rates of melanoma have been steadily rising over the last 30 years.” YCC and YSM skin cancer experts say these tips can help you avoid sun damage and reduce your chances of getting skin cancer: Generously apply high SPF sunscreen. Use a broad-spectrum, water-resistant sunscreen (SPF 30 or greater) every day. Be sure it hasn’t expired and reapply every two hours as well as after swimming or sweating. And apply everywhere on your body, not just your face and upper arms. Seal your lips from the sun’s rays. Lip balms, glosses and sticks often contain SPF ingredients. Opaque lipsticks contain pigments that help block harmful rays, according to the American Academy of Dermatology. More opaque formulas protect better. Create some shade. Clothing made of tightly woven fabric with a high ultraviolet protection factor (UPF) rating can create a physical barrier that protects your skin from the sun. Long sleeves or pants, sunglasses and a hat with a wide brim will also help shade you. Avoid peak sun hours. The sun is most damaging to skin between 10 a.m. and 2 p.m., so plan your outdoor activities before or after the sun is at its strongest. Check yourself out. Using a full-length mirror, scan your skin for spots that look suspicious (unusually shaped moles that are changing shape or are black, red or pink in color) and tell your physician. If you've previously had skin cancer, you should be checked annually by a dermatologist. At Connecticut and Rhode Island beaches this summer, volunteers from the Smilow Cancer Hospital Care Center in Waterford will be handing out sunscreen, lip balm and sun index cards at the locations and times below: Date and Hours Beach July 14th, 9:00AM - 12PM Rocky Neck State Park July 21st, 9:00AM - 12 PM McCook Beach Park Hole in the Wall Beach July 28th, 9:00AM -12PM Waterford Beach Park August 4th, 9:00AM - 12PM Ocean Beach Park August 11th, 9:00AM - 12PM Misquamicut State Beach To learn more about skin cancer screening at Smilow Cancer Hospital go to:https://www.yalecancercenter.org/patient/specialty/screening/types_cancer_screening/skin.aspx About Yale Cancer Center Yale Cancer Center (YCC) is one of only 49 National Cancer Institute (NCI-designated comprehensive cancer) centers in the nation and the only such center in southern New England. Comprehensive cancer centers play a vital role in the advancement of the NCI’s goal of reducing morbidity and mortality from cancer through scientific research, cancer prevention, and innovative cancer treatment.
Newswise — MADISON, Wis. — Modern microscopy has given scientists a front-row seat to living, breathing biology in all its Technicolor glory. But access to the best technologies can be spotty. Jan Huisken, a medical engineering investigator at the Morgridge Institute for Research at the University of Wisconsin–Madison and co-founder of light sheet microscopy, has a new project meant to bridge the technology gap. His Morgridge team has developed a portable, shareable light sheet microscope — an engineering feat that shrinks a tabletop-sized technology down to the weight and dimensions of a suitcase packed for a week’s vacation. The project can be mailed to a lab anywhere in the world, configured remotely by Morgridge engineers, and run one to three months of experiments. The microscope then either begins its mail-order journey to the next lab, or back to the Morgridge lab if a tune-up is needed — all at no cost to users. The first focus will be on sharing with the UW–Madison community. “If we succeed, this project will certainly have a huge impact in the field of fluorescence microscopy and significantly change the way we collaborate,” says Huisken. The technology targets two essential challenges. Labs lucky enough to afford a commercial microscope can keep their entire experiments in-house. But as biologists, not engineers, customizing from one project to the next is difficult and the expensive tool may drift into obsolescence, says Huisken. The budget-challenged may need to take their project to the nearest shared microscopy resource. But biology doesn’t travel well: Delicate samples may get altered or ruined along the way, and experiments may fail in the unfamiliar environment, he says. The team debuted the tool — nicknamed “Flamingo” for its one-legged stand and vertical profile — June 20 at the International Zebrafish Conference meeting at UW–Madison. It’s the perfect starting point for this device, since the zebrafish research community widely wants to use light sheet microscopy. What is light sheet? Huisken’s microscopes illuminate samples from the sides with noninvasive “sheets” of light, giving scientists the ability to image samples over hours and days from every angle. This helps generate a tremendous amount of data quickly and gives researchers a 3D view of development in an almost completely unaltered state. Zebrafish researchers use the technology because it can build striking movies of embryo, limb and organ development. But it’s also being adopted by other model organisms important to research, such as fruit flies and planaria, and for imaging early plant root growth. Susi Power, a Huisken lab member on the Flamingo development team, says the lab for years has been seeing the challenges biologists face in getting access to good imaging. One of the added benefits of the project for the Huisken lab is a kind of research crowd-sourcing. In exchange for using the technology, the lab helps expand the light-sheet user community and gets continual feedback on how to improve its core technology. “It does something magical for a biologist to have a technology like this entirely to themselves, where they can set it up and say, ‘that’s my Flamingo,’” Power says. “I think there will be a huge reward to the science.” The prototype device is built and ready to use. Ongoing work includes designing remote access to help calibrate the device from Morgridge, and building software that will give users real-time desktop and mobile access to the data. Power says the microscope is the opening project in a new Huisken lab initiative called “involv3d,” which is intended to improve collaboration and communication between different research disciplines. The Huisken lab has active members in developmental biology, medicine, physics, botany and others, and they want involv3d to bridge these fields and “help scientists profit from other scientists.” Liz Haynes, a postdoctoral fellow in the lab of UW–Madison neuroscientist Mary Halloran, says Flamingo will help address some challenges in the Halloran lab. They needed a technology that could track the neurodevelopmental consequences of gene editing changes made in zebrafish embryos, and traditional approaches were onerous. She’s looking forward to being one of Flamingo’s first customers. “I’m also excited because it is a beautiful scope and it seems really smartly designed,” Haynes says. “It’s a joy to look at. And, of course, the images you can get from (light sheet) are breathtaking.” —Brian Mattmiller, email@example.com
Newswise — PHILADELPHIA - Influenza A (flu A) hijacks host proteins for viral RNA splicing and blocking these interactions caused replication of the virus to slow, according to new research published in Nature Communications by Kristin W. Lynch, PhD, chair of the department of Biochemistry and Biophysics in the Perelman School of Medicine at the University of Pennsylvania, and doctoral student Matthew Thompson. Their results also suggest that infection with flu A may reduce splicing of some host genes, which could point to novel strategies for antiviral therapies. Influenza A virus is a common human pathogen that causes 250,000 to 500,000 deaths per year worldwide. “Although vaccines and some antiviral drugs are available, it is crucial to understand influenza virus-host interactions at a molecular level in order to identify host vulnerabilities targeted by flu viruses, which could lead to developing new therapeutic options,” said Lynch, whose lab focuses on the specific mechanisms and patterns of alternative RNA splicing and how it relates to human disease, The transcription of DNA into messenger RNA – the process of a single gene encoding a single protein – isn't as straightforward as once thought. The phenomenon of alternative RNA splicing – where a single gene can encode multiple proteins – was discovered over 30 years ago in viruses. The flu A genome is comprised of eight single-strand segments of RNA. Three of these segments use alternative splicing to produce two essential viral proteins each, which are important in helping the virus gain entry into host cells. Working with cultures of human lung cells, the team’s proposed mechanism of how flu A virus interacts with human RNA splicing machinery suggests that keeping human splicing proteins from binding to the viral genome would help to stop its replication. As a result, the researchers found that mutating sequences of the viral genome to prevent host proteins from binding caused viral RNA to splice incorrectly and eventually halt replication—thus slowing the spread of the virus in the body. A balance between the two viral messenger RNAs must be maintained for the virus to successfully infect host cells and replicate. “Regulating splicing of the two viral proteins is a fundamental step in viral-host interaction and so a potentially new anti-viral remedy,” Lynch said. For now, her team is refining their understanding of the intricacies of viral reproduction in host cells. Their hope is to one day identify a specific molecular target for antiviral medications that can be used in the clinic. This research was funded by the National Institutes of Health (R01AI125524, R35GM118048, HHSN272201400008C, U19AI10675, 4R33AI119304-03). 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 $500 million to benefit our community.
Newswise — DALLAS – June 22, 2018 – Men often tolerate stress urinary incontinence for more than two years before seeking medical help – and one-third put up with it for more than five years, making it important for doctors to check for this problem, a new study from UT Southwestern researchers advises. The study, published in the journal Urology, calls on men’s general practitioners and urologists to perform a standing cough test, in which a patient coughs while the doctor watches for any accidental urine release, as a routine part of their male patients’ physicals. “Our goal is to spread the word that effective and safe treatments exist for men with stress urinary incontinence, but also to facilitate an immediate and accurate diagnosis among stress urinary incontinence patients,” said Dr. Joceline Fuchs, Assistant Instructor of Urology and first author of the study. Stress urinary incontinence (SUI) occurs when physical activity or exertion – a cough, heavy lifting, exercise – causes the bladder to leak urine. About 13 million Americans suffer from some degree of incontinence, with women accounting for 85 percent of cases. However, some men who have had prostate cancer treatments involving surgery (prostatectomies) develop the condition. More about incontinence Q&A by Dr. Gary LeMack UTSW Incontinence Services Urinary Incontinence for Women Urology journal article Even though men are slow to complain, “Male SUI is rare but is known to have significant negative psychosocial and emotional effects and represents a common reason for post-treatment anxiety and depression,” said Dr. Allen Morey, Professor of Urology at UT Southwestern and senior author of the study. But there are simple and safe solutions – including minor surgeries that can either help boost a weakened sphincter muscle for patients with minimal leakage (the sling procedure), or replace the sphincter muscle altogether (installation of an artificial urinary sphincter) for more severe cases of leakage. “Using new diagnostic techniques, we are now able to accurately diagnose and streamline treatment recommendations to resolve this bothersome problem for our patients,” said Dr. Morey, who holds the Distinguished Chair in Urology for Urologic Reconstruction, in Honor of Allen F. Morey, M.D., and the Paul C. Peters, M.D. Chair in Urology. “This study highlights an opportunity for improvement.” During the study, UT Southwestern researchers reviewed the cases of 572 men evaluated for anti-incontinence surgery in Dallas between 2007 and 2017. They found the median length of time the men had waited to seek treatment for their SUI was 32 months, with almost a third having waited more than five years. Patients in their 80s had waited a median of more than seven years. Most recovery of urinary control occurs within the first 12 months after a prostatectomy, the study notes. Beyond the first year, improvement is unlikely. Care for such patients should include urologist-directed treatment plans that focus on non-cancer problems such as incontinence, researchers said. Some treatment delay may also be tied to patient reluctance to undergo more surgery or due to limited geographic access to appropriate specialists, researchers said. However, patient satisfaction and quality of life improvement measures for those who do undergo anti-incontinence surgery are high, ranging from 73 to 90 percent, according to the study. The American Cancer Society Prostate Cancer Survivorship Care Guidelines recommend screening for long-term functional effects such as urinary incontinence after prostate cancer treatment, the study points out, and those guidelines have been endorsed by the American Society of Clinical Oncology. Incontinence help UT Southwestern physicians offer patients who suffer from incontinence outstanding expertise in urodynamic studies – the use of X-ray imaging to help diagnose the causes of incontinence. UTSW physicians were the first in North Texas to offer the botulinum toxin injection for neurogenic bladder dysfunction in men and women. UTSW physicians offer unique treatments, like electrical stimulation, to patients who are unresponsive to other therapies and others that are offered at only a few medical institutions in the world. Treatments can include: Behavioral therapy Biofeedback Drug therapy Exercise In-office procedures Incontinence surgery Palliative measures About UT Southwestern Medical Center UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year.