Medicine and Health Sciences Commons^™

Va-Ecmo In Cardiogenic Shock In Adults: Indications And Outcomes, Maya Guglin, Andrew Burchett

The VAD Journal

Background

Use of veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) has become increasingly common as a means of providing hemodynamic support for patients in cardiogenic shock. Data regarding the efficacy of VA-ECMO are provided almost exclusively by single-center, retrospective analyses. These retrospective analyses vary significantly with regards to documentation of the underlying pathophysiologic process resulting in cardiogenic shock.

Methods

Relevant published studies were identified by using a comprehensive search of English-language MEDLINE from 1966 to November 2015. Relevant references found cited in these studies were also analyzed. These studies were analyzed with regard to the indications the authors used for initiation of …

The Tnfα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, And Post-Ischemic Cell Loss, L. Creed Pettigrew, Richard J. Kryscio, Christopher M. Norris

Sanders-Brown Center on Aging Faculty Publications

The cytokine, tumor necrosis factor α (TNFα), is a key regulator of neuroinflammation linked to numerous neurodegenerative conditions and diseases. The present study used transgenic rats that overexpress a murine TNFα gene, under the control of its own promoter, to investigate the impact of chronically elevated TNFα on hippocampal synaptic function. Neuronal viability and cognitive recovery in TNFα Tg rats were also determined following an ischemic insult arising from reversible middle cerebral artery occlusion (MCAO). Basal CA3-CA1 synaptic strength, recorded in acute brain slices, was not significantly different between eight-week-old TNFα Tg rats and non-Tg rats. In contrast, slices from …

Learning From Geographic Variation And Change In Preparedness: The 2016 National Health Security Preparedness Index, Glen P. Mays

Health Management and Policy Presentations

The 2016 release of the National Health Security Preparedness Index tracks the nation's progress in preparing for disasters and other emergencies that create health risks for large groups of people. Recent improvements in the Index computational methodologies and measures allow results to be compared validly across states and over time. The Index aggregates more than 130 individual measures from nearly 60 data sources into valid composite measures for 6 domains and 19 subdomains that reflect core functional areas of emergency preparedness and response. Improvements in normalization, weighting, imputation, and confidence interval construction enhance the validity and reliability of Index estimates …

Compositions And Methods For Treating Retinal Degradation, Jayakrishna Ambati, Benjamin J. Fowler

Ophthalmology and Visual Science Faculty Patents

The present disclosure relates to compositions and methods for treating retinal damage and/or retinal degradation. More specifically, this disclosure relates to methods for treating degradation of the retinal pigment epithelium by administering compositions comprising a nucleoside and/or a nucleoside or nucleotide reverse transcriptase inhibitor.

Calpain-5 Expression In The Retina Localizes To Photoreceptor Synapses, Kellie A. Schaefer, Marcus A. Toral, Gabriel Velez, Allison J. Cox, Sheila A. Baker, Nicholas C. Borcherding, Diana F. Colgan, Vimala Bondada, Charles B. Mashburn, Chen Guang Yu, James W. Geddes, Stephen H. Tsang, Alexander G. Bassuk, Vinit B. Mahajan

Spinal Cord and Brain Injury Research Center Faculty Publications

Purpose: We characterize calpain-5 (CAPN5) expression in retinal and neuronal subcellular compartments.

Methods: CAPN5 gene variants were classified using the exome variant server, and RNA-sequencing was used to compare expression of CAPN5 mRNA in the mouse and human retina and in retinoblastoma cells. Expression of CAPN5 protein was ascertained in humans and mice in silico, in mouse retina by immunohistochemistry, and in neuronal cancer cell lines and fractionated central nervous system tissue extracts by Western analysis with eight antibodies targeting different CAPN5 regions.

Results: Most CAPN5 genetic variation occurs outside its protease core; and searches …

African American Female Offender's Use Of Alternative And Traditional Health Services After Re-Entry: Examining The Behavioral Model For Vulnerable Populations, Carrie B. Oser, Amanda M. Bunting, Erin L. Pullen, Danelle Stevens-Watkins

Sociology Faculty Publications

This is the first known study to use the Gelberg-Andersen Behavioral Model for Vulnerable Populations to predict African American women's use of three types of health services (alternative, hospitalization, and ambulatory) in the 18 months after release from prison. In the multivariate models, the most robust predictors of all three types of service utilization were in the vulnerable theoretical domains. Alternative health services were predicted by ethnic community membership, higher religiosity, and HIV/HCV. Hospitalizations were predicted by the lack of barriers to health care and disability. Ambulatory office visits were predicted by more experiences of gendered racism, a greater number …

Sarcopenic Obesity And Myosteatosis Are Associated With Higher Mortality In Patients With Cirrhosis, Aldo J. Montano-Loza, Paul Angulo, Judith Meza-Junco, Carla M. M. Prado, Michael B. Sawyer, Crystal Beaumont, Nina Esfandiari, Ming Ma, Vickie E. Baracos

Internal Medicine Faculty Publications

Background and aims Obesity is frequently associated with cirrhosis, and cirrhotic patients may develop simultaneous loss of skeletal muscle and gain of adipose tissue, culminating in the condition of sarcopenic obesity. Additionally, muscle depletion is characterized by both a reduction in muscle size and increased proportion of muscular fat, termed myosteatosis. In this study, we aimed to establish the frequency and clinical significance of sarcopenia, sarcopenic obesity and myosteatosis in cirrhotic patients.

Methods We analysed 678 patients with cirrhosis. Sarcopenia, sarcopenic obesity and myosteatosis were analysed by CT scan using the third lumbar vertebrae skeletal muscle and attenuation indexes, using …

Bleeding And Thromboembolic Events In Patients With Heartmate Ii Mechanical Circulatory Support, Salman Allana, Carrie Chapman, Nancy Sweitzer, Maryl Johnson, Takushi Kohmoto, Margaret Murray, David Murray, Zhanhai Li, Peter S. Rahko

The VAD Journal

Background: Bleeding and thromboembolic events (TE) are common complications following HeartMate II (HMII) implantation. The aim of the study was to review our experience related to bleeding and TE events in patients with a HMII and identify factors associated with increased risk of these events.

Methods: We retrospectively reviewed 70 consecutive patients who received a HMII between May 2006 and December 2011. The patients were followed for 12 months or until cardiac transplantation, device explantation or death. Major bleeding was defined by INTERMACS criteria with intracranial bleeding events added.

Results: There were 48 bleeding events in 28 (40%) patients with …

Structural Dynamics Of A Methionine Γ-Lyase For Calicheamicin Biosynthesis: Rotation Of The Conserved Tyrosine Stacking With Pyridoxal Phosphate, Hongnan Cao, Kemin Tan, Fengbin Wang, Lance Bigelow, Ragothaman M. Yennamalli, Robert Jedrzejczak, Gyorgy Babnigg, Craig A. Bingman, Andrzej Joachimiak, Madan K. Kharel, Shanteri Singh, Jon S. Thorson, George N. Phillips Jr.

Pharmaceutical Sciences Faculty Publications

CalE6 from Micromonospora echinospora is a (pyridoxal 5′ phosphate) PLP-dependent methionine γ-lyase involved in the biosynthesis of calicheamicins. We report the crystal structure of a CalE6 2-(N-morpholino)ethanesulfonic acidcomplex showing ligand-induced rotation of Tyr100, which stacks with PLP, resembling the corresponding tyrosine rotation of true catalytic intermediates of CalE6 homologs. Elastic network modeling and crystallographic ensemble refinement reveal mobility of the N-terminal loop, which involves both tetrameric assembly and PLP binding. Modeling and comparative structuralanalysis of PLP-dependent enzymes involved in Cys/Met metabolism shine light on the functional implications of the intrinsic dynamic properties of CalE6 in catalysis and holoenzyme maturation.

Juvenile Justice—Translational Research On Interventions For Adolescents In The Legal System (Jj-Trials): A Cluster Randomized Trial Targeting System-Wide Improvement In Substance Use Services, Danica K. Knight, Steven Belenko, Tisha Wiley, Angela A. Robertson, Nancy Arrigona, Michael Dennis, John P. Bartkowski, Larkin S. Mcreynolds, Jennifer E. Becan, Hannah K. Knudsen, Gail A. Wasserman, Eve Rose, Ralph Diclemente, Carl G. Leukefeld, Jj-Trials Cooperative

Behavioral Science Faculty Publications

Background: The purpose of this paper is to describe the Juvenile Justice—Translational Research on Interventions for Adolescents in the Legal System (JJ-TRIALS) study, a cooperative implementation science initiative involving the National Institute on Drug Abuse, six research centers, a coordinating center, and Juvenile Justice Partners representing seven US states. While the pooling of resources across centers enables a robust implementation study design involving 36 juvenile justice agencies and their behavioral health partner agencies, co-producing a study protocol that has potential to advance implementation science, meets the needs of all constituencies (funding agency, researchers, partners, study sites), and can be implemented …

Effect Of Dietary Starch Source And Concentration On Equine Fecal Microbiota, Brittany E. Harlow, Laurie M. Lawrence, Susan H. Hayes, Andrea Crum, Michael D. Flythe

Animal and Food Sciences Faculty Publications

Starch from corn is less susceptible to equine small intestinal digestion than starch from oats, and starch that reaches the hindgut can be utilized by the microbiota. The objective of the current study was to examine the effects of starch source on equine fecal microbiota. Thirty horses were assigned to treatments: control (hay only), HC (high corn), HO (high oats), LC (low corn), LO (low oats), and LW (low pelleted wheat middlings). Horses received an all-forage diet (2 wk; d -14 to d -1) before the treatment diets (2 wk; d 1 to 14). Starch was introduced gradually so that …

Effects Of Vocal Fold Nodules On Glottal Cycle Measurements Derived From High-Speed Videoendoscopy In Children, Rita R. Patel, Harikrishnan Unnikrishnan, Kevin D. Donohue

Electrical and Computer Engineering Faculty Publications

The goal of this study is to quantify the effects of vocal fold nodules on vibratory motion in children using high-speed videoendoscopy. Differences in vibratory motion were evaluated in 20 children with vocal fold nodules (5–11 years) and 20 age and gender matched typically developing children (5–11 years) during sustained phonation at typical pitch and loudness. Normalized kinematic features of vocal fold displacements from the mid-membranous vocal fold point were extracted from the steady-state high-speed video. A total of 12 kinematic features representing spatial and temporal characteristics of vibratory motion were calculated. Average values and standard deviations (cycle-to-cycle variability) of …

Health Behaviors And Their Correlates Among Participants In The Continuing To Confront Copd International Patient Survey, Hana Müllerová, Sarah H. Landis, Zaurbek Aisanov, Kourtney J. Davis, Masakazu Ichinose, David M. Mannino, Joe Maskell, Ana M. Menezes, Thys Van Der Molen, Yeon-Mok Oh, Maggie Tabberer, Meilan K. Han

Preventive Medicine and Environmental Health Faculty Publications

Background and aims: We used data from the Continuing to Confront COPD International Patient Survey to test the hypothesis that patients with COPD who report less engagement with their disease management are also more likely to report greater impact of the disease.

Methods: This was a population-based, cross-sectional survey of 4,343 subjects aged ≥ 40 years from 12 countries, fulfilling a case definition of COPD based on self-reported physician diagnosis or symptomatology. The impact of COPD was measured with COPD Assessment Test, modified Medical Research Council Dyspnea Scale, and hospital admissions and emergency department visits for COPD in the prior …

Sharing Local Public Health Services Across Jurisdictions: Comparing Practice In 2012 And 2014, Kusuma Madamala, Susan Zahner, Roger Brown

Frontiers in Public Health Services and Systems Research

Objective: Describe cross-jurisdiction service sharing (CJS) by local and tribal health departments (LHD) in Wisconsin in 2014 compared to 2012.

Design: An online survey of 91 LHD directors in Wisconsin was conducted. Results were compared to the results of a 2012 survey. Characteristics of CJS arrangements and differences in results by population size, geographic region, and governance type were described. Standardized proportion differences (h) were estimated using the arcsin transformation. Confidence intervals were estimated using unconditional exact confidence intervals for the difference of proportions.⁸ A forest plot of the estimates and confidence intervals was generated to visualize change in …

Trends In Clinical Billing By Local Health Departments, J. Mac Mccullough

Frontiers in Public Health Services and Systems Research

Background: Billing for clinical services is perceived to be increasingly important for local health departments (LHDs). Yet very little evidence exists regarding the frequency and relative financial importance of clinical billing revenues.

Purpose: The purpose of this study is to report on trends in the frequency and financial scope of clinical billing by LHDs from 2008 to 2013.

Methods: The study used data from the 2008, 2010, and 2013 National Association of City and County Health Officials Profile report surveys. Per capita revenues from clinical billing and percent of total LHD revenues from clinical billing were calculated. …

Tuberculosis And Local Health Department Expenditures On Tuberculosis Services, Michelle P. Yip, Betty Bekemeier

Frontiers in Public Health Services and Systems Research

Background: Although tuberculosis (TB) morbidity and mortality have decreased in recent decades, challenges exist regarding disproportionate distributions of TB among specific populations and geographic areas. Inconsistent local health department (LHD) funding for TB programs poses difficulties for LHDs to sustain resources and personnel that predisposes communities to risks of future outbreaks of TB and drug-resistant TB diseases.

Purpose: This study examined relationships between annual TB incidence rates and LHD expenditures on TB-related services to elucidate potential impacts of TB incidence on LHD TB spending.

Methods: This dataset included county-level TB incidence data with comparable, annual (2000–2010) TB-related service expenditures for …

The Cost Of Public Health Services, F. Douglas Scutchfield Md

Frontiers in Public Health Services and Systems Research

Paying for public health services is and remains a consistent concern among local health departments. The data on the impact of the 2008 recession on public health nationally demonstrated the problems with maintaining staff and services in the face of a declining resource base. This capacity to provide funding for provision of public health services has prompted a number of mechanisms to provide support for dealing with revenue shortfalls. The papers in this issue of Frontiers in PHSSR continue to echo that concern of how best to deal with loss of funding, measuring it and developing tools to ascertain the …

Summary Of Results From The 2016 National Health Security Preparedness Index, Glen P. Mays, Michael T. Childress, Pierre Martin Dominique Zephyr, Anna Goodman Hoover

Health Management and Policy Reports

The National Health Security Preparedness Index tracks the nation’s progress in preparing for, responding to, and recovering from disasters and other large-scale emergencies that pose risks to health and well-being in the United States. Because health security is a responsibility shared by many different stakeholders in government and society, the Index combines measures from multiple sources and perspectives to offer a broad view of the health protections in place for nation as a whole and for each U.S. state. The Index identifies strengths as well as gaps in the protections needed to keep people safe and healthy in the face …

Peptidomimetic Small Molecules Disrupt Type Iv Secretion System Activity In Diverse Bacterial Pathogens, Carrie L. Shaffer, James A.D. Good, Santosh Kumar, K. Syam Krishnan, Jennifer A. Gaddy, John T. Loh, Joseph Chappell, Fredrik Almqvist, Timothy L. Cover, Maria Hadjifrangiskou

Pharmaceutical Sciences Faculty Publications

Bacteria utilize complex type IV secretion systems (T4SSs) to translocate diverse effector proteins or DNA into target cells. Despite the importance of T4SSs in bacterial pathogenesis, the mechanism by which these translocation machineries deliver cargo across the bacterial envelope remains poorly understood, and very few studies have investigated the use of synthetic molecules to disrupt T4SS-mediated transport. Here, we describe two synthetic small molecules (C10 and KSK85) that disrupt T4SS-dependent processes in multiple bacterial pathogens. Helicobacter pylori exploits a pilus appendage associated with the cag T4SS to inject an oncogenic effector protein (CagA) and peptidoglycan into gastric epithelial cells. In …

Network-Driven Plasma Proteomics Expose Molecular Changes In The Alzheimer's Brain, Philipp A. Jaeger, Kurt M. Lucin, Markus Britschgi, Badri Vardarajan, Ruo-Pan Huang, Elizabeth D. Kirby, Rachelle Abbey, Bradley F. Boeve, Adam L. Boxer, Lindsay A. Farrer, Nicole Finch, Neill R. Graff-Radford, Elizabeth Head, Matan Hofree, Ruochun Huang, Hudson Johns, Anna Karydas, David S. Knopman, Andrey Loboda, Eliezer Masliah, Ramya Narasimhan, Ronald C. Petersen, Alexei Podtelezhnikov, Suraj Pradhan, Rosa Rademakers, Chung-Huan Sun, Steven G. Younkin, Bruce L. Miller, Trey Ideker, Tony Wyss-Coray

Pharmacology and Nutritional Sciences Faculty Publications

Background: Biological pathways that significantly contribute to sporadic Alzheimer’s disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.

Results: To access this information we probed relative levels of close to 600 secreted signaling proteins from patients’ blood samples using …

S100a4 Drives Non-Small Cell Lung Cancer Invasion, Associates With Poor Prognosis, And Is Effectively Targeted By The Fda-Approved Anti-Helminthic Agent Niclosamide, Rachel L. Stewart, Brittany L. Carpenter, Dava S. West, Teresa Knifley, Lili Liu, Chi Wang, Heidi L. Weiss, Tamas S. Gal, Eric B. Durbin, Susanne M. Arnold, Kathleen L. O'Connor, Min Chen

Markey Cancer Center Faculty Publications

S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular …

Measuring Progress To Comprehensive Public Health Systems, National Preparedness, And A Culture Of Health, Glen P. Mays

Health Management and Policy Presentations

This update describes recent progress on two national health measurement initiatives: The National Health Security Preparedness Index and the National Longitudinal Survey of Public Health Systems. These longitudinal data sources offer valuable perspectives on how health security practices and public health delivery systems are changing across the U.S.

Tgf-Β Neutralization Enhances Angii-Induced Aortic Rupture And Aneurysm In Both Thoracic And Abdominal Regions, Xiaofeng Chen, Debra L. Rateri, Deborah A. Howatt, Anju Balakrishnan, Jessica J. Moorleghen, Lisa A. Cassis, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

AngII and TGF-β interact in development of thoracic and abdominal aortic diseases, although there are many facets of this interaction that have not been clearly defined. The aim of the present study was to determine the effects of TGF-β neutralization on AngII induced-aortic pathologies. Male C57BL/6J mice were administered with either a rabbit or mouse TGF-β neutralizing antibody and then infused with AngII. The rabbit TGF-β antibody modestly reduced serum TGF-β concentrations, with no significant enhancements to AngII-induced aneurysm or rupture. Administration of this rabbit TGF-β antibody in mice led to high serum titers against rabbit IgG that may have …

Continuing To Confront Copd International Patient Survey: Economic Impact Of Copd In 12 Countries, Jason Foo, Sarah H. Landis, Joe Maskell, Yeon-Mok Oh, Thys Van Der Molen, Meilan K. Han, David M. Mannino, Masakazu Ichinose, Yogesh Punekar

Preventive Medicine and Environmental Health Faculty Publications

Background The Continuing to Confront COPD International Patient Survey estimated the prevalence and burden of COPD across 12 countries. Using data from this survey we evaluated the economic impact of COPD.

Methods This cross-sectional, population-based survey questioned 4,343 subjects aged 40 years and older, fulfilling a case definition of COPD based on self-reported physician diagnosis or symptomatology. Direct cost measures were based on exacerbations of COPD (treated and those requiring emergency department visits and/or hospitalisation), contacts with healthcare professionals, and COPD medications. Indirect costs were calculated from work loss values using the Work Productivity and Activity Impairment scale. Combined direct …

Steroid Binding To Autotaxin Links Bile Salts And Lysophosphatidic Acid Signalling, Willem-Jan Keune, Jens Hausmann, Ruth Bolier, Dagmar Tolenaars, Andreas Kremer, Tatjana Heidebrecht, Robbie P. Joosten, Manjula Sunkara, Andrew J. Morris, Elisa Matas-Rico, Wouter H. Moolenaar, Ronald P. Oude Elferink, Anastassis Perrakis

Gill Heart & Vascular Institute Faculty Publications

Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids. A structure of ATX simultaneously harbouring TUDCA in the tunnel and LPA in the pocket, together with kinetic analysis, reveals that bile salts act as partial non-competitive inhibitors …

Learning From Variation And Change: The 2016 Release Of The National Health Security Preparedness Index, Glen P. Mays

Health Management and Policy Presentations

The 2016 release of the National Health Security Preparedness Index uses an improved computational methodology and validated set of measures to more accurately track national and state progress in protecting the public from the health effects of disasters, outbreaks and other large-scale emergencies. This presentation provides a preview of the new methodology and results.

Resveratrol Supplementation Confers Neuroprotection In Cortical Brain Tissue Of Nonhuman Primates Fed A High-Fat/Sucrose Diet, Michel Bernier, Devin Wahl, Ahmed Ali, Joanne Allard, Shakeela Faulkner, Artur Wnorowski, Mitesh Sanghvi, Ruin Moaddel, Irene Alfaras, Julie A. Mattison, Stefano Tarantini, Zsuzsanna Tucsek, Zoltan Ungvari, Anna Csiszar, Kevin J. Pearson, Rafael De Cabo

Pharmacology and Nutritional Sciences Faculty Publications

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the …

A Patient With Constitutional Ring 1 Chromosome Characterized By Snp Array Cgh, Sheila Saliganan, Joanna Lee, Sainan Wei

Pathology and Laboratory Medicine Faculty Publications

We present a male patient with constitutional ring 1 chromosome and subsequent 6 Mb deletion at 1q43q44. The patient displays overlapping clinical features with reported patients with ring 1 chromosome and 1q43q44 microdeletion syndrome. To our knowledge, this is the first patient with ring 1 chromosome characterized by comparative genomic hybridization.

Understanding The Value Of Multi-Sector Partnerships To Improve Population Health, Glen P. Mays

Health Management and Policy Presentations

We review recent research concerning multi-sectoral partnerships aimed at improving health status on a population-wide basis, with a particular focus on implementation strategies and on health and economic impact. While still preliminary and emerging, research indicates that large health benefits are possible through collective actions that engage the medical, public health, and social sectors. Mechanisms for aligning incentives, dividing responsibilities equitably, and measuring progress regularly appear critical to success.

Measuring Comprehensive Public Health Delivery Systems And Their Contributions To Population Health, Glen P. Mays, Rick Ingram

Health Management and Policy Presentations

We review methods for measuring the structure of public health delivery systems using data from the National Longitudinal Survey of Public Health Systems. A growing body of research using these measures demonstrates how multiple sectors contribute to core public health functions, and how these functions influence community health status over time. We end with a summary of how the Comprehensive Public Health System measure will be used in monitoring the impact of the 21st Century Public Health System initiative.