Kaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes

ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with the human malignancy Kaposi’s sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman’s disease. KSHV establishes lytic infection of monocytes in vivo , which may represent an important cellular reservoir during KS disease progression. KS tumors consist of latently infected endothelial cells; however, lytic phase gene products are important for KS onset. Early KS lesion progression is driven by proinflammatory cytokines supplied by immune cell infiltrates including T cells and monocytes. KSHV-infected monocytes may supply the lytic viral products and the inflammatory milieu conducive to KS tumor progression. To establish successful infection, KSHV extensively modulates the host immune system. KSHV antigens activate both innate and adaptive immune responses including KSHV-specific T cells, but lifelong infection is still established. Programmed death ligand 1 (PD-L1) is a prosurvival cell surface protein that suppresses T-cell-mediated killing. PD-L1 is variably present on various tumor cells and is a targetable marker for cancer treatment. We show that KSHV infection of human monocytes increases PD-L1 expression and transcription in a dose-dependent manner. We also saw evidence of lytic gene expression in the KSHV-infected monocytes. Intact KSHV is needed for full PD-L1 response in human monocytes. KSHV induces a general proinflammatory cytokine milieu including interleukins 1α, 1β, and 6, which have been implicated in early KS lesion progression. KSHV-mediated PD-L1 increase may represent a novel mechanism of KSHV-mediated immune modulation to allow for virus survival and eventually malignant progression. IMPORTANCE KSHV is the etiologic agent of Kaposi’s sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman’s disease. Programmed death ligand 1 (PD-L1) is an immunosuppressive cell surface marker that inhibits T cell activation. We report that KSHV infection of primary human monocytes upregulates PD-L1 transcription and protein expression. Analysis of the cytokine and chemokine milieu following KSHV infection of monocytes revealed that KSHV induces interleukins 1α, 1β, and 6, all of which have been implicated in KS development. Our work has identified another potential immune evasion strategy for KSHV and a potential target for immunotherapy of KSHV-derived disease

ADAMS project: a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the UK

PURPOSE: Genetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of these findings. The genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis (ADAMS) project aims to gather genetic and phenotypic data on a large cohort of ancestrally-diverse individuals with MS living in the UK. PARTICIPANTS: Adults with self-reported MS from diverse ancestral backgrounds. Recruitment is via clinical sites, online (https://app.mantal.co.uk/adams) or the UK MS Register. We are collecting demographic and phenotypic data using a baseline questionnaire and subsequent healthcare record linkage. We are collecting DNA from participants using saliva kits (Oragene-600) and genotyping using the Illumina Global Screening Array V.3. FINDINGS TO DATE: As of 3 January 2023, we have recruited 682 participants (n=446 online, n=55 via sites, n=181 via the UK MS Register). Of this initial cohort, 71.2% of participants are female, with a median age of 44.9 years at recruitment. Over 60% of the cohort are non-white British, with 23.5% identifying as Asian or Asian British, 16.2% as Black, African, Caribbean or Black British and 20.9% identifying as having mixed or other backgrounds. The median age at first symptom is 28 years, and median age at diagnosis is 32 years. 76.8% have relapsing-remitting MS, and 13.5% have secondary progressive MS. FUTURE PLANS: Recruitment will continue over the next 10 years. Genotyping and genetic data quality control are ongoing. Within the next 3 years, we aim to perform initial genetic analyses of susceptibility and severity with a view to replicating the findings from European-ancestry studies. In the long term, genetic data will be combined with other datasets to further cross-ancestry genetic discoveries

Evaluation of the safety of C-spine clearance by paramedics: design and methodology

<p>Abstract</p> <p>Background</p> <p>Canadian Emergency Medical Services annually transport 1.3 million patients with potential neck injuries to local emergency departments. Less than 1% of those patients have a c-spine fracture and even less (0.5%) have a spinal cord injury. Most injuries occur before the arrival of paramedics, not during transport to the hospital, yet most patients are transported in ambulances immobilized. They stay fully immobilized until a bed is available, or until physician assessment and/or X-rays are complete. The prolonged immobilization is often unnecessary and adds to the burden of already overtaxed emergency medical services systems and crowded emergency departments.</p> <p>Methods/Design</p> <p>The goal of this study is to evaluate the safety and potential impact of an active strategy that allows paramedics to assess very low-risk trauma patients using a validated clinical decision rule, the Canadian C-Spine Rule, in order to determine the need for immobilization during transport to the emergency department.</p> <p>This cohort study will be conducted in Ottawa, Canada with one emergency medical service. Paramedics with this service participated in an earlier validation study of the Canadian C-Spine Rule. Three thousand consecutive, alert, stable adult trauma patients with a potential c-spine injury will be enrolled in the study and evaluated using the Canadian C-Spine Rule to determine the need for immobilization. The outcomes that will be assessed include measures of safety (numbers of missed fractures and serious adverse outcomes), measures of clinical impact (proportion of patients transported without immobilization, key time intervals) and performance of the Rule.</p> <p>Discussion</p> <p>Approximately 40% of all very low-risk trauma patients could be transported safely, without c-spine immobilization, if paramedics were empowered to make clinical decisions using the Canadian C-Spine Rule. This safety study is an essential step before allowing all paramedics across Canada to selectively immobilize trauma victims before transport. Once safety and potential impact are established, we intend to implement a multi-centre study to study actual impact.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01188447">NCT01188447</a></p

Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Proceedings of the 8th Annual Conference on the Science of Dissemination and Implementation

A1 Introduction to the 8(th) Annual Conference on the Science of Dissemination and Implementation: Optimizing Personal and Population Health David Chambers, Lisa Simpson D1 Discussion forum: Population health D&I research Felicia Hill-Briggs D2 Discussion forum: Global health D&I research Gila Neta, Cynthia Vinson D3 Discussion forum: Precision medicine and D&I research David Chambers S1 Predictors of community therapists’ use of therapy techniques in a large public mental health system Rinad Beidas, Steven Marcus, Gregory Aarons, Kimberly Hoagwood, Sonja Schoenwald, Arthur Evans, Matthew Hurford, Ronnie Rubin, Trevor Hadley, Frances Barg, Lucia Walsh, Danielle Adams, David Mandell S2 Implementing brief cognitive behavioral therapy (CBT) in primary care: Clinicians' experiences from the field Lindsey Martin, Joseph Mignogna, Juliette Mott, Natalie Hundt, Michael Kauth, Mark Kunik, Aanand Naik, Jeffrey Cully S3 Clinician competence: Natural variation, factors affecting, and effect on patient outcomes Alan McGuire, Dominique White, Tom Bartholomew, John McGrew, Lauren Luther, Angie Rollins, Michelle Salyers S4 Exploring the multifaceted nature of sustainability in community-based prevention: A mixed-method approach Brittany Cooper, Angie Funaiole S5 Theory informed behavioral health integration in primary care: Mixed methods evaluation of the implementation of routine depression and alcohol screening and assessment Julie Richards, Amy Lee, Gwen Lapham, Ryan Caldeiro, Paula Lozano, Tory Gildred, Carol Achtmeyer, Evette Ludman, Megan Addis, Larry Marx, Katharine Bradley S6 Enhancing the evidence for specialty mental health probation through a hybrid efficacy and implementation study Tonya VanDeinse, Amy Blank Wilson, Burgin Stacey, Byron Powell, Alicia Bunger, Gary Cuddeback S7 Personalizing evidence-based child mental health care within a fiscally mandated policy reform Miya Barnett, Nicole Stadnick, Lauren Brookman-Frazee, Anna Lau S8 Leveraging an existing resource for technical assistance: Community-based supervisors in public mental health Shannon Dorsey, Michael Pullmann S9 SBIRT implementation for adolescents in urban federally qualified health centers: Implementation outcomes Shannon Mitchell, Robert Schwartz, Arethusa Kirk, Kristi Dusek, Marla Oros, Colleen Hosler, Jan Gryczynski, Carolina Barbosa, Laura Dunlap, David Lounsbury, Kevin O'Grady, Barry Brown S10 PANEL: Tailoring Implementation Strategies to Context - Expert recommendations for tailoring strategies to context Laura Damschroder, Thomas Waltz, Byron Powell S11 PANEL: Tailoring Implementation Strategies to Context - Extreme facilitation: Helping challenged healthcare settings implement complex programs Mona Ritchie S12 PANEL: Tailoring Implementation Strategies to Context - Using menu-based choice tasks to obtain expert recommendations for implementing three high-priority practices in the VA Thomas Waltz S13 PANEL: The Use of Technology to Improve Efficient Monitoring of Implementation of Evidence-based Programs - Siri, rate my therapist: Using technology to automate fidelity ratings of motivational interviewing David Atkins, Zac E. Imel, Bo Xiao, Doğan Can, Panayiotis Georgiou, Shrikanth Narayanan S14 PANEL: The Use of Technology to Improve Efficient Monitoring of Implementation of Evidence-based Programs - Identifying indicators of implementation quality for computer-based ratings Cady Berkel, Carlos Gallo, Irwin Sandler, C. Hendricks Brown, Sharlene Wolchik, Anne Marie Mauricio S15 PANEL: The Use of Technology to Improve Efficient Monitoring of Implementation of Evidence-based Programs - Improving implementation of behavioral interventions by monitoring emotion in spoken speech Carlos Gallo, C. Hendricks Brown, Sanjay Mehrotra S16 Scorecards and dashboards to assure data quality of health management information system (HMIS) using R Dharmendra Chandurkar, Siddhartha Bora, Arup Das, Anand Tripathi, Niranjan Saggurti, Anita Raj S17 A big data approach for discovering and implementing patient safety insights Eric Hughes, Brian Jacobs, Eric Kirkendall S18 Improving the efficacy of a depression registry for use in a collaborative care model Danielle Loeb, Katy Trinkley, Michael Yang, Andrew Sprowell, Donald Nease S19 Measurement feedback systems as a strategy to support implementation of measurement-based care in behavioral health Aaron Lyon, Cara Lewis, Meredith Boyd, Abigail Melvin, Semret Nicodimos, Freda Liu, Nathanial Jungbluth S20 PANEL: Implementation Science and Learning Health Systems: Intersections and Commonalities - Common loop assay: Methods of supporting learning collaboratives Allen Flynn S21 PANEL: Implementation Science and Learning Health Systems: Intersections and Commonalities - Innovating audit and feedback using message tailoring models for learning health systems Zach Landis-Lewis S22 PANEL: Implementation Science and Learning Health Systems: Intersections and Commonalities - Implementation science and learning health systems: Connecting the dots Anne Sales S23 Facilitation activities of Critical Access Hospitals during TeamSTEPPS implementation Jure Baloh, Marcia Ward, Xi Zhu S24 Organizational and social context of federally qualified health centers and variation in maternal depression outcomes Ian Bennett, Jurgen Unutzer, Johnny Mao, Enola Proctor, Mindy Vredevoogd, Ya-Fen Chan, Nathaniel Williams, Phillip Green S25 Decision support to enhance treatment of hospitalized smokers: A randomized trial Steven Bernstein, June-Marie Rosner, Michelle DeWitt, Jeanette Tetrault, James Dziura, Allen Hsiao, Scott Sussman, Patrick O’Connor, Benjamin Toll S26 PANEL: Developing Sustainable Strategies for the Implementation of Patient-Centered Care across Diverse US Healthcare Systems - A patient-centered approach to successful community transition after catastrophic injury Michael Jones, Julie Gassaway S27 PANEL: Developing Sustainable Strategies for the Implementation of Patient-Centered Care across Diverse US Healthcare Systems - Conducting PCOR to integrate mental health and cancer screening services in primary care Jonathan Tobin S28 PANEL: Developing Sustainable Strategies for the Implementation of Patient-Centered Care across Diverse US Healthcare Systems - A comparative effectiveness trial of optimal patient-centered care for US trauma care systems Douglas Zatzick S29 Preferences for in-person communication among patients in a multi-center randomized study of in-person versus telephone communication of genetic test results for cancer susceptibility Angela R Bradbury, Linda Patrick-Miller, Brian Egleston, Olufunmilayo I Olopade, Michael J Hall, Mary B Daly, Linda Fleisher, Generosa Grana, Pamela Ganschow, Dominique Fetzer, Amanda Brandt, Dana Farengo-Clark, Andrea Forman, Rikki S Gaber, Cassandra Gulden, Janice Horte, Jessica Long, Rachelle Lorenz Chambers, Terra Lucas, Shreshtha Madaan, Kristin Mattie, Danielle McKenna, Susan Montgomery, Sarah Nielsen, Jacquelyn Powers, Kim Rainey, Christina Rybak, Michelle Savage, Christina Seelaus, Jessica Stoll, Jill Stopfer, Shirley Yao and Susan Domchek S30 Working towards de-implementation: A mixed methods study in breast cancer surveillance care Erin Hahn, Corrine Munoz-Plaza, Jianjin Wang, Jazmine Garcia Delgadillo, Brian Mittman Michael Gould S31Integrating evidence-based practices for increasing cancer screenings in safety-net primary care systems: A multiple case study using the consolidated framework for implementation research Shuting (Lily) Liang, Michelle C. Kegler, Megan Cotter, Emily Phillips, April Hermstad, Rentonia Morton, Derrick Beasley, Jeremy Martinez, Kara Riehman S32 Observations from implementing an mHealth intervention in an FQHC David Gustafson, Lisa Marsch, Louise Mares, Andrew Quanbeck, Fiona McTavish, Helene McDowell, Randall Brown, Chantelle Thomas, Joseph Glass, Joseph Isham, Dhavan Shah S33 A multicomponent intervention to improve primary care provider adherence to chronic opioid therapy guidelines and reduce opioid misuse: A cluster randomized controlled trial protocol Jane Liebschutz, Karen Lasser S34 Implementing collaborative care for substance use disorders in primary care: Preliminary findings from the summit study Katherine Watkins, Allison Ober, Sarah Hunter, Karen Lamp, Brett Ewing S35 Sustaining a task-shifting strategy for blood pressure control in Ghana: A stakeholder analysis Juliet Iwelunmor, Joyce Gyamfi, Sarah Blackstone, Nana Kofi Quakyi, Jacob Plange-Rhule, Gbenga Ogedegbe S36 Contextual adaptation of the consolidated framework for implementation research (CFIR) in a tobacco cessation study in Vietnam Pritika Kumar, Nancy Van Devanter, Nam Nguyen, Linh Nguyen, Trang Nguyen, Nguyet Phuong, Donna Shelley S37 Evidence check: A knowledge brokering approach to systematic reviews for policy Sian Rudge S38 Using Evidence Synthesis to Strengthen Complex Health Systems in Low- and Middle-Income Countries Etienne Langlois S39 Does it matter: timeliness or accuracy of results? The choice of rapid reviews or systematic reviews to inform decision-making Andrea Tricco S40 Evaluation of the veterans choice program using lean six sigma at a VA medical center to identify benefits and overcome obstacles Sherry Ball, Anne Lambert-Kerzner, Christine Sulc, Carol Simmons, Jeneen Shell-Boyd, Taryn Oestreich, Ashley O'Connor, Emily Neely, Marina McCreight, Amy Labebue, Doreen DiFiore, Diana Brostow, P. Michael Ho, David Aron S41 The influence of local context on multi-stakeholder alliance quality improvement activities: A multiple case study Jillian Harvey, Megan McHugh, Dennis Scanlon S42 Increasing physical activity in early care and education: Sustainability via active garden education (SAGE) Rebecca Lee, Erica Soltero, Nathan Parker, Lorna McNeill, Tracey Ledoux S43 Marking a decade of policy implementation: The successes and continuing challenges of a provincial school food and nutrition policy in Canada Jessie-Lee McIsaac, Kate MacLeod, Nicole Ata, Sherry Jarvis, Sara Kirk S44 Use of research evidence among state legislators who prioritize mental health and substance abuse issues Jonathan Purtle, Elizabeth Dodson, Ross Brownson S45 PANEL: Effectiveness-Implementation Hybrid Designs: Clarifications, Refinements, and Additional Guidance Based on a Systematic Review and Reports from the Field - Hybrid type 1 designs Brian Mittman, Geoffrey Curran S46 PANEL: Effectiveness-Implementation Hybrid Designs: Clarifications, Refinements, and Additional Guidance Based on a Systematic Review and Reports from the Field - Hybrid type 2 designs Geoffrey Curran S47 PANEL: Effectiveness-Implementation Hybrid Designs: Clarifications, Refinements, and Additional Guidance Based on a Systematic Review and Reports from the Field - Hybrid type 3 designs Jeffrey Pyne S48 Linking team level implementation leadership and implementation climate to individual level attitudes, behaviors, and implementation outcomes Gregory Aarons, Mark Ehrhart, Elisa Torres S49 Pinpointing the specific elements of local context that matter most to implementation outcomes: Findings from qualitative comparative analysis in the RE-inspire study of VA acute stroke care Edward Miech S50 The GO score: A new context-sensitive instrument to measure group organization level for providing and improving care Edward Miech S51 A research network approach for boosting implementation and improvement Kathleen Stevens, I.S.R.N. Steering Council S52 PANEL: Qualitative methods in D&I Research: Value, rigor and challenge - The value of qualitative methods in implementation research Alison Hamilton S53 PANEL: Qualitative methods in D&I Research: Value, rigor and challenge - Learning evaluation: The role of qualitative methods in dissemination and implementation research Deborah Cohen S54 PANEL: Qualitative methods in D&I Research: Value, rigor and challenge - Qualitative methods in D&I research Deborah Padgett S55 PANEL: Maps & models: The promise of network science for clinical D&I - Hospital network of sharing patients with acute and chronic diseases in California Alexandra Morshed S56 PANEL: Maps & models: The promise of network science for clinical D&I - The use of social network analysis to identify dissemination targets and enhance D&I research study recruitment for pre-exposure prophylaxis for HIV (PrEP) among men who have sex with men Rupa Patel S57 PANEL: Maps & models: The promise of network science for clinical D&I - Network and organizational factors related to the adoption of patient navigation services among rural breast cancer care providers Beth Prusaczyk S58 A theory of de-implementation based on the theory of healthcare professionals’ behavior and intention (THPBI) and the becker model of unlearning David C. Aron, Divya Gupta, Sherry Ball S59 Observation of registered dietitian nutritionist-patient encounters by dietetic interns highlights low awareness and implementation of evidence-based nutrition practice guidelines Rosa Hand, Jenica Abram, Taylor Wolfram S60 Program sustainability action planning: Building capacity for program sustainability using the program sustainability assessment tool Molly Hastings, Sarah Moreland-Russell S61 A review of D&I study designs in published study protocols Rachel Tabak, Alex Ramsey, Ana Baumann, Emily Kryzer, Katherine Montgomery, Ericka Lewis, Margaret Padek, Byron Powell, Ross Brownson S62 PANEL: Geographic variation in the implementation of public health services: Economic, organizational, and network determinants - Model simulation techniques to estimate the cost of implementing foundational public health services Cezar Brian Mamaril, Glen Mays, Keith Branham, Lava Timsina S63 PANEL: Geographic variation in the implementation of public health services: Economic, organizational, and network determinants - Inter-organizational network effects on the implementation of public health services Glen Mays, Rachel Hogg S64 PANEL: Building capacity for implementation and dissemination of the communities that care prevention system at scale to promote evidence-based practices in behavioral health - Implementation fidelity, coalition functioning, and community prevention system transformation using communities that care Abigail Fagan, Valerie Shapiro, Eric Brown S65 PANEL: Building capacity for implementation and dissemination of the communities that care prevention system at scale to promote evidence-based practices in behavioral health - Expanding capacity for implementation of communities that care at scale using a web-based, video-assisted training system Kevin Haggerty, David Hawkins S66 PANEL: Building capacity for implementation and dissemination of the communities that care prevention system at scale to promote evidence-based practices in behavioral health - Effects of communities that care on reducing youth behavioral health problems Sabrina Oesterle, David Hawkins, Richard Catalano S68 When interventions end: the dynamics of intervention de-adoption and replacement Virginia McKay, M. Margaret Dolcini, Lee Hoffer S69 Results from next-d: can a disease specific health plan reduce incident diabetes development among a national sample of working-age adults with pre-diabetes? Tannaz Moin, Jinnan Li, O. Kenrik Duru, Susan Ettner, Norman Turk, Charles Chan, Abigail Keckhafer, Robert Luchs, Sam Ho, Carol Mangione S70 Implementing smoking cessation interventions in primary care settings (STOP): using the interactive systems framework Peter Selby, Laurie Zawertailo, Nadia Minian, Dolly Balliunas, Rosa Dragonetti, Sarwar Hussain, Julia Lecce S71 Testing the Getting To Outcomes implementation support intervention in prevention-oriented, community-based settings Matthew Chinman, Joie Acosta, Patricia Ebener, Patrick S Malone, Mary Slaughter S72 Examining the reach of a multi-component farmers’ market implementation approach among low-income consumers in an urban context Darcy Freedman, Susan Flocke, Eunlye Lee, Kristen Matlack, Erika Trapl, Punam Ohri-Vachaspati, Morgan Taggart, Elaine Borawski S73 Increasing implementation of evidence-based health promotion practices at large workplaces: The CEOs Challenge Amanda Parrish, Jeffrey Harris, Marlana Kohn, Kristen Hammerback, Becca McMillan, Peggy Hannon S74 A qualitative assessment of barriers to nutrition promotion and obesity prevention in childcare Taren Swindle, Geoffrey Curran, Leanne Whiteside-Mansell, Wendy Ward S75 Documenting institutionalization of a health communication intervention in African American churches Cheryl Holt, Sheri Lou Santos, Erin Tagai, Mary Ann Scheirer, Roxanne Carter, Janice Bowie, Muhiuddin Haider, Jimmie Slade, Min Qi Wang S76 Reduction in hospital utilization by underserved patients through use of a community-medical home Andrew Masica, Gerald Ogola, Candice Berryman, Kathleen Richter S77 Sustainability of evidence-based lay health advisor programs in African American communities: A mixed methods investigation of the National Witness Project Rachel Shelton, Lina Jandorf, Deborah Erwin S78 Predicting the long-term uninsured population and analyzing their gaps in physical access to healthcare in South Carolina Khoa Truong S79 Using an evidence-based parenting intervention in churches to prevent behavioral problems among Filipino youth: A randomized pilot study Joyce R. Javier, Dean Coffey, Sheree M. Schrager, Lawrence Palinkas, Jeanne Miranda S80 Sustainability of elementary school-based health centers in three health-disparate southern communities Veda Johnson, Valerie Hutcherson, Ruth Ellis S81 Childhood obesity prevention partnership in Louisville: creative opportunities to engage families in a multifaceted approach to obesity prevention Anna Kharmats, Sandra Marshall-King, Monica LaPradd, Fannie Fonseca-Becker S82 Improvements in cervical cancer prevention found after implementation of evidence-based Latina prevention care management program Deanna Kepka, Julia Bodson, Echo Warner, Brynn Fowler S83 The OneFlorida data trust: Achieving health equity through research & training capacity building Elizabeth Shenkman, William Hogan, Folakami Odedina, Jessica De Leon, Monica Hooper, Olveen Carrasquillo, Renee Reams, Myra Hurt, Steven Smith, Jose Szapocznik, David Nelson, Prabir Mandal S84 Disseminating and sustaining medical-legal partnerships: Shared value and social return on investment James Teufe

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes