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Association Of Opioid Use Disorder Treatment With Alcohol-Related Acute Events, Kevin Y. Xu, Ned Presnall, Carrie M. Mintz, Jacob T. Borodovsky, Nisha R. Bhat, Laura J. Bierut, Richard A. Grucza

Open Access Publications

Importance: Persons with opioid use disorder (OUD) and co-occurring alcohol use disorder (AUD) are understudied and undertreated. It is unknown whether the use of medications to treat OUD is associated with reduced risk of alcohol-related morbidity.

Objective: To determine whether the use of OUD medications is associated with decreased risk for alcohol-related falls, injuries, and poisonings in persons with OUD with and without co-occurring AUD.

Design, Setting, and Participants: This recurrent-event, case-control, cohort study used prescription claims from IBM MarketScan insurance databases from January 1, 2006, to December 31, 2016. The sample included persons aged 12 to 64 years in …

Defining Phenotypic And Functional Heterogeneity Of Glioblastoma Stem Cells By Mass Cytometry, Luciano Galdieri, Arijita Jash, Olga Malkova, Diane D Mao, Patrick Desouza, Yunli E Chu, Amber Salter, Jian L Campian, Kristen M Naegle, Cameron W Brennan, Hiroaki Wakimoto, Stephen T Oh, Albert H Kim, Milan G Chheda

Open Access Publications

Most patients with glioblastoma (GBM) die within 2 years. A major therapeutic goal is to target GBM stem cells (GSCs), a subpopulation of cells that contribute to treatment resistance and recurrence. Since their discovery in 2003, GSCs have been isolated using single-surface markers, such as CD15, CD44, CD133, and α6 integrin. It remains unknown how these single-surface marker-defined GSC populations compare with each other in terms of signaling and function and whether expression of different combinations of these markers is associated with different functional capacity. Using mass cytometry and fresh operating room specimens, we found 15 distinct GSC subpopulations in …

Epithelial Il-33 Appropriates Exosome Trafficking For Secretion In Chronic Airway Disease, Ella Katz-Kiriakos, Deborah F Steinberg, Colin E Kluender, Omar A Osorio, Catie Newsom-Stewart, Arjun Baronia, Derek E Byers, Michael J Holtzman, Dawn Katafiasz, Kristina L Bailey, Steven L Brody, Mark J Miller, Jennifer Alexander-Brett

Open Access Publications

IL-33 is a key mediator of chronic airway disease driven by type 2 immune pathways, yet the nonclassical secretory mechanism for this cytokine remains undefined. We performed a comprehensive analysis in human airway epithelial cells, which revealed that tonic IL-33 secretion is dependent on the ceramide biosynthetic enzyme neutral sphingomyelinase 2 (nSMase2). IL-33 is cosecreted with exosomes by the nSMase2-regulated multivesicular endosome (MVE) pathway as surface-bound cargo. In support of these findings, human chronic obstructive pulmonary disease (COPD) specimens exhibited increased epithelial expression of the abundantly secreted IL33Δ34 isoform and augmented nSMase2 expression compared with non-COPD specimens. Using an Alternaria-induced …

Circulating Mitochondrial Dna Is An Early Indicator Of Severe Illness And Mortality From Covid-19, Davide Scozzi, Marlene Cano, Lina Ma, Dequan Zhou, Ji Hong Zhu, Jane A. O'Halloran, Charles Goss, Adriana M. Rauseo, Zhiyi Liu, Sanjaya K. Sahu, Mohsen Ibrahim, Ramsey Hachem, Daniel Kreisel, Philip A. Mudd, Hrishikesh S. Kulkarni, Andrew E. Gelman, Et Al

Open Access Publications

BackgroundMitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.MethodsWe measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with …

Use Of Mechanical Circulatory Support Devices Among Patients With Acute Myocardial Infarction Complicated By Cardiogenic Shock, Sanket S. Dhruva, Joseph S. Ross, Bobak J. Mortazavi, Nathan C. Hurley, Harlan M. Krumholz, Jeptha P. Curtis, Alyssa P. Berkowitz, Frederick A. Masoudi, John C. Messenger, Craig S. Parzynski, Che G. Ngufor, Saket Girotra, Amit P. Amin, Nilay D. Shah, Nihar R. Desai

Open Access Publications

Importance: Mechanical circulatory support (MCS) devices, including intravascular microaxial left ventricular assist devices (LVADs) and intra-aortic balloon pumps (IABPs), are used in patients who undergo percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) complicated by cardiogenic shock despite limited evidence of their clinical benefit.

Objective: To examine trends in the use of MCS devices among patients who underwent PCI for AMI with cardiogenic shock, hospital-level use variation, and factors associated with use.

Design, Setting, and Participants: This cross-sectional study used the CathPCI and Chest Pain-MI Registries of the American College of Cardiology National Cardiovascular Data Registry. Patients who underwent …

Evaluation Of Optimal Blood Culture Incubation Time To Maximize Clinically Relevant Results From A Contemporary Blood Culture Instrument And Media System, Eric M Ransom, Zahra Alipour, Meghan A Wallace, Carey-Ann D. Burnham

Open Access Publications

Timely diagnosis of microorganisms in blood cultures is necessary to optimize therapy. Although blood culture media and systems have evolved for decades, the standard interval for incubation prior to being discarded as negative has remained 5 days. Here, we evaluated the optimal incubation time for the BacT/Alert Virtuo blood culture detection system (bioMérieux) using FA Plus (aerobic) and FN Plus (anaerobic) resin culture bottles in routine clinical use. Following institutional review board (IRB) approval, a retrospective review evaluated the outcomes of 158,710 bottles collected between November 2018 and October 2019. The number of positive blood bottles was 13,592 (8.6%); 99% …

Racial Residential Segregation And Colorectal Cancer Mortality In The Mississippi Delta Region, Aaron J Kruse-Diehr, Justin T Mcdaniel, Marquita W Lewis-Thames, Aimee S James, Musa Yahaya

Open Access Publications

INTRODUCTION: Few studies have examined the effects of racial segregation on colorectal cancer (CRC) outcomes, and none has determined whether rurality moderates the effect of racial segregation on CRC mortality. We examined whether the effect of segregation on CRC mortality varied by rurality in the Mississippi Delta Region, an economically distressed and historically segregated region of the United States.

METHODS: We used data from the US Census Bureau and the 1999-2018 Surveillance, Epidemiology, and End Results (SEER) program to estimate mixed linear regression models in which CRC mortality rates among Black and White residents in Delta Region counties (N = …

Pharmacokinetic And Pharmacodynamic Profiling Of Minocycline For Injection Following A Single Infusion In Critically Ill Adults In A Phase Iv Open-Label Multicenter Study (Acumin), Thomas P Lodise, Yasir Hamad, Et Al

Open Access Publications

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR)

Transcriptomic And Functional Analyses Of Mitochondrial Dysfunction In Pressure Overload-Induced Right Ventricular Failure, Hyuntae V Hwang, Nefthi Sandeep, Ramesh V Nair, Dong-Qing Hu, Mingming Zhao, Ingrid S Lan, Giovanni Fajardo, Scot J Matkovich, Daniel Bernstein, Sushma Reddy

Open Access Publications

Background In complex congenital heart disease patients such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload, leading to RV hypertrophy and eventually RV failure. The mechanisms that promote the transition from stable RV hypertrophy to RV failure are unknown. We evaluated the role of mitochondrial bioenergetics in the development of RV failure. Methods and Results We created a murine model of RV pressure overload by pulmonary artery banding and compared with sham-operated controls. Gene expression by RNA-sequencing, oxidative stress, mitochondrial respiration, dynamics, and structure were assessed in pressure overload-induced RV failure. RV failure …

Reg4 And Its Downstream Transcriptional Activator Cd44icd In Stage Ii And Iii Colorectal Cancer, Jared A. Sninsky, Kumar S. Bishnupuri, Iván González, Nikolaos A. Trikalinos, Ling Chen, Brian K. Dieckgraefe

Open Access Publications

Reg4 is highly expressed in gastrointestinal malignancies and acts as a mitogenic and pro-invasive factor. Our recent works suggest that Reg4 binds with CD44 and induces its proteolytic cleavage to release intra-cytoplasmic domain of CD44 (CD44ICD). The goal of this study is to demonstrate clinical significance of the Reg4-CD44/CD44ICD pathway in stage II/III colon cancer and its association with clinical parameters of aggression. We constructed a tissue microarray (TMA) of 93 stage II/III matched colon adenocarcinoma patients, 23 with recurrent disease. The TMA was immunohistochemically stained for Reg4, CD44, and CD44ICD proteins and analyzed to identify associations with tumor characteristics, …

Hippocampus Guides Adaptive Learning During Dynamic Social Interactions, Oriel Feldmanhall, David F. Montez, Elizabeth A. Phelps, Lila Davachi, Vishnu P. Murty

Open Access Publications

How do we evaluate whether someone will make a good friend or collaborative peer? A hallmark of human cognition is the ability to make adaptive decisions based on information garnered from limited prior experiences. Using an interactive social task measuring adaptive choice (deciding who to reengage or avoid) in male and female participants, we find the hippocampus supports value-based social choices following single-shot learning. These adaptive choices elicited a suppression signal in the hippocampus, revealing sensitivity for the subjective perception of a person and how well they treat you during choice. The extent to which the hippocampus was suppressed was …

Controlling Opioid Receptor Functional Selectivity By Targeting Distinct Subpockets Of The Orthosteric Site, Rajendra Uprety, Tao Che, Balázs R. Varga, Abdelfattah Faouzi, Sarah M. Bernhard, Susruta Majumdar, Et Al

Open Access Publications

Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here, we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with

Treatment Of Patients With Chronic Pruritus Of Unknown Origin With Dupilumab, Jiehyun Jeon, Fang Wang, Asima Badic, Brian S Kim

Open Access Publications

BACKGROUND: Chronic pruritus of unknown origin (CPUO) is a highly debilitating disease that lacks effective treatments. This study explores a new therapeutic strategy with dupilumab.

OBJECTIVES: To examine whether patients with CPUO demonstrate clinical response to dupilumab.

PATIENTS AND METHODS: This is a retrospective case series examining all patients with CPUO who were treated with dupilumab from March 2017 to December 2019 at a tertiary referral clinic at Washington University School of Medicine in St. Louis, MO. Numerical rating scale (NRS) itch score changes over time were recorded and analyzed.

RESULTS: Fifteen patients (67% women; mean [SD] age, 68.7 [12.6] …

Seroprevalence Of Sars-Cov-2 Antibodies In Children And Adults In St. Louis, Missouri, Usa, Brittany K Smith, Andrew B Janowski, Jonathan E Danis, Ian B Harvey, Haiyan Zhao, Ya-Nan Dai, Christopher W Farnsworth, Ann M Gronowski, Stephen Roper, Daved H Fremont, David Wang

Open Access Publications

Reported coronavirus disease 2019 (COVID-19) case counts likely underestimate the true prevalence because mild or asymptomatic cases often go untested. Here, we use a sero-survey to estimate the seroprevalence of IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the St. Louis, MO, metropolitan area in a symptom-independent manner. Five hundred three adult and 555 pediatric serum/plasma samples were collected from patients presenting to Barnes-Jewish Hospital or St. Louis Children's Hospital between 14 April 2020 and 12 May 2020. We developed protocols for in-house enzyme-linked immunosorbent assays (ELISAs) using spike and nucleoprotein and used the assays to estimate …

Gut Helicobacter Presentation By Multiple Dendritic Cell Subsets Enables Context-Specific Regulatory T Cell Generation, Emilie V. Russler-Germain, Jaeu Yi, Shannon Young, Katherine Nutsch, Harikesh S. Wong, Teresa L. Ai, Jiani N. Chai, Vivek Durai, Daniel H. Kaplan, Ronald N. Germain, Kenneth M. Murphy, Chyi-Song Hsieh

Open Access Publications

Generation of tolerogenic peripheral regulatory T (pTreg) cells is commonly thought to involve CD103

Satb2 Induction Of A Neural Crest Mesenchyme-Like Program Drives Melanoma Invasion And Drug Resistance, Maurizio Fazio, Charles K. Kaufman, Et Al

Open Access Publications

Recent genomic and scRNA-seq analyses of melanoma demonstrated a lack of recurrent genetic drivers of metastasis, while identifying common transcriptional states correlating with invasion or drug resistance. To test whether transcriptional adaptation can drive melanoma progression, we made use of a zebrafish mitfa:

The Role Of Endometrial Sampling For Surveillance Of Recurrence In Postmenopausal Patients With Medically Inoperable Stage I Endometrial Cancer, Angelina Carey-Love, Mary M Mullen, Abigail Zamorano, Stephanie Markovina, Andrea R Hagemann, Katherine C Fuh, Premal H Thaker, David G Mutch, Matthew A Powell, Lindsay M Kuroki

Open Access Publications

It is unclear if surveillance for postmenopausal women with medically inoperable stage 1 endometrial cancer (EC) should differ depending on their management strategy. Thus, we investigated the utility of surveillance endometrial sampling among 53 postmenopausal women with medically inoperable, clinical stage I, grade 1 endometrioid EC who received either progestin therapy or radiation between 2009 and 2018, at a single academic institution. Frequency and results of endometrial sampling, as well as recurrence and survival rates were studied. Of 53 patients, 18 (34.0%) received progestin therapy and 35 (66.0%) radiation. Medically managed patients were treated with megestrol acetate (27.7%), a levonorgestrel …

Polygenic Burden Has Broader Impact On Health, Cognition, And Socioeconomic Outcomes Than Most Rare And High-Risk Copy Number Variants, Elmo Christian Saarentaus, Lei Chen, Ira M Hall, Et Al

Open Access Publications

Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on …

Capsule Carbohydrate Structure Determines Virulence In Acinetobacter Baumannii, Yuli Talyansky, Travis B. Nielsen, Jun Yan, Ulrike Carlino-Macdonald, Gisela Di Venanzio, Somnath Chakravorty, Amber Ulhaq, Mario F. Feldman, Thomas A. Russo, Evgeny Vinogradov, Brian Luna, Meredith S. Wright, Mark D. Adams, Brad Spellberg

Open Access Publications

Acinetobacter baumannii is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and …

Prognostic And Predictive Effect Of Kras Gene Copy Number And Mutation Status In Early Stage Non-Small Cell Lung Cancer Patients, Andrea S. Fung, Maryam Karimi, Stefan Michiels, Lesley Seymour, Elisabeth Brambilla, Thierry Le-Chevalier, Jean-Charles Soria, Robert Kratzke, Stephen L. Graziano, Siddhartha Devarakonda, Ramaswamy Govindan, Ming-Sound Tsao, Frances A. Shepherd, Lace-Bio Collaborative Group

Open Access Publications

Background: In the current analysis, we characterize the prognostic significance of

Methods: Clinical and genomic data from the LACE (Lung Adjuvant Cisplatin Evaluation)-Bio consortium was utilized. CNAs were categorized as Gain (CN ≥2) or Neutral (Neut)/Loss;

Results: Of the 946 (399 adenocarcinoma) NSCLC patients, 41 [30] had MUT + Gain, 145 [99] MUT + Neut/Loss, 125 [16] WT + Gain, and 635 [254] WT + Neut/Loss. A non-significant trend towards worse lung cancer-specific survival (LCSS; HR =1.34; 95% CI, 0.83-2.17, P=0.232), DFS (HR =1.34; 95% CI, 0.86-2.09, P=0.202) and OS (HR =1.59; 95% CI, 0.99-2.54, P=0.055) was seen in

Conclusions: …

Suspected Metal Allergy And Femoral Loosening After Total Knee Arthroplasty: A Diagnostic Dilemma, Elizabeth G Lieberman, Robert L Barrack, Thomas P Schmalzried

Open Access Publications

Metal sensitivity is increasingly prevalent and is associated with negative outcomes after total knee arthroplasty (TKA). Currently, there is no consensus on diagnostic criteria for TKA failure from immune reaction. We present a patient who had pain and aseptic effusion 2 years after TKA. Radiographs were concerning femoral loosening. Lymphocyte transformation testing showed nickel sensitivity. During revision surgery, the femoral component was loose. The histologic aseptic lymphocyte-dominated vasculitis-associated lesion score was 4 with elevated CD4+ lymphocytes, consistent with sensitization. Nickel-free revision implants were used. One year after surgery, the patient is symptom-free. This case has features suggestive of an immune …

Flortaucipir (Tau) Pet In Lgi1 Antibody Encephalitis, Gregory S Day, Brian A Gordon, Austin Mccullough, Robert C Bucelli, Richard J Perrin, Tammie L S Benzinger, Beau M Ances

Open Access Publications

The contributors to persistent cognitive impairment and hippocampal atrophy in leucine-rich glioma-inactivated 1 antibody encephalitis (LGI1) patients are unknown. We evaluated whether tau neuropathology measured with [

Ana Webinars: Implementation Of A Conference-Based Virtual Networking Event, Bhooma Aravamuthan, Eric C Landsness, Elizabeth Silbermann

Open Access Publications

OBJECTIVE: To describe the design and implementation of a virtual network event at the American Neurological Association (ANA) annual meeting led by the Junior and Early Career Member (JECM) Committee.

METHODS: We designed a one-hour virtual networking session featuring three 15-minute small group meetings preceded and followed by general remarks. Each small group session consisted of one senior mentor, a junior/early career faculty moderator, and three to four junior/early career mentees. All participants completed an exit survey to evaluate perceived benefit of this event.

RESULTS: We recruited 103 mentees, 26 moderators, and 26 mentors for the event. Mentees were primarily …

Evaluating Cognitive Relationships With Resting-State And Task-Driven Blood Oxygen Level-Dependent Variability, Peter R Millar, Beau M Ances, Brian A Gordon, Tammie L S Benzinger, John C Morris, David A Balota

Open Access Publications

Recent functional magnetic resonance imaging studies have reported that moment-to-moment variability in the blood oxygen level-dependent (BOLD) signal is positively associated with task performance and, thus, may reflect a behaviorally sensitive signal. However, it is not clear whether estimates of resting-state and task-driven BOLD variability are differentially related to cognition, as they may be driven by distinct sources of variance in the BOLD signal. Moreover, other studies have suggested that age differences in resting-state BOLD variability may be particularly sensitive to individual differences in cardiovascular, rather than neural, factors. In this study, we tested relationships between measures of behavioral task …

Global, Cell Non-Autonomous Gene Regulation Drives Individual Lifespan Among Isogenic C. Elegans, Holly E. Kinser, Matthew C. Mosley, Isaac B. Plutzer, Zachary Pincus

Open Access Publications

Across species, lifespan is highly variable among individuals within a population. Even genetically identical

Progress Towards Onchocerciasis Elimination In Côte D'Ivoire: A Geospatial Modelling Study, Obiora A. Eneanya, Benjamin G. Koudou, Meite Aboulaye, Aba Ange Elvis, Yeo Souleymane, Marie-Madeleine Kouakou, Gary J. Weil, Peter U. Fischer

Open Access Publications

BACKGROUND: Côte d'Ivoire has had 45 years of intervention for onchocerciasis by vector control (from 1975 to 1991), ivermectin mass drug administration (MDA) (from 1992 to 1994) and community directed treatment with ivermectin (CDTi) from 1995 to the present. We modeled onchocerciasis endemicity during two time periods that correspond to the scale up of vector control and ivermectin distribution, respectively. This analysis illustrates progress towards elimination during these periods, and it has identified potential hotspots areas that are at risk for ongoing transmission.

METHODS AND FINDINGS: The analysis used Ministry of Health skin snip microfilaria (MF) prevalence and intensity data …

"It's Way More Than Just Writing A Prescription": A Qualitative Study Of Preferences For Integrated Versus Non-Integrated Treatment Models Among Individuals With Opioid Use Disorder, Elizabeth C Saunders, Sarah K Moore, Olivia Walsh, Stephen A Metcalf, Alan J Budney, Patricia Cavazos-Rehg, Emily Scherer, Lisa A Marsch

Open Access Publications

BACKGROUND: Increasingly, treatment for opioid use disorder (OUD) is offered in integrated treatment models addressing both substance use and other health conditions within the same system. This often includes offering medications for OUD in general medical settings. It remains uncertain whether integrated OUD treatment models are preferred to non-integrated models, where treatment is provided within a distinct treatment system. This study aimed to explore preferences for integrated versus non-integrated treatment models among people with OUD and examine what factors may influence preferences.

METHODS: This qualitative study recruited participants (n = 40) through Craigslist advertisements and flyers posted in treatment programs …

Investigating Rare Pathogenic/Likely Pathogenic Exonic Variation In Bipolar Disorder, Xiaoming Jia, Fernando S Goes, Adam E Locke, Duncan Palmer, Weiqing Wang, Et Al

Open Access Publications

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes …

Genomic Characterization Of Emerging Bacterial Uropathogen Neisseria Meningitidis, Which Was Misidentified As Neisseria Gonorrhoeae By Nucleic Acid Amplification Testing, Kimberley V Sukhum, Sophonie Jean, Meghan Wallace, Neil Anderson, C A Burnham, Gautam Dantas

Open Access Publications

No abstract provided.

Central Venous Catheter Adverse Events Are Not Associated With Crowding Indicators, Daniel L Theodoro, Niraj Vyas, Enyo Ablordeppey, Brian Bausano, Stephanie Charshafian, Phillip Asaro, Richard T Griffey

Open Access Publications

OBJECTIVE: Crowding in the emergency department (ED) impacts a number of important quality and safety metrics. We studied ED crowding measures associated with adverse events (AE) resulting from central venous catheters (CVC) inserted in the ED, as well as the relationship between crowding and the frequency of CVC insertions in an ED cohort admitted to the intensive care unit (ICU).

METHODS: We conducted a retrospective observational study from 2008-2010 in an academic tertiary care center. Participants undergoing CVC in the ED or admitted to an ICU were categorized by quartile based on the following: National Emergency Department Overcrowding Scale (NEDOCS); …