tbuckley/cabot-search huggingface dataset:
Legionnaires Disease Surveillance in US Department of Veterans Affairs Medical Facilities and Assessment of Health Care Facility Association
Authors: Shantini D. Gamage, Meredith Ambrose, Stephen M. Kralovic, Loretta A. Simbartl, Gary A. Roselle
Journal: JAMA Network Open (2018)

Legionnaires disease (LD) incidence is increasing in the United States. Health care facilities are a high-risk setting for transmission of Legionella bacteria from building water systems to occupants. However, the contribution of LD in health care facilities to national LD rates is not well characterized.To determine the burden of LD in US Department of Veterans Affairs (VA) patients and to assess the amount of LD with VA exposure.Retrospective cohort study of reported LD data in VA medical facilities in a national VA LD surveillance system from January 1, 2014, to December 31, 2016. The study population included total veteran enrollees and enrollees who used the VA health care system.The primary outcome was assessment of annual LD rates, categorized by VA and non-VA exposure. Legionnaires disease rates for cases with VA exposure were determined on both population and exposure potential levels. Rates by VA exposure potential were calculated using inpatient bed days of care, long-term care resident days, or outpatient encounters. In addition, types and amounts of LD diagnostic testing were calculated. Case and testing data were analyzed nationally and regionally.There were 491 LD cases in the case report surveillance system from January 1, 2014, to December 31, 2016. Most cases (447 [91%]) had no VA exposure or only outpatient VA exposure. The remaining 44 cases had VA exposure from overnight stays. Total LD rates from January 1, 2014, to December 31, 2016, increased for all VA enrollees (from 1.5 to 2.0 per 100 000 enrollees; P = .04) and for users of VA health care (2.3 to 3.0 per 100 000 enrollees; P = .04). The LD rate for the subset who had no VA exposure also increased (0.90 to 1.47 per 100 000 enrollees; P < .001). In contrast, the LD rate for patients with VA overnight stay decreased on a population level (5.0 to 2.3 per 100 000 enrollees; P < .001) and an exposure level (0.31 to 0.15 per 100 000 enrollees; P < .001). Regionally, the eastern United States had the highest LD rates. The urine antigen test was the most used LD diagnostic method; 49 805 tests were performed in 2015-2016 with 335 positive results (0.67%).Data in the VA LD databases showed an increase in overall LD rates over the 3 years, driven by increases in rates of non-VA LD. Inpatient VA-associated LD rates decreased, suggesting that the VA's LD prevention efforts have contributed to improved patient safety.
THU0571 Proteomic identification of systemic-onset juvenile idiopathic arthritis phenotypic biomarkers
Authors: F. Gohar, A. McArdle, M. Jones, N. Callan, B. Hernandez, M. Miranda-Garcia, M. Lavric, C. Kessel, D. Holzinger, O. FitzGerald, S.R. Pennington, D. Foell
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Systemic juvenile idiopathic arthritis (SJIA) is a childhood rheumatic auto-inflammatory disorder of largely unknown pathogenesis. The presence of fever, rash and arthritis support a diagnosis of SJIA, though early in disease arthritis may be minimal, complicating the exclusion of alternative diagnoses such as infection. Furthermore, two clinical phenotypes of SJIA can be identified, a chronic articular-dominant (ART_SJIA) and a classical auto-inflammatory phenotype (AID_SJIA). <h3>Objectives</h3> To identify novel serum protein biomarkers that may discriminate ART_SJIA from AID_SJIA and distinguish AID_SJIA from infection. <h3>Methods</h3> Patients with active SJIA (joint activity plus or minus fever and elevated laboratory inflammation markers) were sub-grouped into the two clinical phenotypes (ART_SJIA and AID_SJIA). Serum from patients with SJIA or confirmed infection was analysed for the standard laboratory markers: C-reactive protein (CRP), white cell count (WCC) and erythrocyte sedimentation rate (ESR). A "discovery cohort" (n=10 per group) of patient serum samples was subjected to unbiased label-free proteomics using liquid chromatography mass spectrometry (LC-MS/MS) and in a separate "verification cohort" (AID_SJIA, n=48; ART_SJIA, n=29; infection, n=32) candidate biomarkers were measured by multiple reaction monitoring MS (MRM-MS; Agilent 6490 and 6495) and microsphere bead-based immunoassay (Luminex). Serum concentrations of S100A12 and MRP8/14 were also measured in all samples using enzyme linked immunoabsorbant assays (ELISAs). <h3>Results</h3> The routine laboratory markers CRP, WCC, ESR, as well as ELISA-measured S100A12 and MRP8/14 serum concentrations were highest in AID_SJIA, followed by infection and were lowest in patients with ART_SJIA. Proteins identified and quantified by LC-MS/MS could differentiate patients with ART_SJIA from those with AID_SJIA (area under the curve, AUC: 0.97). The discrimination between AID_SJIA and infection performed less well, AUC: 0.58. Targeted MRM measurement of novel protein candidate biomarkers verified the discovery cohort data. A combined biomarker panel consisting of MRM, ELISA and Luminex analysis which was evaluated using a Random forest model, indicated the correct overall identification of the clinical groups to be as follows: ART_SJIA: 24/29 (83%), AID_SJIA: 37/45 (82%) and infection: 20/32 (63%). <h3>Conclusions</h3> Significant differences in the serum protein signature between two phenotypes of SJIA suggest that different immunological processes may underlie these phenotypes. Serum protein profiles also distinguished patients with SJIA and infection. Distinguishing these two groups remains an important goal of research and therefore this study could help inform future prospective studies. <h3>Disclosure of Interest</h3> None declared
SAT0415 The mrz reaction helps to distinguish rheumatologic disorders with central nervous involvement from multiple sclerosis
Authors: N. Venhoff, J. Thiel, A.C. Venhoff, S. Rauer, D. Huzly, M.-T. Schleyer, C. Hentze, R.E. Voll, M. Rizzi, U. Salzer, T. Hottenrott
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Some rheumatologic disorders (RD) may initially manifest with central nervous system (CNS) affection, mimicking the clinical, magnetic resonance imaging, and cerebrospinal fluid (CSF) findings of multiple sclerosis (MS). Vice versa MS might be difficult to separate from some RD because of the presence of autoantibodies (e.g. ANA) in up to 50%. The MRZ reaction (MRZR), composed of the three respective antibody indices (AI) against measles, rubella, and varicella zoster virus, has been found positive frequently in MS patients. However, it is unclear whether the MRZR is helpful to distinguish rheumatologic disorders with CNS involvement (RDwCNS) from MS. <h3>Objectives</h3> To investigate the MRZ reaction as a diagnostic tool to distinguish patients with RDwCNS from patients with MS. <h3>Methods</h3> The MRZR was evaluated in 35 patients with RDwCNS and compared to 70 sex- and age- matched MS patients. An AI result ≥1.5 was indicative for intrathecal IgG production against the respective pathogen. Two previously established stringency levels, MRZR-1 (≥1 of 3 AIs positive) and MRZR-2 (≥2 of 3 AIs positive), were applied. CNS involvement of RDwCNS was defined as clinical manifestation with neurological symptoms and signs of inflammation in CSF analysis and/or cerebral/spinal magnetic resonance imaging (MRI). MRZR results were compared using the Fisher's exact test with p&lt;0.05 for statistical significance. <h3>Results</h3> Within the RDwCNS group, 31 patients suffered from systemic lupus erythematosus, four had a small vessel vasculitis. In both groups 77.1% were female, mean age (±SD) was 43.2 years (±18.7) in RDwCNS and 47.5 years (±7.8) in MS (p=n .s.). All RDwCNS patients showed clinical symptoms indicative for CNS involvement and signs of inflammation in CSF analyses and/or MRI of the brain. In 52 MS patients autoantibody screening was performed. 42% were positive for ANA (n=20) or ANCA (n=2) in indirect immunofluorescence. Only 14.3% of RDwCNS patients had a positive MRZR-1 compared to 85.7% within the MS group (p&lt;0.0001). The more specific MRZR-2 was positive in 60% of the MS patients compared to only 8.5% of the RDwCNS patients (p&lt;0.0001). By using a higher threshold of &gt;2.0 for a positive AI, the prevalence of positive MRZR-2 dropped to 5.7% (n=2) in the RDwCNS group compared to 54.3% (n=38) in the MS group (p&lt;0.0001). Oligoclonal bands were found in 94.3% of the MS and 28.6% of the RDwCNS patients (p&lt;0.0001). <h3>Conclusions</h3> Considering the high specificity of the MRZR-2 for MS confirmed in this study, this laboratory test may be a helpful diagnostic tool to distinguish RDwCNS from MS. <h3>Disclosure of Interest</h3> None declared
THU0551 Treatment strategy study in new onset dmard naive juvenile idiopathic arthritis first results on 24 months clinical outcome
Authors: P. Hissink Muller, D. Brinkman, D. Schonenberg-Meinema, W. van den Bosch, Y. Koopman-Keemink, I. Brederije, P. Bekkering, T. Kuijpers, M. van Rossum, L. van Suijlekom-Smit, J.M. van den Berg, S. Boehringer, C.F. Allaart, R. ten Cate
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> In rheumatoid arthritis treatment, targeted treatment has shown to improve disease outcomes including the option of drug tapering and discontinuation. In non-systemic juvenile idiopathic arthritis (nsJIA) this has not been tried in a trial. <h3>Objectives</h3> To investigate which of three treatment strategies, targeting at drug-free inactive disease, is most effective and safe in recent onset DMARD-naive nsJIA. <h3>Methods</h3> We conducted a randomised, multicenter, treatment strategy study with 24 months of follow up. Patients, 2–16 years old with symptom duration &lt;18 months were randomised to 1)Sequential DMARD-monotherapy (sulfasalazine (SSZ) or methotrexate (MTX), 2)Combination therapy MTX +6 weeks prednisolone, 3)Combination therapy MTX +etanercept. Treatment to target entailed three-monthly treatment intensifications in case of persistent disease activity. DMARDs were tapered to nil in case of inactive disease for at least 3 (in oligoarticular) or 6 (in polyarticular) months. After 24 months, primary outcomes were time-to-inactive-disease and time-to-flare after DMARD discontinuation. Secondary outcomes were adapted ACRPedi30/50/70/90scores, functional ability and toxicity. Missing data were imputed. <h3>Results</h3> 94 children (67% girls) with a median (InterQuartile Range) age of 9.1 (4.6–12.9) years were enrolled: 32 in arms 1 and 2, 30 in arm 3. Eleven had oligo-articular JIA, n=73 polyarticular JIA and n=8 juvenile psoriatic arthritis, 37% were ANA positive. At baseline VAS physician was median (IQR) 50<sup>39–58</sup> mm, VAS patient 54<sup>37–70</sup> mm, ESR 6 (2–14) mm/hr, active joints 8,<sup>5–12</sup> limited joints 2.5 (1–5), and CHAQ score 0.9 (0.6–1.5). After 24 months 61% (arm 1), 63% (arm 2) and 61% (arm 3) of patients had inactive disease and 45% (arm 1) 31% (arm 2) and 38% (arm 3) had stopped all DMARD(s). Time to inactive disease (median 9.0 (6.0–12.0) months) was not significantly different between arms, nor was time to flare (18.0 (15.0–21.0) months). Adapted ACRpedi-scores were comparably high between arms. Functional ability improved and remained almost normal. Toxicity reports showed mild events in similar rates across all arms. Results after 24 months by GEE. <h3>Conclusions</h3> Treatment to target drug free inactive disease is feasible in recent onset non-systemic JIA, resulting, regardless of initial treatment, in over 60% of patients in inactive disease and 38% drug free. <h3>Disclosure of Interest</h3> None declared
FRI0592 Scoring mri inflammation and structural lesions in sacroiliac joints of patients with axial spondyloarthritis: is inter-reader reliability dependent on the number of mri slices?
Authors: S. Krabbe, G. Kröber, M. Østergaard, S.J. Pedersen, J. Møller, I.J. Sørensen, B. Jensen, O.R. Madsen, M. Klarlund, U. Weber
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The SPARCC sacroiliac joint (SIJ) scoring system assesses 6 semicoronal MRI slices for inflammation and 5 slices for structural lesions in patients with axial spondyloarthritis (axSpA).<sup>1,2</sup> However, the cartilaginous SIJ compartment may show 1–2 additional slices anteriorly or posteriorly, depending on body size and scan orientation/tilt. <h3>Objectives</h3> To investigate inter-reader reliability of an "all slices" approach versus the standard SPARCC scoring of 6/5 slices. <h3>Methods</h3> Fifty-three patients with axSpA were treated with TNF inhibitor and had MRIs obtained at weeks 0/4/16/52. An experienced (UW) and two newly trained (GK, SK) blinded readers independently scored 199 SIJ MRI scans in chronological order. The cartilaginous SIJ compartment was scored slice by slice by the SPARCC 6/5 slices approach and by all available cartilaginous slices. Initially, the most anterior and posterior slices covering the cartilaginous compartment and the transitional slice were identified. The transitional slice was defined as the most anterior cartilaginous slice with the first portion of the ligamentous compartment, clearly visible on the left and/or right side. We scored SIJ inflammation, fat metaplasia, erosion and backfill, and a combined erosion and backfill score was created. Inter-reader reliability for reader pairs SK-UW/GK-UW/SK-GK was assessed using percent agreement (for individual scores) and intra-class correlation coefficients for sum scores. <h3>Results</h3> Pairwise percent agreement was 67%/63%/79% for identification of anterior slice, 47%/56%/44% for posterior slice and 69%/68%/72% for transitional slice. Using the "all slices" approach, readers UW/SK/GK scored mean 7.2/7.7/7.0 slices per MRI scan. "6/5 slices" and "all slices" correlated closely with each other for status scores at baseline/status scores at week 52, and change scores at week 52; BME 0.983/0.985/0.983; fat metaplasia 0.994/0.982/0.953; erosion 0.981/0.974/0.957; backfill 0.993/0.983/0.978; combined erosion and backfill 0.983/0.971/0.919. <h3>Conclusions</h3> The standardised 6/5 slices SPARCC methods had equal reliability as compared to evaluation of all cartilaginous slices. There was limited reliability to identify the posterior slice in the "all slices" approach, as opposed to good reproducibility to determine the transitional slice in the "6/5 slices" approach. Combining erosion and backfill scores tended to result in superior reliability compared to the 2 lesions separately, indicating a challenge to identify the transition from erosion to backfill. <h3>References</h3> [1] Arthritis Care Res2005;53:703–9. [2] J Rheumatol2015;42:79–86. <h3>Disclosure of Interest</h3> None declared
Distinct immune signatures in directly treated and distant tumors result from TLR adjuvants and focal ablation
Authors: Michael Chavez, Matthew T. Silvestrini, Elizabeth S. Ingham, Brett Z. Fite, Lisa M. Mahakian, Sarah M. Tam, Asaf Ilovitsh, Arta M. Monjazeb, William J. Murphy, Neil E. Hubbard, Ryan R. Davis, Clifford G. Tepper, Alexander D. Borowsky, Katherine W. Ferrara
Journal: Theranostics (2018)

Both adjuvants and focal ablation can alter the local innate immune system and trigger a highly effective systemic response.Our goal is to determine the impact of these treatments on directly treated and distant disease and the mechanisms for the enhanced response obtained by combinatorial treatments.Methods: We combined RNA-sequencing, flow cytometry and TCR-sequencing to dissect the impact of immunotherapy and of immunotherapy combined with ablation on local and systemic immune components.Results: With administration of a toll-like receptor agonist agonist (CpG) alone or CpG combined with same-site ablation, we found dramatic differences between the local and distant tumor environments, where the directly treated tumors were skewed to high expression of F4/80, Cd11b and Tnf and the distant tumors to enhanced Cd11c, Cd3 and Ifng.When ablation was added to immunotherapy, 100% (n=20/20) of directly treated tumors and 90% (n=18/20) of distant tumors were responsive.Comparing the combined ablation-immunotherapy treatment to immunotherapy alone, we find three major mechanistic differences.First, while ablation alone enhanced intratumoral antigen cross-presentation (up to ~8% of CD45 + cells), systemic cross-presentation of tumor antigen remained low.Combining same-site ablation with CpG amplified cross-presentation in the draining lymph node (~16% of CD45 + cells) compared to the ablation-only (~0.1% of CD45 + cells) and immunotherapy-only cohorts (~10% of CD45 + cells).Macrophages and DCs process and present this antigen to CD8 + T-cells, increasing the number of unique T-cell receptor rearrangements in distant tumors.Second, type I interferon (IFN) release from tumor cells increased with the ablation-immunotherapy treatment as compared with ablation or immunotherapy alone.Type I IFN release is synergistic with toll-like receptor activation in enhancing cytokine and chemokine expression.Expression of genes associated with T-cell activation and stimulation (Eomes, Prf1 and Icos) was 27, 56 and 89-fold higher with ablation-immunotherapy treatment as compared to the no-treatment controls (and 12, 32 and 60-fold higher for immunotherapy-only treatment as compared to the no-treatment controls).Third, we found that the ablation-immunotherapy treatment polarized macrophages and dendritic cells towards a CD169 subset systemically, where CD169 + macrophages are an IFN-enhanced subpopulation associated with dead-cell antigen presentation.Conclusion: While the local and distant responses are distinct, CpG combined with ablative focal therapy drives a highly effective systemic immune response.
SAT0642 A cad system in hep-2 iif reading: a multicentre study
Authors: A. Rigon, M. Infantino, M. Merone, G. Iannello, C. Sansone, A. Tincani, I. Cavazzana, M. Manfredi, A. Radice, P. Soda, A. Afeltra
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The indirect immunofluorescence (IIF) on HEp-2 cells is the recommended technique for anti-nuclear antibodies (ANA) detection. Automation of IIF image reading can provide a reliable basis for cost-effective serological diagnostics. Computer-aided diagnosis (CAD) tools based on digital imaging reading can help us to overcome the reader subjectivity. In a recent work<sup>1</sup> we assessed the inter-observer variability using digital images showing the 74.1% of agreement. It improved using "ground truth" as gold standard. <h3>Objectives</h3> To compare classification accuracy between readings provided by expert readers belonging to three different laboratories and those automatically returned by CAD. <h3>Methods</h3> We acquired 1771 images from 583 consecutive sample with an acquisition unit using HEp-2 cells (MBL) at 1:80 screening dilution. Each image was blindly classified as positive, negative, or weak positive by two experienced physicians, with more than ten years of experience in IIF, for each of the three laboratories. We obtained gold standard on the basis of annotations provided by expert physicians. We described a CAD system for HEp-2 classification that relies upon features provided by a deep neural network architecture, namely an Invariant Scattering Convolutional Network (Scatnet). We therefore compared human readings with automatic classification provided by a CAD. <h3>Results</h3> The dataset contains 215 positive samples, 136 weak positive, 219 negative. The CAD-system classification and experts showed a sensitivity of 93% vs 92.9%, 79.4% vs 74.5%, and 92.2% vs. 92.8% on positive, negative and weak positive, respectively (Fig 1). The CAD-system obtained an accuracy of 89.5%, slightly better than average experts' classification (88.5%) and, interestingly, it better recognised the weak positive samples. <h3>Conclusions</h3> Solid gold standard is essential for use CAD systems in routine work lab. The CAD-system classification and the 3 experts have provided comparable results. Laboratories' agreement improves using digital images and comparing each single human evaluation to a potential reference data and for this reason nowadays the CAD system should be considered a reliable tool of standardisation reducing the inter-laboratory variability. <h3>Reference</h3> [1] Rigon A, Infantino M, et al. Autoimmun Rev2017. <h3>Disclosure of Interest</h3> None declared
SAT0053 Identification of novel drugs with senolytic activity as osteoarthritis therapeutics
Authors: U. Nogueira-Recalde, F.J. Blanco, M.I. Loza, D. Grassi, P. Robbins, E. Dominguez, B. Carames
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Disease-modifying treatments for Osteoarthritis (OA) are not available. Aging-related features such as failure of cellular homeostasis mechanisms, including autophagy, cause extracellular matrix damage, chondrocyte senescence and death, which leads to articular cartilage degeneration as well as loss of joint function. <h3>Objectives</h3> <i>The objective of this study was to identify senolytics and activators of autophagy by cell-based imaging of approved drugs in human chondrocytes.</i> <h3>Methods</h3> To induce cellular senescence and reduced autophagy, High Content Screening system. Validation assays with readouts for senescence, autophagic flux, inflammation and apoptosis in primary human chondrocytes were performed. The anabolic effect on human cartilage and chondrocytes was evaluated by Safranin O staining and Nitric oxide production. To define the effects on senescence (senomorphic or senolytic), TC28a2 chondrocytes and human lung fibroblasts (IMR90) were employed. Senescence was induced in TC28a2 and IMR90 by treatment with IL-6 (20 ng/ml) for 72 hours and Etoposide (20 µM) for 48 hours, respectively, and treated with serial dilutions of identified compounds. The number of senescence cells and the number of total cells were determined with Cell Analyzer 6000 Confocal Imaging System. Navitoclax (2,5 µM) and Rapamycin (10 µM) were employed as reference controls for senolytic and senomorphic effects, respectively. <h3>Results</h3> Our primary screen yielded 279 senotherapeutic compounds. The effects of hits at inducing the autophagic flux were evaluated. 37 compounds with both senotherapeutic and pro-autophagy effects were selected. An approved drug with a defined molecular mechanism of action was selected for further validation. The compound reduced senescence (p&lt;0.001) and increased autophagic flux (p&lt;0.0001). Furthermore, we found that it protects against defective autophagy and inflammation in response to IL-6 and IL-1b. This protective effect was confirmed in human cartilage explants by a reduction of proteoglycans loss (p&lt;0.05) and in primary human chondrocytes by a reduction of NO production and chondrocyte death by apoptosis (p&lt;0.0001). Moreover, a significant senolytic effect of the selected compound was observed in both chondrocytes and fibroblasts (p&lt;0.05). This effect was also observed for structurally different compounds sharing the same mechanism of action, suggesting that pharmacological modulation of this mechanism may provide therapeutic benefits in OA. <h3>Conclusions</h3> Our imaging screening methodology provides a unique opportunity to identify drugs and mechanisms to prevent cartilage pathology. Autophagy activation and disruption of senescence may provide benefits for delaying cartilage degeneration. <h3>Acknowledgements</h3> <h3>Disclosure of Interest</h3> None declared