tbuckley/cabot-search huggingface dataset:
Integrating informatics tools and portable sequencing technology for rapid detection of resistance to anti-tuberculous drugs
Authors: Jody E. Phelan, Denise M. O’Sullivan, Diana Machado, Jorge Ramos, Yaa E. A. Oppong, Susana Campino, Justin O’Grady, Ruth McNerney, Martin L. Hibberd, Miguel Viveiros, Jim F. Huggett, Taane G. Clark
Journal: Genome Medicine (2019)

Mycobacterium tuberculosis resistance to anti-tuberculosis drugs is a major threat to global public health. Whole genome sequencing (WGS) is rapidly gaining traction as a diagnostic tool for clinical tuberculosis settings. To support this informatically, previous work led to the development of the widely used TBProfiler webtool, which predicts resistance to 14 drugs from WGS data. However, for accurate and rapid high throughput of samples in clinical or epidemiological settings, there is a need for a stand-alone tool and the ability to analyse data across multiple WGS platforms, including Oxford Nanopore MinION. We present a new command line version of the TBProfiler webserver, which includes hetero-resistance calling and will facilitate the batch processing of samples. The TBProfiler database has been expanded to incorporate 178 new markers across 16 anti-tuberculosis drugs. The predictive performance of the mutation library has been assessed using > 17,000 clinical isolates with WGS and laboratory-based drug susceptibility testing (DST) data. An integrated MinION analysis pipeline was assessed by performing WGS on 34 replicates across 3 multi-drug resistant isolates with known resistance mutations. TBProfiler accuracy varied by individual drug. Assuming DST as the gold standard, sensitivities for detecting multi-drug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) were 94% (95%CI 93–95%) and 83% (95%CI 79–87%) with specificities of 98% (95%CI 98–99%) and 96% (95%CI 95–97%) respectively. Using MinION data, only one resistance mutation was missed by TBProfiler, involving an insertion in the tlyA gene coding for capreomycin resistance. When compared to alternative platforms (e.g. Mykrobe predictor TB, the CRyPTIC library), TBProfiler demonstrated superior predictive performance across first- and second-line drugs. The new version of TBProfiler can rapidly and accurately predict anti-TB drug resistance profiles across large numbers of samples with WGS data. The computing architecture allows for the ability to modify the core bioinformatic pipelines and outputs, including the analysis of WGS data sourced from portable technologies. TBProfiler has the potential to be integrated into the point of care and WGS diagnostic environments, including in resource-poor settings.
PF278 DECITABINE COMBINED WITH HAAG AS INDUCTION CHEMOTHERAPY FOR NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA
Authors: J. Zhu, W. Cui, Q. Zhang, Z. Jin, A. Sun, X. Zhu, H. Qiu, D. Wu, X. Tang
Journal: HemaSphere (2019)

Background: Treatment of newly diagnosed acute myeloid leukemia (AML) remains challenging. Several patients and disease‐related factors contribute to poor outcome in elderly patients or high risk patients with AML, including medical comorbidities, physical frailty, and poor‐risk biologic features. It is confirmed that Decitabine(DAC) has the synergistic reaction with daunomycin or cytarabine. Therefore, we investigated whether DAC combined with HAAG regimen might also be effective for the newly diagnosed of AML patients. Aims: To evaluate the efficacy and toxicity of DAC combined with HAAG regimen as an induction therapy for newly diagnosed AML patients as well as compared with standard IA(IDA 12 mg/m 2 /d ∗ 3d) regimen. Methods: 237 patients with AML who were newly diagnosed in our center between February 2014 and July 2018 were enrolled in this retrospective study. Among them,50 cases received DAC+HAAG regimen(DAC 20 mg/m 2 /d ∗ 5d combined with low dose of homoharringtonine 1 mg/ m 2 / d ∗ 7–14d, cytarabine subcutaneously 10 mg/m 2 /q12h ∗ 7–14d, aclarubicin 10 mg/d ∗ 4–8d and G‐CSF priming). The other 187 patients received standard IA regimen (idarubicin 12 mg/m 2 /d ∗ 3d and cytarabine 100 mg/m 2 /d ∗ 7d).The outcomes of all the patients after one cycle of chemotherapy were evaluated. Results: 1.The complete remission(CR) rate of DAC+HAAG group was significantly superior than that of IA group(96.0% vs 75.9%, P = 0.000). And the overall response rate (ORR) of DAC+HAAG group was also superior than that of IA group(100.0% vs 90.7%, P = 0.0.013).2.One‐year OS of DAC+HAAG and IA group were 75.3% and 74.8%.And two‐year OS were 69.0% and 66.1%,respectively. The median OS of the poor‐risk patients receiving DAC+HAAG and IA were 26 months and 32 months, respectively (P = 0.9625). Although the OS of two groups were similar, but the age of patients in DAC+HAAG group were statistically older than the IA group(P = 0.00).Furthermore,there were more patients with PS ECOG&gt;2 in DAC+HAAG group(P = 0.000).3. Treatment related mortality (TRM), duration of neutropenia and thrombopenia were similar in both groups. Patients in DAC+HAAG group had significantly less infection grade 3–4 compared to the patients in IA group(16.0 vs 34.8%,p = 0.011). While the incidence of adverse events including bleeding, cadiotoxicity,liver damage and mucositis were similar(P = 0.424,0.296,0.259,0.060). Summary/Conclusion: DAC+HAAG regimen is a promising induction chemotherapy for newly diagnosed AML patients with mild toxicity, especially for patients who are not suit for standard induction chemotherapy.
AB0864 THE EFFECT OF ZOLEDRONIC ACID ON CHARCOT NEUROARTHROPATHY
Authors: Soumaya Boussaid, Hiba Bettaieb, Samia Jemmali, Houda Ajlani, Sonia Rekik, Hela Sahli, Elhem Cheour, Mohamed El Euch
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The Charcot foot syndrome is a serious neuroarthropathy that may threaten the functional prognosis of diabetic patient. Some studies had emphasized the beneficial effect of bisphosphonates such as pamidronate and alendronate on the reduction in bone turnover markers in this disease. Though, the use of Zoledronic acid in the treatment of Charcot foot was only evaluated in two clinical trials and its efficacy remains controversial (1, 2). <h3>Objectives</h3> The aim of this study was to investigate the clinical and radiological efficacy of Zoledronic acid in patients with diabetes and acute Charcot neuroarthropathy. <h3>Methods</h3> A prospective 2-year follow-up study was carried out on eight patient with type 2 diabetic and acute Charcot neuroarthropathy. All our patients had a physical examination and podiatry exam. The stage of the neuroarthropathy has been assessed according to the clinical and the radiographic findings (Eichenholtz Classification). All patients were assigned to intravenous infusions of 4 mg Zoledronic acid. <h3>Results</h3> The mean age of the study group was 61.4 +/- 4.5 years. The mean age of the onset of foot pain was 18.3 +/- 1.5 years. The midfoot involvement was bilateral in 6 patients and unilateral in the other two. A biological inflammatory syndrome was found in 3 patients with a mean erythrocyte sedimentation rate (ESR) level at 43 mm after one hour. Foot X-rays were abnormal at all cases. The clinical outcomes at one month after Zoledronic acid infusions were the complete disappearance of acute symptoms in 6 patients and the improvement of the pain in one patient with a decreased Visual Analogue Scale (VAS) for pain by 30%. One patient had a persistence of the pain (VAS for pain at 5mm). A radiological Control was performed after 6 months for 5 patients. All of them had bone consolidation and remineralization. <h3>Conclusion</h3> Our study showed that the Zoledronic acid, given as a single dose, had a beneficial effect on clinical and radiological features in diabetic patients with acute Charcot neuroarthropathy.Despite our encouraging outcomes, further prospective and randomized studies are needed to confirm our preliminary results. <h3>References</h3> [1] Pakarinien TK, Laine HJ, Mäenpää H, et al. the effect of zoledronic acid on the Clinical Resolution of Charcot Neuroarthropathy. Diabetes Care. 2011;34:1514-16. [2] Bharath R, Bal A, Shanmuga S, et al. A comparative study of zoledronic acid and once weekly Alendronate in the management of acute Charcot arthropathy of foot in patients with diabetes mellitus.Indian J Endocrinol Metab. 2013 Jan-Feb; 17(1): 110–116 <h3>Disclosure of Interests</h3> None declared
Abstract 15673: Preoperative Anterior Leaflet Tethering Predicts Outcome of Mitral Valve Repair for Posterior Leaflet Prolapse
Authors: Taichi Sakaguchi, Nobuyuki Kagiyama, Misako Toki, Arudo Hiraoka, Akihiro Hayashida, Toshinori Totsugawa, Kentaro Tamura, Genta Chikazawa, Hidenori Yoshitaka, Kiyoshi Yoshida
Journal: Circulation (2017)

Introduction: Carpentier's techniques for degenerative posterior mitral leaflet (PML) prolapse have been established and excellent long-term results are reported. However, in some cases residual mi...
FRI0484 RESULTS OF BONE MINERAL DENSITY DURING CELIAC DISEASE: ABOUT 83 CASES
Authors: Cyrine Daldoul, Nejla El Amri, Khadija Baccouch, Hela Zeglaoui, Elyes Bouajina
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The prevalence of osteopenia during celiac disease (CD) can range from 38% to 72%. In fact, it is a pathology that causes bone loss and is associated with a higher fracture risk compared to the general population. <h3>Objectives</h3> The aim of this work is to determine the frequency and factors associated with the decline in bone mineral density in adult subjects with CD. <h3>Methods</h3> This is a retrospective study, over a period of 4 years (from January 2014 to December 2018) and including patients followed for MC who had a measurement of bone mineral density (BMD) by DEXA. Clinical, anthropometric and densitometric data (BMD at the femoral and vertebral site) were recorded. The WHO criteria for the definition of osteoporosis and osteopenia have been used. <h3>Results</h3> 83 patients were collected among them 12 were men (sex ratio = 0.16). The average age was 38.2 years old. The average body mass index (BMI) was 21.64 kg/m<sup>2</sup> [13.05-31.9 kg/m<sup>2</sup>]. Undernutrition (BMI &lt;19 kg/m<sup>2</sup>) was found in 24 cases. It was associated with hyperthyroidism in 5 cases, autoimmune hepatitis in 1 case and primary amenorrhoea in 2 cases. 2 patients had a history of fragility fracture, and 5 patients had a history of fragility fracture in a first-degree relative. Osteodensitometry showed low bone mass in 36 cases: osteoporosis in 23 patients (27.7%) and osteopenia in 13 cases. Osteoporosis was found in 21 patients: 1 man and 20 women. Mean femoral BMD was 0.887 g/cm3 and vertebral BMD was 0.999 g/cm3. The mean T-score at the femoral site and the vertebral site were -1.28 SD and -1.26 SD, respectively. No correlation was found between age and BMD and bone status. Comparing patients with a BMI &lt;19 kg/m<sup>2</sup> to those with a BMI ≥ 19 kg/m<sup>2</sup>, BMD at the vertebral site was significantly lower in malnourished subjects (p = 0.01). a significant correlation was found between BMI and vertebral BMD (p=0.000) <h3>Conclusion</h3> The decline in BMD was observed in third of our patients. It seems to be favored by a low BMI, which is common during CD in relation to the associated malabsorption. Thus, screening for osteoporosis should be advocated early in the course of CD. <h3>Disclosure of Interests</h3> None declared
SQUID: transcriptomic structural variation detection from RNA-seq
Authors: Cong Ma, Mingfu Shao, Carl Kingsford
Journal: Genome biology (2018)

Transcripts are frequently modified by structural variations, which lead to fused transcripts of either multiple genes, known as a fusion gene, or a gene and a previously non-transcribed sequence. Detecting these modifications, called transcriptomic structural variations (TSVs), especially in cancer tumor sequencing, is an important and challenging computational problem. We introduce SQUID, a novel algorithm to predict both fusion-gene and non-fusion-gene TSVs accurately from RNA-seq alignments. SQUID unifies both concordant and discordant read alignments into one model and doubles the precision on simulation data compared to other approaches. Using SQUID, we identify novel non-fusion-gene TSVs on TCGA samples.
PB2027 A STUDY FOR RELATIONSHIP BETWEEN FEVER IN NEUTROPENIC PATIENTS AND BACTERIA-DERIVED MICROVESICLES.
Authors: S.-N. Lim, S.-M. Kim, S. Ko, S. Park
Journal: HemaSphere (2019)

Background: Fever is a common problem when neutrophils are reduced by chemotherapy. Clinically proven infections are seen in 20∼30% and bacteremia in 10∼25%. Various bacteria are known to secrete microvesicles. it is presumed that excessive inflow of the bacteria-derived microvesicles into the body through the injured mucosa in neutropenic patients may cause fever or septicemia itself. Aims: The study was designed to assess the role of bacteria-derived microvesicles in fever of neutropenic patients. Methods: Patients who were expected to have neutropenia due to conditioning chemotherapy for allogeneic or autologous hematopoietic stem cell transplantation were enrolled. Blood and urine specimens collected at the time of admission and if there was a fever of over 38oC. Additional blood and urine samples should be collected three days after fever and then collected at weekly intervals. Storage samples were subjected to the metagenomic test for bacteria-derived microvesicles. Results: A total of 22 patients were enrolled between May 2017 and December 2017. Blood and urine samples were collected from a total of 509 and 346, respectively. Alpha diversity analysis showed that in both blood and urine sample groups, the control group had higher richness than the leukopenia group. (Figure 1) At the genus level, both urine and blood sample groups showed distinct clustering and separation of microbial taxa between control and leukopenia groups. At the phylum level, Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes occupied over 85% of both control and leukopenia urine sample group relative abundance. However, there were significant difference among Proteobacteria (34.6% vs. 40.6%) and Firmicutes (35.4% vs. 27.0%) relative abundance between the control and leukopenia groups, respectively (P < 0.05). Similarly, Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes accounted for over 85% relative abundance in blood samples. Among these, significances were detected for Firmicutes (35.5% vs. 32.6%) and Bacteroidetes (9.5% vs. 11.8%) relative abundance between the control and leukopenia groups, respectively (P < 0.05). In both leukopenia group urine and blood specimens, Sphinomonas, Akkermansia, Stenotrophomonas, and Bacteroides had significantly high relative abundances, while Enhydrobacter, Prevotella, Pseudomonas, Lactobacillus, Streptococcus, and Corynebacterium showed significantly low relative abundance in the leukopenia patients microbiome. Bacillus and Anaerococcus in urine (P < 0.04) and Dialister, Butyricimonas, and Oxalobacteraceae (P < 0.05) had significantly higher before fever, respectively.Summary/Conclusion: This study showed the usefulness of bacteria-derived microvesicles as a diagnosis of neutropenic-causing bacteria. For the proper treatment of neutropenic patients, analyses of changes in bacterial microvesicles needs to be analyzed.
PS1132 INHERITED DNA REPAIR AND CELL CYCLE GENE DEFECTS IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: N.S. Moore, S.H. Aldubayan, A. Taylor‐Weiner, S. Stilgenbauer, G. Getz, C.J. Wu, E.M. Van Allen, J.R. Brown
Journal: HemaSphere (2019)

Background: Chronic lymphocytic leukemia (CLL) is among the most heritable cancers, with 60% of disease risk genetically determined. However, most of the genetic heritability of CLL remains unexplained. Previously, we identified ATM as the first CLL risk gene. Aims: Here we leverage a deep‐learning‐based germline variant calling algorithm to explore germline mutational enrichment in DNA repair and cell cycle genes in CLL. Methods: A two‐stage case‐control analysis was conducted using gene‐based mutational enrichment analysis of 50 established cancer predisposition DNA repair and cell cycle genes. In the discovery phase, a total of 285 Spanish patients and 5,608 ancestry‐matched controls were evaluated. In the validation stage, an independent cohort of 514 European patients and 27,173 ancestry‐matched controls were analyzed. An FDR correction was applied to both datasets and genes with a q‐value &lt;0.2 in both cohorts were considered significant. Results: Our joint analysis of 799 CLL patients from 2 genetically distinct cohorts and 32,781 ancestry‐matched cancer‐free controls identified ATM and CHEK2 as significantly enriched in both CLL datasets. First, our analysis recaptured the previously reported finding of ATM variant enrichment in CLL patients. Carriers of pathogenic ATM mutations in our cohorts (n = 9 patients, discovery: 1.05%, validation: 1.17%) were 2.8–3.7 times more likely to develop CLL compared to cancer‐free individuals (discovery: OR = 2.8, 95%CI = 0.7–9.0, q‐value = 0.181; validation: OR = 3.7, 95%CI = 1.6–8.3, q‐value = 0.0454). In addition, our analysis identified 21 CLL patients carrying pathogenic CHEK2 alterations (discovery: 1.40%, validation: 3.31%), making CLL patients 4.4–8.0 times more likely to carry such alterations compared to controls (discovery: OR = 8.0, 95%CI = 2.3–27.0, q‐value = 0.026; validation: OR = 4.4, 95%CI = 2.5–7.3, q‐value &lt;0.001). Summary/Conclusion: Our analysis of genetically distinct CLL cohorts, using a high‐sensitivity variant calling algorithm, supports CHEK2 as a potentially novel CLL predisposition gene that may explain a portion of the missing monogenic heritability of CLL. In addition, this study highlights the DNA repair and cell cycle regulation pathways as potential drivers of CLL susceptibility.
SP0195 IMAGING IN DISEASE AND TREATMENT MONITORING – DOES IT MATTER?
Authors: Xenofon Baraliakos
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Imaging of the axial skeleton is a crucial step in classification and diagnosis of axial Spondyloarthritis. After diagnosis, patients with axSpA are being treated with non-steroidal anti-inflammatory drugs (NSAIDs) or with disease-modifying anti-rheumatic drug (bDMARD). Despite the fact, that the latter treatment is referred to as disease-modifying and modification of the disease is supposed to be relating to the objective course of the disease, as assessed by imaging, recommendations for monitoring of the course of axSpA by imaging are still lacking mostly due to the lack of data. Nevertheless, this aspect is mentioned in the treat-to-target principle for axSpAOverall, earlier data have shown that the course of lesions documented by magnetic resonance imaging (MRI) is correlating well with other objective measures of changes of systemic inflammation such as c-reactive protein (CRP), than with patient-reported measures of disease activity. Similarly, conventional radiographs (CR) are being used for documenting of the development of structural changes over many years. <h3>Objectives:</h3> The objective of this presentation is to show the current evidence of the possibilities of different imaging techniques used in axSpA for assessment of the course of the disease (both for the inflammatory and chronic changes) and give practical tips about when imaging would be advised for monitoring the disease course or where this can be avoided. <h3>Disclosure of Interests:</h3> Xenofon Baraliakos Grant/research support from: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Chugai, Janssen, MSD, Novartis, Pfizer Inc, Roche and UCB, Grant/research support from: AbbVie, Pfizer, Merck Sharp &amp; Dohme, UCB Pharma, Novartis, Consultant for: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Janssen Biologics, Novartis, Pfizer, UCB Pharma, Galapagos, Speakers bureau: AbbVie, Chugai, Janssen, Novartis, Pfizer, UCB Pharma
Abstract 13181: Horizon and Perspective: Critical Choices in Estimating Cost-Effectiveness of Cardiovascular Prevention
Authors: Reto Auer, Dhruv S Kazi, Stephanie R Earnshaw, Michael Pignone, Mark J Pletcher
Journal: Circulation (2012)

Introduction: In order to capture the effects of preventing death, cost-effectiveness models must quantify extra years of life gained and healthcare costs incurred during those years. Different app...
AB0512 ANTI-CARBAMYLATED PROTEIN ANTIBODIES IN SYSTEMIC LUPUS ERYTHEMATOSUS: ARE THEY USEFUL?
Authors: Rajesh Kumar, Ilaria Cavazzana, Micaela Fredi, Roberta Ottaviani, Angela Tincani, Franco Franceschini
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Anti-carbamylated protein antibodies (anti-CarP) have been described not only in Rheumatoid arthritis but in other systemic autoimmune diseases. Recently, they have been reported in different cohorts of Systemic Lupus Erythematosus (SLE) with a prevalence of 9-28% (1-4). Anti-CarP have been proposed as a marker of erosive arthitis in SLE(4). <h3>Objectives:</h3> The aim of this work was to assess the prevalence of anti-CarP in SLE patients from a single center cohort and their association to clinical and laboratory data. <h3>Methods:</h3> Anti-CarP were evaluated using a home-made ELISA (5), with some modifications: all the incubations has been reduced to 1.5 hrs at room temperature and the reaction was developed with diethanolamine and read at 405nm.The cut-off value of 0.350 optical density (OD) was set up, testing 230 healthy controls sera, calculating the average plus 3 times standard deviation. The ROC curve analysis demonstrated a specificity and sensitivity of 0,98 and 0,32, respectively. The OD was converted to arbitrary units (AU) with 20 AU as cut-off value. Clinical data were obtained from clinical charts. <h3>Results:</h3> Anti-CarP antibodies were found in 80/282 (28,3%) SLE patients. Complete clinical and serological data were available for 217 patients (76,9%): 71 positive and 146 negative. No clinical associations were found with anti-CarP antibodies. However, cytopenia and renal involvement were more frequently assessed in patients without anti-CarP antibodies (p: 0,019; OR 0,49; 95%CI 0,26-0,91 and p: 0,07, respectively). Among the patients evaluated, 56 were treated with anti-Blys therapy (belimumab). In this subgroup, sera collected at the first administration (T0), after 6 months (T6) and after 12 months (T12) were tested. At baseline anti-CarP were positive in 10 (17,8%) with a mean titre of 37 AU (SD: 17,9). AntiCarp titre significantly decreased at T6 (p: 0.006) and T12 (p. 0.01). Negative seroconversion was observed in 7/10 sera. Conclusion: the prevalence of anti-CarP antibodies found in our cohort is in line with to what previously reported. In our hands, anti-CarP antibodies are not associated to any clinical SLE features. <h3>References</h3> [1] Ziegelasch M, et al. Arthritis Res and Ther 2016; 18: 289. [2] Nakabo S, et al. J Rheumatol 2017 Sep;44(9):1384-1388. [3] Pecani A, et al. Arthritis Res Ther 2016 Nov 25;18(1):276. [4] Ceccarelli F, et al. Arthritis Res Ther 2018 Jun 14;20(1):126. [5] Shi J, et al. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(42):17372-7. <h3>Disclosure of Interests:</h3> Rajesh Kumar : None declared, Ilaria Cavazzana: None declared, Micaela Fredi: None declared, Roberta Ottaviani: None declared, Angela Tincani Consultant for: UCB, Pfizer, Abbvie, BMS, Sanofi, Roche, GSK, AlphaSigma, Lillly, Jannsen, Cellgene, Novartis, Franco Franceschini: None declared