tbuckley/cabot-search huggingface dataset:
S863 ONE-YEAR EFFICACY OF RAVULIZUMAB (ALXN1210) IN ADULT PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA NAIVE TO COMPLEMENT INHIBITORS
Authors: H. Schrezenmeier, A. Kulasekararaj, L. Mitchell, F. Sicre de Fontbrune, T. Devo, S. Okamoto, R. Wells, S. Rottinghaus, P. Liu, S. Ortiz, L. Shafner, J.W. Lee, G. Socie
Journal: HemaSphere (2019)

Background: GATA2 is the most frequently mutated gene in childhood AML. These patients have germline mutations in one allele of GATA2 and have a high predisposition for MDS/AML. Also, in mouse, Gata2 is required for embryonic HSC generation and survival and complete deletion of Gata2 is lethal at embryonic day (E)10, while Gata2 haploinsufficiency results in a severe reduction in the formation of HSCs. The first HSCs are formed at E10.5 through a process called endothelial-to-hematopoietic transition (EHT) from specialized hemogenic endothelial cells of the dorsal aorta in the aorta-gonad-mesonephros (AGM) region. Aims: As all patients suffering from GATA2 haploinsufficiency syndromes have innate GATA2 mutations, our hypothesis is that embryonic haploinsufficiency of GATA2 is responsible for the phenotype of the patients. Therefore, we want to understand how Gata2 haploinsufficiency affects the generation of HSCs through EHT. Methods: We sorted phenotypic HSPCs (CD31+cKit+ cells) from WT and Gata2+/- E11 AGMs and performed transcriptome analysis. Also, with whole-mount antibody staining performed on the WT and Gata2+/- AGMs, we analysed CD31+cKit+ cell populations. Results: Surprisingly, we found that the hematopoietic transcriptional program is not abrogated in Gata2+/- mouse E11 CD31+cKit+ cells. However, Gata2+/- HSPCs still express the endothelial program indicating that the hematopoietic cells are stuck in the endothelium and cannot complete EHT. We found that Gfi1b is downregulated in Gata2+/- HSPCs. As Gfi1b is known to be required for downregulation of the endothelial program for EHT during primitive hematopoiesis, we hypothesize that Gata2 directly regulates Gfi1b and that this regulation is required for normal EHT. Summary/Conclusion: In conclusion, we showed Gata2+/- HSPCs are transcriptionally different from WT HSPCs. We are currently studying if a specific HSPC subtype can overcome Gata2 haploinsufficiency and will still undergo EHT as this may have implications for the hematopoietic cells that eventually populate the hematopoietic tissues.
Combined single-cell profiling of expression and DNA methylation reveals splicing regulation and heterogeneity
Authors: Stephanie M. Linker, Lara Urban, Stephen J. Clark, Mariya Chhatriwala, Shradha Amatya, Davis J. McCarthy, Ingo Ebersberger, Ludovic Vallier, Wolf Reik, Oliver Stegle, Marc Jan Bonder
Journal: Genome biology (2019)

Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied across human tissues and in genetically diverse populations. This has identified disease-relevant splicing events, as well as associations between splicing and genomic features, including sequence composition and conservation. However, variability in splicing between single cells from the same tissue or cell type and its determinants remains poorly understood. We applied parallel DNA methylation and transcriptome sequencing to differentiating human induced pluripotent stem cells to characterize splicing variation (exon skipping) and its determinants. Our results show that variation in single-cell splicing can be accurately predicted based on local sequence composition and genomic features. We observe moderate but consistent contributions from local DNA methylation profiles to splicing variation across cells. A combined model that is built based on genomic features as well as DNA methylation information accurately predicts different splicing modes of individual cassette exons. These categories include the conventional inclusion and exclusion patterns, but also more subtle modes of cell-to-cell variation in splicing. Finally, we identified and characterized associations between DNA methylation and splicing changes during cell differentiation. Our study yields new insights into alternative splicing at the single-cell level and reveals a previously underappreciated link between DNA methylation variation and splicing.
THU0597 ULTRASOUND REVEALS SUB-CLINICAL ATHEROSCLEROSIS IN PATIENTS WITH GOUT AND ASYMPTOMATIC HYPERURICEMIA
Authors: Chiara Bertolazzi, Jaime Mendoza Torres, Luis Carlos Rodriguez Delgado, Mariana Moreno, Carlos Pineda, Luis Humberto Silveira Torre, Jessica Gutierrez, Marwin Gutierrez
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Accelerated atherosclerosis and the higher risk of developing premature cardiovascular disease are well known in chronic inflammatory rheumatic diseases. Moreover, strong evidence supporting both proatherogenic and protrombotic characteristics of high levels of uric acid have been published. Ultrasound (US) measurement of the carotid intima-media thickness (cIMT) is a non-invasive outcome measure of premature sub-clinical atherosclerosis with a predictive value in terms of vascular events. <h3>Objectives:</h3> To determine the prevalence of increased cIMT, as sign of pre-clinical atherosclerosis, in patients with gout and asymptomatic hyperuricemia by an automated ultrasound (US) method. <h3>Methods:</h3> 342 subjects (138 with gout, 105 with asymptomatic hyperuricemia and 99 healthy control subjects) were enrolled. Before the US assessment, all patients underwent a clinical examination aimed to record age, gender, disease duration, smoking, ischemic cardiopathy, comorbidities (including diabetes mellitus, high blood pressure, dyslipidemia, renal insufficiency, obesity), and current therapy. Moreover, ESR, CRP, total cholesterol, HDL-high-density lipoprotein, triglycerides, fasting serum glucose, serum creatinine and uricemia were recorded. Patients with history of myocardial infarction, cerebrovascular events or autoimmune diseases were excluded. US examinations of the IMT at both common carotids were performed by a rheumatologist expert in US, using a linear probe and an automatic method (QIMT) based on the radio-frequency technology. For the IMT, a cut-off point of 0.8 mm was adopted, according Mannheim cIMT Consensus. <h3>Results:</h3> A total of 684 common carotids were assessed. In 65 (47.10%) out of the 138 patients with gout and 50 (47.62%) out of the 105 patients with asymptomatic hyperuricemia, US detected an increased cIMT and only 9 (0.09%) of the control group patients had an increased cIMT (p=0.0001). The regression analysis found a significant positive correlation between increased cIMT and disease duration in gout group (p=0.001) and between the level of uric acid and increased cIMT in asymptomatic hyperuricemic patients (p=0.009). No significant correlation was found with the other clinical and laboratory parameters. There was a significant difference in cIMT between in gout and control groups (p=0.0001) and between asymptomatic hyperuricemia and control group (p=0.0001). <h3>Conclusion:</h3> Our results demonstrate that patients with gout and hyperuricemia without clinically evident cardiovascular disease have a high prevalence of atherosclerosis represented by the increased cIMT. <h3>Disclosure of Interests:</h3> None declared
Absence of hepatitis E virus RNA in semen samples of infertile male in China
Authors: Lin Wang, Zhe Zhang, Jingyi Shu, Haitao Zhang, Yuzhuo Yang, Zhaochao Liang, Qiyu He, Weijin Huang, Youchun Wang, Hui Zhuang, Hui Jiang, Ling Wang
Journal: Gut (2019)

Hepatitis E virus (HEV) RNA has been recently discovered in semen samples of Chinese infertile man with a remarkably high rate of 28.1% (52/185, table 1).1 All HEV isolates belong to HEV genotype 4 (HEV4), which is the dominant strain prevalent in China. This intriguing discovery has aroused our attention. In a recent response to the work done by Huang et al , researchers in Germany tested 87 semen samples collected from infertile men, but the HEV RNA positive rate is 0% (table 1).2 Germany is prevalent with HEV3, so the authors suggested that HEV genotype-specific or variant-specific pathophysiology may explain the contrary results. However, the two studies both have limitations to reach a more accurate conclusion. The size of patients included in both studies is relatively small, and …
Abstract 17059: Genetic Ablation of c-kit Impairs Cardiac Stem Cell Function, Leading to Attenuated Cardiomyogenesis and Accelerated Myocardial Aging
Authors: Anna Czarna, Fumihiro Sanada, Junghyun Kim, Sergio Signiore, Polina Goihberg, Jan Kajstura, Marcello Rota, Piero Anversa, Annarosa Leri
Journal: Circulation (2013)

The objective of this study was to determine whether defects in c-kit receptor tyrosine activity attenuate cardiac stem cell (CSC) growth, interfering with myocyte renewal and promoting myocardial ...
Advances in rehabilitation for chronic diseases: improving health outcomes and function
Authors: Caroline R Richardson, Barry Franklin, Marilyn L Moy, Elizabeth A Jackson
Journal: BMJ (2019)

Abstract Much of the burden on healthcare systems is related to the management of chronic conditions such as cardiovascular disease and chronic obstructive pulmonary disease. Although conventional outpatient cardiopulmonary rehabilitation programs significantly decrease morbidity and mortality and improve function and health related quality of life for people with chronic diseases, rehabilitation programs are underused. Barriers to enrollment are multifactorial and include failure to recommend and refer patients to these services; poor communication with patients about potential benefits; and patient factors including logistical and financial barriers, comorbidities, and competing demands that make participation in facility based programs difficult. Recent advances in rehabilitation programs that involve remotely delivered technology could help deliver services to more people who might benefit. Problems with intensity, adherence, and safety of home based programs have been investigated in recent clinical trials, and larger dissemination and implementation trials are under way. This review summarizes the evidence for benefit of in-person cardiac and pulmonary rehabilitation programs. It also reviews the literature on newer developments, such as home based remotely mediated exercise programs developed to decrease cost and improve accessibility, high intensity interval training in cardiac rehabilitation, and alternative therapies such as tai chi and yoga for people with chronic obstructive pulmonary disease.
AB0632 MAINTENANCE RITUXIMAB IN ANCA ASSOCIATED VASCULITIS – OBSERVATIONAL DATA FROM UNIVERSITY HOSPITAL COVENTRY, UK
Authors: Megan Rutter, Shirish Dubey, Andrew Short
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Rituximab is considered an effective<sup>1</sup> maintenance therapy in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), with reduced relapse rates post induction therapy and comparable adverse event profile to other agents such as azathioprine<sup>2</sup>. <h3>Objectives</h3> To describe the clinical outcomes of all patients receiving maintenance Rituximab for aAV in University Hospital Coventry in UK. <h3>Methods</h3> Records from the Renal and Rheumatology units were used to identify patients receiving maintenance Rituximab. Electronic patient records (EPR) were used to collate laboratory and clinical data. <h3>Results</h3> We identified 38 patients, with the diagnosis of aAV made 11 months to 19 years previously. 16 (42%) had been diagnosed within the last five years. Age range was 19-87 years old with roughly half (21; 54%) being male. Maintenance Rituximab was started between January 2010 and September 2018. Most patients received a fixed 6 monthly protocol. Seven patients (18%) died within the observation period. More details in table 1 below. <h3>Conclusion</h3> The effectiveness of Rituximab as a maintenance therapy in aAV is borne out by this real world data, with 31/38 patients demonstrating full clinical response. Longer term treatment and low grade disease continue to be issues as evidence for optimal management strategies is lacking. Infections, including severe infections necessitating admission, were common. PR3 positive patients are over-represented, in keeping with the known higher rate of relapse. <h3>References</h3> [1] Smith, Rona M., et al. "Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody–associated vasculitis." arthritis &amp; Rheumatism 64.11 (2012): 3760-3769. [2] Guillevin, Loïc, et al. "Rituximab versus azathioprine for maintenance in aNCA-associated vasculitis." New England Journal of Medicine 371.19 (2014): 1771-1780. <b>I confirm that the abstract fulfils the requirements for a late breaking submission and that the research results were not available at the time of the original deadline (31 January 2019)</b> Yes <h3>Disclosure of interests</h3> Megan Rutter: None declared, Shirish Dubey Grant/research support from: Roche provided a grant 5 years ago, Speakers bureau: Yes, BMS and internis, andrew Short: None declared
Safety and efficacy of topical formulations containing 0·5, 1 and 2% glycopyrronium bromide in patients with primary axillary hyperhidrosis: a randomized, double‐blind, placebo‐controlled study
Authors: C. Masur, M. Soeberdt, A. Kilic, U. Knie, C. Abels
Journal: British Journal of Dermatology (2019)
PB1659 WHOLE EXOME SEQUENCING IN ADULT PATIENT WITH PHILADELPHIA / BCR‐ABL1 POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: P. Chin Lee, Z. Zubaidah, H. Ranjeev, K. Tsung Fei, N. Ching Ching
Journal: HemaSphere (2019)

Background: BCR‐ABL1 gene fusion is detected at approximately 20% of adult acute lymphoblastic leukemia (ALL). Patients with Philadephia (Ph) / BCR‐ABL1 positive are a high risk group that associated with poor prognosis and short duration remission. Patients showed markedly improved with introduction of tyrosine kinase inhibitor combined with chemotherapy regimen but a small fraction of these patients remain refractory and poor response to treatment. Aims: The aim of this study was to determine the somatic mutations profile using whole exome sequencing of patient with Ph‐positive ALL. Methods: DNA from matched tumour‐normal samples for four patients with Ph‐positive ALL was extracted from peripheral blood or bone marrow leukemia cells by QIAamp DNA Mini kit. The exome library was enriched using the Nextera Rapid Capture Expended Enrichement kit (Illumina, San Diego, CA) according to the manufacturer's protocol and were subsequently sequenced on Illumina HiSeq 2500 system. Somatic mutations were separated from germline variants using Genome Analaysis Toolkits (GATK) best practices filtering strategy. Results: We identified a total of 14,804 intragenic somatic mutations (range from 2,948 to 4,165 in each). Of these 760 variants were passed through the variant caller. Among them 462 were single nucleotide variants (SNVs) and 298 were insertion/deletions (InDels). Total of 48 common variants were observed but failed Mutect caller. Among SNVs, 110 variants were nonsynonymous, 46 synonymous, 6 stopgain, 3 unknown and majority 297 (64.3%) null variants. A total of 53 nonsynonymous SNVs and 14 InDeLs (8 were frameshift deletion, 5 frameshift insertion and one stopgain) were identified as possible pathogeneic variants. The identified mutation genes in this study mostly also found in other malignancies disease and two alteration genes MCM7 and STAT5 were found in disease progression of CML. Summary/Conclusion: We have sequenced the whole coding sequence of four Ph / BCR‐ABL1 positive ALLs and corresponding normal samples that allows us to overview of candidate gene in the coding regions that driving Ph‐positive ALL development and as well as enhanced our understanding of the candidate genes in diagnosis testing and prognostic prediction of adult ALLs patient.
Abstract 216: How Many Shocks Should Be Given to Victims with Out-of-Hospital Cardiac Arrest with Shockable Rhythm On-site Before Transportation?
Authors: Hiroyuki Hanada, Naohiro Yonemoto, Takeshi Kimura, Hiroshi Nonoki, Ken Nagao
Journal: Circulation (2011)

Early defibrillation and high quality cardio-pulmonary resuscitation (CPR) are the key of survival with minimal neurologic impairment (good neurological survival (GNS)) in out-of-hospital cardiac arrest (OHCA) cases. But it has not been clarified how long emergency medical service (EMS) personnel stay on site of OHCA and give CPR with defibrillation before transportation to the hospital. To clarify this, we examined the relationship between the number of defibrillation and the rate of GNS which was defined as the Glasgow-Pittsburgh cerebral performance category of 1 or 2 after one month of OHCA. Methods and Results. From January 1, 2005, through December 31, 2009, we conducted a prospective, population-based, observational study involving the consecutive patients across Japan who had OHCA (n=547,218). Since the defibrillation protocol of one shock followed by immediate chest compression and ventilation for 2 minutes had started from January 1, 2007 in Japan, we analyzed from January 1, 2007 to December 31, 2009. We identified 13,152 EMS-treated, witnessed cardiac arrest cases, with the age &gt;18 years old, with the initial rhythm of ventricular fibrillation or tachycardia (VF/VT). Results were shown in the figure. The intervals from witness to start CPR and the rates of by-stander CPR given by citizen were not different among each group. GNS rate was decreased as the number of defibrillation was increased, but GNS rate was still over 10% in the group of 8 shocks. Conclusions. In conclusion, up to two shocks on site before transportation would be acceptable (because GNS was more than 20%), and CPR with defibrillation should not be stopped during transportation as long as VF/VT persists.
Abstract 9552: A Novel Human Cardiac Troponin T upstream Open Reading Frame Peptide Assists in the Diagnosis and Prognosis of NSTEMI Patients
Authors: Chris J Pemberton, Jacqui Lee, Mark Bailey, Sally Aldous, Joanna Young, Martin Than, Richard W Troughton, Mark Richards
Journal: Circulation (2013)

Introduction: High sensitivity assays for cardiac troponin (cTn) have reduced time to NSTEMI diagnosis but 5-10% of NSTEMI patients still remain cTn negative within 2 hours of presentation. We hypothesised that measurement of an upstream open reading frame peptide (uORF) from the human cTnT gene (TnTuORF) could improve sensitivity to detect NSTEMI within 2 hours of hospital presentation. Methods: We developed a specific immunoassay for TnTuORF and measured plasma levels alongside NT-proBNP (Roche Elecsys), standard TnI (Abbott Architect), hsTnT (Roche Elecsys) and hFABP (Hycult Biotech) in 501 patients presenting to Christchurch Hospital, New Zealand with chest pain necessitating rule-out of ACS. Samples were taken at t=0, 1, 2 and 12-24 hours (index TnI) post-presentation along with all demographic, clinical and laboratory information. Correlation analysis was conducted using Spearman’s rank test. Biomarker diagnostic and prognostic efficiencies (AUC, sensitivity, specificity) were conducted using ROC analysis. P&lt;0.05 was considered significant. Results: Plasma TnTuORF tended to display a negative relationship with TnI and hsTnT (r=-0.054, P=0.252) and did not diagnose NSTEMI (AUC=0.446, P=0.117). Instead, when applied as the denominator in a ratio with TnI/hsTnT (Table 1), TnTuORF could improve the sensitivity of both assays, but with reductions in specificity. The ratio TnI x hsTnT/TnTuORF (termed TroponinPLUS) gave the best sensitivity and detected 98% of NSTEMI patients. TroponinPLUS could predict death at 45 days (AUC=0.814, P=0.016, sensitivity = 0.80, specificity = 0.72) and 1 year (AUC=0.741, P&lt;0.001, sensitivity = 0.67, specificity = 0.70). Conclusion: This is the first demonstration of a circulating uORF peptide. The ratio of total cTn to TnTuORF (TroponinPLUS) improved early detection of NSTEMI and has good prognostic ability. We conclude TnTuORF measurement may assist in NSTEMI diagnosis and prognosis. Table 1. ROC data - NSTEMI diagnosis
AB0775 EFFECTIVENESS AND SAFETY OF USTEKINUMAB 90 IN PATIENTS WITH PSORIATIC ARTHRITIS.REAL WORLD EVIDENCE STUDY
Authors: Estefanía Pardo Campo, José andrés Lorenzo Martín, Lilyan Consuelo Charca Benavente, Sara alonso Castro, Mercedes Alperi-López, Luis Marcelino Arboleya Rodríguez, Francisco Javier Ballina-García, Rubén Queiró Silva
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Ustekinumab (UST) is a drug with proven efficacy in two randomized clinical trials in psoriatic arthritis -PsA- (PSUMMIT I and II). The data from these trials suggest that the 90 mg dose may be better than the 45 mg dose. Studies real world evidence (RWE) show that UST is effective and safe, nevertheless most of the evidence is base on the 45mg dose.<sup>1</sup> <h3>Objectives:</h3> Our objective has been to check the effectiveness and safety of UST 90 mg in patients with PsA in RWE conditions. <h3>Methods:</h3> An observational study in RWE conditions was driven. We included 58 patients (37 women, 21 men, age 55 ± 8.7 years) with PsA from a single university hospital. All patients met CASPAR criteria. The observation period was from July 2017 to the present. All patients received the 90 mg dose from the beginning. The average BMI was 29.9 ± 4.41. 50% of patients were obese. To measure the disease activity, the DAPSA index was used. A descriptive statistic was performed and the McNemar test was used to analyse the mean change of the DAPSA (final-basal). A bivariate analysis was performed to identify associated factors with a DAPSA remission/low activity. <h3>Results:</h3> The duration of psoriasis was 14.8 ± 12.8 years, and 6.3 ± 6.5 years for the arthritis. 34.5% were oligoarticular forms, 13.8% polyarticular forms, and the remaining 51.7% were mixed forms. The distal interphalangeal joints synovitis was present in 38% of the patients and dactylitis in 24%. 17 patients were naive to biologic drugs (29.3%), UST was second line in 25.9%, third in 32.8%, fourth in 10.3% and fifth in 1.7% of patients. Half of the patients were treated with MTX. In the baseline situation, 9.4% had low activity, 75% had moderate activity, and 15.6% had high activity by DAPSA index. At the end of the analysis, 12.5% were in remission, 59.4% in low activity, and 28.1% in moderate activity, according to the DAPSA index. There were no patients in high activity. That is, 72% were in DAPSA remission/low activity. The average reduction of DAPSA was 9.53 ± 5.52 (McNemar's p &lt;0.0005). The only factor associated with remission/low DAPSA activity was baseline DAPSA, OR 1.51 (1.02-2.22), p = 0.044. In 6 patients, the drug was discontinued (4 due to lack of efficacy and 2 due to poor tolerance or adverse effects). <h3>Conclusion:</h3> In this RWE series, UST 90 mg was effective and safe in 75% of our patients probability of achieving a remission/low activity state by DAPSA. <h3>References</h3> [1] Ustekinumab in psoriatic arthritis: need for studies from real-world evidence. Queiro R, Coto-Segura P. Expert Opin Biol ther. <b>2018</b> Sep;18(9):931-935. <h3>Disclosure of interests:</h3> None declared