tbuckley/cabot-search huggingface dataset:
THU0725-HPR SCREENING OF SILENT MYOCARDIAL ISCHEMIA USING A STRESS TEST IN RHEUMATOID ARTHRITIS PATIENTS: ASSOCIATION WITH TRADITIONAL RISK FACTORS AND DISEASE ACTIVITY
Authors: Rawdha Tekaya, leila rouached, Habib Ben Ahmed, Aicha Ben Tekaya, Olfa Saidane, Ines Mahmoud, Leila Abdelmoula
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The rheumatoid arthritis is responsible of an increased risk of cardiovascular (CV) morbidity and mortality. <h3>Objectives</h3> The aim of the study is to determine, in established RA patients, the presence of silent myocardial ischemia using a stress test and its association with the disease activity and the CV risk factors and scores. <h3>Methods</h3> It is a transversal and prospective study in a rheumatologic center in Charles Nicolle hospital in Tunisia. 103 RA patients, asymptomatic for CV disease were submitted to a stress test. Demographic data, cardiovascular risk factors and the disease characteristics were assessed for all patients and risk factors of silent myocardial ischemia in RA patients were identified. The comparison of qualitative variables was performed with the Chi square test and the comparison of qualitative variable and quantitative ones was performed with the Student's test. The significance level was set at 0.05. <h3>Results</h3> There were 103 patients (sex-ratio=0.3) with a mean age of 53±10 years. The evaluation of the disease activity showed that the mean DAS28 CRP, CDAI and SDAI were 3.9±1.38, 17.17±11.4 and 33.39±26, respectively. A screening for CV risk factors revealed: 13% of patients had a cardiovascular inheritance, 25% of patients were either smokers or hypertensives, 18% had diabetes, 70% were obese or overweighted and 14 patients had dyslipidemia. The ischemic ratio (CT/HDL) revealed that 42% of patients had a moderate to high myocardial ischemic risk. HeartSCORE was high in 35% of cases. A silent myocardial ischemia in the stress test was found in 11 patients (10.6%) and was associated with male sex (p=0.03), advanced age (p=0.04), erosive character (p=0.05), the advanced age of the rheumatoid arthritis diagnosis (p=0.01) and the ischemic ratio (p=0.06). No relationship was found with the majority of traditional CV factors nor with disease activity variables. <h3>Conclusion</h3> Our results corroborated the hypothesis that the stress test could reveal subclinical CV dysfunction, supported the utility of the Heartscore as a screening tool, and put in perspective the potential usefulness of complementary approaches in CV risk assessment in RA patients. <h3>Disclosure of Interests</h3> None declared
Abstract 333: Simple Conventional Cooling Methods Without Temperature Feedback Regulation Are Not Inferior to Automatic Cooling Device for Improvement of Neurologic Outcome of Cardiac Arrest Patients
Authors: Joo Suk Oh, Sang Hoon Oh, Yeon Young Kyong, Chun Song Youn, Kyung Woon Jeung, Gi Woon Kim, Young-Min Kim, Seung Pill Choi, Kyu Nam Park
Journal: Circulation (2013)

Objective: We assessed the hypothesis that therapeutic hypothermia (TH) implemented by only conventional uncontrolled cooling method is not associated with worse neurologic outcome compared to the cooling device equipped with temperature feedback control, regardless of surface or endovascular cooling. Methods: We performed a multicenter retrospective registry-based study of adult out of cardiac arrest patients treated with TH presenting to 24 hospitals across South Korea during the period from January 2007 to December 2012. Patients who received TH only by conventional methods such as ice packs, cold fluids, and other convective methods were assigned to one group, and those who received TH by automatic device using body wraps, hydrogel pads and endovascular cooling catheter were assigned to another. Choice of method was based upon device availability of the relevant hospital. Results: Of a total of 930 OHCA patients entered in the registry, 851 were included in the analysis, of which 58 underwent only conventional cooling and remaining 793 underwent temperature feedback controlled cooling. More adverse events such as overcooling or rebound hypothermia occurred in the conventional method group, which was significantly associated with poor neurological outcome (cerebral performance category 3-5) at hospital discharge. In multivariate logistic regression analysis, conventional cooling method group was not associated with worse neurologic outcome compared to the automatic cooling device. Conclusions: In our study, conventional cooling method without automatic temperature feedback control was not associated with poor neurological outcome at hospital discharge, although it is associated with more adverse events.
Effects of dapagliflozin and/or insulin glargine on beta cell mass and hepatic steatosis in db/db mice
Authors: Kazuno Omori, Akinobu Nakamura, Hideaki Miyoshi, Kiyohiko Takahashi, Naoyuki Kitao, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Ryo Takagi, Kanako C. Hatanaka, Yasuo Terauchi, Tatsuya Atsumi
Journal: Metabolism (2019)
Cerebral Cavernous Malformations Develop Through Clonal Expansion of Mutant Endothelial Cells
Authors: Matthew R. Detter, Daniel A. Snellings, Douglas A. Marchuk
Journal: Circulation Research (2018)

Rationale: Vascular malformations arise in vessels throughout the entire body. Causative genetic mutations have been identified for many of these diseases; however, little is known about the mutant cell lineage within these malformations. Objective: We utilize an inducible mouse model of cerebral cavernous malformations (CCMs) coupled with a multicolor fluorescent reporter to visualize the contribution of mutant endothelial cells (ECs) to the malformation. Methods and Results: We combined a Ccm3 mouse model with the confetti fluorescent reporter to simultaneously delete Ccm3 and label the mutant EC with 1 of 4 possible colors. We acquired Z-series confocal images from serial brain sections and created 3-dimensional reconstructions of entire CCMs to visualize mutant ECs during CCM development. We observed a pronounced pattern of CCMs lined with mutant ECs labeled with a single confetti color (n=42). The close 3-dimensional distribution, as determined by the nearest neighbor analysis, of the clonally dominant ECs within the CCM was statistically different than the background confetti labeling of ECs in non-CCM control brain slices as well as a computer simulation ( P &lt;0.001). Many of the small (&lt;100 μm diameter) CCMs consisted, almost exclusively, of the clonally dominant mutant ECs labeled with the same confetti color, whereas the large (&gt;100 μm diameter) CCMs contained both the clonally dominant mutant cells and wild-type ECs. We propose of model of CCM development in which an EC acquires a second somatic mutation, undergoes clonal expansion to initiate CCM formation, and then incorporates neighboring wild-type ECs to increase the size of the malformation. Conclusions: This is the first study to visualize, with single-cell resolution, the clonal expansion of mutant ECs within CCMs. The incorporation of wild-type ECs into the growing malformation presents another series of cellular events whose elucidation would enhance our understanding of CCMs and may provide novel therapeutic opportunities.
FRI0005 CHROMATIN CONTACTS AND TRANSCRIPTOMICS IN CD4+ T-CELLS REVEAL GENES IMPLICATED IN RHEUMATOID ARTHRITIS
Authors: Vasanthi Priyadarshini Gaddi, Amanda Mcgovern, James Ding, Nadia Iqbal, Chenfu Shi, Theoni Katopodi, Marialbert Acosta-Herrera, Sofia Vargas, Kate Duffus, Annie Yarwood, Enrique Raya, Javier Martin Ibanez, Paul Martin, Gisela Orozco
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of synovial joints. RA is a clinically heterogeneous disease and treatment response varies between individuals. The pathogenesis of RA is not completely understood yet, but it has been shown that the largest factor influencing disease susceptibility is genetics. Genome-wide association studies have successfully characterized genetic variants that are associated with RA, with the vast majority of them mapping to non-coding regulatory elements. Understanding the mechanisms by which this phenomenon leads to disease is essential to translate results from genetic association studies to the clinic. <h3>Objectives</h3> There is evidence showing that autoimmune diseases are the consequence of erroneous wiring of the regulatory circuitry between enhancers and their target genes. The aim of this study is to characterize non-coding regions containing RA-associated variants, in order to determine the genes and pathways by which these regions act to increase the risk of disease. <h3>Methods</h3> We isolated CD4+ T-cells from blood obtained from RA patients. We stratified patients in two subgroups, high disease activity (DAS28&gt;5.1, n=18) and low disease activity (DAS28&lt;3.2, n=33). All samples were genotyped using Illumina Infinium Exome-24 v1.0 BeadChip arrays. RNA-Seq Libraries were generated for matching RNA samples using the Lexogen QuantSeq Library Prep kit and sequenced on an Illumina NextSeq500. For a subset of 6 samples (3 high disease activity and 3 low disease activity patients), capture Hi-C was performed to characterize chromatin interactions between all RA associated loci and their potential target genes. <h3>Results</h3> We observed numerous chromatin interactions between RA variants and potential causal genes. Preliminary results show that a number of disease-associated SNPs interact with compelling candidate genes situated several megabases away. Whilst some of these chromatin interactions are common to both patients groups, subsets of them are specific to each disease subgroup, which are correlated with differential gene expression. <h3>Conclusion</h3> These results suggests that there might be different biological pathways contributing to disease in RA patients with inactive disease compared to patients with high disease activity. <h3>Disclosure of Interests</h3> None declared
Cancer treatment and survivorship statistics, 2019
Authors: Kimberly D. Miller, Leticia Nogueira, Angela B. Mariotto, Julia H. Rowland, K. Robin Yabroff, Catherine M. Alfano, Ahmedin Jemal, Joan L. Kramer, Rebecca L. Siegel
Journal: CA A Cancer Journal for Clinicians (2019)

The number of cancer survivors continues to increase in the United States because of the growth and aging of the population as well as advances in early detection and treatment. To assist the public health community in better serving these individuals, the American Cancer Society and the National Cancer Institute collaborate every 3 years to estimate cancer prevalence in the United States using incidence and survival data from the Surveillance, Epidemiology, and End Results cancer registries; vital statistics from the Centers for Disease Control and Prevention's National Center for Health Statistics; and population projections from the US Census Bureau. Current treatment patterns based on information in the National Cancer Data Base are presented for the most prevalent cancer types. Cancer-related and treatment-related short-term, long-term, and late health effects are also briefly described. More than 16.9 million Americans (8.1 million males and 8.8 million females) with a history of cancer were alive on January 1, 2019; this number is projected to reach more than 22.1 million by January 1, 2030 based on the growth and aging of the population alone. The 3 most prevalent cancers in 2019 are prostate (3,650,030), colon and rectum (776,120), and melanoma of the skin (684,470) among males, and breast (3,861,520), uterine corpus (807,860), and colon and rectum (768,650) among females. More than one-half (56%) of survivors were diagnosed within the past 10 years, and almost two-thirds (64%) are aged 65 years or older. People with a history of cancer have unique medical and psychosocial needs that require proactive assessment and management by follow-up care providers. Although there are growing numbers of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based resources are needed to optimize care.
Phylogenetic Clustering by Linear Integer Programming (PhyCLIP)
Authors: Alvin X Han, Edyth Parker, Frits Scholer, Sebastian Maurer-Stroh, Colin A Russell
Journal: Molecular Biology and Evolution (2019)

Subspecies nomenclature systems of pathogens are increasingly based on sequence data. The use of phylogenetics to identify and differentiate between clusters of genetically similar pathogens is particularly prevalent in virology from the nomenclature of human papillomaviruses to highly pathogenic avian influenza (HPAI) H5Nx viruses. These nomenclature systems rely on absolute genetic distance thresholds to define the maximum genetic divergence tolerated between viruses designated as closely related. However, the phylogenetic clustering methods used in these nomenclature systems are limited by the arbitrariness of setting intra and intercluster diversity thresholds. The lack of a consensus ground truth to define well-delineated, meaningful phylogenetic subpopulations amplifies the difficulties in identifying an informative distance threshold. Consequently, phylogenetic clustering often becomes an exploratory, ad hoc exercise. Phylogenetic Clustering by Linear Integer Programming (PhyCLIP) was developed to provide a statistically principled phylogenetic clustering framework that negates the need for an arbitrarily defined distance threshold. Using the pairwise patristic distance distributions of an input phylogeny, PhyCLIP parameterizes the intra and intercluster divergence limits as statistical bounds in an integer linear programming model which is subsequently optimized to cluster as many sequences as possible. When applied to the hemagglutinin phylogeny of HPAI H5Nx viruses, PhyCLIP was not only able to recapitulate the current WHO/OIE/FAO H5 nomenclature system but also further delineated informative higher resolution clusters that capture geographically distinct subpopulations of viruses. PhyCLIP is pathogen-agnostic and can be generalized to a wide variety of research questions concerning the identification of biologically informative clusters in pathogen phylogenies. PhyCLIP is freely available at http://github.com/alvinxhan/PhyCLIP, last accessed March 15, 2019.
Impact of the revised haemodynamic definition on the diagnosis of pulmonary hypertension in patients with systemic sclerosis
Authors: Sara Jaafar, Scott Visovatti, Amber Young, Suiyuan Huang, Paul Cronin, Dharshan Vummidi, Vallerie McLaughlin, Dinesh Khanna
Journal: European Respiratory Journal (2019)

Introduction Pulmonary arterial hypertension (PAH) is one of the leading causes of mortality in systemic sclerosis (SSc). We explored the impact of the updated haemodynamic definition of pulmonary hypertension (PH), as proposed by the 6th World Symposium on Pulmonary Hypertension. Methods In this single-centre retrospective analysis, patients with SSc who had right heart catheterisation (RHC) were included. We compared the prior PH definition to the updated PH definition. The prior definition classified PH as mean pulmonary arterial pressure (mPAP) ≥25 mmHg and further divided into pre-capillary PH (PAH and PH due to lung disease and/or hypoxia), post-capillary PH, and combined pre- and post-capillary PH groups. For the updated definition, PH was classified as mPAP &gt;20 mmHg and further divided into the different groups. We validated our findings in the DETECT cohort. Results Between 2005 and March 2019, 268 RHCs were performed in this single-centre cohort. Using the prior definition, 137 (51%) were diagnosed with PH, with 89 classified as pre-capillary PH (56 with PAH and 33 with PH due to lung disease and/or hypoxia), 29 as post-capillary PH, and 19 as combined pre- and post-capillary PH. When the updated definition was applied to the cohort, seven out of 131 (5%) with no PH were reclassified to pre-capillary PH (PAH (n=1), PH due to lung disease (n=3) and post-capillary PH (n=3)). In those with mPAP 21–24 mmHg, with no left heart or significant lung disease, one out of 28 (4%) in our cohort and four out of 36 (11%) in the DETECT cohort were reclassified as PAH. Conclusion The updated PH definition does not appear to have a significant impact on the diagnosis of PH in two different screening cohorts.
PF762 EFFECTS OF TWO DOSES OF ANTITHYMOCYTE GLOBULIN IN CONDITIONING REGIMENS FOR HAPLOIDENTICAL PERIPHERAL BLOOD STEM CELL TRANSPLANTATION
Authors: M. wang, X. fang, Y. jiang, X. sui, Y. li, X. liu, X. wang, H. xu, X. wang
Journal: HemaSphere (2019)

Background: Antithymocyte globulin (ATG), an important in vivo T‐cell depletion strategy, has been used for graft‐versus‐host disease (GVHD) prophylaxis and shown significant clinical benefit. However, the optimal ATG dose remains unclear. Aims: To assess the effectiveness of ATG at a total dose of 10.0 mg/kg and 7.5 mg/kg for haploidentical peripheral blood stem cell transplantation (PBSCT). Methods: We retrospectively analyzed patients who underwent haploidentical PBSCT, receiving myeloablative conditioning and standard GVHD prophylaxis. ATG (rabbit thymoglobulin) at a total dose of 10.0 mg/kg (2.5 mg/kg on days −5 to −2) and 7.5 mg/kg (2.5 mg/kg on days −4 to −2) were used in the two groups. Results: 40 and 35 patients were enrolled in the ATG‐10 and ATG‐7.5 groups, respectively. No significant difference was observed regarding the cumulative incidence of 100‐day grade II‐IV acute GVHD (20.0% vs 14.3%; p = 0.53) and 3‐year chronic GVHD (13.7% vs 15.7%; p = 0.83). The 3‐year probability of overall survival (OS) was 72.6% vs 74.4% (p = 0.81) and the 3‐year probability of GVHD‐free/relapse‐free survival (GRFS) was 69.0% vs 53.0% (p = 0.16). The incidence of relapse in the ATG‐7.5 group (30.9%) was higher compared with the ATG‐10.0 group (17.1%), but this difference was not statistically significant (p = 0.20). In multivariate analysis, the ATG dose was not associated with relapse, while no further respond to therapy (NR) before PBSCT predicted relapse (HR 1.19, p = 0.04). There were 5 patients (12.5%) and 8 patients (22.9%) in NR in the ATG‐10 and ATG‐7.5 groups, respectively (p = 0.19). Additionally, the ATG‐7.5 group had a trend for lower 300‐day incidence of EBV reactivation (92.5% vs 80.0%; p = 0.14) and CMV reactivation (90.5% vs 80.0%; p = 0.16), and lower 100‐day incidence of hemorrhagic cystitis (42.5% vs 28.6%; p = 0.15). Summary/Conclusion: 7.5 mg/kg ATG led to lower incidence of EBV reactivation, CMV reactivation and hemorrhagic cystitis without compromising control of grade II‐IV acute GVHD, chronic GVHD and OS when compared with 10.0 mg/kg ATG. Therefore, ATG at a dose of 7.5 mg/kg could be considered for further study.
Clinical and Molecular Characterization of<i>PROM1</i>-Related Retinal Degeneration
Authors: Jasmina Cehajic-Kapetanovic, Johannes Birtel, Michelle E. McClements, Morag E. Shanks, Penny Clouston, Susan M. Downes, Peter Charbel Issa, Robert E. MacLaren
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The<i>PROM1</i>gene<i>,</i>commonly associated with cone-rod dystrophies, may have dominant or recessive phenotypes that influence disease onset and severity. <h3>Objective</h3> To characterize the clinical phenotype and molecular genetic variations in patients with<i>PROM1</i>variants. <h3>Design, Setting, and Participants</h3> This case-series study was conducted at 2 specialist retinal genetics clinics and examined 19 consecutively enrolled patients with<i>PROM1-</i>related retinal degeneration. Data were collected and analyzed from May 2018 to December 2018. <h3>Main Outcomes and Measures</h3> Results of ophthalmic examination, retinal imaging, and molecular genetic analysis by next-generation sequencing. <h3>Results</h3> Of 19 patients, 13 (68%) were women, and age ranged from 11 to 70 years. All patients presented with central visual loss, with or without photophobia. Individuals with recessive variants commonly had severe loss of visual acuity by their 20s, whereas the dominant variant was associated with a milder phenotype, with most patients retaining good vision into late adulthood. The recessive cases were associated with a panretinal dystrophy of cone-rod phenotype with early macular involvement, whereas the dominant variants were associated with a cone-rod phenotype that was restricted to the macula with predominantly cone dysfunction. Next-generation sequencing identified 3 novel and 9 previously reported variants in<i>PROM1</i>. Recessive mutations included 6 truncating variants (3 nonsense and 3 frameshift), 4 splice site variants, and 1 missense variant. All 6 dominant variants were associated with a c.1117C&gt;T missense variant. The variants were distributed throughout the<i>PROM1</i>genomic sequence with no specific clustering on protein domains. <h3>Conclusions and Relevance</h3> In this case-series study,<i>PROM1</i>recessive variants were associated with early-onset, severe panretinal degeneration. The similar phenotypes observed in patients with homozygous missense variants and splice site variants compared with similarly aged patients with truncating variants suggests that all recessive variants have a null (or loss of function close to null) outcome on<i>PROM1</i>function. In contrast, the dominant missense cases were associated with a milder, cone-driven phenotype, suggesting that the dominant disease is preferentially associated with cones. This has implications for the development of treatments for this severely blinding disease, and adeno-associated viral vector–based gene therapy and optogenetics could become successful treatment options.