tbuckley/cabot-search huggingface dataset:
Transition to HBeAg-negative chronic hepatitis B virus infection is associated with reduced cccDNA transcriptional activity
Authors: Aleksei Suslov, Marie-Anne Meier, Sylvia Ketterer, Xueya Wang, Stefan Wieland, Markus Hermann Heim
Journal: Journal of Hepatology (2020)

HBeAg seroconversion during the natural history of chronic hepatitis B (CHB) is associated with a strong drop in serum HBV DNA levels and a reduction of intrahepatic covalently closed circular DNA (cccDNA) content. Of particular interest is the transition to HBeAg-negative chronic infection (ENCI). ENCI, previously known as inactive carrier state, is characterized by very low or negative viremia and the absence of liver disease. The molecular mechanisms responsible for the transition to ENCI and for the control of viral replication in ENCI are still poorly understood.To identify which step(s) in the viral life cycle are controlled during the transition to ENCI, we quantified cccDNA, pre-genomic RNA (pgRNA), total HBV RNA and DNA replicative intermediates in 68 biopsies from patients in different phases of CHB.HBeAg seroconversion is associated with a reduction of cccDNA amounts as well as transcriptional activity. Silencing of cccDNA is particularly pronounced in ENCI, where there was ~46 times less pgRNA per cccDNA compared to HBeAg-negative CHB. Furthermore, a subgroup of patients with HBeAg-negative CHB can be characterized by reduced replication efficiency downstream of pgRNA.The reduction in serum viral load during the transition to ENCI seems to primarily result from strong inhibition of the transcriptional activity of cccDNA which can be maintained in the absence of liver disease.During the natural course of chronic hepatitis B virus infections, the immune response can gain control of viral replication. Quantification of viral DNA and RNA in liver biopsies of patients in different stages of chronic hepatitis B allowed us to identify the steps in the viral life cycle that are affected during the transition from active to inactive disease. Therapeutic targeting of these steps might induce sustained inhibition of viral transcription.
Abstract 16311: Efficacy and Safety of Inclisiran According to Sex: A Pooled Analysis of the ORION 9, 10 and 11 Trials
Authors: R Scott S Wright, Kausik K Ray, Frederick J Raal, David Kallend, Mark Jaros, Wolfgang Koenig, Lawrence Leiter, Ulf E Landmesser, Gregory G Schwartz, Peter L Wijngaard, John J Kastelein
Journal: Circulation (2020)

Introduction: Despite a later onset in life than males, ASCVD is the leading cause of death in females, additionally mortality is higher compared to males. Disparities in the diagnosis and treatment of CVD risk factors may contribute to this difference. Inclisiran is a novel siRNA that inhibits PCSK9 synthesis and lowers LDL-C. Three Phase III placebo-controlled trials evaluated efficacy and safety of inclisiran in patients with HeFH (ORION-9), ASCVD (ORION-10, -11) and ASCVD risk equivalents (ORION-11). Objective: To assess the impact of sex on the efficacy and safety profile of inclisiran. Methods: Patients from each trial were categorized by sex. The co-primary endpoints were percentage change in LDL-C from baseline to Day 510 and time-adjusted percentage change in LDL-C from baseline after Day 90 up to Day 540. Secondary efficacy and safety parameters were assessed over 18 months. Results: Of a total 3660 patients, 1190 (32.5%) were females and 2470 (67.5%) were males. At baseline, females were less likely to receive statins [high-intensity statins] (90% [70%] vs 93% [76%]), or have ASCVD (73.6% vs 90.3%), were more likely to have ASCVD-risk equivalent (26.4% vs 9.7%) vs males. The efficacy of inclisiran vs placebo in both co-primary endpoints was similar in both sexes. Females had higher LDL-C at baseline (122.9 mg/dL vs 105.8 mg/dL) and (secondary endpoints) placebo-corrected mean absolute reduction in LDL-C at Day 510 (62.6 vs 54.0 mg/dL, P &lt;0.05) and time-adjusted reduction from Days 90 to 540 (59.0 vs 51.5 mg/dL, P &lt;0.05) with inclisiran were greater in females than males. Most AEs were similar between inclisiran vs placebo for both sexes except for injection-site AEs that were higher in the inclisiran arm than placebo (females 9.4% vs 0.2%, males 2.8% vs 0.9%; Table). Conclusions: The efficacy and safety profile of inclisiran was generally similar in both sexes, except for more inclisiran injection-site AEs (mainly mild) vs placebo, which were more frequent in females.
Long-term efficacy and safety outcomes of lenalidomide for cutaneous lupus erythematosus: A multicenter retrospective observational study of 40 patients
Authors: Raphael Aitmehdi, Laurent Arnaud, Camille Francès, Patricia Senet, Jean-Benoît Monfort, Tullia de Risi-Pugliese, Annick Barbaud, Fleur Cohen-Aubart, Julien Haroche, Micheline Pha, Miguel Hie, Véronique Le Guern, Nathalie Costedoat-Chalumeau, Arsène Mékinian, Olivier Fain, Alexis Mathian, Zahir Amoura, François Chasset
Journal: Journal of the American Academy of Dermatology (2020)
Rapid Progress Toward Reliable Blood Tests for Alzheimer Disease
Authors: Elisabeth H. Thijssen, Gil D. Rabinovici
Journal: JAMA Neurology (2020)

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Influence of pre-existing liver disease in the course of COVID-19. in an area with low incidence of SARSCOV2 infection
Authors: M. G. Veloz, P. Del Pino, P. C. Ruiz, C. V. Parrado, M. L. C. Herrera, F. B. Munoz, F. Vega, A. C. Alvarez, I. Carmona
Journal: Hepatology (2020)

Background: Some comorbidities have been associated with a negative impact in the severity of COVID-19 course Patients with advanced chronic liver disease (CLD) may be at increased risk of severe course due to the cirrhosisassociated immune dysfunction However the actual data is scare The aim of our study was to determine the prevalence of CLD in COVID-19 patients and to analyse the course of the infection comparing with patients with non-liver disease Methods: This was a retrospective single centre study in which we included all positive SARS-Cov2 polymerase chainreactions (PCR) from March 23 2020 to April 30 2020 Clinical and biochemical data of patients with and without CLD and COVID-19 were collected using medical records Results: 447 patients with SARS-Cov2 PCR were included, 6 3% had CLD 69 7% of patients with CLD were male, with a median age of 65 5 years, with active alcohol and smoke use 75% had non-advanced liver fibrosis, most of them NAFLD  Patients with advanced liver fibrosis were younger, with a mean age of 58 (SD 9 69) years, underlying COPD (57 2%) Meanwhile patients with CLD without advanced liver fibrosis were older, with a mean age of 68 (SD 12 08) years, and had multiples comorbidities like hypertension in 71 4% and diabetes in 47 6% Hospital admission rate (92 9% vs 47 7% p<0 001) was higer in patients with CLD than those without CLD Concomitant comorbidities (diabetes 38 5 vs 16 5% p=0 011;obesity 30 8 vs 8 5% p=0 033;cancer 23 1 vs 5% p=0 027 and COPD 19 2 vs 9% p=0 009), and concomitant antibiotics treatment (19 3 vs 5%;p= 0 018) were higher in patients with CLD than those without CLD The rate of intesive care admission, respiratory support (invasive mechanical ventilation 7 7 vs 9 5% p=0 055;and continuous positive airway pressure CPAP or non-invasive positive pressure 19 2 vs 19 0% p=0 577) and median stay length (8 (5-15) vs 7 (5-13) p=0 696) were similar in both groups Mortality rate was similar in patients with and without CLD (30 8 vs 19 6% p=0 289) However, in the univariate analysis male (OR= 11 20;95% IC= 1 25-100 31;p=0 031);presence of obesity (OR= 7 20;95% CI= 1 13-45 96;p=0 037), antibiotics concomitant treatment (OR= 12;95% CI= 1 95 -73 97;p=0 007);and presence of COPD (OR=5 25 95% CI= 1-254 9 p=0 050) in multivariate analysis were associated with mortality in patients with CLD 87 5% patients with CLD died due to respiratory failure In the general mortality analysis;CLD was not a risk factor associated with mortality (OR= 1 06;95% CI= 0 35-3 18;p=0 924) like the cardiovascular diseases ( Coronary artery disease OR= 4 95;95% CI 1 51-16 27;p=0 008 and Congestive heart failure OR= 5 66;95% CI= 1 64-19 54;p=0 006) Conclusion: Patients with CLD had a low incidence of SARS-Cov2 infection, but higher risk of hospital admission with worse outcomes associated to other concomitant comorbidities and advanced fibrosis
Abstract 15457: Novel Three-dimensional Principal Strain Analysis for Global Function of Right Ventricle After Repair of Tetralogy of Fallot. Can It Predict Need for Pulmonary Valve Replacement?
Authors: Daisuke Matsubara, Alessandro Satriano, Nowell M Fine, James A White, Gianni Pedrizzetti, Anirban Banerjee
Journal: Circulation (2020)

Introduction: Principal strain analysis (PSA) quantifies 3-dimensional deformation using speckle tracking echocardiography (3D-STE) to objectively define global and regional myocardial shortening amplitude and directionality, which is not affected by through-plane motion. It integrates circumferential (C), longitudinal (L), and C-L shear strains into a single deformation, expressed as PS lines (Fig. 1). Aim of this study was to apply PSA to characterize right ventricular (RV) function after Tetralogy of Fallot (TOF) repair. Hypothesis: PS provides novel description of RV function following TOF repair and may help determine subsequent need for pulmonary valve replacement (PVR). Methods: We prospectively enrolled 40 TOF patients (11.0±4.9 years) evaluated 10.0±4.5 years after corrective surgery, including 7 candidates awaiting PVR, and 40 age-matched controls (12.9±3.7 years). 3D-STE images were analyzed offline using Tomtec and Matlab-based post-processing software. Results: TOF patients had significantly larger RV volumes and decreased RVEF (EDVi: 106±18 versus 63±12 mL/m 2 , RVEF: 48±5 vs 57±4%, respectively, both p&lt; 0.001). All global strain values were significantly decreased in TOF patients (GPS: -22.7±2.5 versus -25.8±2.0%, GCS: -10.6±3.4 versus -15.8±2.5%, GLS: -9.1± 6.3 versus -15.2±2.3%, GLS (2D): -20.3±4.5 versus -24.7±3.9 %, respectively, all p&lt;0.001). Figure 2 shows PS magnitude and angle for control and TOF patient. Compared with controls, TOF patients demonstrated regionally lower PS strain (red areas) with preserved contractile angles. Among global strain amplitudes, PS showed best sensitivity (86%) and specificity (74%) for predicting subsequent need for PVR (Table1) (ROC: 0.76, cut off value: -22.9%). Conclusions: PS provides novel characterization of 3D RV deformation after TOF repair and is associated with subsequent need for PVR. Further research is warranted to determine its incremental value for guiding timing of PVR.
Abstract 329: Predicting Survival from Out-of-hospital Cardiac Arrest
Authors: Ian Drennan, Kevin Thorpe, Sheldon Cheskes, Muhammad Mamdani, Damon Scales, laurie Morrison
Journal: Circulation (2020)

Introduction: Prognostication is a significant challenge early in the post-cardiac arrest period. Common prognostic factors for neurological survival are unreliable (high false positive rates) until 72 hours post-cardiac arrest. It is not known whether there are a combination of factors that can be utilized earlier in the post-cardiac arrest period to accurately predict patient outcome. Our objective was to predict neurological outcome utilizing a novel combination of patient factors early in the post-cardiac arrest period. Methods: We conducted a retrospective cohort study using data from our local registry. We included adult patients who obtained a return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA). We excluded patients who did not survive for at least 24 hours post-ROSC and those who had a do not resuscitate (DNR) order within 2 hours of ROSC. We performed an ordinal regression analysis using the proportional odds model to predict neurological outcome (modified rankin score (mRS)). We included a good neurological outcome (mRS 0-2), poor neurological outcome (mRS 3-5), and dead (mRS 6) as an ordinal outcome. We included a number of patient demographics, intra- and post-cardiac arrest factors as covariates in our model. The predictive performance of our model was analyzed using receiver operating characteristic (ROC) curves for discrimination and Brier statistic for calibration. Results: We included 3448 patients in our analysis. We found that an initial shockable rhythm (odds ratio (OR) 4.1; 95% confidence interval (CI) 3.6, 5.4), the absence of pupillary reflexes (OR 3.5; 95% CI 2.4,4.8) and maximum motor score on the Glasgow Coma Scale (GCS) (OR 1.5; 95% CI 1.4,1.6) had the greatest association with improved neurologic outcome. Longer duration of resuscitation was associate with worse outcomes (OR 0.84, 95% CI 0.82,0.87). The overall performance of our model was excellent with an area under the ROC curve of 0.89 and a Brier statistic of 0.13. Conclusion: Our model predicted good neurological outcome with a high rate of accuracy, however external validation of the model is required. This model may be useful to provide risk stratification of patients in clinical practice and future research on post-cardiac arrest care.
The SUMOylation of TAB2 mediated by TRIM60 inhibits MAPK/NF-κB activation and the innate immune response
Authors: Zhiwen Gu, Xueying Chen, Wenyong Yang, Yu Qi, Hui Yu, Xiaomeng Wang, Yanqiu Gong, Qianqian Chen, Bo Zhong, Lunzhi Dai, Shiqian Qi, Zhiqiang Zhang, Huiyuan Zhang, Hongbo Hu
Journal: Cellular and Molecular Immunology (2020)

Activation of the TAK1 signalosome is crucial for mediating the innate immune response to pathogen invasion and is regulated by multiple layers of posttranslational modifications, including ubiquitination, SUMOylation, and phosphorylation; however, the underlying molecular mechanism is not fully understood. In this study, TRIM60 negatively regulated the formation and activation of the TAK1 signalosome. Deficiency of TRIM60 in macrophages led to enhanced MAPK and NF-κB activation, accompanied by elevated levels of proinflammatory cytokines but not IFN-I. Immunoprecipitation-mass spectrometry assays identified TAB2 as the target of TRIM60 for SUMOylation rather than ubiquitination, resulting in impaired formation of the TRAF6/TAB2/TAK1 complex and downstream MAPK and NF-κB pathways. The SUMOylation sites of TAB2 mediated by TRIM60 were identified as K329 and K562; substitution of these lysines with arginines abolished the SUMOylation of TAB2. In vivo experiments showed that TRIM60-deficient mice showed an elevated immune response to LPS-induced septic shock and L. monocytogenes infection. Our data reveal that SUMOylation of TAB2 mediated by TRIM60 is a novel mechanism for regulating the innate immune response, potentially paving the way for a new strategy to control antibacterial immune responses.
Abstract 144: Role of Iron Metabolism on Outcomes after Cardiac Arrest and Resuscitation in Mice
Authors: Yusuke Miyazaki, Kei Hayashida, Takamitsu Ikeda, Eizo Marutani, Aranya Bagchi, Fumito Ichinose
Journal: Circulation (2020)

Introduction: Ischemia and reperfusion (I/R) induces hepcidin in neurons and macrophages. Hepcidin downregulates ferroportin, the only known iron exporter, thereby inhibiting iron efflux and increases iron in ferroportin rich cells while decreasing serum iron. Increased intracellular iron after I/R induces ferroptosis, a regulated cell death characterized by iron-dependent lipid peroxidation. We hypothesized that hepcidin-induced sequestration of iron in neurons and macrophages, both of which express ferroportin, worsens post-cardiac arrest (CA) brain injury. Methods: Levels of hepcidin, iron, and a lipid peroxidation product, malondialdehyde; and expression of HAMP that encodes hepcidin, transferrin receptor 1, and markers of ferroptosis, PTGS2 and CHAC1, were measured in naïve and post-CA wild-type (WT) mice. To examine the effects of hepcidin on CA outcomes, hepcidin-deficient and WT mice were subjected to potassium-induced 8 min of CA followed by cardiopulmonary resuscitation (CPR). To determine the role of increased intracellular iron after CA/CPR, we administered iron-dextran (300 mg/kg IP) or vehicle to WT mice 24h before CA. The effect of liproxstatin-1, a ferroptosis inhibitor, on cell viability was assessed in murine primary cortical neurons after oxygen-glucose deprivation/reperfusion (OGD/R) with iron-loading. Results: Post-CA WT mice exhibited increased systemic HAMP expression, intracellular iron in spleen, and ferroptosis in brain. Hepcidin deficiency that decreases intracellular iron improved survival and neurological function after CA/CPR, whereas pre-arrest iron-loading that increases intracellular iron worsened survival and neurological function after CA/CPR (Fig. 1). Liproxstatin-1 improved neuron viability after OGD/R with iron-loading. Conclusions: Our data suggest that inhibiting hepcidin improves post-CA neurological outcomes by reducing intracellular iron and ferroptosis-induced neuronal death.
Label-Free Visualization and Quantification of Biochemical Markers of Atherosclerotic Plaque Progression Using Intravascular Fluorescence Lifetime
Authors: Julien Bec, Deborah Vela, Jennifer E. Phipps, Michael Agung, Jakob Unger, Kenneth B. Margulies, Jeffrey A. Southard, L. Maximilian Buja, Laura Marcu
Journal: JACC. Cardiovascular imaging (2020)

This study aimed to systematically investigate whether plaque autofluorescence properties assessed with intravascular fluorescence lifetime imaging (FLIm) can provide qualitative and quantitative information about intimal composition and improve the characterization of atherosclerosis lesions. Despite advances in cardiovascular diagnostics, the analytic tools and imaging technologies currently available have limited capabilities for evaluating in situ biochemical changes associated with luminal surface features. Earlier studies of small number of samples have shown differences among the autofluorescence lifetime signature of well-defined lesions, but a systematic pixel-level evaluation of fluorescence signatures associated with various histological features is lacking and needed to better understand the origins of fluorescence contrast. Human coronary artery segments (n = 32) were analyzed with a bimodal catheter system combining multispectral FLIm with intravascular ultrasonography compatible with in vivo coronary imaging. Various histological components present along the luminal surface (200-μm depth) were systematically tabulated (12 sectors) from each serial histological section (n = 204). Morphological information provided by ultrasonography allowed for the accurate registration of imaging data with histology data. The relationships between histological findings and FLIm parameters obtained from 3 spectral channels at each measurement location (n = 33,980) were characterized. Our findings indicate that fluorescence lifetime from different spectral bands can be used to quantitatively predict the superficial presence of macrophage foam cells (mFCs) (area under the receiver-operator characteristic curve: 0.94) and extracellular lipid content in advanced lesions (lifetime increase in 540-nm band), detect superficial calcium (lifetime decrease in 450-nm band area under the receiver-operator characteristic curve: 0.90), and possibly detect lesions consistent with active plaque formation such as pathological intimal thickening and healed thrombus regions (lifetime increase in 390-nm band). Our findings indicate that autofluorescence lifetime provides valuable information for characterizing atherosclerotic lesions in coronary arteries. Specifically, FLIm can be used to identify key phenomena linked with plaque progression (e.g., peroxidized-lipid–rich mFC accumulation and recent plaque formation).
FRI0123 Cumulative tissue damage in patients with juvenile-onset systemic lupus erythematosus
Authors: I Monteagudo, FJ López-Longo, CM González, AI Turrión, CA Montilla, M Moreno-Zazo, N Caro, R Del Castillo, C González-Montagut, L Cebrián, E Carmona, L Carreño
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> In earlier studies, we found that the juvenile onset of systemic lupus erythematosus (SLE) did not significantly modify the clinical expression of the disease.<sup>1</sup> Although juvenile-onset SLE may have a more sombre prognosis than adult-onset SLE, there have been few comparative studies of these types of SLE. <h3>Objectives</h3> To compare the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR) of a cohort of patients with juvenile-onset SLE and patients with adult-onset SLE. <h3>Methods</h3> We calculated the SLICC/ACR scores of 236 patients diagnosed as SLE between 1988 and 2000. The SLE disease activity index (SLEDAI) of the first hospital study was calculated retrospectively. <h3>Results</h3> In 61 patients (25.8%), SLE had begun before the age of 19 years. This group included 52 women (85.2%). The mean age at onset of SLE was 13.4 years (SD 3.2) and mean duration of the disease was 9.9 years (SD 6.5). The comparison of patients with juvenile-onset SLE and a group of 175 patients with adult-onset SLE did not reveal significant differences in sex, duration of the disease, and SLEDAI score at the onset of the disease (mean 16.31; SD 8.26 vs 14.08; SD 8.08). There were no differences in the SLICC/ACR scores obtained at the last follow-up visit (mean 1.6; SD 1.7 vs 1.45; SD 1.94) (p &gt; 0.05), although kidney disease (proteinuria over 3.5 g/day, treatment by dialysis or transplantation) (24 of 25; 39.3% vs 42 of 211; 24%) (p: 0.03; OR: 2; 95% CI: 1.1–3.8) and avascular necrosis (4 of 25; 6.6% vs 2 of 211; 1.1%) (p: 0.04; OR: 6; 95% CI: 1.08–3.4) were more frequent in patients with juvenile-onset disease. Both groups had a similar mortality (1 of 61; 1.6% vs 7 of 175; 4%) (p &gt; 0.05). <h3>Conclusion</h3> Although kidney disease and avascular necrosis were more frequent in patients with juvenile-onset SLE, the SLICC tissue damage score was similar in patients with juvenile-onset SLE and adult-onset SLE. <h3>Reference</h3> Lupus 1999;8:287–92