tbuckley/cabot-search huggingface dataset:
Amelioration of Murine Macrophage Activation Syndrome by Monomethyl Fumarate in Both a Heme Oxygenase 1–Dependent and Heme Oxygenase 1–Independent Manner
Authors: Chhanda Biswas, Niansheng Chu, Thomas N. Burn, Portia A. Kreiger, Edward M. Behrens
Journal: Arthritis & Rheumatology (2020)

Objective Macrophage activation syndrome (MAS) is characterized by increased serum levels of ferritin and heme oxygenase 1 (HO‐1), and yet no known function is ascribed to these molecules in MAS. Because HO‐1 is antiinflammatory, we hypothesized that pharmacologic activation of HO‐1 could ameliorate MAS disease activity. Dimethyl fumarate (DMF), a treatment approved by the US Food and Drug Administration for multiple sclerosis, activates HO‐1. Monomethyl fumarate (MMF) is the active metabolite of DMF. We therefore evaluated whether MMF could elicit HO‐1–dependent therapeutic improvements in a murine model of MAS. Methods We induced MAS by repeated activation of Toll‐like receptor 9 (TLR‐9) in wild‐type and myeloid‐specific HO‐1–deficient mice. MMF was administered twice daily to test its efficacy. We assessed organ weights, serum cytokine levels, histologic features of the spleen and liver tissue, and complete blood cell counts to evaluate disease activity. Statistical testing was performed using Student’s t ‐test or by 2‐way analysis of variance as appropriate. Results The presence of HO‐1 was required for the majority of TLR‐9–induced interleukin‐10 (IL‐10). IL‐10 production in TLR‐9–induced MAS was found to correlate with the myeloid–HO‐1 gene dose in myeloid cells ( P &lt; 0.001). MMF treatment increased the levels of HO‐1 in splenic macrophages by ~2‐fold ( P &lt; 0.01), increased serum levels of IL‐10 in an HO‐1–dependent manner in mice with TLR‐9–induced MAS ( P &lt; 0.005), and improved multiple disease parameters in both an HO‐1–dependent and HO‐1–independent manner. Conclusion TLR‐9–induced production of IL‐10 is regulated by HO‐1 activity both in vitro and in vivo. Therapeutic enhancement of the HO‐1/IL‐10 axis in a murine model was able to significantly ameliorate MAS disease activity. These results suggest that HO‐1 may be viable as a MAS therapeutic target, and treatment with DMF and MMF should be considered in future investigations of MAS therapy.
Abstract 16223: Cardiac Arrhythmias in Hospitalized Patients With COVID-19
Authors: Jae Hyung Cho, Ali Namazi, Richard Shelton, Archana Ramireddy, Ashkan Ehdaie, Michael Shehata, Xunzhang Wang, Eduardo Marban, Sumeet S Chugh, Eugenio Cingolani
Journal: Circulation (2020)

Introduction: Arrhythmias have been reported frequent in COVID-19 patients, but the incidence and nature have not been well characterized. Hypothesis: Atrial and ventricular arrhythmias are common complications of patients with COVID-19. Methods: Patients admitted with COVID-19 and monitored by telemetry were prospectively enrolled in the study. Baseline characteristics, hospital course, treatment and complications were collected from the patients’ medical records. Telemetry was monitored to detect the incidence of cardiac arrhythmias. The incidence and types of cardiac arrhythmias were analyzed and compared between survivors and non-survivors. Results: Among 143 patients admitted with telemetry monitoring, overall in-hospital mortality was 23.1% (33/143 patients) during the period of observation (mean follow up 19.9 ± 13.7 days). Survivors were younger (68.1 ± 17.2 vs. 77.6 ± 15.9 years old, p=0.006), had higher body mass index (28.1 ± 8.3 vs. 24.3 ± 6.2, p=0.019), were less tachycardic on initial presentation (heart rate 90.6 ± 19.4 vs. 99.8 ± 23.7 bpm, p=0.026) and had lower troponin (peak troponin 0.03 vs. 0.14 ng/ml. p=0.006) and interleukin-6 levels (peak interleukin-6 32 vs. 264 pg/ml, p=0.001). Sinus tachycardia, the most common arrhythmia (occurring in 39.9% [57/143] of patients), occurred more frequently in non-survivors (57.6% vs. 34.5% in survivors, p=0.018). Premature ventricular complexes occurred in 28.7% (41/143), and non-sustained ventricular tachycardia in 15.4% (22/143) of patients, with no difference between survivors and non-survivors. Sustained ventricular tachycardia and ventricular fibrillation were rare (seen only in 1.4% and 0.7% of patients, respectively). Conclusions: In this prospective observational study of hospitalized and monitored patients with COVID-19, sinus tachycardia was the most common rhythm disorder, and its presence was associated with higher mortality. Sustained ventricular tachycardia or ventricular fibrillation were infrequent, contradicting previous reports that malignant ventricular arrhythmias are commonly seen in patients hospitalized with COVID-19.
An Electronically Delivered Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure With Reduced Ejection Fraction
Authors: Larry A. Allen, Grace Venechuk, Colleen K. McIlvennan, Robert L. Page, Christopher E. Knoepke, Laura J. Helmkamp, Prateeti Khazanie, Pamela N. Peterson, Kenneth Pierce, Geoffrey Harger, Jocelyn S. Thompson, Tristan J. Dow, Lance Richards, Janice Huang, James R. Strader, Katy E. Trinkley, David P. Kao, David J. Magid, Peter M. Buttrick, Daniel D. Matlock
Journal: Circulation (2020)

Major gaps exist in the routine initiation and dose up-titration of guideline-directed medical therapies (GDMT) for patients with heart failure with reduced ejection fraction. Without novel approaches to improve prescribing, the cumulative benefits of heart failure with reduced ejection fraction treatment will be largely unrealized. Direct-to-consumer marketing and shared decision making reflect a culture where patients are increasingly involved in treatment choices, creating opportunities for prescribing interventions that engage patients. The EPIC-HF (Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction) trial randomized patients with heart failure with reduced ejection fraction from a diverse health system to usual care versus patient activation tools-a 3-minute video and 1-page checklist-delivered electronically 1 week before, 3 days before, and 24 hours before a cardiology clinic visit. The tools encouraged patients to work collaboratively with their clinicians to "make one positive change" in heart failure with reduced ejection fraction prescribing. The primary endpoint was the percentage of patients with GDMT medication initiations and dose intensifications from immediately preceding the cardiology clinic visit to 30 days after, compared with usual care during the same period. EPIC-HF enrolled 306 patients, 290 of whom attended a clinic visit during the study period: 145 were sent the patient activation tools and 145 were controls. The median age of patients was 65 years; 29% were female, 11% were Black, 7% were Hispanic, and the median ejection fraction was 32%. Preclinic data revealed significant GDMT opportunities, with no patients on target doses of β-blocker, sacubitril/valsartan, and mineralocorticoid receptor antagonists. From immediately preceding the cardiology clinic visit to 30 days after, 49.0% in the intervention and 29.7% in the control experienced an initiation or intensification of their GDMT (P=0.001). The majority of these changes were made at the clinician encounter itself and involved dose uptitrations. There were no deaths and no significant differences in hospitalization or emergency department visits at 30 days between groups. A patient activation tool delivered electronically before a cardiology clinic visit improved clinician intensification of GDMT. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03334188.
Abstract 14725: Image-based Virtual-heart Predictions Co-localize With ECG-based Automated Localization of Scar-related Ventricular Tachycardias
Authors: Shijie Zhou, Eric Sung, Adityo Prakosa, Jonathan Chrispin, Amir AbdelWahab, Konstantinos Aronis, Milan Horacek, John L Sapp, Natalia Trayanova
Journal: Circulation (2020)

Introduction: We previously developed an LGE-MRI-based virtual-heart arrhythmia ablation targeting (VAAT) methodology to non-invasively determine potential ablation targets for infarct-related VT. However, it is unknown whether VAAT’s predictions correspond with surface ECG predictions. Hypothesis: We hypothesized that the VAAT predicted VT circuits and potential ablation lesions would co-localize with ECG-based VT-exit predictions from a previously validated population-derived automated VT exit localization (PAVEL) system. Methods: We retrospectively enrolled 5 post-infarct patients who underwent LV endocardial VT ablation and had pre-procedural 2D LGE-MRIs. The PAVEL system based on a population-derived statistical method was used to localize VT-exit sites onto one of 238 triangles on the patient-specific virtual-heart LV endocardial surface using 8 independent ECG leads (I, II, V1-V6). The VAAT methodology incorporating patient-specific scar and infarct border zone distributions was used to identify potential VT circuits and find ablation lesions. Results: Eleven induced VTs were analyzed. Ten VT-exit sites were localized onto the patient-specific virtual-heart LV endocardial surface by the PAVEL system, and were used for the comparisons. One VT-exit site was too basal to be localized onto the virtual-heart geometry. The spatial resolution of the 10 predicted VT-exit sites was 13.8 ± 1.8 mm. VAAT-predicted VT circuits and ablation lesions correlated well with all 10 predicted VT-exit sites. Lastly, VAAT ablation lesions fell within the regions ablated clinically. Conclusions: The VAAT-predicted VT circuits and ablation lesions matched VT-exit sites predicted by the surface ECG-based PAVEL system. Combining these two complementary technologies may improve accuracy for non-invasively identifying optimal ablation targets to increase ablation efficacy.
Global loss of Tfr2 with concomitant induced iron deficiency greatly ameliorates the phenotype of a murine thalassemia intermedia model
Authors: Paul J. Schmidt, Kevin Fitzgerald, James S. Butler, Mark D. Fleming
Journal: American Journal of Hematology (2020)

Abstract β‐thalassemias result from mutations in β‐globin, causing ineffective erythropoiesis and secondary iron overload due to inappropriately low levels of the iron regulatory hormone hepcidin. Mutations in transferrin receptor 2 (TFR2) lead to hereditary hemochromatosis (HH) as a result of inappropriately increased iron uptake from the diet, also due to improperly regulated hepcidin. TFR2 is also thought to be required for efficient erythropoiesis through its interaction with the erythropoietin receptor in erythroid progenitors. Transmembrane serine protease 6 (TMPRSS6) , a membrane serine protease expressed selectively in the liver, participates in regulating hepcidin production in response to iron stores by cleaving hemojuvelin (HJV). We have previously demonstrated that inhibiting TMPRSS6 expression with a hepatocyte‐specific siRNA formulation, induces hepcidin, mitigates anemia, and reduces iron overload in murine models of β‐thalassemia intermedia and HH. Here, we demonstrate that Tmprss6 siRNA treatment of double mutant Tfr2 Y245X/Y245X HH Hbb th3/+ thalassemic mice induces hepcidin and diminishes tissue and serum iron levels. Importantly, treated double mutant animals produce more mature red blood cells and have a nearly 50% increase in hemoglobin compared to untreated β‐thalassemic mice. Furthermore, we also show that treatment of Tfr2 Y245X/Y245X HH mice leads to increased hepcidin expression and reduced total body iron burden. These data indicate that siRNA suppression of Tmprss6 , in conjunction with the targeting of TFR2, may be superior to inhibiting Tmprss6 alone in the treatment of the anemia and secondary iron loading in β‐thalassemia intermedia and may be useful as a method of suppressing the primary iron overload in TFR2‐related (type 3) hereditary hemochromatosis.
Poorly Differentiated Neuroendocrine Tumor With 18F-Fluciclovine Uptake in a Patient With Metastatic Castrate-Resistant Prostate Cancer
Authors: Olayinka A. Abiodun-Ojo, Akinyemi A. Akintayo, Lara R. Harik, Mehmet Bilen, Raghuveer K. Halkar
Journal: Clinical Nuclear Medicine (2020)

18F-Fluciclovine is an amino acid-based radiopharmaceutical used primarily for PET imaging of patients with biochemical recurrence of prostate cancer. We report a case of a 66-year-old man with recently diagnosed metastatic castrate-resistant prostate cancer and a left supraclavicular lymph node with incidental radiotracer uptake on 18F-fluciclovine PET/CT. Left neck core needle biopsy confirmed high-grade, poorly differentiated carcinoma with neuroendocrine features positive for synaptophysin and chromogranin, and negative for prostate markers.
Abstract 15892: Reliability of Focused Cardiac Ultrasound in the Post-Operative Assessment of Patients With Congenital Heart Disease: A Single Center Experience
Authors: Emina Hodzic, Achiau Ludomirsky, Puneet Bhatla
Journal: Circulation (2020)

Introduction: Early detection of postoperative complications in children with congenital heart disease (CHD) is crucial. The utility of focused cardiac ultrasound (FoCUS) in the assessment of post-operative congenital cardiac surgical patients is not known. Objective: To evaluate the reliability of FoCUS in the assessment of children with CHD in the early post-operative period. Methods: A prospective observational cross-sectional study was performed in a single pediatric center. All FoCUS studies were performed by one imager within two hours of the paired echocardiographic (ECHO) study performed by a different imager. FoCUS studies were obtained using Philips Lumify R and ECHO studies utilized a high-end ultrasound machine (Philips Affiniti R ). Qualitative ventricular (right and left) function, pericardial effusion, pleural effusion, and degree of mitral regurgitation (MR) and tricuspid regurgitation (TR) were compared. All FoCUS and ECHO studies were sent for review in a random and blinded fashion to two independent noninvasive imaging cardiologists. Weighted k statistics were used to determine the level of agreement between FoCUS and ECHO, and between observers. Results: Twenty-three FoCUS studies were performed in 12 patients with a mean age of 16.6 months (range 0-96 months) within two weeks postoperatively. There was inter-observer agreement for ECHO on all parameters and inter-observer agreement for FoCUS on all parameters except for TR. The intra-observer agreement between FoCUS and ECHO for the two cardiologists was fair to moderate for ventricular function (k= 0.470, p&lt; 0.05 and 0.340, p &lt; 0.05), substantial for pericardial effusion (k = 0.617, p&lt; 0.05 and 0.777, p&lt; 0.05), and fair for MR (0.400, p&lt; 0.05). There was no statistically significant agreement for TR and pleural effusion for both observers and MR for one observer. Conclusions: FoCUS demonstrated acceptable reliability in the assessment of ventricular function and presence of pericardial effusions, with a limited value in the assessment of atrioventricular valve regurgitation. This tool is valuable in the early post-operative evaluation of pediatric patients with congenital heart disease in the cardiac intensive care unit.
Abstract 14602: Vascular Calcification is Associated With Major Adverse Cardiovascular Events and Mortality in Men With Recurrent Prostate Cancer Undergoing PET/CT Imaging
Authors: Preet Ayoub Shaikh, Avira Som, Daniel Lenihan, Kathleen W Zhang
Journal: Circulation (2020)

Background: Hormone therapy is a front-line therapy for men with prostate cancer and is associated with adverse cardiovascular events. The utility of vascular calcification for cardiovascular risk stratification in men with prostate cancer is unknown. Methods: 211 consecutive patients who underwent 18F-fluciclovine positron emission tomography (PET)/computed tomography (CT) at a single institution for recurrent prostate cancer were retrospectively identified. Clinical and demographic data were obtained from the medical record. Coronary and aortic calcification were qualitatively assessed on non-gated CT scans using standardized scoring systems. The primary outcome was a composite of subsequent major adverse cardiovascular event (MACE; myocardial infarction, stroke, coronary or peripheral revascularization, heart failure hospitalization) or all-cause mortality. Results: Median age was 69 (IQR 64, 75) years and cardiovascular comorbidities were common (70% hypertension, 65% hyperlipidemia, 47% current or former smoking, 20% diabetes mellitus). Over a median of 16.5 months, 8 patients (4%) met the primary outcome. Patients with MACE or death were older and had higher prevalence of traditional cardiovascular comorbidities (risk ratio [RR] 1.3 for hypertension, 1.4 for hyperlipidemia, 1.3 for diabetes mellitus; p&gt;0.05 for all). Coronary and aortic calcification were more common in patients with MACE or death. Severe coronary calcification (RR=6.1, 95% CI 1.6-23.2, p=0.008) and severe thoracic aortic calcification (RR=9.9, 95% CI 2.0-47.6, p=0.004) were associated with significantly increased risk of MACE or death. Conclusions: Coronary and aortic calcification on PET/CT imaging are associated with significantly increased risk of MACE or death in men with recurrent prostate cancer. Vascular calcification may have utility for cardiovascular risk stratification in men receiving hormone therapy for prostate cancer.
COVID-19 cytokine storm: what is in a name?
Authors: Peter A Nigrovic
Journal: Annals of the Rheumatic Diseases (2020)

It is now almost difficult to imagine back to a time before COVID-19 turned the world upside down. The pandemic has taken an enormous toll on patients, families and communities, working fundamental changes into our lives and into our thoughts. The medical community has formed one of many ‘front lines’ in the battle against COVID-19, and our lives and thoughts have been transformed as well. When the COVID-19 story is told, a key subplot will be how physicians and scientists responded to the virus. The report by Caricchio et al 1 in Annals gives us opportunity to consider the medical response to COVID-19, both at a practical level and with respect to the evolving concept of COVID-associated cytokine storm.1 

These investigators confronted the pandemic at Temple University, in Philadelphia, one of the early epicentres of COVID-19 in the USA. In a period of 5 weeks beginning in March 2020, the Temple team admitted more than 500 adults with characteristic pulmonary ground-glass opacities, all requiring supplemental oxygen and most positive for SARS-CoV-2 by qPCR. Despite this onslaught, the team still managed to collect and analyse data to ask whether clinical or laboratory parameters accurately predicted the severe inflammatory phenotype referred to here as the ‘COVID-19 cytokine storm’ (COVID-CS). Lacking an accepted gold standard, the investigators employed a consensus of expert rheumatologists and pulmonologists to assign 64 patients (12%) to this category, on the basis of worsening respiratory status and elevation in C reactive protein (CRP), ferritin, D-dimer, lactate dehydrogenase (LDH), and/or troponin. COVID-CS criteria were then tested in a second cohort of 258 Temple patients admitted during a 12-day period later in April.

To develop their prediction model, they used univariate logistic regression to identify variables associated with COVID-CS and then principal components analysis to find predictors that clustered together, …
Letter to the Editor: More Efforts for Detecting the Elevated Liver Biochemistries in Patients With Severe COVID‐19
Authors: Yi‐Ming Lin, Ai‐Yong Cui, Da‐Wei Wang, Hua‐Ding Lu
Journal: Hepatology (2020)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read with great interest the recent study by Kovalic et al.(1) showing that patients with severe/critical COVID‐19 may have elevated liver biochemistries. We found that there are some potential methodological pitfalls. First, the authors searched only three databases, which may not be enough to collect all the eligible studies. Since the outbreak of COVID‐19, many studies have been uploaded to preprint websites, such as the Social Science Research Network, bioRxiv, and medRxiv. Omitting these important grey literature publications may lead to exaggerated estimates of pooled effects.(2) Additionally, although the meta‐analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, the protocol was not preregistered in any platforms, such as the Cochrane Library and the International Prospective Register of Systematic Reviews, which may affect its transparency and reproducibility. Second, the authors analyzed publication bias and concluded that there was not significant publication bias in the included studies. It may be inappropriate, however, to use funnel plots or Egger's test to assess publication bias when there are fewer than 10 studies.(3) In the Methods section, the authors stated that the fixed‐effects model was used when no significant heterogeneity was found (I2 < 50%). However, we are confused because some of the pooled results (I2 < 50%) shown in figures 2A and 3 were calculated using the random‐effects model. Third, accumulating evidence indicated that chronic liver diseases (CLDs) were independent prognostic factors for patients with COVID‐19.(4) Therefore, it would be better to evaluate the influence of different stages of CLDs on liver biochemistries in subgroup analysis, which may contribute to risk stratification and individualized treatments for patients with COVID‐19. Additionally, the pooled results of the current meta‐analysis were based on 6 studies with a total of 586 patients, so the potential "small‐sample effect" or "false‐positive effect" cannot be excluded. Consequently, the conclusions should be interpreted with caution, and this limitation should be stated in the Discussion section. We respectfully thank Kovalic et al for providing us with valuable work. Considering the potential methodological flaws, further studies with better scientific designs are warranted to elucidate this problem.
Abstract 15426: Comparison of Multimodality Imaging in Mitral Leaflet Lengths in Patients Undergoing Surgical Myectomy: A Prospective Study in Hypertrophic Obstructive Cardiomyopathy Patients
Authors: Agostina M Fava, Anand Mehta, Barbara Bittel, Andrew Bauer, Zoran B Popovic, Maran Thamilarasan, Harry M Lever, Per Wierup, Nicholas G Smedira, Milind Y Desai
Journal: Circulation (2020)

Introduction: In hypertrophic obstructive cardiomyopathy (HOCM), mitral valve (MV) leaflets in often contribute to left ventricular outflow tract obstruction (LVOTO). Hence, MV assessment is crucial during surgical planning. 2 or 3-dimensional transesophageal echocardiography (2D or 3D TEE) &amp; cardiac magnetic resonance (CMR) are used to measure MV length. Hypothesis: We sought to compare MV leaflet lengths using intraoperative TEE [2D, zoom 3D, automatic quantification of mitral valve (AMVQ)], &amp; preoperative CMR. Methods: We prospectively studied 50 HOCM patients (59±12 years, 46% men, basal septum 18±5 mm, LVOT gradient 87 ±56 mmHg) undergoing surgical relief of LVOTO. We compared MV leaflet length on a) long-axis 2DTEE b) 3DTEE using multiplanar reconstruction c) AMVQ, EchoPAC, General Electric &amp; d) CMR. Results: Mean anterior leaflet lengths (mm) were as follows: 2D TEE (3.3 ±0.3), 3DTEE (2.9±0.5), CMR (3.1±0.4), &amp; AMVQ (2.9±0.5). Mean posterior leaflet lengths were 1.7±0.3, 1.7±0.4, &amp; 1.7±0.2 &amp; 1.9±0.4 mm, respectively. Assuming 3DTEE as the gold standard, the closest correlation for anterior leaflet was with CMR (average overestimation by CMR of 0.5 mm [root mean square deviation or RMSE% 17]), intermediate correlation with 2DTEE (average deviation of 0.6 mm [RMSE%:21]) &amp; no correlation with AMVQ (deviation of 0.7mm [RMSE% 24]), Fig 1A-C &amp; 2A-C. No correlation was found for posterior leaflet,Fig 1D-F &amp; 2D-F. Conclusions: There are significant differences in measuring MV lengths using different imaging techniques. In HOCM patients undergoing surgery, precise measurement of MV leaflet lengths is crucial &amp; extrapolation from one technique to other is not recommended.