tbuckley/cabot-search huggingface dataset:
Association of Acute Kidney Injury During Diabetic Ketoacidosis With Risk of Microalbuminuria in Children With Type 1 Diabetes
Authors: Jia Xin Huang, T. Charles Casper, Casey Pitts, Sage Myers, Lindsey Loomba, Janani Ramesh, Nathan Kuppermann, Nicole Glaser
Journal: JAMA Pediatrics (2021)

Diabetic kidney disease is among the most important causes of end-stage kidney disease worldwide. Risk factors for diabetic kidney disease remain incompletely defined. Recent studies document a high frequency of acute kidney injury (AKI) during diabetic ketoacidosis (DKA) in children, raising the question of whether these AKI episodes might contribute to future risk of diabetic kidney disease.To determine whether episodes of AKI occurring during DKA in children are associated with increased risk of development of microalbuminuria.This retrospective review of medical records included children with type 1 diabetes with 1 or more urine albumin levels measured during routine diabetes care from 2 university-affiliated urban tertiary children's hospitals in the United States from January 2006 to December 2019. Age at diagnosis of diabetes, hemoglobin A1c levels, episodes of DKA, pH and creatinine levels during DKA, and urine albumin and creatinine measurements were analyzed. Cox proportional hazards regression models were used to identify variables affecting the hazard rate for microalbuminuria development. Analyses began January 2021 and ended May 2021.Episodes of DKA and episodes of AKI occurring during DKA.AKI occurrence and AKI stage were determined from serum creatinine measurements during DKA using Kidney Disease: Improving Global Outcomes criteria. Microalbuminuria was defined as urine albumin-to-creatinine ratio of 30 mg/g or more or excretion of 30 mg or more of albumin in 24 hours.Of 2345 children, the mean (SD) age at diagnosis was 9.4 (4.4) years. One or more episodes of DKA occurred in 963 children (41%), and AKI occurred during DKA in 560 episodes (47%). In multivariable models adjusting for the associations of age at diagnosis and mean hemoglobin A1c level since diagnosis, each episode of AKI during DKA was associated with a hazard ratio of 1.56 (95% CI, 1.3-1.87) for development of microalbuminuria. Four or more episodes increased the hazard rate by more than 5-fold. DKA episodes without AKI did not significantly increase the hazard rate for microalbuminuria development after adjusting for other covariates.These data demonstrate that episodes of AKI occurring during DKA in children with type 1 diabetes are significantly associated with risk of developing microalbuminuria. Greater efforts are necessary to reduce the frequency of DKA.
Abstract 10450: Higher Body Mass Index is Associated with a Higher Prevalence of Thin-Cap Fibroatheroma in Younger Patients with Type 2 Diabetes Mellitus
Authors: Masahiro Katamine, Yoshiyasu Minami, Kiyoshi Asakura, Aritomo Katsura, Daisuke Kinoshita, Takuya Hashimoto, RYO KAMEDA, Kentaro Meguro, Takao Shimohama, Junya Ako
Journal: Circulation (2021)

Introduction: High body mass index (BMI) is associated with increased incidence of type 2 diabetes (T2D) and subsequent cardiovascular disease (CVD). However, the association between the BMI and the characteristics of coronary plaque in younger T2D patients with CVD remains to be elucidated. Hypothesis: Higher BMI is associated with a higher prevalence of vulnerable coronary plaque in younger T2D patients with CVD. Methods: A total of 140 consecutive younger (&lt;65 years) T2D patients with CVD, who underwent optical coherence tomography (OCT) imaging of the culprit lesion were included. The patients were classified into either the higher BMI group (BMI ≥25.8 kg/m 2 , n=70) or the lower BMI group (BMI &lt;25.8 kg/m 2 , n=70) according to the median of BMI. The characteristics of culprit plaque assessed by OCT were compared between the two groups. Results: The prevalence of thin-cap fibroatheroma (TCFA) (34.8 vs. 17.4%, p =0.020) and lipid-rich plaque (44.9 vs. 26.1%, p =0.021) was significantly higher in the higher BMI group than in the lower BMI group (Panel A). The prevalence of TCFA was further compared according to the tertile of LDL-C levels. A significant trend toward higher prevalence of TCFA according to the increase in LDL-C levels was observed in patients with higher BMI ( p =0.017) (Panel B), although the trend was not significant in patients with lower BMI ( p =0.487) (Panel C). Conclusions: Higher BMI was associated with a higher prevalence of TCFA in younger T2D patients with CVD. Higher LDL-C level was associated with a higher prevalence of TCFA among patients with higher BMI although the association was not significant among patients with lower BMI.
NCOG-28. THE IMPACT OF MULTIPLE MENINGIOMAS ON PROGRESSION-FREE SURVIVAL: A 10-YEAR MULTI-CENTER STUDY
Authors: Andres Ramos-Fresnedo, Ricardo Domingo, Jesus Sanchez-Garavito, Carlos Perez-Vega, Oluwaseun Akinduro, Mark Jentoft, Paul Brown, Alyx Porter, Bernard Bendok, Michael Link, Erik Middlebrooks, Daniel Trifiletti, Kaisorn Chaichana, Alfredo Quinones-Hinojosa, Wendy Sherman
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Multiple meningiomas (MM) occurs in up to 18% of meningioma patients and progression data are scarce. The objective of this study is to explore the influence of number of lesions and clinical characteristics on progression-free survival (PFS) and time to a second intervention (TTSI) in patients with WHO grade 1 meningiomas. METHODS We retrospectively reviewed records of all adults diagnosed with a meningioma at our three main sites from January 2009 to May 2020. Progression was considered as time from diagnosis until radiographic progression of the originally resected meningioma. A secondary analysis was carried to evaluate the time from diagnosis to time of a second intervention. Univariable and multivariable analyses were conducted to assess whether number of lesions or any associated variables (age, sex, race, radiation, location, and extent of resection) had a significant impact on PFS and TTSI. RESULTS 838 patients were included. Log-rank test evaluating PFS and TTSI between single and multiple lesions showed significantly shorter progression for MM (p&amp;lt; 0.001 and p&amp;lt; 0.001, respectively). Multivariable Cox regression showed significantly inferior PFS on MM vs. single lesion (HR 2.262 [CI 95%, 1.392-3.677], p=0.001) and a significantly inferior TTSI for patients with MM vs. single meningioma (HR 2.377 [CI 95%, 1.617 – 3.494], p=0.001). When input as a continuous variable, PFS was significantly inferior for each additional meningioma (HR 1.350 [CI 95% 1.074-1.698], p=0.010) and TTSI is significantly inferior as well (HR 1.428 [CI 95% 1.189 – 1.716], p&amp;lt; 0.001). African-Americans had an inferior PFS when compared to Non-Hispanic White patients (HR 3.472 [CI 95% 1.083-11.129], p=0.036). CONCLUSION The PFS of meningiomas is influenced by the number of lesions present. Patients with MM are more prone to undergo a second intervention for progressive disease. Hence, a closer follow-up may be warranted in patients who present with multiple lesions.
Abstract 11592: Glycogen Synthase Kinase 3β Localizes to the Z-Disc to Maintain Length Dependent Activation
Authors: Marisa Stachowski, Maria Papadaki, Thomas Martin, Weikang Ma, Henry Gong, Nitha Aima Muntu, Mohit Kumar, Jody Martin, Christine S Moravec, Sakthivel Sadayappan, Thomas Irving, Jonathan A Kirk
Journal: Circulation (2021)

Glycogen Synthase Kinase 3β (GSK-3β) can modulate myofilament function in vitro . However, it’s in vivo role, mechanism, and translational relevance are unknown, which we investigated here using inducible cardiomyocyte specific GSK-3β KO mice. Compared to tamoxifen-treated GSK-3β fl/fl Cre- mice (Con), skinned myocytes from KO mice had reduced calcium sensitivity at long sarcomere lengths (SL = 2.2 μm), but there were no differences at short SL (~1.9 μm). Thus, myocytes from KO mice did not sensitize to calcium with stretch, a mechanism called length dependent activation (LDA) that underlies the organ-level Frank-Starling law. LDA has been attributed to (1) phosphorylation of myofilament proteins, (2) altered lattice-spacing, and (3) changes to titin’s elastic properties. Using mass spectrometry and small energy x-ray diffraction we ruled out the first two mechanisms, however we did find that GSK-3β KO myocytes had decreased passive tension – indicating the loss of LDA was due to loss of titin as a length sensor. Interestingly, immunofluorescence showed that GSK-3β localized to the z-disc when phosphorylated at Y216 and, via mass spectrometry, phosphorylated primarily z-disc proteins including several sites on the structural protein Ablim-1, which we showed also localizes to the z-disc. These data suggested that GSK-3β’s effect on titin is likely through altering its ability to anchor to the z-disc through targeting of these z-disc proteins. To provide further evidence that GSK-3β is specifically altering LDA, we genetically removed a downstream effecter of LDA, cardiac myosin binding protein-C (cMyBP-C). In vitro treatment with exogenous GSK-3β was able to increase calcium sensitivity at long SLs in both KO and WT mice but had no effect on cMyBPC KO mice or mice lacking the c-terminal domains of cMyBPC that are known to be important for LDA. Lastly, we found that human heart failure patients had less myofilament GSK-3β compared to non-failing patients, and that these same samples had a depressed LDA. This work has identified a novel mechanism by which GSK-3β localizes to the myofilament to modulate LDA and indicates that z-disc localized GSK-3β may be a possible therapeutic target to restore the Frank-Starling mechanism in heart failure patients.
Abstract 12641: Performance of Mortality Prediction Models in Dilated Cardiomyopathy Patients and the Incremental Value of Late Gadolinium Enhancement
Authors: Siqi Tang, Yucheng Chen, Qing Zhang
Journal: Circulation (2021)

Introduction: Mortality prediction models assist decision-making for patients with dilated cardiomyopathy (DCM). Published heart failure (HF) models have not been validated in large DCM cohorts; whether late gadolinium enhancement (LGE) provides incremental predictive power remains unclear. Hypothesis: Incorporating LGE location improves the performance of existing HF mortality prediction models. Methods: We used data from a prospective registry enrolling DCM patient who underwent clinical CMR examination between June 2012 and May 2020. Five recent or classic models estimating the risk of all-cause death or heart transplantation in chronic HF patients were examined: SHFM, GISSI-HF, MAGGIC, BIOSTAT-CHF, and PARADIGM-HF score. We added LGE location to the risk scores generated by the original models. Results: Of 524 DCM patients with available data required for all five models (age 48.7 ± 15.1, 71% male), 100 patients (19.1%) died or underwent heart transplantation (median follow-up of 26.3 months). PARADIGM-HF showed the best overall discrimination [Harrell’s C index and 95% CI: 0.75, 0.70-0.80], similar to SHFM and MAGGIC [0.72, 0.67-0.77 and 0.71, 0.66-0.76, respectively; all comparisons P &gt;0.05], and better than GISSI-HF and BIOSTAT-CHF [0.66, 0.60-0.71 and 0.66, 0.60-0.72, respectively]. PARADIGM-HF exhibited decreased discrimination for 2-year and 3-year mortality/heart transplantation risk. The net reclassification by adding LGE location to the models improved the 2-year and 3-year risk prediction in 25-29% of patients, except for MAGGIC; however, 1-year risk prediction remained unaltered. Conclusions: Existing HF mortality prediction models made moderately accurate risk estimates. LGE assisted long-term risk stratification but may have less additive value for the short-term risk prediction.
Abstract 14229: Carcinoid Heart Disease: What Do We Know About Characteristics and Outcomes of Tricuspid Valve Replacement? A Nationwide Analysis
Authors: Agam Bansal, Mohamed Gad, Paul Cremer, Wael A Jaber, Venu Menon, heba wassif
Journal: Circulation (2021)

Introduction: In patients with severe tricuspid and pulmonary valve regurgitation and symptoms of heart failure secondary to carcinoid heart disease, valve replacement is the only effective treatment and can improve survival. Previous data on outcomes of valve replacement in carcinoid heart disease have been limited to case reports or single-centre study. Therefore we aimed to perform a nationwide database to ascertain the outcomes of tricuspid valve replacement (TVR) in carcinoid heart disease. Methodology: We utilized nationwide readmission database (NRD) to identify hospitalizations for tricuspid valve replacement in 2018. Hospitalizations with valve replacement for infective endocarditis were excluded. Characteristics and outcomes were compared between patients undergoing TVR for carcinoid versus other reasons. Multivariable logistic regression was performed to examine the predictors of in-hospital mortality after TVR. Results: A total of 1192 hospitalizations for TVR were included in the analysis of which 57 had carcinoid heart disease. There were no significant differences in short-term outcomes including in-hospital mortality (12.6% vs 11.5%, p=0.839), acute renal failure, blood transfusion, cardiogenic shock, new pacemaker insertion, length of stay and 30-day readmissions between TVR for carcinoid vs other etiologies (Table). The independent predictors of mortality in patients undergoing TVR were advanced liver disease (4.67 (2.59-8.43), p&lt;0.001), end stage renal disease (5.09 (2.10-12.01), p&lt;0.001), acute heart failure (2.00 (1.10-3.67), p=0.022), malnutrition (2.24 (1.13-4.31), p=0.017), and age (1.02 (1.01-1.04), p=0.020), whereas carcinoid heart disease was not an independent predictor of mortality (aOR: 1.52 (0.39-4.65), p=0.497). Conclusion: Tricuspid valve replacement in patients with carcinoid heart disease is associated with comparable short-term outcomes as for other etiologies.
CSIG-21. 5-ALA PDT AND TARGETING MEK/ERK SIGNALING ELICITS SYNERGISTIC ANTITUMOR EFFECTS IN DIFFUSE MIDLINE GLIOMA
Authors: Gabrielle Price, Daniel Rivera, Alexandros Bouras, Constantinos Hadjipanayis
Journal: Neuro-Oncology (2021)

Abstract Diffuse midline gliomas (DMGs) are highly invasive, unresectable tumors in children. To date, there is no effective treatment for DMGs. Fractionated radiotherapy (RT), currently the standard of care, has provided limited disease control. Current obstacles to treatment include the blood brain barrier (BBB) that limits systemic drug delivery, tumor therapy resistance, and brainstem infiltration. Given the unmet need for more effective DMG treatments, photodynamic therapy (PDT), with the precursor photosensitizing agent 5-aminolevulinic acid (5-ALA), is an oncologic treatment that holds promise. 5-ALA PDT of tumors occurs by targeting tumor cells that accumulate the 5-ALA metabolite, protoporphyrin IX (PPIX), with 635 nm light to create deadly reactive oxygen species (ROS). We explore the synergism of 5-ALA PDT with the MEK inhibitor, trametinib, since the RAS/MEK signaling pathway regulates tumor cell proliferation and survival and has been shown to therapeutically enhance PDT in select tumor models. We demonstrated that sub-micromolar levels of 5-ALA PDT and nanomolar levels of trametinib successfully decrease cell proliferation and induce apoptosis in multiple DMG cell lines. Cell viability assays revealed that drug response differs based on the histone mutation (H3.1 or H3.3) of the line. Mechanisms of decreased cell survival involves the generation of reactive oxygen species that induces programmed cell death. Through the use of a DMG genetically engineered mouse model, we also found 5-ALA PDT to induce apoptosis in vivo. The synergistic effects of MEK inhibition and 5-ALA PDT in vitro and apoptotic effects of 5-ALA PDT in vivo, highlights the potential therapeutic efficacy of this treatment modality.
Abstract 10099: Loss of CD70 Impairs Nitric Oxide Homeostasis and Augments Intracellular Oxidative Stress in Endothelial Cells
Authors: Arvind K Pandey, Thomas Michel, Joseph Loscalzo
Journal: Circulation (2021)

Introduction: TNF superfamily ligands exert multiple effects on endothelial cell (EC) function, metabolism, and redox status. CD70 is a TNF superfamily member classically expressed on antigen-presenting cells and drives T memory cell polarization. Despite evidence of expression by ECs, the role of CD70 in endothelial biology has not been defined. We hypothesized that CD70 affects EC function through regulation of nitric oxide (NO) generation and cellular oxidative stress. Methods: Human aortic and pulmonary artery ECs (HAECs and HPAECs, respectively) were transfected with control and CD70-directed siRNA (siCD70). NO levels of individual cells were monitored in real-time after stimulation with ATP using the intracellular fluorescent biosensor c-geNOp. Similarly, intracellular hydrogen peroxide was assayed in real-time using the intracellular fluorescent biosensor Hyper7 following stimulation by auranofin and histamine. For both studies, 70-100 individual cells, averaged over 4 experiments, were analyzed using confocal microscopy. Control and siCD70-treated cell lysates (n = 4-6) were analyzed by Western blot and quantitative RT-PCR, as well as for glutathione peroxidase (GPx) enzyme activity. Results: CD70 knockdown was associated with a reduction in agonist-stimulated NO levels in HAECs and HPAECs by 30% and 40%, respectively. Protein levels of eNOS decreased after CD70 knockdown, with a reduction of 50% in HAECs and 75% in HPAECs. Phosphorylation at Ser1177 of eNOS in response to EC stimulation with ATP was reduced after siCD70 treatment, and expression of the key eNOS-stimulatory protein Hsp90 was decreased. Intracellular hydrogen peroxide was significantly increased (20% in HAECs and 80% in HPAECs) following ROS stimulation in siCD70-treated versus control cells. This change in redox status was associated with a decrease in mitochondrial superoxide dismutase protein and an increase in GPx-1 expression and enzyme activity. Conclusions: Loss of CD70 in ECs is associated with reduced eNOS expression and bioactivity as well as increased susceptibility to intracellular oxidative stress, potentially from a mitochondrial source. These results suggest an important homeostatic role for CD70 in endothelial function and redox status.
Abstract 13795: Deep Learning of Electrocardiogram Waveforms for Diagnosis of Heart Failure With Reduced Left Ventricular Ejection Fraction
Authors: Jung Min Choi, Sungjae Lee, Mineok Chang, Hae-young Lee
Journal: Circulation (2021)

Introduction: A deep learning-aided electrocardiogram (Deep-ECG) was trained to identify left ventricular systolic dysfunction (LVSD) of ejection fraction (EF) less than 40%. We evaluated the performance of Deep-ECG among patients with symptomatic heart failure (HF) in Korean acute HF registry. Hypothesis: Deep-ECG may be useful for identifying EF in HF with reduced EF (HFrEF). Methods: We included 1,292 symptomatic HF patients from 2011 to 2014 who underwent echocardiography and ECG within 30 days. The performance of Deep-ECG for LVSD was determined using receiver-operator characteristic curve (AUC) values. Results: Mean age was 67.8±14.4 years and 56% of patients were men. HFrEF, HF with mid-range EF and HF with preserved EF(HFpEF) was present in 42.3%, 17.9% and 39.8%, respectively. Using the optimal cut-off by Youden’s index, AUC value was 0.844 for identifying HFrEF among HF patients. AUC values were significantly higher for patients with normal AV conduction (0.872 vs. 0.759, p =0.002) and normal interventricular conduction (0.848 vs. 0.812, p=0.037) when compared to each conduction delay. Interestingly, corrective (true-positive) results in Deep-ECG for LVSD were acquired in patients bigger LV end systolic dimension (LVESD) than in false negative group (54.4±10.1mm vs. 49.7±8.7mm, p&lt;0.001). Conclusions: The Deep-ECG algorithm had very good discrimination for HFrEF in real world HF cohort. This algorithm may be useful for identification of LVSD in resource-limited settings. Figure 1. Scatterplot demonstrating LVESD and the performance of Deep-ECG for identifying LVSD (LVEF &lt; 40%)
Abstract 12340: Early Restoration of Coronary Vasomotor Function Following Drug-Coated Balloon Only Angioplasty of de novo Lesions
Authors: Sunwon Kim, Jong-Seok Lee, Sang-Yup Lim, Woo-Hyuk Song, Jeong-Cheon Ahn
Journal: Circulation (2021)

Introduction: We evaluated whether drug-coated balloon (DCB)-treated de novo lesions are prone to vasospasm and how these segments respond to ergonovine and nitrate in comparison with angiographically normal segments and other untreated segments showing prominent vasoreactivity. Hypothesis: DCB angioplasty is an emerging treatment approach for coronary artery disease. Evidences in balloon angioplasty era, however, repeatedly reported the presence of abnormal vasomotor function at balloon-injured segment, leading to fatal spasm. Methods: 68 DCB angioplasty recipients underwent 6-months follow-up coronary angiography. Vasomotor function was assessed using intracoronary injection of incremental dose of ergonovine, followed by nitrate. Percent change of mean lumen diameter was assessed by quantitative coronary angiography at three different sites: DCB-treated segment vs. angiographically normal segment ( control ) vs. normal or mildly diseased segment (diameter stenosis &lt; 30%) showing prominent vasomotor response ( other diseased segment ). Results: All patients were event-free during 6-month follow-up. A total of 87 DCB-treated lesions were analyzed. Significant ergonovine-induced vasospasm developed in 8 patients; however, none of them showed focal spasm involving DCB-treated lesion only. There was no significant difference in mean lumen diameter after ergonovine provocation between DCB-treated lesions vs. angiographically normal segments. However, vasoconstrictor response was greater in other diseased segments than in DCB-treated lesions. After nitrate injection, all segments dilated significantly. Vasoreactivity, defined as combined constrictor and dilator response, was comparable between DCB-treated lesions and controls (p&gt;0.05); while significant difference was found against other diseased segment (p&lt;0.005), implicating the restoration of vasomotor function after DCB angioplasty. Conclusions: Lesion treated by DCB did not harbor increased risk for clinically or angiographically significant vasospasm and showed vasomotor function similar to angiographically normal segments. These findings support feasibility and safety of DCB-only strategy for the treatment of de novo coronary artery disease.