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Supplementary Figures S1-S4.

Purpose: The purpose of this study was to determine whether histone deacetylase (HDAC) inhibitors (HDACI) such as vorinostat or entinostat (SNDX-275) could increase the lethality of the dual Bcr/Abl-Aurora kinase inhibitor KW-2449 in various Bcr/Abl+ human leukemia cells, including those resistant to imatinib mesylate (IM).Experimental Design: Bcr/Abl+ chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) cells, including those resistant to IM (T315I, E255K), were exposed to KW-2449 in the presence or absence of vorinostat or SNDX-275, after which apoptosis and effects on signaling pathways were examined. In vivo studies combining HDACIs and KW2449 were carried out by using a systemic IM-resistant ALL xenograft model.Results: Coadministration of HDACIs synergistically increased KW-2449 lethality in vitro in multiple CML and Ph+ ALL cell types including human IM resistant cells (e.g., BV-173/E255K and Adult/T315I). Combined treatment resulted in inactivation of Bcr/Abl and downstream targets (e.g., STAT5 and CRKL), as well as increased reactive oxygen species (ROS) generation and DNA damage (γH2A.X). The latter events and cell death were significantly attenuated by free radical scavengers (TBAP). Increased lethality was also observed in primary CD34+ cells from patients with CML, but not in normal CD34+ cells. Finally, minimally active vorinostat or SNDX275 doses markedly increased KW2449 antitumor effects and significantly prolonged the survival of murine xenografts bearing IM-resistant ALL cells (BV173/E255K).Conclusions: HDACIs increase KW-2449 lethality in Bcr/Abl+ cells in association with inhibition of Bcr/Abl, generation of ROS, and induction of DNA damage. This strategy preferentially targets primary Bcr/Abl+ hematopoietic cells and exhibits enhanced in vivo activity. Combining KW-2449 with HDACIs warrants attention in IM-resistant Bcr/Abl+ leukemias. Clin Cancer Res; 17(10); 3219–32. ©2011 AACR.

A 45-year-old woman presented to our clinic in July 2019 for evaluation of intermittent fever, rigors, diaphoresis, malaise, and urinary symptoms of frequency and urgency of 5 days’ duration. Her history was notable for Graves disease after total thyroidectomy 8 months previously after failed medical management, with no neck swelling or pain at present; an incidentally discovered and resected papillary thyroid microcarcinoma; and hypertension. A reconciled medication list included levothyroxine (125 μg/d), sertraline (100 mg/d), amphetamine-dextroamphetamine (20 mg/d), propranolol (40 mg twice daily), selenium (200 μg/d), and biotin (10 mg/d). She reported no relevant family history or sick contacts, but she may have had tick exposure. Physical examination revealed a temperature of 39.4 °C, heart rate of 64 beats/min, blood pressure of 98/56 mm Hg, weight of 85 kg, exophthalmos and lagophthalmos, and healed Kocher incision with no neck masses or tenderness. Abdominal examination revealed mild suprapubic tenderness. The differential diagnosis included infection (urinary tract infection [UTI], viral syndrome, tick-borne illness) and hyperthyroidism in the setting of ongoing levothyroxine therapy and her history of Graves disease. Subsequent laboratory studies revealed the following (reference ranges provided parenthetically): hemoglobin, 10.7 g/dL (11.6 to 15.0 g/dL); white blood cell count, 16.7 × 10(9)/L (3.4 to 9.6 × 10(9)/L); creatinine, 0.91 mg/dL (0.59 to 1.04 mg/dL); 2 sets of blood cultures with negative results; urine culture growing Escherichia coli, greater than 100,000 colony-forming units per milliliter; and negative results on a tick-borne pathogen panel including Lyme disease serology. Chest radiography revealed no abnormalities. Thyroid function testing (TFT) revealed the following: thyrotropin, 0.01 mIU/L (0.3 to 4.2 mIU/L); free thyroxine (fT4), 1.3 ng/dL (0.9 to 1.7 ng/dL); and free triiodothyronine (fT3) 2.4 pg/mL (2.8 to 4.4 pg/mL). Antimicrobial therapy was initiated for a UTI.

BACKGROUND Due to the volume of COVID-19-related misinformation exceeding the capabilities of fact checkers, automated and web-based approaches can provide effective deterrents to online misinformation. Despite the progress of initial, rapid interventions, the volume of COVID-19-related misinformation remains immense and continues to overwhelm fact checkers. OBJECTIVE Improvement in automated and machine-learned methods for infodemic response. METHODS Machine learning was used to evaluate whether training a machine learning model on only COVID-19-related fact-checked data, only on general fact-checked data, or on both would result in the highest model performance. Fact-checked, ‘false’ content was combined with programmatically-retrieved ‘true’ content to create a COVID-19-related labeled misinformation dataset with ~7,000 entries. 20,000 votes were crowdsourced to human label this dataset. RESULTS We found that although inclusion of COVID-19 misinformation data maintained or improved model performance, the best-performing model tested used a combination of general-topic and COVID-19-topic content. Our Bi-LSTM model trained on COVID-19 specific data achieved an internal validation accuracy of 93% and external validation accuracy of 75%, confirming the utility of our model. A crucial contribution of our study is that we were able to build a combined model that outperformed human votes of misinformation. Specifically, when we considered outputs where the machine learning model agreed with human votes, we achieved an accuracy of 90%, which outperformed human votes alone (accuracy of 73%). CONCLUSIONS General-topic content may supplement limited amounts of specific-topic content in low-data situations (e.g., future pandemics) to increase accuracy. Achieving an external validation accuracy of 75% with a Bi-LSTM shows that machine learning can produce much better-than-random results for the difficult task of classifying the veracity of COVID-19 content. The 90% accuracy on a “high-confidence” subsection comprising 58.7% of the dataset (when combining machine learned and human labels) suggests that even suboptimal machine learned labels can be augmented with crowdsourced votes to improve accuracy above human-only levels. These results support the utility of supervised machine learning to deter and combat future health-related disinformation.

Background The volume of COVID-19–related misinformation has long exceeded the resources available to fact checkers to effectively mitigate its ill effects. Automated and web-based approaches can provide effective deterrents to online misinformation. Machine learning–based methods have achieved robust performance on text classification tasks, including potentially low-quality-news credibility assessment. Despite the progress of initial, rapid interventions, the enormity of COVID-19–related misinformation continues to overwhelm fact checkers. Therefore, improvement in automated and machine-learned methods for an infodemic response is urgently needed. Objective The aim of this study was to achieve improvement in automated and machine-learned methods for an infodemic response. Methods We evaluated three strategies for training a machine-learning model to determine the highest model performance: (1) COVID-19–related fact-checked data only, (2) general fact-checked data only, and (3) combined COVID-19 and general fact-checked data. We created two COVID-19–related misinformation data sets from fact-checked “false” content combined with programmatically retrieved “true” content. The first set contained ~7000 entries from July to August 2020, and the second contained ~31,000 entries from January 2020 to June 2022. We crowdsourced 31,441 votes to human label the first data set. Results The models achieved an accuracy of 96.55% and 94.56% on the first and second external validation data set, respectively. Our best-performing model was developed using COVID-19–specific content. We were able to successfully develop combined models that outperformed human votes of misinformation. Specifically, when we blended our model predictions with human votes, the highest accuracy we achieved on the first external validation data set was 99.1%. When we considered outputs where the machine-learning model agreed with human votes, we achieved accuracies up to 98.59% on the first validation data set. This outperformed human votes alone with an accuracy of only 73%. Conclusions External validation accuracies of 96.55% and 94.56% are evidence that machine learning can produce superior results for the difficult task of classifying the veracity of COVID-19 content. Pretrained language models performed best when fine-tuned on a topic-specific data set, while other models achieved their best accuracy when fine-tuned on a combination of topic-specific and general-topic data sets. Crucially, our study found that blended models, trained/fine-tuned on general-topic content with crowdsourced data, improved our models’ accuracies up to 99.7%. The successful use of crowdsourced data can increase the accuracy of models in situations when expert-labeled data are scarce. The 98.59% accuracy on a “high-confidence” subsection comprised of machine-learned and human labels suggests that crowdsourced votes can optimize machine-learned labels to improve accuracy above human-only levels. These results support the utility of supervised machine learning to deter and combat future health-related disinformation.

Background Patients with type 2 diabetes mellitus are at an increased risk of adverse cardiovascular events compared to those without diabetes. The timing, relative to disease onset, and degree of glycemic control that reduces the risk of adverse cardiovascular events remains uncertain. Coronary microvascular dysfunction is prevalent in patients with type 2 diabetes mellitus and is linked to adverse cardiovascular events. We assessed the association between endothelial-dependent and endothelial-independent coronary microvascular dysfunction and glycemic control in patients presenting with chest pain and nonobstructive coronary disease at angiography. Methods Patients presenting with chest pain and found to have non-obstructive CAD (stenosis 140 mg/dL was significantly associated with an abnormal CFRAdn Ratio, 4.28 (1.43–12.81). Conclusion Poor glycemic control is associated with coronary microvascular dysfunction amongst female diabetics presenting with chest pain and non-obstructive CAD. These findings highlight the importance of sex specific risk stratification models and treatment strategies when managing cardiovascular risk amongst diabetics. Further studies are required to identify additional risk prevention tools and therapies targeting microvascular dysfunction as an integrated index of cardiovascular risk. Electronic supplementary material The online version of this article (10.1186/s12933-019-0833-1) contains supplementary material, which is available to authorized users.

To our knowledge, natural history has not been reported for cardiac sarcoidosis (CS) diagnosed by pathologic evaluation of the apical core at left ventricular assist device (LVAD) implantation or cardiac transplantation. We retrospectively identified 232 consecutive patients meeting CS criteria. Of these patients, 54 were diagnosed by pathologic confirmation of CS, 10 after evaluation of the apical core (LVAD implant) or explanted heart (transplant). We compared clinical characteristics at initial evaluation and outcomes for these 10 patients with those of 10 patients with known CS before LVAD implant/transplant. In the study group, five patients (50%) had confirmed extracardiac sarcoidosis before LVAD implant/transplant; five had not been diagnosed with sarcoidosis. Mean (standard deviation) left ventricular ejection fraction at initial evaluation was 23% (16%), and left ventricular end-diastolic dimension was 61 (10) mm. Four patients died during follow-up; however, no survival difference was found for the 10 patients diagnosed incidentally and the group with a previous diagnosis or institutional LVAD/transplant cohorts. Patients diagnosed with CS on pathological examination of the apical core/explanted heart may have severe dilated cardiomyopathy as the initial presentation. Outcomes for patients with CS after advanced heart failure therapies may be comparable with those of non-CS patients.

Sarcoidosis is a multisystem inflammatory condition with occasional cardiac involvement (CS), which may be associated with risk of venous thromboembolism (VTE). As data on VTE in CS are sparse and corticosteroid therapy has not been previously examined, we aim to determine the association between CS, corticosteroid treatment for CS, and VTE. Patients referred to our institution with concern for sarcoidosis and underwent a positron emission tomography (PET) scan were retrospectively assessed. Chi-squared and multivariate regression analyses were conducted to determine the association between a diagnosis of sarcoidosis, CS, corticosteroid use, and VTE events. Six hundred and forty nine patients were split into 3 categories: 235 with no sarcoidosis (NS), 91 with extra-cardiac sarcoidosis only (ECS), and 323 with CS (isolated CS and/or CS with extra cardiac sarcoid). Thirty nine CS, 7 ECS, and 9 NS patients developed PE while 44 CS, 3 ECS, and 18 NS patients developed DVT. On multivariate regression, neither CS nor ECS was an independent risk factor for VTE (p0.05) but corticosteroid use was independently associated with VTE (HR 3.06, p = 0.007 for PE, HR 6.21, p0.0001 for DVT). On logistic regression analysis, corticosteroid dose was found to be independently associated with both PE (p = 0.001) and DVT (p = 0.007). Optimal threshold for defining VTE risk with corticosteroid therapy was a prednisone-equivalent dose of 17.5 mg. In conclusion, contrary to previous studies, this current study found that neither sarcoidosis nor CS is an independent risk factor for VTE. Rather, corticosteroid therapy was associated with an increased risk of VTE.

Background Sarcoidosis is an infiltrative inflammatory condition affecting multiple organs, with cardiac involvement designated as cardiac sarcoidosis (CS). It has been proposed that inflammatory conditions like sarcoid increase the risk of venous thromboembolism (VTE), defined as pulmonary embolism (PE) and deep vein thrombosis (DVT) due to the hypercoagulable environment created by inflammation. Purpose Although previous studies have demonstrated an association with sarcoidosis and VTE, these studies failed to account for steroid use (crucial for sarcoid treatment) as an important confounder. Also, no major studies have been done previously assessing the risk of VTE in CS specifically. The objective of this investigation is to determine the association between CS, steroid treatment for CS, and VTE. Methods Patients referred to our institution with concern for sarcoid/CS were retrospectively assessed. Specific variables of interest including general baseline characteristics and those specific to CS were analyzed for their association with VTE development. Results Using Heart Rhythm Society guidelines, 649 patients were split into three categories: 235 with no sarcoid (NS), 91 with extra-cardiac sarcoid (ECS) only, and 323 with CS. In univariate analysis, 39 (12%) CS patients developed a PE vs 9 (4%) NS patients (OR 3.44, p=0.0003) and 44 (14%) CS patients developed DVT vs 18 (8%) NS patients (OR 1.90, p=0.02). In multivariate regression analysis however, neither CS nor ECS was an independent risk factor for VTE (p>0.05) but steroid use was a strong predictor of VTE (HR 3.12, p=0.007 for PE, HR 6.17, p17.5 mg daily on a receiver operating characteristic curve). Conclusion Contrary to previous studies, the current study found that neither sarcoidosis nor CS is an independent risk factor for VTE. Rather, steroid therapy for CS treatment leads to an increased prevalence of VTE, specifically at a dose above 17.5 mg daily. More research is required to clarify this relationship and assess the importance of steroid-sparing immunosuppressive therapy and potentially VTE prophylaxis in CS management. Steroid use and time to PE/DVT Funding Acknowledgement Type of funding source: None

Background Histologic evidence is required for a definitive diagnosis of cardiac sarcoidosis (CS) by published guidelines; however, the sporadic nature of the disease may produce false negative biopsy results, causing CS to be underdiagnosed. We sought to establish a clinical category of CS absent histologic findings. Methods Patients evaluated for CS were stratified into 3 groups: probable CS and definite CS based on Heart Rhythm Society (HRS) criteria and presumed CS, ie, patients without any histologic evidence of sarcoidosis, but with unexplained high-grade atrioventricular block or ventricular arrhythmia and findings suggestive of CS on either cardiac magnetic resonance imaging or positron emission tomography. The primary end point was hospitalization-free and overall survival at 10 years. Results A total of 383 patients were included in the study: 59, definite CS; 223, probable CS; and 101, presumed CS (62, isolated CS and 39, systemic CS). Compared with patients meeting HRS criteria for CS, patients with presumed CS had lower odds of New York Heart Association class III or IV symptoms (odds ratio [OR], 0.44 [95% CI, 0.23–0.83]; P = .01) but greater odds of previous ventricular tachycardia (OR, 2.4 [95% CI, 1.4–4.0]; P = .001) or history of resuscitated sudden cardiac arrest (OR, 2.9 [95% CI, 1.0–8.6]; P = .05). Hospitalization-free and overall survival were similar among groups (P = .51 and P = .71, respectively). Conclusions Clinical categorization of patients with presumed CS identified a high-risk cohort comparable to patients with histologic evidence of disease, although caution should be exercised in reaching this diagnosis without paying due diligence to the differential diagnosis.

A 25-year-old Caucasian American woman without significant medical history presented to the travel clinic with a 1-week history of worsening diarrhea and bloating. She had recently returned from an 8-month trip to Ethiopia, where she worked as a Peace Corps volunteer. While in Ethiopia, she resided

Background Cardiac sarcoidosis (CS) is an infiltrative inflammatory condition defined by infiltration of noncaseating granulomas into the heart. Based on the location of sarcoid lesion involvement, patients can present with symptoms of congestive heart failure, arrhythmias, and even sudden cardiac death. Purpose Diagnosis of CS has been somewhat challenging, with the Heart Rhythm Society (HRS) and Japanese Ministry of Health and Welfare (JMHW) being the 2 widely accepted diagnostic guidelines. Endomyocardial biopsy is the gold standard to prove definite CS but has a low sensitivity. Imaging studies have been helpful as non-invasive methods to diagnose probable CS but these can be logistically difficult and expensive. Thus, investigating for laboratory biomarkers that can act as both diagnostic and prognostic can be crucial in how we diagnose and manage CS in the future. Methods Patients meeting HRS for CS were evaluated at a single institution (n=217). Biomarkers of interest included angiotensin-converting enzyme (ACE), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), N-terminal pro B-type natriuretic peptide (NT-proBNP), troponin-T, 1,25 dihydroxyvitamin D (1,25-OHVit-D), and creatinine. Biomarkers were stratified by clinical variables of interest and their association with prognosis was examined. The primary endpoint was LVAD implantation, transplantation, or death. Results Mean values on presentation were: ACE 32.9±28, ESR 12±13, CRP 7.4±19, NT-proBNP 1630±2923, Troponin-T 0.03±0.1, 1,25-OHVit-D 55.5±20, and creatinine 1.12±0.3. None of the biomarkers differed by sex, definite or probable CS, or a history of immunosuppression. ACE levels were associated with the presence of cardiac fibrosis on cardiac MRI (mean difference 14.7, p=0.032). Troponin-T (p=0.006; HR 1.06 per 0.01 ng/mL), NT-proBNP (p=0.0003; HR 1.31 per 1,000 pg/mL), and creatinine (p=0.01; HR 4.02 per mg/dL) were each associated with the primary endpoint (52/217 patients). Biomarkers associated with long term outcomes in patients with cardiac sarcoidosis Biomarker Hazard ratio P value Troponin-T 1.06 (1.02–1.11)* 0.006 NT-pro BNP 1.31 (1.15–1.48)** 0.0003 Creatinine 4.02 (1.41–9.94)*** 0.01 *Per 0.01 ng/mL change; 99th percentile upper reference limit Conclusion Troponin-T, NT-proBNP, and creatinine at presentation predict outcomes in patients with CS. Further investigation on the utility of biomarkers for assessment of disease activity and treatment response is warranted.

Background Patients with type 2 diabetes are at an increased risk of cardiovascular events compared to individuals without diabetes. The role glycemic control plays in reducing cardiovascular risk remains uncertain. Coronary microvascular dysfunction (CMD) is more frequent in women compared to men, is prevalent in patients with type 2 diabetes and is linked to adverse cardiovascular events. We compared the association between CMD and glycemic control across sexes in patients with chest pain and non-obstructive coronary artery disease (CAD). Methods Patients with chest pain who were found to have non-obstructive CAD (stenosis Results Between 1993 and 2012, 1,469 patients (mean age 50.4 years, 35% male) underwent coronary angiography and invasive testing for CMD, of which 129 (8.8%) had type 2 diabetes. Fifty one (39.5%) had an abnormal %ΔCBFAch and 49 (38.0%) had an abnormal CFRAdn. Conventional cardiovascular risk factors did not vary significantly between groups. Females with an abnormal CFRAdn or abnormal %ΔCBFAch had a significantly higher HbA1c compared to those with a normal CFRAdn or %ΔCBFAch respectively: HbA1c % (standard deviation) 7.4 (2.1) vs. 6.5 (1.1), p=0.035 and 7.3 (1.9) vs. 6.4 (1.2), p=0.022, respectively. Females with an abnormal CFRAdn had significantly higher fasting serum glucose concentrations compared to those with a normal CFRAdn: fasting serum glucose mg/dL (standard deviation) 144.4 (55.6) vs. 121.9 (28.1), p=0.035. These effects were not observed in men. Amongst female diabetics, a higher HbA1c was significantly associated with any CMD after adjusting for covariates: odds ratio (95% confidence interval) 1.69 (1.01 – 2.86) p=0.049; and a fasting serum glucose >140 mg/dL was significantly associated with an abnormal CFRAdn, 4.28 (1.43–12.81). Conclusion Poor glycemic control is associated with CMD in females with diabete who present with chest pain and non-obstructive CAD. These findings highlight the importance of sex-specific risk stratification models and treatment strategies when managing cardiovascular risk in diabetics. Acknowledgement/Funding Mayo Foundation

Both elevated serum uric acid (SUA) and peripheral endothelial dysfunction (PED) are associated independently with cardiovascular disease (CVD). However, the association between SUA and PED is yet to be established. We hypothesized that high normal range of SUA is associated with PED.We performed a retrospective cross-sectional analysis of patients who were referred to Mayo Clinic between 2006 and 2014 for routine cardiovascular evaluation and who underwent evaluation of Reactive Hyperemia Peripheral Arterial Tonometry (index2 consistent with PED). A high UA was defined as ≥5 mg/dL, in keeping with previous studies evaluating the link between SUA and CVD outcomes.One hundred forty patients were included (mean age 50.7 ± 12.9 years, 86 (61.4%) female). Twenty four patients (17.1%) had pre-existing CVD (8 (9.3%) in females). Thirty patients (21.6%) had a Framingham score 10% (8 (9.4%) in females). Fifty eight (41.4%) had PED and 77 (55.0%) had an elevated SUA. SUA levels were higher in patients with PED compared to those without (5.5 ± 1.4 vs 4.8 ± 1.2 mg/dL; p = 0.004). In an univariate analysis, elevated SUA levels were associated with PED (Odds Ratio (OR): 2.7; 95% confidence interval [CI] 1.33-5.48; p = 0.005). In a multivariate analysis adjusting for age, sex, presence of obstructive CVD and Framingham score10, elevated SUA levels were associated with PED (OR 2.45; 95% CI 1.08-5.52; p = 0.031). After stratifying by sex, this association persisted in females only.High normal SUA levels are associated with PED in women who are otherwise at low risk for CVD. Thus, SUA is a promising circulating biomarker that could be used to assist in risk stratification in female patients with chest pain and/or those undergoing evaluation of CVD risk.

Current Heart Rhythm Society (HRS) guidelines regarding the diagnosis of cardiac sarcoidosis (CS) require histologic evidence of sarcoidosis. Due to limitations of endomyocardial biopsy (EMB) and variable extra-cardiac involvement, CS may be under-diagnosed. Patients evaluated for CS (n=277) were

Although most commonly diagnosed via endomyocardial biopsy, a diagnosis of definite cardiac sarcoidosis (CS) can be achieved through pathologic evaluation of apical cores at LVAD placement or on explanted hearts at cardiac transplantation. However, patients diagnosed at the time of advanced heart

Purpose: The purpose of this study was to determine whether histone deacetylase (HDAC) inhibitors (HDACI) such as vorinostat or entinostat (SNDX-275) could increase the lethality of the dual Bcr/Abl-Aurora kinase inhibitor KW-2449 in various Bcr/Abl+ human leukemia cells, including those resistant to imatinib mesylate (IM). Experimental Design: Bcr/Abl+ chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) cells, including those resistant to IM (T315I, E255K), were exposed to KW-2449 in the presence or absence of vorinostat or SNDX-275, after which apoptosis and effects on signaling pathways were examined. In vivo studies combining HDACIs and KW2449 were carried out by using a systemic IM-resistant ALL xenograft model. Results: Coadministration of HDACIs synergistically increased KW-2449 lethality in vitro in multiple CML and Ph+ ALL cell types including human IM resistant cells (e.g., BV-173/E255K and Adult/T315I). Combined treatment resulted in inactivation of Bcr/Abl and downstream targets (e.g., STAT5 and CRKL), as well as increased reactive oxygen species (ROS) generation and DNA damage (γH2A.X). The latter events and cell death were significantly attenuated by free radical scavengers (TBAP). Increased lethality was also observed in primary CD34+ cells from patients with CML, but not in normal CD34+ cells. Finally, minimally active vorinostat or SNDX275 doses markedly increased KW2449 antitumor effects and significantly prolonged the survival of murine xenografts bearing IM-resistant ALL cells (BV173/E255K). Conclusions: HDACIs increase KW-2449 lethality in Bcr/Abl+ cells in association with inhibition of Bcr/Abl, generation of ROS, and induction of DNA damage. This strategy preferentially targets primary Bcr/Abl+ hematopoietic cells and exhibits enhanced in vivo activity. Combining KW-2449 with HDACIs warrants attention in IM-resistant Bcr/Abl+ leukemias. Clin Cancer Res; 17(10); 3219–32. ©2011 AACR.