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Accurate RNA structure models are crucial for designing small molecule ligands that modulate their functions. This study assesses six standalone RNA 3D structure prediction methods-DeepFoldRNA, RhoFold, BRiQ, FARFAR2, SimRNA and Vfold2, excluding web-based tools due to intellectual property concerns. We focus on reproducing the RNA structure existing in RNA-small molecule complexes, particularly on the ability to model ligand binding sites. Using a comprehensive set of RNA structures from the PDB, which includes diverse structural elements, we found that machine learning (ML)-based methods effectively predict global RNA folds but are less accurate with local interactions. Conversely, non-ML-based methods demonstrate higher precision in modeling intramolecular interactions, particularly with secondary structure restraints. Importantly, ligand-binding site accuracy can remain sufficiently high for practical use, even if the overall model quality is not optimal. With the recent release of AlphaFold 3, we included this advanced method in our tests. Benchmark subsets containing new structures, not used in the training of the tested ML methods, show that AlphaFold 3's performance was comparable to other ML-based methods, albeit with some challenges in accurately modeling ligand binding sites. This study underscores the importance of enhancing binding site prediction accuracy and the challenges in modeling RNA-ligand interactions accurately., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: In recent years, a very close relationship between miRNA and cardiovascular diseases has been found. RAH and T2DM are accompanied by a change in the microRNA expression spectrum., Objectives: This study aimed to evaluate the clinical characteristics and expression of selected microRNAs in patients with idiopathic RAH and T2DM., Patients and Methods: A total of 115 patients with RAH were included in this study. Among them were 53 patients (46.09%) with T2DM. miRNA levels were determined using quantitative real-time polymerase chain reaction. The expression of the examined genes was calculated from the formula RQ = 2 -ΔΔCT ., Results: Analysis using the Mann-Whitney U test showed a statistically significant ( p < 0.05) difference in the expression of MIR1-1 ( p = 0.031) and MIR195 ( p = 0.042) associated with the occurrence of T2DM in the subjects. The value of MIR1-1 gene expression was statistically significantly higher in patients with T2DM (median: 0.352; mean: 0.386; standard deviation: 0.923) compared to patients without T2DM (median: 0.147; mean: -0.02; standard deviation: 0.824). The value of MIR195 gene expression was statistically significantly higher in patients with T2DM (median: 0.389, mean: 0.442; standard deviation: 0.819) compared to patients without T2DM (median: -0.027; mean: 0.08; standard deviation: 0.942)., Conclusions: The values of MIR1-1 and MIR195 gene expression were statistically significantly higher in patients with RAH and T2DM compared to patients with RAH and without T2DM. Further studies are necessary to precisely clarify the roles of miRNAs in patients with RAH and T2DM. They should demonstrate the utility of these genetic markers in clinical practice.

Background: Despite its benefits, oral anticoagulant (OAC) therapy in patients with atrial fibrillation (AF) is associated with hemorrhagic complications., Aims: We aimed to evaluate clinical characteristics of AF patients at high risk of bleeding and the frequency of OAC use as well as identify factors that predict nonuse of OACs in these patients., Methods: Consecutive AF patients hospitalized for urgent or planned reasons in cardiac centers were prospectively included in the registry in 2019. Patients with HAS-BLED ≥3 (high HAS-BLED group) were assumed to have a high risk of bleeding., Results: Among 3598 patients enrolled in the study, 29.2% were at high risk of bleeding (44.7% female; median [Q1-Q3] age 72 [65-81], CHA2DS2-VASc score 5 [4-6], HAS-BLED 3 [3-4]). In this group, 14.5% of patients did not receive OACs, 68% received NOACs, and 17.5% VKAs. In multivariable analysis, the independent predictors of nonuse of oral OACs were as follows: creatinine level (odds ratio [OR], 1.441; 95% confidence interval [CI], 1.174-1.768; P <0.001), a history of gastrointestinal bleeding (OR, 2.918; 95% CI, 1.395-6.103; P = 0.004), malignant neoplasm (OR, 3.127; 95% CI, 1.332-7.343; P = 0.009), and a history of strokes or transient ischemic attacks (OR, 0.327; 95% CI, 0.166-0.642; P = 0.001)., Conclusions: OACs were used much less frequently in the group with a high HAS-BLED score than in the group with a low score. Independent predictors of nonuse of OACs were creatinine levels, a history of gastrointestinal bleeding, and malignant neoplasms. A history of stroke or transient ischemic attack increased the chances of receiving therapy.

Background: According to the present guidelines, transesophageal echocardiography (TEE) before scheduled catheter ablation (CA) for atrial arrhythmias (atrial fibrillation [AF] or atrial flutter [AFL]) is not deemed obligatory for optimally anticoagulated patients. However, daily clinical practice significantly differs from the recommendations., Aims: We aimed to identify transthoracic echocardiographic parameters that could be useful in identifying patients without left atrial thrombus (LAT), which makes it possible to avoid unnecessary TEE before scheduled CA., Methods: This is a sub-analysis of a multicenter, prospective, observational study - the LATTEE registry. A total of 1346 patients referred for TEE before scheduled CA of AF/AFL were included., Results: LAT was present in 44 patients (3.3%) and absent in the remaining 1302, who were younger, more likely to have paroxysmal AF, and displayed sinus rhythm during TEE. Additionally, they exhibited a lower incidence of heart failure, diabetes, systemic connective tissue disease, and chronic obstructive pulmonary disease. Furthermore, they had a lower CHA2DS2-VASc score and a higher prevalence of direct oral anticoagulants. Echocardiographic parameters, including left ventricular ejection fraction (LVEF) >65%, left atrial diameter (LAD) <40 mm, left atrial area (LAA) <20 cm2, left atrial volume (LAV) <113 ml, and left atrial volume index (LAVI) <51 ml/m2, demonstrated 100% sensitivity and 100% negative predictive value for the absence of LAT and were met by 417 patients. Additional echocardiographic indices: LVEF/LAD ≥1.4, LVEF/LAVI ≥1.6, and LVEF/LAA ≥2.7 identified 57 additional patients, bringing the total of predicted LAT-free patients to 474 (35%)., Conclusions: Simple echocardiographic parameters could help identify individuals for whom TEE could be safely omitted before elective CA due to atrial arrhythmias.

Aims: Transoesophageal echocardiography (TOE) is often performed before catheter ablation or cardioversion to rule out the presence of left atrial appendage thrombus (LAT) in patients on chronic oral anticoagulation (OAC), despite associated discomfort. A machine learning model [LAT-artificial intelligence (AI)] was developed to predict the presence of LAT based on clinical and transthoracic echocardiography (TTE) features., Methods and Results: Data from a 13-site prospective registry of patients who underwent TOE before cardioversion or catheter ablation were used. LAT-AI was trained to predict LAT using data from 12 sites (n = 2827) and tested externally in patients on chronic OAC from two sites (n = 1284). Areas under the receiver operating characteristic curve (AUC) of LAT-AI were compared with that of left ventricular ejection fraction (LVEF) and CHA2DS2-VASc score. A decision threshold allowing for a 99% negative predictive value was defined in the development cohort. A protocol where TOE in patients on chronic OAC is performed depending on the LAT-AI score was validated in the external cohort. In the external testing cohort, LAT was found in 5.5% of patients. LAT-AI achieved an AUC of 0.85 [95% confidence interval (CI): 0.82-0.89], outperforming LVEF (0.81, 95% CI 0.76-0.86, P < .0001) and CHA2DS2-VASc score (0.69, 95% CI: 0.63-0.7, P < .0001) in the entire external cohort. Based on the proposed protocol, 40% of patients on chronic OAC from the external cohort would safely avoid TOE., Conclusion: LAT-AI allows accurate prediction of LAT. A LAT-AI-based protocol could be used to guide the decision to perform TOE despite chronic OAC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The determination of the selected antihypertensive drugs in human plasma samples with the novel solvent front position extraction (SFPE) technique is presented. The SFPE procedure combined with LC-MS/MS analysis was used for the first time to prepare a clinical sample containing the drugs mentioned above from different therapeutic groups. The effectiveness of our approach was compared with the precipitation method. The latter technique is usually used to prepare biological samples in routine laboratories. During the experiments, the substances of interest and the internal standard were separated from other matrix components using a prototype horizontal chamber for thin-layer chromatography/high-performance thin-layer chromatography (TLC/HPTLC) with a moving pipette powered by a 3D mechanism, which distributed the solvent on the adsorbent layer. Detection of the six antihypertensive drugs was performed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring (MRM) mode. Results obtained by SFPE were very satisfactory (linearity R 2  ≥ 0.981; %RSD ≤ 6%; LOD and LOQ were in the range of 0.06-9.78 ng/mL and 0.17-29.64 ng/mL, respectively). The recovery was in the range of 79.88-120.36%. Intra-day and inter-day precision had a percentage coefficient of variation (CV) in the range of 1.10-9.74%. The procedure is simple and highly effective. It includes the automation of TLC chromatogram development, which significantly reduced the number of manual operations performed, the time of sample preparation and solvent consumption.

Background: Data on sex differences in terms of action of antiarrhythmic agents (AADs) are limited. This study aimed to evaluate the clinical profile of patients with atrial fibrillation (AF), and efficacy and safety of AADs used for pharmacological cardioversion (PCV) of AF., Methods: This research was a sub-analysis of the retrospective multicenter Cardioversion with ANTazoline II (CANT) registry, which comprised 1365 patients with short-duration AF referred for urgent PCV with the use of AAD. Patients were categorized according to and compared in terms of clinical parameters and PCV outcomes. The primary endpoint was return of sinus rhythm within 12 hours after drug infusion, and the composite safety endpoint involved bradycardia <45 bpm, hypotension, syncope, or death., Results: The sex distribution of patients qualified for PCV was even (men, n = 725; 53.1%). Females were older and more symptomatic and had higher CHA2DS2-VASc scores, higher prevalence of tachyarrhythmia, and higher use of chronic anticoagulation. The overall efficacy (71.4% vs. 70.1%; P = 0.59) and safety (5.2% vs. 4.6%; P = 0.60) of PCV was comparable in men and women. Amiodarone (68.3% vs. 65.9%; P = 0.66) and antazoline (77.1% vs. 80.0%; P = 0.19) had similar efficacy in men and women, but propafenone had a lower rate of rhythm conversion in men (64.7% vs. 79.3%; P = 0.046). None of the assessed AADs differed in terms of safety profile in both sexes., Conclusion: Female patients with AF have different clinical profiles but similar efficacy and safety of AADs as compared to male participants. Propafenone has significantly lower efficacy in men, which requires further investigation.

Aims: The aim of the study was to evaluate the prevalence of left atrial thrombus (LAT) on transoesophageal echocardiography (TOE) in patients with atrial fibrillation or atrial flutter (AF/AFl) with reference to the presence of heart failure (HF) and its subtypes., Methods and Results: The research is a sub-study of the multicentre, prospective, observational Left Atrial Thrombus on Transoesophageal Echocardiography (LATTEE) registry, which comprised 3109 consecutive patients with AF/AFl undergoing TOE prior to direct current cardioversion or catheter ablation. TOE parameters, including presence of LAT, were compared between patients with and without HF and across different subtypes of HF, including HF with preserved (HFpEF), mid-range (HFmrEF), and reduced ejection fraction (HFrEF). HF was diagnosed in 1336 patients (43%). HF patients had higher prevalence of LAT than non-HF patients (12.8% vs. 4.4%; P < 0.001). LAT presence increased with more advanced type of systolic dysfunction (HFpEF vs. HFmrEF vs. HFrEF: 7.4% vs. 10.5% vs. 20.3%; P < 0.001). Univariate analysis revealed that HFrEF (odds ratio [OR] 4.13; 95% confidence interval [95% CI]: 3.13-5.46), but not HFmrEF or HFpEF, was associated with the presence of LAT. Multivariable logistic regression indicated that lower left ventricular ejection fraction (OR per 1%: 0.94; 95% CI 0.93-0.95) was an independent predictor of LAT formation. Receiver operator characteristic analysis showed LVEF ≤48% adequately predicted increased risk of LAT presence (area under the curve [AUC] 0.74; P < 0.0001)., Conclusion: The diagnosis of HFrEF, but neither HFmrEF nor HFpEF, confers a considerable risk of LAT presence despite widespread utilization of adequate anticoagulation., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: The left atrium appendage thrombus (LAAT) formation is a complex process. A CHA 2 DS 2 -VASc scale is an established tool for determining the thromboembolic risk and initiation of anticoagulation treatment in patients with atrial fibrillation or flutter (AF/AFL). We aimed to identify whether any transthoracic echocardiography (TTE) parameters could have an additional impact on LAAT detection., Methods: That is a sub-study of multicenter, prospective, observational study LATTEE (NCT03591627), which enrolled 3,109 consecutive patients with AF/AFL referred for transesophageal echocardiography (TEE) before cardioversion or ablation., Results: LAAT was diagnosed in 8.0% of patients. The univariate logistic regression analysis [based on pre-specified in the receiver operating characteristic (ROC) analysis cut-off values with AUC ≥ 0.7] identified left ventricular ejection fraction (LVEF) ≤ 48% and novel TTE parameters i.e., the ratios of LVEF and left atrial diameter (LAD) ≤ 1.1 (AUC 0.75; OR 5.64; 95% CI 4.03-7.9; p < 0.001), LVEF to left atrial area (LAA) ≤ 1.7 (AUC 0.75; OR 5.64; 95% CI 4.02-7.9; p < 0.001), and LVEF to indexed left atrial volume (LAVI) ≤ 1.1 (AUC 0.75, OR 6.77; 95% CI 4.25-10.8; p < 0.001) as significant predictors of LAAT. In a multivariate logistic regression analysis, LVEF/LAVI and LVEF/LAA maintained statistical significance. Calculating the accuracy of the abovementioned ratios according to the CHA 2 DS 2 -VASc scale values revealed their highest predictive power for LAAT in a setting with low thromboembolic risk., Conclusion: Novel TTE indices could help identify patients with increased probability of the LAAT, with particular applicability for patients at low thromboembolic risk., Competing Interests: Authors AK-C, BW-K, and MRK received honoraria for lectures from Bayer, Boehringer Ingelheim, and Pfizer, outside the submitted work. Author LD-S received speaker fees from Bayer, Boehringer Ingelheim, and Pfizer–outside the submitted work. Author KM-S received speaker fees from Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Novartis, and Servier–outside the submitted work. Author AT-K received speaker fees from Boehringer-Ingelheim–outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kaufmann, Wabich, Kapłon-Cieślicka, Gawałko, Budnik, Uziębło-Życzkowska, Krzesiński, Starzyk, Wożakowska-Kapłon, Wójcik, Błaszczyk, Hiczkiewicz, Budzianowski, Mizia-Stec, Wybraniec, Kosmalska, Fijałkowski, Szymańska, Dłużniewski, Haberka, Kucio, Michalski, Kupczyńska, Tomaszuk-Kazberuk, Wilk-Śledziewska, Wachnicka-Truty, Koziński, Burchardt and Daniłowicz-Szymanowicz.)

Background: Our aim was to assess the characteristics and to identify predictors of left atrial thrombus (LAT) in patients under age 65 with atrial fibrillation (AF) or atrial flutter (AFl)., Methods: We conducted a subanalysis of a multicenter, prospective, observational study [the LATTEE registry]. Consecutive AF/AFl patients referred for cardioversion or ablation were enrolled., Results: Of the 3,109 patients included in the study, 1,276 were under age 65 (41%). Compared to non-LAT patients, those with LAT ( n = 76) had higher CHA 2 DS 2 -VASc score ( p < 0.001), more frequently had non-paroxysmal AF/AFl ( p < 0.001), heart failure ( p < 0.001), history of diabetes mellitus ( p = 0.001), transient ischemic attack ( p = 0.04), coronary artery disease ( p = 0.02), and chronic kidney disease ( p < 0.001). The LAT patients were also more often smokers ( p = 0.004) and were more frequently treated with vitamin K antagonists (VKAs) ( p < 0.001). Transthoracic echocardiography revealed a higher left atrial area ( p < 0.001), lower left ventricular ejection fraction (LVEF) ( p < 0.001), and lower value of LA appendage emptying volume in LAT than in non-LAT patients ( p < 0.001). LVEF (OR 2.95; 95% CI: 1.32-6.59, p = 0.008), non-paroxysmal AF/AFl (OR 7.1; 95% CI: 2.05-24.63, p = 0.002) and treatment with VKAs (OR 4.92; 95% CI: 2.48-9.75, p < 0.001) were identified as independent predictors of LAT in younger patients., Conclusions: Our study, which focused on younger patients with AF/AFl, indicated substantial clinical and echocardiographic differences between participants with and without LAT. In the AF/AFl patients younger than age 65, the independent predictors of LAT included non-paroxysmal AF/AFl, lower LVEF, and treatment with VKAs., Competing Interests: Author AK-C honoraria for lectures from Bayer, Boehringer Ingelheim, Pfizer, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Uziȩbło-Życzkowska, Kapłon-Cieślicka, Gawałko, Budnik, Starzyk, Wożakowska-Kapłon, Daniłowicz-Szymanowicz, Kaufmann, Wójcik, Błaszczyk, Hiczkiewicz, Łojewska, Mizia-Stec, Wybraniec, Kosmalska, Fijałkowski, Szymańska, Gos, Haberka, Kucio, Michalski, Kupczyńska, Tomaszuk-Kazberuk, Wilk-Śledziewska, Wachnicka-Truty, Koziński, Burchardt and Krzesiński.)

Background: The aim of our study was to assess if patients with AF (atrial fibrillation) and a history of ischemic stroke (IS) excessively receive reduced doses of NOACs (non-vitamin K antagonist oral anticoagulants)., Methods: The Polish AF (POL-AF) registry is a prospective, observational, multicenter study, including patients with AF from 10 cardiology hospital centers. In this study we focused on patients with IS in their past., Results: Among 3999 patients enrolled in the POL-AF registry, 479 (12%) had a previous history of IS. Compared to patients without IS history, post-stroke subjects had a higher CHA 2 DS 2 -VASc score (median score 7 vs. 4, p < 0.05). Of these subjects, 439 (92%) had anticoagulation therapy, 83 (18.9%) were treated with a vitamin K antagonist (VKA), 135 (30.8%) with rivaroxaban, 112 (25.5%) with dabigatran, and 109 (24.8%) with apixaban. There were a significant number of patients after IS with reduced doses of NOACs (48.9% for rivaroxaban, 45.5% for dabigatran, and 36.7% for apixaban). In many cases, patients were prescribed reduced doses of NOACs without any indication for reduction (28.8% of rivaroxaban use, 56.9% of dabigatran use, and 60.0% of apixaban use-out of reduced dosage groups, p = 0.06)., Conclusions: A significant proportion of AF patients received reduced doses of NOAC after ischemic stroke in a sizeable number of cases, without indication for dose reduction.

An increased body mass index (BMI) is associated with a higher incidence of atrial fibrillation (AF) and a higher risk of thromboembolic complications in AF patients. The aim of this study was to investigate the effect of BMI on the risk of left atrial thrombi (LATs) in patients with nonvalvular AF/atrial flutter (AFl) (NV AF/AFl). Patients diagnosed with NVAF/AFl (between November 2018 and May 2020) were selected from the multicenter, prospective, observational Left Atrial Thrombus on Transesophageal Echocardiography (LATTEE) registry that included AF/AFl patients referred for cardioversion or ablation followed by transesophageal echocardiography. A total of 2816 AF/AFl patients (63.6% males; mean age 65.8 years; mean BMI 29.8 kg/m2) were included in the study. Two hundred and twenty-two of them (7.9%) had LATs. Compared with normal-weight patients, those with BMIs ≥ 25 kg/m2 more frequently presented clinical factors potentially provoking LATs, such as non-paroxysmal AF/AFl (p = 0.04), hypertension (p < 0.001), and diabetes (p < 0.001); had higher CHA2DS2 scores (p < 0.001); and had larger LA dimensions (LA diameter and LA area) (p < 0.001 for both parameters). On the other hand, they showed some features negatively related to thromboembolic risk; for example, they were younger (p < 0.001) and were more often male (p = 0.002). In addition, patients with abnormal BMIs were more likely to be smokers (p = 0.006) and to be treated with oral anticoagulants (p = 0.005). Despite these differences in the prevalence of thromboembolic risk factors, the incidence of LATs was not increased in patients with abnormal body weight (overweight and obese compared to normal-weight patients) in this large real-life cohort of AF/AFl patients. This is probably due to the balanced composition regarding the prevalence of positive and negative thromboembolic risk factors.

Background: Arginases play essential roles in metabolic pathways, determining the fitness of both immune and tumour cells. Along with the previously validated role of ARG1 in cancer, the particular significance of ARG2 as a therapeutic target has emerged as its levels correlate with malignant phenotype and poor prognosis. These observations unveil arginases, and specifically ARG2, as well-validated and promising therapeutic targets. OATD-02, a new boronic acid derivative, is the only dual inhibitor, which can address the benefits of pharmacological inhibition of arginase 1 and 2 in cancer., Methods: The inhibitory activity of OATD-02 was determined using recombinant ARG1 and ARG2, as well as in a cellular system using primary hepatocytes and macrophages. In vivo antitumor activity was determined in syngeneic models of colorectal and kidney carcinomas (CT26 and Renca, respectively), as well as in an ARG2-dependent xenograft model of leukaemia (K562)., Results: OATD-02 was shown to be a potent dual (ARG1/ARG2) arginase inhibitor with a cellular activity necessary for targeting ARG2. Compared to a reference inhibitor with predominant extracellular activity towards ARG1, we have shown improved and statistically significant antitumor efficacy in the CT26 model and an immunomodulatory effect reflected by Treg inhibition in the Renca model. Importantly, OATD-02 had a superior activity when combined with other immunotherapeutics. Finally, OATD-02 effectively inhibited the proliferation of human K562 leukemic cells both in vitro and in vivo., Conclusions: OATD-02 is a potent small-molecule arginase inhibitor with optimal drug-like properties, including PK/PD profile. Excellent activity against intracellular ARG2 significantly distinguishes OATD-02 from other arginase inhibitors. OATD-02 represents a very promising drug candidate for the combined treatment of tumours, and is the only pharmacological tool that can effectively address the benefits of ARG1/ARG2 inhibition. OATD-02 will enter clinical trials in cancer patients in 2022.

Introduction: Due to safety concerns about available antiarrhythmic drugs (AADs), reliable agents for termination of atrial fibrillation (AF) are requisite., Objectives: The aim of the study was to evaluate the efficacy and safety of antazoline, a first‑generation antihistamine, for cardioversion of recent‑onset AF in the setting of an emergency department., Patients and Methods: This multicenter, retrospective registry covered 1365 patients (median [interquartile range] age, 69.0 [61.0-76.0] years, 53.1% men) with new‑onset AF submitted to urgent pharmacological cardioversion. AAD allocation was performed by the attending physician: antazoline alone was utilized in 600 patients (44%), amiodarone in 287 (21%), propafenone in 150 (11%), and ≥2 AADs in 328 patients (24%). Antazoline in monotherapy or combination was administered to 897 patients (65.7%). Matched antazoline and nonantazoline groups were identified using propensity score matching (PSM, n = 330). The primary end point was return to sinus rhythm within 12 hours after initiation of the treatment., Results: Before PSM, antazoline alone was superior to amiodarone (78.3% vs 66.9%; relative risk [RR], 1.17; 95% CI, 1.07-1.28; P <0.001) and comparable to propafenone (78.3% vs 72.7%; RR, 1.08; 95% CI, 0.97-1.20; P = 0.14) in terms of rhythm conversion rate. In the post‑PSM population, the rhythm conversion rate was higher among patients receiving antazoline alone than in the nonantazoline group (84.2% vs 66.7%; RR, 1.26; 95% CI, 1.11-1.43; P <0.001), and the risk of adverse events was comparable (P = 0.2)., Conclusions: Antazoline appears to be an efficacious agent for termination of AF in real‑world setting. Randomized controlled trials are required to evaluate its safety in specific patient populations.

Hyperuricemia is associated with the risk of developing atrial fibrillation (AF) and heart failure. However, coexisting chronic kidney disease and certain cardiovascular drugs make it difficult to determine whether hyperuricemia is a risk factor or merely a marker of pathology. We retrieved data from the Polish Atrial Fibrillation (POL-AF) registry, which included consecutive patients hospitalized with AF from January to December, 2019. We included 829 patients (mean age: 72.7 ± 11.1 years) with data on serum uric acid (UA, mean: 6.56 ± 1.78 mg/dL) and estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2. We found that UA and ejection fraction (EF) were significantly correlated (r = −0.15, p < 0.05), but not EF and eGFR or eGFR and UA. A multiple regression analysis adjusted for age, body mass index, eGFR, and UA, showed that UA was significantly associated with a reduced EF (R2: 0.021; p < 0.001). The UA cut-off indicative of an EF < 40% was 6.69 mg/dL (AUC, area under the curve: 0.607; 95% CI: 0.554−0.660; p = 0.001). Among drugs known to effect UA concentrations, we found that only diuretics were used more frequently in patients with high UA (above the median) than in patients with low UA (77.5% vs. 67%, p < 0.001). Among patients that used diuretics, UA remained significantly correlated with EF. Thus, we showed that reduced EF was associated with UA in patients with AF and normal renal function, independent of eGFR and diuretic use.

Background: Atrial fibrillation (AF) and flutter (AFl) increase the risk of thromboembolism. The aim of the study was to assess the prevalence of left atrial thrombus (LAT) in AF/AFl in relation to oral anticoagulation (OAC). Methods: LATTEE (NCT03591627) was a multicenter, prospective, observational study enrolling consecutive patients with AF/AFl referred for transesophageal echocardiography before cardioversion or ablation. Results: Of 3109 patients enrolled, 88% were on chronic, 1.5% on transient OAC and 10% without OAC. Of patients on chronic OAC, 39% received rivaroxaban, 30% dabigatran, 14% apixaban and 18% vitamin K antagonists (VKA). Patients on apixaban were oldest, had the worst renal function and were highest in both bleeding and thromboembolic risk, and more often received reduced doses. Prevalence of LAT was 8.0% (7.3% on chronic OAC vs. 15% without OAC; p < 0.01). In patients on VKA, prevalence of LAT was doubled compared to patients on non-VKA-OACs (NOACs) (13% vs. 6.0%; p < 0.01), even after propensity score weighting (13% vs. 7.5%; p < 0.01). Prevalence of LAT in patients on apixaban was higher (9.8%) than in those on rivaroxaban (5.7%) and dabigatran (4.7%; p < 0.01 for both comparisons), however, not after propensity score weighting. Conclusions: The prevalence of LAT in AF is non-negligible even on chronic OAC. The risk of LAT seems higher on VKA compared to NOAC, and similar between different NOACs.

Pharmacological cardioversion (PCV) is commonly a primary option for termination of recent-onset atrial fibrillation (AF) in emergency departments (ED). This is a subanalysis of the CANT II study, evaluating the effectiveness and safety of antazoline in patients (n = 777) at three stages of chronic kidney disease (CKD): Group I > 60 mL/min (n = 531), Group II 45−59 mL/min (n = 149), and Group III < 45 mL/min (n = 97). Patients in Group III were older and with a higher prevalence of co-morbidities; however, we did not find statistically significant differences in the overall effectiveness of PCV in comparison with the other groups. In patients receiving amiodarone, the PCV success rate was similar in all the studied groups, but along with a renal function decline, it decreased in patients receiving antazoline (79.1 vs. 35%; p < 0.001), and it increased almost significantly in patients receiving propafenone (69.9 vs. 100%; p = 0.067). In patients in Group I, antazoline restored a sinus rhythm as effectively as propafenone and amiodarone; however, in patients in Group III, both antazoline and amiodarone became less effective in restoring a sinus rhythm than propafenone (p = 0.002 and p = 0.034, respectively). The rate of safety endpoint was the highest in patients in Group III (eGFR < 45 mL/min), and it was significantly higher than in patients in Groups I and II (p = 0.008 and p = 0.036, respectively). We did not observe antazoline-related adverse events in any of the studied groups of patients. This real-world registry analysis revealed a different influence of CKD on the effectiveness of individual drugs, and while propafenone and amiodarone maintained their AF termination efficacy, antazoline became significantly less effective in restoring sinus rhythm.

Solvent front position extraction procedure was used to prepare biological samples containing selected antihypertensive drugs (ramipril, lercanidipine, indapamide, valsartan, hydrochlorothiazide, perindopril, and nebivolol). Substances separated from the biological matrix components (bovine serum albumin) were quantified by means of liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Sample preparation process was performed with the use of a prototype horizontal chamber with a moving pipette driven by a 3D printer mechanism enabling a controlled eluent flow velocity. Application of this device was advantageous for simultaneous preparation of several samples for further quantitative analysis, with a synchronized reduction of manual operations and solvent consumption. Quantitative results obtained for the majority of the investigated antihypertensive drugs in a complex biological matrix were satisfactory. The values of the %RSD were around 5% for six of the seven substances (with the exception of indapamide). The method exhibits a suitable accuracy (the relative error percentage was below 10% for most drugs). The values of LOD and LOQ were in the range of 1.19 µg/L-8.53 µg/L and 3.61 µg/L-25.8 µg/L, respectively.

Background: Most atrial fibrillation (AF) patients are at high risk of thromboembolic, and the use of oral anticoagulants (OACs) is advised in such cases. The aim of the study was to evaluate the frequency at which OACs were used in patients with AF and high risk thromboembolic complications, and identify factors that result in OACs not being used in the researched group of patients., Methods: The prospective, multicenter and non-interventional POL-AF registry is a study that includes AF patients from ten Polish cardiology centers. They were consecutively hospitalized between January and December of 2019. All the patients in the study were of high stroke risk., Results: A total of 3614 patients with AF and high stroke risk were included. Among the total study population, 91.5% received OAC therapy; antiplatelet therapy was prescribed for 3.7% of patients, heparin for 2.7%, and 2.1% of patients did not receive any stroke prevention therapy. Independent predictors of no OAC prescription were intracranial bleeding (OR 0.15, 95%CI 0.07-0.35, p < 0.001), gastrointestinal bleeding (OR 0.25, 95%CI 0.17-0.37, p < 0.001), cancer (OR 0.37, 95%CI 0.25-0.55, p < 0.001), hospitalization due to acute coronary syndrome (OR 0.48, 95%CI 0.33-0.69, p < 0.001), and anemia (OR 0.62, 95%CI 0.48-0.81, p < 0.001)., Conclusions: Most AF patients with a high thromboembolic risk received OACs. The factors predisposing a lack of OAC use in these patients were conditions that significantly increased the risk of bleeding complications.

Glioblastomas (GBM) are the common and aggressive primary brain tumors that are incurable by conventional therapies. Immunotherapy with immune checkpoint inhibitors is not effective in GBM patients due to the highly immunosuppressive tumor microenvironment (TME) restraining the infiltration and activation of cytotoxic T cells. Clinical and experimental studies showed the upregulation of expression of the arginase 1 and 2 (ARG1 and ARG2, respectively) in murine and human GBMs. The elevated arginase activity leads to the depletion of L-arginine, an amino-acid required for the proliferation of T lymphocytes and natural killer cells. Inhibition of ARG1/2 in the TME may unblock T cell proliferation and activate effective antitumor responses. To explore the antitumor potential of ARG1/2 inhibition, we analyzed bulk and single-cell RNA sequencing (scRNA-seq) data from human and murine gliomas. We found the upregulation of ARG1/2 expression in GBMs, both in tumor cells and in tumor infiltrating microglia and monocytes/macrophages. We employed selective arginase inhibitors to evaluate if ARG1/2 inhibition in vitro and in vivo exerts the antitumor effects. A novel, selective ARG1/2 inhibitor - OAT-1746 blocked microglia-dependent invasion of U87-MG and LN18 glioma cells in a Matrigel invasion assay better than reference compounds, without affecting the cell viability. OAT-1746 effectively crossed the blood brain barrier in mice and increased arginine levels in the brains of GL261 glioma bearing mice. We evaluated its antitumor efficacy against GL261 intracranial gliomas as a monotherapy and in combination with the PD-1 inhibition. The oral treatment with OAT-1746 did not affect the immune composition of TME, it induced profound transcriptomic changes in CD11b + cells immunosorted from tumor-bearing brains as demonstrated by RNA sequencing analyses. Treatment with OAT-1746 modified the TME resulting in reduced glioma growth and increased antitumor effects of the anti-PD-1 antibody. Our findings provide the evidence that inhibition of ARG1/2 activity in tumor cells and myeloid cells in the TME unblocks antitumor responses in myeloid cells and NK cells, and improves the efficacy of the PD-1 inhibition., Competing Interests: MG, PS, and RB are employees of OncoArendi Therapeutics. PD is a former employee of OncoArendi Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pilanc, Wojnicki, Roura, Cyranowski, Ellert-Miklaszewska, Ochocka, Gielniewski, Grzybowski, Błaszczyk, Stańczak, Dobrzański and Kaminska.)

Background : Hyperuricemia is an established risk factor for cardiovascular disease, including atrial fibrillation (AF). The prevalence of hyperuricemia and its clinical significance in patients with already diagnosed AF remain unexplored. Methods : The Polish Atrial Fibrillation (POL-AF) registry includes consecutive patients with AF hospitalized in 10 Polish cardiology centers from January to December 2019. This analysis included patients in whom serum uric acid (SUA) was measured. Results : From 3999 POL-AF patients, 1613 were included in the analysis. The mean age of the subjects was 72 ± 11.6 years, and the mean SUA was 6.88 ± 1.93 mg/dL. Hyperuricemia was found in 43% of respondents. Eighty-four percent of the respondents were assigned to the high cardiovascular risk group, and 45% of these had SUA >7 mg/dL. Comparison of the extreme SUA groups (<5 mg/dL vs. >7 mg/dL) showed significant differences in renal parameters, total cholesterol concentration, and left ventricular ejection fraction (EF). Multivariate regression analysis showed that SUA >7 mg/dL (OR 1.74, 95% CI 1.32-2.30) and GFR <60 mL/min/1.73 m 2 (OR 1.94, 95% CI 1.46-2.48) are significant markers of EF <40% in the study population. Female sex was a protective factor (OR 0.74, 95% CI 0.56-0.97). The cut-off point for SUA with 60% sensitivity and specificity indicative of an EF <40% was 6.9 mg/dL. Conclusions : Although rarely assessed, hyperuricemia appears to be common in patients with AF. High SUA levels may be a significant biomarker of reduced left ventricular EF in AF patients.

Background: We aimed to assess characteristics and treatment of AF patients with and without heart failure (HF)., Methods: The prospective, observational Polish Atrial Fibrillation (POL-AF) Registry included consecutive patients with AF hospitalized in 10 Polish cardiology centers in 2019-2020., Results: Among 3999 AF patients, 2822 (71%) had HF (AF/HF group). Half of AF/HF patients had preserved ejection fraction (HFpEF). Compared to patients without HF (AF/non-HF), AF/HF patients were older, more often male, more often had permanent AF, and had more comorbidities. Of AF/HF patients, 98% had class I indications to oral anticoagulation (OAC). Still, 16% of patients were not treated with OAC at hospital admission, and 9%-at discharge (regardless of the presence of HF and its subtypes). Of patients not receiving OAC upon admission, 61% were prescribed OAC (most often apixaban) at discharge. AF/non-HF patients more often converted from AF at admission to sinus rhythm at discharge compared to AF/HF patients (55% vs. 30%), despite cardioversion performed as often in both groups. Class I antiarrhythmics were more often prescribed in AF/non-HF than in AF/HF group (13% vs. 8%), but still as many as 15% of HFpEF patients received them., Conclusions: Over 70% of hospitalized AF patients have coexisting HF. A significant number of AF patients does not receive the recommended OAC.

Background: Atrial fibrillation (AF) can cause severe symptoms, but it is frequently asymptomatic. We aimed to compare the clinical features of patients with asymptomatic and symptomatic AF., Methods: A prospective, observational, multicenter study was performed (the Polish Atrial Fibrillation (POL-AF) registry). Consecutive hospitalized AF patients over 18 years of age were enrolled at ten centers. The data were collected for two weeks during each month of 2019., Results: A total of 2785 patients were analyzed, of whom 1360 were asymptomatic (48.8%). Asymptomatic patients were more frequently observed to have coronary artery disease (57.5% vs. 49.1%, p < 0.0001), heart failure with preserved ejection fraction (39.8% vs. 26.5%, p < 0.0001), a previous thromboembolic event (18.2% vs. 13.1%, p = 0.0002), and paroxysmal AF (52.3% vs. 45.2%, p = 0.0002). In multivariate analysis, history of electrical cardioversion, paroxysmal AF, heart failure, coronary artery disease, previous thromboembolic event, and higher left ventricular ejection fraction were predictors of a lack of AF symptoms. First-diagnosed AF was a predictor of AF symptoms., Conclusions: In comparison to symptomatic patients, more of those hospitalized with asymptomatic AF had been previously diagnosed with this arrhythmia and other cardiovascular diseases. However, they presented with better left ventricular function and were more frequently treated with cardiovascular medicines.

Background: Although triple antithrombotic therapy (TAT) is recommended in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI), guidelines allow an option of dual antithrombotic therapy (DAT). This study assesses the everyday practice of 10 cardiology departments in antithrombotic therapy in AF patients undergoing PCI and its agreement with current guidelines., Methods: This analysis included medical data of AF patients enrolled in the prospective, observational registry (The POLish Atrial Fibrillation-POL-AF) that underwent PCI [elective or due to acute coronary syndrome (ACS)]., Results: Of the 3,999 consecutive subjects included, a final analysis was performed on 359 patients that underwent PCI: 148 with urgent PCI due to ACSand 211 patients with elective PCI. Eighty patients in the ACS-group and 120 patients in the elective-PCI group were treated with TAT, although guidelines also allowed DAT. Of 316 patients treated with oral anticoagulants as a part of combination therapy, 275 were on non-vitamin K antagonist oral anticoagulant (NOAC). Reduced doses of NOAC were used in 74 patients treated with rivaroxaban, 60 patients with dabigatran, and 54 patients with apixaban. The proportion of patients treated with reduced NOAC doses adequately to the guidelines was 29%, 100%, and 33% for rivaroxaban, dabigatran, and apixaban, respectively. Inappropriate low doses of NOACs were used in 71% of subjects on rivaroxaban and 67% on apixaban., Conclusions: In patients with AF undergoing PCI, NOACs are definitely preferred over vitamin-K antagonists (VKAs) in TAT/DAT, and an aggressive antithrombotic strategy with TAT is frequently chosen even if DAT is permissible by the guidelines. Label adherence of using reduced NOAC dose during combination therapy is not satisfactory for apixaban and rivaroxaban and probably results from too cautious an approach to the known indications for reduced therapy. The study is registered in the database Clinical Trials-NCT04419012., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-839). IG reports personal fees from Bayer and Boehringer-Ingelheim; AKC reports honoraria for lectures from Bayer, outside the submitted work; ATK reports research grant from Boehringer-Ingelheim, consultant for Boehringer-Ingelheim, Bayer, speaker for Boehringer-Ingelheim; BWK reports personal fees from Boehringer-Ingelheim, Bayer, Pfizer, outside the submitted work. The other authors have no conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Background: Current guidelines do not suggest in which groups of patients with atrial fibrillation (AF) individual non-vitamin K antagonist oral anticoagulants (NOACs) should be used for the prevention of thromboembolic complications. The aim of this study was to evaluate the frequency of use of apixaban, dabigatran, and rivaroxaban, and attempt to identify factors predisposing their administration., Methods: The Polish Atrial Fibrillation (POL-AF) registry is a prospective, non-interventional study, including consecutive patients with AF hospitalized in ten Polish cardiology centers during the period ranging from January to December 2019. In this study, all patients were treated with NOACs., Results: Among the 2971 patients included in the analysis, 40.4% were treated with rivaroxaban, 32% with apixaban, and 27.6% with dabigatran. The mean age of the total population was 72 ± 11.5 years and 43% were female. A reduced dose of NOAC was used in 35% of patients treated with apixaban, 39.7% of patients treated with dabigatran, and 34.4% of patients treated with rivaroxaban. Independent predictors of the use of apixaban were previous bleeding (OR 2.37, CI 1.67–3.38), GFR < 60 mL/min (OR 1.38, CI 1.25–1.64), heart failure (OR 1.38, CI 1.14–1.67) and age (per 5 years) (OR 1.14, CI 1.09–1.19). GFR < 60 mL/min (OR 0.79, CI 0.66–0.95), female (OR 0.8, CI 0.67–0.96) and age (per 5 years) (OR 0.95, CI 0.91–0.99) diminished the chance of using dabigatran. Previous bleeding (OR 0.43, CI 0.28–0.64), vascular disease (OR 0.84, CI 0.70–0.99), and age (per 5 years) (OR 0.94, CI 0.90–0.97) diminished the chance of choosing rivaroxaban., Conclusions: In hospitalized patients with AF, the most frequently chosen NOAC was rivaroxaban. Apixaban was chosen more often in patients after bleeding, and in those who were advanced in years, with heart failure and impaired renal function. Impaired renal function and female gender were factors that diminished the chance of using dabigatran. Previous bleeding and vascular disease was the factor that diminished the chance of using rivaroxaban. Dabigatran and rivaroxaban have been used less frequently in elderly patients., Competing Interests: O.J., B.U.-Z., M.Ch., M.M., M.W., R.B., M.B., M.G., T.T., R.R.-S., J.B., M.Wo., A.S., E.B.-A., A.Sz., M.We., M.M.: None. I.G.: research grant from Boehringer-Ingelheim and speaker for Boehringer-Ingelheim and Bayer. A.K.-C.: speaker for Boehringer-Ingelheim, Bayer, Pfizer. J.Be.: speaker for Boehringer-Ingelheim, Bayer, Pfizer. A.T-K.: research grant from Boehringer-Ingelheim, consultant for Boehringer-Ingelheim and Bayer and speaker for Boehringer-Ingelheim. B.W.-K.: speaker for Boehringer-Ingelheim, Bayer, Pfizer.

Background and Aim: We aimed to evaluate the prevalence and determinants of different stress coping strategies in Polish patients suffering from heart failure with reduced ejection fraction (HFREF)., Methods: This manuscript is a sub-study of the CAPS-LOCK-HF multicentre psychological status assessment of patients with HFREF. Patients with > six-month history of HFREF and clinical stability for ≥ three months and left ventricular ejection fraction (LVEF) < 45% were enrolled in the study. Demographic and clinical variables were obtained from medical records, while a standardised Coping Inventory for Stressful Situations (CISS) was applied to all subjects., Results: The study comprised 758 patients (599 men; 79%) with a median age of 64 years (IQR 58-71). Median LVEF was 33% (25-40). Subjects most commonly used task-oriented coping strategies (median CISS score 55 points; IQR 49-61), followed by avoidance (45 points; 39-50) and emotion-oriented coping strategies (41 points; 34-48). Distraction-based avoidance coping strategies (20 points; 16-23) were more pronounced than social diversion strategies (16 points; 14-19). Multiple regression analysis showed that higher New York Heart Association (NYHA) class and lower systolic blood pressure were independent predictors of task-oriented style. Emotion-oriented coping was more common among females and higher NYHA classes, and in patients who did not take angiotensin-converting enzyme inhibitors. Patients who used avoidance-oriented strategies were more frequently those in sinus rhythm on assessment and those who had less history of neoplastic disease., Conclusions: Patients with HFREF most commonly use favourable task-oriented coping strategies. However, female patients and those with higher NYHA classes tend to use potentially detrimental emotion-oriented coping strategies.

Background: The issue of self-perceived health control and related sense of self-efficacy has not received any attention in patients with heart failure (HF), although these psychological features have been established to determine the patients' approach towards healthcare professionals and their recommendations, which strongly affects compliance., Methods: A total of 758 patients with systolic HF (age: 64 ± 11 years, men: 79%, NYHA class III–IV: 40%, ischaemic aetiology: 61%) were included in a prospective Polish multicentre Caps-Lock-HF study. A Multidimensional Health Locus of Control (MHLC) scale was used to assess subjective perception of health control in three dimensions (internal control, external control by the others, and by chance); the Generalised Self Efficacy scale (GSES) was used to estimate subjective sense of self-efficacy; and the Beck Depression Inventory (BDI) was used to determine depressive symptoms., Results: The majority of patients perceived the external control (by the others) and internal control of their health as high (77% and 63%, respectively) or moderate (22% and 36%, respectively), whereas self-efficacy was perceived as high or moderate (63% and 27%), which was homogenous across the whole spectrum of the HF cohort, being unrelated to HF severity, HF duration, the presence of co-morbidities, and the applied treatment. The stronger the perception of internal health control, the higher the self-efficacy (p < 0.05); both features were related to less pronounced depressive symptoms (p < 0.05)., Conclusions: The established pattern of self-perceived control of own health and self-efficacy indicates that patients with HF acknowledge the role of others (i.e. healthcare providers) and themselves in the process of the management of HF, and are convinced about the high efficacy of their undertaken efforts. Such evidence supports implementation of a partnership model of specialists’ care of patients with HF.

Electron ionization mass spectrometry and density functional theory (DFT) calculations have been used to study the fragmentation of diastereoisomers of protected 1,2-diaminoalkylphosphonic acids. The loss of a diethoxyphosphoryl group and the elimination of diethyl phosphonate were found to be competitive fragmentation processes, which can be used to differentiate both stereoisomers. Selective deuterated analogs and product- and precursor-ion mass spectra allowed the elucidation of the fragmentation mechanisms. The structures of the transition states and product ions were optimized using the density functional theory (DFT), and free energy calculations confirmed the observed differences in the formation and relative intensities of specific fragment ions.

Diastereoisomers of diethyl 5-substituted (2-thioxo-imidazolidin-4-yl)phosphonates, which can be regarded as protected diethyl 1,2-diaminoalkylphosphonates, have been analyzed by electron ionization mass spectrometry. Significant differences in the fragmentation of cis- and trans-diastereoisomers were found. The stereospecificity of the elimination of diethyl phosphonate and the loss of the diethoxyphosphoryl group were studied using specific labeled compounds and collision-induced dissociation. The relative abundances of ions formed via these fragmentation processes can be used for differentiation of both diastereoisomers., (2010 John Wiley & Sons, Ltd.)