Diringytė, Gintautė

Background Atrial fibrillation (AF) is the most common arrhythmia worldwide, affecting 10 million in the US and carries a lifetime risk of 1 in 3. Symptom and rhythm control are achieved using antiarrhythmic drug (AAD) therapy, which often requires hospitalization due to the rare risk of ventricular arrhythmias (VA), such as Torsades de Pointes (TdP). This study evaluated whether early QTc changes (ΔQTc) predict adverse events (AEs) during AAD loading. Methods We conducted a retrospective study of patients admitted for dofetilide or sotalol loading between July 2022 and April 2023 at a single center. Demographics, AF history, AAD dosing, and ECG parameters, including ΔQTc (baseline QTc - post dose 1 QTc), were analyzed using logistic regression to identify predictors of AEs (VA or prolonged QT). Results Among 110 patients (median age 70; 69.1% male), 101 received dofetilide and 9 underwent sotalol therapy. Baseline QTc was 442.6 ± 33.0 ms, with a mean ΔQTc of 22.7 ± 33.4 ms (5.36 ± 0.08% increase). AEs, including VA and prolonged QT, occurred in 47 patients (42.7%). A ΔQTc >10.5% after the first dose was a strong independent predictor of AE risk (ACCc = 136.87). In fully adjusted models, QTc increase >48 ms (OR 17.80, 95% CI: 4.73-67.01) and ΔQTc >10.5% (OR 18.58, 95% CI 4.96-69.65) showed the strongest associations. The univariate model using ΔQTc >10.5% had the greatest predictive performance. Conclusion An initial QTc increase >10.5% was the strongest predictor of adverse events during AAD initiation, outperforming traditional risk factors. This novel biomarker may serve as a simple, early indicator of AF patients that may be at higher risk for adverse events, enhancing risk stratification and patient-specific care strategies.

Background Antiarrhythmic drugs (AAD) sotalol and dofetilide are commonly used to treat atrial fibrillation (AF). Both medications may cause arrhythmogenic adverse events (AEs), although incredibly rare (<0.6%), including ventricular arrhythmias. We performed a pharmacovigilance and disproportionality study to compare proarrhythmic AEs of dofetilide and sotalol reported to the FDA Adverse Event Reporting System (FAERS) database. Methods The FAERS database was searched for AF patients prescribed sotalol or dofetilide. Proarrhythmic AEs, including ventricular tachycardia (VT), TdP, cardiac arrest, and bradycardia events were identified for the target population. Additionally, recurrent AF episodes were noted. The reporting odds ratios (RORs) were calculated between sotalol and dofetilide for each proarrhythmic event (VT, TdP, cardiac arrest, bradycardia) and AF recurrence (Table I). Results From 2004-2023, 3,097 cardiac AEs were reported for sotalol and dofetilide. Recurrent AF was recorded in 436 cases (222 dofetilide, 214 sotalol) and dofetilide displayed a greater ROR for AF recurrence [27 (95% CI: 25-29), sotalol: [17 (16-19)]. Sotalol demonstrated greater ROR values for TdP [76 (66-87) vs. 53 (44-63)] and bradycardia [15 (13, 17) vs. 2 (2, 3)]. Conclusion Cardiac AEs and AF recurrence are commonly reported to the FDA in patients taking sotalol and dofetilide. While TdP was found to be more common in patients prescribed sotalol, AF recurrence was most commonly reported with dofetilide use. These factors may influence decision-making when selecting AADs for AF patients. These findings underscore the need for careful patient selection, close monitoring, and individualized risk assessment. Further research is required to determine the clinical implications of AADs and AEs.

Background The growth of artificial intelligence (AI) over the past few years and its integration across many scientific fields has rapidly increased. Large language models (LLMs) are machine learning (ML)-based tools that aim to reproduce human language by training on extensive databases. The goal of this work is to improve documentation processes, specifically for patients receiving antiarrhythmic drug therapy (AAD), by generating automated titration summaries from electronic medical records (EMR). Methods Protected health information was deidentified from 36 action log files generated from the EMRs, which were then fed into OpenAI (GPT-4o or o3-mini-high) and organized into the following categories; date, drug name, dosage, day of administration, and dose number. The outputs from GPT-4o and o3-mini-high OpenAI platforms were collected and accuracy was evaluated by comparing to the original EMR files. Results The output from both models were manually verified by comparing to the original EMR dataset. The comparison resulted in 27 incorrect values generated by the GPT-4o model, yielding an accuracy of 94.4%, while the o3-mini-high model produced 10 incorrect values, yielding an accuracy of 98.9%. The o3-mini-high model was statistically more accurate than the GPT-4o model output (p = 3.31 x10-7). Conclusion The results of this study support our hypothesis that LLMs can extract highly accurate data directly from EMRs. Extreme efficiency and speed were observed, suggesting implementation of this model may reduce provider workload required for AAD initiation, which has the potential to improve healthcare resource utilization.

Introduction Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 7% of cancer-related deaths [1]. Despite advancements in cancer research, the five-year survival rate remains at 9%, primarily due to late diagnosis and limited treatment options [2,3]. Investigating differential gene expression between tumor tissue and peripheral blood mononuclear cells (PBMCs) may uncover potential biomarkers and therapeutic targets for early diagnosis and personalized treatment [4,5]. A key target in this pilot study was the aryl hydrocarbon receptor (AHR) and its pathways, implicated in immune suppression, oxidative stress, inflammation, angiogenesis, and tumor progression [6–9]. Aim To analyze transcriptional differences between PBMCs and PDAC tissues, focusing on the AHR signaling and related genes to understand their roles in disease progression. Methods PDAC tissue and PBMC samples were collected from six patients on the day of surgery, including one postneoadjuvant treatment. RNA sequencing libraries were prepared using the ILMN Stranded Total RNA Library with Ribo-Zero PLUS and sequenced on the NextSeq550 platform. Data were processed with the Nextflow RNA-seq workflow, using STAR for sequence alignment and RSEM for transcript quantification. Differential gene expression analyses were performed in RStudio, focusing on AHR signaling and related genes. Results PBMC samples exhibited similar immune gene expression profiles, while PDAC tissues demonstrated greater variability due to tumor heterogeneity and mutations. The principal component analysis identified two outliers: one reflecting the impact of neoadjuvant therapy, showing unique expression patterns, and another linked to a poor prognosis characterized by lymph node involvement and vascular invasion. Targeted gene analysis revealed that IL-4 expression was higher in tumor tissues compared to PBMCs, while AHRR, CYP1A1, IL-6, and IL-10 were more highly expressed in PBMCs than in tumor tissues, indicating immune modulation. Further studies should be done to validate these findings in larger cohorts and explore the impact of neoadjuvant treatments on gene expression to predict patient outcomes and therapeutic responses. Conclusions This study reveals significant transcriptional differences between PBMCs and PDAC tissues, reflecting tumor heterogeneity and variation in immune responses. IL-4 expression was higher in tumor tissues, suggesting its role in tumor progression and immune evasion, while AHRR, CYP1A1, IL-6, and IL-10 were more highly expressed in PBMCs.

Introduction Cell-free DNA (cfDNA) detection in liquid biopsies is a promising non-invasive diagnostic procedure for cancers diagnosed at advanced stages, such as pancreatic ductal adenocarcinoma (PDAC). (1) CfDNA content, fragmentation patterns, DNA methylation profiles, mutation levels and mutated genes are all potential biomarkers for malignancy detection, and cancer type identification with different proven efficacy, accuracy and consistency. (1-4) There is a critical need to understand how cfDNA and single nucleotide polymorphisms (SNPs) levels differ between PDAC patients and healthy individuals for the improvement of early detection and diagnostic strategies. Aim Compare plasma cell-free DNA content between patients with PDAC and healthy controls. Methods The patient plasma cfDNA was sequenced according to “Oxford Nanopore tech” kits using Promethion flow cells and Native barcoding kit. The sequenced data was analysed using: “MinKnow” software for basecalling, “Nanoplot” for read calculation, “Minimap2” for DNA mapping to reference genome and “Deepvariant” for mutation calling. 10 PDAC patients and 8 healthy controls were analysed. Results Significant increase of circulating cfDNA concentration was observed in PDAC patients as compared to healthy patients, with a median of 77.60 ng/ml for PDAC patients and 19.75 ng/ml for healthy patients (p<0.0001). Single nucleotide polymorphisms (SNPs) in PDAC patients per 100 reads were significantly higher (median 2.567 vs 2.098, p = 0.0005) than in healthy subjects. The proportion of clinically relevant SNPs in PDAC patients per 100 000 reads was significantly higher (median 1.748 vs 1.589, p = 0.0044) than healthy controls. Lastly, the number of PDAC related gene mutations in affected patients was significantly higher compared to healthy patients. Conclusions PDAC patients had higher cfDNA content, more SNPs, clinically relevant mutations and PDAC related mutations compared to healthy controls. These findings could frame the development of simpler initial diagnostic tests in the detection of malignancy, which can guide targeted investigations to identify the specific type of cancer, however further research is needed to establish a clear clinical pattern.

Introduction Epithelial-to-mesenchymal transition (EMT) is a cellular process when epithelial cells lose their epithelial characteristics and acquire mesenchymal traits of migration and invasion. There are known EMT transcription factors (EMT TFs), such as SNAIL-1, SNAIL-2, ZEB1, ZEB2, and TWIST, that regulate EMT by controlling gene expression. ELAVL1 is an RNA-binding protein, also known as human antigen R, that selectively binds AU-rich (AREs) elements found in untranslated regions of mRNAs. This protein plays a key role in posttranscriptional gene regulation, which is dysregulated in pancreatic ductal adenocarcinoma (PDAC) cells. ELAVL1 participates in EMT regulation by stabilizing mRNAs of EMT TFs, which can promote cancer progression. Aim The aim of this study was to investigate the effects of ELAVL1 protein inhibition on EMT-TF RNA expression in different pancreatic cancer cell lines. Methods In this investigation cell lines such as BxPC-3 and MiaPaCa-2 were used. BxPC-3 is a cell line which exhibits epithelial morphology derived from primary pancreatic adenocarcinoma. MiaPaCa-2 is an epithelial cell line derived from adenocarcinoma metastatic to the liver. ELAVL1 protein was inhibited by dihydrotranshinone-I (DHTS) for 24 hours after which RNA was extracted, converted to cDNA and analysed by qRT-PCR method. Results The results showed that MiaPaCa-2 (advanced tumour) cells had higher ZEB1 (52-fold) and SNAIL-1 (18-fold) and lower ELAVL1 (76 %), ZEB2 (44 %) and SNAIL-2 (10 %) expression when compared to that of BxPC-3 cell line (primary cancer). When comparing the effects of ELAVL1 protein inhibition, the results show that it does not affect any investigated RNA expression in BxPC-3 cell line, however decreases all investigated RNA expression in MiaPaCa-2 cell line (ELAVL1 to 71%, ZEB1 to 50 %, ZEB2 to 47 %, TWIST to 48 %, SNAIL-1 to 59 %, SNAIL-2 to 65 %). Conclusions The EMT-TF expression levels of native cells show obvious differences between cell lines, however, the inhibition of ELAVL1 protein alters the expression of EMT-TF in cells from advanced PDAC while not altering the expression in cells from primary PDAC cancer. This suggests that inhibition of ELAVL1 could positively affect advanced PDAC, but further investigation is required.

Background and objective: carotid artery stenosis contributes significantly to ischemic strokes, with management options including carotid endarterectomy (CEA) and carotid artery stenting (CAS) ischemic stroke risk can be reduced. Controversies persist regarding their efficacy and factors influencing complications, and understanding the relationship between atherosclerotic plaque characteristics and stent restenosis after CAS is crucial. Methods: we conducted a retrospective study involving 221 patients who underwent CAS for symptomatic or asymptomatic carotid artery stenosis. Comprehensive assessments of plaque morphology were performed using contrast-enhanced ultrasound (CEUS) before CAS. Patient demographics, including smoking status and diabetes, were also recorded. Stent restenosis was diagnosed using various imaging modalities, including ultrasound, angiography, and digital subtraction angiography (DSA). Results: plaque analysis using CEUS revealed a significant association between plaque grade and restenosis incidence (p < 0.001), particularly with grade 0 (11.1%) and grade 2 plaques (66.7%). Smoking was notably associated with plaque vascularization and restenosis (p < 0.001), while diabetes did not significantly impact plaque characteristics or restenosis risk (p > 0.05). The mean duration of restenosis was 17.67 months. Stenting was the most frequent treatment modality for restenosis (70.6%). However, no significant relationship was found between restenosis type and plaque morphology (p = 0.268). Furthermore, while no clear relationship was observed between plaque morphology and the type of restenosis, our findings underscored the importance of plaque characterization in predicting post-CAS outcomes. Conclusions: this study highlights the utility of CEUS in predicting stent restenosis following CAS. There was a significant association between stent restenosis within 12–24 months after the carotid stenting procedure and an elevated grade of plaque vascularization. Moreover, one of the main factors possibly determining the grade of plaque vascularization was smoking. Further research is warranted to elucidate the underlying mechanisms and refine risk stratification in this patient population.

Background and aim of the study: The incidence of stroke after on-pump cardiac surgery during the perioperative period can affect up to 4% of patients with significant unilateral carotid artery stenosis of 80-99. Between 3% to 10% of individuals who undergo coronary artery bypass grafting (CABG) display notable narrowing of the carotid arteries, which can be improved by either simultaneous or staged carotid endarterectomy and CABG. The aim of the study was to determine the association between the degree of plaque vascularization detected with contrast-enhanced ultrasound and postoperative complications. Methods and materials: A single center retrospective study of 62 patients was performed from 2019 to 2022 who underwent simultaneous CABG/CEA. Exclusion criteria: staged carotid endarterectomy and CABG procedures, off-pump CABG, urgent cases. The focus of our study was on patients who underwent elective CABG. These individuals were diagnosed with coronary artery disease (CAD) and exhibited either asymptomatic internal carotid artery stenosis greater than 70% or symptomatic ipsilateral carotid stenosis exceeding 50%. Before the procedure each patient underwent contrast enhanced ultrasound, the atherosclerotic lesions were classified based on Nakamura et al. classification. Results: Postoperative complications were analyzed within 30 days after surgery and type of plaque morphology detected by contrast-enhanced ultrasound, a statistically significant correlation was found between the presence of a higher grade plaque vascularization and ischemic stroke (r=0.329, p=0.008). Monte Carlo calculations of Chi-square test showed that higher grade of plaque vascularization was significantly associated with peripheral artery disease (χ2=15.175, lls=2 , p=0.003). Conclusions: Ischemic stroke after carotid endarterectomy following CABG within 30 days after surgery has a significant correlation with the presence of a higher grade of plaque vascularization detected by contrast-enhanced ultrasound.

Background and aim of the study. Carotid artery stenosis poses a significant risk for ischemic strokes, necessitating effective management strategies such as carotid endarterectomy (CEA) and carotid artery stenting (CAS). However, controversies persist regarding their comparative efficacy and factors influencing post-procedural complications. Understanding the relationship between atherosclerotic plaque characteristics and stent restenosis following CAS is vital for optimizing patient care. Methods and materials. In our retrospective study of 221 patients undergoing CAS fo symptomatic or asymptomatic carotid artery stenosis, comprehensive assessments of plaque morphology using contrastenhanced ultrasound (CEUS) were conducted before CAS. Patient demographics, including smoking and diabetes, were also recorded. Stent restenosis was diagnosed using various imaging modalities, including ultrasound, angiography, and digital subtraction angiography (DSA). Results. Plaque analysis revealed a significant correlation between plaque type and restenosis incidence (p < 0.001), notably with type 0 (11.1%) and type 2 plaques (66.7%). Smoking was significantly associated with plaque vascularization and restenosis (p < 0.001), while diabetes did not significantly impact plaque characteristics or restenosis risk (p > 0.05). The average duration of restenosis was 17.67 months, with angiography and ultrasound commonly used for diagnosis, showing significant differences (p = 0.016). Stenting was the predominant treatment for restenosis (70.6%), although no significant relationship was found between restenosis type and plaque morphology (p = 0.268). Furthermore, while no clear relationship was observed between plaque morphology and the type of restenosis, our findings underscored the importance of plaque characterization in predicting post-CAS outcomes. Conclusions. This study highlights the utility of CEUS in assessing plaque vulnerability and predicting stent restenosis following CAS. There is a significant correlation between the occurrence of stent restenosis within 12-24 months after the carotid stenting procedure and the presence of an elevated grade of plaque vascularization. Further research is needed to elucidate underlying mechanisms and refine risk stratification.

Background and aim of the study. Stroke risk after on-pump cardiac surgery during the perioperative period can affect up to 2% of patients, often linked to carotid artery disease. Unilateral carotid artery stenosis of 80-99% increases stroke risk to 4%. Between 3% and 10% of coronary artery bypass grafting (CABG), patients have significant carotid artery narrowing, which could be improved by either simultaneous or staged carotid endarterectomy and CABG to reduce the chances of stroke and mortality. The aim of this study was to find out whether early postoperative stroke risk in simultaneous CABG/CAE procedures depends on carotid plaque morphological characteristics via contrast-enhanced ultrasound. Methods and materials. A single-center retrospective analysis of 62 patients (2019-2022) who underwent simultaneous CABG/CEA was performed. We did not include patients who underwent staged carotid endarterectomy and CABG procedures, off-pump CABG, or those who required urgent CABG. The focus of our study was solely on patients who satisfied the criteria for elective CABG. These individuals were diagnosed with either triple-vessel or left main trunk symptomatic coronary artery disease (CAD) and exhibited either asymptomatic a. carotis internae (ACI) greater than 70% or symptomatic ipsilateral carotid stenosis exceeding 50%. Before the CEA/CABG procedure, each patient had a contrast-enhanced ultrasound done, and the atherosclerotic lesions were classified based on the Nakamura et al. classification. Results. Analyzing postoperative complications within 30 days after surgery and the type of plaque morphology detected by contrast-enhanced ultrasound, a statistically significant correlation was found between the presence of a higher grade of plaque vascularization and ischemic stroke (r=0.329, p=0.008). Monte Carlo calculations of the Chi-square test showed that a higher grade of plaque vascularization was significantly associated with peripheral artery disease (χ2=15.175, lls=2, p=0.003). Conclusions. Ischemic stroke after carotid endarterectomy following CABG within 30 days after surgery has a significant correlation with the presence of a higher grade of plaque vascularization detected by contrastenhanced ultrasound.