Classicism Research Articles

Pročelja crkava u Međimurju u razdoblju baroka. Prilog poznavanju tipologije sakralne arhitekture kontinentalne Hrvatske

An overview of the façades of Međimurje churches built during the Baroque period reveals a typological affinity with comparable regions in continental Croatia – Hrvatsko Zagorje, Varaždin County, and Križevci-Koprivnica County – as well as some characteristic peculiarities. Most have a bell tower in front of the façade, following a traditional form since the Middle Ages, including churches in Sveti Martin na Muri, Selnica, Prelog, Gornji Mihaljevec, Sveti Križ, Cirkovljan, Donji Kraljevec, Dekanovec, Mursko Središće, Podturen, Sveta Marija, Ivanovec, Sveti Juraj u Trnju, Belica, Nedelišće, Kotoriba, and Razkrižje. The oldest among these are the churches of St Martin in Sveti Martin na Muri and St Mark in Selnica, with bell towers in front of the façade supported by buttresses, along with the likewise older parish church in Prelog. The bell tower of the church in Kotoriba stands out with its curved sides as a high-Baroque design. Apart from being positioned in front of the façade, the bell tower is sometimes located next to it, as observed in the parish church in Goričan and the Franciscan church in Čakovec, where the bell tower’s position follows the tradition of spatial organization in Franciscan building complexes. A third variant within this group is the bell tower’s placement next to the sanctuary, as yet another example of continued tradition, seen in churches in Donji Vidovec, Lopatinec (Sveti Juraj na Bregu), and Štrigova. These examples of adding a Baroque bell tower to the Gothic sanctuary emphasizes continuity and long duration, important features of re-Catholicization in regions with widespread Protestantism. Stylistically more pronounced is the type of façade with an integrated bell tower, prevalent in 18th-century architecture across Central Europe and exemplified by churches in Legrad, Novo Selo Rok, and Kapelščak. The most complex in terms of design are church façades with two bell towers, such as St Jerome in Štrigova and St Rochus in Draškovec. The Pauline church in Štrigova shows numerous parallels with the Maria Trost church in Graz, executed by the Stengg construction workshop – including its prominent position in the landscape, the wide façade with bell towers on the sides, the curved contour of the central gable, and the originally rich architectural articulation. The church in Draškovec is an exquisite combination of late Baroque style in its interior design and emphasized Classicism in the design of the façade and the bell tower. In addition to numerous common features, such as the typology and adoption of certain traditional solutions, the peculiarity of this group of churches in relation to other regions of continental Croatia is the appearance of dynamically shaped façades and bell towers. Churches in Lopatinec and, to a lesser extent, in Legrad have façades along the curve of the ground plan, while the bell tower of the church in Kotoriba has an accentuated dynamic plan, with recessed sides and prominent corners with pilasters. These examples demonstrate the adoption of influences from neighbouring Styria, especially the sacral architecture of Graz’s architect Johann Georg Stengg. Another specificity of the corpus of Međimurje churches is the number of churches designed in the Classicist style, with high-quality achievements in a combination with late Baroque, reflecting the proximity and connectedness of Međimurje to the Hungarian artistic circles. The analysis of bell tower and façade designs in this corpus has shown that within the typological groups present across the area, along with the general features of Baroque architecture, one also finds very specific solutions that corresponded to the needs of the environment. In other words, the adoption of models and their adaptation to the local context is an example of cultural transfer expressing the local character, in which the commissioning environment has left its visible mark.

Abstract B070: Histone deacetylation inhibition promotes bi-directional subtype switch in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with 5-year survival of just 11%. Recent large-scale transcriptomic studies have identified two prognostically relevant neoplastic tumor subtypes, i.e. the well-differentiated classical (CLA) subtype with better prognosis, characterized by epithelial gene expression, as well as the dedifferentiated, invasive basal-like (BL) subtype, which displays mesenchymal stemness-related gene signatures. These subtypes have shown to be highly plastic and responsive to extrinsic signals, e.g. from the microenvironment or treatment-induced. Here, we investigate master transcription factor networks governing lineage determination in the different subtypes and the role of histone deacetylation (HDAC) co-regulators in their maintenance. We utilized established, subtype-defined PDAC cell lines in vitro and in orthotopic transplantation models to determine subtype plasticity in response to HDAC inhibition by the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). By integration of RNA-seq, ATAC-seq as well as HiChIP for the activating mark histone 3 lysine 27 acetylation (H3K27ac), we show that the subtype-dependent chromatin organization and regulatory networks can be influenced by pharmacological inhibition of chromatin remodelers, in turn promoting changes in transcription of lineage-determining factors. Targeting these transcription factor networks by HDAC inhibition can lead both to a favorable switch from BL to CLA identity, as well as a detrimental CLA to BL switch. Functional assay such as trans-well invasion further supported the changes in subtype identity following SAHA treatment. This bi-directional subtype switch was additionally validated in patient-derived xenograft cell lines. Together, our findings highlight the importance of understanding the underlying transcriptional and epigenetic mechanisms of the pancreatic cancer subtypes, as they may exhibit opposing responses to targeted therapies. Citation Format: Lukas Klein, Mengyu Tu, Eva K. Schmitt, Frederike Penz, Athanasia Mizi, Stefan Küffer, Elisabeth Hessmann, Argyris Papantonis, Volker Ellenrieder, Shiv K. Singh. Histone deacetylation inhibition promotes bi-directional subtype switch in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B070.

Relationship between mandibular third molars and mandibular angle and condylar fractures.

Assess the correlation between the position of the third molar (M3) and fractures of the mandibular angle and condyle using panoramic radiographs to offer valuable data references for oral clinical research. A retrospective cross-sectional study was undertaken, involving the collection of 409 cases of mandibular fracture in the Yanbian University Hospital. The case records and panoramic radiographs of mandibular angle fracture (78 cases) and condylar fracture (106 cases) were evaluated. In the comparative analysis between the mandibular angle fracture group and the condylar fracture group, statistical significance was observed in the variables of M3 existence (P = 0.002), eruption of M3 from the alveolar cavity (P = 0.003), P&G position classification (P = 0.001), deep impactions (Classes IC, IIC, IIIB, and IIIC) (P < 0.001), and the presence of impacted M3 in both groups (P < 0.001).Regarding M3 roots, the mandibular angle fracture group exhibited the highest prevalence of multiple roots at 75.4%, surpassing the 64.6% observed in the condylar fracture group. The prevalence of proximal angles in the mandibular angle group and the condyle group was the highest, accounting for 64.6% and 61.5%, respectively. The percentage of M3 in the two groups was 80% and 43.1%, respectively, with a significant difference (P < 0.001). Impacted mandibular third molars (M3) elevate the risk of mandibular angle fractures, while their absence or normal eruption reduces this risk and protects against condylar process fractures. The fracture risk is influenced by the M3's position: P&G Class II and Class B impactions, where M3s emerge partially from the alveolar bone, are significantly associated with mandibular angle fractures. In contrast, the absence of M3 or its placement in P&G Class I and Class A positions tends to correlate with a higher incidence of condylar process fractures.

PENERAPAN STRATEGI PBL DENGAN MEDIA MABERDI UNTUK MENINGKATKAN TANGGUNG JAWAB DAN DISIPLIN PESERTA DIDIK

The purpose of this development is to increase discipline and responsibility students with PBL strategies by MABERDI learning media. The subjects used were 30 students in class Ic UPT SD Negeri 06 Gresik who were used on the recommendation of the teacher. The media used is a type of board game media, a combination of monopoly and snakes and ladders that has been modified. Based on the research results obtained from quantitative data, namely from the average score of the student discipline attitude and responsibility questionnaire obtained through the questionnaire, the average score was 4.6, categorized as very good. Supported by qualitative data obtained from interviews, it also explains that students experience changes in attitudes of discipline and responsibility. Supported by the results of observations carried out for three days which obtained average results which increased every day. From these data it can be concluded that the use of PBL strategies with the help of MABERDI media can improve discipline and responsibility students.

Suicide attempt of young woman by Propafenone overdose - case report

Introduction and purpose: Over the last few years, the number of suicide attempts in Polish women has been steadily increasing. This report presents a case of a 18 years old woman hospitalized in the Toxicology and Cardiology Department due to poisoning with antiarrhythmic drug – Propafenone, taken for suicide purpose.&#x0D; Brief description of the state of knowledge: Propafenone is an antiarrhythmic drug which belongs to class IC according to the Vaughan-Williams classification. The overdose of this drug can cause various symptoms and complications such as cardiac arrhythmias, liver damage, cardiac arrest and even death. This drug has no specific antidote. &#x0D; Conclusions: Propafenone poisoning is a significant clinical challenge and the consequences are often unpredictable and life-threatening. Treatment options such as natrium bicarbonicum, insulin, intravenous lipid emulsion, calcium gluconate seem to be good choices and the effects of treatment with these drugs are promising for the future.

ANGI-02. CELL MIGRATION SIMULATOR-BASED BIOMARKERS FOR GLIOBLASTOMA

Abstract Glioblastoma is the most aggressive malignant brain tumor with the poor survival due to its invasive nature driven by cell migration. There is still no effective treatment targeting glioma cell migration based on their transcriptomic information, due to the lack of understanding in the links to the fundamental mechanics of cell migration. In the previous studies, we developed a physics-based motor-clutch model, the cell migration simulator (CMS), to identify the basic mechanisms of cell migration in various cell types. In this study, we found that glioblastoma patient-derived (xenograft) (PD(X)) cell lines across mesenchymal (MES), proneural (PN), classical (CL) subtypes and two institutions (N = 13 patients) had optimal motility and traction force on stiffnesses around 9.3kPa, with otherwise heterogeneous and uncorrelated motility, traction, and F-actin flow. We applied the CMS as a consistent framework to describe the physical parameters of glioblastoma patient cell migration. Using single cell migration and force generation data on compliant 2D surfaces, we found all glioma PD(X) lines (11 patients) had balanced myosin/adhesion ratios resulting in effective migration. Mesenchymal (MES) lines had enhanced F-actin polymerization resulting in higher motility. Adherent PDX lines had increased myosin-adhesion amount resulting in higher traction force. The CMS also predicted the differential cell migration under cytoskeletal drugs between glioma subtypes. Finally, we found 18 genes in actin cytoskeleton and focal adhesion pathways significantly correlated with the glioma physical parameters, which were being used to estimate the physical parameters of a larger cohort (66 patients) and to strategize targeting their cell migration. Overall, we described a consistent physics-based framework for parameterizing individual glioblastoma patients, connecting to clinical transcriptomic data, and predicting drug effects, that can potentially be used to develop subtype and patient-specific anti-migratory therapeutic strategies.

Epidemiology and clinical impact of chronic obstructive pulmonary disease in patients with atrial fibrillation: findings from an european prospective observational registry

Abstract Background The interplay between atrial fibrillation (AF) and chronic obstructive pulmonary disease (COPD) has been poorly investigated and understood, with previous studies reporting unsatisfactory management and poor prognosis of patients with AF and COPD. Purpose To describe the epidemiology, management and natural history of AF patients with COPD using a contemporary European prospective cohort. Methods From a European-wide prospective observational AF registry, we identified patients with COPD as reported by the investigators. We analysed the association between COPD and the odds of receiving oral anticoagulants (OAC) and other pharmacological treatments using multivariable logistic regression models. We also assessed the associations between COPD and risk of major outcomes using multivariable Cox-regression models. Our primary outcome was all-cause mortality; secondary outcome was the risk of major adverse cardiovascular events (MACE). We finally evaluated the interaction between disease-specific treatments for COPD and the risk of major outcomes in AF-COPD patients. Results A total of 10,219 AF patients were included in this analysis (mean age 69.2 ± 11.4 years; 40.3% females); COPD was found in 909 patients (8.9%). Patients with COPD were older, more likely males, and had a higher burden of thromboembolic and bleeding risk factors. No differences were observed in the likelihood of receiving OAC or non-vitamin K antagonist oral anticoagulants (NOAC) in COPD vs. no COPD patients (OR: 1.00, 95%CI: 0.81-1.24, and OR: 0.91, 95%CI: 0.77-1.06, respectively for OAC vs. non OAC and NOAC vs. VKA prescription). Patients with COPD were less likely treated with ACE inhibitors, beta-blockers, amiodarone and class IC antiarrhythmics, while they showed higher odds of receiving diuretic, digoxin, and non-dihydropyridinic calcium channel blockers (Figure 1). Over a median follow-up of 24.3 [IQR: 23.0-25.0] months, the risk of all-cause death was higher among COPD patients (HR: 1.52, 95%CI: 1.28-1.80), as well as the risk of MACE (HR: 1.49, 95%CI: 1.22-1.83) and the composite outcome of ‘all-cause death and MACE’ (HR: 1.50, 95%CI: 1.29-1.74) (Figure 2). No statistically significant interactions were observed between the use of beta-blockers, beta-2 agonists and anticholinergic drugs, and the risk of death in COPD patients. Conclusions COPD was common in AF patients and was associated with higher prescription of rate-control (except for beta-blockers) and lower prescription of rhythm control drugs, with no differences in OAC treatment. COPD was associated with worse prognosis, without significant interaction observed for beta-blockers or other COPD-specific treatment.Figure 1Figure 2

Abstract 16362: Does Extra-Pulmonary Triggers or Autonomic Neural Activity Affect the Rhythm Control by Anti-Arrhythmic Drugs in Patients With Post-Ablation Atrial Fibrillation Recurrence?

Introduction: Although the EAST-AFNET trial demonstrated the usefulness of atrial fibrillation (AF) rhythm control, including antiarrhythmic drugs (AADs), little is known about their effect on recurred AF after catheter ablation (CA). Hypothesis: We explored the effect of AADs depending on the presence of extra-pulmonary vein triggers (ExPVT) or post-ablation heart rate variability (HRV) in patients who recurred after AFCA. Methods: In this retrospective analysis of a single-center cohort, we analyzed 2,036 patients who underwent de-novo AFCA, and 486 of them had recurrent AF and subsequently underwent rhythm control with AADs. We investigated the effects of the extra-pulmonary vein (PV) triggers and post-procedural 3 rd month HRV (rMSSD; cut-off determined by Youden index) on the AAD responsiveness. Results: The post-AFCA recurrence was significantly higher in patients with ExPVT (Log-rank p&lt;0.001, HR 1.45 [1.16-1.83], p=0.001) or higher 3 rd month post procedure HRV-rMSSD (Log-rank p&lt;0.001, HR 1.36 [1.11-1.65], p=0.003) than their counterparts. Patients with ExPVT at de novo procedure had significantly higher 3 rd month rMSSD (15.0 [11.0-23.0] vs. 17.0 [11.0-28.0], p=0.022) and patients with high 3 rd month rMSSD showed a higher rate of ExPVT identified at the 2 nd repeat procedure (n=160, 41.0% vs. 22.2%, p=0.019). Among those patients how recurred AF after AFCA, post-AAD recurrence did not differ depending on ExPVT (Log-rank p=0.455, HR 1.12 [0.78-1.69], p=0.436) or rMSSD (Log-rank p=0.457, HR 1.16 [0.87-1.55], p=0.300). Post-AAD recurrence did not differ between class IC and III AADs (p for interaction = 0.311). Conclusion: ExPVT and post-procedural high rMSSD are independent risk factors for post-AFCA recurrences but not for AAD response in recurred AF patients. Whether AADs may suppress ExPVT and modulate cardiac autonomic activity after post-AFCA recurrences need further investigation.

Abstract 16815: Outcomes of Cardiac Sympathetic Denervation via Cautery Ablation for Ventricular Arrhythmia: A Single Center Study

Introduction: Cardiac sympathectomy denervation (CSD) has been demonstrated to reduce ventricular arrhythmia (VA) burden and to improve arrhythmia-free survival. Early evidence for the clinical antiarrhythmic benefits for CSD was established in patients with long-QT syndrome and catecholaminergic polymorphic VT (CPVT). Its benefit has subsequently been shown to extend to other undifferentiated cardiomyopathies. Hypothesis: Literature on CSD for VA has been limited due to a small number of patients. Our retrospective study is to review patients who underwent CSD for VA at our center via cautery ablation. Methods: We identified 9 patients who underwent CSD from 4/2018 to 2/2022. Electronic medical record was reviewed for clinical history and outcomes. Results: Mean age was 52±17 and 5 patients (55.6%) were male. Seven patients (77.8%) had nonischemic cardiomyopathy (NICM) and 2 patients (22.2%) had CPVT. Mean LVEF was 43±19% and 5 patients (55.6%) had heart failure with NYHA class 3±0.7. Five patients (55.6%) underwent CSD in outpatient setting and 4 patients (44.4%) had polymorphic VT. Six patients (66.7%) had prior catheter-based VT ablation, 1 patient (11.1%) had prior ganglion block, and 4 patients (44.4%) had history of VT storm. All patients were on antiarrhythmics ranging from a beta blocker monotherapy to a combination of class Ic, class III, and a beta blocker. Seven patients (77.8%) had a defibrillator prior to CSD. All patients underwent CSD (7 with bilateral and 2 with left only) without any procedural complication. Five patients (55.6%) had recurrence of VA in 423±567 days with follow-up duration of 729±478 days. Three patients (33.3%) underwent heart transplant or LVAD and three patients (33.3%) died in 426±396 days since CSD. Overall, 3 patients (33.3%) including 2 CPVT patients and one NICM patient with normal EF were free of death, sustained VT, or advanced heart failure therapies. Conclusions: CSD via cautery ablation is safe and effective for patients with refractory VA to antiarrhythmics and/or VT ablation. Success rate appeared to be higher in patients with CPVT and normal EF. Lower rate of survival and freedom from VT or transplant/LVAD compared to published literature may reflect our sick population.

Features of the compound ALM-802 antiarrhythmic action

Introduction. Cardiovascular diseases (CVD) remain one of the leading causes of death worldwide, claiming over 17 million lives annually. This highlights the urgent need to develop innovative drugs to combat CVD. One potential target for such drugs is type 2 ryanodine receptors (RyR2), as they play an important role in maintaining ion homeostasis in cardiomyocytes, and their abnormal activity plays a key role in the genesis of cardiac arrhythmias.Research objective is to study the mechanisms underlying the antiarrhythmic action of ALM-802.Methods. In the first stage, in vivo experiments were performed using models of aconitine, calcium chloride, barium chloride arrhythmia, and reperfusion arrhythmias to evaluate the antiarrhythmic effect of the compound ALM-802. The second stage of the study involved electrophysiological experiments performed on hippocampal cells of newborn rats to evaluate the effect of the compound on voltage-gated transmembrane Na+, K+, and Ca2+ ion channels, as well as its effect on intracellular ion concentration of Ca2+. Experiments performed on an isolated myocardial strip evaluated the effect of the compound ALM-802 on the activity of RyR2.Results. In in vivo experiments, the compound ALM-802 (2 mg/kg, iv) exhibits significant antiarrhythmic activity comparable/superior to that shown by the reference drugs procainamide, verapamil, and amiodarone on the models mentioned above. In in vitro experiments, it was shown that ALM-802 (69.8 µM) initiates the inactivation of K+ and Na+ ion channels and does not affect the activity of Ca2+ ion channels. The compound ALM-802 effectively prevents the increase of Ca2+ ion concentration in the cytosol during depolarization of contraction. In addition, experiments on isolated myocardial strips showed that the compound ALM-802 (5x10-5 M) blocks RyR2.Conclusion. Thus, based on the spectrum of its antiarrhythmic activity, the compound ALM-802 combines the properties of antiarrhythmic drugs of class IA or IC and class III according to the E.M. Vaughan Williams classification. In addition, the ALM-802 compound exhibits antagonistic activity towards RyR2. The latter is also considered significant, as it is known that under conditions of myocardial pathology, abnormal activity of RyR2 initiates diastolic leakage of Ca2+ ions from the sarcoplasmic reticulum cysterns, which leads to a decrease in the inotropic function of the left ventricle of the heart and significantly increases the risk of developing malignant cardiac arrhythmias.

The injured monocyte: The link to chronic critical illness and mortality following injury.

This study aimed to understand the altered innate immune response in severely injured patients leading to chronic critical illness (CCI). Specifically, it focused on characterizing the monocyte populations and their correlation with CCI development and long-term complications. Over a 3-year period, we monitored patients with severe injuries for up to 1-year postinjury. Chronic critical illness was defined as an ICU stay exceeding 14 days with persistent organ failure. Blood samples were collected on Days 1 and 5 for monocyte phenotypic expression analysis using cytometry by time flight. The monocyte subpopulations studied were classical (CL), intermediate (INT), and nonclassical (NC), along with cell surface receptor expression and activation. Out of 80 enrolled patients, 26 (32.5%) developed CCI. Patients with CCI had more severe injuries (Injury Severity Score, 32.4 + 5.2 vs. 29.6 + 4.1, p = 0.01) and received a higher number of red blood cells (8.9 + 4.1 vs. 4.7 + 3.8 units, p < 0.01) compared with those without CCI. In patients with CCI, the NC monocytes were significantly reduced by over twofold early, and significantly increased later, compared with those without CCI. Moreover, significant changes in intracellular cytokine expression and cell receptors were observed within each monocyte subpopulation in patients with CCI, indicating an increased proinflammatory phenotype but decreased phagocytic capacity and antigen presentation. The development of CCI and the presence of this unique monocyte phenotype were associated with a significantly increased risk of infection, discharge to a long-term care facility, and 1-year mortality of 27%. Development of CCI following severe injury is associated with significant long-term morbidity and unacceptably high mortality. The altered NC phenotype with reduced phagocytic capacity and antigen presentation in patients developing CCI after severe injury is appears partially responsible. Early identification of this unique phenotype may help predict and treat patients at risk for CCI, leading to improved outcomes. Prognostic and Epidemiological; Level III.

Medical cardioversion of atrial fibrillation and flutter with class IC antiarrhythmic drugs in young patients with and without congenital heart disease.

The use of flecainide and propafenone for medical cardioversion of atrial fibrillation (AF) and atrial flutter/intra-atrial reentrant tachycardia (IART) is well-described in adults without congenital heart disease (CHD). Data are sparse regarding their use for the same purpose in adults with CHD and in adolescent patients with anatomically normal hearts and we sought to describe the use of class IC drugs in this population and identify factors associated with decreased likelihood of success. Single center retrospective cohort study of patients who received oral flecainide or propafenone for medical cardioversion of AF or IART from 2000 to 2022. The unit of analysis was each episode of AF/IART. We performed a time-to-sinus rhythm analysis using a Cox proportional hazards model clustering on the patient to identify factors associated with increased likelihood of success. We identified 45 episodes involving 41 patients. As only episodes of AF were successfully cardioverted with medical therapy, episodes of IART were excluded from our analyses. Use of flecainide was the only factor associated with increased likelihood of success. There was a statistically insignificant trend toward decreased likelihood of success in patients with CHD. Flecainide was more effective than propafenone. We did not detect a difference in rate of conversion to sinus rhythm between patients with and without CHD and were likely underpowered to do so, however, there was a trend toward decreased likelihood of success in patients with CHD. That said, medical therapy was effective in >50% of patients with CHD with AF.

Predictors of class IC antiarrhythmic drugs efficacy in patients with paroxysmal form of atrial fibrillation

Background. Class IC antiarrhythmic drugs (IC-AADs) are recommended as first-line therapy in treatment of lone paroxysmal atrial fibrillation (AF) along with catheter ablation of pulmonary veins. Despite previous attempts to identify predictors of IC-AADs` efficacy, the choice between IC-AADs agents is still most often carried out using empirical approach.&#x0D; Aim. To determine the predictors of IC-AADs ` efficacy in patients with paroxysmal AF in the absence of structural heart disease.&#x0D; Materials and methods. Seventy four patients (22 men, 52 women, average age 65 [57; 70] years) were treated with IC-AADs: 26 patients were prescribed lappaconitine hydrobromide (Al) (allapinin at a dosage of 75 mg/day or allaforte 50–100 mg/day), 25 patients were prescribed propafenone (P) 450–600 mg/day, 23 patients – diethylaminopropionylethoxycarbonylaminophenothiazine hydrochloride (ethacizine, E) 150 mg/day. The average frequency of AF paroxysms was 2 [0.4; 6.25] per month. Patients were divided into 2 groups depending on the effect of AADs.&#x0D; Results. Over a 12 months follow-up IC-AADs therapy was effective in 28 (37.8%) patients (Eff+ group), in the remaining 46 (62.2%) patients AF recurrences or side effects demanding AADs withdrawal were registered (Eff-group). A DC value greater or equal to 5 ms predicted the effectiveness of IC-AADs therapy with 79% sensitivity and 77% specificity (OR 12, 95% CI 3.07–49.5, p0.0001). In the Al group the deceleration capacity (DC) value greater or equal to 5.25 ms allowed predicting therapy effectiveness with 86% sensitivity and 100% specificity (OR 7, 95% CI 1.14; 43; p=0.002). In the E group, the DC index was characterized by high sensitivity (80%) and specificity (85%) for a threshold value of 5.9 ms. In case of DC above this value, the probability of E therapy efficacy increased by 22-times (OR 22, 95% CI 1.5; 314; p=0.009). In group P, the DC medians in the Eff+ and Eff- groups did not differ significantly (p=0.821). However, at low DC values (less than 4 ms) P turned out to be the most effective compared to other two IC-AADs: its effectiveness was 50%, which was significantly higher compared to E (0%) and Al (0%) (p=0.046).&#x0D; Conclusion. Estimation of the DC level before starting IC-AADs can make it easier to choose a specific drug from this group and improve treatment results: at DC above 5.2 ms, it is advisable to use Al, at DC≥6 ms – Al or E, at DC less than 4 ms – P.

Left Atrial Posterior Wall Isolation with Pulsed Field Ablation in Persistent Atrial Fibrillation.

Left atrial posterior wall isolation (LAPWI) may improve rhythm control in addition to pulmonary vein isolation (PVI) in persistent atrial fibrillation (persAF) patients undergoing catheter ablation (CA). However, LAPWI may be challenging when using thermal energy sources. This study aimed to investigate the efficacy and safety of LAPWI performed by non-thermal pulsed field ablation (PFA) in CA for persAF. Consecutive persAF patients from two German centers were prospectively enrolled. There were two study cohorts: (1) the LAPWI cohort, which included PFA-guided (re-)PVI with LAPWI for first-time and/or repeat ablation procedures; and (2) a comparative persAF cohort with a PFA PVI-only approach without LAPWI for first-time ablation within the same timeframe. Patients were followed up by routine Holter ECGs. In total, 79 persistent AF patients were included in the study: 59/79 patients were enrolled in the LAPWI cohort, including 16/59 index (27%) and 43/59 repeat ablation procedures (73%). Sixteen patients (16/79; 21%) were in the PVI-only cohort without LAPWI. Of the patients treated with LAPWI, procedure time and fluoroscopy time was 91 ± 30 min and 15 ± 7 min, respectively. The acute PVI rate was 100% in all first-time ablation patients (32 patients (16 PVI only, 16 PVI plus LAPWI), 196/196 PVs). Of the 43 re-do patients in the LAPWI cohort, re-PVI was necessary in 33% (14/43) of patients (27 PVs; 1.9 PV per-patient); in 67% (29/43), all PVs were isolated, and antral ablation of the PV ostia was performed in 48% (14/29). LAPWI was performed successfully in all 59 (100%) patients of the LAPWI cohort. Two minor complications occurred. No esophageal lesion was detected in the LAPWI cohort (n = 33/59 (56%) patients underwent endoscopy). After 354 ± 197 days of follow-up, freedom from atrial arrhythmias was 79.3% (95-CI: 62-95%) in the complete LAPWI cohort (n = 14/59 (24%) on AAD: class Ic n = 9, class III n = 5). There was no difference regarding acute procedural and clinical outcome compared to the PVI-only cohort. LAPWI guided by PFA is feasible and safe in patients undergoing CA for persAF and shows favorable outcomes. In the context of durable PVI, PFA-guided LAPWI may be an effective adjunctive treatment option.

Sex Differences in Anderson-Fabry Cardiomyopathy: Clinical, Genetic, and Imaging Analysis in Women.

Anderson-Fabry Disease (AFD) is a rare, systemic lysosomal storage disease triggered by mutations in the GLA gene, leading to α-galactosidase A (α-Gal A) deficiency. The disease's X-linked inheritance leads to more severe, early-onset presentations in males, while females exhibit variable, often insidious, manifestations, notably impacting cardiac health. This study aims to examine gender-based AFD cardiac manifestations in correlation with the variant type: classical (CL), late-onset (LO), or variants of uncertain significance (VUS). We analyzed data from 72 AFD patients (53 females, 19 males) referred to the "G. Rodolico" University Hospital, employing enzyme activity measurements, genetic analysis, periodic lyso-Gb3 monitoring, comprehensive medical histories, and advanced cardiac imaging techniques. Statistical analysis was performed using SPSS version 26. Our AFD cohort, with an average age of 45 ± 16.1 years, comprised 12 individuals with hypertrophy (AFD-LVH) and 60 without (AFD-N). Women, representing about 75% of the subjects, were generally older than men (47.2 ± 16.2 vs. 38.8 ± 14.6, p = 0.046). In the female group, 17% had CL variants, 43.3% LO, and 39.6% had VUS, compared to 21.1%, 36.8%, and 31.6% in the male group, respectively. Females exhibited significantly higher α-Gal A values (median 7.9 vs. 1.8 nmol/mL/h, p < 0.001) and lower lyso-Gb3 levels (1.5 [IQR 1.1-1.7] vs. 1.9 [1.5-17.3] nmol/L, p = 0.02). Regarding the NYHA class distribution, 70% of women were in class I and 28% in class II, compared to 84% and 16% of men, respectively. Among women, 7.5% exhibited ventricular arrhythmias (10.5% in men), and 9.4% had atrial fibrillation (10.5% in men). Cardiac MRIs revealed fibrosis in 57% of examined women, compared to 87% of men. Even among patients without LVH, significant differences persisted in α-Gal A and lyso-Gb3 levels (p = 0.003 and 0.04), as well as LVMi (61.5 vs. 77.5 g/sqm, p = 0.008) and GLS values (-20% vs. -17%, p = 0.01). The analysis underscored older age, decreased lyso-Gb3 deposition, reduced hypertrophy, and lesser GLS compromise in females, suggesting later disease onset. Severe cardiac patterns were associated with classic variants, while more nuanced manifestations were noted in those with VUS. Early GLS impairment in males, irrespective of hypertrophy, emphasized the role of subclinical damage in AFD.

P02.12.B UNDERSTANDING THE ROLES OF EPHRIN A5 IN GLIOBLASTOMA AND ITS POTENTIAL AS A THERAPEUTIC TARGET

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive malignant primary brain cancer and is associated with very poor patient outcomes. GBM has been classified into three cell subtypes (proneural (PN), classical (CL), and mesenchymal (MES)), which have been further defined into four plastic cell states (neural-progenitor-like (NPC-like), oligodendrocyte-progenitor-like (OPC-like), astrocyte-like (AC-like), and mesenchymal-like (MES-like)). Existing treatment options have had limited success in improving overall survival, with the extreme heterogeneity present in GBM presenting a major barrier to effective therapy. Thus, there is an urgent need to develop more effective therapeutic strategies which better capture heterogeneity and delay tumour relapse. Several erythropoietin-producing human hepatocellular (Eph) receptors and ephrin ligands have been shown to be functionally overexpressed in cancer and have become attractive therapeutic targets. EphA3 has previously been shown to be a functional, tumour-specific target, frequently elevated in the MES subtype. We identified ephrin A5, the high-affinity ligand of EphA3, to be frequently co-expressed with EphA3 in GBM tumours. However, unlike EphA3, the mechanisms of ephrin A5 in GBM remain understudied. We therefore believe that ephrin A5 serves as an attractive synergistic target for the treatment of GBM. MATERIAL AND METHODS We examined the expression of ephrin A5 in a panel of GBM patient specimens. A panel of GBM tumours were also selected for immunohistochemical and spatial transcriptomics analysis. For in vitro functional studies, ephrin A5 was overexpressed in several GBM primary cell lines. Assays examining proliferation, stemness and differentiation were performed. RESULTS Expression of ephrin A5 was comparable to EphA3 in GBM. 64% of GBM tumours analysed showed higher levels of ephrin A5, relative to the highest normal brain specimen. Initial immunohistochemistry analysis suggests EphA3 and ephrin A5 to be expressed discretely on over 75% of the total tumour mass. Spatial transcriptomics analysis suggests ephrin A5 to be enriched in cells of the AC-like cell state. In vitro overexpression of ephrin A5 was shown to reduce neurosphere formation and induce differentiation of GBM cells. CONCLUSION EphA3 and ephrin A5 are overexpressed in a portion of GBM tumours. Critically, there was a strong mutually exclusive expression to different compartments of the GBM tumour, covering the vast majority of the total tumour mass. Our data suggests that ephrin A5 overexpression drives a less aggressive, more differentiated AC-like tumour phenotype. Thus, dual targeting of EphA3 and ephrin A5 in GBM could provide an opportunity to better capture tumour heterogeneity and achieve more durable therapeutic responses.

Are antiarrhythmic agents indicated in premature ventricular complex-induced cardiomyopathy and when?

Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia that are encountered in the clinical practice. Recent data suggests that high PVC burden may lead to the development of PVC-induced cardiomyopathy (PVC-CM) even in patients without structural heart disease. Treatment for effective suppression of PVCs, can reverse PVC-CM. Both antiarrhythmic drugs (AADs) and catheter ablation (CA) are recognized treatment modalities for any cardiac arrhythmias. However, with increasing preference of CA, the role of AADs needs further defining regarding their efficacy, safety, indications and patient selection to treat PVC-CM. To ascertain the role of AADs to treat PVC-CM; whether they are indicated to treat PVC-CM, and if so, when, we interrogated PubMed and other search engines for English language publications with key words premature ventricular complexes (PVCs), cardiomyopathy, anti-arrhythmic drugs, catheter ablation, and pharmacological agents. All publications were carefully reviewed and scrutinized by the authors for their inclusion in the review paper. For illustration of cases, ethical standard was observed as per the 1975 Declaration of Helsinki, and the patient was treated as per the prevailing standard of care. Informed consent was obtained from the patient for conducting the ablation procedure. Our literature search specifically the pharmacological treatment of PVC-CM with AADs revealed significant paradigm shift in treatment approach for PVCs and PVC-induced cardiomyopathy. No major large, randomized control trials of AADs versus CA for PVC-CM were found. We found that beta-blockers and calcium channel blockers are particularly effective in the treatment of PVCs originating from right ventricular outflow tract. For Class Ic AADs - flecainide and propafenone, small clinical studies showed Class Ic AADs to be effective in PVC suppression, but their usage was not recommended in patients with significant coronary artery disease. Mexiletine was found to have modest effect on PVC suppression. Studies showed sotalol to significantly reduce PVCs frequency in patients receiving both low and high doses. Studies also showed amiodarone to have higher successful PVC suppression, but not recommended as a first-line treatment for patients with idiopathic PVCs in the absence of symptoms and left ventricular dysfunction. For dronedarone, no major clinical data were available. Based on the available data in the literature, we conclude that AADs play important role in the treatment of PVC-induced cardiomyopathy. However, appropriate patient selection criteria are vitally important, and in general terms AADs are indicated or polymorphic PVCs, epicardial PVCs; and when CA procedure is contraindicated, or not feasible or failed.

Tube-first Technique as a Conduit for Easy and Fast Nasal Fiberoptic Intubation

Background: Classical nasal fiberoptic bronchoscope intubation may be a challenging and lengthy procedure with a 1-10% failure rate. Objectives: This study aimed to compare among patients with difficult airway intubation undergoing general anesthesia, the safety, and efficacy of Tube-First (TF) nasal fiberoptic bronchoscope intubation against the Classic (CL) procedure. Methods: This single-blinded, parallel-group, randomized trial enrolled 40 adult patients with known difficult airways and scheduled for surgery under general anesthesia. The patients were randomly allocated into two (n=20 each) patient groups. In the CL group, the endotracheal tube and fiberoptic bronchoscope were inserted together through the nostril; in the TF group, the endotracheal tube insertion preceded the fiberoptic bronchoscope. In both groups, the bronchoscope was used to visualize the vocal cords and removed after ensuring the endotracheal tube position. The primary (efficacy) outcomes were the time elapsing from the bronchoscope insertion and visualizing the vocal cords (T1) and the time elapsing from the bronchoscope advancing initiation to its removal (T2). The secondary (safety) outcomes included oxygen saturation and hemodynamic parameters during the procedure. Results: The TF group showed a significant T1 and T2 mean reduction compared to those of the CL group (37.15 ± 3.87 and 64.25 ± 8.28 vs. 55.05±4.52 and 88.25±5.49 seconds, respectively; p &lt; 0.0001). The oxygen saturation was comparable in both groups with no desaturation (SpO2 &lt; 90%) cases. The heart rate and mean arterial blood pressure changes were significantly lower in the TF group compared to the CL group. Conclusion: Among patients with difficult airway intubation undergoing general anesthesia, we found the Tube-First intubation approach was quicker and safer compared to the classical intubation technique.

Idiopathic premature ventricular complexes treatment: Comparison of flecainide, propafenone, and sotalol.

Beta-blockers (BB) or dihydropyridine calcium channel blockers (CCBs) are still the first choices in the treatment of idiopathic premature ventricular complexes (PVCs), with low-modest efficacy. Antiarrhythmic drugs (AADs) of Ic class are moderate to highly efficient but the evidence on their benefits is still limited. To compare effectiveness and safety of flecainide, propafenone, and sotalol in the treatment of symptomatic idiopathic PVCs. Our single-center retrospective study analyzed 104 consecutive patients with 130 medication episodes of frequent idiopathic PVCs treated with AADs flecainide, propafenone (Ic class) or sotalol (III class). The primary outcome was complete/near complete reduction of PVCs after medication episode (PVCs burden reduction >99%), and the secondary outcome was significant PVC burden reduction (≥80%). The complete/near complete PVCs burden reduction occurred in 31% and was significant in 43% of treated patients. A reduction of PVC burden for >99% was achieved in 56% of patients on flecainide, in 11% of patients on propafenone (p = .002), and in 21% of patients receiving sotalol (p = .031). There was no difference between propafenone and sotalol (p = .174). A reduction of PVC burden for ≥80% was achieved in 64% of patients on flecainide, in 30% of patients on propafenone (p = .009), and 33% of patients on sotalol (p = .020). There was no difference between propafenone and sotalol (p = .661). The efficacy of AADs class Ic and III in the treatment of idiopathic PVCs was modest. Flecainide was the most effective AAD in the achievement of complete/near complete or significant PVC burden reduction, compared to propafenone and sotalol.

Encainide, a class Ic anti-arrhythmic agent, blocks voltage-dependent potassium channels in coronary artery smooth muscle cells.

Voltage-dependent K+ (Kv) channels are widely expressed on vascular smooth muscle cells and regulate vascular tone. Here, we explored the inhibitory effect of encainide, a class Ic anti-arrhythmic agent, on Kv channels of vascular smooth muscle from rabbit coronary arteries. Encainide inhibited Kv channels in a concentration-dependent manner with an IC50 value of 8.91 ± 1.75 μM and Hill coefficient of 0.72 ± 0.06. The application of encainide shifted the activation curve toward a more positive potential without modifying the inactivation curve, suggesting that encainide inhibited Kv channels by altering the gating property of channel activation. The inhibition by encainide was not significantly affected by train pulses (1 and 2 Hz), indicating that the inhibition is not use (state)-dependent. The inhibitory effect of encainide was reduced by pretreatment with the Kv1.5 subtype inhibitor. However, pretreatment with the Kv2.1 subtype inhibitor did not alter the inhibitory effects of encainide on Kv currents. Based on these results, encainide inhibits vascular Kv channels in a concentration-dependent and use (state)-independent manner by altering the voltage sensor of the channels. Furthermore, Kv1.5 is the main Kv subtype involved in the effect of encainide.